U.S. patent application number 11/608922 was filed with the patent office on 2007-05-03 for n-(2-arylethyl)benzylamines as antagonists of the 5-ht6 receptor.
Invention is credited to Zhaogen Chen, Michael Philip Cohen, Matthew Joseph Fisher, Bruno Giethlen, James Ronald Gillig, Jefferson Ray McCowan, Shawn Christopher Miller, John Mehnert Schaus.
Application Number | 20070099909 11/608922 |
Document ID | / |
Family ID | 26959969 |
Filed Date | 2007-05-03 |
United States Patent
Application |
20070099909 |
Kind Code |
A1 |
Chen; Zhaogen ; et
al. |
May 3, 2007 |
N-(2-ARYLETHYL)BENZYLAMINES AS ANTAGONISTS OF THE 5-HT6
RECEPTOR
Abstract
The present invention provides compounds of formula (I), which
are antagonists of the 5-HT.sub.6 receptor. ##STR1##
Inventors: |
Chen; Zhaogen; (Noblesville,
IN) ; Cohen; Michael Philip; (Indianapolis, IN)
; Fisher; Matthew Joseph; (Mooresville, IN) ;
Giethlen; Bruno; (Altorf, FR) ; Gillig; James
Ronald; (Indianapolis, IN) ; McCowan; Jefferson
Ray; (Indianapolis, IN) ; Miller; Shawn
Christopher; (Morgantown, IN) ; Schaus; John
Mehnert; (Zionsville, IN) |
Correspondence
Address: |
ELI LILLY & COMPANY
PATENT DIVISION
P.O. BOX 6288
INDIANAPOLIS
IN
46206-6288
US
|
Family ID: |
26959969 |
Appl. No.: |
11/608922 |
Filed: |
December 11, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10472741 |
Feb 27, 2004 |
7157488 |
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PCT/US02/05115 |
Mar 15, 2002 |
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11608922 |
Dec 11, 2006 |
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60279928 |
Mar 29, 2001 |
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60329449 |
Oct 15, 2001 |
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Current U.S.
Class: |
514/227.5 ;
514/237.5; 514/252.12; 514/317; 514/365; 514/374; 514/400; 514/408;
514/419; 514/649; 544/162; 544/399; 544/59; 546/229; 548/205;
548/235; 548/335.5; 548/495; 548/561; 564/373 |
Current CPC
Class: |
C07C 211/52 20130101;
C07D 417/12 20130101; C07D 403/12 20130101; C07C 217/60 20130101;
C07C 211/56 20130101; C07D 403/06 20130101; C07D 213/65 20130101;
C07D 307/91 20130101; A61P 25/28 20180101; C07D 239/34 20130101;
C07D 471/04 20130101; A61P 25/18 20180101; C07D 333/20 20130101;
C07F 7/0812 20130101; C07D 401/12 20130101; A61P 25/22 20180101;
A61P 43/00 20180101; C07D 209/14 20130101; C07D 209/16 20130101;
C07D 209/86 20130101; C07C 323/32 20130101; C07C 317/34 20130101;
C07D 213/38 20130101; C07D 213/74 20130101; C07C 225/16 20130101;
C07D 213/68 20130101; C07D 233/24 20130101; C07D 277/34 20130101;
C07D 209/08 20130101; C07C 217/58 20130101; A61P 25/00 20180101;
C07D 213/64 20130101; C07D 405/12 20130101; C07C 311/37
20130101 |
Class at
Publication: |
514/227.5 ;
514/237.5; 514/252.12; 514/317; 514/365; 514/374; 514/400; 514/408;
514/649; 544/059; 544/399; 546/229; 544/162; 548/205; 548/235;
548/335.5; 548/561; 564/373; 514/419; 548/495 |
International
Class: |
A61K 31/54 20060101
A61K031/54; A61K 31/5375 20060101 A61K031/5375; A61K 31/405
20060101 A61K031/405; A61K 31/495 20060101 A61K031/495; A61K 31/426
20060101 A61K031/426; A61K 31/421 20060101 A61K031/421; A61K
31/4172 20060101 A61K031/4172; A61K 31/445 20060101 A61K031/445;
A61K 31/137 20060101 A61K031/137 |
Claims
1. A compound of the formula formula I ##STR123## wherein X is
selected from the group consisting of --O--, --NH--, --S--,
--SO2--, --CH2--, --CH(F)--, --CH(OH)--, and --C(O)--; R1 is
selected from the group consisting of optionally substituted
phenyl, optionally substituted naphthyl, optionally substituted 5
to 6 membered monocyclic aromatic heterocycle having one heteroatom
selected from the group consisting of nitrogen, oxygen, and sulfur
and which 5 to 6 membered monocyclic aromatic heterocycle is
optionally benzofused; R2 is selected from the group consisting of
hydrogen and C.sub.1-C.sub.3 alkyl; R3 is selected from the group
consisting of hydrogen, fluoro, and methyl; R4 is selected from the
group consisting of hydrogen, allyl, C2-C4 alkyl, fluorinated C2-C4
alkyl, optionally substituted phenyl, optionally substituted
phenylsulfonyl, optionally substituted benzyl, and optionally
substituted 5 to 6 membered monocyclic aromatic heterocycle having
one or two heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, provided that R.sub.4 is not
optionally substituted phenylsulfonyl when X is --SO2--, --CH2--,
CH(F)--, --CH(OH)--, or --C(O)--; and pharmaceutically acceptable
salts thereof.
2-56. (canceled)
57. A method of treating disorders associated with the 5-HT6
receptor, comprising administering to a patient in need thereof an
effective amount of
N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benz-
ylamine.
Description
[0001] The present invention relates to the field of pharmaceutical
and organic chemistry and is concerned with compounds which are
antagonists of the 5-HT.sub.6 receptor.
[0002] The 5-HT.sub.6 receptor is a member of the G-protein coupled
receptor superfamily of serotonin receptors, and, like the
5-HT.sub.4 and 5-HT.sub.7 receptors, it is positively coupled to
adenylate cyclase..sup.1 The rat 5-HT.sub.6 receptor was first
cloned in 1993.sup.2,3 and the cloning of the human homologue, to
which it shares a 89% sequence identity, was reported in
1996..sup.4 The localization of 5-HT.sub.6 receptors in rat brain
has been studied using mRNA quantification by Northern analysis and
RT-PCR, immunohistochemistry, and autoradiography..sup.2,3,5,6,7,8
These methods have consistently found high levels of the receptor
in olfactory tubercle, hippocampus, striatum, nucleus accumbens,
and cortical regions. 5-HT.sub.6 receptors are either absent or
present in very low levels in peripheral tissues..sup.2,3
[0003] To date, there are no known high affinity, selective
agonists at the 5-HT.sub.6 receptor. Serotonin itself has only
moderate affinity for the 5-HT.sub.6 receptor (Ki=65 nM) and the
most selective agonist reported to date,
N,N-dimethyl-2-ethyl-5-methoxytryptamine, has Ki=81 nM and only
3.5-fold selectivity versus the 5-HT.sub.2A receptor..sup.9
[0004] Much of the recent interest in the 5-HT.sub.6 receptor is
due to the observation that several psychotropic agents are high
affinity antagonists at the human 5-HT.sub.6 receptor..sup.4,10
These compounds include amitriptyline (Ki=65 nM) and the atypical
antipsychotics clozapine (Ki=9.5 nM), olanzapine (Ki=10 nM), and
quetiapine (33 nM). None of these compounds, however, are
selective. The first selective 5-HT.sub.6 receptor antagonists
reported are Ro 04-6790 and Ro 63-0563. Their usefulness is limited
by their moderate affinity (Ki=50 nM and 12 nM, respectively) and
poor pharmacokinetics..sup.11 A series of 5-HT.sub.6 receptor
antagonists, culminating in SB-271,046, has been reported..sup.12
This compound has high affinity (Ki=1.2 nM) and selectivity
(>200-fold versus >55 receptors, enzymes and ion channels)
and is 80% bioavailable. A selective radioligand
[.sup.125I]-SB-258,585 has been used for radioligand binding and
autoradiographic studies..sup.13,14 These compounds are useful
tools for preclinical studies on the 5-HT.sub.6 receptor.
[0005] The rationale for the use of selective 5-HT.sub.6 receptor
antagonists to treat cognitive dysfunction is based on three lines
of reasoning: the ability of selective 5-HT.sub.6 receptor
antagonists to modulate cholinergic and glutamatergic neuronal
function, clinical studies of the atypical antipsychotics clozapine
and olanzapine on cognitive function, the activity of selective
5-HT.sub.6 receptor antagonists in animal models of cognitive
function.
[0006] Selective 5-HT.sub.6 receptor antagonists modulate
cholinergic and glutamatergic neuronal function. Cholinergic and
glutamatergic neuronal systems play important roles in cognitive
function. Cholinergic neuronal pathways are known to be important
to memory formation and consolidation. Centrally acting
anticholinergic agents impair cognitive function in animal and
clinical studies and loss of cholinergic neurons is one of the
hallmarks of Alzheimer's disease. Conversely, stimulation of
cholinergic function has been known to improve cognitive
performance and the only two agents currently approved for the
treatment of cognitive deficit in Alzheimer's disease, tacrine and
donepezil, are both acetylcholinesterase inhibitors. The
glutamatergic system in the prefrontal cortex is also known to be
involved in cognitive function..sup.26,27
[0007] Blocking 5-HT.sub.6 receptor function has been shown to
elicit procholinergic effects in vivo. Administration (icv) to rats
of antisense oligonucleotides targeting the 5-HT.sub.6 receptor
sequence induced yawning and stretching behavior that was blocked
by the cholinergic antagonist atropine..sup.15 The selective
5-HT.sub.6 receptor antagonist Ro 046790 induced stretching
behavior in a dose-dependent manner. This behavior was blocked by
the centrally acting anticholinergic agents scopolamine and
atropine but not by methyl-scopolamine at doses known to be
peripherally selective..sup.16 Ro 04-6790 was also shown to block
the rotational behavior induced by scopolamine administration to
rats with unilateral nigrostriatal 6-OH-DA lesions. It did not
block rotational behavior induced by L-DOPA or amphetamine..sup.17
Ro 04-6790 reversed scopolamine induced performance deficits in the
object recognition test, a model of cognitive function. Another
selective 5-HT.sub.6 receptor antagonist, SB-271046, potentiated
the yawning behavior induced by the cholinesterase inhibitor
physostigmine..sup.18 These studies suggest that 5-HT.sub.6
receptor blockade facilitates cholinergic transmission. In in vivo
microdialysis studies, SB-271,046 (10 mg/kg, sc) increases
glutamate release in the prefrontal cortex through a neuronal
mechanism..sup.25
[0008] Clinical studies of the atypical antipsychotics clozapine
and olanzapine on cognitive function. The atypical antipsychotics
clozapine and olanzapine are both high affinity, albeit
nonselective, 5-HT.sub.6 receptor antagonists..sup.4 On the other
hand, risperidone and the typical antipsychotic haloperidol do not
have significant affinity for the 5-HT.sub.6 receptor. Clinical
differences seen with these sets of drugs may be attributable to
5-HT.sub.6 receptor blockade. Goldberg et al. reported no
beneficial cognitive effect of clozapine treatment in a small
(N=15) trial in treatment resistant schizophrenics..sup.19 In
contrast, Meltzer et al. in a larger study of treatment-resistant
schizophrenics (N=36), observed improvements in several domains of
neuropsychological function at six weeks and six months following
initiation of clozapine treatment. In non-treatment resistant
schizophrenics, clozapine was more effective than placebo in
improving cognitive function by several measures..sup.21 This
effect was seen at six months and persisted throughout the 12 month
study. The effect of olanzapine, risperidone, and haloperidol on
cognitive function has been compared in a multicenter, double blind
study in schizophrenics..sup.22 The olanzapine group showed a
statistically significant improvement in cognitive function over
either haloperidol or risperidone treatment. This effect was
apparent after 6 weeks treatment and continued throughout the 54
weeks of the study. Animal studies suggest that these effects could
be mediated through the release of acetylcholine in the prefrontal
cortex..sup.23
[0009] Activity of selective 5-HT.sub.6 receptor antagonists in
animal models of cognitive function. With the recent development of
the selective 5-HT.sub.6 receptor antagonists Ro-04,6790 and
SB-271,046, there have been several reports on the activity of
these compounds in models of cognitive function. The selective
5-HT.sub.6 receptor antagonist SB-271,046 improved performance in
the Morris water maze..sup.24 These results are consistent with the
finding that chronic icv administration of antisense
oligonucleotides directed toward the 5-HT.sub.6 receptor sequence
led to improvements in some measures of performance in the Morris
water maze..sup.16 SB-271,046 treatment also led to improvements in
the spatial alternation operant behavior test in aged
rats..sup.24
[0010] The compounds of the present invention are selective, high
affinity antagonists of 5-HT.sub.6, and thus, provide a valuable
treatment for 5-HT.sub.6 receptor mediated disorders.
[0011] Background References [0012] 1. Branchek, T. A., et al.
(2000). Annu Rev Pharmacol Toxicol 40: 319-34. [0013] 2. Monsma, F.
J., Jr., et al. (1993). Mol Pharmacol 43(3): 320-7. [0014] 3. Ruat,
M., et al. (1993). Biochem Biophys Res Commun 193(1): 268-76.
[0015] 4. Kohen, R., et al. (1996). J Neurochem 66(1): 47-56.
[0016] 5. Ward, R. P., et al. (1996). J Comp Neurol 370(3): 405-14.
[0017] 6. Ward, R. P., et al. (1995). Neuroscience 64(4): 1105-11.
[0018] 7. Gerard, C., et al. (1997). Brain Res 746(1-2): 207-19.
[0019] 8. Gerard, C., et al. (1996). Synapse 23(3): 164-73. [0020]
9. Glennon, R. A., et al. (2000). J Med Chem 43(5): 1011-8. [0021]
10. Roth, B. L., et al. (1994). J Pharmacol Exp Ther 268(3):
1403-10. [0022] 11. Sleight, A. J., et al. (1998). Br J Pharmacol
124(3): 556-62. [0023] 12. Routledge, C., et al. (2000). Br. J.
Pharmacol. 130(7): 1606. [0024] 13. Hirst, W. D., et al. (1999).
Br. J. Pharmacol. Suppl. ((in press)). [0025] 14. Hirst, W. D., et
al. (2000). Br. J. Pharmacol. 130: 1597. [0026] 15. Bourson, A., et
al. (1995). J Pharmacol Exp Ther 274(1): 173-80. [0027] 16.
Bentley, J. C., et al. (1999). Br J Pharmacol 126(7): 1537-42.
[0028] 17. Bourson, A., et al. (1998). Br J Pharmacol 125(7):
1562-6. [0029] 18. Routledge, C., et al. (1999). Br. J. Pharmacol.
127(Suppl.): 21P. [0030] 19. Goldberg, T. E., et al. (1993). Br J
Psychiatry 162: 43-8. [0031] 20. Hagger, C., et al. (1993). Biol
Psychiatry 34(10): 702-12. [0032] 21. Lee, M. A., et al. (1994). J
Clin Psychiatry 55 Suppl B: 82-7. [0033] 22. Purdon, S. E., et al.
(2000). Arch Gen Psychiatry 57(3): 249-58. [0034] 23. Parada, M.
A., et al. (1997). J Pharmacol Exp Ther 281(1): 582-8. [0035] 24.
Rogers, D. C., et al. (1999). Br J Pharmcol 127(suppl.): 22P.
[0036] 25. Dawson, L. A., et al. (2000). Br J Pharmacol 130(1):
23-6. [0037] 26. Dudkin, K. N., et al. (1996). Neurosci Behav
Physiol 26(6): 545-51. [0038] 27. Koechlin, E., et al. (1999).
Nature 399(6732): 148-51.
[0039] The present invention provides compounds of formula I:
##STR2## wherein [0040] X is selected from the group consisting of
--O--, --NH--, --S--, --SO.sub.2--, --CH.sub.2--, --CH(F)--,
--CH(OH)--, and --C(O)--; [0041] R.sub.1 is selected from the group
consisting of optionally substituted phenyl, optionally substituted
naphthyl, optionally substituted 5 to 6 membered monocyclic
aromatic heterocycle having one heteroatom selected from the group
consisting of nitrogen, oxygen, and sulfur and which 5 to 6
membered monocyclic aromatic heterocycle is optionally benzofused;
[0042] R.sub.2 is selected from the group consisting of hydrogen
and C.sub.1-C.sub.3 alkyl; [0043] R.sub.3 is selected from the
group consisting of hydrogen, fluoro, and methyl; [0044] R.sub.4 is
selected from the group consisting of hydrogen, allyl,
C.sub.2-C.sub.4 alkyl, fluorinated C.sub.2-C.sub.4 alkyl,
optionally substituted phenyl, optionally substituted
phenylsulfonyl, optionally substituted benzyl, and optionally
substituted 5 to 6 membered monocyclic aromatic heterocycle having
one or two heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, provided that R.sub.4 is not
optionally substituted phenylsulfonyl when X is --SO.sub.2--,
--CH.sub.2--, --CH(F)--, --CH(OH)--, or --C(O)--; and
pharmaceutically acceptable salts thereof.
[0045] The present invention also provides compounds of formula II:
##STR3## wherein [0046] Y is selected from the group consisting of
O, NH, and NR.sub.9, wherein R.sub.9 is selected from the group
consisting of C.sub.1-C.sub.4 alkyl, and optionally substituted
phenyl; [0047] R.sub.5 and R.sub.6 are hydrogen or taken together
with the atoms to which they are attached form a benzo ring,
provided that R.sub.5 and R.sub.6 are hydrogen when Y is NR.sub.9;
[0048] R.sub.7 is selected from the group consisting of optionally
substituted phenyl, optionally substituted naphthyl, optionally
substituted 5 to 6 membered monocyclic aromatic heterocycle having
one heteroatom selected from the group consisting of nitrogen,
oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic
heterocycle is optionally benzofused; [0049] R.sub.8 is selected
from the group consisting of hydrogen and C.sub.1-C.sub.3 alkyl;
and pharmaceutically acceptable salts thereof.
[0050] The present invention also provides for novel pharmaceutical
compositions, comprising: a compound of the formula I or II and a
pharmaceutically acceptable diluent.
[0051] Because the compounds of formula I and II are antagonists of
5-HT.sub.6 receptor, the compounds of formula I and B are useful
for the treatment of a variety of disorders. Thus, in another
embodiment the present invention provides methods of treating
disorders associated with 5-HT.sub.6, comprising: administering to
a patient in need thereof an effective amount of a compound of
formula I or II. That is, the present invention provides for the
use of a compound of formula I or II and pharmaceutical
compositions thereof for the treatment disorders associated with
5-HT.sub.6. More specifically, the present invention provides a
method of treating disorders selected from the group consisting of
cognitive disorders, age-related cognitive disorder, mild cognitive
impairment, mood disorders (including depression, mania, bipolar
disorders), psychosis (in particular schizophrenia), anxiety
(particularly including generalized anxiety disorder, panic
disorder, and obsessive compulsive disorder), idiopathic and
drug-induced Parkinson's disease, epilepsy, convulsions, migraine
(including migraine headache), substance withdrawal (including,
substances such as opiates, nicotine, tobacco products, alcohol,
benzodiazepines, cocaine, sedatives, hypnotics, etc.), sleep
disorders (including narcolepsy), attention deficit/hyperactivity
disorder, conduct disorder, learning disorders, dementia (including
Alzheimer's disease and AIDS-induced dementia), Huntington's
Chorea, cognitive deficits subsequent to cardiac bypass surgery and
grafting, stroke, cerebral ischemia, spinal cord trauma, head
trauma, perinatal hypoxia, cardiac arrest, and hypoglycemic
neuronal damage, vascular dementia, multi-infarct dementia,
amylotrophic lateral sclerosis, and multiple sclerosis, comprising:
administering to a patient in need thereof an effective amount of a
compound of formula I or an effective amount of a compound of
formula II.
[0052] In addition, the present invention also provides processes
for preparing the compounds of formula I and II and intermediate
thereof.
[0053] As used herein, the following terms have the meanings
indicated:
[0054] The term "C.sub.1-C.sub.3 alkyl" refers to a straight or
branched alkyl chain having from one to three carbon atoms, and
includes methyl, ethyl, propyl, and iso-propyl.
[0055] The term "optionally substituted phenyl" refers to a radical
of the formula ##STR4##
[0056] wherein R.sub.a is from 1 to 3 groups independently selected
from the group consisting of hydrogen, hydroxy, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, halogen, benzyloxy, carboxy,
C.sub.1-C.sub.4 alkoxycarbonyl, amido, N--(C.sub.1-C.sub.4
alkyl)amido, sulfonylamido, cyano, trifluoromethyl,
trifluoromethoxy, nitro, and phenyl optionally substituted with
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, cyano, and
trifluoromethyl.
[0057] The term "optionally substituted naphthyl" refers to a
radical of the formula ##STR5##
[0058] wherein R.sub.c is from 1 to 2 groups independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, cyano, trifluoromethyl, and
nitro.
[0059] The term "optionally substituted 5 to 6 membered monocyclic
aromatic heterocycle having one heteroatom selected from the group
consisting of nitrogen, oxygen, and sulfur and which 5 to 6
membered monocyclic aromatic heterocycle is optionally benzofused"
refers to radicals of the formula ##STR6## wherein Q.sub.1 is
selected from the group consisting of --O--, --S--, and
--NR.sub.g-- wherein R.sub.g is selected from the group consisting
of hydrogen and C.sub.1-C.sub.4 alkyl; and Q.sub.2 is --N.dbd.,
R.sub.d, each R.sub.e, and R.sub.f are each independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, cyano, and trifluoromethyl, or
R.sub.d and R.sub.e (or one of R.sub.e) are taken together with the
atoms to which they are attached to form an benzo ring which benzo
ring is optionally substituted with 1 to 4 substituents
independently selected from the group consisting of hydrogen,
hydroxy, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, halogen,
carboxy, C.sub.1-C.sub.4 alkoxycarbonyl, amido, N--(C.sub.1-C.sub.4
alkyl)amido, amino, (C.sub.1-C.sub.4 alkyl)amino, acylamino wherein
the acyl group is selected from the group consisting of
C.sub.1-C.sub.4 alkyl and phenyl; cyano, nitro, sulfonylamido,
phenyl optionally substituted with C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, cyano, and trifluoromethyl;
phenoxy, benzyloxy, --NHS(O).sub.2R.sub.h, wherein R.sub.h is
selected from the group consisting of C.sub.1-C.sub.4 alkyl and
phenyl; and --S(O).sub.pR.sub.i, wherein p is 0, 1, or 2 and
R.sub.i is selected from the group consisting of C.sub.1-C.sub.4
alkyl and phenyl optionally substituted with C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, cyano, and trifluoromethyl; and
R.sub.f is selected from the group consisting of hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, trifluoromethyl, and
halogen. The term specifically includes furyl, thienyl, pyrrolyl,
pyridyl, benzofuryl, benzothienyl, indolyl and quinolinyl; each
optionally substituted as described above.
[0060] The term "fluorinated C.sub.2-C.sub.4 alkyl" refers to a
straight or branched alkyl chain having from two to four carbon
atoms substituted with one or more fluorine atoms. The term
includes 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,
3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl,
2,2,3,3,3-pentafluoropropyl, 2,2,3,3-tetrafluoropropyl,
4,4,4-trifluorobutyl, 3,3,4,4,4-pentafluorobutyl, and the like.
[0061] The term "optionally substituted phenylsulfonyl" refers to a
radical of the formula ##STR7##
[0062] wherein R.sub.j is from 1 to 3 groups independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, cyano, trifluoromethyl, nitro, and
phenyl.
[0063] The term "optionally substituted benzyl" refers to a radical
of the formula ##STR8##
[0064] wherein R.sub.k is from 1 to 3 groups independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, cyano, nitro, trifluoromethyl, and
halogen.
[0065] The term "optionally substituted 5 to 6 membered monocyclic
aromatic heterocycle having one or two heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur" refers to
radicals of the formula ##STR9## wherein Q.sub.3 is selected from
the group consisting of --O--, --S--, and --NR.sub.g'-- wherein
R.sub.g' is selected from the group consisting of hydrogen and
C.sub.1-C.sub.4 alkyl; and Q.sub.4 and Q.sub.5 are --CR.sub.m,
wherein each R.sub.m is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.4 allyl, halogen, and
trifluoromethyl or one or both of Q.sub.4 and Q.sub.5 is --N.dbd.;
and wherein one or two of Q.sub.6 are --N.dbd., while the others
are --CR.sub.n; wherein each R.sub.n is independently selected from
the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, cyano, nitro, and trifluoromethyl.
The term specifically includes furyl, thienyl, thiazolyl,
pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl,
thioisoxazolyl, pyridyl, pyrimidyl, pyridazinyl, and pyrazidinyl;
each optionally substituted as described above.
[0066] The term "C.sub.1-C.sub.4 alkyl" refers to a straight or
branched alkyl chain having from one to four carbon atoms, and
includes methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,
iso-butyl, and t-butyl.
[0067] The term "C.sub.2-C.sub.4 alkyl" refers to a straight or
branched alkyl chain having from two to four carbon atoms, and
includes ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl,
and t-butyl.
[0068] The term "C.sub.1-C.sub.4 alkoxy" refers to a straight or
branched alkyl chain having from one to four carbon atoms attached
to an oxygen atom, and includes methoxy, ethoxy, propoxy,
iso-propoxy, butoxy, iso-butoxy, sec-butoxy, and t-butoxy.
[0069] The term "halogen" refers to a chloro, fluoro, bromo or iodo
atom.
[0070] The term "pharmaceutically-acceptable addition salt" refers
to an acid addition salt.
[0071] The compound of formula I or II and the intermediates
described herein form pharmaceutically acceptable acid addition
salts with a wide variety of organic and inorganic acids and
include the physiologically acceptable salts which are often used
in pharmaceutical chemistry. Such salts are also part of this
invention. A pharmaceutically-acceptable addition salt is formed
from a pharmaceutically-acceptable acid as is well known in the
art. Such salts include the pharmaceutically acceptable salts
listed in Journal of Pharmaceutical Science, 66, 2-19 (1977) which
are known to the skilled artisan. Typical inorganic acids used to
form such salts include hydrochloric, hydrobromic, hydriodic,
nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric,
pyrophosphoric, and the like. Salts derived from organic acids,
such as aliphatic mono and dicarboxylic acids, phenyl substituted
alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids,
aromatic acids, aliphatic and aromatic sulfonic acids, may also be
used. Such pharmaceutically acceptable salts thus include chloride,
bromide, iodide, nitrate, acetate, phenylacetate, trifluoroacetate,
acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, methylbenzoate,
o-acetoxybenzoate, isobutyrate, phenylbutyrate,
.alpha.-hydroxybutyrate, butyne-1,4-dicarboxylate,
hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate,
formate, fumarate, glycollate, heptanoate, hippurate, lactate,
malate, maleate, hydroxymaleate, malonate, mandelate, mesylate,
nicotinate, isonicotinate, oxalate, phthalate, teraphthalate,
propiolate, propionate, phenylpropionate, salicylate, sebacate,
succinate, suberate, benzenesulfonate, p-bromobenzenesulfonate,
chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate,
methylsulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,
naphthalene-1,5-sulfonate, p-toluenesulfonate, xylenesulfonate,
tartrate, and the like.
[0072] As with any group of pharmaceutically active compounds, some
groups are preferred in their end use application. Preferred
embodiments of the present invention are given for the compounds of
formula I below:
[0073] Compounds in which wherein X is selected from the group
consisting of --O--, --NH--, and --S-- are preferred, with
compounds in which X is --O-- being more preferred.
[0074] Compounds in which R.sub.1 is optionally substituted phenyl
or optionally substituted 5 to 6 membered monocyclic aromatic
heterocycle having one heteroatom selected from the group
consisting of nitrogen, oxygen, and sulfur and which 5 to 6
membered monocyclic aromatic heterocycle is optionally benzofused
are preferred.
[0075] When R.sub.1 is optionally substituted phenyl preferred
substituents are 1 to 3 groups independently selected from the
group consisting of hydrogen, C.sub.1-C.sub.4 alkyl, halogen,
benzyloxy, carboxy, C.sub.1-C.sub.4 alkoxycarbonyl, amido,
N--(C.sub.1-C.sub.4 alkyl)amido, sulfonylamido, cyano,
trifluoromethyl, trifluoromethoxy, nitro, and phenyl optionally
substituted with C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, cyano, and trifluoromethyl.
[0076] When R.sub.1 is optionally substituted phenyl more preferred
substituents are 1 to 3 groups independently selected from the
group consisting of hydrogen, C.sub.1-C.sub.4 alkyl, halogen,
cyano, and trifluoromethyl.
[0077] Compounds in which R.sub.3 is hydrogen or fluorine are
preferred.
[0078] Compound in which R.sub.1 is optionally substituted 5 to 6
membered monocyclic aromatic heterocycle having one heteroatom
selected from the group consisting of nitrogen, oxygen, and sulfur
and which 5 to 6 membered monocyclic aromatic heterocycle is
optionally benzofused, the compounds which are benzo fused are
preferred, with indolyl being preferred, and indol-3-yl being even
more preferred.
[0079] When R.sub.1 is indol-3-yl, preferred groups are depicted as
the radical below: ##STR10## a) R.sub.o is selected from the group
consisting of hydrogen and C.sub.1-C.sub.4 alkyl, with hydrogen
being more preferred; b) R.sub.p is selected from the group
consisting of hydrogen and C.sub.1-C.sub.4 alkyl, with hydrogen
being more preferred; c) R.sub.q is selected from the group
consisting of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, and halogen, with hydrogen being more preferred; d)
R.sub.q' is selected from the group consisting of hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, trifluoromethoxy,
2,2,2-trifluoroethoxy, trifluoromethyl halogen, and
--S(O).sub.pR.sub.i wherein p is 2 and R.sub.i is phenyl optionally
substituted with C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
trifluoromethyl, with halogen being more preferred; e) R.sub.q'' is
selected from the group consisting of hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, halogen, nitro, cyano,
trifluoromethyl, and --S(O).sub.pR.sub.i, wherein p 2 and R.sub.i
is phenyl optionally substituted with C.sub.1-C.sub.4 alkyl, with
halogen being more preferred; and f) R.sub.q''' is selected from
the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, trifluoromethyl, cyano, and nitro,
with hydrogen and halogen being preferred.
[0080] Compounds in which R.sub.4 is selected from the group
consisting of C.sub.2-C.sub.4 alkyl, fluorinated C.sub.2-C.sub.4
alkyl and optionally substituted phenyl are preferred.
[0081] When R.sub.4 is C.sub.2-C.sub.4 alkyl, particularly
preferred groups include propyl, isopropyl, and butyl.
[0082] When R.sub.4 is fluorinated C.sub.2-C.sub.4 alkyl, preferred
groups include 2,2-difluoroethyl, 2,2,2-trifluoroethyl,
3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl,
2,2,3,3,3-pentafluoropropyl, and 2,2,3,3-tetrafluoropropyl.
[0083] When R.sub.4 is optionally substituted phenyl preferred
groups include 1 to 3 groups independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, cyano, and trifluoromethyl.
[0084] Preferred embodiments of the present invention are given for
the compounds of formula II below:
[0085] Compounds in which R.sub.7 is optionally substituted phenyl
or optionally substituted 5 to 6 membered monocyclic aromatic
heterocycle having one heteroatom selected from the group
consisting of nitrogen, oxygen, and sulfur and which 5 to 6
membered monocyclic aromatic heterocycle is optionally benzofused
are preferred.
[0086] When R.sub.7 is optionally substituted phenyl preferred
substituents are 1 to 3 groups independently selected from the
group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, cyano, trifluoromethoxy, and
trifluoromethyl.
[0087] Compounds in which R.sub.7 is optionally substituted 5 to 6
membered monocyclic aromatic heterocycle having one heteroatom
selected from the group consisting of nitrogen, oxygen, and sulfur
and which 5 to 6 membered monocyclic aromatic heterocycle is
optionally benzofused, the compounds which are benzo fused are
preferred, with indolyl being preferred, and indol-3-yl being even
more preferred, with the indol-3-yl depicted above for formula I
being more preferred.
[0088] Preferred compounds of formula II having the points of
attachment depicted below: ##STR11##
[0089] While only compounds of formula I are depicted, the
compounds of formula I and II are prepared as described in Schemes
A and B below. In the Schemes below all substituents, unless
otherwise indicated, are as previously defined, and all starting
materials and reagents are well known and appreciated in the art
and readily available or prepared by methods described herein. In
the Schemes below, it is understood that protecting groups can be
used, where appropriate to allow for elaboration of a portion of
the compounds of formula I or II. The selection, use, and removal
of suitable protecting groups is well known and appreciated in the
art (Protecting Groups in Organic Synthesis, Theodora Greene
(Wiley-Interscience)). ##STR12##
[0090] Scheme A depicts alternative methods for the preparation of
compounds of formula I by reductive amination.
[0091] In one alternative of Scheme A, step a, an appropriate
compound of formula (1) is contacted with an appropriate compound
of formula (2) in a reductive amination reaction to give a compound
of formula I. An appropriate compound of formula (1) is one in
which R.sub.1 and R.sub.2 are as desired in the final product of
formula I or give rise to groups desired in the final product of
formula I. An appropriate compound of formula (2) is one in which
X, R.sub.3, and R.sub.4 are as desired in the final product of
formula I, or give rise to groups desired in the final product of
formula I.
[0092] In another alternative of Scheme A, step a, an appropriate
compound of formula (3) is contacted with an appropriate compound
of formula (4) in a reductive amination reaction to give a compound
of formula I. An appropriate compound of formula (3) is one in
which R.sub.1 and R.sub.2 are as desired in the final product of
formula I or give rise to groups desired in the final product of
formula I. An appropriate compound of formula (4) is one in which
X, R.sub.3, and R.sub.4 are as desired in the final product of
formula I or give rise to groups desired in the final product of
formula I.
[0093] The reductive amination depicted in Scheme A, step a, can be
carried out under a variety of conditions, such as by hydrogenation
using a suitable catalyst or using a suitable reducing agent.
[0094] For example, an appropriate amine of formula (1) is
contacted with an appropriate aldehyde of formula (2) (or
alternately an appropriate amine of formula (4) and an appropriate
aldehyde of formula (3)) and a suitable reducing agent to give a
compound of formula I. The reaction is carried out in a suitable
solvent, such as methanol, ethanol, tetrahydrofuran, or mixtures of
methanol or ethanol and tetrahydrofuran, dichloromethane, and
1,2-dichloroethane. The reaction may be carried out in the presence
of a drying agent, such as sodium sulfate, cupric sulfate, or
molecular sieves. The reaction is carried out in the presence of
from about 1 to 20 molar equivalents of a suitable reducing agent,
such as, sodium borohydride, sodium cyanoborohydride, and sodium
triacetoxyborohydride. It may be advantageous to allow Schiff base
formation to proceed before addition of the suitable reducing
agent. When sodium cyanoborohydride is used it may be advantageous
to monitor and adjust the pH during the course of the reaction as
is known in the art. The reaction is generally carried out at
temperatures of from 0.degree. C. to the refluxing temperature of
the solvent. Generally, the reactions require 1 to 72 hours. The
product can be isolated and purified by techniques well known in
the art, such as filtration, extraction, evaporation, trituration,
chromatography, and recrystallization. Scheme A, optional step b,
not shown, an acid addition salt of a compound of formula I is
formed using a pharmaceutically-acceptable acid. The formation of
acid addition salts is well known and appreciated in the art.
##STR13##
[0095] Scheme B depicts alternative methods for the preparation of
compounds of formula I by formation and reduction of an amide.
[0096] In one alternative, Scheme B, step a, depicts contacting an
appropriate compound of formula (1) with an appropriate compound of
formula (5) in a amide forming reaction to give a compound of
formula (6). An appropriate compound of formula (1) is as described
in Scheme A. An appropriate compound of formula (5) is one in which
A is an activating group, taking the form of an acid halide,
activated ester, activated amide, or anhydride, and X, R.sub.3, and
R.sub.4 are as desired in the final product of formula I, or give
rise to groups desired in the final product of formula I.
[0097] In another alternative, Scheme B, step a, depicts contacting
an appropriate compound of formula (7) with an appropriate compound
of formula (4) in a amide forming reaction to give a compound of
formula (8). An appropriate compound of formula (7) is one in which
A is an activating group as described above and R.sub.1 is as
desired in the final product of formula I. An appropriate compound
of formula (4) is as described in Scheme A. Appropriate compounds
of formula (4) and (7) are generally available from commercial
sources and can also be prepared by methods described herein and by
methods described in the art.
[0098] The amide formation reaction depicted in Scheme B, step a,
is readily accomplished by a number of methods readily available to
the skilled person, including those which are conventionally
conducted for peptide synthesis. Such methods can be carried out on
the acid, acid halide, activated esters, activated amides, and
anhydrides.
[0099] For example, well known coupling reagents such as a
carbodiimides with or without the use of well known additives such
as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used
to facilitate amide formation. Such coupling reactions are
typically use about 1 to 1.5 molar ratios of acid, amine, and
coupling reagent and are conventionally conducted in an inert
aprotic solvent such as pyridine, dimethylfomamide,
dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile,
tetrahydrofuran and the like. It may be advantageous to use a
suitable base, such as triethylamine or N,N-diisopropylethylamine,
in such coupling reactions. The reaction is preferably conducted at
from about 0.degree. C. to about 60.degree. C. until reaction
completion which typically occurs within 1 to about 48 hours. Upon
reaction completion, the product can be isolated and purified by
techniques well known in the art, such as filtration, extraction,
evaporation, trituration, chromatography, and
recrystallization.
[0100] Alternatively, for example, an acid halide can be employed
in the reaction. It may be advantageous to use a suitable base to
scavenge the acid generated during the reaction, suitable bases
include, by way of example, triethylamine,
N,N-diisopropylethylamine, N-methylmorpholine, pyridine, and the
like. Typically, about 1 to 1.5 molar ratios of the acid halide and
amine are used. The reaction can be carried out in a variety of
inert aprotic solvents such as pyridine, dichloromethane,
chloroform, 1,2-dichloroethane, tetrahydrofuran, and the like. The
reaction is preferably conducted at from about 0.degree. C. to
about 60.degree. C. until reaction completion which typically
occurs within 1 to about 12 hours. Upon reaction completion, the
product can be isolated and purified by techniques well known in
the art, such as filtration, extraction, evaporation, trituration,
chromatography, and recrystallization.
[0101] Alternatively, for example, an acid halide can be employed
in the reaction under Schotten-Baumann conditions. Typically, under
such conditions 1 to 10 molar equivalents of amine are used. Such
couplings generally use a suitable base to scavenge the acid
generated during the reaction, such as sodium hydroxide, potassium
hydroxide, sodium carbonate, potassium carbonate, sodium
bicarbonate, potassium bicarbonate, and the like. The reaction can
be carried out in a variety of mixed solvent systems such as
dichloromethane, chloroform, ethyl acetate, tetrahydrofuran and the
like; and water. The reaction is preferably conducted at from about
0.degree. C. to about 80.degree. C. until reaction completion which
typically occurs within 1 to about 6 hours. Upon reaction
completion, the product can be isolated and purified by techniques
well known in the art, such as filtration, extraction, evaporation,
trituration, chromatography, and recrystallization.
[0102] Alternatively, for example, an anhydride (either symmetrical
or mixed) can be employed in the reaction. Such anhydrides are
formed by numerous methods known in art. Typically, about 1 to 1.5
molar equivalents of the anhydride and amine are used. It may be
advantageous to use a suitable base to scavenge the acid generated
during the reaction. Suitable bases include, by way of example,
triethylamine, N,N-diisopropylethylamine, N-methylmorpholine,
pyridine, sodium carbonate, potassium carbonate, sodium
bicarbonate, and the like. The reaction can be carried out in a
variety of solvents. The reaction is preferably conducted at from
about 0.degree. C. to about 60.degree. C. until reaction completion
which typically occurs within 1 to about 12 hours. Upon completion,
the product can be isolated and purified by techniques well known
in the art, such as filtration, extraction, evaporation,
trituration, chromatography, and recrystallization.
[0103] Scheme B, steps b, depicts reduction of a compound of
formula (6) or (8) to give a compound of formula I.
[0104] For example, a compound of formula (6) or (8) is contacted
with a suitable reducing agent to give a compound of formula I.
Suitable reducing agents are those which are capable of reducing an
amide to an amine and include, borane reagents, such as borane
dimethyl sulfide complex, hydride transfer reagents, such as
aluminum hydride and lithium aluminum hydride, and the like. The
reaction is carried out in a solvent, such as tetrahydrofuran or
diethyl ether, typically using 1 to 10 equivalents of reducing
agent. The reaction is generally conducted at from about 0.degree.
C. the refluxing temperature of the selected solvent and typically
occurs within 1 to about 48 hours. The product can be isolated and
purified by techniques well known in the art, such as quenching,
filtration, extraction, evaporation, trituration, chromatography,
and recrystallization.
[0105] Scheme B, as an optional step, not shown, an acid addition
salt of a compound of formula I is formed using a
pharmaceutically-acceptable acid. The formation of acid addition
salts is well known and appreciated in the art.
[0106] In Schemes A and B, as an optional step, not shown, as will
be appreciated by the skilled person, a compound of formula I in
which R.sub.2 is hydrogen can be alkylated to give a compound in
which R.sub.2 is not hydrogen. Methods for alkylating such
secondary amines are will known in the art and discussed in Scheme
C, step c, below.
[0107] In Schemes A and B, as will be appreciated by the skilled
person, compounds of formula II are also prepared by the methods
described in Schemes A and B using compounds of the formula (9) and
(10), below: ##STR14##
[0108] An appropriate compound of formula (9) is one in which Y,
R.sub.5 and R.sub.6 are as desired in the final product of formula
II and an appropriate compound of formula (10) is one in which A is
an activating group, as described above, and Y, R.sub.5 and R.sub.6
are as desired in the final product of formula II.
[0109] Starting material for Schemes A and B are prepared in the
Schemes below. In the Schemes below all substituents, unless
otherwise indicated, are as previously defined, and all starting
material and reagents are well known and appreciated in the
art.
[0110] Scheme C describes methods for preparing compounds of
formula (1). ##STR15##
[0111] Scheme C, step a, depicts the reaction of an appropriate
aldehyde of formula (24) and nitromethane to give the compound of
formula (25). An appropriate aldehyde of formula (24) is one in
which R.sub.1 is as desired in the final product of formula I. The
reaction of the anion of nitromethane with aldehydes to give nitro
olefins is well known and appreciated in the art. Modern Synthetic
Reactions, H. O. House (2nd ed. The Benjamin/Cummings Publishing
Company 1972).
[0112] For example, an appropriate aldehyde of formula (24) is
condensed with nitromethane to give the compound of formula (25).
Typically the reaction is carried out in the presence of an excess
of nitromethane. The reaction is performed in a suitable solvent,
such as tetrahydrofuran, nitromethane, and dimethyl sulfoxide. The
reaction is performed using from about 1.1 to about 3 molar
equivalents of a suitable base, such as sodium
bis(trimethylsilyl)amide, potassium t-butoxide, sodium hydride,
sodium acetate, triethylamine, N,N-diisopropylethylamine, ammonium
salts, such as ammonium acetate. The reaction is carried out at
temperatures of from about -20.degree. C. to the reflux temperature
of the selected solvent and generally require from 6 hours to 48
hours. The product of the coupling reaction can be isolated and
purified using techniques well known in the art, including
extraction, evaporation, chromatography and recrystallization.
[0113] Scheme C, step b, depicts the reduction of a compound of
formula (25) to give a compound of formula (1) in which R.sub.2 is
hydrogen.
[0114] For example, an appropriate compound of formula (25) is
hydrogenated over a suitable catalyst, such as Raney.RTM. nickel or
a palladium catalyst. When Raney nickel is used, the reaction is
carried out in a suitable solvent, such as ethanol, methanol,
water, and mixtures thereof. It may be advantageous to carry out
the hydrogenation under acidic conditions, for example, using
hydrochloric or sulfuric acid. When a palladium catalyst is used
palladium-on-carbon is preferred and the reaction is carried out in
a suitable solvent, such as ethanol, methanol, tetrahydrofuran,
water, and mixtures thereof. It may be advantageous to carry out
the hydrogenation under acidic conditions, for example, using
hydrochloric, trifluoroacetic acid, or sulfuric acid. The reaction
is generally carried out at temperatures of from ambient
temperature to 70.degree. C. The reaction is carried out with
hydrogen at pressures of from 15 psi to 120 psi in an apparatus
designed for carrying out reactions under pressure, such as a
Parr.RTM. hydrogenation apparatus. The product can be isolated by
carefully removing the catalyst by filtration and evaporation. The
product can be purified by extraction, evaporation, trituration,
chromatography, and recrystallization.
[0115] Alternately, for example, an appropriate compound of formula
(25) is contacted with a suitable reducing agent. Suitable reducing
agents include hydride transfer reagents, such as aluminum hydride
and lithium aluminum hydride, and the like. The reaction is carried
out in a solvent, such as tetrahydrofuran or diethyl ether,
typically using 1 to 10 equivalents of reducing agent. The reaction
is generally conducted at from about 0.degree. C. the refluxing
temperature of the selected solvent and typically occurs within 1
to about 48 hours. The product can be isolated and purified by
techniques well known in the art, such as quenching, filtration,
extraction, evaporation, trituration, chromatography, and
recrystallization.
[0116] Additionally, an appropriate compound of formula (25) can be
reduced in two steps to a compound of formula (1). For example, the
vinyl group of a compound of formula (25) can be reduced using
reagents such as sodium borohydride. The reaction is typically
carried out using an excess of borohydride in a solvent, such as
methanol, ethanol, isopropanol, water, and the like. The
intermediate 2-nitroethyl compound can be isolated and purified by
techniques well known in the art, such as quenching, filtration,
extraction, evaporation, trituration, chromatography, and
recrystallization. The intermediate 2-nitroethyl compound can then
be reduced using a variety of methods, such as the hydrogenation
and hydride transfer reagents as discussed above. Also, the
intermediate 2-nitroethyl compound can be reduced using metals such
as zinc to give the desired anine of formula (1) in which R.sub.2
is hydrogen.
[0117] Scheme C, step c, depicts the optional alkylation of a
compound of formula (1) in which R.sub.2 is hydrogen to give a
compound of formula (1) in which R.sub.2 is not hydrogen.
[0118] For example, a compound of formula (1) in which R.sub.2 is
hydrogen is contacted with a suitable alkylating agent. A suitable
alkylating agent is one which transfers a group R.sub.2 as is
desired in the final product of formula I. Suitable alkylating
agents include C.sub.1-C.sub.3 alkyl halides. The reaction is
carried out in a suitable solvent, such as dioxane,
tetrahydrofuran, tetrahydrofuran/water mixtures, or acetonitrile.
The reaction is carried out in the presence of from 1.0 to 6.0
molar equivalents of a suitable base, such as sodium carbonate,
sodium bicarbonate, potassium carbonate, potassium bicarbonate,
triethylamine, or N,N-diisopropylethylamine. The reaction is
generally carried out at temperatures of from -78.degree. C. to the
refluxing temperature of the solvent. Generally, the reactions
require 1 to 72 hours. The product can be isolated and purified by
techniques well known in the art, such as extraction, evaporation,
trituration, chromatography, and recrystallization.
[0119] Alternately, for example, a compound of formula (1) in which
R.sub.2 is hydrogen undergoes a reductive amination with an
aldehyde or ketone which gives a compound of formula (1) in which
R.sub.2 is not hydrogen. Suitable aldehydes include formaldehyde,
acetaldehyde, propionaldehyde, and acetone. The reaction is carried
out as described in Scheme A, step a.
[0120] In another alternate, for example, a compound of formula (1)
in which R.sub.2 is hydrogen undergoes amide or carbamate formation
followed by reduction to give a compound of formula (1) in which
R.sub.2 is not hydrogen. Suitable aldehydes include formaldehyde,
acetaldehyde, propionaldehyde, and acetone. The reaction is carried
out as described in Scheme A, step a.
[0121] Scheme C, steps d and e, depict an alternative approach to
preparing the compounds of formula (1) via formation of an amide
using an appropriate compound of formula (7) and an appropriate
amine of formula (26) to give an amide of formula (27), followed by
reduction to give a compound of formula (1). An appropriate
compound of formula (7) is as described in Scheme B. An appropriate
amine of formula (26) is one which gives R.sub.2 as desired in
final compound of formula I. The skilled person will recognize that
many of the amides of formula (27) are commercially available and
available in the art.
[0122] The amide formation and reduction in Scheme C are carried
out as described in the Scheme B.
[0123] Scheme D describes methods for preparing compounds of
formula (1) in which R.sub.1 is optionally substituted indol-3-yl.
##STR16##
[0124] Scheme D, step a, depicts the two-step reaction of an
appropriate indole of formula (28) with oxalyl chloride followed by
an appropriate amine of formula (26), R.sub.2NH.sub.2 to give a
compound of formula (29). An appropriate indole of formula (28) is
one in which Z' represents optional substituents on the indole 2-
and 4- to 7-positions as desired in the final product of formula I.
An appropriate amine of formula (26) is as described in Scheme C,
above.
[0125] For example, an appropriate indole of formula (28) is
contacted with about 1 to 2 molar equivalents of oxalyl chloride to
give an intermediate keto-acid chloride. The reaction is carried
out in a suitable solvent, such a diethyl ether or tetrahydrofuran.
The reaction is generally carried out at temperatures of from
0.degree. C. to 40.degree. C. and generally require from 6 hours to
48 hours. The intermediate keto-acid chloride product can be
isolated and purified using techniques well known in the art,
including extraction, evaporation, chromatography and
recrystallization. Generally, the intermediate keto-acid chloride
product is used directly after isolation. The intermediate
keto-acid chloride product is contacted with an appropriate amine,
R.sub.2NH.sub.2, as defined above and using the procedures
described above.
[0126] Scheme D, step b, depicts the reduction of a compound of
formula (29) to give a compound of formula (1) in which R.sub.1 is
optionally substituted indol-3-yl.
[0127] For example, a compound of formula (29) is reduced using a
suitable reducing reagent such as, lithium aluminum hydride to give
a compound of formula (1) which R.sub.1 is optionally substituted
indol-3-yl. The reaction is carried out in a solvent, such as
tetrahydrofuran or diethyl ether, typically using 1 to 12 molar
equivalents of reducing agent. The reaction is generally conducted
at from about 0.degree. C. the refluxing temperature of the
selected solvent and typically occurs within 12 to about 48 hours.
The product can be isolated and purified by techniques well known
in the art, such as quenching, filtration, extraction, evaporation,
trituration, chromatography, and recrystallization.
[0128] In Scheme D, step c, an appropriate indole of formula (28)
is formylated to give a compound of formula (30). An appropriate
indole of formula (28) is as described in step a, above.
[0129] For example, an appropriate indole of formula (28) is
reacted with a suitable formyl transfer reagent, such as the
Vilsmeier reagent formed from dimethylformamide. Generally, about 1
molar equivalent of formyl transfer reagent is used. The reaction
is performed in a suitable solvent, such as benzene,
dimethylformamide, tetrahydrofuran, or diethyl ether. The reaction
is carried out at temperature of from about -70.degree. C. to about
20.degree. C. and generally require from 1 hours to 6 hours. The
product of the reaction can be isolated and purified using
techniques well known in the art. These techniques include
extraction, evaporation, chromatography and recrystallization.
[0130] In Scheme D, step d, an appropriate indole of formula (28)
is contacted with (CH.sub.3).sub.2N--CH.dbd.CH--NO.sub.2 to give a
compound of formula (30). An appropriate indole of formula (28) is
as described in step a, above.
[0131] For example, an appropriate indole of formula (28) is
reacted with 1-dimethylamino-2-nitroethylene. Generally, about 1
equimolar amounts of reagents. The reaction is performed in a
suitable solvent, such as trifluoroacetic acid or dichloromethane
containing about 2 to 15 equivalents of trifluoroacetic acid. The
reaction is carried out at temperature of from about -70.degree. C.
to about 20.degree. C. and generally require from 1 hours to 24
hours. The product of the reaction can be isolated and purified
using techniques well known in the art. These techniques include
extraction, evaporation, chromatography and recrystallization.
[0132] Scheme D, steps e and f, depict an the reaction of an
aldehyde of formula (30) to give a nitro olefin of formula (31) and
the reduction of the nitro olefin to give a compound of formula (1)
in which R.sub.1 is optionally substituted indol-3-yl. These steps
can be carried out using the methods described in Scheme C.
[0133] As will be appreciated by the skilled person, in steps not
shown, the indole nitrogen of a compound of formula (1) can be
substituted, as desired, using suitable amine protecting groups to
give compounds in which R.sub.1 is 1-substituted indol-3-yl. Also
as will be appreciated by the skilled person, in steps described in
Scheme C, R.sub.2 groups which are not hydrogen can be introduced
by various methods.
[0134] Scheme E describes methods for preparing compounds of
formula (2) in which X is --O-- or --S--. ##STR17##
[0135] Scheme E, step a, depicts the formation of an acetal of an
appropriate compound of formula (11) to give a compound of formula
(12). An appropriate compound of formula (11) is one in which X and
R.sub.3 are as desired in the final compound of formula I. Such
acetal formation reactions are readily accomplished by methods well
known in the art. (Protecting Groups in Organic Synthesis, Theodora
Greene (Wiley-Interscience)).
[0136] For example, a compound formula (11) is contacted under acid
catalysis with an appropriate alcohol, HOR. An appropriate alcohol
is one which gives an acetal with is stable to the reaction in step
b and can be removed in step c to give a compound of formula (2).
Appropriate alcohols include methanol, ethanol, propanol,
1,3-propane diol, ethylene glycol, and the like.
[0137] In Scheme E, step b, an appropriate compound of formula
(11), (12), or (14) is reacted with an R.sub.4 group transfer
reagent, as desired, to give a compound of formula (2), (13), or
(15); respectively. Appropriate compounds of formula (11), (12),
and (14) are ones in which X and R.sub.3 are as desired in the
final product of formula 1. A variety of reagents that transfers an
R.sub.4 as desired in the final product are available and suitable
for the reaction depicted in Scheme E. Such reagents include
halopyridines, halopryidine N-oxides, allyl halides,
C.sub.2-C.sub.4 alkanols, C.sub.2-C.sub.4 alkyl halides and
sulfonates, fluorinated C.sub.2-C.sub.4 alkanols, fluorinated
C.sub.2-C.sub.4 alkyl halides and sulfonates, optionally
substituted phenyl having at least one fluoro or chloro atom,
optionally substituted phenylsulfonyl halides or anhydrides, and
optionally substituted benzyl halides.
[0138] For example, where the appropriate R.sub.4 group transfer
reagent is a halide, sulfonate, or anhydride, an appropriate
compound of formula (11), (12), or (14) is coupled under basic
conditions to give a compound of formula (2), (13), or (15);
respectively. The reaction is performed in a suitable solvent, such
as acetonitrile, dimethylformamide, dimethylacetamide,
tetrahydrofuran, pyridine, and dimethyl sulfoxide. The reaction is
carried out in the presence of from about 1 to about 3 molar
equivalents of a suitable base, such as potassium hydride, sodium
hydroxide, sodium hydride, sodium carbonate, potassium carbonate,
cesium carbonate, N,N-diisopropylethylamine, triethylamine, and the
like. The reaction is carried out at temperature of from about
-30.degree. C. to about 100.degree. C. and generally require from 6
hours to 48 hours. The product of the reaction can be isolated and
purified using techniques well known in the art. These techniques
include extraction, evaporation, chromatography and
recrystallization.
[0139] Of course, when a halopyridine N-oxide is used the N-oxide
is remove by reduction to give the R.sub.4 as desired in the final
product of formula I. Such reductions are readily accomplished by
the skilled person, and include catalytic reduction over palladium
catalysts using hydrogen or ammonium formate in a suitable solvent
such as methanol, ethanol, water, and mixtures thereof.
[0140] Alternately, for example, where the appropriate R.sub.4
group transfer reagent is an alkanol, the coupling can be carried
out under Mitsunobu conditions which are well known in the art. The
reaction is carried out in a suitable solvent, such as
tetrahydrofuran and diethyl ether using a phosphine, such as
triphenylphosphine or a resin bound phosphine and a dialkyl
azodicarboxylate, such as diethyl azodicarboxylate, diisopropyl
azodicarboxylate or di-t-butyl azodicarboxylate. The reaction is
generally carried out at temperatures of from ambient temperatures
to 60.degree. C. The reaction generally requires from 1 hour to 12
hours. The product can be isolated by techniques well known in the
art, such as extraction and evaporation. The product can then be
purified by techniques well known in the art, such as distillation,
chromatography, or recrystallization.
[0141] Scheme E, step c, depicts the deprotection of an acetal of
formula (13) to give a compound of formula (2). Such deprotections
are readily accomplished by methods well known in the art.
(Protecting Groups in Organic Synthesis, Theodora Greene
(Wiley-Interscience)).
[0142] For example, a compound formula (13) is contacted under acid
under aqueous conditions to give a compound of formula (2).
[0143] In Scheme E, step d, a bromo compound of formula (15) is
formylated to give a compound of formula (2).
[0144] For example, a compound of formula (15) is metalated by
treatment with a metalation reagent such as butyl lithium. The
reaction is performed in a suitable solvent, such as hexane,
benzene, toluene, tetrahydrofuran or diethyl ether. The reaction is
typically carried out in the presence of from about 1 to about 1.5
molar equivalents of a metalating reagent. The metalation reaction
is cared out at temperature of from about -70.degree. C. to about
20.degree. C. and generally require from 1 hours to 6 hours. The
metalated species is then treated with a formyl transfer reagent,
such as dimethylformamide or an alkyl chloroformate to give a
compound of formula (2) or a alkoxycarbonyl compound which can be
elaborated to an aldehyde as described herein. The product of the
reaction can be isolated and purified using techniques well known
in the art. These techniques include extraction, evaporation,
chromatography and recrystallization.
[0145] Scheme F describes methods for preparing compounds of
formula (2) from the versatile intermediate, compound (17), which
readily prepared by acetal formation as described above.
##STR18##
[0146] Scheme F, step a, depicts an aromatic displacement reaction
of an appropriate compound of formula (17) and an appropriate
alcohol (R.sub.4OH) or an appropriate thiol (R.sub.4SH) to give a
compound of formula (13) in which X is --O-- or --S-- are defined
above in Scheme E. An appropriate compound of formula (17) is one
in which R.sub.3 is as desired in the final product of formula I.
In an appropriate alcohol (R.sub.4OH) or an appropriate thiol
(R.sub.4SH), R.sub.4 is as desired in the final product of formula
J, and includes C.sub.2-C.sub.4 alkyl alcohols and thiols,
fluorinated C.sub.2-C.sub.4 alkyl alcohols and thiols, optionally
substituted phenols and thiophenols, optionally substituted benzyl
alcohols and thiols.
[0147] For example, an appropriate compound of formula (17) and an
appropriate alcohol (R.sub.4OH) or an appropriate thiol (R.sub.4SH)
are coupled give a compound of formula (13). The reaction is
performed in a suitable solvent, such as dimethylformamide,
dimethylacetamide, and dimethyl sulfoxide. The reaction is
performed using from about 1.1 to about 3 molar equivalents of an
appropriate alcohol or thiol. The reaction is carried out in the
presence of from about 1 to about 6 molar equivalents of a suitable
base, such as potassium hydride, sodium hydroxide, potassium
carbonate, sodium carbonate, or sodium hydride. The coupling is
performed using a suitable catalyst, such as copper salts. The
reaction generally requires from 6 hours to 48 hours. The product
of the coupling reaction can be isolated and purified using
techniques well known in the art. These techniques include
extraction, evaporation, chromatography and recrystallization.
[0148] Scheme F, steps b-e, depict a number of reactions of an
appropriate compound of formula (17), after metalation as described
in Scheme E, step d, to give compounds of formula (18)-(21),
respectively. In these steps an appropriate compound of formula
(17) is one in which R.sub.3 is as desired in the final product of
formula I and is not adversely affected by the metalation
conditions of the reaction. Generally, these reactions are
performed in the solvent used and at the temperature used to form
the metalated species. The products of these reactions can be
isolated and purified using techniques well known in the art,
include quenching, extraction, evaporation, trituration,
chromatography, and recrystallization.
[0149] For example, in Scheme F, step b, a metalated compound of
formula (17) is contacted with an appropriate disulfide
(R.sub.4S--).sub.2, to give a compound of formula (18). An
appropriate disulfide is one that gives R.sub.4 as desired in the
final product of formula I and gives rise to compounds in which X
is --S--. Appropriate disulfides include C.sub.1-C.sub.4 alkyl
disulfides, optionally substituted phenyl disulfides, and
optionally substituted benzyl disulfides. The reaction is performed
using from about 1 to about 2 molar equivalents of an appropriate
disulfide. The reaction is typically carried out in the same
solvent used for the metallation and at temperatures of about
-78.degree. C. to about 50.degree. C. The reaction generally
require from 12 hours to 48 hours.
[0150] For example, in Scheme F, step c, a metalated compound of
formula (17) is contacted with an appropriate sulfonyl fluoride
(R.sub.4SO.sub.2F) to give a compound of formula (19). An
appropriate sulfonyl fluoride is one that transfers R.sub.4 as
desired in the final product of formula I and gives rise to
compounds in which X is --SO.sub.2--. Appropriate sulfonyl
fluorides include an optionally substituted phenyl sulfonyl
fluoride. The reaction is performed using from about 1 to about 3
molar equivalents of an appropriate sulfonyl fluoride. The reaction
is typically carried out in the same solvent used for the
metallation and at temperatures of about -78.degree. C. to about
0.degree. C. The reaction generally require from 2 hours to 12
hours.
[0151] For example, in Scheme F, step d, a metalated compound of
formula (17) is contacted with an appropriate acid chloride
(R.sub.4C(O)Cl) to give a compound of formula (20). An appropriate
acid chloride is one that transfers R.sub.4 as desired in the final
product of formula I and gives rise to compounds in which X is
--C(O)--. Appropriate acid chlorides include C.sub.2-C.sub.4 alkyl
acid chlorides, fluorinated C.sub.2-C.sub.4 allyl acid chlorides,
optionally substituted phenyl acid chlorides, optionally
substituted benzyl acid chlorides, and optionally substituted 5 to
6 membered monocyclic aromatic heterocycle acid chlorides. The
reaction is performed using from about 0.8 to about 1.2 molar
equivalents of an appropriate acid chloride. The reaction is
typically carried out in the same solvent used for the metallation
and at temperatures of about -78.degree. C. to about 50.degree. C.
The reaction generally require from 1 hours to 12 hours.
[0152] For example, in Scheme F, step e, a metalated compound of
formula (17) is contacted with an appropriate aldehyde
(R.sub.4C(O)H) to give a compound of formula (21). An appropriate
aldehyde is one that transfers R.sub.4 as desired in the final
product of formula I and gives rise to compounds in which X is
--CH(OH)--. Appropriate aldehydes include C.sub.2-C.sub.4 alkyl
aldehyde, fluorinated C.sub.2-C.sub.4 alkyl aldehyde, optionally
substituted phenyl aldehyde, optionally substituted benzyl
aldehyde, and optionally substituted 5 to 6 membered monocyclic
aromatic heterocycle aldehyde. The reaction is performed using from
about 1 to about 3 molar equivalents of an appropriate aldehyde.
The reaction is typically carried out in the same solvent used for
the metallation and at temperatures of about -50.degree. C. to
about 50.degree. C. The reaction generally requires from 4 hours to
24 hours.
[0153] As will be appreciate by the skilled person, compounds of
formula (18)-(21) can undergo a number of other transformations
which are depicted in Scheme F, steps f-i, to give, ultimately,
compounds of formula I having various groups at X. These
transformations are trivial and well within the ability of the
skilled person. These transformations include oxidation of sulfides
(step f) which can be accomplished by peroxide, peracids, and other
reagents known in the art; reduction of a benzyl alcohol (step g)
which can be accomplished by a variety of reagents, such as
triethylsilane/trifluoroacetic acid; halogenation of a benzyl
alcohol to give fluoro (step h) using reagents such as DAST and
fluorinating reagents; reduction of a ketone (step i) using various
hydride transfer reagents or oxidation of a benzylic alcohol (step
i) which can be accomplished by manganese dioxide or Swern
conditions.
[0154] In Scheme F, step j, compounds of the formula (13) and
(18)-(23) are deprotected to give an aldehyde of formula (2) as
described in Scheme E, step c.
[0155] Scheme G describes methods for preparing compounds of
formula (5). ##STR19##
[0156] Scheme G, step a, a bromo compound of formula (15) is
carboxylated to give a compound of formula (5) in which A is
--OH.
[0157] For example, a compound of formula (15) is metalated as
described in Scheme E, step d, and the metalated species is then
treated with carbon dioxide to give a compound of formula (5) in
which A is --OH. The product of the reaction can be isolated and
purified using techniques well known in the art. These techniques
include extraction, evaporation, chromatography and
recrystallization.
[0158] Scheme G, step b, a bromo compound of formula (15) is
alkoxyformylated using an appropriate chloroformate or carbonate to
give a compound of formula (32). An appropriate chloroformate or
carbonate is one that transfers an RO(O)C-- group in which R is
methyl, ethyl, or benzyl.
[0159] For example, a compound of formula (15) is metalated as
described in Scheme E, step d, and the metalated species is then
treated with about 1 to 3 molar equivalents of an appropriate
chloroformate or carbonate. The reaction is typically carried out
in the same solvent used for the metallation and at temperatures of
about -78.degree. C. to about 50.degree. C. The reaction typically
requires from 1 to 24 hours. The product of the reaction can be
isolated and purified using techniques well known in the art. These
techniques include extraction, evaporation, chromatography and
recrystallization.
[0160] In Scheme G, step c, an appropriate compound of formula (33)
is reacted with an R.sub.4 group transfer reagent, as desired, to
give a compound of formula (32). An appropriate compound of formula
(33) is one in which X and R.sub.3 are as desired in the final
product of formula I. Reagents that transfers an R.sub.4 are as
described in Scheme E.
[0161] For example, where the appropriate R.sub.4 group transfer
reagent is a halide or anhydride, an appropriate compound of
formula (34) is coupled under basic conditions with to give a
compound of formula (33). The reaction is performed in a suitable
solvent, such as dimethylformamide, tetrahydrofuran, or pyridine.
The reaction is typically carried out in the presence of from about
1 to about 3 molar equivalents of a suitable base, such as sodium
carbonate, potassium carbonate, cesium carbonate,
N,N-diisopropylethylamine, triethylamine, and the like. The
reaction is carried out at temperature of from about -30.degree. C.
to about 100.degree. C. and generally require from 6 hours to 48
hours. The product of the reaction can be isolated and purified
using techniques well known in the art. These techniques include
extraction, evaporation, chromatography and recrystallization.
[0162] Alternately, for example, where the appropriate R.sub.4
group transfer reagent is an alkanol, the coupling can be carried
out under Mitsunobu conditions which are well known in the art and
described in Scheme E.
[0163] Scheme G, step d, an ester of formula (32) is deprotected to
give a compound of formula (5) in which A is --OH. Such
deprotections are readily accomplished by methods well known in the
art. (Protecting Groups in Organic Synthesis, Theodora Greene
(Wiley-Interscience)).
[0164] Scheme G, step e, a compound of formula (5) in which A is
--OH is converted to a compound of formula (5) in which A is an
activating group, such as acid halide, activated ester, activated
amide, or anhydride. The formation of such activated intermediates
is well known and appreciated in the art.
[0165] For example, an acid halide can be prepared by a variety of
reagent such as oxalyl chloride, oxalyl bromide, thionyl chloride,
thionyl bromide, phosphorous oxychloride, phosphorous trichloride,
and phosphorous pentachloride; a mixed anhydride of substituted
phosphoric acid, such as dialkylphosphoric acid, diphenylphosphoric
acid, halophosphoric acid; of aliphatic carboxylic acid, such as
formic acid, acetic acid, propionic acid, butyric acid, isobutyric
acid, pivalic acid, 2-ethylbutyric acid; an activated ester, such
as phenol ester, p-nitrophenol ester, N-hydroxysuccinimide ester,
N-hydroxyphthalimide ester, 1-hydroxybenztriazole ester, or
activated amide, such as imidazole, dimethylpyrazole, triazole; are
prepared by method which are well known and appreciated in the art.
Such activated intermediates may be prepared and used directly or
are prepared and isolated before use in the schemes above.
[0166] Scheme H describes methods for preparing compounds of
formula (4). ##STR20##
[0167] Scheme H, step a, a bromo compound of formula (15) is
converted to a nitrile of formula (35).
[0168] For example, a compound of formula (15) is treated with
copper (I) cyanide to give a compound of formula (35). The reaction
is performed in a suitable solvent, such as dimethylformamide. The
reaction is typically carried out in the presence of from about 1
to about 3 molar equivalents of copper (I) cyanide. The reaction is
carried out at temperature of from about ambient temperature to
about 100.degree. C. and generally require from 6 hours to 48
hours. The product of the reaction can be isolated and purified
using techniques well known in the art. These techniques include
extraction, evaporation, chromatography and recrystallization.
[0169] Scheme H, step b, a nitrile compound of formula (35) reduced
to give a compound formula (4) in which R.sub.2 is hydrogen.
[0170] For example, a nitrile compound of formula (35) is contacted
with sodium borohydride in the presence of cobalt chloride. The
reaction is carried out in a suitable solvent, such as methanol, or
ethanol. The reaction is generally carried out at temperatures of
from 0.degree. C. to 50.degree. C. Generally, the reactions require
1 to 72 hours. The product can be isolated and purified by
techniques well known in the art, such as extraction with aqueous
acid, evaporation, trituration, chromatography, and
recrystallization.
[0171] Alternately, for example, a nitrile compound of formula (35)
is hydrogenated over a suitable catalyst, such as Raney.RTM.
nickel. The reaction is carried out in a suitable solvent, when
Raney.RTM. nickel is used as the catalyst, suitable solvents will
generally contain ammonia, such as ethanol/ammonium hydroxide. The
reaction is generally carried out at temperatures of from ambient
temperature to 50.degree. C. The reaction is carried out at
pressures of from 15 psi (103 kPa) to 120 psi (827 kPa) in an
apparatus designed for carrying out reactions under pressure, such
as a Parr hydrogenation apparatus. The product can be isolated by
carefully removing the catalyst by filtration and evaporation. The
product can be purified by extraction, evaporation, trituration,
chromatography, and recrystallization.
[0172] Scheme H, step c, a nitrile compound of formula (35) is
converted to a amide of formula (36).
[0173] For example, a compound of formula (35) is treated with acid
or base under hydrolysis conditions to give a compound of formula
(36). The reaction is performed in a suitable solvent, such as
ethanol, isopropanol, dimethylsulfoxide, each containing water. The
hydrolysis of an aromatic nitrile to an amide is well known and
appreciated in the art. The product of the reaction can be isolated
and purified using techniques well known in the art. These
techniques include extraction, evaporation, chromatography and
recrystallization.
[0174] Scheme H, step d, depicts formation of an amide of formula
(37) by reacting a compound of formula (5) and an appropriate amine
of formula H.sub.2NR.sub.2 in a amide forming reaction. An
appropriate amine of formula H.sub.2NR.sub.2 is one which gives
R.sub.2 as desired in the final product of formula I. Suitable
methods of forming amides are well known in the art and are
described in Scheme B, above.
[0175] Scheme H, step e, a amide compound of formula (36) or (37)
is reduced to a compound of formula (4). Such reductions of amides
are readily carried out as described in Scheme B, above, and as
known in the art.
[0176] Scheme H, step f, a compound of formula (2) and an
appropriate amine of formula H.sub.2NR.sub.2 undergo reductive
amination to give a compound of formula (4). Such reductive
aminations are readily carried out as described in Scheme B, above,
and by other methods known in the art.
[0177] As will be appreciated by the skilled person, the compounds
of formula II are readily prepared by methods analogous to those
described above.
[0178] The present invention is further illustrated by the
following examples and preparations. These examples and
preparations are illustrative only and are not intended to limit
the invention in any way.
[0179] The terms used in the examples and preparations have their
normal meanings unless otherwise designated. For example, ".degree.
C." refers to degrees Celsius; "N" refers to normal or normality;
"M" refers to molar or molarity; "mmol" refers to millimole or
millimoles; "g" refers to gram or grams; "mL" refers milliliter or
milliliters; "mp" refers to melting point; "brine" refers to a
saturated aqueous sodium chloride solution; etc. In the .sup.1H
NMR, all chemical shifts are given in 6, unless otherwise
indicated.
EXAMPLE 1
2-(3-(4-Fluorophenoxy)phenyl)-(1,3)dioxolane
[0180] Combine 4-fluorophenol (3.0 g, 227.8 mmol),
2-(3-bromophenyl)-1,3-dioxolane (5.0 ml, 33.3 mmol), potassium
carbonate (anhydrous, 8.0 g, 55.6 mmol), and dry pyridine (50 ml).
Heat to 90.degree. C. and add copper oxide (5.5 g, 69.5 mmol). Heat
at reflux. After 24 hours, cool to room temperature, dilute with
dichloromethane, and filter. Concentrate the filtrate in vacuum to
give a yellow oil. Chromatograph the oil on silica gel eluting with
95:5 hexane:EtOAc to give the title compound.
[0181] By the method of Example 1 the following compounds were
prepared: a) 2-(3-(2-Fluorophenoxy)phenyl)-(1,3)dioxolane; [0182]
b) 2-(3-(3-Fluorophenoxy)phenyl)-(1,3)dioxolane; [0183] c)
2-(3-(Naphth-2-yloxy)phenyl)-(1,3)dioxolane; [0184] d)
2-(3-(Naphth-1-yloxy)phenyl)-(1,3)dioxolane; [0185] e)
2-(3-(Pyrid-3-yloxy)phenyl)-(1,3)dioxolane; [0186] f)
3-(Pyridin-3-yloxy)benzaldehyde; [0187] g)
3-(Pyrimidin-5-yloxy)benzaldehyde; and [0188] h)
3-(Pyridin-4-yloxy)benzaldehyde.
EXAMPLE 2
3-[1,3]Dioxolan-2-ylphenyl)phenylamine
[0189] Combine 2-(3-bromophenyl)-1,3-dioxolane (0.7 ml, 4.3 mmol),
aniline (0.4 ml, 4.7 mmol), sodium t-butoxide (0.6 g, 6.0 mmol),
BINAP (10.0 mg, 0.03 mol), Pd.sub.2(dba).sub.3 (30.0 mg, 0.01 mmol)
and toluene (20 ml). Heat at 80.degree. C. After 18 hours, cool to
room temperature, dilute with ether (40 ml), filter, and
concentrate to give a residue. Chromatograph the residue on silica
gel eluting with 9:1 hexane:EtOAc to give the title compound.
[0190] By the method of Example 2 the following compounds were
prepared: a) Benzyl-(3-[1,3]dioxolan-2-ylphenyl)-amine; [0191] b)
(3-[1,3]Dioxolan-2-ylphenyl)-pyridin-3-ylamine; [0192] c)
(3-[1,3]Dioxolan-2-ylphenyl)-pyridin-4-yl amine; and [0193] d)
(3-[1,3]Dioxolan-2-ylphenyl)-pyridin-2-ylamine.
EXAMPLE 3
2-(3-Phenylsulfanylphenyl)-[1,3]-dioxolane
[0194] Combine 2-(3-bromophenyl)-1,3-dioxolane (3.0 ml, 20.0 mmol)
and tetrahydrofuran (100 ml). Cool to about -78.degree. C. Add
dropwise a solution of n-butyllithium, 1.6 M solution in hexane
(13.4 ml, 21.0 mmol). After 10 minutes, add phenyl disulfide (4.3
g, 20.0 mmol) as a solution in tetrahydrofuran (50 ml). After 1
hour, warm to room temperature over 1 hour then quenched with water
(150 ml) and extract with ether. Extract the combined organic
layers sequentially with distilled water and brine and then dry
(Na.sub.2SO.sub.4), filter, and concentrate to give a residue.
Chromatograph the residue eluting with 9:1 hexane:EtOAc gives the
title compound.
[0195] By the method of Example 3 the following compounds were
prepared: a) 2-(3-p-Tolylsulfanylphenyl)-[1,3]-dioxolane.
EXAMPLE 4
2-(3-Benzenesulfonylphenyl)-[1,3]-dioxolane
[0196] Combine 2-(3-phenylsulfanylphenyl)-[1,3]-dioxolane (1.0 g,
3.6 mmol) and dichloromethane (15 ml). Cool to about -78.degree. C.
Add a slurry of m-chloroperbenzoic acid (2.3 g, 7.2 mmol) in
dichloromethane (10 ml). After 30 minutes, warm to room temperature
then add a solution 1N of sodium thiosulfate (20 ml). After 15
minutes, add a solution of saturated sodium bicarbonate. Separate
the organic layer and extract the aqueous layer with
dichloromethane. combine the organic layers and wash sequentially
with distilled water and brine and then dry (Na.sub.2SO.sub.4),
filter, and concentrate to give a residue. Chromatograph the
residue eluting with EtOAc to give the title compound.
[0197] By the method of Example 4 the following compounds were
prepared: a) 2-(3-(Toluenesulfonyl)-phenyl)-[1,3]-dioxolane.
EXAMPLE 5
(3-[1,3]Dioxolan-2-ylphenyl)phenylmethanol
[0198] Combine 2-(3-bromophenyl)-1,3-dioxolane (10.0 ml, 66.0 mmol)
and tetrahydrofuran (100 ml) and cool to about -78.degree. C. Add
dropwise a solution of n-butyllithium, 1.6 M solution in hexane
(44.0 ml, 66.0 mmol). After 10 min, add a solution of benzaldehyde
(7.6 ml, 66.0 mmol) in tetrahydrofuran (50 ml) via cannula. After 1
hour, warm to room temperature. After 18 hours, quench into water
and extract with dichloromethane. Combine the organic layers and
wash sequentially with distilled water and brine and then dry
(Na.sub.2SO.sub.4), filter, and concentrate to give a residue.
Chromatograph the residue eluting with 7:3 hexane:EtOAc to give the
title compound.
EXAMPLE 6
(3-[1,3]Dioxolan-2-ylphenyl)phenylmethanone
[0199] Combine (3-[1,3]dioxolan-2-ylphenyl)-phenyl-methanol (5.0 g,
18.5 mmol) and 18-crown-6 (160 mg, 0.6 mmol) in dichloromethane.
Add potassium permanganate (8.8 g, 55.5 mmol). Heat to about
40.degree. C. After 4 hours, cool to room temperature add water and
sodium hydrogensulfite (6.0 g). Basify with a solution of 1N sodium
hydroxide (about 60 ml) and extract with dichloromethane. Combine
the organic layers and wash sequentially with distilled water and
brine and then dry (Na.sub.2SO.sub.4), filter, and concentrate to
give a residue. Chromatograph the residue eluting with EtOAc to
give the title compound.
EXAMPLE 7
3-Benzylbenzaldehyde
[0200] Combine (3-[1,3]dioxolan-2-ylphenyl)-phenyl-methanol (2.3 g,
8.7 mmol) and sodium iodide (5.3 g, 35.0 mmol) in acetonitrile (25
ml). Add dichloromethylsilane (2.1 ml, 17.4 mmol) via syringe.
After 10 min, dilute with EtOAc and wash with water, saturated
sodium bicarbonate, 10% sodium thiosulfate, and then brine. Dry the
organic layers (Na.sub.2SO.sub.4), filter, and concentrate to give
a residue. Chromatograph the residue eluting with 9:1 hexane:EtOAc
to give the title compound.
EXAMPLE 8
2-(3-(.alpha.-Fluorobenzyl)phenyl)-[1,3]-dioxolane
[0201] Combine (3-[1,3]-dioxolan-2-ylphenyl)phenylmethanol (2.3 g,
8.9 mmol) and dichloromethane (50 ml). Cool to about -78.degree. C.
Add dropwise a solution of (diethylamino)sulfur trifluoride (1.7
ml, 12.9 mmol). After 10 minutes, quench with water and extract
with dichloromethane. Combine the organic layers and wash
sequentially with distilled water and brine and then dry
(Na.sub.2SO.sub.4), filter, and concentrate to give a residue.
Chromatograph the residue eluting with 7:3 hexane:EtOAc to give the
title compound.
EXAMPLE 9
3-Nitrodibenzofuran
[0202] Combine dibenzofurane (20.0 g, 0.11 mol) and acetic acid (80
ml). Heat to 65.degree. C. Add 98% nitric acid (20.0 g, 11.8 mol).
After 3 hours, cool to room temperature to give a solid. Collect
the solid by filtration, rinse with water, and dry to give the
title compound.
EXAMPLE 10
N-Dibenzofuran-3-ylamine
[0203] Combine 3-nitrodibenzofuran (22.0 g, 0.1 mol) and Raney
nickel (2.75 g), and ethanol (365 ml) and hydrogenate at room
temperature and 40 psi (276 kPa). After 18 hours, filter and
concentrate the filtrate to residue. Chromatograph the residue
eluting with 9:1 hexane:EtOAc to give the title compound.
EXAMPLE 11
3-Bromodibenzofuran
[0204] Combine N-dibenzofuran-3-ylamine (2.0 g, 10.8 mmol), water
(20 ml), and conc. hydrobromic acid (6 ml). Cool to 0.degree. C.
Add a solution of sodium nitrite (0.7 g, 10.8 mmol) in water (16
ml). After 15 minutes add the mixture above to a mixture of copper
bromide (1.7 g, 12.3 mmol) in water (9.2 ml) and hydrobromic acid
(4 ml). Warm to ambient temperature. After 18 hours, add water and
extract with dichloromethane. Combine the organic layers and wash
sequentially with distilled water and brine and then dry
(Na.sub.2SO.sub.4), filter, and concentrate to give a residue.
Chromatograph the residue eluting with 8:2 hexane:EtOAc to give the
title compound.
EXAMPLE 12
Dibenzofuran-3-carbaldehyde
[0205] Combine 3-bromodibenzofuran (0.5 g, 2.0 mmol) and
tetrahydrofuran (30 ml). Cool to about -78.degree. C. Add a
solution of t-butyllithium, 1.6 M solution in hexane (2.2 ml, 3.0
mmol), then warn to about 0.degree. C. for 10 min. Cool to about
-78.degree. C. and add dimethylformamide (0.5 ml, 5.9 mmol). Warm
to room temperature, quench with water, and extract with
dichloromethane. Combine the organic layers and wash sequentially
with distilled water and brine and then dry (Na.sub.2SO.sub.4),
filter, and concentrate to give a residue. Chromatograph the
residue eluting with 8:2 hexane:EtOAc to give the title
compound.
EXAMPLE 13
3-(Thiazol-2-yloxy)benzaldehyde
[0206] In a sealed tube, combine 2-bromo-thiazole (2.0 ml, 22.2
mmol), 3-hydroxy-benzaldehyde (1.8 g, 15.0 mmol) and potassium
carbonate (2.1 g, 15.0 mmol) in dimethylformamide (20 ml). Heat to
100.degree. C. After 48 hours, cool, pour into water (150 ml), and
extract with ether. Combine the organic layers and wash
sequentially with distilled water and brine and then dry
(Na.sub.2SO.sub.4), filter, and concentrate to give a residue.
Chromatograph the residue eluting with 9:1 hexane:EtOAc to give the
title compound.
EXAMPLE 14
6-Bromo-1H-indole
[0207] Combine 4-bromo-2-nitrotoluene (5.0 g, 23.1 mmol),
dimethylformamide (50 ml), DMF-dimethylacetal (9.0 ml, 69.4 mmol),
and pyrrolidine (2.0 ml, 23.1 mmol). Heat to 110.degree. C. After 3
hours, cool to room temperature, dilute with ether, and wash with
water. Combine the organic layers, and concentrate to give a
residue. Combine the residue and 80% aq. acetic acid (120 ml) and
heat at 75.degree. C. Add zinc dust (13.1 g, 200.5 mmol)
portionwise. Heat to 85.degree. C. After 2 hours, cool and filter.
Dilute the filtrate with ether, wash with water dry
(Na.sub.2SO.sub.4), and concentrate to give a residue.
Chromatograph the residue eluting with 9:1 hexane:EtOAc to give the
title compound.
[0208] By the method of Example 14 the following compounds were
prepared: 4-Bromo-1H-indole.
EXAMPLE 15
1H-Indole-6-carbaldehyde
[0209] Combine hexane washed potassium hydride (1.3 g, 10.7 mmol)
and ether (20 ml). Cool to about 0.degree. C. and add a solution of
6-bromo-1H-indole (2.1 g, 10.7 mmol) in ether (5 ml). After 15 min,
cool to about -78.degree. C. and add a solution of t-butyllithium,
1.4 M solution in hexane (14.0 ml, 10.7 mmol). After 10 min, add
dimethylformamide (1.7 ml, 20.0 mmol) in ether (5 ml). Slowly warm
to room temperature and then pour into a ice cold solution of 1M
phosphoric acid and extract with EtOAc. Combine the organic layers
and wash sequentially with distilled water and brine and then dry
(Na.sub.2SO.sub.4), filter, and concentrated to give a residue.
Chromatograph the residue eluting with 9:1 hexane:EtOAc to give the
title compound.
[0210] By the method of Example 15 the following compounds were
prepared: 1H-Indole-4-carbaldehyde.
EXAMPLE 16
1-Phenyl-1H-indole-6-carbaldehyde
[0211] Combine in a sealed tube 1H-indole-6-carbaldehyde 0.9 g, 6.2
mmol), copper(I) trifluoromethanesulfate-complex (0.2 g, 0.3 mmol),
phenanthroline (1.3 g, 6.2 mmol), transdibenzylidenacetone (0.1 g,
0.3 mmol), cesium carbonate (2.6 g, 7.9 mmol) and iodobenzene (1.6
ml, 14.3 mmol) in xylene (40 ml). Heat at about 110.degree. C.
After 24 hours, cool to room temperature, dilute with
dichloromethane and saturated ammonium chloride. Separate the layer
and Extract the aqueous layer with dichloromethane. Combine the
organic layers and wash sequentially with distilled water and brine
and then dry (Na.sub.2SO.sub.4), filter, and concentrated to give a
residue. Chromatograph the residue eluting with 8:2 hexane:EtOAc to
give the title compound.
[0212] By the method of Example 16 the following compounds were
prepared: 1-Phenyl-1H-indole-4-carbaldehyde.
EXAMPLE 17
3-Phenylsulfanylbenzaldehyde
[0213] Combine 2-(3-phenylsulfanylphenyl)-[1,3]-dioxolane (0.3 g,
1.1 mmol) and acetonitrile (8.0 ml) add a solution of hydrochloric
acid (1N, 2.0 ml). After 18 hours, concentrate in vacuum to remove
most of the acetonitrile, dilute with water and extract with ether.
Combine the organic extracts and wash once with saturated sodium
bicarbonate, then with brine. Dry (Na.sub.2SO.sub.4) the organics,
filter, and concentrated to give the title compound.
[0214] By the method of Example 17 the following compounds were
prepared: a) 3-Benzenesulfonylbenzaldehyde; [0215] b)
3-p-Tolylsulfanylbenzaldehyde; [0216] c) 3-(p-Tosyl)benzaldehyde;
[0217] d) 3-Benzylaminobenzaldehyde; [0218] e)
3-Phenylaminobenzaldehyde; [0219] f) 3-Benzoylbenzaldehyde; [0220]
g) 3-(.alpha.-Fluorobenzyl)benzaldehyde; [0221] h)
3-(4-Fluorophenoxy)benzaldehyde; [0222] i)
3-(2-Fluorophenoxy)benzaldehyde; [0223] j)
3-(3-Fluorophenoxy)benzaldehyde; [0224] k)
3-(Naphth-2-yloxy)benzaldehyde; [0225] l)
3-(Naphth-1-yloxy)benzaldehyde; [0226] m)
3-(Pyridin-3-ylamino)benzaldehyde; [0227] n)
3-(Pyridin-4-ylamino)benzaldehyde; [0228] o)
3-(Pyridin-2-ylamino)benzaldehyde; and [0229] p)
3-(Pyridin-2-yloxy)benzaldehyde.
EXAMPLE 18
2-Naphth-2-ylethylamine
[0230] Combine naphth-2-ylacetonitrile (1.0 g, 6.0 mmol) and nickel
(II) chloride hexahydrate (0.7 g, 3.0 mmol) and tetrahydrofuran (30
ml). Add dropwise borane-tetrahydrofuran complex, 1M solution in
tetrahydrofuran (24.0 ml, 24.0 mmol). After 1 hour, evaporate to
give a residue. Chromatograph on silica gel eluting with 8:2
EtOAc:MeOH+2% NH.sub.4OH) to give the title compound.
[0231] By the method of Example 18 the following compounds were
prepared: 2-Naphth-1-ylethylamine.
EXAMPLE 19
5-Methanesulfonyltryptamine
[0232] Combine 2-(3-Chloropropyl)-(1,3)-dioxolane (6.69 g, 44.5
mmol), (4 methanesulfonylphenyl) hydrazine hydrochloride (9.92 g,
44.5 mmol), and Na.sub.2HPO.sub.4 (1.58 g, 11.1 mmol) in 300 ml of
methanol/water (1:1). Heat to reflux. After 4.5 hours, cool to
ambient temperature, then evaporate to residue. Dissolve the
residue in 1 N NaOH and extract with dichloromethane. Combine the
organic extracts, wash with brine, dry (Na.sub.2SO.sub.4), filter,
then concentrate to residue. Chromatograph the residue on silica
gel eluting with dichloromethane/2N NH.sub.3(methanol) (84/16) to
give the title compound as a light brown solid: mp 134-138.degree.
C., MS (ACPI): m/e 239.1 (M+1). Analysis for
C.sub.11H.sub.14N.sub.2O.sub.2S: Calcd: C, 55.44; H, 5.92; N,
11.76; found: C, 55.33; H, 5.97; N, 11.48.
EXAMPLE 20
N-t-Butoxycarbonyl-2-(6-chloro-1H-indol-3-yl)ethylamine
[0233] Combine di-tert-butyl dicarbonate (1.2 g, 5.34 mmol),
6-chlorotryptamine (866.4 mg, 4.45 mmol)d and NaHCO.sub.3 (598.2
mg) in dioxane (50 ml). Stir at ambient temperature. After 15
hours, evaporate to residue, partition the residue between water
and dichloromethane. Separate the layer and extract the aqueous
layer with dichloromethane. Combine the organic extracts, wash with
brine, dry (Na.sub.2SO.sub.4), filter and then evaporated to give
the title compound as a light yellow oil.
EXAMPLE 21A
N-Methyl-2-(6-chloro-1H-indol-3-yl)ethylamine
[0234] Combine
N-t-butoxycarbonyl-2-(6-chloro-1H-indol-3-yl)ethylamine (1.3 g,
4.41 mmol) and dry THF (20 ml) and add dropwise to an ice bath
cooled suspension of LiAlH.sub.4 (1.0 g, 26.5 mmol) in dry THF (30
ml). Heat to reflux. After 2 hours, cool to ambient temperature and
stir. After 15 hours, quench with saturated NaSO.sub.4 (100
ml/mol), stir for 1 hour at ambient temperature, then filter under
vacuum. Wash precipitate with THF and evaporated filtrate and
washes to residue. Chromatograph the residue on silica gel eluting
with dichloromethane/2N NH.sub.3(methanol) (84/16) to give the
title compound: MS (ACPI): m/e 209.0 (M+1).
EXAMPLE 21B
5-(4-Fluorophenyl)-1H-indole
[0235] Combine 5-bromoindole (5.00 g, 25.50 mmol) and
Pd(Ph.sub.3P).sub.4 (1.47 g, 1.28 mmol) in toluene (510 ml). After
30 minutes, add a solution of 4-fluorobenzeneboronic acid (5.35 g,
38.26 mmol) in ethanol (153 ml) then add saturated NaHCO.sub.3 (255
ml). Heat to reflux. After 4 hours, cool to ambient temperature,
pour into saturated NaCl (250 ml), and separate the organic layer.
Extract the aqueous layer with ethyl acetate. Combine the organic
extracts, wash with brine, dried, then evaporate to residue.
Chromatograph the residue on silica gel eluting with ethyl
acetate/hexanes (10/90) to give the title compound: mp
84-89.degree. C. MS (ACPI): m/e 212.0 (M+1). Analysis for
C.sub.14H.sub.10FN: Calcd: C, 79.60; H, 4.77; N, 6.63; found: C,
79.33; H, 4.92; N, 6.64.
[0236] By the method of Example 21 the following compounds were
prepared: a) 5-Phenyl-1H-indole: mp 71-74.degree. C. MS (ACPI): m/e
194.0 (M+1). Analysis for C.sub.14H.sub.11N: Calcd: C, 87.01; H,
5.74; N, 7.25; found: C, 86.67; H, 5.82; N, 7.31.
[0237] b) 4-Phenylphenethylamine hydrochloride:
(Exception-Chromatograph the residue on silica gel using
dichloromethane/2N N.sub.3(methanol) (90/10) to give the final
product. The HCl salt was prepared in ethyl acetate: MS (ACPI): m/e
198.1 (M+1). Analysis for C.sub.14H.sub.16ClN: Calcd: C, 71.94; H,
6.90; N, 5.99; found: C, 71.66; H, 6.90; N, 5.94.
EXAMPLE 22
7-Cyano-1H-indole
[0238] Combine 7-bromoindole (4.72 g, 24.0 mmol) and copper cyanide
(4.30 g, 48.1 mmol) in 1-methyl-2-pyrrolidine (40 mL). Heat to
200.degree. C. After 2.5 hours, cool to room temperature, add
water-ethyl acetate (200 mL, 1/1) to give a solid. Filter through
the celite, extract the filtrate with ethyl acetate, combine the
organic layers, wash with brine, dry over Na.sub.2SO.sub.4, filter
and evaporate in vacuo to give a residue. Chromatograph the residue
on silica gel eluting with hexanes:ethyl acetate (10:1) to give
(1.87 g) of the title compound as a yellow solid: .sup.1H NMR (300
MHz, DMSO-d.sub.6)) 6.64-6.66 (m, 1H), 7.17 (t, 1H, J=7.6 Hz),
7.51-7.53 (m, 1H), 7.60-7.62 (m, 1H), 7.94 (d, 1H, J=8.0H), 12.03
(br, 1H).
EXAMPLE 23
3-Formyl-5-cyano-1H-indole
[0239] Add phosphorous oxychloride (11.76 g, 76.67 mmol) dropwise
to DMF (24.3 ml) wile maintaining the temperature at less than
110.degree. C. Warm to ambient temperature and stir for 15 minutes
at ambient temperature. Add dropwise 5-cyanoindole (10.00 g, 70.34
mmol) as a solution in DMF (30 ml) while keeping the temperature
below 35.degree.. After 1 hour, pour the reaction mixture into
ice/water (300 ml) and then add 5N NaOH (54 ml) with stirring. Add
slowly an additional amount of 5N NaOH (19.7 ml) and then heated to
90.degree. for 1 minute and then cooled to ambient temperature to
give a precipitate. Filter the precipitate and washed with water
and dry to give the title compound: mp 248-250.degree. C. MS
(ACPI): m/e 171.0 (M+1). Analysis for C.sub.10H.sub.6N.sub.2O:
Calcd: C, 70.58; H, 3.55; N, 16.46; found: C, 70.41; H, 3.53; N,
16.33.
[0240] By the method of Example 23 the following compounds were
prepared: a) 3-Formyl-5-(4-fluorophenyl)-1H-indole; mp
215-217.degree. C. MS (ACPI): m/e 239.1 (M+1). Analysis for
C.sub.15H.sub.10FNO: Calcd: C, 75.30; H, 4.21; N, 5.85; found: C,
74.94; H, 4.17; N, 5.84;
[0241] b) 3-Formyl-5-phenyl-1H-indole; mp>250.degree. C. MS
(ACPI): m/e 222.1 (M+1). Analysis for C.sub.15H.sub.11NO: Calcd: C,
81.43; H, 5.01; N, 6.33; found: C, 81.04; H, 5.05; N, 6.36;
[0242] c) 3-Formyl-6-methyl-1H-indole; mp 178-180.degree. C. MS
(ACPI): m/e 159.9 (M+1). Analysis for C.sub.10H.sub.9NO: Calcd: C,
75.45; H, 5.70; N, 8.80; found: C, 75.60; H, 5.78; N, 8.97;
[0243] d) 3-Formyl-6cyano-1H-indole; mp 246.degree. C. MS (ACPI):
m/e 171.0 (M+1). Analysis for C.sub.10H.sub.6N.sub.2O: Calcd: C,
70.58; H, 3.55; N, 16.46; found: C, 70.51; H, 3.59; N, 16.40;
and
[0244] e) 3-Formyl-6-trifluoromethoxy-1H-indole; mp 189-192.degree.
C. MS (ACPI): m/e 230.0 (M+1). Analysis for
C.sub.10H.sub.6F.sub.3NO.sub.2: Calcd: C, 52.41; H, 2.64; N, 6.11;
found: C, 52.31; H, 2.61; N, 6.09.
[0245] f) 3-Formyl-7-cyano-1H-indole; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 7.41 (t, 1H, J=7.6 Hz), 7.80-7.82 (m, 1H),
8.42-8.50 (m, 2H), 10.02 (s 1H), 13.06 (br, 1H).
[0246] g) 3-Formyl-6-bromo-1H-indole; mp 197-200.degree. C.
Analysis for C.sub.9H.sub.6BrNO: Calcd: C, 48.25; H, 2.70; N, 6.25;
found: C, 47.87; H, 2.68; N, 6.17.
[0247] h) 3-Formyl-7-fluoro-1H-indole; mp 211-214.degree. C.
MS(ACPI): m/e 163.9 (M+1). Analysis for C.sub.9H.sub.6FNO: Calcd:
C, 66.26; H, 3.71; N, 8.59; found: C, 66.12; H, 3.67; N, 8.56.
EXAMPLE 25
3-(2-Nitrovinyl)-5-cyano-1H-indole
[0248] Combine 3-formyl-5-cyano-1H-indole (10.60 g, 63.32 mmol) and
a solution of ammonium acetate (10.60 g) in nitromethane (660 ml).
Heat to 90.degree. C. After 2 hours, cool to ambient temperature to
give a precipitate. Collect the precipitate by filtration, wash
with 1:1 MeOH/water (500 ml), and dry to give the title compound:
mp 247-251.degree. C. MS (ACPI): m/e 214.0 (M+1).
[0249] By the method of Example 25 the following compounds were
prepared: a) 3-(2-Nitrovinyl)-5-(4-fluorophenyl)-1H-indole; mp
217-220.degree. C. MS (ACPI): m/e 282.2 (M+1). Analysis for
C.sub.15H.sub.10FN.sub.2O.sub.2: Calcd: C, 68.08; H, 3.93; N, 9.92;
found: C, 67.73; H, 3.92; N, 9.73;
[0250] b) 3-(2-Nitrovinyl)-5-phenyl-1H-indole; MS (ACPI): m/e 265.1
(M+1);
[0251] c) 3-(2-Nitrovinyl)-6-methyl-1H-indole; MS (ACPI): m/e 203.1
(M+1);
[0252] d) 3-(2-Nitrovinyl)-6-cyano-1H-indole; mp>250.degree. C.
MS (ACPI): m/e 212.0 (M-1). Analysis for
C.sub.11H.sub.7N.sub.3O.sub.2: Calcd: C, 61.97; H, 3.31; N, 19.71;
found: C, 62.09; H, 3.34; N, 20.06; and
[0253] e) 3-(2-Nitrovinyl)-6-trifluororo methoxy-1H-indole; mp
139-143.degree. C. MS (ACPI): m/e 273.0 (M+1).
[0254] f) 3-(2-Nitrovinyl)-6-phenoxy-1H-indole: .sup.1H NMR (DMSO
d6) 12.1 (s, 1H), 8.38-8.34 (d, 1H), 8.20-8.19 (m, 1H), 8.01-7.97
(m, 2H), 7.39-7.35 (m, 2H), 7.14-7.07 (m, 2H), 7.02-7.00 (m, 2H),
6.95-6.92 (m, 1H).
[0255] g) 3-(2-Nitro-vinyl)-5-(pyridin-3-yloxy)-1H-indole: ISMS 282
(M+1); .sup.1H NMR (DMSO-d.sub.6) 9.5 (bs, 1H), 8.36-8.32 (m, 2H),
8.26-8.24 (m, 2H), 7.98-7.95 (m, 1H), 7.79-7.78 (m, 1H), 7.55-7.53
(m, 1H), 7.34-7.31 (m, 1H), 7.27-7.24 (m, 1H), 7.02-7.00 (m,
1H).
[0256] h) 3-(2-Nitro-vinyl)-7-cyano-1H-indole: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.36 (t, 1H, J=7.7 Hz), 7.76 (d, 1H, J=7.2
Hz), 8.09-8.14 (m, 1H), 8.36-8.46 (m, 3H); MS (electrospray), m/e:
212.1 (M-1)
[0257] i) 3-(2-Nitrovinyl)-6-bromo-1H-indole; mp 210.degree. C.,
dec. Analysis for C.sub.10H.sub.7BrN.sub.2O.sub.2: Calcd: C, 44.97;
H, 2.64; N, 10.49; found: C, 44.62; H, 2.70; N, 10.49.
[0258] j) 3-(2-Nitrovinyl)-7-fluoro-1H-indole; mp 176-180.degree.
C. MS (ACPI): m/e 207.1 (M+1). Analysis for
C.sub.10H.sub.7FN.sub.2O.sub.2: Calcd: C, 58.26; H, 3.42; N, 13.59;
found: C, 58.01; H, 3.31; N, 13.26.
EXAMPLE 26
3-(2-Nitroethyl)-5-cyano-1H-indole
[0259] Add sodium borohydride (25.65 g, 678 mmol) to an ice bath
cooled solution of 3-(2-nitrovinyl)-5-cyano-1H-indole (12.68 g,
59.5 mmol) in 1:1 MeOH/DMF (600 ml). After 1.5 hours, add brine
(600 ml) then adjust the pH to approximately 7 with 5N HCl.
Evaporate under reduced pressure to remove the methanol and then
extract with dichloromethane. Combine the organic extracts, wash
with brine, dry (Na.sub.2SO.sub.4), then evaporate to residue.
Chromatograph the residue on silica gel eluting with
dichloromethane to give, after evaporation, the title compound as
colorless prisms: mp 132-136.degree. C. MS (ACPI): m/e 215.0 (M+1).
Analysis for C.sub.11H.sub.9N.sub.3O.sub.2: Calcd: C, 61.39; H,
4.22; N, 19.52; found: C, 61.09; H, 4.10; N, 19.16.
[0260] By the method of Example 26 the following compounds were
prepared: a) 3-(2-nitro-ethyl)-7-cyano-1H-indole; .sup.1H NMR (300
MHz, DMSO-d.sub.6) 3.39 (t, 2H, J=6.9 Hz), 4.87 (t, 2H, J=7.0 Hz),
7.17 (t, 1H, J=7.4 Hz), 7.38 (m, 1H), 7.63 (d, 1H, J=7.4 Hz), 7.99
(d, 1H, J=7.9 Hz), 11.96 (br, 1H). MS (electrospray), m/e: 214.1
(M-1).
EXAMPLE 27
5-Cyanotryptamine
[0261] Add zinc powder (16.22 g, 248.1 mmol) in four portions to 2N
HCl (300.0 ml). Add dropwise 3-(2-nitroethyl)-5-cyano-1H-indole
(2.25 g, 10.5 mmol) as a solution in methanol (300.0 ml). Heat to
reflux. After 2.5 hours, cool to ambient temperature and adjust the
pH to 11 using 5N NaOH, filter through Celite, wash with water,
then extract the filtrate with dichloromethane. Combine the organic
extracts, wash with brine, dry (Na.sub.2SO.sub.4), then evaporated
to give the title compound: mp 102-105.degree. C., MS (ACPI): m/e
186.1 (M+1). Analysis for C, H.sub.11N.sub.3: Calcd: C, 71.33; H,
5.99; N, 22.69; found: C, 71.03; H, 5.91; N, 22.64.
[0262] By the method of Example 27 the following compounds were
prepared: a) 3-(2-aminoethyl)-7-cyano-1H-indole; .sup.1H NMR (300
MHz, DMSO-d.sub.6) 2.76-2.82 (m, 4H), 7.15 (t, 1H, J=7.6 Hz), 7.31
(s, 1H), 7.58 (d, 1H, J=7.4 Hz), 7.91-7.94 (m, 1H), 11.80 (br, 1H);
MS (electrospray), m/e: 186.1 (M+1), 184.1 (m-1).
[0263] By the method of Example 27 the following compound was
prepared: a) 6-Bromotryptamine; mp 114-116.degree. C. Analysis for
C.sub.10H.sub.11BrN.sub.2: Calcd: C, 50.23; H, 4.64; N, 11.72;
found: C, 49.96; H, 4.49; N, 11.47.
EXAMPLE 28
N-t-Butoxycarbonyl-2-(5-cyano-1H-indol-3-yl)ethylamine
[0264] Combine di-tert-butyl dicarbonate and a solution of
5-cyanotryptamine (1.33 g, 7.15 mmol) and 2N NaOH (4.2 ml) in THF
(60 ml). After 3 hours at ambient temperature, evaporate to
residue. Dissolve the residue in water and extract with
dichloromethane. Combine the organic extracts, wash with brine, dry
(Na.sub.2SO.sub.4), and evaporate to residue. Chromatograph the
residue on silica gel eluting with dichloromethane/2N
NH.sub.3(methanol) (97/3)) to give the title compound: mp
129-132.degree. C. MS (ACPI): m/e 286.2 (M+1). Analysis for
C.sub.16H.sub.19N.sub.3O.sub.2: Calcd: C, 67.35; H, 6.71; N, 14.73;
found: C, 67.16; H, 6.68; N, 14.46.
[0265] By the method of Example 28 the following compounds were
prepared: a)
N-t-Butoxycarbonyl-2-(6-cyano-1H-indol-3-yl)ethylamine.
EXAMPLE 29
N-t-Butoxycarbonyl-2-(5-amido-1H-indol-3-yl)ethylamine
[0266] Combine water (64.0 ml) and NaOH (8.53 g) and cool to about
5.degree. C. in an ice bath. Add a solution of
N-t-butoxycarbonyl-2-(5-cyano-1H-indol-3-yl)ethylamine (1.85 g,
6.50 mmol) in ethanol (128.0 ml) then added to the chilled
solution. Add dropwise 30% peroxide (6.4 ml) while keeping the
temperature below 5.degree. C. After 30 minutes, warm to ambient
temperature. After 22 hours, decompose the excess peroxide by
adding a 20% sodium bisulfite solution (45.0 ml) with stirring.
After 30 minutes, evaporate under reduced pressure to remove the
ethanol and extract the resulting aqueous solution with ethyl
acetate. Combine the organic extracts, wash with brine, dry
(Na.sub.2SO.sub.4), then evaporate to residue. Chromatograph the
residue on silica gel eluting with dichloromethane/2N
NH.sub.3(methanol) (96/4) to give, after evaporation, the title
compound: mp 65-68.degree. C. MS (ACPI): m/e 304.2 (M+1). Analysis
for C.sub.16H.sub.21N.sub.3O.sub.3: Calcd: C, 63.35; H, 6.98; N,
13.85; found: C, 63.26; H, 6.99; N, 13.71.
[0267] By the method of Example 28 the following compounds were
prepared: a)
N-t-Butoxycarbonyl-2-(6-amido-1H-indol-3-yl)ethylamine: MS (ACPI):
m/e 302.3 (M-1).
EXAMPLE 30
5-Amidotryptamine
[0268] Dissolve
N-t-butoxycarbonyl-2-(5-amido-1H-indol-3-yl)ethylamine (1.83 g,
6.04 mmol) in dioxane (25.0 ml). Add dropwise a 4M HCl in dioxane
(7.5 ml). After 18 hours, collect the solid by filtration and wash
with diethyl ether to give, after drying, the title compound as the
hydrochloride: mp 192-195.degree. C. MS (ACPI): m/e 202.0
(M+1).
[0269] By the method of Example 30 the following compounds were
prepared: a) 6-Amidotryptamine: mp 169-173.degree. C. MS (ACPI):
m/e 204.1 (M+1).
EXAMPLE 32
5-(4-Fluorophenyl)tryptamine
[0270] Combine LiAlH.sub.4 (2.66 g, 70.17 mmol) and dry THF (70.0
ml) and cool the suspension in an ice bath. Add dropwise a solution
of 5-(4-fluorophenyl)-3-(2-nitrovinyl)-1H-indole (3.30 g, 11.69
mmol) in dry THF (30.0 ml). Heat to reflux. After 1 hour, cool to
ambient temperature and stir. After 15 hours, quench with saturated
Na.sub.2SO.sub.4 (100 ml/mol) and stir at ambient temperature.
After 1 hour, filter, rinse the precipitate with THF, and evaporate
the filtrate to residue. Chromatograph the residue on silica gel
eluting with dichloromethane/2N NH.sub.3(methanol) (80/20) to give
the title compound. Prepare the HCl salt in diethyl ether:
mp>250.degree. C. MS (ACPI): m/e 255.0 (M+1). Analysis for
C.sub.16H.sub.16ClFN.sub.2: Calcd: C, 66.09; H, 5.55; N, 9.63;
found: C, 65.78; H, 5.48; N, 9.58.
[0271] By the method of Example 32 the following compounds were
prepared: a) 5-Phenyltryptamine; mp 244-246.degree. C. MS (ACPI):
m/e 237.1 (M+1). Analysis for C.sub.16H.sub.17ClN.sub.2: Calcd: C,
70.45; H, 6.28; N, 10.27; Found: C, 70.75; H, 6.33; N, 10.27.
(isolated as the hydrochloride);
[0272] b) 6-Methyltryptamine; mp 139-141.degree. C. MS (ACPI): m/e
175.0 (M+1). Analysis for C.sub.11H.sub.14N.sub.2: Calcd: C, 75.82;
H, 8.10; N, 16.08; Found: C, 76.05; H, 8.26; N, 16.12.
[0273] c) 6-Trifluoromethoxtryptamine; MS (ACPI): m/e 245.0 (M+1).
Analysis for C.sub.11H.sub.11F.sub.3N.sub.2O: Calcd: C, 54.10; H,
4.54; N, 11.47; Found: C, 53.92; H, 4.50; N, 11.06.
[0274] d) 7-Fluorotryptamine; MS (ACPI): m/e 179.0 (M+1). Analysis
for C.sub.10H.sub.11FN.sub.2: Calcd: C, 67.40; H, 6.22; N, 15.72;
Found: C, 67.06; H, 6.11; N, 15.48.
EXAMPLE 33
6-Ethoxycarbonyl-1H-indole
[0275] Combine 6-carboxy-1H-indole and ethanol (110 ml) and cool to
5.degree. C. Add dropwise concentrated H.sub.2SO.sub.4 (96%, 11.08
ml) while keeping the temperature below 10.degree. C. Heat to
reflux. After 4 hours, cool and pour onto ice/water, adjust the pH
to about pH 9 and extract with ethyl acetate. Combine the organic
extracts, wash with brine, dry (Na.sub.2SO.sub.4), then concentrate
to residue. Chromatograph the residue on silica gel eluting with
chloroform to give, after evaporation, the title compound: mp
72-75.degree. C. MS (ACPI): m/e 189.9 (M+1).
EXAMPLE 34
3-(2-Nitrovinvyl-6-ethoxycarbonyl-1H-indole
[0276] Combine 1-dimethylamino-2-nitroethylene (1.93 g, 16.58 mmol)
and TFA (10.0 ml) and stir until dissolved. Add
6-ethoxycarbonyl-1H-indole (3.14 g, 16.58 mmol) and stir at ambient
temperature. After 1 hour, pour the reaction mixture into
ice/water, extract with ethyl acetate, then evaporate to residue.
Stir the residue in warm ethanol, cool to ambient temperature, then
filter and dry to give the title compound as a dark yellow powder:
mp 241.degree. C. MS (ACPI): m/e 261.1 (M+1). Analysis for
C.sub.13H.sub.12N.sub.2O.sub.4: Calcd: C, 60.00; H, 4.65; N, 10.76;
found: C, 59.99; H, 4.63; N, 10.59.
EXAMPLE 35
3-(2-Nitroethyl)-6-ethoxycarbonyl-1H-indole
[0277] Combine 3-(2-nitrovinyl)-6-ethoxycarbonyl-1H-indole (4.0 g,
15.37 mmol) and NaBH.sub.4 (726.7 mg, 19.21 mmol) in 100 ml of
THE/Methanol (9:1) and stir at ambient temperature. After 1.5
hours, concentrate to residue. Partition the residue between brine
and ethyl acetate, wash with brine, combine the organic layers, dry
(Na.sub.2SO.sub.4), then evaporate to give the title compound as a
yellow powder: mp 124-127.degree. C. MS (ACPI): m/e 263.0 (M+1).
Analysis for C.sub.13H.sub.14N.sub.2O.sub.4: Calcd: C, 59.54; H,
5.38; N, 10.68; found: C, 59.40; H, 5.36; N, 10.53.
[0278] By the method of Example 35 the following compounds were
prepared: a) 3-(2-Nitroethyl)-6-cyano-1H-indole: m/e 214.1 (M-1).
Analysis for C.sub.11H.sub.9N.sub.3O.sub.2: Calcd: C, 61.39; H,
4.22; N, 19.52; found: C, 61.05; H, 4.09; N, 19.19.
[0279] b) 3-(2-Nitroethyl)-6-bromo-1H-indole;
[0280] c) 3-(2-Nitroethyl)-6-methanesulfonyl-1H-indole; mp
162-164.degree. C. MS (ACPI): m/e 269.1 (M+1).
[0281] d) 3-(2-Nitroethyl)-6-benzenesulfonyl-1H-indole (exception:
75 ml of THF was used).
EXAMPLE 36
6-Ethoxycarbonyltryptamine
[0282] Combine Pt.sub.2O (440 mg) and a solution of
3-(2-nitroethyl)-6-ethoxycarbonyl-1H-indole (3.55 g, 13.54 mmol) in
ethyl acetate (100 ml). Hydrogenate at 60 psi (410 kPa) and ambient
temperature. After 4 hours, filter through celite and concentrate
the filtrate to residue. Chromatograph the residue on silica gel
eluting with dichloromethane/2N NH.sub.3(methanol) (85/15) to give,
after evaporation, the title compound as an off-white powder: mp
127-131.degree. C. MS (ACPI): m/e 233.0 (M+1). Analysis for
C.sub.13H.sub.16N.sub.2O.sub.2: Calcd: C, 67.22; H, 6.94; N, 12.06;
found: C, 66.87; H, 6.86; N, 11.86.
[0283] By the method of Example 36 the following compounds were
prepared: a) 6-Cyanotryptamine: mp 144-147.degree. C. MS (ACPI):
m/e 186.0 (M+1). Analysis for C.sub.11H.sub.11N.sub.3: Calcd: C,
71.33; H, 5.99; N, 22.69; found: C, 71.10; H, 5.89; N, 22.38.
[0284] b) 6-Methanesulfonyltryptamine: mp 149-153.degree. C. MS
(ACPI): m/e 239.1 (M+1). Analysis for C, 1H.sub.14N.sub.2O.sub.2S:
Calcd: C, 55.44; H, 5.92; N, 11.76; found: C, 55.12; H, 5.82; N,
11.97.
[0285] c) 6-Benzenesulfonyltryptamine: mp 169-172.degree. C. MS
(ACPI): m/e 301.0 (M+1).
EXAMPLE 38
6-Trifluoromethoxy-1H-indole
[0286] Combine 1-methyl-4-trifluoromethoxybenzene (5.44 g, 30.87
mmol) and H.sub.2SO.sub.4 (96%, 30.9 ml). Cool to about 0.degree.
C. Add dropwise filming HNO.sub.3 (2.06 g, 32.72 mmol) while
maintaining the temperature below 10.degree. C. When the addition
is complete, warm to ambient temperature. After 2.5 hours, pour the
mixture onto ice/water, extract with dichloromethane. Combine the
organic extracts, wash with brine, dry (Na.sub.2SO.sub.4), then
concentrate to residue. Chromatograph the residue on silica gel
eluting with hexanes/ethyl acetate (75/25) to give, after
evaporation, 1-methyl-2-nitro-4-trifluoromethoxybenzene: MS (ACPI):
m/c 220.1 (M-1).
[0287] Combine 1-methyl-2-nitro-4-trifluoromethoxybenzene (3.73 g,
16.86 mmol), pyrrolidine (1.32 g, 18.55 mmol),
N,N-dimethylformamide dimethyl acetal (6.03 g, 50.58 mmol), and dry
DMF (35 ml). Heat to about 1050. After 19 hours, remove the DMF
under reduced pressure to give an oily residue. Combine the residue
and ethyl acetate, wash with brine, dry (Na.sub.2SO.sub.4), then
concentrate to give
N,N-dimethyl-2-(2-nitro-4-trifluoromethoxyphenyl)vinylamine.
[0288] Combine
N,N-dimethyl-2-(2-nitro-4-trifluoromethoxyphenyl)vinylamine (4.64
g, 16.8 mmol) and Raney.RTM. nickel (900 mg) in ethanol (100 ml).
Hydrogenate at 60 psi (410 kPa). and ambient temperature. After 18
hours, filter through celite, concentrate the filtrate to residue,
and chromatograph on silica gel eluting with hexanes/ethyl acetate
(30/70) to give, after evaporation, the title compound as an
off-white powder: mp 59.degree. C. MS (ACPI): m/e 200.0 (M-1).
EXAMPLE 39
2-Phenylphenethylamine
[0289] Combine 2-phenylphenylacetonitrile (4.69 g, 24.26 mmol) and
diethyl ether (10 ml) and add dropwise to a cooled (-10.degree.)
solution of LiAlH.sub.4 (2.76 g, 72.81 mmol) in diethyl ether (100
ml). Warm to ambient temperature. After 2 hours, quench with
saturated sodium sulfate (100 ml/mol). Filter to remove the
precipitate, dry (Na.sub.2SO.sub.4) the filtrate, filter, and
concentrate to residue. Chromatograph the residue on silica gel
eluting with dichloromethane/2N NH.sub.3(methanol) (95/5) to give
the title compound as a yellow oil. Prepare the HCl salt in diethyl
ether: mp 197-199.degree. C. MS (ACPI): m/e 198.1 (M+1). Analysis
for C.sub.14H.sub.16ClN: Calcd: C, 71.94; H, 6.90; N, 5.99; found:
C, 72.15; H, 6.84; N, 6.09.
EXAMPLE 40
7-Chloro-1H-indole
[0290] By the method of J. Med. Chem. 1990, 33, 2777), add dropwise
2-chloroaniline (5.8 g, 45.45 mmol) in anhydrous toluene (80 mL) to
a cold 1M solution of BCl.sub.3 (50 mL) in dichloromethane. After
addition, allow the reaction to stir at 0.degree. C. for 10
minutes. After 10 minutes at 0.degree. C., add chloroacetonitrile
(13.72 g, 11.53 mL, 181.8 mmol, 4 eq) and aluminum trichloride
(6.67 g, 50 mmol, 1.1 eq) in 5 equal portions over 45 minutes and
then beat to reflux (.about.65.degree. C.). After 6 hours, cool to
room temperature. After 16 hours, cool the reaction in an ice bath
and add 2N HCl (61.4 mL) and then heat the reaction to reflux.
After 45 minutes, cool in an ice bath, neutralize the acid with 2N
NaOH keeping the temperature of the reaction below 15C..degree.
until the pH is about S. Transfer the reaction to a separatory
funnel and remove the organic layer. Extract the aqueous layer with
dichloromethane (2.times.200 mL). Combine the organic layers, dry
over MgSO.sub.4, filter, and remove the solvent in vacuo to give
1-(2-amino-3-chlorophenyl)-2-chloroethanone which may be used
without further purification.
[0291] Dissolve 1-(2-amino-3-chlorophenyl)-2-chloroethanone (7.0 g,
34.30 mmol) in 10% aqueous 1,4-dioxane (75 mL). Carefully add
NaBH.sub.4 (2.6 g, 68.6 mmol, 2 eq.) as a solid. Heat to reflux.
After 4 hours, cool to room temperature, dilute with water (300
mL), and extract with dichloromethane (2.times.200 mL). Combine the
organic layers, dry over MgSO.sub.4, filter, and remove the solvent
in vacuo leaving a light brown oil in the flask. Purify the oil by
HPLC (silica gel mobile phase: 100% hexane to 50% EtOAc in hexanes
over 50 minutes), to give the title compound as a brown oil:
.sup.1H NMR (300 MHz, d6-DMSO-d6): 5.16 (m, 1H), 5.39 (d, 1H), 5.70
(bs, 1H), 6.59 (t, 1H), 7.09 (m, 2H); MS (ES+): m/z 154, 152
(M+H).sup.+.
[0292] By the method of Example 40 the following compounds were
prepared: a) 5-Bromo-7-ethyl-1H-indole: .sup.1H NMR (300 MHz,
d6-DMSO-d6): 1.25 (t, 3H), 2.85 (m, 2H), 6.41 (m, 1H), 7.02 (M,
1H), 7.36 (m, 1H), 7.55 (m, 1H), 11.28 (bs, 1H); MS(ES+): m/z 224,
226 (M+H).sup.+; Analysis for C.sub.10H.sub.10BrN: Calcd.; C,
53.60; H, 4.50; N, 6.25; found; C, 53.50; H, 4.34; N, 6.22.
EXAMPLE 42
6-Trifluoromethyl-1H-indole
[0293] Combine 2-bromo-5-trifluoromethylphenylamine (27.06 g,
112.74 mmol) and 200 mL of pyridine. Cool in an ice bath and add
ethyl chloroformate (18.35 g, 169.11 mL, 1.5 eq). After addition
was complete, allow the reaction to gradually warming to room
temperature. After 18 hours, evaporate in vacuo to give a residue.
Dissolve the residue in Et.sub.2O/water and transfer to a
separatory funnel. Separate the layer and extract the aqueous layer
with Et.sub.2O (2.times.300 mL), combine the organic layers, dry
over MgSO.sub.4, filter, and evaporate in vacuo to give
N-(2-bromo-5-trifluoromethylphenyl)carbamic acid ethyl ester which
may be used without further purification.
[0294] Following the procedure described in J. Org. Chem. 1997, 62,
6507, combine N-(2-bromo-5-trifluoromethylphenyl)carbamic acid
ethyl ester (34.33 g, 110 mmol), triethylamine (300 mL),
dichlorobis(triphenylphosphine)palladium(II) (5.4 g, 7.7 mmol), and
copper (I) iodide (1.47 g, 7.7 mmol). Evacuate the dark solution
and fill with N.sub.2 twice and then quickly add
(trimethylsilyl)acetylene (16.21 g, 165 mmol, 23.32 mL) with
vigorous stirring. Heat to 80.degree. C. When TLC indicates absence
of the starting material, add water and Et.sub.2O and filter
through celite and evaporate the filtrate in vacuo to give a
residue. Dilute residue with water and extract with Et.sub.2O,
combine the organic layers and remove the evaporate to give a dark
brown oil. Absorb the oil onto silica gel and load onto a short
column of silica gel equilibrated with 100% hexanes. Wash with 100%
hexanes (2 L) and elute the product with 1% EtOAc in hexanes. Pool
fractions containing the product and remove in vacuo the solvent to
give 5-trifluoromethyl-2-trimethylsilanylethynyl phenylamine as a
red/brown oil; MS (IS): m/z 330 (M+H).sup.+.
[0295] Carefully add NaH (10.83 g, 60% in oil, 270.8 mmol, 4 eq.)
to EtOH (200 mL). When cool, add a solution of
5-trifluoromethyl-2-trimethylsilanylethynylphenylamine (22.3 g,
67.7 mmol) in EtOH (400 mL) with vigorous stirring. After 2 hours,
heat to reflux. After 4 hours, evaporate in vacuo to remove the
EtOH and dilute the residue obtained with water and extract with
Et.sub.2O. Combine the organic layers and wash with brine, dry over
MgSO.sub.4, filter, and evaporate to give a dark oil. Absorbed the
oil onto silica gel and load onto short column of silica gel. Elute
with 20% EtOAc in hexanes. Pool fractions containing the product
and remove the solvent leaving a dark brown oil. Further
purification of the oil by HPLC (silica column) using a gradient 1%
Et.sub.2O in hexanes to 15% Et.sub.2O in hexanes. Pool fractions
containing the product and remove the solvent to give the title
compound as an orange solid: .sup.1H NMR (300 MHz, d6-DMSO-d6):
6.58 (m, 1H), 7.28 (m, 1H), 7.61 (t, 1H), 7.74 (m, 2H), 11.51 (bs,
1H); MS(EI+): m/z 185 (M+).
[0296] By the method of Example 42 the following compounds were
prepared: a) 5-Isopropyl-1H-indole: MS(ES+): m/z 160 (M+H).sup.+;
(ES)-: m/z 158 (M-H).sup.-.
EXAMPLE 44
6-Fluoro-5-methoxy-1H-indole
[0297] Dissolve fuming nitric acid (24 mL) in concentrated
H.sub.2SO.sub.4 in a round bottom flask. Add
3,4-difluorobromobenzene (20 g, 104 mmol) dropwise via pipette with
vigorous stirring. After addition, stir the reaction at room
temperature for 2 hours, pour the reaction into ice water and
extract with Et.sub.2O (2.times.250 mL). Collect and combine the
organic layers, dry over MgSO.sub.4, filter, and remove the solvent
to give 1-bromo-4,5-difluoro-2-nitrobenzene as a light yellow
oil.
[0298] Add 1-bromo-4,5-difluoro-2-nitrobenzene (24 g, 100 mmol) to
a solution of sodium methoxide (1.2 eq) in MeOH. After addition,
stir the reaction at room temperature for 2.5 hours. Remove the
solvent in vacuo and dilute the residue with water and extract with
Et.sub.2O (2.times.250 mL). Combine the organic layers, dry over
MgSO.sub.4, filter, and the remove solvent in vacuo to give
1-bromo-4-fluoro-5-methoxy-2-nitrobenzene as a yellow solid:
.sup.1H NMR (300 MHz, CDCl.sub.3): 3.99 (s, 3H), 7.26 (m, 1H), 7.83
(d, 1H); MS(FD+): m/z 249, 251 (M+); Analysis for
C.sub.7H.sub.5BrFNO.sub.3: Calcd.: C, 33.63; H, 2.02; N, 5.60;
found: C, 33.79; H, 1.98; N, 5.62.
[0299] Combine 1-bromo-4-fluoro-5-methoxy-2-nitrobenzene (20.5 g,
82 mmol) and Pt-on-carbon (sulfided) in THE (600 mL) and
hydrogenate at 60 psi (414 kPa) over for 4 hours. Filter the
reaction through celite to remove the catalyst and remove the
solvent to give 2-bromo-5-fluoro-4-methoxyaniline as a brown solid
which may taken on without further purification.
[0300] Using 2-bromo-5-fluoro-4-methoxyaniline, the method of
Example 42 gives N-(2-bromo-5-fluoro-4-methoxyphenyl)carbamic acid
ethyl ester as a brown solid: .sup.1H NMR (300 MHz, CDCl.sub.3):
1.33 (t, 3H), 3.85 (s, 3H), 4.23 (q, 2H), 7.09 (d, 1H), 7.97 (bd,
1H); MS(FD+): m/z 291, 293 (M+);
N-(5-fluoro-4-methoxy-2-trimethylsilanylethynylphenyl)carbamic acid
ethyl ester as a yellow solid: MS(ES+): m/z 310 (M+H).sup.+; (ES-):
m/z 308 (M-H).sup.-; and the title compound as a solid: .sup.1H NMR
(300 MHz, CDCl.sub.3): 3.93 (s, 3H), 6.48 (m, 1H), 7.15 (m, 3H),
8.11 (bs, 1H); MS(ES+): m/z 166 (M+H).sup.+; (ES-): m/z 164
(M-H).sup.-; Analysis for C.sub.9H.sub.8FNO: Calcd.: C, 65.45; H,
4.88; N, 8.48; found: C, 65.17; H, 4.97; N, 8.70.
EXAMPLE 45
5,6-Difluoro-1H-indole
[0301] Using the method of Example 42 gives
2-bromo-4,5-difluoroaniline; which gives
N-(2-bromo-4,5-difluorophenyl)carbamic acid ethyl ester; which
gives N-(4,5-Difluoro-2-trimethylsilanylethynylphenyl)carbamic acid
ethyl ester; which gives the title compound as an orange solid:
.sup.1H NMR (300 MHz, d6-DMSO-d6): 6.43 (m, 1H), 7.38 (m, 2H), 7.50
(m, 1H), 11.25 (bs, 1H); MS(ES-): m/z 152 (M-H).sup.-; Analysis for
C.sub.8H.sub.5F.sub.2N: Calcd.: C, 62.75; H, 3.29; N, 9.15; found:
C, 62.41; H, 3.12; N, 8.98.
EXAMPLE 46
5-Trifluoromethoxy-1H-indole
[0302] Using the method of Example 42 and
2-bromo-4-(trifluoromethoxy)aniline gives
N-(2-bromo-4-trifluoromethoxyphenyl)carbamic acid ethyl ester:
.sup.1H NMR (300 MHz, CDCl.sub.3): 1.34 (t, 3H), 4.25 (m, 2H), 7.19
(m, 1H), 7.41 (m, 1H), 8.20 (d, 1H); MS(ES-): m/z 326, 328
(M-H).sup.-; Analysis for C.sub.10H.sub.9BrF.sub.3NO.sub.3: Calcd.;
C, 36.6096; H, 2.7650; N, 4.2692; found; C, 36.50; H, 2.67; N,
3.97; which gives
N-(4-Trifluoromethoxy-2-trimethylsilanylethynylphenyl)carbamic acid
ethyl ester; which gives the title compound as a yellow oil:
MS(ES-): m/z 200 (M-H).sup.-.
EXAMPLE 47
4-Phenyl-1H-indole
[0303] Using the method of Carrera and Sheppard in Synlett. 1994,
93-94, 4-bromoindole gives the title compound: .sup.1H NMR (300
MHz, d6-DMSO-d6): 6.56 (m, 1H), 7.08 (m, 1H), 7.17 (m, 1H), 7.43
(m, 5H), 7.67 (m, 2H), 11.27 (bs, 1H); MS(ES+): m/z 194
(M+H).sup.+; (ES-): m/z 192 (M-H).sup.-.
EXAMPLE 48
(2-Nitro-5-trifluoromethylphenyl)-acetonitrile
[0304] By the method of Liebigs Ann. Chem. 1988, 203-208, using
4-nitrobenzotrifluoride (15 g, 78.49 mmol) gives the title
compound: MS(ES-): m/z 229 (M-H).sup.-.
EXAMPLE 49
5-Trifluoromethyl-1H-indole
[0305] By the method of Liebigs Ann. Chem. 1988, 203-208 using
(2-nitro-5-trifluoromethylphenyl)acetonitrile gives the title
compound as a white solid: .sup.1H NMR (300 MHz, d6-DMSO-d6): 6.60
(m, 1H), 7.36 (m, 1H), 7.53 (m, 1H), 7.57 (m, 1H), 7.94 (m, 1H),
11.51 (bs, 1H); MS(ES-): m/z 184 (M-H).sup.-.
EXAMPLE 50
3-Formyl-4-methoxy-1-indole
[0306] Add phosphorus oxychloride (1.1 eq.) with vigorous stirring
to DMF (cooled in an ice bath). After the addition is complete,
allow to stir in the ice bath for .about.10 minutes, then add a
solution of 4-methoxy-1H-indole (5 g) in anhydrous DMF with
vigorous stirring. Allow to stir at 0.degree. C. After 1 hour, warn
to room temperature. After 16 hours, carefully add 4 eq. of 2N NaOH
with vigorous stirring. Heat to about 80.degree. C. and then cool.
Pour the reaction mixture into cold water with vigorous stirring to
give a solid. Collect the solid by filtration and dry in a vacuum
oven at room temperature to give the title compound. Acidify the
filtrate and extract with EtOAc. Combine the organic layers and
wash with 50% brine. Collect the organic layer, dry (MgSO.sub.4)
filter, and remove the solvent to give the title compound as a
light purple solid. Total yield of the title compound is 5.44 g: MS
(ES+): m/z 175 (M+H).sup.+, 160 (M-CH.sub.3).sup.+; (ES-): m/z 174
(M-H).sup.-.
[0307] By the method of Example 50 the following compounds were
prepared: a) 3-Formyl-6-methoxy-1H-indole, .sup.1H NMR (300 MHz,
d6-DMSO): 3.79 (s, 3H); 6.85 (dd, 1H); 6.98 (m, 1H); 7.92 (d, 1H);
8.15 (s, 1H); 9.86 (s, 1H); 11.92 (bs, 1H); MS (ES+): m/z 176
(M+H).sup.+; (ES-): m/z 174 (M-H).sup.-;
[0308] b) 3-Formyl-7-methoxy-1H-indole;
[0309] c) 3-Formyl-4-chloro-1H-indole;
[0310] d) 3-Formyl-6-chloro-1H-indole, .sup.1H NMR (300 MHz,
d6-DMSO-d6): 7.24 (dd, 1H), 7.56 (d, 1H), 8.06 (d, 1H), 8.33 (s,
1H), 9.93 (s, 1H), 12.21 (bs, 1H); MS (ES+): m/z 182, 180
(M+H).sup.+; (ES-): m/z 180, 178 (M-H).sup.-;
[0311] e) 3-Formyl-7-chloro-1H-indole, .sup.1H NMR (300 MHz,
d6-DMSO): 7.23 (t, 1H), 7.35 (d, 1H), 8.05 (d, 1H), 8.38 (bs, 1H),
9.95 (s, 1H), 12.54 (bs, 1H); MS (ES+): m/z 182, 180 (M+H).sup.+;
(ES-): m/z 180, 178 (M-H).sup.-;
[0312] f) 3-Formyl-4-fluoro-1H-indole, .sup.1H NMR (300 MHz,
d6-DMSO): 7.01 (m, 1H), 7.24 (m, 1H), 7.36 (d, 1H), 8.30 (s, 1H),
10.03 (d, 1H), 12.48 (bs, 1H); MS (ES+): m/z 164 (M+H).sup.+;
(ES-): m/z 162 (M-H).sup.-;
[0313] g) 3-Formyl-5-methoxy-6-trifluoromethyl-1H-indole, .sup.1H
NMR (300 MHz, d6-DMSO): 3.91 (s, 3H), 7.77 (dd, 1H), 7.95 (bs, 1H),
8.42 (s, 1H), 9.96 (s, 1H), 12.29 (bs, 1H); MS (ES+): m/z 244
(M+H).sup.+; (ES-): m/z 242 (M-H).sup.-;
[0314] h) 3-Formyl-6-chloro-5-methoxy-1H-indole, .sup.1H NMR (300
MHz, d6-DMSO): 3.88 (s, 3H), 7.58 (s, 1H), 7.71 (s, 1H), 8.26 (s,
1H), 9.91 (s, 1H), 12.08 (bs, 1H); MS (ES+): m/z 210, 212
(M+H).sup.+; (ES-): m/z 208, 210 (M-H).sup.-;
[0315] i) 3-Formyl-4-chloro-5-methoxy-1H-indole, .sup.1H NMR (300
MHz, d6-DMSO): 3.89 (s, 3H), 7.13m (dd, 1H), 7.47 (dd, 1H), 8.23
(s, 1H), 10.5 (s, 1H), 12.39 (bs, 1H); MS (ES+): m/z 210, 212
(M+H).sup.+ (ES-): m/z 208, 210 (M-H).sup.-;
[0316] j) 3-Formyl-6-trifluoromethyl-1H-indole, .sup.1H NMR (300
MHz, d6-DMSO): 7.52 (d, 1H), 8.27 (d, 1H), 8.51 (m, 1H), 9.99 (s,
1H), 12.47 (bs, 1H). MS(ES+): m/z 214 (M+H).sup.+; (ES-): m/z 212
(M-H).sup.-;
[0317] k) 3-Formyl-5-methoxy-2-methyl-1H-indole, .sup.1H (300 MHz,
d6-DMSO): 2.65 (s, 3H), 3.76 (s, 3H), 6.78 (dd, 1H), 7.27 (d, 1H),
7.56 (m, 1H), 10.00 (s, 1H), 11.85 (bs, 1H); MS(ES+): m/z 190
(M+H).sup.+; (ES-): m/z 188 (M-H).sup.-;
[0318] l) 3-Formyl-6-fluoro-5-methoxy-1H-indole, .sup.1H NMR (300
MHz, d6-DMSO): 3.87 (s, 3H), 7.35 (d, 1H), 7.71 (d, 1H), 8.21 (s,
1H), 9.89 (s, 1H), 12.03 (bs, 1 h); MS(ES+): m/z 194 (M+H).sup.+;
(ES-): m/z 192 (M-H).sup.-;
[0319] m) 3-Formyl-5,6-difluoro-1H-indole, .sup.1H NMR (300 MHz,
d6-DMSO): 7.56 (m, 1H), 7.92 (m, 1H), 8.36 (s, 1H), 9.92 (s, 1H),
12.25 (bs, 1H); MS(ES+): m/z 182 (M+H).sup.+; (ES-): m/z 180
(M-H).sup.-;
[0320] n) 3-Formyl-6-chloro-5-fluoro-1H-indole, .sup.1H NMR (300
MHz, d6-DMSO): 7.72 (d, 1H), 7.91 (d, 1H), 8.40 (s, 1H), 9.93 (s,
1H), 12.29 (bs, 1H); MS(ES+): m/z 198 (M+H).sup.+; (ES-): m/z 196
(M-H).sup.-;
[0321] o) 3-Formyl-5-trifluoromethoxy-1H-indole, .sup.1H NMR (300
MHz, d6-DMSO): 7.24 (m, 1H), 7.61 (m, 1H), 7.97 (bs, 1H), 8.42 (d,
1H), 9.95 (s, 1H), 12.35 (bs, 1H); MS(ES+): m/z 230 (M+H).sup.+;
(ES-): m/z 228 (M-H).sup.-; Analysis for
C.sub.10H.sub.6F.sub.3NO.sub.2: Calcd.; C, 52.4138; H, 2.6391; N,
6.1122; found; C, 52.70; H, 2.73; N, 6.13;
[0322] p) 3-Formyl-4,6-difluoro-5-methoxy-1H-indole, MS(ES+): 212
(M+H).sup.+; (ES-): 210 (M-H).sup.-;
[0323] q) 3-Formyl-4-phenyl-1H-indole, .sup.1H NMR (300 MHz,
d6-DMSO): 7.07 (m, 1H), 7.30 (m, 1H), 7.46 (m, 6H), 7.53 (m, 1H),
8.20 (bs, 1H), 9.37 (s, 1H), 12.40 (bs, 1H). MS(ES+): m/z 222
(M+H).sup.+; (ES-): m/z 220 (M-H).sup.-;
[0324] r) 3-formyl-6-phenyl-1H-indole, .sup.1H NMR (300 MHz,
d6-DMSO): 7.35 (m, 1H), 7.49 (m, 3H), 7.71 (m, 3H), 8.15 (m, 1H),
8.33 (d, 1H), 9.96 (s, 1H), 12.20 (bs, 1H). MS(EI+): m/z 221
(M).sup.+;
[0325] s) 3-Formyl-5-isopropyl-1H-indole, .sup.1H NMR (300 MHz,
d6-DMSO): 1.24 (d, 6H), 2.99 (m, 1H), 7.15 (m, 1H), 7.41 (m, 1H),
7.94 (m, 1H), 8.22 (m, 1H), 9.90 (s, 1H), 12.02 (bs, 1H); MS(ES+):
188 (M+H).sup.+; (ES-): m/z 186 (M-H).sup.-;
[0326] t) 3-Formyl-4,6-difluoro-5-methoxy-1-methyl-1H-indole:
.sup.1H NMR (300 MHz, CDCl.sub.3): 3.81 (s, 3H), 4.02 (s, 3H), 6.92
(m, 1H), 7.77 (s, 1H), 10.14 (d, 1H); MS(ES+): m/z 226 (M+H).sup.+;
and
[0327] u) 3-Formyl-4,6-difluoro-1-methyl-1H-indole: .sup.1H NMR
(300 MHz, d6-DMSO): 3.87 (s, 3H), 7.10 (m, 1H), 7.41 (m, 1H), 8.32
(s, 1H), 9.93 (d, 1H); MS(ES+): 196 (M+H).sup.+.
EXAMPLE 51
3-(2-Nitrovinyl)-4-methoxy-1H-indole
[0328] Combine ammonium acetate (dried from treatment with toluene
and removal of the toluene in vacuo) as a solid (0.75 eq.),
nitromethane (20 eq.), and 4-methoxy-1H-indole-3-carbaldehyde (5.4
g; 30.82 mmol). Heat to about 65.degree. C. After the reaction is
judged to be near completion (by TLC), add silica gel and evaporate
in vacuo to remove the nitromethane. Load the silica gel from the
reaction mixture on top of short column of silica gel and elute
with 25% acetone in hexanes to give, after evaporation, the title
compound which may be used in the next step without further
purification.
[0329] By the method of Example 51 the following compounds were
prepared: a) 3-(2-Nitrovinyl)-6-methoxy-1H-indole;
[0330] b) 3-(2-Nitrovinyl)-7-methoxy-1H-indole, .sup.1H NMR (300
MHz; d6-DMSO): 3.95 (s, 3H), 5.02 (m, 1H), 6.86 (d, 1H), 7.17 (t,
1H), 7.50 (d, 1H), 8.38 (d, 1H), 12.40 (bs, 1H); MS (ES+): m/z 219
(M+H).sup.+; (ES-): m/z 217 (M-H).sup.-;
[0331] c) 3-(2-Nitrovinyl)-4-chloro-1H-indole, .sup.1H NMR (300
MHz, d6-DMSO): 5.08 (m, 1H), 7.24 (m, 2H), 7.51 (dd, 1H), 8.12 (d,
1H), 8.92 (d, 1H), 12.6 (bs, 1H); MS(ES-): m/z 221, 223
(M-H).sup.-;
[0332] d) 3-(2-Nitrovinyl)-6-chloro-1H-indole, .sup.1H NMR (300
MHz, d6-DMSO): 5.03 (m, 1H), 7.22 (dd, 1H), 7.58 (d, 1H), 8.03 (m,
2H), 8.38 (d, 1H), 12.23 (bs, 1H); MS (ES-): m/z 223, 221
(M-H).sup.-;
[0333] e) 3-(2-Nitrovinyl)-7-chloro-1H-indole, .sup.1H NMR (300
MHz, d6-DMSO): 7.23 (t, 1H), 7.36 (d, 1H), 7.97 (d, 1H), 8.06 (d,
1H), 8.33 (bs, 1H), 8.40 (d, 1H), 12.58 (bs, 1H); MS (ES+): m/z
225, 223 (M+H).sup.+; (ES-): m/z 223, 221 (M-H).sup.-;
[0334] f) 3-(2-Nitrovinyl)-4-fluoro-1H-indole,
[0335] g) 3-(2-Nitrovinyl)-5-methoxy-6-trifluoromethyl-1H-indole,
MS (ES+): m/z 286 (M+); (ES-): m/z 285 (M-H).sup.-;
[0336] h) 3-(2-Nitrovinyl)-6-chloro-5-methoxy-1H-indole,
[0337] i) 3-(2-Nitrovinyl)-4-chloro-5-methoxy-1H-indole, .sup.1H
NMR (300 MHz, d6-DMSO): 3.88 (s, 3H), 5.03 (m, 2H), 7.13 (d, 1H),
7.46 (d, 1H), 8.08 (d, 1H), 12.42 (bs, 1H); MS(ES-): m/z 151, 153
(M-H).sup.-;
[0338] j) 3-(2-Nitrovinyl)-6-trifluoromethyl-1H-indole, MS(ES+):
m/z 257 (M+H).sup.+; (ES-): m/z 255 (M-H).sup.-;
[0339] k) 3-(2-Nitrovinyl)-5-methoxy-2-methyl-1H-indole, .sup.1H
NMR (300 MHz, d6-DMSO): 2.58 (s, 3H), 3.84 (s, 3H), 6.82 (m, 1H),
7.28 (m, 2H), 7.89 (d, 1H), 8.29 (d, 1H), 12.14 (bs, 1H); MS(ES+):
m/z 233 (M+H).sup.+; (ES-): m/z 231 (M-H).sup.-;
[0340] l) 3-(2-Nitrovinyl)-6-fluoro-5-methoxy-1H-indole;
[0341] m) 3-(2-Nitrovinyl)-5,6-difluoro-1H-indole;
[0342] n) 3-(2-Nitrovinyl)-6-chloro-5-fluoro-1H-indole;
[0343] o) 3-(2-Nitrovinyl)-5-trifluoromethoxy-1H-indole;
[0344] p) 3-(2-Nitrovinyl)-4,6-difluoro-5-methoxy-1H-indole;
[0345] q) 3-(2-Nitrovinyl)-4-phenyl-1H-indole;
[0346] r) 3-(2-Nitrovinyl)-6-phenyl-1H-indole;
[0347] s) 3-(2-Nitrovinyl)-5-isopropyl-1H-indole;
[0348] t)
3-(2-Nitrovinyl)-4,6-difluoro-5-methoxy-1-methyl-1H-indole: .sup.1H
NMR (300 MHz, d6-DMSO): 3.82 (t, 3H), 3.92 (s, 3H), 7.53 (m, 1H),
7.84 (m, 1H), 8.30 (m, 2H); MS(ES+): m/z 269 (M+H).sup.+; and
[0349] u) 3-(2-Nitrovinyl)-4,6-difluoro-1-methyl-1H-indole.
EXAMPLE 52
4-Methoxytryptamine
[0350] Combine LiAlH.sub.4 (6.78 g; 178.74 mmol; 6 eq) and
anhydrous THF. Dissolve 3-(2-nitrovinyl)-4-methoxy-1H-indole (6.5
g; 29.79 mmol) in anhydrous THF and add dropwise to the LiAlH.sub.4
solution with vigorous stirring. After the addition is complete,
heat to reflux. After 1 hour cool to ambient temperature and stir.
After 16 hours, quench the excess LiAlH.sub.4 as described in J.
Med. Chem. 1995, 38, 2050. Filter the gray suspension through
celite and rinse the celite with ethyl acetate. Evaporate the
filtrate in vacuo to residue. Chromatograph the residue on silica
gel eluting with 1 L of CHCl.sub.3/MeOH/NH.sub.4OH (95:10:1) and
then 1 L of CHCl.sub.3/MeOH/NH.sub.4OH (90:10:1) as the mobile
phase. Pool fractions containing the product and evaporate to give
the title compound as a tan solid: .sup.1H NMR (300 MHz,
d.sub.6-DMSO): 2.96 (t, 2H); 3.42 (t, 2H); 3.83 (s, 3H); 6.42 (dd,
1H); 6.93 (m, 3H); 10.7 (s, 1H); MS (ES+): m/z 191 (M+H).sup.+; 174
(M-NH.sub.2).sup.+; 159 (M-OCH.sub.3).sup.+; (ES-): m/z 189
(M-H).sup.-.
[0351] By the method of Example 52 the following compounds were
prepared: a) 6-Methoxytryptamine, .sup.1H NMR (300 MHz; d6-DMSO):
2.86 (t, 2H); 3.42 (t, 2H); 3.75 (s, 3H); 6.62 (dd, 1H); 6.83 (m,
1H); 6.97 (bs, 1H); 7.37 (m, 1H); 10.55 (s, 1H); MS (ES+): m/z 191
(M+H).sup.+; 174 (M-NH.sub.2).sup.+; (ES-): m/z 189
(M-H).sup.-;
[0352] b) 7-Methoxytryptamine, .sup.1H NMR (300 MHz, d6-DMSO): 2.88
(t, 2H), 3.42 (t, 2H), 3.89 (s, 3H), 6.61 (d, 1H), 6.89 (t, 1H),
7.02 (m, 1H), 7.10 (d, 1H), 10.85 (bs, 1H); MS (ES+): m/z 191
(M+H).sup.+, 174 (M-NH.sub.2); (ES-): m/z 189 (M-H).sup.-;
[0353] c) 4-Chlorotryptamine, .sup.1H NMR (300 MHz, d6-DMSO): 3.11
(t, 2H), 3.44 (t, 2H), 6.99 (m, 2H), 7.22 (m, 1H), 7.30 (d, 1H),
11.19 (bs, 1H); MS(ES+): m/z 178, 180 (M+H).sup.+; (ES-): m/z 193
(M-H).sup.-;
[0354] d) 6-Chlorotryptamine, .sup.1H NMR (300 MHz, d6-DMSO): 2.89
(t, 2H), 3.42 (t, 2H), 6.96 (dd, 1H), 7.17 (bs, 1H), 7.35 (m, 1H),
7.52 (d, 1H), 10.91 (bs, 1H); MS (ES+): m/z 197, 195 (M+H).sup.+,
180, 178 (M-NH.sub.2).sup.+; (ES-): m/z 195, 193 (M-H).sup.-;
[0355] e) 7-Chlorotryptamine, .sup.1H NMR (300 MHz, d6-DMSO): 2.91
(t, 2H), 3.43 (t, 2H), 6.98 (t, 1H), 7.13 (d, 1H), 7.20 (bs, 1H),
7.51 (d, 1H), 11.15 (bs, 1H); MS (ES+): m/z 197, 195 (M+H).sup.+,
180, 178 (M-NH.sub.2).sup.+; (ES-): m/z 195, 193 (M-H).sup.-;
[0356] f) 4-Fluorotryptamine,
[0357] g) 5-Methoxy-6-trifluoromethyltryptamine,
[0358] h) 6-Chloro-5-methoxytryptamine, .sup.1H NMR (300 MHz,
d6-DMSO): 2.89 (t, 2H), 3.42 (t, 2H), 3.84 (s, 3H), 7.12 (bs, 1H),
7.19 (s, 1H), 7.36 (s, 1H), 8.01 (bs, 1H); MS (ES+): m/z 225, 227
(M+H).sup.+, 208, 210 (M-NH.sub.2).sup.+; (ES-): m/z 223, 225
(M-H).sup.-;
[0359] i) 4-Chloro-5-methoxytryptamine, .sup.1H NMR (300 MHz,
d6-DMSO): 3.10 (t, 2H), 3.43 (t, 2H), 3.81 (s, 3H), 6.95 (d, 1H),
7.18 (m, 1H), 7.25 (dd, 1H), 10.93 (bs, 1H); MS(ES+): m/z 208, 210
(M-NH2).sup.+ (ES-): m/z 223, 225 (M-H).sup.-;
[0360] j) 6-Trifluoromethyltryptamine,
[0361] k) 5-Methoxy-2-methyltryptamine, .sup.1H NMR (300 MHz,
d6-DMSO): 2.28 (s, 3H), 2.80 (t, 2H), 3.31 (bt, 2H), 6.59 (dd, 1H),
6.88 (d, 1H), 7.09 (d, 1H); MS(ES+): m/z 188
(M-NH.sub.2).sup.+(ES-): m/z 203 (M-H).sup.-;
[0362] l) 6-Fluoro-5-methoxytryptamine;
[0363] m) 5,6-Difluorotryptamine;
[0364] n) 6-Chloro-5-fluorotryptamine;
[0365] o) 5-Trifluoromethoxytryptamine;
[0366] p) 4,6-Difluoro-5-methoxytryptamine;
[0367] q) 4-Phenyltryptamine;
[0368] r) 6-Phenyltryptamine;
[0369] s) 5-Isopropyltryptamine;
[0370] t) 4,6-Difluoro-5-methoxy-1-methyltryptamine: .sup.1H NMR
(300 MHz, CDCl.sub.3): 3.0 (m, 4H), 3.67 (s, 3H), 3.98 (s, 3H),
6.85 (m, 2H); and
[0371] u) 4,6-Difluoro-5-methoxy-1-methyltryptamine: .sup.1H NMR
(300 MHz, d6-DMSO): 2.92 (t, 2H), 3.39 (t, 2H), 3.69 (s, 3H), 6.75
(m, 1H), 7.13 (m, 2H); MS(ES+): m/z 211; (M+H).sup.+ 194
(M-NH.sub.2).sup.+.
EXAMPLE 53
4-Methoxytryptamine hydrochloride
[0372] Dissolve 4-methoxytryptamine (1 g, 5.26 mmol) in MeOH and
add of NH.sub.4Cl (0.97 eq, 0.27 g, 5.10 mmol). After 30 minutes,
evaporate in vacuo to remove the MeOH leaving a thick orange oil.
Dissolve the oil in MeOH and add dropwise to Et.sub.2O (200 mL)
with vigorous stirring giving a gummy white precipitate. Stir with
heating to give the title compound as a solid: .sup.1H NMR
(d.sub.6-DMSO, 300 MHz): 3.06 (bs, 4H); 3.86 (s, 3H); 6.46 (dd,
1H); 7.06-6.9 (m, 3H); 7.93 (bs, 1H); 10.9 (s, 1H); MS (ES+): m/z
191 (M+H).sup.+; 175 (M-CH.sub.3).sup.+; 174 (M-NH.sub.2).sup.+;
(ES-): 189 (M-H).sup.-; Analysis for C.sub.11H.sub.15ClN.sub.2O:
Calcd.: C, 58.2788; H, 6.6692; N, 12.3566; found C, 58.18; H, 6.73;
N, 12.15.
EXAMPLE 54
5,6-Difluorotryptamine hydrochloride
[0373] Prepare by the method of Example 53 to give the title
compound: .sup.1H NMR (300 MHz, d6-DMSO): 2.97 (m, 4H), 7.27 (m,
1H), 7.36 (m, 1H), 7.53 (m, 1H), 11.20 (bs, 1H); MS(ES+): m/z 197
(M+H).sup.+, 180 (M-NH.sub.2).sup.+; (ES-): m/z 195
(M-H).sup.-.
EXAMPLE 55
4-Phenyltryptamine hydrochloride
[0374] Add a solution of HCl (4.6 mL of 4 M HCl in 1,4-dioxane)
dropwise to a solution of 4-phenyltryptamine (3.33 g, 14.09 mmol)
in EtOAc/Et.sub.2O to give a solid. Collect the solid by filtration
and dry overnight in a vacuum oven at room temperature to give the
title compound as an off white solid: .sup.1H NMR (300 MHz,
d6-DMSO): 2.54 (m, 4H), 6.82 (m, 1H), 7.14 (t, 1H), 7.27 (m, 1H),
7.41 (m, 5H), 7.68 (bs, 2H), 11.28 (bs, 1H); MS(ES+): m/z 237
(M+H).sup.+, 220 (M-NH.sub.2).sup.+; (ES-): m/z 235 (M-H).sup.-;
Analysis for C.sub.16H.sub.17ClN.sub.2; Calcd.; C, 70.4517; H,
6.2818; N, 10.2696; found; C, 70.26; H, 6.16; N, 10.20.
EXAMPLE 56
5-Chloro-6-fluorotryptamine hydrochloride
[0375] Prepare by the method of Example 55 to give the title
compound: .sup.1H NMR (300 MHz, d6-DMSO): 3.00 (m, 4H), 7.37 (m,
1H), 7.53 (d, 1H), 7.59 (d, 1H), 11.28 (bs, 1H); MS(ES+): m/z 213
(M+H).sup.+, 196, 198 (M-NH.sub.2).sup.+; (ES-): m/z 211, 213
(M-H).sup.-.
EXAMPLE 57
4-Chlorotryptamine oxalate
[0376] Add dropwise oxalic acid (1.32 g, 1.3 eq.) in MeOH to a
solution of 4-chlorotryptamine in EtOAc (2.2 g, 11.3 mmol) with
vigorous stirring. When addition was complete, add Et.sub.2O to the
cloud point and place flask in the freezer to give a solid. Collect
the solid by filtration and wash with ether. Dry in a vacuum oven
at room temperature to give the title compound as an off-white
solid: .sup.1H NMR (300 MHz, d6-DMSO): 3.11 (m, 2H), 3.2 (m, 2H),
7.04 (m, 2H), 7.34 (m, 2H), 11.44 (bs, 1H); MS (ES+): m/z 195
(M+H).sup.+, 178 (M-NH.sub.2).sup.+; (ES-): m/z 193 (M-H).sup.-;
Analysis for C.sub.12H.sub.13ClN.sub.2O.sub.4: Calcd.: C, 50.6263;
H, 4.6026; N, 9.8396; found: C, 50.56; H, 4.57; N, 9.66.
[0377] Using the method of Example 57 gives the following
compounds: a) 6-Phenyltryptamine oxalate: 3.05 (m, 4H), 7.31 (m,
3H), 7.45 (t, 2H), 7.65 (m, 4H), 11.10 (bs, 1H). MS(ES+): m/z 237
(M+H).sup.+, 220 (M-NH.sub.2).sup.+; (ES-): m/z 235
(M-H).sup.-;
[0378] b) 4,6-Difluoro-5-methoxytryptamine oxalate: .sup.1H NMR
(300 MHz, d6-DMSO): 3.04 (m, 4H), 3.85 (s, 3H), 7.10 (m, 1H), 7.22
(m, 1H), 11.29 (bs, 1H); MS(ES+): m/z 227 (M+H).sup.+; (ES-): m/z
225 (M-H).sup.-; Analysis for
C.sub.13H.sub.14F.sub.2N.sub.2O.sub.5: Calcd.; C, 49.3718; H,
4.4620; N, 8.8576; found; C, 49.68; H, 4.57; N, 8.60; and
[0379] c) 5-Isopropyltryptamine oxalate: .sup.1H NMR (300 MHz,
d6-DMSO): 1.25 (d, 6H), 3.01 (m, 4H), 6.99 (m, 1H), 7.17 (m, 1H),
7.27 (m, 1H), 7.36 (bs, 1H), 10.85 (bs, 1H); MS(ES+): m/z 203
(M+H).sup.+, 186 (M-NH.sub.2).sup.+; (ES-): m/z 201
(M-H).sup.-.
EXAMPLE 58
5-Trifluoromethoxytryptamine oxalate
[0380] Add oxalic acid (1.3 eq.) in acetone to a solution of
5-trifluoromethoxytryptamine in acetone. Warm and add Et.sub.2O to
the cloud point and then placed in the freezer overnight to obtain
the title compound as a white crystalline solid: .sup.1H NMR (300
MHz, d6-DMSO): 3.02 (m, 4H), 7.06 (m, 1H), 7.39 (m, 1H), 7.45 (d,
1H), 7.55 (m, 1H), 11.30 (bs, 1H). MS(ES+): m/z 245 (M+H).sup.+,
228 (M-NH.sub.2).sup.+; (ES-): m/z 243 (M-H).sup.-; Analysis for
C.sub.11H.sub.11F.sub.3N.sub.2O: Calcd.; C, 46.7144; H, 3.9203; N,
8.3809; found; C, 46.55; H, 3.62; N, 8.27.
[0381] Using the method of Example 58 gives the following
compounds: a) 4,6-Difluoro-5-methoxytryptamine oxalate: .sup.1H NMR
(300 MHz, d6-DMSO): 3.04 (m, 4H), 3.85 (s, 3H), 7.10 (m, 1H), 7.22
(m, 1H), 11.29 (bs, 1H); MS(ES+): m/z 227 (M+H).sup.+; (ES-): m/Z
225 (M-H).sup.-; Analysis for
C.sub.13H.sub.14F.sub.2N.sub.2O.sub.5: Calcd.; C, 49.3718; H,
4.4620; N, 8.8576; found; C, 49.68; H, 4.57; N, 8.60.
EXAMPLE 60
4-Fluorotryptamine oxalate
[0382] Add dropwise oxalic acid (1.44 g, 1.2 eq.) in acetonitrile
to an acetonitrile solution of 4-fluorotryptamine with vigorous
stirring. Warm add MeOH to make a solution. Add Et.sub.2O to the
cloud point and cool the solution in the freezer to give a solid.
Collect the solid by filtration and dry in a vacuum oven overnight
at 45.degree. C. to give the title compound as a tan solid: .sup.1H
NMR (300 MHz, d6-DMSO): 3.07 (m, 4H), 6.73 (m, 1H), 7.04 (m, 1H),
7.22 (m, 2H), 11.30 (bs, 1H); MS (ES+): m/z 179 (M+H).sup.+; (ES-):
m/z 177 (M-H).sup.-.
EXAMPLE 61
6-Fluoro-5-methoxytryptamine oxalate
[0383] Add oxalic acid (3.91 g, 1.2 eq.) in MeOH dropwise to an
EtOAc/MeOH solution of 6-fluoro-5-methoxytryptamine with vigorous
stirring. Add Et.sub.2O to give a solid and collect the solid by
filtration and dry overnight in a vacuum oven at 60.degree. C. to
give the title compound: .sup.1H NMR (300 MHz, d6-DMSO): 3.0 (m,
4H), 3.85 (s, 3H), 7.21 (m, 3H), 10.89 (bs, 1H); MS(ES+): m/z 209
(M+H).sup.+; Analysis for C.sub.13H.sub.15FN.sub.2O.sub.5: Calcd.:
C, 52.3496; H, 5.0690; N, 9.3919; Found: C, 52.06; H, 4.91; N,
9.20.
EXAMPLE 62
2-(2-(7-Fluoro-1H-indol-3-yl)ethyl)isoindole-1,3-dione
[0384] Combine 2-fluorohydrazine hydrochloride (3.25 g, 20 mmol)
and 2-(4,4-diethoxy-butyl)-isoindole-1,3-dione (6.99 g, 24 mmol)
and dissolve in 4% aqueous H.sub.2SO.sub.4. Heat the reaction to
reflux. After 2 hours, cool to ambient temperature. Basify the
reaction mixture with 30% aqueous NH.sub.4OH to pH of about 11.
Extract with dichloromethane (2.times.100 mL). Combine the organic
phases, dry over MgSO.sub.4, filter, and remove the solvent leaving
an orange oil. Absorb the oil onto silica gel and load on top short
column of silica gel equilibrated with 15% EtOAc in hexanes. Eluent
with 15% EtOAc in hexanes (1500 mL) and then 30% EtOAc in hexanes
(2000 mL) to give, after evaporation, the title compound as a
yellow solid: .sup.1H NMR (300 MHz, d6-DMSO): 3.03 (t, 2H), 3.85
(t, 2H), 6.91 (m, 2H), 7.25 (m, 1H), 7.36 (d, 1H), 7.83 (m, 4H),
11.32 (bs, 1H); MS (FD): m/z 308 (M+).
EXAMPLE 63
7-Fluorotryptamine oxalate
[0385] Dissolve
2-(2-(7-fluoro-1H-indol-3-yl)ethyl)isoindole-1,3-dione in 25 mL of
THF. Add ethanolamine (63.4 g, 62.65 mL, 1038 mmol, 100 eq.) with
vigorous stirring and heat to 70.degree. C. After 1.5 hours, cool
to room temperature. After 18 hours, pour reaction mixture into of
water (250 mL) containing of 5N NaOH (3 mL) and extract with
Et.sub.2O (2.times.200 mL). Combine the organic layers and wash
with 0.1 N NaOH. Collect the organic layer, dry over MgSO.sub.4,
filter, and remove the solvent in vacuo to give the title compound
as a yellow oil.
[0386] Add oxalic acid (0.62 g, 1.2 eq.) in MeOH dropwise to an
EtOAc solution of the base (1.02 g, 5.72 mmol) with vigorous
stirring. Heat the cloudy suspension to reflux for 30 minutes and
then cool to give a solid. Collect the solid by filtration and dry
overnight in a vacuum oven at 60.degree. C. to give the title
compound as an off-white solid: .sup.1H NMR (300 MHz, d6-DMSO):
3.04 (m, 4H), 6.96 (m, 2H), 7.30 (m, 1H), 7.38 (d, 1H), 11.51 (bs,
1H); MS (ES+): m/z 179 (M+H).sup.+, 162 (M-NH.sub.2).sup.+; (ES-):
m/z 177 (M-H).sup.-; Analysis for C.sub.12H.sub.13FN.sub.2O.sub.4:
Calcd.: C, 53.7318; H, 4.8849; N, 10.4431; found: C, 53.50; H,
4.86; N, 10.32.
EXAMPLE 64
6-Trifluoromethyltryptamine oxalate
[0387] Add 6-trifluoromethyltryptamine to 1:1 acetone/Et.sub.2O.
Add dropwise of oxalic acid (1.2 eq.) in acetone to give a solid.
Collect the solid by filtration and dry overnight in the vacuum
oven to obtain the title compound: MS(ES+): m/z 212
(M-NH.sub.2).sup.+; (ES-): m/z 227 (M-H).sup.-.
EXAMPLE 65
4,6-Difluoro-5-methoxy-1H-indole
[0388] Dissolve 2,6-difluoro-4-nitrophenol (J. Heterocyclic. Chem.
1976, 13, 1253; 10 g, 57.11 mmol) in 300 mL of benzene. Add
dropwise a solution of 1-methyl-3-p-tolyltriazene (9.37 g, 62.82
mmol, 1.1 eq.) in benzene (150 mL). After TLC indicates absence of
starting material, transfer the reaction mixture to a separator
funnel and wash with 1 N HCl, then saturated NaHCO.sub.3, and then
water. Dry the organic layer over MgSO.sub.4, filter, and remove
the solvent to give a residue. Crystallize the residue from
MeOH/water to give 1,3-difluoro-2-methoxy-5-nitrobenzene as white
needles: .sup.1H NMR (300 MHz, CDCl.sub.3): 4.25 (t, 3H), 7.80 (d,
2H).
[0389] Combine 1,3-difluoro-2-methoxy-5-nitrobenzene (10.12 g,
53.51 mmol) and 4 chlorophenoxyacetonitrile (11.21 g, 66.89 mmol,
1.25 eq.) in DMSO (150 mL). Add dropwise to a suspension of solid
NaOH (powdered, 10.70 g, 267.55 mmol, 5 eq.) over 5 hours. After 18
hours, pour the reaction mixture into cold, aqueous HCl and extract
with Et.sub.2O (2.times.150 mL). Combine the organic layers, wash
with brine, and evaporate to give a residue. Chromatograph the
residue on silica gel and eluting with 20% EtOAc in hexanes to
give, after evaporation,
(2,4-difluoro-3-methoxy-6-nitrophenyl)acetonitrile as a yellow oil:
MS(ES-): m/z 227 (M-H).sup.-.
[0390] Using (2,4-difluoro-3-methoxy-6-nitrophenyl)acetonitrile in
the cyclization as described in Israel J. Chem. 1966, 4, 155-159
gives an oil. Chromatograph the oil on silica gel eluting with 20%
EtOAc in hexanes to give, after evaporation, the title compound as
a purple solid; .sup.1H NMR (300 MHz, d6-DMSO): 3.85 (bs, 3H), 6.46
(m, 1H), 7.12 (d, 1H), 7.36 (m, 1H), 11.35 (bs, 1H); MS(ES-): m/z
182 (M-H).sup.-.
[0391] Using the method of Example 65 gives the following
compounds: a) 4,6-Difluoro-1H-indole: .sup.1H NMR (300 MHz,
CDCl.sub.3): 4.68 (d, 2H), 6.14 (m, 2H), 6.57 (bs, 2H); MS(ES+):
m/z 205, 207 (M+H).sup.+ which gives the title compound.
EXAMPLE 66
4,6-Difluoro-5-methoxy-1-methyl-1H-indole
[0392] Combine 4,6-difluoro-5-methoxy-1H-indole (7.5 g, 40.95 mmol)
and cold DMF (100 mL) and treat with NaH (1.8 g, 45.05 mmol, 1.1
eq.) and with vigorously stirring. After about 10 minutes, add
dropwise iodomethane (11.62 g, 81.90 mmol, 2 eq.). After the
addition was complete, allow the reaction to stir at room
temperature for several hours until TLC indicates the absence of
starting material. Dilute the reaction with water and extract with
Et.sub.2O (2.times.150 mL). Combine the organic layers, dry over
MgSO.sub.4, filter, and remove the solvent leaving an oil.
Chromatograph the oil on silica gel eluting with 10% EtOAc in
hexanes to give, after evaporation, the title compound as a light
yellow oil: .sup.1H NMR (300 MHz, CDCl.sub.3): 3.72 (s, 3H), 3.97
(s, 3H), 6.50 (d, 1H), 6.84 (d, 1H), 6.98 (d, 1H); MS(ES+): m/z 198
(M+H).sup.+; Analysis for C.sub.10H.sub.9F.sub.2NO: Calcd.: C,
60.91; H, 4.60; N, 7.10; found: C, 60.93; H, 4.63; N, 7.25.
[0393] Using the method of Example 66 gives the following
compounds: a) 4,6-Difluoro-1-methyl-1H-indole.
EXAMPLE 67
N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine
[0394] ##STR21##
[0395] Combine 3-phenoxybenzaldehyde (5.6 ml, 26.7 mmol),
5-methoxytryptamine (5.0 g, 26.7 mmol) and 3 .ANG. molecular sieves
(1.0 g) in methanol (50 ml) and under argon and heat at reflux for
4 hours. Remove the molecular sieves by filtration and then slowly
add sodium borohydride (3.0 g, 60.0 mmol) portionwise. Stir at room
temperature for 1 hour and concentrate under reduced pressure,
dissolve the concentrated reaction mixture in sodium hydroxide 1N
(100 ml) and extract with dichloromethane (3.times.50 ml). Combine
organic layers and wash sequentially with distilled water (50 ml)
and brine (50 ml), dry (Na.sub.2SO.sub.4) the organic layer, and
concentrate to give a residue. Chromatograph the residue on silica
gel eluting with 9:1 EtOAc:MeOH with 2% NH4OH gives the title
compound.
[0396] Formation of oxalate salt: Add a solution of the free base
(8.7 g, 23.5 mmol) in EtOAc (50 ml) to a solution of oxalic acid
(2.1 g, 23.5 mmol) in EtOAc (5 ml) to give a precipitate. Collect
the precipitate and recrystallize from methanol/diethyl ether to
give a solid. Collect the solid by filtration, rinse with diethyl
ether, and dry in a vacuum oven at 50.degree. C. overnight to give
the title compound as the oxalate, mp 188-190.degree. C., RMN
consistent, Mass: m/z 373.2 (M+), Anal. Calcd for
C.sub.26H.sub.26N.sub.2O.sub.6: C, 67.52; H, 5.67; N, 6.06. Found:
C, 67.38; H, 5.46; N, 6.04.
[0397] By the method of Example 67 the following compounds were
prepared, isolated as the oxalate except where noted:
TABLE-US-00001 ##STR22## No. Z' X R.sub.4 Data 68 H --O-- phenyl mp
203-205.degree. C., Mass: m/z 343.1 (M.sup.+), Anal. Calcd for
C.sub.25H.sub.24N.sub.2O.sub.5: C, 69.43; H, 5.59; N, 6.48 Found:
C, 69.25; H, 5.42; N, 6.37 69 H --S-- phenyl mp 106-108.degree. C.,
Mass: m/z 359.2 (M.sup.+), Anal. Calcd for
C.sub.22H.sub.24N.sub.2O.sub.4S: C, 66.95; H, 5.39; N, 6.25 Found:
C, 66.19; H, 5.49; N, 6.13 70 H --SO.sub.2-- phenyl mp
203-205.degree. C., Mass: m/z 391.2 (M.sup.+), Anal. Calcd for
C.sub.25H.sub.24N.sub.2O.sub.6S: C, 62.49; H, 5.03; N, 5.83 Found:
C, 62.05; H, 5.21; N, 5.82 71 5-methoxy --S-- phenyl mp
198-200.degree. C., Mass: m/z 389.3 (M.sup.+), Anal. Calcd for
C.sub.26H.sub.26N.sub.2O.sub.5S: C, 65.25; H, 5.48; N, 5.85 Found:
C, 64.50; H, 5.63; N, 5.73 72 5-methoxy --SO.sub.2-- phenyl mp
142-144.degree. C., Mass: m/z 421.1 (M.sup.+), Anal. Calcd for
C.sub.26H.sub.26N.sub.2O.sub.7S: C, 61.16; H, 5.13; N, 5.49 Found:
C, 61.14; H, 5.38; N, 5.25 73 H --S-- 4- mp 190-192.degree. C.,
Mass: m/z 373.2 methylphenyl (M.sup.+), Anal. Calcd for
C.sub.26H.sub.26N.sub.2O.sub.4S: C, 67.51; H, 5.67; N, 6.06 Found:
C, 67.44; H, 5.69; N, 6.13 74 H --SO.sub.2-- 4-methyl mp
212-214.degree. C., Mass: m/z 405.4 phenyl (M.sup.+), Anal. Calcd
for C.sub.26H.sub.26N.sub.2O.sub.6S: C, 63.14; H, 5.30; N, 5.66
Found: C, 62.59; H, 5.70; N, 5.29 75 5-methoxy --CH(F)-- phenyl mp
214-216.degree. C., Mass: m/z 389.3 (M.sup.+), Anal. Calcd for
C.sub.27H.sub.27FN.sub.2O.sub.5: C, 67.77; H, 5.69; N, 5.85 Found:
C, 67.52; H, 5.77; N, 5.64 76 H --CH(F)-- phenyl mp 216-218.degree.
C., Mass: m/z 359.2 (M.sup.+), Anal. Calcd for
C.sub.26H.sub.25FN.sub.2O.sub.4: C, 69.63; H, 5.62; N, 6.25 Found:
C, 69.55; H, 5.36; N, 5.95 77 5-methoxy --CH.sub.2-- phenyl mp
199-202.degree. C., Mass: m/z 371.1 (M.sup.+), Anal. Calcd for
C.sub.27H.sub.28N.sub.2O.sub.5: C, 70.42; H, 6.13; N, 6.08 Found:
C, 69.73; H, 6.25; N, 6.05 78 H --CH.sub.2-- phenyl mp
222-224.degree. C., Mass: m/z 341.2 (M.sup.+), Anal. Calcd for
C.sub.26H.sub.26N.sub.2O.sub.4: C, 72.54; H, 6.09; N, 6.51 Found:
C, 72.23; H, 6.08; N, 6.37 79 5-methoxy --CH(OH)-- phenyl mp
146-148, Mass: m/z 387.2, Anal. Calcd for
C.sub.27H.sub.28N.sub.2O.sub.5: C, 68.05; H, 5.92; N, 5.88 Found:
C, 67.29; H, 6.03; N, 5.51 80 H --CH(OH)-- phenyl mp
167-169.degree. C., Mass: m/z 357.3 (M.sup.+), Anal. Calcd for
C.sub.26H.sub.26N.sub.2O.sub.5: C, 69.94; H, 5.87; N, 6.27. Found:
C, 68.11; H, 6.07; N, 6.06 81 5-methoxy --NH-- phenyl mp
170-172.degree. C., Mass: m/z 372.3 (M.sup.+), Anal. Calcd for
C.sub.26H.sub.27N.sub.3O.sub.5: C, 67.67; H, 5.90; N, 9.10 Found:
C, 67.24; H, 6.08; N, 8.54 82 H --NH-- phenyl mp 196-198.degree.
C., Mass: m/z 342.2 (M.sup.+), Anal. Calcd for
C.sub.25H.sub.25N.sub.3O.sub.4: C, 69.59; H, 5.84; N, 9.74 Found:
C, 67.57; H, 6.06; N, 8.84 83 5-methoxy --NH-- benzyl mp
203-205.degree. C., Mass: m/z 386.2 (M.sup.+), Anal. Calcd for
C.sub.27H.sub.29N.sub.3O.sub.5: C, 68.20; H, 6.15; N, 8.84 Found:
C, 67.46; H, 6.14; N, 8.79 84 H --NH-- benzyl mp 204-206.degree.
C., Mass: m/z 356.3 (M.sup.+), Anal. Calcd for
C.sub.26H.sub.27N.sub.3O.sub.4: C, 70.10; H, 6.11; N, 9.43. Found:
C, 68.48; H, 5.95; N, 9.26. 85 5-methoxy --O-- H mp 126-128.degree.
C., Mass: m/z 297.5 (M.sup.+), Anal. Calcd for
C.sub.18H.sub.20N.sub.2O.sub.2: C, 72.94; H, 6.80; N, 9.45. Found:
C, 71.78; H, 6.71; N, 9.20. (isolated as the base) 86 H --O-- H mp
143-145.degree. C., Mass: m/z 267.3 (M.sup.+), Anal. Calcd for
C.sub.17H.sub.18N.sub.2O: C, 76.66; H, 6.81; N, 10.51. Found: C,
75.11; H, 6.61; N, 10.22 (isolated as the base) 87 5-fluoro --O--
phenyl mp 204-206.degree. C., Mass: m/z 361.1 (M.sup.+), Anal.
Calcd for C.sub.25H.sub.23FN.sub.2O.sub.5: C, 66.66; H, 5.15; N,
6.22. Found: C, 66.83; H, 5.17; N, 6.30. 88 5-methoxy --O--
naphth-1-yl mp 196-198.degree. C., Mass: m/z 423.1 (M.sup.+), Anal.
Calcd for C.sub.30H.sub.26N.sub.2O.sub.6: C, 70.30; H, 5.51; N,
5.47. Found: C, 68.11; H, 5.56; N, 5.52. 89 H --O-- naphth-1-yl mp
210-212.degree. C., Mass: m/z 393.2 (M.sup.+), Anal. Calcd for
C.sub.29H.sub.24N.sub.2O.sub.5: C, 72.19; H, 5.43; N, 5.81. Found:
C, 72.10; H, 5.40; N, 6.66. 90 5-methoxy --O-- 3-fluoro mp
186-188.degree. C., Mass: m/z 391.2 phenyl (M.sup.+), Anal. Calcd
for C.sub.26H.sub.25FN.sub.2O.sub.6: C, 64.99; H, 5.24; N, 5.83.
Found: C, 63.10; H, 5.11; N, 5.67. 91 H --O-- 3-fluoro mp
217-219.degree. C. in 75% yield, RMN phenyl consistent, Mass: m/z
361.1 (M.sup.+), Anal. Calcd for C.sub.25H.sub.23FN.sub.2O.sub.5:
C, 66.66; H, 5.15; N, 6.22. Found: C, 66.12; H, 5.22; N, 6.34. 92
5-methoxy --O-- 2-fluoro mp 184-186.degree. C., Mass: m/z 391.2
phenyl (M.sup.+), Anal. Calcd for C.sub.26H.sub.25FN.sub.2O.sub.6:
C, 64.99; H, 5.24; N, 5.83. Found: C, 65.06; H, 5.23; N, 5.85. 93 H
--O-- 2-fluoro mp 206-208.degree. C., Mass: m/z 361.1 phenyl
(M.sup.+), Anal. Calcd for C.sub.25H.sub.23FN.sub.2O.sub.5: C,
66.66; H, 5.15; N, 6.22. Found: C, 66.30; H, 4.97; N, 6.21. 94
5-methoxy --O-- 4-fluoro mp 184-186.degree. C., Mass: m/z 391.2
phenyl (M.sup.+), Anal. Calcd for C.sub.26H.sub.25FN.sub.2O.sub.6:
C, 64.99; H, 5.24; N, 5.83. Found: C, 63.99; H, 4.95; N, 5.75. 95 H
--O-- 4-fluoro mp 222-224.degree. C., Mass: m/z 361.1 phenyl
(M.sup.+), Anal. Calcd for C.sub.25H.sub.23FN.sub.2O.sub.5: C,
66.66; H, 5.15; N, 6.22. Found: C, 65.74; H, 4.81; N, 6.13. 96
5-methoxy --O-- naphth-2-yl mp 198-200.degree. C., Mass: m/z 423.1
(M.sup.+), Anal. Calcd for C.sub.30H.sub.26N.sub.2O.sub.6: C,
70.30; H, 5.51; N, 5.47. Found: C, 68.97; H, 5.43; N, 5.44. 97 H
--O-- naphth-2-yl mp 219-221.degree. C., Mass: m/z 393.2 (M.sup.+),
Anal. Calcd for C.sub.29H.sub.24N.sub.2O.sub.5: C, 72.19; H, 5.43;
N, 5.81. Found: C, 71.65; H, 5.32; N, 5.91. 98 5-methoxy --O--
benzyl mp 204-206.degree. C., Mass: m/z 387.2 (M.sup.+), Anal.
Calcd for C.sub.27H.sub.28N.sub.2O.sub.6: C, 68.05; H, 5.92; N,
5.87. Found: C, 67.26; H, 5.80; N, 5.86. 99 H --O-- benzyl mp
211-213.degree. C., Mass: m/z 357.3 (M.sup.+), Anal. Calcd for
C.sub.26H.sub.26N.sub.2O.sub.5: C, 69.94; H, 5.86; N, 6.27. Found:
C, 69.46; H, 5.75; N, 6.16. 100 5-hydroxy --O-- phenyl mp
188-190.degree. C., Mass: m/z 359.2 (M.sup.+), Anal. Calcd for
C.sub.25H.sub.24N.sub.2O.sub.6: C, 66.95; H, 5.39; N, 6.24. Found:
C, 63.56; H, 5.01; N, 5.86. 101 5-methoxy --O-- pyrimid-5-yl mp
191-193.degree. C., Mass: m/z 375.2 (M.sup.+), Anal. Calcd for
C.sub.24H.sub.24N.sub.4O.sub.6: C, 62.06; H, 5.20; N, 12.06. Found:
C, 61.66; H, 5.41; N, 10.87. 102 H --O-- pyrimid-5-yl mp
188-190.degree. C., Mass: m/z 345.1 (M.sup.+), Anal. Calcd for
C.sub.23H.sub.22N.sub.4O.sub.5: C, 63.58; H, 5.10; N, 12.89. Found:
C, 62.52; H, 5.28; N, 11.58. 103 5-methoxy --O-- pyrid-4-yl mp
124-126.degree. C., Mass: m/z 374.2 (M.sup.+), Anal. Calcd for
C.sub.23H.sub.25Cl.sub.2N.sub.3O.sub.2: C, 61.88; H, 5.64; N, 9.41.
Found: C, 61.26; H, 5.70; N, 9.14. (isolated as the hydrochloride)
104 H --O-- pyrid-4-yl mp 147-149.degree. C., Mass: m/z 344.2
(M.sup.+), Anal. Calcd for C.sub.22H.sub.23Cl.sub.2N.sub.3O: C,
63.46; H, 5.56; N, 10.09. Found: C, 61.47; H, 5.33; N, 9.43.
(isolated as the hydrochloride) 105 6-chloro --O-- pyrid-4-yl mp
150-152.degree. C., Mass: m/z 378.2 (M.sup.+), Anal. Calcd for
C.sub.22H.sub.22Cl.sub.3N.sub.3O: C, 58.61; H, 4.91; N, 9.32.
Found: C, 57.28; H, 4.61; N, 8.85. 106 5-methoxy --O-- pyrid-3-yl
mp 178-180.degree. C., Mass: m/z 374.2 (M.sup.+), Anal. Calcd for
C.sub.25H.sub.25N.sub.3O.sub.6: C, 64.78; H, 5.43; N, 9.06. Found:
C, 63.02; H, 5.30; N, 8.87. 107 H --O-- pyrid-3-yl mp
190-192.degree. C., Mass: m/z 344.1 (M.sup.+), Anal. Calcd for
C.sub.24H.sub.23N.sub.3O.sub.5: C, 66.50; H, 5.34; N, 9.69. Found:
C, 65.69; H, 5.21; N, 9.20. 108 5-fluoro --O-- pyrid-3-yl mp
135-137.degree. C., Mass: m/z 362.3 (M.sup.+), Anal. Calcd for
C.sub.22H.sub.22Cl.sub.2FN.sub.3O: C, 60.83; H, 5.10; N, 9.67.
Found: C, 61.49; H, 5.31; N, 9.70. (isolated as the hydrochloride)
109 6-chloro --O-- pyrid-3-yl mp 160-162.degree. C., Mass: m/z
378.1 (M.sup.+), Anal. Calcd for C.sub.22H.sub.22Cl.sub.3N.sub.3O:
C, 58.61; H, 4.91; N, 9.32. Found: C, 58.18; H, 4.89; N, 9.01.
(isolated as the hydrochloride) 110 5-methoxy --O-- pyrid-2-yl mp
202-204.degree. C., Mass: m/z 374.2 (M.sup.+), Anal. Calcd for
C.sub.23H.sub.25Cl.sub.2N.sub.3O.sub.2: C, 61.88; H, 5.64; N, 9.41.
Found: C, 60.57; H, 6.35; N, 10.89. (isolated as the hydrochloride)
111 H --O-- pyrid-2-yl mp 196-198.degree. C., Mass: m/z 344.2
(M.sup.+), Anal. Calcd for C.sub.22H.sub.23Cl.sub.2N.sub.3O: C,
63.46; H, 5.56; N, 10.09. Found: C, 63.69; H, 6.09; N, 11.62.
(isolated as the hydrochloride) 112 6-chloro --O-- pyrid-2-yl mp
149-151.degree. C., Mass: m/z 378.1 (M.sup.+), Anal. Calcd for
C.sub.22H.sub.22Cl.sub.3N.sub.3O: C, 58.61; H, 4.91; N, 9.32.
Found: C, 61.96; H, 4.91; N, 9.73. (isolated as the hydrochloride)
113 5-methoxy --O-- thiazol-2-yl mp 180-182.degree. C., Mass: m/z
380.3 (M.sup.+), Anal. Calcd for C.sub.23H.sub.23N.sub.3O.sub.6S:
C, 58.83; H, 4.93; N, 8.94. Found: C, 58.11; H, 4.79; N, 8.84. 114
H --O-- thiazol-2-yl mp 203-205.degree. C., Mass: m/z 350.3
(M.sup.+), Anal. Calcd for C.sub.22H.sub.21N.sub.3O.sub.5S: C,
60.12; H, 4.81; N, 9.56. Found: C, 59.73; H, 4.83; N, 9.36. 115
5-methoxy --O-- 2,6-difluoro mp 137-139.degree. C., Mass: m/z 473.1
phenylsulfonyl (M.sup.+) Anal. Calcd for
C.sub.26H.sub.24F.sub.2N.sub.2O.sub.8S: C, 55.51; H, 4.30; N, 4.97.
Found: C, 55.90; H, 4.47; N, 5.12. 116 H --O-- 2,6-difluoro mp
185-187.degree. C., Mass: m/z 443.2 phenylsulfonyl (M.sup.+), Anal.
Calcd for C.sub.25H.sub.22F.sub.2N.sub.2O.sub.7S: C, 56.38; H,
4.16; N, 5.26. Found: C, 56.96; H, 4.39; N, 5.31. 117 5-methoxy
--NH-- pyrid-2-yl mp 174-176.degree. C., Mass: m/z 373.1 (M.sup.+),
Anal. Calcd for C.sub.23H.sub.26Cl.sub.2N.sub.4O.sub.6: C, 62.02;
H, 5.88; N, 12.57. Found: C, 61.45; H, 5.91; N, 12.22. (isolated as
the hydrochloride) 118 H --NH-- pyrid-2-yl mp 168-170.degree. C.,
Mass: m/z 343.1 (M.sup.+), Anal. Calcd for
C.sub.22H.sub.24Cl.sub.2N.sub.4: C, 63.61; H, 5.82; N, 13.48.
Found: C, 62.18; H, 6.12; N, 12.11. (isolated as the hydrochloride)
119 6-chloro --NH-- pyrid-2-yl mp 164-166.degree. C., Mass: m/z
377.1 (M.sup.+), Anal. Calcd for C.sub.22H.sub.23Cl.sub.3N.sub.4:
C, 58.74; H, 5.15; N, 12.45. Found: C, 57.75; H, 5.07; N, 11.94.
(isolated as the hydrochloride) 120 5-methoxy --NH-- pyrid-3-yl mp
150-154.degree. C., Mass: m/z 373.2 (M.sup.+) Anal. Calcd for
C.sub.23H.sub.26Cl.sub.2N.sub.4O.sub.6: C, 62.02; H, 5.88; N,
12.57. Found: C, 61.30; H, 6.58; N, 10.87. (isolated as the
hydrochloride) 121 H --NH-- pyrid-3-yl mp 140-142.degree. C., Mass:
m/z 343.2 (M.sup.+), Anal. Calcd for C.sub.22H.sub.22N.sub.4: C,
77.16; H, 6.47; N, 16.36. Found: C, 75.73; H, 6.54; N, 15.58.
(isolated as the base) 122 6-chloro --NH-- pyrid-3-yl mp
172-174.degree. C., Mass: m/z 377.2
(M.sup.+), Anal. Calcd for C.sub.22H.sub.23Cl.sub.3N.sub.4: C,
58.74; H, 5.15; N, 12.45. Found: C, 57.05; H, 5.16; N, 11.84.
(isolated as the hydrochloride) 123 5-methoxy --NH-- pyrid-4-yl mp
170-172.degree. C., Mass: m/z 373.3 (M.sup.+), Anal. Calcd for
C.sub.23H.sub.26Cl.sub.2N.sub.4O.sub.6: C, 62.02; H, 5.88; N,
12.57. Found: C, 61.05; H, 6.08; N, 11.97. (isolated as the
hydrochloride) 124 H --NH-- pyrid-4-yl mp 174-176.degree. C., Mass:
m/z 343.4 (M.sup.+), Anal. Calcd for
C.sub.22H.sub.24Cl.sub.2N.sub.4: C, 63.61; H, 5.82; N, 13.48.
Found: C, 62.32; H, 6.20; N, 12.44. (isolated as the hydrochloride)
125 6-chloro --NH-- pyrid-4-yl mp 158-160.degree. C., Mass: m/z
377.2 (M.sup.+), Anal. Calcd for C.sub.22H.sub.23Cl.sub.3N.sub.4:
C, 58.74; H, 5.15; N, 12.45. Found: C, 57.17; H, 5.19; N, 11.69.
(isolated as the hydrochloride) 126 5-methoxy- --NH-- 2,2,2- mp
151-153.degree. C., Mass: m/z 397.2 6-fluoro trifluoroethyl
(M.sup.+), Anal. Calcd for C.sub.24H.sub.24F.sub.4N.sub.2O.sub.6:
C, 56.25; H, 4.72; N, 5.46. Found: C, 56.38; H, 4.76; N, 5.53.
(isolated as the maleate) 127 5-methoxy- --NH-- 2,2,3,3,3- mp
145-147.degree. C., Mass: m/z 447.2 6-fluoro pentafluoro (M.sup.+),
Anal. Calcd for propyl C.sub.25H.sub.24F.sub.6N.sub.2O.sub.6: C,
53.38; H, 4.30; N, 4.98. Found: C, 53.36; H, 4.29; N, 5.00.
(isolated as the maleate) 128 5-methoxy- --O-- 2,2,3,3- mp
143-145.degree. C., Mass: m/z 429.2 6-fluoro tetrafluoro (M.sup.+),
Anal. Calcd for propyl C.sub.25H.sub.25F.sub.5N.sub.2O.sub.6: C,
55.14; H, 4.62; N, 5.14. Found: C, 55.10; H, 4.62; N, 5.18.
(isolated as the maleate) 129 5-methoxy --C(O)-- phenyl mp
163-166.degree., Mass: m/z 385.2 (M.sup.+), Anal. Calcd for
C.sub.27H.sub.26N.sub.2O.sub.6: C, 68.34; H, 5.52; N, 5.90. Found:
C, 66.64; H, 5.56; N, 5.90. 130 H --C(O)-- phenyl mp
168-170.degree. C., Mass: m/z 355.3 (M.sup.+), Anal. Calcd for
C.sub.26H.sub.24N.sub.2O.sub.5: C, 70.26; H, 5.44; N, 6.30. Found:
C, 69.51; H, 5.52; N, 6.22. 130 6-fluoro --O-- pyrid-4-yl mp:
123.4-124.9.degree. C. Mass (ES+): A m/z 363.0 (M + 1). Anal.
Calcd. for C.sub.22H.sub.20FN.sub.3O: C, 73.11; H, 5.58; N, 11.63.
Found: C, 73.36; H, 5.41; N, 11.57. (isolated as the free base) 130
6-fluoro --O-- pyrid-3-yl mp 169.0-170.8.degree. C. Mass (APCI): B
m/z 362.1 (M + 1). Anal. Calcd for
C.sub.22H.sub.20F.sub.1N.sub.3O.1.0 C.sub.4H.sub.4O.sub.4: C,
65.40; H, 5.07; N, 8.80. Found: C, 65.45; H, 5.12; N, 8.70.
(isolated as the maleate salt) 130 5-methoxy --O-- 2,2,2 trifluoro
mp 151-153.degree. C. Mass: m/z 397.2 C 6-fluoro ethyl (M.sup.+),
Anal. Calcd for C.sub.24H.sub.24F.sub.4N.sub.2O.sub.6: C, 56.25; H,
4.72; N, 5.46. Found: C, 56.38; H, 4.76; N, 5.53. (isolated as the
maleate salt)
[0398] By the method of Example 67 the following compounds were
prepared, isolated as late except where noted: TABLE-US-00002
##STR23## No. Z' X R.sub.4 Data 131 3-chloro --O-- phenyl mp
222-224.degree. C., Mass: m/z 338.2 (M.sup.+), Anal. Calcd for
C.sub.23H.sub.22ClNO.sub.5: C, 64.56; H, 5.18; N, 3.27. Found: C,
64.24; H, 5.02; N, 3.89. 132 3-trifluoro --O-- phenyl mp
220-222.degree. C., Mass: m/z 372.2 methyl (M.sup.+), Anal. Calcd
for C.sub.24H.sub.22F.sub.3NO.sub.5: C, 62.47; H, 4.81; N, 3.04.
Found: C, 62.69; H, 4.78; N, 3.10. 133 4-methoxy --O-- phenyl mp
221-223.degree. C., Mass: m/z 334.2 (M.sup.+), Anal. Calcd for
C.sub.24H.sub.25NO.sub.6: C, 68.07; H, 5.95; N, 3.31. Found: C,
67.98; H, 5.92; N, 3.29. 134 3,4- --O-- phenyl Mp 209-211.degree.
C., Mass: m/z 364.2 dimethoxy (M.sup.+), Anal. Calcd for
C.sub.25H.sub.27N.sub.7: C, 66.21; H, 6.00; N, 3.09. Found: C,
66.28; H, 6.07; N, 3.27. 135 3-methoxy --O-- phenyl Mp
210-212.degree. C., Mass: m/z 334.1 (M.sup.+), Anal. Calcd for
C.sub.24H.sub.25NO.sub.6: C, 68.07; H, 5.95; N, 3.31. Found: C,
68.31; H, 5.78; N, 3.36. 136 3,4- --O-- phenyl mp 219-221.degree.
C., Mass: m/z 372.1 dichloro (M.sup.+), Anal. Calcd for
C.sub.23H.sub.21Cl.sub.2NO.sub.5: C, 59.75; H, 4.58; N, 3.03.
Found: C, 58.98; H, 4.63; N, 3.66. 137 3-chloro --O-- 3- mp
214-216.degree. C., Mass: m/z 406.4 trifluoromethyl (M.sup.+),
Anal. Calcd for phenyl C.sub.24H.sub.21ClF.sub.3NO.sub.5: C, 58.13;
H, 4.27; N, 2.82. Found: C, 58.28; H, 4.53; N, 2.86. 138 3-chloro
--O-- 4-t-butyl mp 221-223.degree. C., Mass: m/z 394.2 phenyl
(M.sup.+), Anal. Calcd for C.sub.27H.sub.30ClNO.sub.5: C, 67.00; H,
6.25; N, 2.89. Found: C, 66.36; H, 5.83; N, 2.94. 139 3-chloro
--O-- 4-chloro mp 212-214.degree. C., Mass: m/z 372.1 phenyl
(M.sup.+), Anal. Calcd for C.sub.23H.sub.21Cl.sub.2NO.sub.5: C,
59.75; H, 4.58; N, 3.03. Found: C, 61.50; H, 4.77; N, 3.20. 140
3-chloro --O-- 4-methoxy mp 207-209.degree. C., Mass: m/z 368.2
phenyl (M.sup.+), Anal. Calcd for C.sub.24H.sub.24ClNO.sub.6: C,
62.95; H, 5.28; N, 3.06. Found: C, 63.17; H, 5.32; N, 3.19. 141
3-chloro --O-- 4-methyl mp 206-208.degree. C., Mass: m/z 352.4
phenyl (M.sup.+), Anal. Calcd for C.sub.24H.sub.24ClNO.sub.5: C,
65.23; H, 5.47; N, 3.17. Found: C, 67.52; H, 5.68; N, 3.30. 142
3-chloro --O-- 3,5-dichloro mp 223-225.degree. C., Mass: m/z 406.3
phenyl (M.sup.+), Anal. Calcd for C.sub.23H.sub.20Cl.sub.3NO.sub.5:
C, 55.61; H, 4.06; N, 2.82. Found: C, 56.08; H, 3.83; N, 2.26. 143
3-chloro --O-- 3,4-dichloro mp 217-219.degree. C., Mass: m/z 406.4
phenyl (M.sup.+), Anal. Calcd for C.sub.23H.sub.20Cl.sub.3NO.sub.5:
C, 55.61; H, 4.06; N, 2.82. Found: C, 55.73; H, 4.38; N, 3.02. 144
H --O-- phenyl mp 162-164.degree. C., Mass: m/z 304.2 (M.sup.+),
Anal. Calcd for C.sub.23H.sub.23NO.sub.5: C, 70.22; H, 5.89; N,
3.56. Found: C, 70.70; H, 5.38; N, 3.78. 145 4-chloro --O-- phenyl
mp 222-224.degree. C., Mass: m/z 338.2 (M.sup.+), Anal. Calcd for
C.sub.23H.sub.22ClNO.sub.5: C, 64.56; H, 5.18; N, 3.27. Found: C,
63.65; H, 5.18; N, 3.25. 146 3-chloro --S-- phenyl mp
122-124.degree. C., Mass: m/z 354.3 (M.sup.+), Anal. Calcd for
C.sub.23H.sub.22ClNO.sub.4S: C, 62.23; H, 4.99; N, 3.15. Found: C,
63.08; H, 5.09; N, 3.15. 147 3-chloro --SO.sub.2-- phenyl mp
110-112.degree. C., Mass: m/z 386.1 (M.sup.+), Anal. Calcd for
C.sub.23H.sub.22ClNO.sub.6S: C, 58.04; H, 4.66; N, 2.94. Found: C,
58.91; H, 4.78; N, 3.05. 148 H --S-- phenyl mp 111-113.degree. C.,
Mass: m/z 320.1 (M.sup.+), Anal. Calcd for
C.sub.23H.sub.23NO.sub.4S: C, 67.46; H, 5.66; N, 3.42. Found: C,
67.66; H, 5.77; N, 3.41. 149 H --SO.sub.2-- phenyl mp
127-129.degree. C., Mass: m/z 352.4 (M.sup.+), Anal. Calcd for
C.sub.23H.sub.23NO.sub.6S: C, 62.57; H, 5.25; N, 3.17. Found: C,
62.75; H, 5.16; N, 3.26. 150 3-chloro --S-- 4-methyl mp
222-224.degree. C., Mass: m/z 368.1 phenyl (M.sup.+), Anal. Calcd
for C.sub.24H.sub.24ClNO.sub.4S: C, 62.94; H, 5.28; N, 3.06. Found:
C, 63.11; H, 5.35; N, 3.11. 151 3-chloro --SO.sub.2-- 4-methyl mp
226-228.degree. C., Mass: m/z 400.1 phenyl (M.sup.+), Anal. Calcd
for C.sub.24H.sub.24ClNO.sub.6S: C, 58.83; H, 4.94; N, 2.86. Found:
C, 58.79; H, 4.94; N, 2.93. 152 3-chloro --NH-- benzyl mp
206-208.degree. C., Mass: m/z 351.5 (M.sup.+), Anal. Calcd for
C.sub.24H.sub.25ClN.sub.2O.sub.4: C, 65.38; H, 5.72; N, 6.35.
Found: C, 65.23; H, 5.86; N, 6.29. 153 3-chloro --NH-- phenyl mp
196-198.degree. C., Mass: m/z 337.2 (M.sup.+), Anal. Calcd for
C.sub.23H.sub.23ClN.sub.2O.sub.4: C, 64.71; H, 5.43; N, 6.56.
Found: C, 56.60; H, 4.90; N, 5.64. 154 3-chloro --CH(OH)-- phenyl
mp 193-195.degree. C., Mass: m/z 352.4 (M.sup.+), Anal. Calcd for
C.sub.24H.sub.24ClN.sub.2O.sub.5: C, 65.23; H, 5.47; N, 3.17.
Found: C, 64.96; H, 5.60; N, 3.32. 155 3-chloro --CH.sub.2-- phenyl
mp 220-222.degree. C., Mass: m/z 336.1 (M.sup.+), Anal. Calcd for
C.sub.24H.sub.24ClNO.sub.4: C, 67.68; H, 5.68; N, 3.29. Found: C,
67.65; H, 5.83; N, 3.42. 156 3-chloro --CH(F)-- phenyl mp
182-184.degree. C., Mass: m/z 354.3 (M.sup.+), Anal. Calcd for
C.sub.24H.sub.23ClFNO.sub.4: C, 64.94; H, 5.22; N, 3.16. Found: C,
65.21; H, 5.26; N, 3.09. 157 3-chloro --O-- 4-fluoro mp
218-220.degree. C., Mass: m/z 356.2 phenyl (M.sup.+), Anal. Calcd
for C.sub.23H.sub.21ClFNO.sub.5: C, 61.96; H, 4.75; N, 3.14. Found:
C, 60.56; H, 4.67; N, 3.17. 158 3-trifluroro --O-- 4-fluoro mp
221-223.degree. C., Mass: m/z 390.2 methyl phenyl (M.sup.+), Anal.
Calcd for C.sub.24H.sub.21F.sub.4NO.sub.5: C, 60.13; H, 4.42; N,
2.92. Found: C, 59.18; H, 4.30; N, 2.91. 159 3-chloro --O--
2-fluoro mp 214-216.degree. C., Mass: m/z 356.2 phenyl (M.sup.+),
Anal. Calcd for C.sub.23H.sub.21ClFNO.sub.5: C, 61.96; H, 4.75; N,
3.14. Found: C, 61.42; H, 4.68; N, 3.21. 160 3-trifluroro --O--
2-fluoro mp 218-220.degree. C., Mass: m/z 390.2 methyl phenyl
(M.sup.+), Anal. Calcd for C.sub.24H.sub.21F.sub.4NO.sub.5: C,
60.13; H, 4.42; N, 2.92. Found: C, 59.83; H, 4.34; N, 2.96. 161
3-chloro --O-- 3-fluoro mp 219-221.degree. C., Mass: m/z 356.2
phenyl (M.sup.+), Anal. Calcd for C.sub.23H.sub.21ClFNO.sub.5: C,
61.96; H, 4.75; N, 3.14. Found: C, 61.26; H, 4.74; N, 3.11. 162
3-trifluroro --O-- 3-fluoro mp 221-223.degree. C., Mass: m/z 390.2
methyl phenyl (M.sup.+), Anal. Calcd for
C.sub.24H.sub.21F.sub.4NO.sub.5: C, 60.13; H, 4.42; N, 2.92. Found:
C, 58.79; H, 4.28; N, 2.88. 163 3-chloro --O-- naphth-2-yl mp
229-231.degree. C., Mass: m/z 388.1 (M.sup.+), Anal. Calcd for
C.sub.27H.sub.24ClNO.sub.5: C, 67.85; H, 5.06; N, 2.93. Found: C,
67.71; H, 5.02; N, 3.03. 164 3-trifluroro --O-- naphth-2-yl mp
225-227.degree. C., Mass: m/z 422.0 methyl (M.sup.+), Anal. Calcd
for C.sub.28H.sub.24F.sub.3NO.sub.5: C, 65.75; H, 4.73; N, 2.74.
Found: C, 65.72; H, 4.84; N, 2.88. 165 3-chloro --O-- naphth-1-yl
mp 208-210.degree. C., Mass: m/z 388.1 (M.sup.+), Anal. Calcd for
C.sub.27H.sub.24ClNO.sub.5: C, 67.85; H, 5.06; N, 2.93. Found: C,
66.71; H, 5.11; N, 3.26. 166 3-trifluroro --O-- naphth-1-yl mp
211-213.degree. C., Mass: m/z 422.0 methyl (M.sup.+), Anal. Calcd
for C.sub.28H.sub.24F.sub.3NO.sub.5: C, 65.75; H, 4.73; N, 2.74.
Found: C, 64.30; H, 4.76; N, 2.90. 167 3-chloro --O-- H mp
96-98.degree. C., Mass: m/z 262.0 (M.sup.+), Anal. Calcd for
C.sub.15H.sub.15ClNO: C, 68.83; H, 6.16; N, 5.35. Found: C, 68.59;
H, 5.99; N, 5.37. (isolated as the base) 168 3-trifluroro --O-- H
mp 101-103.degree. C., Mass: m/z 296.3 methyl (M.sup.+), Anal.
Calcd for C.sub.16H.sub.16F.sub.3NO: C, 65.07; H, 5.46; N, 4.74.
Found: C, 65.06; H, 5.42; N, 4.80. (isolated as the base) 169
3-trifluroro --O-- benzyl mp 223-225.degree. C., Mass: m/z 386.1
methyl (M.sup.+), Anal. Calcd for C.sub.25H.sub.24F.sub.3NO.sub.5:
C, 63.15; H, 5.08; N, 2.94. Found: C, 63.22; H, 4.97; N, 3.02. 170
3-chloro --O-- 2,4-difluoro mp 201-203.degree. C., Mass: m/z 438.0
phenylsulfonyl (M.sup.+), Anal. Calcd for
C.sub.23H.sub.20ClF.sub.2NO.sub.7S: C, 52.32; H, 3.81; N, 2.65.
Found: C, 52.26; H, 3.80; N, 2.71. 171 3-trifluroro --O--
2,4-difluoro mp 202-204.degree. C., Mass: m/z 472.2 methyl
phenylsulfon- (M.sup.+), Anal. Calcd for yl
C.sub.24H.sub.20F.sub.5NO.sub.7S: C, 51.34; H, 3.59; N, 2.49.
Found: C, 51.61; H, 3.65; N, 2.54. 172 3-chloro --O-- thiazol-2-yl
mp 216-218.degree. C., Mass: m/z 345.0 (M.sup.+), Anal. Calcd for
C.sub.20H.sub.19ClN.sub.2O.sub.5S: C, 55.23; H, 4.40; N, 6.44.
Found: C, 55.15; H, 4.16; N, 6.43. 173 3-trifluroro --O--
thiazol-2-yl mp 222-224.degree. C., Mass: m/z 379.4 methyl
(M.sup.+), Anal. Calcd for C.sub.21H.sub.19F.sub.3N.sub.2O.sub.5S:
C, 53.84; H, 4.08; N, 5.98. Found: C, 53.71; H, 3.95; N, 5.96. 174
3-chloro --O-- pyrid-3-yl mp 213-215.degree. C., Mass: m/z 339.1
(M.sup.+), Anal. Calcd for C.sub.22H.sub.21ClN.sub.2O.sub.5: C,
61.61; H, 4.93; N, 6.53. Found: C, 60.40; H, 4.89; N, 6.74. 175
3-trifluroro --O-- pyrid-3-yl mp 221-223.degree. C., Mass: m/z
373.1 methyl (M.sup.+), Anal. Calcd for
C.sub.23H.sub.21F.sub.3N.sub.2O.sub.5: C, 59.74; H, 4.57; N, 6.05.
Found: C, 59.17; H, 4.47; N, 6.93. 176 3-methoxy --O-- pyrid-3-yl
mp 101-103.degree. C., Mass: m/z 335.2 (M.sup.+), Anal. Calcd for
C.sub.21H.sub.24Cl.sub.2N.sub.2O.sub.2: C, 61.92; H, 5.93; N, 6.87.
Found: C, 61.43; H, 6.07; N, 6.25. (isolated as the hydrochloride)
177 3-chloro --O-- pyrid-4-yl mp 154-156.degree. C., Mass: m/z
339.1 (M.sup.+), Anal. Calcd for C.sub.20H.sub.21Cl.sub.3N.sub.2O:
C, 58.34; H, 5.14; N, 6.80. Found: C, 58.35; H, 5.18; N, 6.69.
(isolated as the hydrochloride) 178 3-trifluoro --O-- pyrid-4-yl mp
208-210.degree. C., Mass: m/z 373.1 methyl (M.sup.+), Anal. Calcd
for C.sub.21H.sub.21Cl.sub.2F.sub.3N.sub.2O: C, 56.64; H, 4.75; N,
6.29. Found: C, 56.57; H, 4.68; N, 6.20. (isolated as the
hydrochloride) 179 3-chloro --O-- pyrimid-5-yl mp 205-207.degree.
C., Mass: m/z 340.1 (M.sup.+), Anal. Calcd for
C.sub.21H.sub.20ClN.sub.3O.sub.5: C, 58.67; H, 4.68; N, 9.77.
Found: C, 57.66; H, 4.70; N, 8.17. 180 3-trifluoro --O--
pyrimid-5-yl mp 218-220.degree. C., Mass: m/z 374.1 methyl
(M.sup.+), Anal. Calcd for C.sub.22H.sub.20F.sub.3N.sub.3O.sub.5:
C, 57.02; H, 4.35; N, 9.06. Found: C, 56.55; H, 4.44; N, 8.89. 181
3-chloro --O-- pyrid-2-yl mp 93-95.degree. C., Mass: m/z 339.1
(M.sup.+), Anal. Calcd for C.sub.20H.sub.21Cl.sub.3N.sub.2O: C,
58.34; H, 5.14; N, 6.80. Found: C, 62.31; H, 5.30; N, 7.36.
(isolated as the hydrochloride)
182 3-trifluoro --O-- pyrid-2-yl mp 86-88.degree. C., Mass: m/z
373.1 (M.sup.+), methyl Anal. Calcd for
C.sub.21H.sub.21Cl.sub.2F.sub.3N.sub.2O: C, 56.64; H, 4.75; N,
6.29. Found: C, 60.00; H, 4.92; N, 6.76. (isolated as the
hydrochloride) 183 3-chloro --NH-- pyrid-3-yl mp 158-160.degree.
C., Mass: m/z 338.3 (M.sup.+), Anal. Calcd for
C.sub.22H.sub.22ClN.sub.3O.sub.4: C, 61.75; H, 5.18; N, 9.82.
Found: C, 58.90; H, 4.64; N, 8.87. 184 3-trifluroro --NH--
pyrid-3-yl mp 182-184.degree. C., Mass: m/z 372.3 methyl (M.sup.+),
Anal. Calcd for C.sub.23H.sub.22F.sub.3N.sub.3O.sub.4: C, 59.86; H,
4.80; N, 9.10. Found: C, 58.33; H, 4.44; N, 8.60. 185 3-chloro
--NH-- pyrid-4-yl mp 156-158.degree. C., Mass: m/z 338.3 (M.sup.+),
Anal. Calcd for C.sub.20H.sub.22Cl.sub.3N.sub.3: C, 58.48; H, 5.39;
N, 10.22. Found: C, 57.13; H, 5.49; N, 9.80. (isolated as the
hydrochloride) 186 3-trifluroro --NH-- pyrid-4-yl mp
142-144.degree. C., Mass: m/z 372.3 methyl (M.sup.+), Anal. Calcd
for C.sub.21H.sub.22Cl.sub.2F.sub.3N.sub.3: C, 56.76; H, 4.99; N,
9.45. Found: C, 55.05; H, 4.88; N, 9.33. (isolated as the
hydrochloride) 187 3-chloro --NH-- pyrid-2-yl mp 142-144.degree.
C., Mass: m/z 338.0 (M.sup.+), Anal. Calcd for
C.sub.20H.sub.22Cl.sub.3N.sub.3: C, 58.48; H, 5.39; N, 10.22.
Found: C, 58.12; H, 5.39; N, 10.08. (isolated as the hydrochloride)
188 3-trifluroro --NH-- pyrid-2-yl mp 144-146.degree. C., Mass: m/z
372.1 methyl (M.sup.+), Anal. Calcd for
C.sub.21H.sub.22Cl.sub.2F.sub.3N.sub.3: C, 56.76; H, 4.99; N, 9.45.
Found: C, 56.60; H, 5.04; N, 9.32. (isolated as the hydrochloride)
189 3-chloro --O-- benzyl MS m/e 351.9 (m + 1) 190 3-trifluroro
--NH-- phenyl mp = 205-207.degree. C.; ms: m + 1 = 371.1 methyl
[0399] By the method of Example 67 the following compounds were
prepared, isolated as late except where noted: TABLE-US-00003
##STR24## No. R.sub.1 Data 191 pyrid-4-yl mp 176-178.degree. C.,
Mass: m/z 305.2 (M.sup.+), Anal. Calcd for
C.sub.22H.sub.22N.sub.2O.sub.5: C, 66.99; H, 5.62; N, 7.10. Found:
C, 67.55; H, 5.70; N, 7.24. 192 pyrid-3-yl mp 198-200.degree. C.,
Mass: m/z 305.2 (M.sup.+), Anal. Calcd for
C.sub.22H.sub.22N.sub.2O.sub.5: C, 66.99; H, 5.62; N, 7.10. Found:
C, 64.98; H, 5.43; N, 6.86. 193 thien-2-yl mp 234-236.degree. C.,
Mass: m/z 310.2 (M.sup.+), Anal. Calcd for
C.sub.21H.sub.21NO.sub.5S: C, 63.14; H, 5.29; N, 3.50. Found: C,
62.25; H, 5.18; N, 3.53. 194 imidazol-4-yl mp 194-196.degree. C.,
Mass: m/z 294.2 (M.sup.+), Anal. Calcd for
C.sub.20H.sub.20N.sub.3O.sub.5: C, 62.65; H, 5.52; N, 10.95. Found:
C, 59.94; H, 5.30; N, 10.12. 195 naphth-2-yl mp 223-225.degree. C.,
Mass: m/z 354.4 (M.sup.+), Anal. Calcd for
C.sub.27H.sub.25NO.sub.5: C, 73.12; H, 5.68; N, 3.16. Found: C,
73.38; H, 5.94; N, 3.40. 196 naphth-1-yl mp 223-225.degree. C.,
Mass: m/z 354.4 (M.sup.+), Anal. Calcd for
C.sub.27H.sub.25NO.sub.5: C, 73.12; H, 5.68; N, 3.16. Found: C,
73.18; H, 5.52; N, 3.23.
[0400] By the method of Example 67 the following compounds were
prepared, isolated as late except where noted: TABLE-US-00004
##STR25## No. R.sub.1 Data 197 3-chlorophenyl mp 240-242.degree.
C., Mass: m/z 336.0 (M.sup.+), Anal. Calcd for
C.sub.23H.sub.20ClNO.sub.5: C, 55.23; H, 4.40; N, 6.44. Found: C,
55.15; H, 4.16; N, 6.43. 198 3-trifluoromethyl mp 255-257.degree.
C., Mass: m/z 370.0 (M.sup.+), Anal. Calcd for phenyl
C.sub.24H.sub.20F.sub.3NO.sub.5: C, 62.74; H, 4.38; N, 3.04. Found:
C, 62.95; H, 4.27; N, 3.08. 199 5-methoxy-1H- mp 232-234.degree.
C., Mass: m/z 371.1 (M.sup.+), Anal. Calcd for indol-3-yl
C.sub.26H.sub.24N.sub.2O.sub.6: C, 67.81; H, 5.25; N, 6.08. Found:
C, 67.46; H, 4.44; N, 5.44. 200 1H-indol-3-yl mp 221-223.degree.
C., Mass: m/z 341.1 (M.sup.+), Anal. Calcd for
C.sub.25H.sub.22N.sub.2O.sub.5: C, 69.75; H, 5.15; N, 6.50. Found:
C, 71.99; H, 4.48; N, 6.40.
[0401] By the method of Example 67 the following compounds were
prepared, isolated as late except where noted: TABLE-US-00005
##STR26## No. R.sub.1 R.sub.9 Data 201 3-chlorophenyl phenyl mp
225-227.degree. C., Mass: m/z 361.1 (M+), Anal. Calcd for
C.sub.25H.sub.23ClN.sub.2O.sub.4: C, 66.59; H, 5.14; N, 6.21.
Found: C, 66.21; H, 5.02; N, 6.14. 202 3-trifluoromethyl phenyl mp
216-218.degree. C., Mass: m/z 395.1 (M+), Anal. phenyl Calcd for
C.sub.25H.sub.25F.sub.3N.sub.2O.sub.4: C, 64.45; H, 4.78; N, 5.78.
Found: C, 63.98; H, 4.67; N, 5.76. 203 5-methoxy-1H- phenyl mp
208-210.degree. C., Mass: m/z 394.2 (M+), Anal. indol-3-yl Calcd
for C.sub.28H.sub.27N.sub.3O.sub.5: C, 69.26; H, 5.60; N, 8.62.
Found: C, 67.78; H, 5.29; N, 8.42. 204 1H-indol-3-yl phenyl mp
227-229.degree. C., Mass: m/z 364.3 (M+), Anal. Calcd for
C.sub.27H.sub.25N.sub.3O.sub.4: C, 71.19; H, 5.53; N, 9.22. Found:
C, 70.02; H, 5.33; N, 8.95. 205 5-methoxy-1H- H mp 170-172.degree.
C., Mass: m/z 318.2 (M+), Anal. indol-3-yl Calcd for
C.sub.22H.sub.23N.sub.3O.sub.5: C, 64.53; H, 5.62; N, 10.26. Found:
C, 56.16; H, 4.98; N, 8.75.
[0402] By the method of Example 67 the following compounds were
prepared, isolated as late except where noted: TABLE-US-00006
##STR27## No. R.sub.1 R.sub.9 Data 206 3-chlorophenyl phenyl mp
237-239.degree. C., Mass: m/z 361.1 (M.sup.+), Anal. Calcd for
C.sub.25H.sub.23ClN.sub.2O.sub.4: C, 66.59; H, 5.14; N, 6.21.
Found: C, 66.55; H, 5.16; N, 6.20. 207 3-trifluoromethyl phenyl mp
239-241.degree. C., Mass: m/z 395.1 (M.sup.+), Anal. phenyl Calcd
for C.sub.25H.sub.25F.sub.3N.sub.2O.sub.4: C, 64.45; H, 4.78; N,
5.78. Found: C, 64.59; H, 4.83; N, 5.83. 208 5-methoxy-1H- phenyl
mp 194-196.degree. C., Mass: m/z 396.2 (M.sup.+), Anal indol-3-yl
Calcd for C.sub.28H.sub.27N.sub.3O.sub.5: C, 69.26; H, 5.60; N,
8.62. Found: C, 68.33; H, 5.37; N, 8.52. 209 1H-indol-3-yl phenyl
mp 206-208.degree. C., Mass: m/z 366.2 (M.sup.+), Anal. Calcd for
C.sub.27H.sub.25N.sub.3O.sub.4: C, 71.19; H, 5.53; N, 9.22. Found:
C, 69.23; H, 5.42; N, 8.86. 210 5-methoxy-1H- H mp 186-188.degree.
C., Mass: m/z 318.2 (M.sup.+), Anal. indol-3-yl Calcd for
C.sub.22H.sub.23N.sub.3O.sub.5: C, 64.53; H, 5.66; N, 10.26. Found:
C, 62.88; H, 4.61; N, 9.27.
EXAMPLE 220
N-(2-(3-Chlorophenyl)ethyl)-3-benzoylbenzylamine
[0403] ##STR28##
[0404] Combine 3-benzoylbenzaldehyde (0.45 g, 2.1 mmol), and
(3-chlorophenyl)ethylamine (0.3 ml, 2.1 mmol) and 3 .ANG. molecular
sieves (1.0 g) in MeOH (30 ml). Heat to reflux. After 3 hours,
cool, filter, and concentrate to give a residue. Dissolve the
residue in dichloroethane (20 ml), add acetic acid (0.12 ml, 2.1
mmol) and sodium triacetoxyborohydride (0.6 g, 2.94 mmol) and stir
at ambient temperature. After 2 hours, concentrate the reaction
mixture and add dichloromethane (90 ml) and extract sequentially
with distilled water (50 ml) and then brine (50 ml). Dry the
organic layer over Na.sub.2SO.sub.4 and give a residue.
Chromatograph the residue on silica gel eluting with EtOAc to give
the title compound as the base.
[0405] The oxalate using the method of Example 67 to give the title
compound: mp 196-198.degree. C., Mass: m/z 350.4 (M+), Anal. Calcd
for C.sub.24H.sub.22ClNO.sub.5: C, 65.53; H, 5.04; N, 3.18. Found:
C, 65.27; H, 5.20; N, 3.13.
EXAMPLE 221
N-(2-(3-Chlorophenyl)ethyl)-3-ethoxybenzylamine
[0406] ##STR29##
[0407] Combine 3-ethoxybenzaldehyde (3.38 g, 22.5 mmol),
2-(3-chlorophenyl)ethylamine (2.33 g, 15.0 mol), and 3 .ANG.
molecular sieves (2.88 g) in ethanol (230 ml). Stir the reaction
mixture at reflux for 4 hours. Filter to remove the molecular
sieves and then slowly add sodium borohydride (1.70 g, 45.0 mmol)
to the filtrate and stir at ambient temperature. After 15 hours,
concentrate the reaction mixture to a residue, dissolve the residue
in 1 N NaOH, and extract with dichloromethane. Combine organic
extracts, wash with brine, dry over Na.sub.2SO.sub.4, and
concentrate to a residue. Chromatograph the residue on silica gel
eluting with ethyl acetate to give the title compound. The HCl salt
was prepared in ethyl acetate to give the title compound: mp
178-180.degree. C.; MS (ACPI): m/e 290.1 (M+1); Analysis for
C.sub.17H.sub.21Cl.sub.2NO: Calcd: C, 62.58; H, 6.49; N, 4.29;
Found: C, 62.65; H, 6.53; N, 4.32.
[0408] By the method of Example 221 the following compounds were
prepared, isolated as the maleate except where noted:
TABLE-US-00007 ##STR30## No. Z'' R.sub.4 Data 222 3-chloro propyl
mp 138-140.degree. C. MS (ACPI): m/e 304.1 (M + 1). Analysis for
C.sub.18H.sub.23Cl.sub.2NO: Calcd: C, 63.53; H, 6.81; N, 4.12;
found: C, 63.74; H, 6.81; N, 4.22. (isolated as the hydrochloride)
223 3- propyl mp 145-147.degree. C. MS (ACPI): m/e 338.1 (M + 1).
trifluoro Analysis for C.sub.23H.sub.26F.sub.3NO.sub.5: Calcd: C,
60.92; H, methyl 5.78; N, 3.09; found: C, 60.77; H, 5.60; N, 3.12.
224 3- ethyl mp 164-166.degree. C. MS (ACPI): m/e 324.2 (M + 1).
trifluoro Analysis for C.sub.18H.sub.21ClF.sub.3NO: Calcd: C,
60.09; H, methyl 5.88; N, 3.89; found: C, 60.42; H, 5.80; N, 3.93.
(isolated as the hydrochloride) 225 2-phenyl 2,2,2-trifluoro mp
181-183.degree. C. MS (ACPI): m/e 386.2 (M + 1). ethyl Analysis for
C.sub.27H.sub.26F.sub.3NO.sub.5: Calcd: C, 64.67; H, 5.23; N, 2.79;
found: C, 64.52; H, 5.01; N, 2.85. 226 4-phenyl 2,2,2-trifluoro mp
39.degree. C. MS (ACPI): m/e 386.2 (M + 1). ethyl (Exception- one
equivalent of triethylamine in the reaction) (isolated as the free
base)
[0409] By the method of Example 221 the following compounds were
prepared, isolated as the maleate except where noted:
TABLE-US-00008 ##STR31## No. Z' R.sub.4 Data 227 5-chloro ethyl mp
153-156.degree. C., MS (ACPI): m/e 329.1 (M + 1). Analysis for
C.sub.23H.sub.25ClN.sub.2O.sub.5: Calcd: C, 62.09; H, 5.66; N,
6.30; found: C, 62.27; H, 5.38; N, 6.19 228 5-chloro propyl mp
163-166.degree. C. MS (ACPI): m/e 343.1 (M + 1). Analysis for
C.sub.24H.sub.27ClN.sub.2O.sub.5: Calcd: C, 62.81; H, 5.93; N,
6.10; found: C, 63.07; H, 5.80; N, 6.07. 229 5-chloro 2,2,2- mp
178-181.degree. C., MS (ACPI): m/e 383.1 (M + 1). trifluoroethyl
Analysis for C.sub.23H.sub.22ClF.sub.3N.sub.2O.sub.5: Calcd: C,
55.37; H, 4.44; N, 5.62; found: C, 55.71; H, 4.39; N, 5.66. 230
5-chloro 3-fluoropropyl mp 167-170.degree. C., MS (ACPI) m/e 361.1
(M + 1). Analysis for C.sub.24H.sub.26ClFN.sub.2O.sub.5: Calcd: C,
60.44; H, 5.49; N, 5.87; found: C, 60.30; H, 5.25; N, 5.78. 231
5-chloro 2,2,3,3,3- mp 170-173.degree. C. MS (ACPI) m/e 433.1 (M +
1). pentafluoro Analysis for
C.sub.24H.sub.22ClF.sub.5N.sub.2O.sub.5: Calcd: C, 52.52; H, propyl
4.04; N, 5.10; found: C, 52.49; H, 4.06; N, 5.16. 232 5-chloro
2,2,3,3- mp 163-167.degree. C., MS (ACPI) m/e 415.1 (M + 1).
tetrafluoro Analysis for C.sub.24H.sub.23ClF.sub.4N.sub.2O.sub.5:
Calcd: C, 54.30; H, propyl 4.37; N, 5.28; found: C, 54.47; H, 4.36;
N, 5.33. 233 5- 2,2,2- mp 179-182.degree. C., MS (ACPI): m/e 379.1
(M + 1). methoxy trifluoroethyl Analysis for
C.sub.24H.sub.25F.sub.3N.sub.2O.sub.6: Calcd: C, 58.30; H, 5.10; N,
5.67; found: C, 58.26; H, 5.09; N, 5.69. 234 6-chloro 2,2,3,3- mp
156-160.degree. C., MS (ACPI): m/e 415.1 (M + 1). tetrafluoro
Analysis for C.sub.24H.sub.23ClF.sub.4N.sub.2O.sub.5: Calcd: C,
54.30; H, propyl 4.37; N, 5.28; found: C, 54.31; H, 4.34; N, 5.31.
235 5-cyano 2,2,2- mp 176-178.degree. C. MS (ACPI) m/e 374.0 (M +
1). trifluoroethyl Analysis for C.sub.20H.sub.19ClF.sub.3N.sub.30:
Calcd: C, 58.61; H, 4.67; N, 10.25; found: C, 58.52; H, 4.61; N,
10.17. (isolated as the hydrochloride) 236 5-methyl 2,2,2-trifluoro
mp 193-195.degree. C. MS (ACPI) m/e 429.9 (M + 1). sulfonyl ethyl
Analysis for C.sub.24H.sub.25F.sub.3N.sub.2O.sub.7S: Calcd: C,
53.13; H, 4.64; N, 5.16; found: C, 53.12; H, 4.58; N, 5.20. 237
5-cyano 3,3,3-trifluoro mp 150-154.degree. C. MS (ACPI): m/e 387.9
(M + 1). propyl Analysis for C.sub.25H.sub.24F.sub.3N.sub.3O.sub.5:
Calcd: C, 59.64; H, 4.80; N, 8.35; found: C, 59.55; H, 4.77; N,
8.38. 238 5-methyl 3,3,3-trifluoro mp 178-181.degree. C. MS (ACPI):
m/e 440.9 (M + 1). sulfonyl propyl Analysis for
C.sub.25H.sub.27F.sub.3N.sub.2O.sub.7S: Calcd: C, 53.95; H, 4.89;
N, 5.03; found: C, 53.87; H, 4.86; N, 5.04. 239 4-fluoro
2,2,2-trifluoro mp 199-202.degree. C. MS (ACPI) m/e 367.2 (M + 1).
ethyl Analysis for C.sub.19H.sub.19ClF.sub.4N.sub.2O: calcd: C,
56.65; H, 4.75; N, 6.95; found: C, 56.82; H, 4.65; N, 6.84.
(isolated as the hydrochloride) 240 4-fluoro 2,2,3,3,3- mp
118-121.degree. C. MS (ACPI): m/e 417.2 (M + 1). pentafluoro
Analysis for C.sub.24H.sub.22F.sub.6N.sub.2O.sub.5: Calcd: C,
54.14; H, propyl 4.16; N, 5.26; found: C, 54.39; H, 4.25; N, 5.30.
241 4-fluoro 2,2,3,3- mp 188-191.degree. C. MS (ACPI) m/e 399.0 (M
+ 1). tetrafluoro Analysis for C.sub.20H.sub.20ClF.sub.5N.sub.2O:
Calcd: C, 55.24; H, propyl 4.64; N, 6.44; found: C, 55.03; H, 4.53;
N, 6.34. (isolated as the hydrochloride) 242 7-fluoro
2,2,2-trifluoro mp 157-160.degree. C. MS (ACPI) m/e 367.2 (M + 1).
ethyl Analysis for C.sub.23H.sub.22F.sub.4N.sub.2O.sub.5: Calcd: C,
57.26; H, 4.60; N; 5.81; found: C, 57.34; H, 4.39; N, 6.11. 243
7-fluoro 2,2,3,3,3- mp 166-168.degree. C. MS (ACPI): m/e 417.2 (M +
1). pentafluoro Analysis for C.sub.24H.sub.22F.sub.6N.sub.2O.sub.5:
Calcd: C, 54.14; H, propyl 4.16; N, 5.26; found: C, 53.99; H, 3.98;
N, 5.61. 244 7-fluoro 2,2,3,3- mp 170-173.degree. C. MS (ACPI): m/e
399.2 (M + 1). tetrafluoro Analysis for
C.sub.24H.sub.24F.sub.5N.sub.2O.sub.5: Calcd: C, 56.03; H, propyl
4.51; N, 5.45; found: C, 55.73; H, 4.30; N, 5.66. 245 5-amido
3,3,3-trifluoro mp 143-147.degree. C. MS (ACPI): m/e 406.1 (M + 1).
propyl Analysis for C.sub.21H.sub.22F.sub.3N.sub.3O.sub.2: Calcd:
C, 62.22; H, 5.47; N, 10.36; found: C, 61.96; H, 5.42; N, 10.13.
(isolated as the base) 246 5-amido 2,2,2-trifluoro mp
125-130.degree. C. MS (ACPI) m/e 392.1 (M + 1). ethyl Analysis for
C.sub.20H.sub.21ClF.sub.3N.sub.3O.sub.2: Calcd: C, 56.15; H, 4.95;
N, 9.82; found: C, 55.80; H, 4.93; N, 9.71. (isolated as the
hydrochloride) 247 6-phenyl 2,2,2-trifluoro mp 117-120.degree. C.
MS (ACPI): m/e 425.1 (M + 1). ethyl Analysis for
C.sub.24H.sub.23F.sub.3N.sub.2O: Calcd: C, 70.74; H, 5.46; N, 6.60;
found: C, 70.75; H, 5.42; N, 6.66. (isolated as the base) 248
6-methyl 2,2,3,3,3- m.p. 168-170.degree. C. MS (ACPI): m/e 413.2 (M
+ 1). pentafluoro Analysis for C.sub.21H.sub.22F.sub.5N.sub.2O:
Calcd: C, 56.82; H, propyl 4.77; N, 5.30; found: C, 57.21; H, 4.46;
N, 5.33 249 6-phenyl 2,2,3,3,3- mp 110.5-113.5.degree. C. MS
(ACPI): m/e 475.1 pentafluoro (M + 1). Analysis for
C.sub.26H.sub.23F.sub.5N.sub.2O: Calcd: C, propyl 65.82; H, 4.89;
N, 5.90; found: C, 65.70; H, 4.84; N, 5.93. (isolated as the base)
250 6-phenyl 2,2,3,3- mp 94-98.degree. C. MS (ACPI): m/e 457.1 (M +
1). tetrafluoro Analysis for C.sub.26H.sub.24F.sub.4N.sub.2O:
calcd: C, 68.41; H, propyl 5.30; N, 6.14; found: C, 68.18; H, 5.28;
N, 6.06 (isolated as the base) 251 6-methyl 2,2,2-trifluoro mp
176-178.degree. C. MS (ACPI): m/e 363.1 (M + 1). ethyl Analysis for
C.sub.20H.sub.22ClF.sub.3N.sub.2O: Calcd: C, 60.23; H, 5.56; N,
7.02; found: C, 60.16; H, 5.43; N, 6.98. (isolated as the
hydrochloride) 252 6-methyl 2,2,3,3- mp 156-158.degree. C. MS
(ACPI): m/e 395.1 (M + 1). tetrafluoro Analysis for
C.sub.21H.sub.23ClF.sub.4N.sub.2O: Calcd: C, 58.54; H, propyl 5.38;
N, 6.50; found: C, 58.60; H, 5.32; N, 6.55. (isolated as the
hydrochloride). 253 6-ethoxy 2,2,3,3- mp 166-168.degree. C. MS
(ACPI): m/e 453.1 (M + 1). carbonyl tetrafluoro Analysis for
C.sub.23H.sub.25ClF.sub.4N.sub.2O.sub.3: Calcd: C, 56.50; H, propyl
5.15; N, 5.73; found: C, 56.18; H, 5.00; N, 5.66. (isolated as the
hydrochloride) 254 6-ethoxy 2,2,2-trifluoro mp 169.5-171.5.degree.
C. MS (ACPI): m/e 421.2 (M + 1). carbonyl ethyl Analysis for
C.sub.26H.sub.27F.sub.3N.sub.2O.sub.7: Calcd: C, 58.21; H, 5.07; N,
5.22; found: C, 58.43; H, 4.85; N, 5.27. 255 6-cyano
2,2,2-trifluoro mp 175-177.degree. C. MS (ACPI) m/e 374.1 (M + 1).
ethyl Analysis for C.sub.24H.sub.22F.sub.3N.sub.3O.sub.5: Calcd: C,
58.90; H, 4.53; N, 8.59; found: C, 58.62; H, 4.48; N, 8.50. 256
6-cyano 2,2,3,3- mp 167-169.degree. C. MS (ACPI) m/e 406.1 (M + 1).
tetrafluoro Analysis for C.sub.25H.sub.23F.sub.4N.sub.3O.sub.5:
Calcd: C, 57.58; H, propyl 4.45; N, 8.06; found: C, 57.31; H, 4.35;
N, 8.08. 257 6-amido 2,2,2- mp 102.degree. C. MS (ACPI) m/e 392.2
(M + 1). tetrafluoro Analysis for
C.sub.20H.sub.20F.sub.3N.sub.3O.sub.2: Calcd: C, 61.38; H, ethyl
5.15; N, 10.74; found: C, 61.68; H, 5.11; N, 10.65. (isolated as
the base) 258 6-amido 2,2,3,3- mp 120.degree. C. MS (ACPI): m/e
424.3 (M + 1). tetrafluoro Analysis for
C.sub.21H.sub.21F.sub.4N.sub.3O.sub.2: Calcd: C, 59.57; H, propyl
5.00; N, 9.92; found: C, 59.33; H, 4.82; N, 9.79. (isolated as the
base) 259 6- 2,2,3,3- mp 132-134.degree. C. MS (ACPI): m/e 465.1 (M
+ 1). trifluoro tetrafluoro Analysis for
C.sub.21H.sub.20ClF.sub.7N.sub.2O.sub.2: Calcd: C, 50.36; H,
methoxy propyl 4.03; N, 5.59; found: C, 50.25; H, 3.96; N, 5.58.
(isolated as the hydrochloride) 260 6- 2,2,2-trifluoro mp
160-164.degree. C. MS (ACPI): m/e 433.1 (M + 1). trifluoro ethyl
Analysis for C.sub.20H.sub.19ClF.sub.6N.sub.2O.sub.2: Calcd: C,
51.24; H, methoxy 4.08; N, 5.98; found: C, 51.26; H, 3.99; N, 5.96.
(isolated as the hydrochloride) 260A 7-chloro 2,2,3,3- mp
153.6-154.4.degree. C. MS (APCI): m/e 415.1 tetrafluoro (M + 1).
Anal. Calcd. for C.sub.20H.sub.19ClF.sub.4N.sub.2O.1.0HCl: propyl
C, 53.23; H, 4.47; N, 6.21. Found: C, 52.89; H, 4.40; N, 6.18.
(isolated as the hydrochloride) 260B 7-chloro 2,2,2- mp
193.4-194.9.degree. C. Mass (ES+): m/z 383.17 trifluoroethyl (M +
1). Anal. Calcd. for C.sub.19H.sub.18ClF.sub.3N.sub.2O.1.0HCl: C,
54.43; H, 4.57; N, 6.68. Found: C, 54.66; H, 4.39; N, 6.66.
(isolated as the hydrochloride)
EXAMPLE 261
N-(2-(7-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylam-
ine hydrochloride
[0410] Add acetyl chloride (2.4 mL, 33.8 mmol) dropwise to
anhydrous ethanol (50 mL) and stir the solution for 10 min at
ambient temperature and add to a solution of
N-(2-(7-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzyla-
mine (12.0 g, 30.1 mmol) in ethyl acetate. Concentrate the
resulting solution under reduced pressure to give a yellow solid.
Recrystallize the yellow solid from ethyl acetate/ethanol/diethyl
ether to give the title compound: nip 142-143.degree. C. MS(m/e):
399 (M+1), 397 (M-1). Calculated for
C.sub.20H.sub.19F.sub.5N.sub.2O.HCl: Calcd: C, 55.24; H, 4.64; N,
6.44. Found: C, 55.44; H, 4.66; N, 6.46.
EXAMPLE 262
(N-(2-(7-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzyla-
mine hydrochloride L(+)tartrate
[0411] Add L-(+)-tartaric acid (49 mg, 0.33 mmol) and methanol to a
solution of
(N-(2-(7-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzyl-
amine (130 mg, 0.33 mmol) in ethyl acetate. Evaporate the solvent
to give a gum. Crystallize the gum from diethyl ether/ethyl acetate
to give the title compound: mp 192-194.degree. C.
EXAMPLE 263
N-(2-(7-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine
hydrochloride
[0412] Add dropwise acetyl chloride (2.3 mL, 32.4 mmol) to
anhydrous ethanol (50 mL) and stir the solution for 10 min at
ambient temperature and add to a solution
N-(2-(7-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine
(10.7 g, 29.2 mmol) in diethyl ether. Concentrate the resulting
solution under reduced pressure to give a yellow solid.
Recrystallize the yellow solid from ethyl acetate/methanol to give
the title compound: mp 163-164.degree. C.; MS(m/e): 367 (M+1), 365
(M-1); Calculated for C.sub.19H.sub.18F.sub.4N.sub.2O HCl: Calcd:
C, 56.65; H, 4.75; N, 6.95. Found: C, 56.45; H, 4.54; N, 6.90.
EXAMPLE 264
N-(2-(7-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine
L(+)tartrate
[0413] Add L-(+)-tartaric acid (295 mg, 1.96 mmol) in methanol to a
solution of
N-(2-(7-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine
(720 mg, 1.96 mmol) in ethyl acetate. Concentrate under reduced
pressure the resulting solution to give a clear colorless oil.
Crystallize the oil from diethyl ether to give the title compound:
mp 118-119.degree. C. MS(m/e): 367 (M+1), 365 (M-1). Calculated for
C.sub.19H.sub.18F.sub.4N.sub.2O.C.sub.4H.sub.6O.sub.6: Calcd: C,
53.49; H, 4.68; N, 5.42. Found: C, 53.21; H, 4.55; N, 5.41.
EXAMPLE 270
N-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-3-propoxybenzylamine
hydrochloride
[0414] ##STR32##
[0415] Combine 3-propoxybenzaldehyde (2.96 g, 18.0 mmol),
5-fluorotryptamine hydrochloride (2.58 g, 12.0 mol), triethylamine
(1.15 g), and 3 .ANG. molecular sieves (2.27 g) in ethanol (200
ml). Stir the reaction mixture at reflux for 4 hours. Filter to
remove the molecular sieves and then slowly add sodium borohydride
(1.36 g, 36.0 mmol) to the filtrate and stir at ambient
temperature. After 15 hours, concentrate the reaction mixture to a
residue, dissolve the residue in 1 N NaOH, and extract with
dichloromethane. Combine organic extracts, wash with brine, dry
over Na.sub.2SO.sub.4, and concentrate to a residue. Chromatograph
the residue on silica gel eluting with ethyl acetate yielded 3.31 g
of an oil. The HCl salt was prepared in diethyl ether: mp
197-199.degree. C.; MS (ACPI): m/e 327.2 (M+1); Analysis for
C.sub.20H.sub.24ClFN.sub.2O: Calcd: C, 66.20; H, 6.67; N, 7.72;
found: C, 66.06; H, 6.63; N, 7.76.
[0416] By the method of Example 270 the following compounds were
prepared, isolated as the maleate except where noted:
TABLE-US-00009 ##STR33## No. Z' R.sub.4 Data 271 5-fluoro ethyl mp
196-198.degree. C., MS (ACPI): m/e 313.1 (M + 1). Analysis for
C.sub.19H.sub.22ClFN.sub.2O: Calcd: C, 65.42; H, 6.36; N, 8.03;
found: C, 65.48; H, 6.30; N, 8.04. (isolated as the hydrochloride)
272 5-trifluoro ethyl mp 156-160.degree. C., MS (ACPI): m/e 363.1
(M + 1). methyl Analysis for C.sub.24H.sub.25F.sub.3N.sub.2O.sub.5:
Calcd: C, 60.25; H, 5.27; N, 5.85; found: C, 60.47; H, 5.26; N,
5.79. 273 5-trifluoro propyl mp 169-172.degree. C., MS (ACPI): m/e
377.1 (M + 1). methyl Analysis for
C.sub.25H.sub.27F.sub.3N.sub.2O.sub.5: Calcd: C, 60.97; H, 5.53; N,
5.69; found: C, 60.95; H, 5.54; N, 5.70 274 5-trifluoro 2,2,2- mp
180-184.degree. C. MS (ACPI): m/e 417.1 (M + 1). methyl trifluoro
Analysis for C.sub.24H.sub.22F.sub.6N.sub.2O.sub.5: Calcd: C,
54.14; H, ethyl 4.16; N, 5.26; found: C, 53.99; H, 4.07; N, 5.61.
275 5-trifluoro 3,3,3- mp 158-161.degree. C., MS (ACPI): m/e 431.1
(M + 1). methyl trifluoro Analysis for
C.sub.25H.sub.24F.sub.6N.sub.2O.sub.5: Calcd: C, 54.95; H, propyl
4.43; N, 5.13; found: C, 54.84; H, 4.46; N, 5.03. 276 4-methoxy
2,2,3,3- mp 144-147.degree. C. MS (ACPI): m/e 411.1 (M + 1).
tetrafluoro Analysis for C.sub.25H.sub.26F.sub.4N.sub.2O.sub.6:
Calcd: C, 57.03; H, propyl 4.98; N, 5.32; found: C, 56.84; H, 4.94;
N, 5.34. 277 5-cyano 2,2,3,3- mp 172-174.degree. C. MS (ACPI): m/e
406.2 (M + 1). tetrafluoro Analysis for
C.sub.25H.sub.23F.sub.4N.sub.3O.sub.5: Calcd: C, 57.58; H, propyl
4.45; N, 8.06; found: C, 57.91; H, 4.13; N, 8.34. 278 5-cyano
2,2,3,3,3- mp 168-170.degree. C. MS (ACPI): m/e 424.1 (M + 1).
pentafluoro Analysis for C.sub.25H.sub.22F.sub.5N.sub.3O.sub.5:
Calcd: C, 55.66; H, propoxy 4.11; N, 7.79; found: C, 55.54; H,
4.16; N, 7.71. 279 5-(4- 2,2,3,3- p 161-165.degree. C. MS (ACPI):
m/e 475.1 (M + 1). fluorophenyl) tetrafluoro Analysis for
C.sub.26H.sub.24ClF.sub.5N.sub.2O: Calcd: C, 61.12; propyl H, 4.73;
N, 5.48; found: C, 61.18; H, 4.64; N, 5.50. (isolated as the
hydrochloride) 280 5-(4- 2,2,3,3,3- (isolated as the hydrochloride)
mp 168-171.degree. C. fluorophenyl) pentafluoro MS (ACPI): m/e
493.1 (M + 1). Analysis for propoxy
C.sub.26H.sub.23ClF.sub.6N.sub.2O: Calcd: C, 59.04; H, 4.38; N,
5.30; found: C, 59.15; H, 4.28; N, 5.30. (isolated as the
hydrochloride) 281 5-phenyl 2,2,3,3- mp 148-151.degree. C. MS
(ACPI): m/e 457.1 (M + 1). tetrafluoro Analysis for
C.sub.26H.sub.25ClF.sub.4N.sub.2O: Calcd: C, 63.35; propyl H, 5.11;
N, 5.68; found: C, 63.16; H, 4.99; N, 5.67. (isolated as the
hydrochloride) 282 5-phenyl 2,2,3,3,3- mp 65-70.degree. C., dec. MS
(ACPI): m/e 475.1 pentafluoro (M + 1). Analysis for
C.sub.26H.sub.24ClF.sub.5N.sub.2O: Calcd: C, prop 61.12; H, 4.73;
N, 5.48; found: C, 60.98; H, 4.66; N, 5.41. (isolated as the
hydrochloride) 283 5-(4- 2,2,2- mp 214-216.degree. C. MS (ACPI):
m/e 443.1 (M + 1). fluorophenyl) trifluoro Analysis for
C.sub.25H.sub.23ClF.sub.4N.sub.2O: Calcd: C, 62.70; ethyl H, 4.84;
N, 5.85; found: C, 62.47; H, 4.71; N, 5.79. (isolated as the
hydrochloride) 284 5-phenyl 2,2,2- mp 171-174.degree. C., dec. MS
(ACPI): m/e 425.1 trifluoro (M + 1). Analysis for
C.sub.25H.sub.24ClF.sub.3N.sub.2O: Calcd: C, ethyl 65.15; H, 5.25;
N, 6.08; found: C, 65.46; H, 5.17; N, 6.10. (isolated as the
hydrochloride) 285 4-phenyl 2,2,3,3,3- mp 55.degree. C., dec. MS
(ACPI): m/e 475.1 (M + 1). pentafluoro Analysis for
C.sub.26H.sub.24ClF.sub.5N.sub.2O: Calcd: C, 61.12; propyl H, 4.73;
N, 5.48; found: C, 61.11; H, 4.83; N, 5.40. (isolated as the
hydrochloride) 286 4-phenyl 2,2,2- mp 60.degree. C., dec. MS
(ACPI): m/e 425.1 (M + 1). trifluoro Analysis for
C.sub.25H.sub.24ClF.sub.3N.sub.2O: Calcd: C, 65.15; ethyl H, 5.25;
N, 6.08; found: C, 65.08; H, 5.42; N, 5.93. (isolated as the
hydrochloride) 287 4-phenyl 2,2,3,3- mp 56.degree. C., dec. MS
(ACPI): m/e 457.1 (M + 1). tetrafluoro Analysis for
C.sub.26H.sub.25ClF.sub.4N.sub.2O: Calcd: C, 63.35; propyl H, 5.11;
N, 5.68; found: C, 63.60; H, 5.35; N, 5.48. (isolated as the
hydrochloride) 288 7-fluoro pyrid-4-yl mp 212-214.degree. C. MS
(ACPI): m/e 362.2 (M + 1). (isolated as the oxalate) 289 7-fluoro
pyrid-3-yl mp 167-169.degree. C. MS (ACPI): m/e 362.3 (M + 1).
(isolated as the oxalate) 299 7-phenyl 2,2,2- mp 116-120.degree. C.
MS (ACPI): m/e 425.3 (M + 1). trifluoro Analysis for
C.sub.29H.sub.27F.sub.3N.sub.2O.sub.5: Calcd: C, 64.44; H, ethyl
5.03; N, 5.18; found: C, 64.47; H, 4.96; N, 5.24. 300 7-phenyl
2,2,3,3- mp 108-111.degree. C. MS (ACPI): m/e 457.3 (M + 1).
tetrafluoro Analysis for C.sub.30H.sub.28F.sub.4N.sub.2O.sub.5:
Calcd: C, 62.93; H, propyl 4.93; N, 4.89; found: C, 63.02; H, 4.91;
N, 4.96.
EXAMPLE 301
N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-N-methyl-3-(2,2,3,3-tetrafluoropropoxy-
)benzylamine maleate
[0417] ##STR34##
[0418] Add 3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde (232.6 mg,
0.98 mmol) to a solution of
N-(2-(6-chloro-1H-indol-3-yl)ethyl)-N-methylamine (205.6 mg, 0.98
mmol) and sodium triacetoxy borohydride (305.3 mg, 1.37 mmol) in
dichloroethane (50 ml). Stir at ambient temperature. After 24
hours, evaporate to residue and dissolve the residue in 1N NaOH
then extract with dichloromethane. Combine the organic extracts,
washed with brine, dry (Na.sub.2SO.sub.4), filter, and evaporate to
a residue. Chromatograph the residue on silica gel eluting with
ethyl acetate to give the title compound. The maleate salt was
prepared in diethyl ether: mp 125-128.degree. C. MS (ACPI): m/e
429.3 (M+1). Analysis for C.sub.25H.sub.25ClF.sub.4N.sub.2O.sub.5:
Calcd: C, 55.10; H, 4.62; N, 5.14; found: C, 55.13; H, 4.59; N,
5.09.
[0419] By the method of Example 301 the following compounds were
prepared: TABLE-US-00010 ##STR35## No. Z' R.sub.4 Data 302
5-methoxy 2,2,2-trifluoro mp 144-147.degree. C. MS (ACPI): m/e
393.1 (M + 1). ethyl Analysis for
C.sub.23H.sub.25F.sub.3N.sub.2O.sub.6: Calcd: C, 57.26; H, 5.22; N,
5.81; found: C, 56.89; H, 5.16; N, 5.82. (isolated as the oxalate)
303 4-methoxy 2,2,3,3- mp 104-109.degree. C. MS (ACPI): m/e 425.2
(M + 1). tetrafluoro Analysis for
C.sub.24H.sub.26F.sub.4N.sub.2O.sub.6: Calcd: C, 56.03; H, propyl
5.09; N, 5.45; found: C, 55.85; H, 5.05; N, 5.43. (isolated as the
oxalate) 304 4-fluoro 2,2,2-trifluoro mp 199-202.degree. C. MS
(ACPI): m/e 367.2 (M + 1). ethyl Analysis for
C.sub.19H.sub.19ClF.sub.4N.sub.2O: Calcd: C, 56.65; H, 4.75; N,
6.95; found: C, 56.82; H, 4.65; N, 6.84. (isolated as the
hydrochloride) 305 6-phenyl 2,2,3,3- mp 94-98.degree. C. MS (ACPI):
m/e 457.1 (M + 1). tetrafluoro Analysis for
C.sub.26H.sub.24F.sub.4N.sub.2O: Calcd: C, 68.41; H, propyl 5.30;
N, 6.14; found: C, 68.18; H, 5.28; N, 6.06. (isolated as the
base)
EXAMPLE 306
N-(2-(6-Carboxy-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzyla-
mine
[0420] ##STR36##
[0421] Combine
N-(2-(6-ethoxycarbonyl-1H-indol-3-yl)ethyl)-N-(2,2,3,3-tetrafluoropropoxy-
benzyl)amine (1.09 g, 2.4 mmol) and 2N NaOH (4.8 ml) in ethanol
(4.8 ml). Heat to reflux. After 2 hours, cool to ambient
temperature, evaporate under vacuum to remove the ethanol, and then
neutralize with 5N HCl (1.92 ml) to give a solid. Collect the solid
by filtration and dry under vacuum to give the title compound as a
white powder: mp 186.degree. C., dec, MS (ACPI): m/e 425.1
(M+1).
EXAMPLE 307
N-(2-(6-Carboxy-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine
[0422] ##STR37##
[0423] The method of Example 306 gives the title compound:
[0424] mp 232-235.degree. C. MS (ACPI): m/e 393.2 (M+1).
EXAMPLE 310
5-Phenoxy-1H-indole
[0425] Combine potassium hydroxide (3 g, 0.054 mol) and phenol (15
g, 0.16 mol), and heat to 110.degree. C. until the potassium
hydroxide is dissolved. Cool the mixture to room temperature and
add 5-fluoro-2-nitrotoluene (7.75 g, 0.05 mol) in one aliquot. Heat
the reaction mixture to 130.degree. C. for 30 min, cool to room
temperature, and then pour into 10% NaOH (200 mL). Extract the
aqueous solution with ether (2.times.100 mL), combine the organic
layers and wash with 10% NaOH (2.times.100 mL), water (2.times.100
mL), dry over Na.sub.2SO.sub.4 and concentrate in vacuo.
Chromatograph on silica gel eluting with hexanes/ethyl acetate to
give 2-nitro-5-phenoxytoluene as a solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) 2.59 (s, 3H), 6.81-6.85 (m, 2H), 7.06-7.09 (m, 2H),
7.22-7.26 (m, 1H), 7.40-7.45 (m, 2H), 8.03-8.06 (m, 1H).
[0426] Combine 2-nitro-5-phenoxytoluene (1.15 g, 5.0 mmol) and
tris(dimethylamino)methane (0.87 g, 6.0 mmol) in 10 mL dry toluene
and heat to reflux under nitrogen. After 2 hours, cool the reaction
mixture to room temperature and evaporate the toluene under reduced
pressure to form a residue. Dissolve the residue in 15 mL EtOAc,
mix with Pd/C (10%, 100 mg), stir at room temperature under 1
atmosphere of hydrogen for 1.5 days. Filter off catalyst and
concentrate the filtrate. Chromatograph on silica gel eluting with
hexanes/EtOAc give the title compound as a solid: .sup.1H NMR (300
MHz, CDCl.sub.3) 6.49-6.50 (m, 1H), 6.93-7.03 (m, 4H), 7.22-7.27
(m, 5H), 8.15 (br, 1H).
[0427] By the method of Example 310 the following compounds were
prepared: a) 4 Tolyloxy)-2-methylnitrobenzene: .sup.1H NMR (300
MHz, CDCl.sub.3) 2.35 (s, 3H), 2.57 (s, 3H), 6.77-6.80 (m, 2H),
6.93-7.03 (m, 2H), 7.18-7.24 (m, 2H), 8.00-8.03 (m, 1H);
[0428] b) 5-p-Tolyloxy-1H-indole: .sup.1H NMR (300 MHz, CDCl.sub.3)
2.31 (s, 3H), 6.48-6.49 (m, 1H), 6.87-6.96 (m, 3H), 7.07-7.10 (m,
2H), 7.20-7.35 (m, 3H), 8.15 (br, 1H);
[0429] c) 4-(o-Tolyloxy)-2-methylnitrobenzene: .sup.1H NMR (400
MHz, CDCl.sub.3) 2.16 (s, 3H), 2.57 (s, 3H), 6.50-6.78 (m, 2H),
6.93-7.03 (m, 3H), 7.18-7.35 (m, 1H), 8.00-8.03 (m, 1H);
[0430] d) 5-o-Tolyloxy-1H-indole: .sup.1H NMR (400 MHz, CDCl.sub.3)
2.31 (s, 3H), 6.45-6.46 (m, 1H), 6.78-6.80 (m, 1H), 6.90-6.00 (m,
2H), 7.01-7.10 (m, 2H), 7.13-7.24 (m, 2H), 7.32-7.34 (m, 1H), 8.11
(br, 1H);
[0431] e) 4-(m-Tolyloxy)-2-methylintrobenzene: .sup.1H NMR (300
MHz, CDCl.sub.3) 2.37 (s, 3H), 2.60 (s, 3H), 6.80-6.88 (m, 4H),
7.03-7.06 (m, 1H), 7.27-7.32 (m, 1H), 8.03-8.06 (m, 1H);
[0432] f) 5-m-Tolyloxy-1H-indole: 6.0 g (54%) was obtained (red
oil). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.25 (s, 3H), 6.51-6.52 (m,
1H), 6.76-6.98 (m, 4H), 7.14-7.39 (m, 4H), 8.17 (br, 1H);
[0433] g) 4-(4-Fluorophenoxy)-2-methylnitrobenzene: .sup.1H NMR
(300 MHz, CDCl.sub.3) 2.60 (s, 3H), 6.80-6.82 (m, 2H), 7.03-7.12
(m, 4H), 8.03-8.06 (m, 1H); and
[0434] h) 5-(4-Fluorophenoxy)-1H-indole: 2.68 g (26%) was obtained
(red oil). .sup.1H NMR (300 MHz, CDCl.sub.3) 6.50-6.52 (m, 1H),
6.91-7.01 (m, 5H), 7.24-7.38 (m, 3H), 8.18 (br, 1H). a)
5-p-tolyloxy-1H-indole.
EXAMPLE 311
2-Oxo-(5-phenoxy-1H-indol-3-yl)acetyl chloride
[0435] Combine 5-phenoxy-indole (1.57 g, 7.5 mmol) and anhydrous
ether (35 mL) and add oxalyl chloride (1.07 g, 8.25 mmol) in 8 mL
ether. A precipitate forms. Stir the reaction over night. Collect
the precipitate, dry in vacuo, to give the title compound: .sup.1H
NMR (300 MHz, DMSO-d.sub.6) 6.99-7.15 (m, 4H), 7.37-7.42 (m, 2H),
7.60 (d, 1H, J=8.7 Hz), 7.75 (d, 1H, J=2.4 Hz), 8.47 (d, 1H, J=3.2
Hz), 12.49, (br, 1H).
[0436] By the method of Example 311 the following compounds were
prepared: a) 2-Oxo-(5-p-tolyloxy-1H-indol-3-yl)acetyl chloride;
[0437] b) 2-Oxo-(5-o-tolyloxy-1H-indol-3-yl)acetyl chloride:
.sup.1H NMR (300 MHz, CDCl.sub.3) 2.83 (s, 3H), 6.86-6.89 (m, 1H),
7.03-7.16 (m, 5H), 7.26-7.27 (m, 1H). 7.40-7.44 (m, 1H), 7.87 (m,
1H), 8.20-8.32 (m, 2H), 8.90 (br, 1H);
[0438] c) 2-Oxo-(5-n-tolyloxy-1H-indol-3-yl)acetyl chloride;
and
[0439] d) 2-Oxo-((4-fluorophenoxy)-1H-indol-3-yl)acetyl
chloride.
EXAMPLE 312
2-Oxo-2-(5-phenoxy-1H-indol-3-yl)acetamide
[0440] Combine 2-oxo-(5-phenoxy-1H-indol-3-yl)acetyl chloride (2.15
g, 7.18 mmol), and ammonium hydroxide (28-30%, 32 ml, 680 mmol) and
stir for 2 hours. Pour the reaction mixture into 10% (aq.) HCl,
extract with dichloromethane, combine the organic layers and dry
over Na.sub.2SO.sub.4, evaporate solvent in vacuo to give 1.94 g
(96%) of title compound: .sup.1H NMR (300 MHz, CDCl.sub.3) 4.87 (s,
2H), 7.51-7.91 (m, 7H), 8.13-8.24 (m, 3H).
[0441] By the method of Example 312 the following compounds were
prepared: a) 2-Oxo-2-(5-p-tolyloxy-1H-indol-3-yl)acetamide;
[0442] b) 2-Oxo-2-(5-o-tolyloxy-1H-indol-3-yl)acetamide; and
[0443] c) 2-Oxo-2-(5-m-tolyloxy-1H-indol-3-yl)acetamide.
EXAMPLE 314
5-Phenoxytryptamine oxalate
[0444] Add 9-oxo-2-(5-phenoxy-1H-indol-3-yl)acetamide (1.9 g, 6.86
mmol) in THF (60 mL) dropwise to a solution of LiAlH.sub.4-THF (1.0
M, 41 mL, 41.0 mmol) in THF at room temperature. Heat the reaction
mixture to reflux for 4 hours and cool to room temperature. Quench
the reaction mixture with water (6 mL), followed by NaOH (2N, 3
mL). Collect the precipitate by filtration, and wash with ether
(3.times.50 mL). Dry the filtrate over Na.sub.2SO.sub.4,
concentrate in vacuo, purify the residue by flash chromatography
(dichloromethane/MeOH/NH.sub.4OH) to obtain 1.0 g (59%) of free
amine of the title compound. The oxalic salt of the title compound
gives: m.p. 156-157.degree. C.; .sup.1H NMR (300 MHz, DMSO-d6) 2.94
(t, 2H, J=7.3 Hz), 3.00 (t, 2H, J=7.3 Hz), 5.00 (br, 2H), 6.83-7.04
(m, 4H), 7.26-7.41 (m, 5H), 11.05 (br, 1H); MS (ELECTROSPRAY), m/e:
341.1 (M-1); Anal. Calcd. C.sub.18H.sub.18N.sub.2O.sub.5: C, 63.15;
H, 5.30; N, 8.18. Found: C, 62.97; H, 5.25; N, 8.20.
[0445] By the method of Example 314 the following compounds were
prepared and isolated as the oxalate, unless otherwise noted: a)
5-p-Tolyloxytryptamine: .sup.1H NMR (300 MHz, CDCl.sub.3) 2.31 (s,
3H), 2.83 (t, 2H, J=6.4 Hz), 2.98 (t, 2H, J=6.3 Hz), 6.86-6.96 (m,
3H), 7.07-7.10 (m, 3H), 7.24-7.33 (m, 2H), 8.02 (br, 1H) (isolated
as the base);
[0446] b) 5-o-Tolyloxytryptamine: m.p. 187-188.degree. C. .sup.1H
NMR (300 MHz, DMSO-d6) 2.27 (s, 3H), 2.90-3.05 (m, 4H), 6.66-6.68
(m, 1H), 6.76-6.79 (m, 1H), 6.93-6.98 (m, 1H), 7.06-7.16 (m, 2H),
7.24-7.39 (m, 3H), 7.66 (br, 2H), 11.05 (br, 1H); MS (ELECTROSPRAY)
m/e: 265.1 (M-1-C.sub.2H.sub.2O.sub.4); Anal. Calcd.
C.sub.19H.sub.22N.sub.2O.sub.5: C, 64.04; H, 5.66; N, 7.86. Found:
C, 63.90; H, 5.72; N, 7.83; and
[0447] c) 5-m-Tolyloxytryptamine: m.p. 164-165.degree. C.; .sup.1H
NMR (250 MHz, DMSO-d6) 2.26 (s, 3H), 2.89-3.07 (m, 4H), 4.52 (br,
2H), 6.68-6.72 (m, 2H), 6.82-6.86 (m, 2H), 7.17-7.42 (m, 4H), 11.06
(br, 1H); MS (ELECTROSPRAY) m/e: 265.1
(M-1-C.sub.2H.sub.2O.sub.4).
EXAMPLE 315
6-Chloro-7-fluoro-1H-indole
[0448] Combine boron trichloride (36.0 mL, 1.0 M solution in
heptane, 36 mmol) and 1,2-dichloroethane (40 mL) and cool to
5.degree. C. Add dropwise a solution of 2-fluoro-3-chloroaniline
(4.36 g, 30.0 mmol) in 20 mL 1,2-dichloroethane. Warm the reaction
mixture to room temperature and stir for 30 min. Add to the
reaction mixture, chloroacetonitrile (2.71 g, 36.0 mmol), followed
by TiCl.sub.4 (6.83 g, 3.84 mL, 36.0 mmol). Heat the reaction
mixture to reflux overnight. Cool the reaction mixture to room
temperature, add 55.0 mL of 2.5 N HCl, heat to 85.degree. C. for 30
min. Cool to room temperature, extract with dichloromethane
(3.times.25 mL), combine the organic layers, wash with brine, dry
over Na.sub.2SO.sub.4, concentrate in vacuo to give 5.1 g of
1-(2-amino-2-fluoro-3-chlorophenyl)-2-chloroethanone: .sup.1H NMR
(300 MHz, CDCl.sub.3) 4.63 (s, 2H), 6.49 (br, 2H), 6,62-6.69 (m,
1H), 7.36-7.39 (m, 1H).
[0449] Dissolve
1-(2-amino-2-fluoro-3-chlorophenyl)-2-chloroethanone in 50 mL (10%
water in 1,4-dioxane, v/v) and add NaBH.sub.4 (0.86 g, 22.8 mmol)
cautiously at room temperature. Reflux the reaction mixture for
about 4 hour, cool to room temperature. Add 35 mL of 1N HCl and
stir at room temperature for half an hour, extract with
dichloromethane (20 mL.times.3), combine the organic layers and
wash with H.sub.2O and brine, dry over Na.sub.2SO.sub.4, and
concentrate in vacuo. Chromatograph on silica gel eluting with
EtOAc/hexanes to give the title compound 0.94 g (24%): .sup.1H NMR
(300 MHz, CDCl.sub.3) 6.55-6.58(m, 1H), 7.04-7.10 (m, 1H),
7.22-7.33 (m, 2H), 8.38 (br, 1H).
[0450] By the method of Example 315 the following compounds were
prepared: a) 5,7-Difluoro-1H-indole: .sup.1H NMR (300 MHz,
CDCl.sub.3) 6.55-6.56 (m, 1H), 6.71-6.78 (m, 1H), 7.01-7.11 (m,
1H), 7.26-7.28 (m, 1H), 8.34 (br, 1H);
[0451] b) 6,7-Difluoro-1H-indole: .sup.1H NMR (300 MHz, CDCl.sub.3)
6.53-6.56 (m, 1H), 6.90-6.99 (m, 1H), 7.22-7.31 (m, 2H), 8.39 (br,
1H);
[0452] c) 5,6,7-Trifluoro-1H-indole: .sup.1H NMR (300 MHz,
CDCl.sub.3) 6.52-6.55 (m, 1H), 7.13-7.20 (m, 1H), 7.26-7.27 (m,
1H), 8.35 (br, 1H); and
[0453] d) 4,5,7-Trifluoro-1H-indole: .sup.1H NMR (300 MHz,
DMSO-d.sub.6) 6.68-6.71 (m, 1H), 7.20-7.29 (m, 1H), 7.57-7.59 (m,
1H), 12.07 (br, 1H); MS (electrospray) m/e: 170.0 (M-1).
[0454] e) 4,7-Difluoro-1H-indole: .sup.1H NMR (400 MHz,
dmso-d.sub.6): 11.91 (br s, 1H), 7.44 (t, 1H, J=2.8 Hz), 6.84-6.90
(m, 1H), 6.69-6.74 (m, 1H), 6.54-6.56 (m, 1H); MS (ES-): m/e 152.0
(M-1).
EXAMPLE 316
3-Formyl-6-chloro-7-fluoro-1H-indole
[0455] Add phosphorus oxychloride (0.94 g, 6.16 mmol) to DMF (12
mL, cooled in an ice bath) with vigorous stirring. After about 10
minutes, add 6-chloro-7-fluoro indole (0.93 g, 5.6 mmol) in
anhydrous DMF (4 mL), stir at 0.degree. C. for 1 hour, warm to room
temperature and stir overnight at room temperature (.about.16 hrs).
Treat with 14.0 mL of 2N NaOH (4 eq.) with vigorous stirring. Heat
the reaction to 80.degree. C. for half an hour then cool. Pour the
reaction into cold water with vigorous stirring to give a solid.
Collect the solid by filtration and dry overnight in a vacuum oven
at room temperature, to give the title compound: .sup.1H NMR (300
MHz, CD.sub.3COCD.sub.3/CDCl.sub.3) 7.09 (t, 1H, J=7.7 Hz),
7.83-7.86 (m, 2H), 9.89 (s, 1H). By the method of Example 316 the
following compounds were prepared: a)
3-Formyl-5,7-difluoro-1H-indole: .sup.1H NMR (300 MHz,
CD.sub.3COCD.sub.3) 6.98-7.06 (m, 1H), 7.71-7.75 (m, 1H), 8.35 (s,
1H), 10.04 (s, 1H);
[0456] b) 3-Formyl-6,7-difluoro-1H-indole: .sup.1H N (300 MHz,
CDCl.sub.3) 7.10-7.19 (m, 1H), 7.86-7.88 (m, 1H), 7.98-8.03 (m,
1H), 8.95 (br, 1H), 10.06 (s, 1H);
[0457] c) 3-Formyl-5,6,7-trifluoro-1H-indole: .sup.1H NMR (300 MHz,
CD.sub.3COCD.sub.3) 7.87-7.93 (m, 1H), 8.42 (s, 1H), 10.07 (s, 1H);
and
[0458] d) 3-Formyl-4,5,7-trifluoro-1H-indole: .sup.1H NMR (300 MHz,
DMSO-d.sub.6) 7.46-7.55 (m, 1H), 8.49 (s, 1H), 10.02 (d, 1H, J=3.7
Hz), 13.19 (br, 1H).
[0459] e) 3-Formyl-4,7-difluoro-1H-indole: .sup.1H NMR (400 MHz,
dmso-d.sub.6): .delta. 13.03 (br s, 1H), 10.00 (d, 1H, J=3.2 Hz),
8.36 (s, 1H), 7.07-7.13 (m, 1H), 6.94-7.00 (m, 1H); MS (APCI): m/e
182.0 (M+1).
[0460] f) 3-Formyl-4,5,6,7-tetrafluoro-1H-indole: .sup.1H NMR (400
MHz, dmso-d.sub.6): .delta. 13.33 (br s, 1H), 9.94 (d, 1H, J=4.4
Hz), 8.49 (s, 1H); MS (ES-): m/e 216.0 (M-1).
EXAMPLE 317
3-(2-Nitrovinyl)-6-chloro-7-fluoro-1H-indole
[0461] Combine 3-formyl-6-chloro-7-fluoro-1H-indole (1.00 g, 5.06
mmol), ammonium acetate (292 mg, 3.8 mmol, 0.75 eq.) (dry by
treating with toluene and remove the toluene in vacuo), and
nitromethane (6.17 g, 101.2 mmol, 20 eq.). Warm to 65.degree. C.
When the reaction is complete (by TLC), add silica gel and remove
the nitromethane in vacuo. Load the silica gel on top of short
column of silica gel and elute with 25% acetone in hexanes to give,
after evaporation, the title compound.
[0462] By the method of Example 317 the following compounds were
prepared: a) 3-(2-Nitrovinyl)-5,7-difluoro-1H-indole: .sup.1H NMR
(300 MHz, CDCl.sub.3) 6.68-6.81 (m, 1H), 7.16-7.21 (m, 1H), 7.60
(d, 1H, J=13.5 Hz), 7.73 (d, 1H, J=2.7 Hz), 8.18 (d, 1H, J=13.5
Hz), 10.95 (br, 1H);
[0463] b) 3-(2-Nitrovinyl)-6,7-difluoro-1H-indole: .sup.1H NMR (300
MHz, CDCl.sub.3) 6.93-7.00 (m, 1H), 7.30-7.35 (m, 1H), 7.58 (d, 1H,
J=13.5 Hz), 7.69 (d, 1H, J=2.9 Hz), 8.10 (d, 1H, J=13.5 Hz), 1.18
(br, 1H): MS (electrospray) m/e: 225 (M+1), 223 (M-1);
[0464] c) 3-(2-Nitrovinyl)-5,6,7-trifluoro-1H-indole.
[0465] d) 3-(2-Nitrovinyl)-4,5,7-trifluoro-1H-indole.
[0466] e) 3-(2-Nitrovinyl)-4,7-difluoro-1H-indole: MS (ES-): m/e
223.0 (M-1).
[0467] f) 3-(2-Nitrovinyl)-4,5,6,7-tetrafluoro-1H-indole: MS(ES-):
m/e 259.0 (M-1).
EXAMPLE 318
6-Chloro-7-fluorotryptamine
[0468] Add dropwise 3-(2-nitrovinyl)-6-chloro-7-fluoro-1H-indole
(1.20 g, 5.06 mmol) in anhydrous THF to a solution of lithium
aluminum hydride (30.0 mL, 30.0 mmol, 1.0 M solution in THF). Heat
to reflux for 2 hour and then cool to room temperature. Quench by
carefully adding 1N NaOH to give a suspension. Filter the
suspension through celite and rinse repeatedly with ether.
Evaporate the filtrate in vacuo to give a residue. Chromatograph
the residue on silica gel eluting with dichloromethane, methanol,
and ammonium hydroxide (10:1:01) to give, after evaporation, the
title compound: .sup.1H NMR (300 MHz, CDCl.sub.3) 2.87 (t, 2H,
J=6.6 Hz), 3.02 (t, 2H, J=6.7 Hz), 7.03-7.08 (m, 2H), 7.26-7.29 (m,
1H), 8.51 (br, 1H).
[0469] By the method of Example 318 the following compounds were
prepared: a) 5,7-Difluorotryptamine: .sup.1H NMR (300 MHz,
CDCl.sub.3) 2.46 (t, 2H, J=6.5 Hz), 3.01 (t, 2H, J=6.4 Hz),
6.69-6.77 (m, 1H), 7.03-7.11 (m, 2H), 8.29 (br, 1H);
[0470] b) 6,7-Difluorotryptamine: .sup.1H NMR (300 MHz, CDCl.sub.3)
2.87 (t, 2H, J=6.6 Hz), 3.02 (t, 2H, J=6.7 Hz), 6.88-6.97 (m, 1H),
7.04 (m, 1H), 7.20-7.25 (m, 1H), 8.64 (br, 1H);
[0471] c) 5,6,7-Trifluorotryptamine: .sup.1H NMR (300 MHz,
CDCl.sub.3) 2.83 (t, 2H, J=6.6 Hz), 3.00 (t, 2H, J=6.7 Hz),
7.08-7.14 (m, 2H), 8.71 (br, 1H); MS (electrospray), m/e: 215.0
(M+1); and
[0472] d) 4,5,7-Trifluorotryptamine: .sup.1H NMR (300 MHz,
CDCl.sub.3) 2.93 (t, 2H, J=6.6 Hz), 3.03 (t, 2H, J=6.4 Hz),
6.73-6.82 (m, 1H), 7.02 (s, 1H), 8.58 (br, 1H); MS (electrospray),
m/e: 215.0 (M+1), 213.0 (M-1).
[0473] f) 4,7-Difluorotryptamine: .sup.1HMR (400 MHz,
dmso-d.sub.6): 11.57 (br s, 1H), 7.19 (s, 1H), 6.80-6.85 (m, 1H),
6.61-6.67 (m, 1H), 2.79 (s, 4H). MS (ES+): m/e 197.0 (M+1) 180.0
(M-NH.sub.2).
[0474] g) 4,5,6,7-Tetrafluorotryptamine: .sup.1H NMR (400 MHz,
dmso-d.sub.6): .delta. 7.31 (s, 1H), 2.78 (s, 4H); MS (ES+): m/e
233.0 (M+1) 216.0 (M-16).
EXAMPLE 319
N-(2-(5-Phenoxy-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine
[0475] ##STR38##
[0476] Combine 5-phenoxytryptamine (0.400 g, 1,59 mmol),
3-phenoxybenzaldehyde (0.377 g, 1.90 mmol) and molecular sieves 4
.ANG. (0.40 g) in methanol (15 mL) and stir for 4 h. Filter and
wash the molecular sieves several times with MeOH. Add NaBH.sub.4
(61.5 mg, 1.59 mmol) in portions to the filtrate and stir at room
temperature for 1 h. Remove the MeOH under vacuum to give a
residue, dilute the residue with dichloromethane/water, separate
the layers, extract the aqueous layer with dichloromethane, combine
the organic layers, and dry over Na.sub.2SO.sub.4. Concentrate in
vacuo and chromatograph on silica gel eluting with
dichloromethane/MeOH the title compound. Form the oxalate salt of
the title compound: m.p. 196-198.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d6) 2.95-3.15 (m, 4H), 4.15 (s, 2H), 6.85-7.46 (m, 18H), 11.06
(br, 1H); MS (ELECTROSPRAY) m/e: 435.3 (M+1); HRMS (ES+) calcd for
C.sub.29H.sub.27N.sub.2O.sub.2 (M+H) 435.2084 found 435.2073.
[0477] By the method of Example 319 the following compounds were
prepared, isolated as the oxalate except where noted:
TABLE-US-00011 ##STR39## No. Z' R.sub.4 Data 320 5-p-tolyloxy
phenyl m.p. 204-206.degree. C.; .sup.1H NMR (250 MHz, DMSO-d6) 2.25
(s, 3H), 2.97-3.12 (m, 4H), 4.01 (br, 2H), 4.16 (s, 2H), 6.78-6.84
(m, 3H), 7.00-7.10 (m, 10H), 7.13-7.43 (m, 4H), 11.05 (br, 1H); MS
(ELECTROSPRAY) m/e: 449.1 (M + 1 - C.sub.2H.sub.2O.sub.4); Analysis
calcd: C.sub.32H.sub.30N.sub.2O.sub.6: C, 71.36; H, 5.61; N, 5.20.
Found: C, 71.22; H, 5.59; N, 5.28 321 5-o-tolyloxy phenyl m.p.
191-192.degree. C.; .sup.1H NMR (300 MHz, DMSO-d6) 2.28 (s, 3H),
2.99-3.15 (m, 4H), 4.17 (s, 2H), 6.63-6.66 (m, 1H), 6.75 6.79 (m,
1H), 6.92-7.42 (m, 15H), 9.50 (br, 2H), 11.05 (br, 1H); MS
(ELECTROSPRAY) m/e: 449.1 (M + 1 - C.sub.2H.sub.2O.sub.4); Anal.
calcd. C.sub.32H.sub.30N.sub.2O.sub.6: C, 71.36; H, 5.61; N, 5.20.
Found C, 71.11; H, 5.59; N, 5.18 322 5-m-tolyloxy phenyl m.p.
174-175.degree. C. .sup.1H NMR (250 MHz, DMSO-d6) 2.51 (s, 3H),
3.00-3.13 (m, 4H), 4.15 (s, 2H), 6.81-7.03 (m, 7H), 7.11-7.42 (m,
11H), 11.05 (br, 1H): MS (ELECTROSPRAY) m/e: 449.1 (M + 1 -
C.sub.2H.sub.2O.sub.4) 323 6-chloro-7- 2,2,2- mp 186-187.degree. C.
.sup.1H NMR (300 MHz, DMSO-d6) 3.13 (s, 4H), 4.15 s, 2H), 4.78 (q,
2H, J=8.7 Hz), 7.07-7.12 fluoro trifluoro (m, 2H), 7.21-7.24 (m,
1H), 7.37-7.45 (m, 4H), 9.44 (br, 1H), 11.72 (br, 1H): ms
(electrospray) m/e: 401.2 ethyl (M + 1 - HCl), 399.2 (M - 1 - HCl):
Anal. calcd. C.sub.19H.sub.17ClF.sub.4N.sub.2O.cndot.HCl: C, 52.19;
H, 4.15; N, 6.41. Found: C, 52.15; H, 4.14; N, 6.38 (isolated as
the hydrochloride) 324 6-chloro-7- 2,2,3,3- mp. 155-156.degree. C.;
1H NMR (300 MHz, DMSO-d6) 3.13 (s, 4H), 4.16 (s, 2H), 4.61 (t, 2H,
J=13.5 Hz), 6.70 fluoro tetrafluoro (tt, 1H, J=51.9 Hz, J=5.5 Hz),
7.08-7.10 (m, 2H), 7.11-7.12 (m, 1H), 7.21-7.45 (m, 4H), 9.41 (br,
1H), 11.72 propyl (br, 1H); MS (electrospray) m/e: 433.2 (M + 1 -
HCl), 431.2 (M - 1 - HCl); Anal. calcd.
C.sub.20H.sub.18ClF.sub.5N.sub.2O.cndot.HCl: C, 51.19; H, 4.08; N,
5.97. Found: C, 51.27; H, 4.10; N, 6.07 (isolated as the
hydrochloride) 325 5,7-difluoro 2,2,2- m.p.: 179-180.degree. C.;
.sup.1H NMR (300 MHz, DMSO-d6) 3.11 (s, 4H), 4.16 (s, 2H), 4.77 (q,
2H, J=8.7 Hz), 6.93-6.97 trifluoro (m, 1H), 7.00-7.14 (m, 1H),
7.21-7.43 (m, 5H), 9.41 (br, 1H), 11.61 (br, 1H); ms (electrospray)
m/e: 385.2 ethyl (M + 1 - HCl), 383.0 (M - 1 - HCl); Anal. calcd.
C.sub.19H.sub.17F.sub.5N.sub.2O.cndot.HCl.cndot.0.1H.sub.2O: C,
54.00; H, 4.34; N, 6.63. Found: C, 53.71; H, 4.24; N, 6.70
(isolated as the hydrochloride) 326 5,7-difluoro 2,2,3,3- mp.
109-110.degree. C.; .sup.1H NMR (300 MHz, DMSO-d6) 2.71-2.84 (m,
4H), 3.71 (s, 2H), 4.53 (t, 2H, J=13.5 Hz), tetrafluoro 6.67 (tt,
1H, J=51.9 Hz, J=5.5 Hz), 6.87-7.02 (m, 4H), 7.12-7.28 (m, 3H),
11.40 (br, 1H); MS (electrospray) propyl m/e: 417.0 (M + 1), 415.0
(M - 1); Anal. calcd.
C.sub.20H.sub.18F.sub.6N.sub.2O.cndot.0.1H.sub.2O: C, 57.45; H,
4.39; N, 6.70. Found: C, 57.24; H, 4.08; N, 6.68 327 6,7-difluoro
2,2,2- m.p.: 164-165.degree. C.; .sup.1H NMR (300 MHz, DMSO-d6)
3.13 (s, 4H), 4.16 (s, 2H), 4.77 (q, 2H, J=9.1 Hz), 7.00-7.13
trifluoro (m, 2H), 7.20-7.23 (m, 1H), 7.33-7.43 (m, 4H), 9.36 (br,
1H), 11.57 (br, 1H); MS (electrospray) m/e: 385.2 ethyl (M + 1 -
HCl), 383.3 (M - 1 - HCl); Anal. calcd.
C.sub.19H.sub.17F.sub.5N.sub.2O.cndot.HCl: C, 54.23; H, 4.31; N,
6.66. Found: C, 53.86; H, 4.28; N, 6.58 (isolated as the
hydrochloride) 328 6,7-difluoro 2,2,3,3- m.p.: 214-215.degree. C.;
.sup.1H NMR (300 MHz, DMSO-d6) 3.02-3.17 (m, 4H), 4.16 (s, 2H),
4.59 (t, 2H, J=13.5 Hz), tetrafluoro 6.68 (tt, 1H, J=51.9 Hz, J=5.5
Hz), 7.00-7.17 (m, 5H), 7.21-7.42 (m, 4H), 11.65 (br, 1H); MS
(electrospray) propyl m/e: 417.0 (M + 1 - C.sub.4H.sub.4O.sub.4),
415.0 (M - 1 - C.sub.4H.sub.4O.sub.4); Anal. calcd.
C.sub.20H.sub.18F.sub.6N.sub.2O.cndot.C.sub.4H.sub.4O.sub.4.cndot.0.9H.su-
b.2O: C, 52.54; H, 4.37; N, 5.11. Found: C, 52.14; H, 3.95; N, 5.49
(isolated as the maleate) 329 5,6,7-trifluoro 2,2,2- m.p.:
111-112.degree. C.; .sup.1H NMR (300 MHz, DMSO-d6) 2.72-2.81 (m,
4H), 3.71 (s, 2H), 4.68 (q, 2H, J=8.8 Hz), trifluoro 6.87-7.00 (m,
3H), 7.22-7.40 (m, 3H), 11.58 (br, 1H); MS (electrospray) m/e:
403.1 (M + 1), 401.2 (M - 1). ethyl Anal. calcd.
C.sub.19H.sub.16F.sub.6N.sub.2O: C, 56.72; H, 4.01; N, 6.96. Found:
C, 56.61; H, 3.92; N, 6.96 (isolated as the base) 330
5,6,7-trifluoro 2,2,3,3- m.p.: 223-224.degree. C.; .sup.1H NMR (300
MHz, DMSO-d6) 3.11 (s, 4H), 4.15 (s, 2H), 4.61 (t, 2H, J=13.5 Hz),
6.70 (tt, tetrafluoro 1H, J=51.9 Hz, J=5.5 Hz), 7.08-7.12 (m, 1H),
7.19-7.25 (m, 1H), 7.36-7.43 (m, 3H), 7.52-7.58 (m, 1H), 9.50
propyl (br, 1H), 11.78 (br, 1H); MS (electrospray) m/e: 435.1 (M +
1 - HCl), 433.1 (M - 1 - HCl); Anal. calcd.
C.sub.20H.sub.18F.sub.6N.sub.2O.cndot.HCl.cndot.0.1H.sub.2O: C,
50.83; H, 3.88; N, 5.93. Found: C, 50.60; H, 3.74; N, 6.07
(isolated as the hydrochloride) 331 4,5,7-trifluoro 2,2,2- m.p.:
243-244.degree. C.; .sup.1H NMR (300 MHz, DMSO-d6) 3.16-3.21 (m,
4H), 4.18 (s, 2H), 4.75 (q, 2H, J=8.8 Hz), trifluoro 7.11-7.25 (m,
3H, 7.39-7.45 (m, 3H), 9.37 (br, 1H), 11.90 (br, 1H); MS
(electrospray) m/e: 403.1 (M + 1 - HCl), ethyl 401.0 (M - 1 - HCl);
Anal. calcd. C.sub.19H.sub.16F.sub.6N.sub.2O.cndot.HCl: C, 52.00;
H, 3.91; N, 6.38. Found: C, 51.83; H, 3.62; N, 6.55 (isolated as
the hydrochloride 332 4,5,7-trifluoro 2,2,3,3- m.p.:
261-262.degree. C.; .sup.1H NMR (300 MHz, DMSO-d6) 3.18 (s, 4H),
4.17 (s, 2H), 4.61 (t, 2H, J=13.5 Hz), 6.69 (tt, tetrafluoro 1H,
J=51.9 Hz, J=5.5 Hz), 7.09-7.13 (m, 1H), 7.17-7.26 (m, 2H),
7.32-7.42 (m, 3H), 9.37 (br, 1H), 11.92 (br, 1H); propyl MS
(electrospray) m/e: 435.1 (M + 1 - HCl), 433.1 (M - 1 - HCl); Anal.
calcd. C.sub.20H.sub.17F.sub.7N.sub.2O.cndot.HCl, C, 51.02; H,
3.85; N, 5.95. Found: C, 50.62; H, 3.79; N, 6.00 (isolated as the
hydrochloride) 333 7-cyano 2,2,2- mp. 241-242.degree. C.; .sup.1H
NMR (300 MHz, DMSO-d6) 3.15 (s, 4H), 4.17 (s, 2H), 4.78 (q, 2H,
J=8.7 Hz), 7.10-7.22 trifluoro (m, 3H), 7.33-7.43 (m, 3H),
7.60-7.62 (m, 1H), 7.95-7.97 (m, 1H), 9.29 (br, 2H), 11.90 (br,
1H); MS ethyl (electrospray) m/e: 374.2 (M + 1 - HCl), 372.0 (M - 1
- HCl); Anal. calcd.
C.sub.20H.sub.18F.sub.3N.sub.3O.cndot.HCl.cndot.0.2 H.sub.2O: C,
58.10; H, 4.73; N, 10.16. Found: C, 57.91; H, 4.56; N, 10.08. 334
7-cyano 2,2,3,3- mp. 212-213.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d6) 3.16 (s, 4H), 4.16 (s, 2H), 4.61 (t, 2H, J=13.6 Hz), 6.69
(tt, tetrafluoro 1H, J=51.9 Hz, J=5.5 Hz), 7.09-7.22 (m, 3H),
7.33-7.43 (m, 3H), 7.60-7.63 (m, 1H), 7.96-7.98 (m, 1H), 9.34 (br,
ethyl 2H), 11.92 (br, 1H); MS (electrospray) m/e: 406.2 (M + 1 -
HCl), 404.0 (M - 1 - HCl); Anal. calcd.
C.sub.21H.sub.19F.sub.4N.sub.3O.cndot.HCl, C, 57.08; H, 4.56; N,
9.51. Found: C, 57.12; H, 4.61; N, 9.53.
EXAMPLE 335
2-Fluoro-3-phenoxybenzaldehyde
[0478] Cool a solution of 2,2,6,6-tetramethylpiperidine (5.1 mL,
30.0 mmol) in THF (40 mL) to -75.degree. C. Add dropwise
n-Butyllithium (18.7 mL, 30.0 mmol, 1.6M in hexanes) and stir for
10 min at -78.degree. C. Add dropwise 2-fluorophenyl phenyl ether
(4.7 g, 25.0 mmol), stir 2 h at -78.degree. C. Add
N,N-dimethylformamide (2.3 mL, 30.0 mmol) dropwise over 15 min.
Stir the resulting mixture for 3 h at -78.degree. C. and allow to
warm to ambient temperature over 16 h. Quench the reaction mixture
with water (50 mL), extract with ethyl acetate, dry over
Na.sub.2SO.sub.4, filter and concentrate under reduced pressure to
give an oil. Crystallize the oil with hexanes to give a solid,
collect and recrystallize from hexanes/ethyl acetate/methylene
chloride to give the title compound: mp 75-77.degree. C.; MS(m/e):
216 (M.sup.+); Calculated for C.sub.13H.sub.9FO.sub.2: Calcd: C,
72.22; H, 4.20. Found: C, 72.41; H, 4.23. Purification of the
mother liquors by silica gel chromatography (2-3% ethyl
acetate/hexanes) gives an additional amount of the title compound:
MS(m/e): 216 (M.sup.+).
[0479] By the method of Example 335 the following compound was
prepared: a) 6-Fluoro-3-phenoxybenzaldehyde: MS(m/e): 216
(M.sup.+).
EXAMPLE 336
3-Ethoxybenzaldehyde
[0480] Combine 3-hydroxybenzaldehyde (5.6 g, 46 mmol) and
1-iodoethane (10.7 g, 69 mmol) in DMSO (25 mL) and warm to
80.degree. C. Treat with of cesium carbonate (22.4 g, 69 mmol) in
portions. During the addition the temperature begin to rise so the
bath is removed. Stir the reaction at 80.degree. C. for 1 hour,
pour into 200 mL brine and extract twice with 150 n-L diethyl
ether. Wash the combine extracts twice with 200 mL brine, dry over
MgSO.sub.4 and concentrate under vacuum to give an oil.
Purification by chromatography (SiO.sub.2; 2.5% EtOAc in hexanes)
affords 5.73 g (38 mmol; 83%) of the title compound as an oil:
.sup.1H NMR (CDCl.sub.3) 9.94 (s, 1H), 7.42-7.41 (m, 2H), 7.36-7.35
(m, 1H), 7.16-7.13 (m, 1H), 4.10-4.04 (q, 2H), 1.64-1.40 (t,
3H).
[0481] By the method of Example 336 the following compounds were
prepared: a) 3-Propoxybenzaldehyde: .sup.1H NMR (CDCl.sub.3) 9.95
(s, 1H), 7.43-7.41 (m, 2H), 7.37-7.36 (m, 1H), 7.17-7.14 (m, 1H),
9.98-3.95 (t, 2H), 1.84-1.79 (m, 2H), 1.05-1.02 (t, 3H).
EXAMPLE 337
p-Toluene-3-(2,2,3,3-tetrafluoropropoxy)tosylate
[0482] Add pyridine (1.9 L) (dried over molecular sieves 4 .ANG.)
to a round-bottomed flask (5 L), under inert atmosphere and
equipped with a mechanical agitator and add
2,2,3,3-tetrafluoro-1-propanol (604.5 g, 4.58 mol). Cool the
mixture to 0.degree. C. with an ice-bath. Add p-toluenesulfonyl
chloride (960 g, 5.04 mol) over 20 min in 4 portions to the
reaction mixture and stir. After 20 min., cooling on an ice-bath),
a precipitate is formed. Stir the reaction mixture for 1 h at
0.degree. C. and 2 h at 20.degree. C. Pour the reaction mixture,
with agitation, over an ice-water mixture (1.44 L) and leave
overnight (18 h) at 2.degree. C. The crude tosylate derivative
separates from the aqueous mixture as an oily material (1.34 kg)
containing 14% w/w pyridine which corresponds to 1.15 kg of the
tosylate (87.8%). The crude material is carried to the next
reaction step without further purification: .sup.1H-RMN is
consistent.
EXAMPLE 338
3-(2,2,3,3,3-Pentafluoropropoxy)benzaldehyde
[0483] Combine 3-hydroxybenzaldehyde (137.6 g, 1.127 mol),
p-toluene-3-(2,2,3,3,3-pentafluoropropoxy)tosylate (243 g, 0.799
mol), potassium carbonate (220 g, 1.597 mol) and dimethylformamide
(2451 mL) in a double-wall 4 L reactor equipped with a reflux
condenser and a mechanical agitator, and heat at 110.degree. C. for
46.5 h under argon atmosphere. Cool the reaction mixture to room
temperature and filter through a bed of 400 g of silica gel. Elute
silica gel bed with 2.451 mL of ethyl acetate. Pour the combined
organic layers over 7.3 L of ice-water. Add 10 N sodium hydroxide
(500 mL) to this mixture and stir for 1 h. Separate the aqueous
phase and extract with ethyl acetate (1000 mL). Pool the organic
phase, wash with water (1000 mL) and brine (750 mL). Evaporation of
the organic solvents under reduced pressure provides 159.79 g of a
brown oily material containing the crude title compound.
Purification by fractional distillation (two successive cycles)
under reduced pressure (2 mm Hg) using a distillation apparatus
equipped with a 30 cm length adiabatic column to gives a fraction
of 52.4 g of the expected product (96.2% area by HPLC).
EXAMPLE 339
3-(3,3,3-Trifluoropropoxy)benzaldehyde
[0484] Combine 3-hydroxybenzaldehyde (130.2 g, 1.066 mol),
3,3,3-trifluoropropoxy tosylate (143 g, 0.533 mol), potassium
carbonate (147.35 g, 1,066 mol) and absolute ethanol (1430 mL) in a
three-necked round-bottomed flask equipped with a reflux condenser
and a magnetic stirred and reflux for 4 h under argon atmosphere.
Concentrate the reaction mixture under reduced pressure. Pour the
concentrated mixture over 1N sodium hydroxide (2145 mL), stir for
30 min and extract with dichloromethane (2145 mL). Decant the
organic layer wash with 1N sodium hydroxide (2145 mL). After
separation, wash the organic layer successively twice by 1 L water
(pH aqueous phase 7), dry over 30 g magnesium sulfate, evaporate
the dichloromethane organic layer to dryness under reduced pressure
to yield 55.4 g of the title compound (0.254 mol, 47.6% yield) as a
slightly yellow oily material.
EXAMPLE 340
N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-2-fluoro-3-phenoxy-benzylamine
[0485] ##STR40##
[0486] Combine 6-fluorotryptamine (419 mg, 2.35 mmol) and
2-fluoro-3-phenoxybenzaldehyde (610 mg, 2.82 mmol) in absolute
ethanol (6 mL). Heat the mixture to 65.degree. C. to give a
homogeneous solution. Add 3 .ANG. molecular sieves (400 mg) to the
mixture and heat to reflux temperatures for 5 h. Cool the reaction
mixture to ambient temperature and add sodium borohydride (267 mg,
7.1 mmol). Stir the mixture for 18 h at ambient temperature. Cool
the reaction mixture on a water bath, quench with acetone, dilute
with ethanol and acetone, and filter the molecular sieves.
Concentrate the filtrate under reduced pressure, dilute with 1N
NaOH, extract with ethyl acetate, wash with brine, dry
(Na.sub.2SO.sub.4), filter and concentrate under reduced pressure
to give 1.0 g of an oil. Chromatograph on silica gel eluting with
1%, 4% 2N ammonia in methanol/methylene chloride gives a clear
colorless oil. Formation of the hydrochloride salt in ethyl
acetate/methanol gives the hydrochloride of the title compound: mp
173-174.5.degree. C.; MS(m/e): 379 (M+1), 377 (M-1); Calculated for
C.sub.23H.sub.20F.sub.2N.sub.2O.HCl: Calcd: C, 66.59; H, 5.10; N,
6.75. Found: C, 66.50; H, 5.09; N, 6.73.
EXAMPLE 341
N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-6-fluoro-3-phenoxy-benzylamine
[0487] ##STR41##
[0488] The method of Example 340 gives the hydrochloride of the
title compound: mp 183.5-185.5.degree. C.; MS(m/e): 379 (M+1), 377
(M-1); Calculated for C.sub.23H.sub.20F.sub.2N.sub.2O.HCl: Calcd:
C, 66.59; H, 5.10; N, 6.75. Found: C, 66.54; H, 5.11; N, 6.68.
[0489] By the method of Example 340 the following compounds were
prepared, isolated as the hydrochloride except where noted:
TABLE-US-00012 ##STR42## No. Z' R.sub.4 Data 342 5-methoxy ethyl
ISMS 325 (M + 1); Analysis for
C.sub.20H.sub.25C.sub.1N.sub.2O.sub.2 0.2EtOH 0.1H.sub.2O: calcd:
C, 65.88; H, 7.16; N, 9.53; found: C, 65.90; H, 6.97; N, 7.16;
.sup.1H NMR (DMSO-d6) 10.85 (s, 1H), 9.43 (bs, 2H), 7.42-7.22 (m,
4H), 7.18-7.10 (m, 2H), 7.05-7.0 (m, 1H), 6.32-6.15 (m, 1H),
4.3-4.15 (m, 2H), 4.15-4.05 (q, 2H), 3.85 (s, 3H), 3.15 (s, 4H),
1.45-1.35 (t, 3H) 343 5-methoxy propyl ISMS 339 (M + 1); Analysis
for C.sub.21H.sub.27ClN.sub.2O.sub.2: calcd: C, 67.28; H, 7.23; N,
7.47; found: C, 67.28; H, 7.30; N, 7.13; .sup.1H NMR (DMSO-d6)
10.85 (s, 1H), 9.43 (bs, 2H), 7.35-7.15 (m, 4H), 7.1-7.05 (m, 2H),
7.0-6.92 (m, 1H), 6.7-6.6 (m, 1H), 4.3-4.16 (m, 1H), 4.15-4.05 (q,
2H), 3.85 (s, 3H), 3.15 (s, 4H), 1.45-1.35 (t, 3H) 344 5-fluoro
2,2,2- ISMS 367 (M + 1); Analysis for
C.sub.19H.sub.19ClF.sub.4N.sub.2O: calcd: C, 56.65; H, 4.75; N,
6.95; found: C, 56.37; H, 4.83; N, trifluoro 6.81 (base) ethyl 345
5-methoxy 2,2,2- Analysis for
C.sub.20H.sub.22ClF.sub.3N.sub.2O.sub.2: calcd: C, 57.91; H, 5.34;
N, 6.75; found: C, 57.72; H, 5.17; N, 6.61; ISMS 379 trifluoro (M +
1) ethyl 346 5-fluoro 2,2,3,3,3- ISMS 417 (M + 1); Analysis for
C.sub.20H.sub.18F.sub.6N.sub.2O C.sub.2H.sub.2O.sub.4: calcd: C,
51.18; H, 3.98; N, 5.53; found: C, 51.18; H, pentafluoro 3.91; N,
5.51 (isolated as the oxalate) propyl 347 5-methoxy 2,2,3,3,3- ISMS
429 (M + 1); Analysis for C.sub.21H.sub.21F.sub.5N.sub.2O .sub.2
1.2C.sub.2H.sub.2O.sub.4 0.8H.sub.2O: calcd: C, 51.02; H, 4.57; N,
5.09; found: pentafluoro C, 50.64; H, 4.23; N, 5.15 (isolated as
the oxalate) propyl 348 5-methoxy 2,2,3,3- ISMS 411 (M + 1)
Analysis for C.sub.21H.sub.22F.sub.4N.sub.2O.sub.2
C.sub.2H.sub.2O.sub.4 0.1H.sub.2O: C, 55.0; H, 4.86; N, 5.58;
found: C, 54.74; tetrafluoro calcd: H, 4.74; N, 5.58 (isolated as
the oxalate) propyl 349 5-methoxy 3,3,3- Analysis for
C.sub.21H.sub.23F.sub.3N.sub.2O.sub.2 HCl: calcd: C, 58.81; H,
5.64; N, 6.53; found: C, 58.42; H, 5.44; N, 6.51; ISMS 393
trifluoro (M + 1) propyl 350 5-fluoro 2,2,3,3- Analysis for
C.sub.20H.sub.20F.sub.4N.sub.2O HCl: calcd: C, 57.63; H, 5.08; N,
6.72; found: C, 57.49; H, 5.04; N, 6.76; ISMS 381 tetrafluoro (M +
1) propyl 351 4-chloro-5- 2,2,2- Analysis for
C.sub.20H.sub.20ClF.sub.3N.sub.2O.sub.2 HCl: calcd: C, 53.47; H,
4.71; N, 6.24; found: C, 53.33; H, 4.65; N, 6.21; ISMS methoxy
trifluoro 413 (M + 1) ethyl 352 4-chloro-5- 2,2,3,3- Analysis for
C.sub.21H.sub.21ClF.sub.4N.sub.2O.sub.2 HCl: calcd: C, 52.40; H,
4.61; N, 5.82; found: C, 52.25; H, 4.50; N, 5.80; ISMS methoxy
tetrafluoro 445 (M + 1) propyl 353 4-chloro-5- 3,3,3- Analysis for
C.sub.21H.sub.22ClF.sub.3N.sub.2O.sub.2 HCl: calcd: C, 54.4; H,
5.00; N, 6.05; found: C, 54.18; H, 4.86; N, 6.06; ISMS 427 methoxy
trifluoro (M + 1) propyl
[0490] By the method of Example 340 the following compounds were
prepared, isolated as the hydrochloride except where noted:
TABLE-US-00013 ##STR43## No. Z' R.sub.4 Data 360 3-chloro
2,2,2-trifluoro ISMS 344 (M + 1); Analysis for ethyl
C.sub.17H.sub.18ClF.sub.3NO calcd: C, 53.70; H, 4.77; N, 3.68;
found: C, 53.61; H, 4.96; N, 3.66 361 3-trifluoro 2,2,2-trifluoro
ISMS 378 (M + 1); Analysis for C.sub.20H.sub.19F.sub.6NO5: methyl
ethyl calcd: C, 51.40; H, 4.10; N, 3.0; found: C, 51.26; H, 4.06;
N, 3.07 (isolated as the oxalate) 362 3-chloro 2,2,3,3,3- ISMS 394
(M + 1); Analysis for pentafluoro
C.sub.18H.sub.18C.sub.12F.sub.5NO: calcd: C, 50.25; H, 4.22; N,
propyl 3.26; found: C, 50.38; H, 4.03; N, 3.45 363 3-trifluoro
2,2,3,3,3- ISMS 428 (M + 1); Analysis for C.sub.19H.sub.17F.sub.8NO
methyl pentafluoro C.sub.2H.sub.2O.sub.4: calcd: C, 48.75; H, 3.70;
N, 2.70; propyl found: C, 48.76; H, 3.67; N, 2.79 (isolated as the
oxalate) 364 3-chloro 2,2,3,3- Analysis for
C.sub.18H.sub.18ClF.sub.4NO C.sub.2H.sub.2O.sub.4: tetrafluoro
calcd: C, 51.57; H, 4.33; N, 3.01; propyl found: C, 51.92; H, 4.29;
N, 3.08; ISMS 376 (M + 1) 365 3-trifluoro 2,2,3,3- Analysis for
C.sub.19H.sub.18F.sub.7NO C.sub.2H.sub.2O.sub.4: calcd: C, methyl
tetrafluoro 50.51; H, 4.04; N, 2.81; found: C, 50.48; H, propyl
4.02; N, 2.85; ISMS 410 (M + 1) (isolated as the oxalate) 366
3-trifluoro 3,3,3-trifluoro Analysis for C.sub.19H.sub.19F.sub.6NO
HCl: calcd: methyl propyl C, 53.34; H, 4.71; N, 3.27; found: C,
53.23; H, 4.73; N, 3.28; ISMS 392 (M + 1) 367 3-chloro
3,3,3-trifluoro Analysis for C.sub.18H.sub.19ClF.sub.3NO HCl:
calcd: C, propyl 54.84; H, 5.11; N, 3.55; found: C, 54.74; H, 5.02;
N, 3.11; ISMS 358 (M + 1)
EXAMPLE 370
N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine
[0491] ##STR44##
[0492] Combine 6-fluorotryptamine oxalate (350 mg, 1.3 mmol),
N,N-diisopropylethylamine (506 mg, 3.9 mmol),
3-(2,2,2-trifluoroethoxy)benzaldehyde (266 mg, 1.3 mmol), and 4
.ANG. molecular sieves (4 g) in EtOH (30 mL) and reflux for 7
hours. Decant the liquid into a separate flask and treat with
NaBH.sub.4 (148 mg, 3.9 mmol). Stir 1 hour, concentrate the mixture
in vacuo to give a residue. Partition the residue between 25 mL 5 N
NaOH and 25 mL dichloromethane. Extract the aqueous layer with 25
mL dichloromethane, combine the organic layers, dry over
MgSO.sub.4, and concentrate to approximately a 20 mL volume.
Chromatograph on silica gel eluting with 1% MeOH in CHCl.sub.3
mixed with conc. NH.sub.4OH to give the title compound. Combine an
EtOAc solution of the title compound with an EtOAc solution of one
equivalent of oxalic acid to give a solid, filter, and dry under
vacuum to give the oxalate salt of the title compound: ISMS 367
(M+1); Analysis for C.sub.9H.sub.19CIF.sub.4N.sub.2O: calcd: C,
55.27; H, 4.42; N, 6.14; found: C, 55.17; H, 4.38; N, 6.09.
[0493] By the method of Example 370 the following compounds were
prepared, isolated as the hydrochloride except where noted:
TABLE-US-00014 ##STR45## No. Z' R.sub.4 Data 372 5-fluoro 2,2,3,3-
ISMS 399 (M + ); Analysis for C.sub.19H.sub.17F.sub.8NO tetrafluoro
C.sub.2H.sub.2O.sub.4 H.sub.2O: calcd: C, 53.51; H, 4.41; N, propyl
5.67; found: C, 53.12; H, 4.21; N, 5.63 (isolated as the oxalate)
373 6-fluoro 2,2,3,3,3- Analysis for
C.sub.20H.sub.18F.sub.6N.sub.2O HCl: calcd: C, pentafluoro 53.05;
H, 4.23; N, 6.19; found: C, 52.88; H, propyl 4.05; N, 6.12; ISMS
417 (M + 1) 374 6-chloro-5- 2,2,2-trifluoro Analysis for
C.sub.20H.sub.20ClF.sub.3N.sub.2O.sub.2 HCl: calcd: C, methoxy
ethyl 53.47; H, 4.71; N, 6.24; found: C, 53.65; H, 4.85; N, 6.45;
ISMS 413 (M + 1) (Form the salt in 50 mL 50/50 THF/EtOH using
polyvinyl pyridine hydrochloride) 375 6-chloro-5- 2,2,3,3- Analysis
for C.sub.21H.sub.21ClF.sub.4N.sub.2O.sub.2 HCl: calcd: C, methoxy
tetrafluoro 52.40; H, 4.61; N, 5.82; found: C, 52.15; H, propyl
4.51; N, 5.69; ISMS 445 (M + 1) 376 6-fluoro 2,2,3,3- Analysis for
C.sub.20H.sub.19F.sub.5N.sub.20HCl: calcd: C, tetrafluoro 55.24; H,
4.64; N, 6.44; found: C, 55.06; H, propyl 4.63; N, 6.44; ISMS 399
(M + 1) 377 6-fluoro 3,3,3-trifluoro Analysis for
C.sub.20H.sub.20F.sub.4N.sub.2O HCl: calcd: C, propyl 54.83; H,
5.11; N, 3.55; found: C, 54.74; H, 5.02; N, 3.11; ISMS 381 (M + 1)
378 5-trifluoro 2,2,3,3,3- Analysis for
C.sub.21H.sub.18F.sub.8N.sub.2O.sub.2 HCl: calcd: C, methoxy
pentafluoro 48.62; H, 3.69; N, 5.40; found: C, 48.55; H, propyl
3.48; N, 5.33; ISMS 483 (M + 1) 379 5-trifluoro 2,2,3,3- Analysis
for C.sub.21H.sub.19F.sub.7N.sub.2O.sub.2 HCl: calcd: C, methoxy
tetrafluoro 50.36; H, 4.02; N, 5.59; found: C, 50.27; H, propyl
3.92; N, 5.63; ISMS 465 (M + 1) 380 5-trifluoro 2,2,2-trifluoro
Analysis for C.sub.20H.sub.18F.sub.6N.sub.2O.sub.2 HCl: calcd: C,
methoxy ethyl 51.24; H, 4.08; N, 5.98; found: C, 51.33; H, 4.09; N,
6.26; ISMS 433 (M + 1)
EXAMPLE 381
N-t-Butoxycarbonyl-2-(5-in-tolyloxy-1H-indol-3-yl)ethylamine
[0494] The method of Example 20 gives the title compound: .sup.1H
NMR (300 MHz, CDCl.sub.3) 1.41 (s, 9H), 2.30 (s, 3H), 2.89 (t, 2H,
J=6.7 Hz), 3.41(m, 2H), 6.74-6.85 (m, 3H), 6.93-6.99 (m, 1H),
7.07-7.35 (m, 4H), 8.05 (br, 1H).
EXAMPLE 382
N-Methyl-2-(5-m-tolyl)tryptamine
[0495] The method of Example 21 gives the title compound and
formation of the oxalate salt gave: m.p. 182-183.degree. C.;
.sup.1H NMR (250 MHz, DMSO-d6) 2.26 (s, 3H), 2.59 (s, 3H),
2.98-3.18 (m, 4H), 6.68-6.72 (m, 2H), 6.82-6.86 (m, 2H), 7.17-7.22
(m, 1H), 7.29-7.42 (m, 3H), 11.06 (br, 1H); MS (ELECTROSPRAY) m/e:
281.2 (M+1-C.sub.2H.sub.2O.sub.4); Anal. calcd.
C.sub.20H.sub.22N.sub.2O.sub.5: C, 64.85; H, 5.99; N, 7.56. Found:
C, 65.01; H, 5.74; N, 7.71.
EXAMPLE 383
N-Methyl-N-(2-(5-m-tolyloxy-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine
[0496] ##STR46##
[0497] The method of Example 301 gives the title compound and
formation of the oxalate salt gave: m.p. 142-144.degree. C.;
.sup.1H NMR (250 MHz, DMSO-d6) 2.24 (s, 3H), 2.634 (s, 3H),
3.01-3.12 (m, 4H), 3.92 (br, 2H)), 4.16 (s, 2H), 6.65-6.70 (m, 2H),
6.81-6.84 (m, 2H), 6.99-7.03 (m, 3H), 7.12-7.26 (m, 6H), 7.34-7.43
(m, 4H), 11.00 (br, 1H); MS (ELECTROSPRAY) m/e: 463.4
(M+1+C.sub.2H.sub.2O.sub.4); Anal. calcd.
C.sub.33H.sub.32N.sub.2O.sub.6: C, 71.72; H, 5.84; N, 5.07. Found:
C, 71.44; H, 5.89; N, 4.99.
EXAMPLE 384
5-Nitrotryptamine
[0498] Warm mixture of 5-nitroindole (10 g, 62 mmol) and 200 mL
glacial acetic acid to 70.degree. C. and treat with Eschenmoser's
salt (12 g, 65 mmol). Concentrate after 1 hour the reaction under
vacuum to dryness. Mix the residue with 200 mL toluene,
reconcentrate to dryness then partition between 200 mL concentrated
ammonium hydroxide and 200 mL EtOAc. When all solids dissolved,
Separate the layers and extract the aqueous layer 200 mL EtOAc. Dry
the combined organic layer over MgSO.sub.4 and concentrate to give
N,N-dimethyl-5-nitrotryptamine as a solid. Dissolve the
N,N-dimethyl-5-nitrotryptamine obtained above in 200 mL dry DMSO,
treat with iodomethane (7.7 mL, 17.5 g, 124 mmol), and stir for 1
hour at ambient temperature. Add KCN (40 g, 621 mmol) and
18-crown-6 (0.5 g). Warm the reaction to 110.degree. C. for 45
minutes, cool, poured onto ice then saturate with NaCl. Extract the
quenched reaction mixture with EtOAc, combine the extracts, and
wash 3 times with brine. Dry over MgSO.sub.4 and concentrate under
vacuum. chromatograph on silica gel eluting with 1% MeOH in
CHCl.sub.3 to give (5-nitro-1H-indol-3-yl)acetonitrile as a solid:
FDMS 201 (M+); Analysis for C.sub.10H.sub.7N.sub.3O.sub.2: calcd:
C, 59.70; H, 3.51; N, 20.89; found: C, 59.32; H, 3.52; N,
20.56.
[0499] Dissolve (5-nitro-1H-indol-3-yl)-acetonitrile (9 g, 44.7
mmol) in 250 mL dry THF and treat with 90 mL 1 M B.sub.3 in THF at
ambient temperature. Stir overnight and quench the reaction
cautiously by the dropwise addition of 10 mL water. Concentrate to
dryness under vacuum and partition the residue between 5 N HCl and
EtOAc. Extract the aqueous layer with EtOAc and combine with the
original EtOAc layer. Treat the aqueous layer with 5 N NaOH and
extract 3 times with 10% MeOH in EtOAc. Purify by flushing the
extracts through a pad of 100 g SCX ion exchange resin, rinsing
with 2 liters of MeOH which was discarded, and then eluting with
the 2 M N3 in MeOH and concentrating to give the title compound as
a dark solid: ISMS 206 (M+1); Analysis for
C.sub.20H.sub.18F.sub.6N.sub.2O.sub.2 0.3H.sub.2O
0.1C.sub.7H.sub.8: calcd: C, 57.34; H, 5.74; N, 19.29; found: C,
57.30; H, 5.38; N, 19.08; .sup.1H NMR (DMSO-d6) 11.9-11.2 (bs, 1H),
8.50-8.49 (d, 1H), 7.95-7.92 (m, 1H), 7.47-7.45 (m, 1H), 7.38 (s,
1H), 2.79 (s, 4H), 2.2-1.3 (bs, 2H).
EXAMPLE 385
6-Nitrotryptamine
[0500] The method of Example 384 gives
(6-nitro-1H-indol-3-yl)-acetonitrile: ISMS 200 (M-1); Analysis for
C.sub.10H.sub.7N.sub.3O.sub.2 0.1H.sub.2O: calcd: C, 59.17; H,
3.58; N, 20.70; found: C, 59.04; H, 3.28; N, 20.39 which gives the
title compound: ISMS 206 (M+1); .sup.1H NMR (DMSO-d6) 11.5 (bs,
2H), 8.26 (s, 1H), 7.84-7.81 (m, 1H), 7.68-7.66 (m, 1H), 7.57 (s,
1H), 2.80-74 (m, 4H) (indole N--H not observable).
EXAMPLE 390
N-(2-(5-Nitro-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine
[0501] ##STR47##
[0502] The method of Example 340 gives the title compound, salt
formation in 10 mL EtOH with 0.25 mL 5 N HCl and 40 mL toluene then
concentrating to a solid give the hydrochloride of the title
compound: Analysis for C.sub.23H.sub.21N.sub.3O.sub.3 HCl 0.2 EtOH:
calcd: C, 64.62; H, 5.17; N, 9.75; found: C, 64.89; H, 5.40; N,
9.75; ISMS 388 (M+1).
[0503] By the method of Example 390 the following compounds were
prepared, isolated as the hydrochloride except where noted:
TABLE-US-00015 ##STR48## No. Z' R.sub.4 Data 391 5-nitro
2,2,2-trifluoro ISMS 444 (M + 1); Analysis for ethyl
C.sub.20H.sub.20ClF.sub.4N.sub.3O.sub.3.cndot.0.1 H2O: calcd: C,
52.87; H, 4.48; N, 9.74; found: C, 52.63; H, 4.34, N, 9.67 392
5-nitro 2,2,3,3- ISMS 444 (M + 1); Analysis for tetrafluoro
C.sub.20H.sub.20ClF.sub.4N.sub.3O.sub.3: calcd: C, 52.01; H, 4.36;
N, propyl 9.10; found: C, 51.94; H, 4.19; N, 8.93 393 6-nitro
2,2,2-trifluoro ISMS 394 (M + 1); .sup.1H NMR (CDCl.sub.3-freebase)
ethyl 8.47 (bs, 1H), 8.31-8.30 (m, 1H), 8.01-7.98 (m, 1H),
7.63-7.61 (m, 1H), 7.32-7.31 (m, 1H), 7.24-7.21 (m, 1H), 6.94-6.92
(m, 1H), 6.88 (s, 1H), 6.80-6.77 (m, 1H), 4.33-4.26 (m, 2H), 3.79
(s, 2H), 3.00-2.93 (m, 4H), 1.54 (s, 1H) 394 6-nitro 2,2,3,3- ISMS
426 (M + 1); Analysis for C.sub.20H.sub.19F.sub.4N.sub.3O.sub.3:
tetrafluoro calcd: C, 52.01; H, 4.36; N, 9.10; found: C, propyl
51.96; H, 4.16; N, 8.76 395 6-nitro 2,2,3,3,3- ISMS 444 (M + 1);
Analysis for C.sub.20H.sub.18F.sub.5N.sub.3O.sub.3: pentafluoro
calcd: C, 50.06; H, 3.99; N, 8.76; found: C, propyl 49.76; H, 3.86;
N, 8.67
EXAMPLE 396
5-Amino-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine
[0504] ##STR49##
[0505] Combine
N-(2-(5-nitro-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine
hydrochloride (250 mg, 0.64 mmol) and NiCl.sub.2-6H.sub.2O (460 mg,
1.9 mmol) in 30 mL MeOH and treat with NaBH.sub.4 (73 mg, 1.9
mmol). After 1 hour concentrate to dryness, partition between EtOAc
and concentrated NH.sub.4OH. Extract the aqueous layer with EtOAc,
combine the organic layer, dry over MgSO.sub.4 and concentrate to
dryness. Chromatograph on silica gel eluting with a stepwise
gradient 20/75/5 THF/hexanes/Et.sub.3N then 40/55/5
THF/hexanes/Et.sub.3N gives the title compound as an oil.
Additional chromatograph on silica gel eluting with 1% MeOH in
CHCl.sub.3 mixed with conc. NH.sub.4OH gives the title compound as
an oil. Treatment with in 10 mL EtOH with 0.25 mL 5 N HCl and 40 mL
toluene then concentrating give the title compound as the
hydrochloride: Analysis for C.sub.23H.sub.23N.sub.3O 2.6 HCl 0.6
EtOH: calcd: C, 59.66; H, 5.83; N, 9.07; found: C, 59.30; H, 5.48;
N, 8.82; ISMS 358 (M+1).
[0506] By the method of Example 396 the following compounds were
prepared, isolated as the hydrochloride except where noted:
TABLE-US-00016 ##STR50## No. Z' R.sub.4 Data 397 5-amino
2,2,2-trifluoro Analysis for C.sub.19H.sub.20F.sub.3N.sub.3O 2HCl
0.2 CHCl.sub.3 0.3 ethyl CH.sub.3OH: calcd: C, 49.85; H, 5.02; N,
8.94; found: C, 50.05; H, 4.99; N, 8.73; ISMS 364 (M + 1) 398
5-amino 2,2,3,3- .sup.1H NMR (DMSO-d6) 11.3 (bs, 1H), 10.25 (bs,
tetrafluoro 3H), 9.6 (bs, 2H), 7.6 (s, 1H), 7.5-7.35 (m, 4H),
propyl 7.3-7.2 (m, 1H), 7.2-7.0 (m, 2H), 6.9-6.5 (d, 1H), 4.65-4.5
(t, 2H), 4.25 (s, 2H), 3.3 (s, 4H); Analysis for
C.sub.20H.sub.21F.sub.4N.sub.3O 2HCl: calcd: C, 51.29; H, 4.95; N,
8.97; found: C, 51.26; H, 4.98; N, 8.26 399 6-amino 2,2,2-trifluoro
ISMS 363 (M+); C.sub.19H.sub.22C.sub.12F.sub.3N.sub.3O.cndot.0.4
H2O: ethyl calcd: C, 51.45; H, 5.18; N, 9.48; found: C, 51.45; H,
5.10; N, 9.63 400 6-amino 2,2,3,3- ISMS 393 (M+);
C.sub.20H.sub.23C.sub.12F.sub.4N.sub.3O.cndot.0.2 H2O: tetrafluoro
calcd: C, 50.90; H, 5.00; N, 8.90; found: C, propyl 50.73; H, 4.82;
N, 8.65
EXAMPLE 401
6-Fluorotryptamine
[0507] Combine 6-fluoroindole (108 g, 0.8 mol) and dichloromethane
(324 ml). Cool in an ice bath. Add trifluoroacetic acid (308 ml)
over a few minutes (exothermic). Add a solution of
Z-1-dimethylamino-2-nitroethylene (94.7 g, 0.816 mol) in
dichloromethane (600 ml) during 40 minutes while maintaining the
temperature at about 0-5.degree. C. After 45 minutes, warm to about
20.degree. C. After 2 hours, pour over 1.2 L ice water and stirring
overnight with seeding to give a solid. Collect the solid by
filtration, wash first with 100 ml of a mixture
dichloromethane-cyclohexane 1/1, then with 750 ml of water and dry
at 40.degree. C. to give 3-(2-nitrovinyl)-6-fluoroindole.
[0508] Combine LiAlH.sub.4 (48.8 g, 1.286 moles, 5 equiv.) and THF
(848 ml) and cool in an ice-water bath to about 6.degree. C. while
keeping the temperature below 32.degree. C. Add a solution of
3-(2-nitrovinyl)-6-fluoroindole (53 g, 0.257 mol, 1 equiv.) in THF
(694 ml) while keeping the temperature below about 31.degree. C.
Allow to stir at ambient temperature. After 2.5 hours, quench with
a mixture of 49 ml of water and 49 ml of THF, then with 49 ml of
NaOH 15% and finally with 49 ml of water. Keep the temperature
below -32.degree. C. during the quench. Stir for 1.5 hours, filter
through a celite bed and wash with THF. Evaporate to residue,
dissolve in 750 ml of diethyl ether and cool in an ice-water bath.
Add a solution of HCl/diethyl ether to give a solid. Stir for 1
hour, collect the solid by filtration, wash with diethyl ether, and
dry under reduced pressure at 45.degree. C. to give the
hydrochloride of the title compound.
EXAMPLE 402
N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylam-
ine
[0509] ##STR51##
[0510] Combine 6-fluorotryptamine hydrochloride (90 g, 0.419 mol)
and water (900 ml). Add an aqueous solution of NaOH (2N, 230 ml)
and dichloromethane (900 ml). After 1 hour, separate the organic
layer, extract the aqueous layer with dichloromethane, combine the
organic layers, wash water, dry over MgSO.sub.4, and evaporate to a
residue. Combine the residue and toluene (200 ml) and evaporate to
give 78.45 g of a brown oil. Combine the above 78.45 g with another
41.4 g batch to provide 6-fluorotryptamine. Combine
6-fluorotryptamine (119.85) and ethanol (3.325 L), add
2,2,3,3-tetrafluoropropylbenzaldehyde (176 g, 0.745 moles, 1.2
equiv.) and 150 g of molecular sieve 3 .ANG.. Heat to reflux. After
2 hours, cool to RT room temperature and add NaBH.sub.4 (35.2 g,
0.93 mol, 1.5 equiv.). After 1 hour, filter through celite and wash
with 500 ml of ethanol. Evaporate the filtrate under reduced
pressure to give an oily residue. Partition the residue between
water and dichloromethane. Separate the layers, extract the aqueous
later with dichloromethane, combine organic layers, wash with brine
and dry over MgSO.sub.4. Filter and evaporate under reduced
pressure to give the title compound.
[0511] The HCl salt is formed as follows: Combine
N-(2-(6-fluror-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropyl)benzylam-
ine (387 g, 0.97 moles) and diethyl ether (3.95 L) of at room
temperature. Add dropwise a solution of HCl/Et.sub.2O (298 ml) over
15 minutes until the pH is about 3 to give a solid. Stir for 1 hour
and collect the solid, wash with ether, and dry under reduced
pressure for at 40.degree. C. to give the title compound as the
hydrochloride.
EXAMPLE 410
(5-Bromo-1H-indol-3-yl)acetonitrile
[0512] The method of Example 384 using 5-bromoindole gives the
title compound: ISMS 234 (M-1); Analysis for
C.sub.10H.sub.7BrN.sub.2 0.1H.sub.2O: calcd: C, 50.70; H, 3.06; N,
11.83; found: C, 50.69; H, 2.90; N, 11.64; .sup.1H NMR (CDCl.sub.3)
8.22 (s, 1H), 7.70-7.69 (m, 1H), 7.33-7.31 (m, 1H), 7.24 (s, 1H),
7.23-7.22 (m, 1H), 3.78-3.77 (m, 4H).
EXAMPLE 411
5-Bromotryptamine
[0513] Dissolve 5-bromo-1H-indole-3-carbonitrile (9.5 g, 40.4 mmol)
in 200 mL dry THF and treat with 80 mL 1 M B.sub.3 in THF at
ambient temperature. Stir overnight, the reaction and cautiously
quench by dropwise addition of 5 mL water. Concentrate to dryness
under vacuum and the residue. Partition between 1 N HCl and EtOAc.
Extract the organic layer with 1 N HCl which was combined with the
original aqueous layer. The Treat the aqueous layer with 5 N NaOH
and extract with EtOAc. Saturate with NaCl and extract again with
EtOAc. Combine the extracts dry over MgSO.sub.4 and concentrate to
dryness to give 4.72 g (19.7 mmol, 49%) of an oil which
crystallized.
[0514] Conversion to the oxalate salt by treating an EtOAc solution
of the compound with a solution of one equivalent of oxalic acid.
Filter the resulting solid and dry under vacuum: Analysis for
C.sub.10H.sub.11BrN.sub.2C.sub.2H.sub.2O.sub.2H.sub.2O: calcd: C,
43.08; H, 4.10; N, 8.37; found: C, 43.26; H, 3.91; N, 8.20; ISMS
240 (M+1).
EXAMPLE 413
5-Methoxycarbonyl-1H-indole
[0515] Combine 5-carboxyindole (7.2 g, 44.7 mmol) in 400 mL
dichloromethane and 100 mL MeOH and treat dropwise with 35 mL 2 M
TMS diazomethane in hexanes. Stir overnight at ambient temperature.
Concentration under vacuum to give the title compound as a solid:
Analysis for C.sub.10H.sub.9NO.sub.2 0.1H.sub.2O: calcd: C, 67.86;
H, 5.24; N, 7.91; found: C, 68.03; H, 5.15; N, 7.98; .sup.1H NMR
(CDCl.sub.3) 8.44 (bs, 1H), 8.412-8.409 (m, 1H), 7.91-7.88 (m, 1H),
7.46-7.38 (m, 1H), 7.26-7.24 (m, 1H), 6.64-6.63 (m, 1H), 3.92 (s,
3H); ISMS 176 (M+1).
EXAMPLE 414
3-Formyl-5-methoxycarbonyl-1H-indole
[0516] Place anhydrous DMF (25 mL) in a flask under an atmosphere
of nitrogen, cool to 10.degree. C. and treat dropwise with
POCl.sub.3 (8.22 g, 54 mmol) while keeping the temperature below
15.degree. C. Add a solution of 5-methoxycarbonyl-1H-indole in 30
mL DMF portionwise keeping the temperature below 20.degree. C.
Remove the cooling bath and stir the mixture at ambient temperature
for 1 hour then pour onto ice. Addition of 50 mL 5 N NaOH
precipitated a solid which is filtered and rinsed with water and
EtOAc to give the title compound: .sup.1H NMR (DMSO-d6) 9.95 (s,
1H), 8.76 (s, 1H), 8.4 (s, 1H), 7.9-7.8 (m, 1H), 7.5-7.7 (d, 1H),
3.85 (s, 3H), 1.7 (s, 1H); ISMS 204 (M+1).
EXAMPLE 415
3-(2-Nitroethyl)-5-methoxycarbonyl-1H-indole
[0517] The method of Example 317 to give the title compound:
.sup.1H NMR (DMSO-d6) 12.5 (bs, 1H), 8.38-8.37 (m, 1H), 8.37-8.34
(m, 1H), 8.23 (s, 1H), 7.87-7.84 (m, 1H), 7.80-7.77 (m, 1H),
7.57-7.55 (d, 1H), 3.85 (s, 3H); ISMS 246 (M+1).
EXAMPLE 416
3-(2-Nitroethyl)-5-methoxycarbonyl-1H-indole
[0518] Treat a solution of
3-(2-nitrovinyl)-5-methoxycarbonyl-1H-indole (57 mg, 0.23 mmol) in
9 mL THF and 2 mL MeOH with NaBH.sub.4 (26 mg, 0.69 mmol). Stir at
ambient temperature overnight, concentrate to dryness and partition
between conc. NH.sub.4OH (10 mL) and dichloromethane. Extract the
aqueous layer with dichloromethane, acidify with conc. HCl and
extract twice with dichloromethane. Combine the organic layers,
concentrate, and chromatograph on silica gel eluting with 1% MeOH
in CHCl.sub.3 to give the title compound as a solid: .sup.1H NMR
(CDCl.sub.3) 8.35 (bs, 1H), 8.32 (s, 1H), 7.92-7.90 (m, 1H),
7.38-7.36 (d, 1H), 7.12-7.11 (m, 1H), 4.69-4.65 (t, 2H), 3.93 (s,
3H), 3.51-3.48 (t, 2H); ISMS 248 (M+).
EXAMPLE 417
5-Methoxycarbonyltryptamine
[0519] Combine 3-(2-nitroethyl)-5-methoxycarbonyl-1H-indole (280
mg, 1.1 mmol), PtO.sub.2 (200 mg) and 15 mL MeOH and hydrogenate at
atmospheric pressure overnight. Filter reaction mixture through a
pad of celite, concentrate the filtrate, and chromatograph on
silica gel eluting with 5% MeOH in CHCl.sub.3 mixed with conc.
NH.sub.4OH to give the title compound as an oil: ISMS 219 (M+1);
.sup.1H NMR (CDCl.sub.3) 9.01 (s, 1H), 8.36 (s, 1H), 7.88-7.85 (m,
1H), 7.32-7.24 (m, 1H), 7.05 (s, 1H), 3.91 (s, 3H), 3.05-3.01 (m,
2H), 2.93-2.89 (m, 2H), 1.22 (bs, 2H).
EXAMPLE 418
2-(2-(5-Benzyloxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione
[0520] Combine 5-benzyloxytryptamine hydrochloride (1 g, 3.3 mmol),
phthalic anhydride (0.56 g, 4.0 mmol) and N,N-diisopropylethylamine
(0.86 g, 6.6 mmol) in 25 mL anhydrous pyridine and reflux for 1
hour, cool to room temperature and treat with 4 g 3 .ANG. molecular
sieves. Refluxing was continued for 60 hours then the mixture was
filtered. Concentrate under vacuum to give a residue which is mixed
with 25 mL CHCl.sub.3 and filtered to give a solid. Purification of
the filtrate by chromatography on silica gel eluting with 1% MeOH
in CHCl.sub.3 to give an additional amount of title compound: ISMS
397 (M+1); Analysis for C.sub.25H.sub.20N.sub.2O.sub.3 0.3H.sub.2O
C.sub.7H.sub.8: calcd: C, 75.09; H, 5.25; N, 6.82; found: C, 75.00;
H, 5.22; N, 6.96.
[0521] By the method of Example 418 the following compounds were
prepared: a)
2-(2-(5-Hydroxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione: (4.5 mmol,
95%); .sup.1H NMR (DMSO-d6) 10.47 (s, 1H), 8.59 (bs, 1H), 7.84-7.78
(m, 4H), 7.09-7.06 (d, 1H), 7.03-7.02 (d, 1H), 6.85-6.84 (d, 1H),
6.56-6.54 (m, 1H), 3.79-3.75 (t, 2H), 2.91-2.87 (m, 2H).
EXAMPLE 419
2-(2-(5-Hydroxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-di-
one
[0522] Combine a mixture of an oil dispersion of KH (40%, 1 g) in
30 mL anhydrous THF and a suspension of
2-(2-(5-benzyloxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione (1.2 g, 3
mmol) in 30 mL THF portionwise. Stir for 1 hour at ambient
temperature, cooled to 0.degree. C., add
triisopropylsilyltrifluoromethanesulfonate (1.85 g, 6 mmol) and
stir an additional 1 hour at ambient temperature. Pour the reaction
into a rapidly stirring solution of saturated NaHCO.sub.3 and
extract with 2.times.50 mL EtOAc. Combine the organic layer, dry
over MgSO.sub.4 and concentrate to dryness and chromatograph on
silica gel eluting with 1% MeOH in CHCl.sub.3 to give
2-(2-(5-benzyloxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-
-dione as an oil.
[0523] Combine
2-(2-(5-benzyloxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-
-dione and EtOAc (40 mL) and hydrogenated overnight with 1 g 5%
Pd/C at atmospheric pressure. Filter through celite, concentrate to
dryness, and chromatograph on silica gel eluting stepwise with a
gradient 10% EtOAc in hexanes to 30% EtOAc in hexanes to give the
title compound as a solid: FDMS 462 (M+1) Analysis for
C.sub.27H.sub.24N.sub.2O.sub.3Si H.sub.2O: calcd: C, 69.55; H,
7.44; N, 6.01; Found: C, 69.44; H, 7.17; N, 6.00.
EXAMPLE 420
2-(2-(5-Propoxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-di-
one
[0524] Combine
2-(2-(5-hydroxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-d-
ione (0.7 g, 1.5 mmol), cesium carbonate (1 g, 3 mmol) and
1-iodopropane (0.4 g, 2.3 mmol) in DMF (25 mL) and stir at ambient
temperature overnight. Pour the reaction mixture into 50% EtOAc in
hexanes and wash three times with brine. Dry the organic layer over
MgSO.sub.4 and concentrate under vacuum to give an oil.
Chromatograph the oil on silica gel eluting with 5% EtOAc in
hexanes to give the title compound: ISMS 505 (M+1); .sup.1H NMR
(CDCl.sub.3) 7.80-7.78 (m, 2H), 7.67-7.65 (m, 2H), 7.30-7.27 (d,
1H), 7.12-7.11 (d, 1H), 7.02 (s, 1H), 6.77-6.74 (m, 1H), 4.01-3.96
(m, 4H), 3.12-3.08 (m, 2H), 1.86-1.81 (in 2H), 1.64-1.57 (m, 3H),
1.08-1.04 (m, 21H).
EXAMPLE 421
5-Propoxy-1-triisopropylsilanyltryptamine
[0525] Combine
2-(2-(5-propoxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-d-
ione (416 mg, 0.8 mmol) in 20 mL EtOH and 1 mL hydrazine hydrate.
Reflux for 3 hours, filter through celite and concentrate to
residue. Dissolve the residue in 10 mL MeOH and load onto a 12 g
SCX ion exchange cartridge and rinse sequentially with MeOH, DMF,
then MeOH. Elute the product with 2 M N3 in MeOH to give the title
compound as an oil: ISMS 375 (M+1); .sup.1H NMR (CDCl.sub.3)
7.34-7.32 (d, 1H), 7.02 (s, 1H), 7.00-6.99 (d, 1H), 6.80-6.77 (m,
1H), 3.97-3.94 (m, 2H), 3.01-2.98 (m, 2H), 2.86-2.83 (m, 2H),
1.88-1.76 (m, 2H), 1.70-1.58 (m, 3H), 1.3 (bs, 2H), 1.14-1.08 (m,
18H), 1.06-1.02 (t, 3H).
EXAMPLE 422
6-Benzyloxytryptamine
[0526] Add to a mixture of LAH (6.2 g, 163.1 mmol) and 300 mL dry
THF a solution of 3-(2-nitrovinyl)-6-benzyloxy-1H-indole (9 g, 30.6
mmol) in 200 mL THF. Reflux the mixture overnight and then cool to
0.degree. C. and quench sequentially with 6.2 mL water, 6.2 mL 15%
aqueous NaOH and 18.6 mL water. After stirring 2 hours, filter
through celite and concentrate to give 7.9 g (96%) of the title
compound as an oil: .sup.1H NMR (CDCl.sub.3) 8.06 (bs, 1H),
7.47-7.43 (m, 3H), 7.38-7.35 (m, 2H), 7.32-7.28 (m, 1H), 6.88-6.84
(m, 3H), 5.08 (s, 2H), 3.01-2.97 (m, 2H), 2.87-2.83 (m, 2H), 1.6
(bs, 2H).
EXAMPLE 423
N-t-Butoxycarbonyl-2-(6-benzyloxy-1H-indol-3-yl)ethylamine
[0527] The method of Example 20 gives the title compound: .sup.1H
NMR (CDCl.sub.3) 7.84 (bs, 1H), 9.36 (s, 2H), 8.91 (s, 1H),
7.38-7.33 (m, 2H), 7.28-7.26 (m, 1H), 7.20-7.18 (m, 1H), 7.09-7.07
(m, 1H), 6.94-6.93 (m, 1H), 6.68-6.67 (m, 1H), 6.50-6.47 (m, 1H),
4.79-4.72 (m, 2H), 4.13 (s, 2H), 3.05-3.02 (m, 4H).
EXAMPLE 425
N-t-Butoxycarbonyl-2-(6-hydroxy-1H-indol-3-yl)ethylamine
[0528] The method of Example 471 gives the title compound.
EXAMPLE 428
2-(2-(5-Ethoxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione
[0529] Combine
2-(2-(5-hydroxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione (900 mg,
2.9 mmol), cesium carbonate (960 mg, 2.9 mmol) and 1-iodoethane
(920 mg, 5.9 mmol) in N-methylpyrrolidinone (5 mL) and stir at
ambient temperature for 4 hours, pour into brine and extract twice
with EtOAc. Wash the combined extracts three times with brine, dry
over MgSO.sub.4, and concentrate under vacuum to give an oil.
Chromatograph the oil on silica gel eluting with 20% EtOAc in
hexanes to give the title compound as a white solid: ISMS 335
(M+1); Analysis for C.sub.20H).sub.8N.sub.2O.sub.3: calcd: C,
71.84; H, 5.43; N, 8.38; found: C, 71.97; H, 5.47; N, 8.36.
[0530] By the method of Example 428 the following compounds were
prepared:
[0531] a)
2-(2-(5-Isopropoxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione: ISMS
348 (M+) .sup.1H NMR (CDCl.sub.3) 7.94 (bs, 1H), 7.82-7.80 (m, 2H),
7.70-7.67 (m, 2H), 7.21-7.19 (d, 1H), 7.18 (s, 1H), 7.05-7.04 (d,
1H), 6.82-6.79 (m, 1H), 4.55-4.49 (m, 1H), 3.99-3.95 (m, 2H),
3.11-3.07 (m, 2H), 1.64-1.33 (d, 6H);
[0532] b)
2-(2-(5-(2,2,2-Trifluoroethoxy)-1H-indol-3-yl)ethyl)isoindole-1-
,3-dione: ISMS 389 (M+1); Analysis for
C.sub.20H.sub.15F.sub.3N.sub.2O.sub.3: calcd: C, 61.86; H, 3.89; N,
7.21; found: C, 61.77; H, 3.83; N, 7.20;
[0533] c) 2-(2-(5-Butoxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione:
ISMS 363 (M+1); Analysis for C.sub.22H.sub.22N.sub.2O.sub.3: calcd:
C, 72.91; H, 6.11; N, 7.73; found: C, 72.76; H, 6.09; N, 7.42;
.sup.1H NMR (CDCl.sub.3) 7.86-7.81 (m, 3H), 7.72-7.68 (m, 2H),
7.23-7.20 (m, 1H), 7.16-7.15 (m, 1H), 7.08-7.07 (m, 1H), 6.85-6.84
(m, 1H), 6.4.02-3.98 (m, 4H), 3.13-3.09 (m, 2H), 1.83-1.76 (m, 2H),
1.56-148 (m, 2H), 1.01-0.98 (t, 3H);
[0534] d) 2-(2-(5-Nitro-1H-indol-3-yl)ethyl)isoindole-1,3-dione:
ISMS 334 (M-1); Analysis for C.sub.18H.sub.13N.sub.3O.sub.4
0.1H.sub.2O: calcd: C, 64.13; H, 3.95; N, 12.47; found: C, 64.05;
H, 3.82; N, 12.27.
[0535] By the method of Example 421 the following compounds were
prepared:
[0536] a) 5-Ethoxytryptamine: ISMS 205 (M+1); Analysis for
C.sub.12H.sub.16N.sub.2O H.sub.2O: calcd: C, 69.33; H, 7.95; N,
13.48; found: C, 69.62; H, 7.75; N, 13.30;
[0537] b) 5-Isopropoxytryptamine: ISMS 219 (M+1); .sup.1H NMR
(CDCl.sub.3) 8.57 (bs, 1H), 7.20-7.18 (d, 1H), 7.08-7.07 (d, 1H),
6.95 (s, 1H), 6.84-6.82 (m, 1H), 4.54-4.48 (m, 1H), 3.01-2.98 (m,
2H), 2.86-2.83 (m, 2H), 1.38 (bs, 2H), 1.35-1.33 (d, 6H);
[0538] c) 5-(2,2,2-Trifluoroethoxy)tryptamine: ISMS 258 (M+);
.sup.1H NMR (CDCl.sub.3) 9.33 (bs, 1H), 7.26-7.24 (d, 1H),
7.09-7.08 (d, 1H), 7.03-7.02 (m, 1H), 6.90-6.87 (m, 1H), 4.40-4.34
(m, 2H), 3.03-3.00 (m, 2H), 2.87-2.84 (m, 2H), 1.44 (bs, 2H);
[0539] d) 5-Butyloxytryptamine: .sup.1H NMR (CDCl.sub.3) 8.08 (bs,
1H), 7.23-7.21 (d, 1H), 7.03-7.02 (d, 1H), 7.03-7.02 (m, 1H),
6.98-6.83 (m, 1H), 4.01-3.98 (m, 2H), 3.02-2.99 (m, 2H), 2.87-2.84
(m, 2H), 1.82-1.74 (m, 2H), 1.56-1.50 (m, 2H), 1.32 (bs, 2H)
1.00-0.96 (t, 3H);
EXAMPLE 429
5-Benzenesulfonyl-1H-indole
[0540] Place a 35% oil dispersion of KH (6 g) in a flask under
nitrogen, rinse with 50 mL hexanes and dry under vacuum. Cool the
solid suspension in 100 mL anhydrous DMF to 0.degree. C. Add
dropwise over 10 minutes a solution of 5-bromoindolc (10.3 g, 52.5
mmol) in 25 mL DMF. Stir the mixture 1 hour at 0.degree. C. then
treat with triisopropylsilyltrifluoromethane sulfonate (32.2 g,
105.1 mmol). Remove the cooling bath and stir the reaction 72 hours
before pouring into 500 mL water and extracting with EtOAc. Dilute
the combined extracts with hexanes, wash with brine then dry over
MgSO.sub.4. Concentration under vacuum and chromatograph on silica
gel eluting with 1% EtOAc in hexanes to give
5-Bromo-1-triisopropylsilanyl-1H-indole as a colorless oil: .sup.1H
NMR (CDCl.sub.3) 7.73-7.72 (d, 1H), 7.36-7.34 (d, 1H), 7.24-7.23
(d, 1H), 7.21-7.19 (m, 1H), 6.55-6.54 (m, 1H), 1.72-1.61 (m, 3H),
1.13-1.10 (m, 18H).
[0541] Cool a solution of 5-bromo-1-triisopropylsilanyl-1H-indole
(9 g, 25.5 mmol) in 550 mL anhydrous THF to -75.degree. C. under
argon and treat with 1.7 M t-butyl lithium (33 mL, 56.2 mmol) while
keeping the temperature below 60.degree. C. After the addition,
recool the reaction mixture to about -73.degree. C. before adding a
solution of phenylsulfonyl fluoride (4.6 g, 28.7 mmol) in 30 mL
THF. Stir the reaction at -78.degree. C. for 1 hour then quench
with saturated NaHCO.sub.3 followed by brine. Separate the layers
and extract the aqueous layer with EtOAc. Treat the combined
organic layers with 1 M tetrabutylammonium fluoride (35 mL) in THF
for 1 hour at ambient temperature, then concentrate to dryness.
Combine the residue with EtOAc, wash twice with 1 N HCl, dry over
MgSO.sub.4, and concentrate to an oil. Chromatograph the oil on
silica get eluting stepwise with 50% CHCl.sub.3 in hexanes followed
by 50% CHCl.sub.3 in MeOH give an oily solid. Triturate the oily
solid with CHCl.sub.3 to give the title compound as a solid:
Analysis for C.sub.14H.sub.11NO.sub.2S H.sub.2O: calcd: C, 64.89;
H, 4.36; N, 5.41; found: C, 64.76; H, 4.45; N, 5.33; ISMS 257
(M+).
EXAMPLE 430
2-(2-(5-Amino-1H-indol-3-yl)ethyl)isoindole-1,3-dione
[0542] Combine a mixture of
2-(2-(5-nitro-1H-indol-3-yl)ethyl)isoindole-1,3-dione (1.8 g, 5.4
mmol), PtO.sub.2 (500 mg), 100 mL MeOH and 100 mL THF and
hydrogenate at atmospheric pressure overnight. Filter the reaction
through a pad of celite and concentrate to dryness. Redissolve the
residue in 50/50 chloroform/dichloromethane and refilter through a
pad of celite. Concentration under vacuum give the title compound
as a dark solid: ISMS 306 (M+1); Analysis for
C.sub.18H.sub.13N.sub.3O.sub.4 0.1C.sub.7H.sub.8 0.2
dichloromethane: calcd: C, 68.70; H, 4.89; N, 12.58; found: C,
69.08; H, 4.75; N, 12.69; .sup.1H NMR (CDCl.sub.3) 7.9-7.8 (m, 3H),
7.75-7.65 (m, 2H), 7.2-7.1 (m, 1H), 7.05-7.0 (m, 2H), 6.7-6.6 (m,
1H), 4.0-3.9 (m, 2H), 3.4 (bs, 2H), 3.1-3.0 (m, 2H).
EXAMPLE 431
2-(2-(5-Benzoylamino-1H-indol-3-yl)ethyl)isoindole-1,3-dione
[0543] Combine
2-(2-(5-amino-1H-indol-3-yl)ethyl)isoindole-1,3-dione (0.5 g, 1.64
mmol) and 4-dimethylaminopyridine (0.3 g, 2.5 mmol) and dissolve in
30 mL dichloromethane and cool to 0.degree. C. Treat the reaction
mixture with benzoyl chloride (276 mg, 1.96 mmol) and stir
overnight during which the temperature was allowed to warm to room
temperature. Concentrate to residue and chromatograph the residue
on silica gel eluting with 0.5% MeOH in CHCl.sub.3 to give the
title compound as a solid: ISMS 410 (M+1); .sup.1H NMR (CDCl.sub.3)
7.86-7.85 (m, 2H), 7.79 (s, 1H), 7.72-7.68 (m, 2H), 7.60-7.57 (m,
2H), 7.46-7.42 (m, 1H), 7.4-7.36 (m, 3H), 7.13-7.11 (d, 1H),
6.89-6.88 (m, 1H), 3.88-3.84 (t, 2H), 3.00-2.97 (t, 2H).
[0544] By the method of Example 431 the following compounds were
prepared:
[0545] a)
2-(2-(5-Methanesulfonylamino-1H-indol-3-yl)ethyl)isoindole-1,3--
dione: ISMS 384 (M+1); .sup.1H NMR (CDCl.sub.3) 10.84 (s, 1H), 9.21
(s, 1H), 7.83-7.76 (m, 4H), 7.39-7.38 (m, 1H), 7.27-7.24 (m, 1H),
7.17-7.16 (m, 1H), 6.96-6.93 (m, 1H), 3.83-3.80 (m, 2H), 2.98-2.94
(m, 2H), 2.79 (s, 3H), 3.88-3.84 (t, 2H), 3.00-2.97 (t, 2H).
[0546] By the method of Example 421 the following compounds were
prepared:
[0547] a) 5-Benzoylaminotryptamine: .sup.1H NMR (CD.sub.3OD)
7.94-7.92 (m, 2H), 7.85 (s, 1H), 7.54-7.47 (m, 3H), 7.34-7.29 (m,
2H), 7.08 (s, 1H), 4.86 (s, 2H), 3.33 (s, 2H), 2.95-2.86 (m, 4H);
and
[0548] b) 5-Methanesulfonylaminotryptamine: ISMS 253 (M+); .sup.1H
NMR (CD.sub.3OD) 7.46-7.45 (d, 1H), 7.31-7.28 (d, 1H), 7.08 (s,
1H), 7.04-7.01 (m, 1H), 4.86 (s, 4H), 2.89-2.83 (m, 7H).
EXAMPLE 432
5-Ethoxycarbonyl-1H-indole
[0549] Combine 5-carboxyindole (4.8 g, 29.8 mmol) in 150 mL THF and
carbonyldiimidazole (9.7 g, 59.6 mmol) and stir overnight at
ambient temperature. Treat the reaction mixture with 25 mL EtOH and
1.2 g (29.8 mmol) of a 60% oil dispersion of NaH and stir for 2
hours. Concentration under vacuum gives a residue. Partition the
residue between 150 mL EtOAc and 100 mL brine. Separate the layers,
dry the organic layer over MgSO.sub.4, filter, and concentrated to
an oil. Chromatograph on silica gel eluting with 1% MeOH in
CHCl.sub.3 to give 7.2 g of an oil. Crystallize the oil from
toluene gives the title compound: Analysis for
C.sub.11H.sub.11NO.sub.2: calcd: C, 69.83; H, 5.86; N, 7.40; found:
C, 69.82; H, 5.90; N, 7.38; ISMS 190 (M+1).
EXAMPLE 433
5-(N-Butylamido)-1H-indole
[0550] Dissolve mixture of 5-carboxyindole (5 g, 31 mmol) in 150 mL
THF and treat with carbonyldiimidazole (5 g, 31 mmol) and stir
overnight at ambient temperature. Treat the reaction mixture with
n-butylamine 4.5 g (62 mmol) and reflux for 1 hour. Concentration
under vacuum gives a residue which is dissolved in EtOAc. Wash
sequentially with 5 N HCl, 5 N NaOH, and then brine. Dry the
organic layer over MgSO.sub.4 and concentrated to give the title
compound as an oil: .sup.1H NMR (CDCl.sub.3) 8.54 (bs, 1H),
8.07-8.06 (m, 1H), 7.63-7.61 (m, 1H), 7.39-7.37 (m, 1H), 7.26-7.24
(m, 1H), 6.60-6.59 (m, 1H), 6.14 (bs, 1H), 3.5-3.45 (m, 2H),
1.64-1.57 (m, 2H), 1.47-1.37 (m, 2H), 0.97-0.93 (m, 3H); EIMS 217
(M+1).
EXAMPLE 434
5-(N-Propylamido)-1H-indole
[0551] The method of Example 433 gives the title compound: .sup.1H
NMR (CDCl.sub.3) 8.07 (bs, 1H), 8.07 (s, 1H), 7.63-7.60 (m, 1H),
7.38-7.36 (m, 1H), 7.25-7.24 (m, 1H), 6.59-6.58 (m, 1H), 6.21 (bs,
1H), 3.46-3.41 (m, 2H), 1.69-1.60 (m, 2H), 1.00-0.96 (m, 3H); EIMS
203 (M+1).
[0552] By the method of Example 414 the following compounds were
prepared:
[0553] a) 3-Formyl-5-benzenesulfonyl-1H-indole: ISMS 286 (M+1);
.sup.1H NMR (DMSO-d6) 9.83 (s, 1H), 8.55 (s, 1H), 7.89-7.86 (m,
2H), 7.61 (s, 2H), 7.59-7.52 (m, 3H), 1.70 (s, 3H).
[0554] b) 3-Formyl-5-ethoxycarbonyl-1H-indole: Analysis for
C.sub.12H.sub.11NO.sub.3: calcd: C, 66.35; H, 5.10; N, 6.45; found:
C, 65.97; H, 5.17; N, 6.46; ISMS 218 (M+1);
[0555] c) 3-Formyl-N-butylamido-1H-indole: Analysis for
C.sub.14H.sub.16N.sub.2O.sub.2 0.1H.sub.2O: calcd: C, 68.33; H,
6.64; N, 11.38; found: C, 68.35; H, 6.24; N, 11.30; ISMS 245
(M+1);
[0556] d) 3-Formyl-5-(N-propylamido)-1H-indole: Analysis for
C.sub.13H.sub.14N.sub.2O.sub.2: calcd: C, 67.81; H, 6.13; N, 12.16;
found: C, 67.42; H, 6.04; N, 12.10; .sup.1H NMR (DMSO-d6) 9.95 (s,
1H), 8.6 (s, 1H), 8.48-8.45 (t, 1H), 8.36-8.35 (m, 1H), 7.76-7.73
(m, 1H), 7.52-7.50 (d, 1H), 3.32 (bs, 1H), 3.24-3.19 (m, 2H),
1.58-1.48 (m, 2H), 0.90-0.86 (m, 3H); EIMS 230 (M+);
[0557] e) 3-Formyl-6-benzyloxy-1H-indole: .sup.1H NMR (DMSO-d6)
11.93 (s, 1H), 9.83 (s, 1H), 8.12-8.11 (m, 1H), 7.92-7.90 (m, 1H),
7.45-7.27 (m, 5H), 7.04-7.03 (m, 1H), 6.92-6.89 (m; 1H), 5.11 (s,
2H).
[0558] By the method of Example 415 the following compounds were
prepared: a) 5-Benzenesulfonyl-3-(2-nitrovinyl)-1H-indole: Analysis
for C.sub.16H.sub.12N.sub.2O.sub.4S 0.1H.sub.2O: calcd: C, 58.42;
H, 3.83; N, 8.31; found: C, 58.63; H, 3.52; N, 8.02; ISMS 229
(M+1);
[0559] b) 3-(2-Nitrovinyl)-5-ethoxycarbonyl-1H-indole: Analysis for
C.sub.16H.sub.12N.sub.2O.sub.4S 0.1H.sub.2O: calcd: C, 58.42; H,
3.83; N, 8.31; found: C, 58.63; H, 3.52; N, 8.02; ISMS 229
(M+1);
[0560] c) 3-(2-Nitro-vinyl)-N-butylamido-1H-indole: Analysis for
C.sub.15H.sub.17N.sub.3O.sub.3: calcd: C, 62.71; H, 5.96; N, 14.62;
found: C, 62.46; H, 5.81; N, 14.38; ISMS 288 (M+1);
[0561] d) 3-(2-Nitro-vinyl)-N-propylamido 1H-indole: ISMS 273
M(+1); .sup.1H NR (DMSO-d6) 12.38 (s, 1H), 8.62-8.59 (t, 1H),
8.43-8.39 (d, 1H), 8.37 (s, 1H), 8.31-8.30 (d, 1H), 8.18-8.15 (d,
1H), 7.84-7.82 (m, 1H), 7.55-7.53 (d, 1H), 3.31-3.24 (m, 2H),
1.61-1.52 (m, 2H), 0.92-0.89 (t, 3H); Analysis for
C.sub.14H.sub.15N.sub.3O.sub.3 0.1H.sub.2O: calcd: C, 61.12; H,
5.57; N, 15.28; found: C, 61.06; H, 5.38; N, 15.05;
[0562] e) 3-(2-Nitro-vinyl)-6-benzyloxy-1H-indole: .sup.1H NMR
(DMSO-d6) 11.85 (bs, 1H), 8.32-8.29 (m, 1H), 8.09 (s, 1H),
7.94-7.91 (m, 1H), 7.83-7.81 (m, 1H), 7.45-7.43 (m, 2H), 7.38-7.31
(m, 2H), 7.29-7.27 (m, 1H), 7.05-7.04 (m, 1H), 6.92-6.89 (m, 1H),
5.13 (s, 2H).
[0563] By the method of Example 416 the following compounds were
prepared:
[0564] a) 5-Benzenesulfonyl-3-(2-nitroethyl)-1H-indole: Analysis
for C.sub.16H.sub.14N.sub.2O.sub.4S 0.1H.sub.2O: calcd: C, 57.85;
H, 4.31; N, 8.43; found: C, 57.72; H, 4.22; N, 8.25; ISMS 329
(M-1);
[0565] b) 3-(2-Nitroethyl)-5-ethoxycarbonyl-1H-indole: Analysis for
C.sub.13H.sub.14N.sub.2O.sub.4: calcd: C, 59.54; H, 5.38; N, 10.68;
found: C, 59.23; H, 5.25; N, 10.53; ISMS 263 (M+1),
[0566] c) 3-(2-Nitroethyl)-N-butylamido-1H-indole: Analysis for
C.sub.15H.sub.19N.sub.3O.sub.3: calcd: C, 62.27; H, 6.62; N, 14.52;
found: C, 61.98; H, 6.39; N, 14.42: ISMS 290 (M+1); and
[0567] d) 3-(2-Nitroethyl)-N-propylamido-1H-indole: .sup.1H NMR
(CDCl.sub.3) 8.52 (bs, 1H), 8.06 (s, 1H), 7.58-7.55 (m, 1H),
7.35-7.33 (m, 1H), 7.10-7.09 (m, 1H), 6.23 (bs, 1H), 4.65-4.61 (t,
2H), 3.48-3.43 (m, 4H), 1.71-1.62 (m, 2H), 1.01-0.98 (t, 3H);
Analysis for C.sub.14H.sub.17N.sub.3O.sub.3 0.1H.sub.2O: calcd: C,
60.68; H, 6.26; N, 15.16; found: C, 60.88; H, 6.05; N, 15.07.
[0568] By the method of Example 421 the following compounds were
prepared:
[0569] a) 5-Benzenesulfonyltryptamine: ISMS 301 (M+1); .sup.1H NMR
(HCl-DMSO-d6) (s, 1H), 8.3 (s, 1H), 8.2 (bs, 2H), 8.0-8.9 (m, 2H),
7.4-7.2 (m, 5H), 7.1-7.0 (m, 1H), 3.2-3.0 (s, 4H);
[0570] b) 5-Ethoxycarbonyltryptamine (isolated as the oxalate
salt): Analysis for
C.sub.13H.sub.16N.sub.2O.sub.2C.sub.2H.sub.2O.sub.4: calcd: C,
55.90; H, 5.63; N, 8.69; found: C, 56.07; H, 5.54; N, 8.29; ISMS
233 (M+1); and
[0571] c) 5-N-Butylamidotryptamine: Analysis for
C.sub.15H.sub.21N.sub.3O 0.3H.sub.2O: calcd: C, 68.05; H, 8.22; N,
15.87; found: C, 68.36; H, 8.11; N, 15.49; ISMS 260 (M+1); and
[0572] d) 5-N-Propylamidotryptamine:(isolated as the oxalate salt):
Analysis for C.sub.14H.sub.19N.sub.3O C.sub.2H.sub.2O.sub.4
0.1EtOAc: calcd: C, 57.23; H, 6.38; N, 12.21; found: C, 57.48; H,
6.53; N, 12.12; .sup.1H NMR (DMSO-d6) 11.2 (s, 1H), 8.4 (t, 1H),
8.2 (s, 1H), 7.75-7.65 (m, 1H), 7.6 (bs, 4H), 7.4-7.35 (m, 1H),
7.3-7.25 (d, 1H), 3.3-3.2 (m, 2H), .delta. 3.15-3.0 (m, 4H),
1.6-1.45 (m, 2H), 0.9-0.8 (t, 3H); ISMS 246 (M+1).
EXAMPLE 435
N-t-Butoxycarbonyl-2-(6-butoxy-1H-indol-3-yl)ethylamine
[0573] Combine
N-t-butoxycarbonyl-2-(6-hydroxy-1H-indol-3-yl)ethylamine (250 mg,
0.9 mmol), cesium carbonate (295 mg, 0.9 mmol) and 1-iodobutane
(200 mg, 1.1 mmol) and N-methylpyrrolidinone (10 mL) and stir at
ambient temperature for 2 hours and pour into 75 mL brine. Extract
the mixture twice with 25 mL EtOAc. Wash the combined extracts with
brine 2.times.50 mL, dry over MgSO.sub.4, and concentrate under
vacuum to give an oil.
[0574] Chromatograph the oil on silica gel eluting with 30% EtOAc
in hexanes to give the title compound as a solid: ISMS 333 (M+1);
Analysis for C.sub.19H.sub.28N.sub.2O.sub.3: calcd: C, 68.65; H,
8.49; N, 8.43; found: C, 68.83; H, 8.18; N, 8.33.
[0575] By the method of Example 435 the following compounds were
prepared: a)
N-t-Butoxycarbonyl-2-(6-ethoxy-1H-indol-3-yl)ethylamine: ISMS 305
(M+1); Analysis for C.sub.17H.sub.24N.sub.2O.sub.3: calcd: C,
67.08; H, 7.95; N, 9.20; found: C, 66.85; H, 7.79; N, 9.14.
EXAMPLE 436
6-Butoxytryptamine
[0576] Combine
N-t-butoxycarbonyl-2-(6-butoxy-1H-indol-3-yl)ethylamine (430 mg,
1.3 mmol), 1 mL anisole and 5 mL trifluoroacetic acid and stir at
room temperature for 2 hours. Concentrate the reaction to dryness
under vacuum, mix with 10 mL concentrated NH.sub.4OH and extract
with 20 mL dichloromethane. Dry the extract over MgSO.sub.4 and
concentrated to 300 mg oil (1.3 mmol, 100%).
[0577] By the method of Example 436 the following compounds were
prepared: a) 6-Ethoxytryptamine: ISMS 305 (M+1); Analysis for
C.sub.17H.sub.24N.sub.2O.sub.3: calcd: C, 67.08; H, 7.95; N, 9.20;
found: C, 66.85; H, 7.79; N, 9.14
EXAMPLE 437
N-t-Butoxycarbonyl-2-(6-phenylsulfonate-1H-indol-3-yl)ethylamine
[0578] Combine
N-t-butoxycarbonyl-2-(6-hydroxy-1H-indol-3-yl)ethylamine (750 mg,
2.7 mmol) and pyridine (430 mg, 5.4 mmol) in dichloromethane (30
mL) and cool to 0.degree. C. and treat with benzene sulfonyl
chloride (480 mg, 2.7 mmol). Allow the reaction to warm to room
temperature and stir overnight. Concentrate to dryness the mixture
under vacuum, mix with dichloromethane and chromatograph on silica
gel eluting with 30% EtOAc in hexanes to give
N-t-butoxycarbonyl-2-(6-phenylsulfonate-1H-indol-3-yl)ethylamine as
an oil: ISMS 415 (M-1); .sup.1H NMR (CDCl.sub.3) 8.14 (bs, 1H),
7.66-7.62 (m, 2H), 7.51-7.47 (m, 1H), 7.40-7.38 (m, 2H), 7.10 (s,
1H), 7.04-7.03 (m, 2H), 6.59-6.57 (m, 1H), 4.57 (bs, 1H), 3.40-3.80
(m, 2H), 2.89-2.86 (m, 2H), 1.41 (s, 9H).
[0579] Place
N-t-butoxycarbonyl-2-(6-phenylsulfonate-1H-indol-3-yl)ethylamine
(0.5 g, 1.2 mmol) in a flask with a stream of N.sub.2 passing
through it and heat to 200.degree. C. overnight and cool to room
temperature. Dissolve the residue in dichloromethane and
chromatography on silica gel eluting with 2% MeOH in
CHCl.sub.3--NH.sub.4OH to give the title compound as an oil.
[0580] By the method of Example 425 the following compounds were
prepared and isolated as the hydrochloride except where noted:
TABLE-US-00017 ##STR52## No. Z' R.sub.4 Data 438 5-propoxy phenyl
ISMS 401 (M + 1); Analysis for C.sub.20H.sub.18N.sub.2O.sub.3
0.1H.sub.2O: calcd: C, 71.17; H, 6.71; N, 6.38; found: C, 71.02; H,
6.54; N, 6.33; .sup.1H NMR (Free base-CDCl.sub.3) 7.93 (bs, 1H),
7.34-7.30 (m, 2H), 7.35-7.28 (m, 2H), 7.12-707 (m, 1H), 7.06-6.96
(m, 6H), 6.89-6.84 (m, 2H), 3.97-3.94 (m, 2H), 3.79 (s, 2H),
2.97-2.94 (m, 4H), 1.89-1.7 (m, 2H), 1.51 (bs, 1H), 1.07-1.04 (t,
3H)
EXAMPLE 440
N-(2-(5-Propoxy-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzyla-
mine
[0581] ##STR53##
[0582] Combine 2-(5-propoxy-1-triisopropylsilanyltryptamine (138
mg, 0.37 mmol), 3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde (87 mg,
1.8 mmol) and 1 g 3 .ANG. molecular sieves in 25 mL EtOH and reflux
overnight. Decant the liquid into a separate flask, cool to
0.degree. C. and treat with 42 mg (1.1 mmol) NaBH.sub.4. Stir the
reaction at ambient temperature for 1 hour, treat with 0.74 mmol of
tetrabutylammonium fluoride and stir for an additional hour.
Concentrate under vacuum to give a residue. Chromatograph the
residue on silica gel eluting with 10% MeOH in CHCl.sub.3 to give
the title compound. Treat the title compound with 10 mL EtOH with
0.25 mL 5 N HCl and 40 mL toluene then concentrating gives the
hydrochloride of the title compound: ISMS 439 (M+1); .sup.1H NMR
(Free base-CDCl.sub.3) 7.89 (bs, 1H), 7.23-7.21 (m, 1H), 7.03-7.02
(d, 1H), 6.99-6.98 (d, 1H), 6.94-6.92 (m, 1H), 6.89-6.83 (m, 2H),
6.78-6.75 (m, 1H), 6.18-5.90 (m, 1H), 4.29-4.23 (m, 2H), 3.95-3.91
(m, 2H), 3.78 (s, 2H), 2.95 (s, 4H), 1.85-1.75 (m, 2H), 1.51 (bs,
1H), 1.06-1.03 (t, 3H).
[0583] By the method of Example 440 the following compounds were
prepared and isolated as the hydrochloride except where noted:
TABLE-US-00018 ##STR54## No. Z' R.sub.4 Data 441 5-n-propyl
2,2,2-trifluoro ISMS 434 (M + 1); amido ethyl
C.sub.23H.sub.26F.sub.3N.sub.3O.sub.2.cndot.HCl.cndot.0.8H.sub.2O.cndot.0-
.1C.sub.7H.sub.8: calcd: C, 57.67; H, 6.00; N, 8.51; found: C,
57.55; H, 5.77; N, 8.43 442 5-ethoxy 2,2,3,3- ISMS 453 (M + 1);
C.sub.23H.sub.27ClF.sub.3N.sub.3O.sub.2: carbonyl tetrafluoro
calcd: C, 56.50; H, 5.15; N, 5.73; propyl found: C, 56.26; H, 5.04;
N, 5.76 443 5-ethoxy phenyl ISMS 415 (M + 1);
C.sub.26H.sub.27ClN.sub.2O.sub.3.cndot.0.1H.sub.2O: carbonyl calcd:
C, 68.97; H, 6.06; N, 6.19; found: C, 68.78; H, 5.87; N, 6.19 445
5-phenoxy 2,2,3,3- ISMS 473 (M + 1); tetrafluoro
C.sub.26H.sub.25ClF.sub.4N.sub.2O.sub.2.cndot.0.5H.sub.2O: calcd:
C, propyl 60.29; H, 5.06; N, 5.41; found: C, 60.27; H, 4.81; N,
5.33 (isolated as the base) 456 H 2,2,2-trifluoro ISMS 349 (M + 1);
C.sub.19H.sub.20ClF.sub.3N.sub.2O.cndot.0.2H.sub.2O: ethyl calcd:
C, 58.75; H, 5.29; N, 7.21; found: C, 58.62; H, 5.04; N, 7.08 457 H
2,2,3,3,3- ISMS 385 (M + 1);
C.sub.19H.sub.18ClF.sub.5N.sub.2O.cndot.0.2H.sub.2O: pentafluoro
calcd: C, 53.77; H, 4.37; N, 6.60; found: C, propyl 53.81; H, 4.19;
N, 6.59 458 5-phenyl phenyl Analysis for
C.sub.29H.sub.26N.sub.2O.cndot.HCl.cndot.0.2H.sub.2O: calcd: C,
75.95; H, 6.02; N, 6.11; found: C, 76.01; H, 5.92; N, 5.97 ISMS 419
(M + 1) 459 5-(4- phenyl Analysis for fluorophenyl)
C.sub.29H.sub.25FN.sub.2O.cndot.HCl.cndot.0.2H.sub.2O: calcd: C,
73.08; H, 5.58; N, 5.88; found: C, 72.99; H, 5.38; N, 5.83 ISMS 437
(M + 1) 460 5-(N- 2,2,2-trifluoro Analysis for butylamido) ethyl
C.sub.24H.sub.28F.sub.3N.sub.3O.sub.2.cndot.HCl.cndot.0.7H.sub.2O:
calcd: C, 58.05; H, 6.17; N, 8.46; found: C, 57.86; H, 5.98; N,
8.39 ISMS 448 (M + 1) 461 5-hydroxy 2,2,2-trifluoro ISMS 365 (M +
1) ethyl .sup.1H NMR (DMSO-d6) 10.6 (bs, 1H), 9.4 (bs, 2H), 8.75
(s, 1H), 7.45-6.6 (m, 7H), 4.9-4.7 (m, 2H), 4.2 (bs, 2H), 3.2-2.9
(m, 4H); 462 5-benzyloxy 2,2,3,3,3- Analysis for
C.sub.27H.sub.25F.sub.5N.sub.2O.sub.2.cndot.HCl: pentafluoro calcd:
C, 58.87; H, 4.95; N, 5.09; propyl found: C, 59.02; H, 4.76; N, 5.1
ISMS 505 (M + 1)4 463 6-benzyloxy 2,2,2-trifluoro ISMS 455 (M + 1)
ethyl .sup.1H NMR (CDCl.sub.3-freebase) 7.88 (bs, 1H), 7.48-7.45
(m, 3H), 7.41-7.34 (m, 2H), 7.35-7.30 (m, 1H), 7.25- 7.23 (m, 1H),
6.95-6.93 (m, 1H), 6.91-6.90 (m, 2H), 6.88-6.86 (m, 2H), 6.81-6.79
(m, 1H), 5.10 (s, 2H), 4.31-4.25 (m, 2H), 3.79 (s, 2H), 2.96 (s,
4H), 1.65 (bs, 1H) 464 6-benzyloxy 2,2,3,3- ISMS 487 (M + 1)
tetrafluoro Analysis for
C.sub.27H.sub.27F.sub.4N.sub.2O.sub.2.cndot.HCl: propyl calcd: C,
62.01; H, 5.20; N, 5.36; found: C, 61.69; H, 5.07; N, 5.33 465
6-butyloxy 2,2,2-trifluoro .sup.1H NMR (CDCl.sub.3-freebase) 7.86
(bs, 1H), ethyl 7.45-7.43 (m, 1H), 7.23-7.19 (m, 1H), 6.94- 6.92
(m, 1H), 6.89-6.88 (m, 1H), 6.84-6.75 (m, 4H), 4.29-4.23 (m, 2H),
3.99-3.96 (m, 2H), 3.78 (s, 2H), 2.94 (s, 4H), 1.81-1.74 (m, 2H),
1.55-1.45 (m, 3H), 0.99-0.95 (m, 3H); Analysis for
C.sub.23H.sub.27F.sub.3N.sub.2O.sub.2 HCl: calcd: C, 60.46; H,
6.18; N, 6.13; found: C, 60.23; H, 5.99; N, 6.01 466 5-butyloxy
2,2,3,3- Analysis for
C.sub.24H.sub.28F.sub.4N.sub.2O.sub.2.cndot.HCl: tetrafluoro calcd:
C, 58.96; H, 5.98; N, 5.73; propyl found: C, 58.62; H, 5.96; N,
5.77 ISMS 453 (M + 1) 467 6-ethoxy 2,2,2-trifluoro ISMS 393 (M +
1); Analysis for ethyl C.sub.21H.sub.23F.sub.3N.sub.2O.sub.2 HCl:
calcd: C, 58.81; H, 5.64; N, 6.53; found: C, 58.94; H, 5.58; N,
6.55 468 6-phenyl 2,2,2-trifluoro ISMS 505 (M + 1); Analysis for
sulfonate ethyl C.sub.25H.sub.23F.sub.3N.sub.2O.sub.4S HCl: calcd:
C, 55.51; H, 4.47; N, 5.18; found: C, 55.27; H, 4.41; N, 5.15 469
6-phenyl 2,2,3,3- ISMS 536 (M + 1); Analysis for sulfonate
tetrafluoro C.sub.26H.sub.24F.sub.4N.sub.2O.sub.4S HCl: calcd: C,
54.50; H, propyl 4.40; N, 4.89; found: C, 54.63; H, 4.41; N, 4.86
470 6-phenyl phenyl ISMS 419 (M + 1); Analysis for
C.sub.26H.sub.24F.sub.4N.sub.2O.sub.4S HCl 0.3H.sub.2O: calcd: C,
75.65; H, 6.04; N, 6.08; found: C, 75.63; H, 5.89; N, 6.07 470A
6-butyloxy 2,2,3,3- Analysis for tetrafluoro
C.sub.23H.sub.27F.sub.3N.sub.2O.sub.2.HCl.HCl: Cald: C, 58.52;
propyl H, 6.02; N, 5.69; found: C, 58.15; H, 5.64; N, 5.58.
EXAMPLE 471
N-(2-(5-Hydroxy-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine
[0584] ##STR55##
[0585] Combine
N-(2-(5-benzyloxy-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylami-
ne hydrochloride (295 mg, 0.6 mmol) and 25 mL EtOH and treat with
0.3 mL 5 N HCl and 300 mg 5% Pd/C and hydrogenate at atmospheric
pressure overnight. Filter the reaction through a pad of celite and
concentrate to dryness then chromatograph on silica gel to give the
title compound: ISMS 365 (M+1); .sup.1H NMR (DMSO-d6) 10.6 (bs,
1H), 9.4 (bs, 2H), 8.75 (s, 1H), 7.45-6.6 (m, 7H), 4.9-4.7 (m, 2H),
4.2 (bs, 2H), 3.2-2.9 (m, 4H).
[0586] By the method of Example 471 the following compounds were
prepared and isolated as the hydrochloride except where noted:
TABLE-US-00019 ##STR56## No. Z' R.sub.4 Data 472 5-hydroxy 2,2,3,3-
ISMS 397 (M + 1); Analysis for
C.sub.20H.sub.20F.sub.4N.sub.2O.sub.2 tetrafluoro HCl H.sub.20:
calcd: C, 53.28; H, 5.14; N, 6.21; propyl found: C, 53.31; H, 4.91;
N, 6.33 473 6-hydroxy 2,2,2-trifluoro ISMS 487 (M + 1); .sup.1H NMR
(DMSO-d6) .delta.10.52 ethyl (bs, 1H), 9.36 (s, 2H), 8.91 (s, 1H),
7.38-7.33 (m, 2H), 7.28-7.26 (m, 1H), 7.20-7.18 (m, 1H), 7.09-7.07
(m, 1H), 6.94-6.93 (m, 1H), 6.68-6.67 (m, 1H), 6.50-6.47 (m, 1H),
4.79-4.72 (m, 2H), 4.13 (s, 2H), 3.05-3.02 (m, 4H) 474 6-hydroxy
2,2,3,3- ISMS 397 (M + 1); Analysis for
C.sub.20H.sub.20F.sub.4N.sub.2O.sub.2 tetrafluoro HCl H.sub.2O:
calcd: C, 53.28; H, 5.14; N, 6.21; propyl found: C, 53.33; H, 4.76;
N, 6.12
EXAMPLE 475
N-(2-(5-Carboxy-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine
[0587] ##STR57##
[0588] Combine
N-(2-(5-methoxycarbonyl-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)ben-
zylamine (200 mg, 0.5 mmol) in 50 mL THF and 1 mL 3 N NaOH. Reflux
the mixture overnight, treat with 0.7 mL 5 N HCl and concentrate to
dryness. Chromatograph to give the title compound: ISMS 393 (M+1);
Analysis for C.sub.20H.sub.19F.sub.3N.sub.2O.sub.3 CF.sub.3COOH
1.2C.sub.7H.sub.8 2.1H.sub.2O: calcd: C, 55.76; H, 5.20; N, 4.28;
found: C, 55.51; H, 5.47; N, 4.50.
EXAMPLE 480
3-(3-Fluoropropoxy)benzaldehyde
[0589] Combine 1-bromo-3-fluoropropane (10.0 g, 77.1 mmol) and
3-hydroxybenzaldehyde (10.4 g, 92.5 mmol) in dimethylformamide (220
mL) and stir at room temperature. Treat with potassium carbonate in
portions (21.3 g, 144.2 mmol). Heat the reaction mixture at
100.degree. C. for 36 hours, then pour into a 1:1 mixture of ice
water and dichloromethane. Separate the phases and extract the
aqueous layer with additional dichloromethane. Wash the combined
organic extracts sequentially with 1.0 N sodium hydroxide,
saturated sodium bicarbonate, brine, and then dry over sodium
sulfate. Filtration and removal of the solvent in vacuo provides a
residue. Chromatograph the residue on silica gel eluting with 40%
ethyl acetate in hexanes to give the title compound as a yellow
oil: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.98 (s, 1H), 7.50-7.42 (m,
2H), 7.42-7.38 (m, 1H), 7.22-7.16 (m, 1H), 4.66 (dt, 2H, J=46.8,
5.8 Hz), 4.17 (t, 2H, J=6.0 Hz), 2.19 (d quintuplets, 2H, J=26.0,
6.0 Hz); MS (APCI): m/e 183.1 (M+1).
EXAMPLE 481
2,2-Difluoroethyltosylate
[0590] Combine p-toluenesulfonyl chloride (12.9 g, 67.4 mmol) in
pyridine (15 mL) at room temperature and treat dropwise with
2,2-difluoroethanol (5.0 g, 60.9 mmol) via syringe. Stir the
reaction mixture under nitrogen for 72 hours, partition between
water (20 mL) and dichloromethane (20 mL). Separate the aqueous
phase and extract with additional dichloromethane (2.times.40 mL).
Combine the organic extracts and wash sequentially with 1 N
hydrochloric acid (2.times.50 mL), sodium bicarbonate (2.times.50
mL), and brine (2.times.50 mL). Dry the organic layer over sodium
sulfate and concentrate in vacuo to give the title compound as a
yellowish oil: .sup.1H NMR (300 MHz, CDCl.sub.3): 7.82 (d, 2H,
J=9.0 Hz), 7.40 (d, 2H, J=9.0 Hz), 5.92 (tt, 1H, J=55.0, 0.4 Hz),
4.19 (td, 2H, J=12.6, 4.0 Hz), 2.48 (s, 3H).
EXAMPLE 482
3-(2,2-Difluoroethoxy)benzaldehyde
[0591] The method of Example 480 gives the title compound as a
yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.97 (s, 1H),
7.56-7.44 (m, 2H), 7.41-7.37 (m, 1H), 7.21 (ddd, 1H, J=8.0, 2.8,
1.2 Hz), 6.11 (tt, 1H, J=55.0, 4.0 Hz), 4.24 (td, 2H, J=12.6, 4.0
Hz).
EXAMPLE 483
N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-3-(3-fluoropropoxy)benzylamine
[0592] ##STR58##
[0593] Combine 6-chlorotryptamine (1.4 g, 7.2 mmol),
3-(3-fluoropropoxy)benzaldehyde (1.3 g, 7.2 mmol), and molecular
sieves in ethanol (150 mL), and heat at 78.degree. C. overnight.
Filter the reaction mixture through a plug of celite, and treat the
resulting filtrate with sodium borohydride (817 mg, 21.6 mmol) and
stir overnight at room temperature. Evaporate the solvent in vacuo
to give a residue. Chromatograph the residue on silica gel eluting
with 9:1 mixture of dichloromethane and 1N ammonia in methanol to
give a residue. Chromatograph that residue on 10 g SCX column (wash
column with methanol then elute with 1 N ammonia in methanol) and
concentrate in vacuo to give a light yellow oil. Dissolve the oil
in methanol and treated with a methanolic solution of ammonium
chloride (112 mg, 2.1 mmol). Sonicate the resulting mixture for 10
minutes, remove the solvent in vacuo, and triturate the resulting
residue with ether containing a few drops of acetonitrile to give a
solid. Collect the solid by filtration to give the title compound
as the hydrochloride: mp 177.8-178.9.degree. C.; .sup.1H NMR (400
MHz, dmso-d.sub.6): 11.15 (br s, 1H), 9.41 (br s, 2H), 7.57 (d, 1H,
J=8.0 Hz), 7.39 (d, 1H, J=2.0 Hz), 7.32 (t, 1H, J=7.8 Hz), 7.26 (d,
1H, J=2.4 Hz), 7.25-7.21 (m, 1H), 7.11 (d, 1H, J=8.0 Hz), 7.01 (dd,
1H, J=8.8, 2.0 Hz), 6.97 (dd, 1H, J=8.0, 2.0 Hz), 4.60 (dt, 2H,
J=47.6, 6.0 Hz), 4.13 (br s, 2H), 4.08 (t, 2H, J=6.4 Hz), 3.10 (br
s, 4H), 2.11 (d quintuplets, 2H, J=26.0, 6.0 Hz); MS (ES+): m/e
361.3 (M+1); CHN (for C.sub.20H.sub.22ClFN.sub.2O.HCl) calcd: C,
60.46; H, 5.83; N, 7.05; found: C, 60.48; H, 5.86; N, 7.16.
[0594] By the method of Example 483 the following compounds were
prepared and isolated as the hydrochloride except where noted:
TABLE-US-00020 ##STR59## No. Z' R.sub.4 Data 484 6-fluoro 3-fluoro
mp: 174.8-176.0.degree. C.; .sup.1H NMR (400 MHz, dmso-d6): 11.03
(br s, 1H), 9.35 (br s, 2H), 7.52 (dd, 1H, J=8.8, propyl 5.2 Hz),
7.30 (t, 1H, J=7.8 Hz), 7.22-7.17 (m, 2H), 7.13-7.06 (m, 2H), 6.95
(dd, 1H, J=7.8, 2.2 Hz), 6.83 (ddd, 1H, J=9.6, 8.8, 2.4 Hz), 4.58
(dt, 2H, J=47.2, 5.8 Hz), 4.11 (s, 2H), 4.06 (t, 2H, J=6.2 Hz),
3.08 (br s, 4H), 2.08 (d quintuplets, 2H, J=26.0, 6.0 Hz); MS
(ES+): m/e 345.3 (M + 1); CHN (for C.sub.20H.sub.22F.sub.2N.sub.2O
HCl) calcd: C 63.07, H 6.09, N 7.36; found: C 62.82, H 6.13, N 7.57
485 6-fluoro 2,2-difluoro mp 165.0-166.5.degree. C. .sup.1H NMR
(400 MHz, dmso-d6): 11.08 (br s, 1H), 7.56 (dd, 1H, J=8.7, 5.2 Hz),
7.39-7.31 ethyl (m, 2H), 7.21 (d, 1H, J=2.0 Hz), 7.18 (d, 1H, J=6.9
Hz), 7.12 (dd, 1H, J=10.4, 1.7 Hz), 7.04 (dd, 1H, J=8.7, 1.7 Hz),
6.89-6.81 (m, 1H), 6.42 (tt, 1H, J=53.9, 3.5 Hz), 4.32 (td, 2H,
J=11.3, 3.2 Hz), 4.14 (s, 2H), 3.20-3.00 (m, 4H); MS: (ES+): m/e
349.0 (M + 1) 486 6-chloro 2,2-difluoro mp 131.6-133.degree. C.:
.sup.1H NMR (400 MHz, dmso-d6): 11.15 (br s, 1H), 9.50 (br s, 2H),
7.57 (d, 1H, J=8.8 Hz), 7.39 ethyl (d, 1H, J=2.0 Hz), 7.36 (t, 1H,
J=8.2 Hz), 7.32 (br s, 1H), 7.26 (d, 1H, J=2.0 Hz), 7.17 (d, 1H,
J=7.6 Hz), 7.04 (dd, 1H, J=7.8, 2.2 Hz), 7.01 (dd, 1H, J=8.4, 2.0
Hz), 6.41 (tt, 1H, J=54.4, 3.4 Hz), 4.32 (td, 2H, J=14.8, 3.6 Hz),
4.14 (br s, 2H), 3.11 (br s, 4H); MS (ES+): m/e 365.3 (M + 1); CHN
(for C.sub.19H.sub.19F.sub.2ClN.sub.2O.cndot.HCl.cndot.0.3
H.sub.20) calcd: C 56.11; H 5.11; N 6.89; found: C 56.03; H 4.95; N
7.18 487 6-chloro 2,2,3,3,3- mp 199.8-201.1.degree. C.; .sup.1H NMR
(400 MHz, dmso-d6): 11.15 (br s, 1H), 9.35 (br s, 2H), 7.57 (d, 1H,
J=8.4 Hz), pentafluoro 7.44-7.32 (m, 3H), 7.26 (d, 1H, J=2.0 Hz),
7.22 (d, 1H, J=8.0 Hz), 7.10 (dd, 1H, J=8.4, 2.0 Hz), 7.00 (dd, 1H,
propyl J=8.6, 1.8 Hz), 4.85 (t, 2H, J=13.2 Hz), 4.13 (s, 2H), 3.10
(br s, 4H); MS (ES+): m/e 433.0 (M + 1); CHN (for
C.sub.20H.sub.18ClF.sub.5N.sub.2O.cndot.0.97HCl) calcd: C 51.31, H
4.08, N 5.98; found: C 51.61, H 4.07, N 6.00 488 5-isopropyl
2,2,3,3,3- mp 168.5-171.0.degree. C.; MS (ES+): m/e 441.1 (M + 1);
CHN (for
C.sub.23H.sub.25F.sub.5N.sub.2O.cndot.HCl.cndot.0.3H.sub.20) calcd:
C 57.28, pentafluoro H 5.56, N 5.81; found: C 57.10, H 5.21, N 6.03
propyl 489 5-isopropyl 2,2,3,3- mp 167.0-168.2.degree. C.; .sup.1H
NMR (400 MHz, dmso-d6): 10.72 (br s, 1H), 7.44 (t, 1H, J=7.8 Hz),
7.34 (br s, 1H), tetrafluoro 7.22-7.15 (m, 2H), 7.14 (br s, 1H Hz),
7.06 (d, 1H, J=7.6 Hz), 7.01 (dd, 1H, J=8.4, 1.6 Hz), 6.69 (tt, 1H,
J=51.6, propyl 5.6 Hz), 5.86 (s, 1H), 4.70-4.50 (m, 2H), 3.50-3.25
(m, 4H, overlapping with H.sub.2O), 3.17-3.05 (m, 1H), 3.05-2.91
(m, 2H), 1.24 (d, 6H, J=6.8 Hz); MS (ES+): m/e 422.1 (M + 1)
EXAMPLE 490
N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-N-methyl-3-(2,2-difluoroethoxy)benzyla-
mine
[0595] ##STR60##
[0596] Combine
N-(2-(6-chloro-1H-indol-3-yl)ethyl)-3-(2,2-difluoroethoxy)benzylamine
(276 mg, 0.76 mmol) and formaldehyde (55.5 .mu.L of a 38% aqueous
solution, 0.76 mmol) in dichloroethane (115 mL) and stir at room
temperature for 10 minutes; then add in two portions over 10
minutes sodium triacetoxyborohydride (321 mg, 1.51 mmol). Stir the
reaction mixture at room temperature overnight and dilute with
methanol (10 mL) and quench with one drop of glacial acetic acid.
Remove the solvent in vacuo, to give a residue, redissolve the
crude residue in methanol and directly load onto a 10 g SCX column.
After washing the column thoroughly with methanol, elute with 2 N
ammonia in methanol. Concentrate in vacuo to give the title
compound as an oil. Dissolve the oil (239 mg, 0.64 mmol) in
methanol (20 mL) and treat with a solution of ammonium chloride (36
mg, 0.67 mmol) in methanol (5 mL). Sonicate the mixture for 10
minutes before removal of the solvent in vacuo to give the title
compound as the hydrochloride salt. Dissolve the salt in 10 mL of
1:1 acetonitrile-water and lyophilize overnight, providing a fluffy
white solid. Triturate the solid with diethyl ether (10 mL) and
acetonitrile (2 drops), filter, and dry to give the title compound
as the hydrochloride salt: mp: 63.8-65.8.degree. C.; .sup.1H NMR
(400 MHz, dmso-d6): 11.10 (br s, 1H), 7.52 (d, 1H, J=8.4 Hz) 7.36
(d, 1H, J=2.0 Hz), 7.40-7.26 (m, 2H), 7.22 (d, 1H, J=2.4 Hz),
7.20-7.11 (m, 1H), 7.04 (br d, 1H, J=7.6 Hz), 6.96 (dd, 1H, J=8.6,
1.4 Hz), 6.38 (tt, 1H, J=54.4, 3.6, Hz), 4.50-4.02 (br m, 2H), 4.30
(td, 2H, J=14.4, 3.2 Hz), 3.15 (br s, 4H), 2.68 (br s, 3H); MS
(ES+): m/e 378.9 (M+1.
[0597] By the method of Example 490 the following compounds were
prepared and isolated as the hydrochloride except where noted:
TABLE-US-00021 ##STR61## No. Z' R.sub.4 Data 491 6-fluoro
2,2-difluoro mp: 70.8-73.0.degree. C.; .sup.1H NMR (400 MHz,
CDCl.sub.3): ethyl 9.01(br s, 1H), 7.40-7.35(m, 1H), 7.35(dd, 1H,
J=8.8, 5.6 Hz), 7.31-7.25(m, 1H), 7.10-7.02 (m, 2H), 6.97-6.91(m,
2H), 6.77(td, 1H, J=9.2, 2.0 Hz), 6.05(tt, 1H, J=54.8, 4.0 Hz),
4.21(td, 2H, J=13.0, 4.0 Hz), 4.08(br s, 2H), 3.30-3.18 (m, 2H),
3.18-3.05(m, 2H), 2.66(s, 3H); MS (APCI): m/e 363.1 (M + 1) 492
6-fluoro 3-fluoro mp: 66.4-69.3.degree. C.; .sup.1H NMR (300 MHz,
dmso- propyl d.sub.6): 11.04(s, 1H), 11.20-10.70(br s, 1H), 7.52
(dd, 1H, J=8.8, 5.5 Hz), 7.34(t, 1H, J=7.9 Hz), 7.30-7.20(m, 1H),
7.20(d, 1H, J=2.2 Hz), 7.12(AB.sub.q, 2H, J.sub.AB=22.4 Hz,
.DELTA.J.sub.AB=9.8 Hz), 7.00(br d, 1H, J=8.4 Hz), 6.84(ddd, 1H, J=
9.9, 8.8, 2.2 Hz), 4.61(dt, 2H, J=47.2, 5.9 Hz), 4.44-4.03(br m,
2H), 4.08(t, 2H, J=6.4 Hz), 3.17(br s, 4H), 2.68(br s, 3H), 2.11
(dquintuplets, 2H, J=25.6, 6.1 hz); MS (ES+): m/e 358.9 (M + 1) 493
6-chloro 3-fluoro mp: 61.4-63.4.degree. C.; .sup.1H NMR (400 MHz,
DMSO- propyl d.sub.6): 11.14(s, 1H), 7.54(d, 1H, J=8.4 Hz), 7.40
(d, 1H, J=2.4 Hz), 7.35(t, 1H, J=8.0 Hz), 7.32-7.23(m, 2H), 7.13(br
d, 1H, J=7.2 Hz), 7.07-7.00(m, 1H), 6.99(dd, 1H, J=8.6, 1.8 Hz),
4.60(dt, 2H, J=46.8, 5.8 Hz), 4.50-4.15 (br m, 2H), 4.08(t, 2H,
J=6.4 Hz), 3.18(br s, 4H), 2.72(br s, 3H), 2.11(dquintuplets, 2H,
J= 26.0, 6.4 Hz); MS (APCI): m/e 375.1 (M + 1) 494 6-chloro
2,2,3,3,3- mp 206.6-207.5.degree. C.; .sup.1H NMR (400 MHz,
pentafluoro methanol-d.sub.4): 7.97(d, 1H, J=8.0 Hz 7.93-7.85
propyl (m, 2H), 7.75-7.68(m, 2H), 7.65(br d, 1H, J= 7.2 Hz),
7.58(br d, 1H, J=8.0 Hz), 7.47(br d, 1H, J=9.2 Hz), 5.21(t, 2H,
J=13.0 Hz), 4.60 (br s, 2H), 3.61(br s, 4H), 3.14(br s, 3H); MS
(ES+): m/e 447.1 (M + 1); CHN (for
C.sub.21H.sub.20ClF.sub.5N.sub.2O.cndot.HCl) calcd: C 52.19; H
4.38; N 5.80; found: C 52.16; H 4.29; N 5.82
EXAMPLE 495
N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-N-isopropyl-3-(2,2,3,3-pentafluoroprop-
oxy)benzylamine
[0598] ##STR62##
[0599] Combine
N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-3-(2,2,3,3,3-pentafluoropropoxy)benzy-
lamine (254 mg, 0.59 mmol) in 20 mL of 95:5 methanol-acetic acid,
treat with acetone (441 .mu.L, 5.9 mmol) followed by sodium
cyanoborohydride in portions (148 mg, 2.3 mmol). Stir the reaction
mixture at 50.degree. C. overnight; then at room temperature for an
additional 2 days. Remove the solvent in vacuo to give a residue.
Chromatograph the residue on silica gel eluting with 4% methanol in
dichloromethane to give the title compound as a colorless oil.
Dissolve the oil (237 mg, 0.49 mmol) in methanol (15 mL) and treat
with a solution of ammonium chloride (27 mg, 0.49 mmol) in methanol
(5 mL). Sonicate the mixture for 10 minutes before concentrating it
to a tacky white solid. Dissolve the tacky solid in 10 mL of 1:1
acetonitrile-water and lyophilize to give 241 mg (96%) of the title
compound as the hydrochloride: mp: 77.0-80.2.degree. C.; .sup.1H
NMR (400 MHz, methanol-d.sub.4): 7.31 (br t, 1H, J=7.8 Hz),
7.26-7.21 (m, 1H), 7.16 (br d, 1H, J=8.4 Hz), 7.15-7.07 (m, 2H),
7.05-6.95 (m, 2H), 6.83 (dd, 1H, J=8.0, 2.0 Hz), 4.52 (t, 2H,
J=12.8 Hz), 4.12 (br s, 2H), 3.53 (br s, 1H), 3.11 (br s, 2H), 2.89
(br s, 2H), 1.27 (br s, 6H); MS (APCI): m/e 475.1 (M+1).
[0600] By the method of Example 495 the following compounds were
prepared and isolated as the maleate: TABLE-US-00022 ##STR63## No.
Z' R Data 496 6-chloro propyl mp 92.4-94.6.degree. C. Mass (ES+):
m/z 475.0 (M + 1). Elemental Analysis Calculated for
C.sub.23H.sub.24ClF.sub.5N.sub.2O.cndot.1.0C.sub.4H.sub.4O.sub.4.cndot.-
0.5H.sub.2O: C, 53.30; H, 4.93; N, 4.57. Found: C, 53.00; H, 4.55;
N, 4.86. 497 6-chloro ethyl mp 101.0-1-104.0.degree. C. Mass (ES+):
m/z 461.0 (M + 1).
EXAMPLE 500
N-(2-(6-Chloro-5-methoxy-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropox-
ybenzylamine
[0601] ##STR64##
[0602] Combine 5-methoxy-6-chlorotrypatamine (0.2 mmol) in
dichloromethane (1 mL) and
3-(2,2,3,3-tetrapropylfluororpropoxy)benzaldehyde (0.32 mmol) in
dichloromethane (1 mL) and rotate. After 2 h, add sodium
borohydride (37.83 mg, 1.0 mmol) as a stock solution in
dichloromethane (1 mL). After overnight rotation, dilute the
reaction mixture with 1 mL of methanol, and apply the resulting
solution directly to a 2 g SCX column. Thoroughly wash the column
with methanol, elute with 2 M ammonia-methanol and concentrate to a
residue. If a TLC of eluent, indicates that the reaction was not
complete. Dilute the residue with dichloromethane (1 mL) and add a
second stock solution of sodium borohydride (37.83 mg, 1.0 mmol) in
1-methyl-2-pyrrolidinone (1 mL). After rotation for 2 h, dilute the
reaction mixture with 1 mL of methanol, and directly apply the
resulting solution to a 2 g SCX column. Thoroughly wash the column
with methanol, elute with 2 M ammonia-methanol and concentrate to a
residue. Further purification on a SI column. Elution with straight
ethyl acetate. Compound was characterized using LC method 1 or 2.
LCMS R.sub.t 2.749 min at 254 nm, 2.800 min at 220 nm; m/e 445
(M+1).
General LC Methods:
Method 1: (Shimadzu QP8000) 10-90 in 4.5 min. Solvent A: water 0.1%
trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic
acid. Column: C18 Metachem, monochrom 3 micron, 2.5.times.25.
Method 2: (Shimadzu) 10-80 in 9 min. Solvent A: water 0.1%
trifluoroacetic acid, Solvent B: acetonitrile 0.08% trifluoroacetic
acid. Column: C18 Metachem, monochrom 5 micron, 4.6.times.50.
[0603] The following compounds were prepared in a manner similar to
Example 500 and isolate as the base unless otherwise indicated:
TABLE-US-00023 ##STR65## No. Z' R.sub.4 Data 501 3-CF.sub.3 2,2,2-
Method 2: LC Rf 3.90 min at 220 nm, trifluoroethyl 3.908 min at 264
nm. 502 3,5-dimethoxy 2,2,2- Method 2: LC Rf 3.620 min at 254 nm,
trifluoroethyl 3.62 min at 220 nm, m/e 367 (M + 1). 503 3-chloro
2,2,3,3- Method 1: LCMS Rf 2.800 min at 220 tetrafluoro nm, m/e 376
(M + 1). propyl 504 3-CF.sub.3 2,2,3,3- Method 1: LCMS Rf 2.885 min
at 254 tetrafluoro nm, m/e 410 (M + 1). propyl 506 3-chloro
2-fluoroethyl Method 2: LC Rf 3.420 min at 254 nm, 3.42 min at 220
nm. 507 3-trifluoromethyl 2-fluoroethyl Method 2: LC Rf 3.580 min
at 254 nm, 3.58 min at 220 nm. 508 3,5-dimethoxy 2-fluoroethyl
Method 2: LC Rf 3.212 min at 254 nm, 3.22 min at 220 nm. 509
3-trifluoromethyl propyl Method 2: LC Rf 3.892 min at 254 nm, 3.89
min at 220 nm. 510 2-chloro phenyl Method 1: LCMS Rf 2.479 min at
2854 nm, m/e 338 (M + 1). 511 3-trifluoromethyl phenyl Method 1:
LCMS Rf 2.969 min at 254 nm, m/e 372 (M + 1).
[0604] TABLE-US-00024 ##STR66## No. Z' R.sub.4 Data 512 5-methoxy
6- 2,2,2- Method 1: LCMS Rf 2.651 min at 220 chloro trifluoroethyl
nm, m/e 413 (M + 1). 513 6-fluoro 2,2,2- Method 1: LCMS Rf 2.618
min at 254 trifluoroethyl nm, 2.700 min at 220 nm, m/e 367 (M + 1).
514 4-chloro 2,2,2- Method 1: LCMS Rf 2.683 min at 254 5-methoxy
trifluoroethyl nm, 2.661 min at 220 nm, m/e 399 (M + 1). 515
5-methoxy 2,2,3,3- Method 1: LCMS Rf 2.749 min at 254 6-chloro
tetrafluoropropyl nm, 2.800 min at 220 nm, m/e 445 (M + 1). 516
6-fluoro 2,2,3,3- Method 1: LCMS Rf 2.683 min at 254
tetrafluoropropyl nm, 2.661 min at 220 nm, m/e 399 (M + 1). 517
4-chloro 2,2,3,3- Method 1: LCMS Rf 2.682 min at 254 5-methoxy
tetrafluoropropyl nm, 2.663 min at 220 nm, m/e 445 (M + 1). 522
5-methoxy 2-fluoroethyl Method 2: LC Rf 3.19 min at 220 nm.
EXAMPLE 523
N-(2-(6-Trifluoromethyl-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine
[0605] ##STR67##
[0606] Combine 5-trifluoromethyltryptamine (0.1 mmol) in methanol
(1 mL) and 3-phenoxybenzaldehyde (0.2 mmol) in methanol (1 mL) and
rotate. After 3 h, add sodium borohydride (18 mg, 0.5 mmol) as a
stock solution in 1-methyl-2-pyrrolidinone (0.5 mL). After
overnight rotation, dilute the reaction mixture with 1 mL of
methanol, directly apply the resulting solution to a 2 g SCX
column. Wash thoroughly the column with methanol, and elute with 2
M ammonia-methanol and concentrate the eluent. Further purification
on SI column eluting with ethyl acetate affords the desired
compound. Characterization of the compound is achieve by using
method 1. LCMS R.sub.f 2.954 min at 254 nm, 2.954 min at 220 nm,
m/e 411 (M+1).
LC Method:
Method 1: (Shimadzu QP8000) 10-90 in 4.5 min. Solvent A: water 0.1%
trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic
acid. Column: C18 Metachem, monochrom 3 micron, 2.5.times.25.
[0607] The following compounds were prepared following a similar
procedure as in Example 523 and isolated as the base unless
otherwise indicated: TABLE-US-00025 ##STR68## No. Z' R.sub.4 Data
524 6-trifluoro phenyl Method 1: LCMS Rf 2.954 min at 254 nm,
methyl 2.954 min at 220 nm, m/e 411 (M + 1). 525 6-fluoro phenyl
Method 1: LCMS Rf 2.712 min at 254 nm, 2.712 min at 220 nm, m/e 361
(M + 1). 526 5-methoxy phenyl Method 1: LCMS Rf 2.757 min at 254
nm, 6-chloro 2.757 min at 220 nm, m/e 407 (M + 1). 527 4-chloro
propyl Method 1: LCMS Rf 2.578 min at 254 nm, 5-methoxy 2.577 min
at 220 nm, m/e 373 (M + 1). 528 6-trifluoro propyl Method 1: LCMS
Rf 2.850 min at 254 nm, methyl 2.849 min at 220 nm, m/e 377 (M +
1). 529 6-fluoro propyl Method 1: LCMS Rf 2.576 min at 254 nm,
2.576 min at 220 nm, m/e 327 (M + 1). 530 5-methoxy propyl Method
1: LCMS Rf 2.637 min at 220 nm, m/e 6-chloro 373 (M + 1).
EXAMPLE 531
N-(2-(4-Sulfonamidophenyl)ethyl)-3-(2,2,3,3,3-pentafluoropropoxybenzylamin-
e
[0608] ##STR69##
[0609] Combine 4-sulfonamidophenylethylamine (0.2 mmol) in methanol
(1 mL) and 3-(2,2,3,3,3-pentapropylfluororpropoxy)benzaldehyde
(0.32 mmol) in methanol (1 mL) and rotate. After 1 hour add sodium
borohydride (18 mg, 1.0 mmol) as a stock solution in
1-methyl-2-pyrrolidinone (1 mL). After overnight rotation, dilute
the reaction mixture with 1 mL of methanol, and directly apply the
resulting solution to a 2 g SCX column. After thoroughly washing
with methanol, elute the column with 2 M ammonia-methanol and
concentrate the eluent to a residue. Further purification by Gilson
UV prep system afforded the desired compound and the compound was
characterized using method 1. LCMS R.sub.f 2.345 min at 254 nm,
2.347 min at 220 nm, m/e 439 (M+1) 461 (M+22).
LC Method:
Method 1: (Shimadzu QP8000) 10-90 in 4.5 min. Solvent A: water 0.1%
trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic
acid. Column: C18 Metachem, monochrom 3 micron, 2.5.times.25.
[0610] The following compounds were prepared using a similar
procedure as in Example 531 and isolated as the base unless
otherwise indicated: TABLE-US-00026 ##STR70## No. Z' R.sub.4 Data
532 2,5- 2,2,3,3,3- Method 1: LCMS Rf 2.816 min at 254 dimethoxy
pentafluoropropyl nm, 2.815 min at 220 nm, m/e 420 (M + 1). 533
3,4- 2,2,3,3,3- Method 1: LCMS Rf 2.634 min at 254 dimethoxy
pentafluoropropyl nm, 2.637 min at 220 nm, m/e 420 (M + 1). 534 4-
2,2,3,3- Method 1: LCMS Rf 2.155 min at 254 sulfonamide
tetrafluoropropyl nm, 2.156 min at 220 nm, m/e 421 (M + 1). 535 4-
3-fluoropropyl Method 1: LCMS Rf 1.816 min at 254 sulfonamide nm,
1.818 min at 220 nm, m/e 367 (M + 1), 389 (M + 22). 537 4-
2-fluoroethyl Method 1: LCMS Rf 1.606 min at 254 sulfonamide nm,
1.606 min at 220 nm, m/e 375 (M + 22). 538 3,4- phenyl Method 1:
LCMS Rf 2.511 min at 254 dimethoxy nm, 2.511 min at 220 nm, m/e 364
(M + 1). 539 4- 2,2-difluoroethyl Method 1: LCMS Rf 1.782 min at
254 sulfonamide nm, 1.782 min at 220 nm, m/e 371 (M + 1), 393 (M +
22). 540 2,5- 2,2-difluoroethyl Method 1: LCMS Rf 2.359 min at 254
dimethoxy nm, m/e 352 (M + 1). 541 3,4- 2,2-difluoroethyl Method 1:
LCMS Rf 2.085 min at 254 dimethoxy nm, 2.070 min at 220 nm, m/e 335
(M + 1), 352 (M + 22). 542 4- 2,2-difluoroethyl Method 1: LCMS Rf
1.816 min at 254 sulfonamide nm, 1.818 min at 220 nm, m/e 367 (M +
1), 389 (M + 22). 543 2,5- 3-fluoropropyl Method 1: LCMS Rf 2.387
min at 254 dimethoxy nm, 2.381 min at 220 nm, m/e 348 (M + 1).
EXAMPLE 545
N-(2-(6-Methoxy-1H-indol-3-yl)ethyl)-3-(2,2,3,3,3-pentafluoropropoxybenzyl-
amine
[0611] ##STR71##
[0612] Combine amine (0.2 mmol) in 1-methyl-2-pyrrolidinone (1 mL)
and aldehyde (0.32 mmol) in dichloromethane (1 mL) and rotate.
After 1 h, add sodium borohydride (18 mg, 1.0 mmol) as a stock
solution in 1-methyl-2-pyrrolidinone (1 mL). After rotation
overnight, dilute the reaction mixture with 1 mL of 10% acetic
acid/methanol, and directly apply the resulting solution to a 2 g
SCX column. Thoroughly wash with methanol, elute the column with 2
M ammonia-methanol and concentrate the eluent to a residue, which
was further purified by Gilson UV prep system. Characterize the
compound using method 1. LCMS R.sub.f 3.752 min at 254 nm, 3.753
min at 220 nm, m/e 429 (M+1).
LC Method:
Method 1: (Shimadzu QP8000) 10-90 in 4.5 min. Solvent A: water 0.1%
trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic
acid. Column: C18 Metachem, monochrom 3 micron, 2.5.times.25.
[0613] The following compounds were prepared by following a similar
procedure to Example 545: TABLE-US-00027 ##STR72## No. Z' R.sub.4
Data 546 4-chloro 2,2,3,3,3- Method 1: LCMS Rf 3.873 min at 254 nm,
pentafluoro 3.877 min at 220 nm, m/e 433 (M + 1). propyl 547
4-methoxy 2,2,3,3,3- Method 1: LCMS Rf 3.828 min at 254 nm,
pentafluoro 3.833 min at 220 nm, m/e 429 (M + 1). propyl 548
5-methoxy 2,2,3,3,3- Method 1: LCMS Rf 3.802 min at 254 nm,
2-methyl pentafluoro 3.805 min at 220 nm, m/e 433 (M + 1). propyl
549 7-methoxy 2,2,3,3,3- Method 1: LCMS Rf 3.800 min at 254 nm,
pentafluoro 3.806 min at 220 nm, m/e 429 (M + 1). propyl 550
6-chloro 2,2,3,3,3- Method 1: LCMS Rf 3.947 min at 254 nm,
pentafluoro 3.952 min at 220 nm, m/e 433 (M + 1). propyl 551
4-methoxy 2,2,3,3- Method 1: LCMS Rf 3.695 min at 254 nm,
tetrafluoro 3.695 min at 220 nm, m/e 411 (M + 1). propyl 552
5-methoxy 2,2,3,3- Method 1: LCMS Rf 3.654 min at 254 nm, 2-methyl
tetrafluoro 3.654 min at 220 nm, m/e 425 (M + 1). propyl 553
7-methoxy 2,2,3,3- Method 1: LCMS Rf 3.659 min at 254 nm,
tetrafluoro 3.661 min at 220 nm, m/e 411 (M + 1). propyl 554
6-chloro 2,2,3,3- Method 1: LCMS Rf 3.821 min at 254 nm,
tetrafluoro 3.821 min at 220 nm, m/e 415 (M + 1). propyl 555
6-methoxy 2-fluoroethyl Method 1: LCMS Rf 3.169 min at 254 nm,
3.169 min at 220 nm, m/e 345 (M + 1). 556 4-chloro 2-fluoroethyl
Method 1: LCMS Rf 3.411 min at 254 nm, 3.412 min at 220 nm, m/e 347
(M + 1). 557 4-methoxy 2-fluoroethyl Method 1: LCMS Rf 3.303 min at
254 nm, 3.304 min at 220 nm, m/e 343 (M + 1). 558 5-methoxy
2-fluoroethyl Method 1: LCMS Rf 3.236 min at 254 nm, 2-methyl 3.236
min at 220 nm, m/e 357 (M + 1). 559 7-methoxy 2-fluoroethyl Method
1: LCMS Rf 3.263 min at 254 nm, 3.264 min at 220 nm, m/e 343 (M +
1). 560 6-chloro 2-fluoroethyl Method 1: LCMS Rf 3.465 min at 254
nm, 3.466 min at 220 nm, m/e 347 (M + 1). 561 6-methoxy 2,2- Method
1: LCMS Rf 3.190 min at 254 nm, difluoroethyl 3.190 min at 220 nm.
562 6-chloro phenyl Method 1: LCMS Rf 3.795 min at 254 nm, 3.795
min at 220 nm, m/e 377 (M + 1). 563 6-fluoro 2-fluoroethyl Method
1: LCMS Rf 3.305 min at 254 nm, 3.306 min at 220 nm, m/e 331 (M +
1). 571 4-chloro propyl Method 1: LCMS Rf 3.668 min at 254 nm,
3.668 min at 220 nm, m/e 343 (M + 1). 572 4-methoxy propyl Method
1: LCMS Rf 3.581 min at 254 nm, 3.582 min at 220 nm, m/e 339 (M +
1). 573 5-methoxy propyl Method 1: LCMS Rf 3.524 min at 254 nm,
2-methyl 3.524 min at 220 nm, m/e 353 (M + 1). 574 7-methoxy propyl
Method 1: LCMS Rf 3.553 min at 254 nm, 3.554 min at 220 nm, m/e 339
(M + 1). 575 6-chloro propyl Method 1: LCMS Rf 3.736 min at 254 nm,
3.736 min at 220 nm, m/e 343 (M + 1). 576 4,6- phenyl Method 1:
LCMS Rf 3.830 min at 254 nm, difluoro 3.832 min at 220 nm, m/e 423
(M + 1). 5-methoxy 577 6-methoxy phenyl Method 1: LCMS Rf 3.527 min
at 254 nm 3.531 min at 220 nm, m/e 373 (M + 1). 578 4-chloro phenyl
Method 1: LCMS Rf 3.749 min at 254 nm, 3.749 min at 220 nm, m/e 377
(M + 1). 579 4-methoxy phenyl Method 1: LCMS Rf 3.657 min at 254
nm, 3.658 min at 220 nm, m/e 373 (M + 1). 580 5-methoxy- phenyl
Method 1: LCMS Rf 3.609 min at 254 nm, 2-methyl 3.609 min at 220
nm, m/e 3387 (M + 1). 581 7-methoxy phenyl Method 1: LCMS Rf 3.622
min at 254 nm, 3.622 min at 220 nm, m/e 373 (M + 1). 582 6-chloro
phenyl Method 1: LCMS Rf 3.795 min at 254 nm, 3.795 min at 220 nm,
m/e 377 (M + 1). 583 4,6- 2,2-difluoro Method 1: LCMS Rf 3.514 min
at 254 nm, difluoro ethyl 3.519 min at 220 nm, m/e 411 (M + 1).
5-methoxy 585 4-chloro 2,2-difluoro Method 1: LCMS Rf 3.418 min at
254 nm, ethyl 3.419 min at 220 nm, m/e 365 (M + 1). 586 4-methoxy
2,2-difluoro Method 1: LCMS Rf 3.301 min at 254 nm, ethyl 3.305 min
at 220 nm, m/e 361 (M + 1). 587 5-methoxy- 2,2-difluoro Method 1:
LCMS Rf 3.269 min at 254 nm, 2-methyl ethyl 3.269 min at 220 nm,
m/e 375 (M + 1). 588 7-methoxy 2,2-difluoro Method 1: LCMS Rf 3.265
min at 254 nm, ethyl 3.271 min at 220 nm, m/e 361 (M + 1). 589
6-chloro 2,2-difluoro Method 1: LCMS Rf 3.476 min at 254 nm, ethyl
3.476 min at 220 nm, m/e 365 (M + 1). 590 6-fluoro 2,2-difluoro
Method 1: LCMS Rf 3.326 min at 254 nm, ethyl 3.326 min at 220 nm,
m/e 349 (M + 1). 592 6-methoxy 3-fluoropropyl Method 1: LCMS Rf
3.170 min at 254 nm, 3.176 min at 220 nm, m/e 357 (M + 1). 593
4-chloro 3-fluoropropyl Method 1: LCMS Rf 3.400 min at 254 nm,
3.407 min at 220 nm, m/e 361 (M + 1). 594 4-methoxy 3-fluoropropyl
Method 1: LCMS Rf 3.326 min at 254 nm, 3.327 min at 220 nm, m/e 357
(M + 1). 595 5-methoxy- 3-fluoropropyl Method 1: LCMS Rf 3.277 min
at 254 nm, 2-methyl 3.277 min at 220 nm, m/e 371 (M + 1). 596
7-methoxy 3-fluoropropyl Method 1: LCMS Rf 3.290 min at 254 nm,
3.291 min at 220 nm, m/e 357 (M + 1). 597 6-chloro 3-fluoropropyl
Method 1: LCMS Rf 3.498 min at 254 nm, 3.499 min at 220 nm, m/e 361
(M + 1). 598 6-fluoro 3-fluoropropyl Method 1: LCMS Rf 3.329 min at
254 nm, 3.330 min at 220 nm, m/e 345 (M + 1). 600 6-methoxy 2,2,2-
Method 1: LCMS Rf 3.288 min at 254 nm, trifluoroethyl 3.228 min at
220 nm, m/e 379 (M + 1). 601 4-chloro 2,2,2- Method 1: LCMS Rf
3.518 min at 254 nm, trifluoroethyl 3.518 min at 220 nm, m/e 383 (M
+ 1). 602 4-methoxy 2,2,2- Method 1: LCMS Rf 3.427 min at 254 nm,
trifluoroethyl 3.428 min at 220 nm, m/e 379 (M + 1). 603 5-methoxy-
2,2,2- Method 1: LCMS Rf 3.378 min at 254 nm, 2-methyl
trifluoroethyl 3.378 min at 220 nm, m/e 393 (M + 1). 604 7-methoxy
2,2,2- Method 1: LCMS Rf 3.234 min at 254 nm, trifluoroethyl 3.255
min at 220 nm, m/e 379 (M + 1). 605 6-chloro 2,2,2- Method 1: LCMS
Rf 3.587 min at 254 nm, trifluoroethyl 3.587 min at 220 nm, m/e 383
(M + 1).
[0614] The following compounds were prepared by following a similar
procedure to Example 545: TABLE-US-00028 ##STR73## No. Z' R.sub.4
Data 606 6-methoxy 2,2-difluoro- Method 1: LCMS Rf 3.190 min at 254
nm, ethyl 3.190 min at 220 nm. 607 4-fluoro 3- Method 1: LCMS Rf
3.390 min at 254 nm, 5-methoxy fluoropropyl 3.395 min at 220 nm,
m/e 401 (M + 1). 6-fluoro 608 4-fluoro 2,2,2- Method 1: LCMS Rf
3.442 min at 254 nm, 6-fluoro trifluoroethyl 3.453 min at 220 nm,
m/e 429 (M + 1). 5-methoxy
EXAMPLE 620
N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)-3-(2,2,3,3,3-pentafluoropropoxy)benzy-
lamine
[0615] ##STR74##
[0616] Combine amine (0.2 mmol) in dichloromethane (0.5 mL) and
aldehyde (0.4 mmol) in dichloromethane (1 mL) and rotate. After 1
h, add sodium triacetoxyborohydride (82 mg, 0.8 mmol) as a stock
solution in 1-methyl-2-pyrrolidinone (1 mL) and rotate. After
overnight rotation, dilute the reaction mixture with 1 mL of
methanol and directly apply to a 2 g SCX column. After thoroughly
washing with methanol, elute the column with 2 M ammonia-methanol
and concentrate the eluent to a residue, which was further purified
by Gilson UV prep system. Compound was characterized using method
3. LCMS R.sub.f 4.823 min at 254 nm, 4.823 min at 220 nm, m/e 443
(M+1).
LC Method:
Method 3: (Shimadzu QP8000) 5-90 in 4.5 min. Solvent A: water 0.1%
trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic
acid. Column: C18 Metachem, monochrom 3 micron, 2.5.times.25.
[0617] The following compounds were prepared using a similar
procedure as in Example 620: TABLE-US-00029 ##STR75## No. R.sup.4
Data 622 2,2,3,3-tetrafluoropropyl Method 3: LCMS Rf 4.681 min at
254 nm, 4.692 min at 220 nm, m/e 425 (M + 1). 623
2,2,2-trifluoroethyl Method 3: LCMS Rf 4.639 min at 254 nm, 4.643
min at 220 nm, m/e 393 (M + 1).
EXAMPLE 624
N-(2-(6-Fluoro-1-methyl-1H-indol-3-yl)ethyl)-N-methyl-3-propoxybenzylamine
[0618] ##STR76##
[0619] Combine
N-methyl-N-(2-(6-fluoro-1-methyl-1H-indol-3-yl)ethylamine (0.2
mmol) in 1-methyl-2-pyrrolidinone (0.5 mL) and
3-propyloxybenzaldehyde (0.32 mmol) in dichloromethane (1 mL) and
rotate. After overnight rotation, add sodium borohydride (1.0 mmol)
as a stock solution in 1-methyl-2-pyrrolidinone (0.5 mL) and
rotate. After rotation for 3 h, dilute the reaction mixture with 1
mL of 10% acetic acid/methanol, and directly apply the resulting
solution to a 2 g SCX column. After thoroughly washing with
methanol, elute the column with 2 M ammonia-methanol and
concentrate the eluent to a residue, which was further purified by
Gilson UV prep system.
LC method:
[0620] Method 1: (Shimadzu QP8000) 10-90 in 4.5 min. Solvent A:
water 0.1% trifluoroacetic acid, Solvent B: acetonitrile 0.1%
trifluoroacetic acid. Column: C18 Metachem, monochrom 3 micron,
2.5.times.25.
[0621] The following compounds were prepared following a similar
procedure as found in Example 624: TABLE-US-00030 ##STR77## Z'
R.sub.3 R.sub.4 Data 625 3-trifluoromethyl 4-CH.sub.3 propyl Method
1: LCMS Rf 3.214 min 4-fluoro at 254 nm, 3.213 min at 220 nm, m/e
371 (M + 1). 626 3-trifluoromethyl H 3,3,3- Method 1: LCMS Rf 3.042
min 4-fluoro trifluoropropyl at 254 nm, 3.042 min at 220 nm, m/e
410 (M + 1). 627 3-trifluoromethyl H 2,2-difluoro Method 1: LCMS Rf
2.828 min 4-fluoro ethyl at 254 nm, 2.828 min at 220 nm, m/e 378 (M
+ 1). 628 3-trifluoromethyl H 2,2,3,3,3penta method 1: LCMS Rf
3.196 min 4-fluoro fluoro at 254 nm, 3.196 min at 220 nm, propyl
m/e 446 (M + 1). 629 3-trifluoromethyl H 2,2,2- Method 1: LCMS Rf
2.984 min 4-fluoro trifluoroethyl at 254 nm, 2.984 min at 220 nm,
m/e 396 (M + 1). 630 3-trifluoromethyl H 3-fluoro Method 1: LCMS Rf
2.855 min 4-fluoro propyl at 254 nm, 2.855 min at 220 nm, m/e 374
(M + 1).
[0622] TABLE-US-00031 ##STR78## No. Z' R.sub.3 R.sub.4 Data 632
5-fluoro 4- propyl Method 1: LCMS Rf 3.141 min at 254 6-chloro
methyl nm, 3.140 mm at 220 nm, m/e 375 (M + 1). 633 6- H
3,3,3-trifluoro Method 1: LCMS Rf 3.065 min at 254 trifluoro propyl
nm, 3.066 min at 220 nm, m/e 431 methyl (M + 1). 634 5-fluoro H
3,3,3-trifluoro Method 1: LCMS Rf 2.977 min at 254 6-chloro propyl
nm, 2.977 min at 220 nm, m/e 415 (M + 1). 635 5,6- H
3,3,3-trifluoro Method 1: LCMS Rf 2.871 min at 254 difluoro propyl
nm, 2.872 min at 220 nm, m/e 399 (M + 1). 636 6- H 3,3,3-trifluoro
Method 1: LCMS Rf 3.065 min at 254 trifluoro propyl nm, 3.066 min
at 220 nm, m/e 431 methyl (M + 1). 637 5-fluoro H 2,2-difluoro
Method 1: LCMS Rf 2.782 min at 254 6-chloro ethyl nm, 2.782 min at
220 nm, m/e 383 (M + 1). 638 5,6- H 2,2-difluoro Method 1: LCMS Rf
2.655 min at 254 difluoro ethyl nm, 2.655 min at 220 nm, m/e 367 (M
+ 1). 639 6- H 2,2-difluoro Method 1: LCMS Rf 2.876 min at 254
trifluoro ethyl nm, 2.875 min at 220 nm, m/e 399 (M + 1). methyl
640 6- H 2,2,2 trifluoro Method 1: LCMS Rf 3.009 min at 254
trifluoro ethyl nm, 3.009 min at 220 nm, m/e 417 (M + 1). methyl
641 5-fluoro H 2,2,3,3,3- Method 1: LCMS Rf 3.135 min at 254
6-chloro pentafluoro nm, 3.135 min at 220 nm, m/e 451 (M + 1).
propyl 642 5,6- H 2,2,3,3,3- Method 1: LCMS Rf 3.027 min at 254
difluoro pentafluoro nm, 3.027 min at 220 nm, m/e 435 (M + 1).
propyl 643 6- H 2,2,3,3,3- Method 1: LCMS Rf 3.202 min at 254
trifluoro pentafluoro nm, 3.202 min at 220 nm, m/e 467 (M + 1).
methyl propyl 645 5,6- H 2,2,2-trifluoro Method 1: LCMS Rf 2.982
min at 254 difluoro ethyl nm, 2.982 min at 220 nm, m/e 396 (M + 1)
646 6- H 2,2,2- Method 1: LCMS Rf 3.009 min at 254 trifluoro
trifluoroethyl nm, 3.009 min at 220 nm, m/e 417 (M + 1). methyl 647
5-fluoro H 3-fluoro Method 1: LCMS Rf 2.796 min at 254 6-chloro
propyl nm, 2.796 min at 220 nm, m/e 379 (M + 1). 648 5,6- H
3-fluoro Method 1: LCMS Rf 2.644 m/e at 254 difluoro propyl nm,
2.646 min at 220 nm, m/e 363 (M + 1). 649A 6- H 3-fluoro Method 1:
LCMS Rf 2.900 min at 254 trifluoro propyl nm, 2.900 min at 220 nm,
m/e 395 (M + 1). methyl
[0623] TABLE-US-00032 ##STR79## No. Z' R.sub.3 R.sub.4 Data 631
6-fluoro 4-methyl propyl Method 1: LCMS Rf 3.152 min at 220 nm, m/e
355 (M + 1). 633A 6-fluoro H 3,3,3- Method 1: LCMS Rf 2.949 min at
254 trifluoro nm, 2.953 min at 220 nm, m/e 395 propyl (M + 1). 640A
6-fluoro H 2,2,3,3,3- Method 1: LCMS Rf 3.112 min at 254
pentafluoro nm, 3.117 min at 220 nm, m/e 431 propyl (M + 1). 649
6-fluoro H 2,2,2- Method 1: LCMS Rf 2.895 min at 254 trifluoro nm,
2.898 min at 220 nm, m/e 381 ethyl (M + 1).
EXAMPLE 650
N-2-(3-chlorophenyl)ethyl-3-hydroxybenzylamine
[0624] ##STR80##
[0625] Combine 2-(3-chlorophenyl)ethylamine (1.866 gm; 15.28 mmol)
and 3-hydroxybenzaldehyde (1.567 gm; 10.07 mmol) in 40 mL of
methanol and stir at room temperature for 20 min and treat with
sodium borohydride (0.950 gm; 25.1 mmol) in one portion. Stir the
mixture at room temperature. After 15 h, add water (10 mL), and
remove the methanol by rotary evaporation. Add to this slurry water
(25 mL) and dichloromethane (50 mL), separate the layers and
extract the aqueous layer with dichloromethane (50 mL). Wash the
combined organic layers with saturated brine (3.times.), dry over
MgSO.sub.4, and concentrate to give the title compound.
EXAMPLE 650A
N-t-Butoxycarbonyl-N-2-(3-chlorophenyl)ethyl-3-hydroxybenzylamine
[0626] Combine N-2-(3-chlorophenyl)ethyl-3-hydroxybenzylamine,
dichloromethane (40 mL), and di-tert-butyl dicarbonate (1.556 gm;
7.131 mmol) and triethylamine (1.0 mL; 7.2 mmol). After 18 hours,
pour into water (50 mL), separate the layers, and extract the
aqueous layer with dichloromethane. Wash combined organic layers
with water, dry over MgSO.sub.4, and concentrate. Chromatograph on
silica gel eluting with 5% ethyl acetate in hexanes to give the
title compound.
EXAMPLE 651
N-t-Butoxycarbonyl-N-2-(3-chlorophenyl)ethyl-3-propoxybenzylamine
[0627] Add a solution of 50% sodium hydroxide in water (0.8 mL) to
a solution of
N-t-butoxycarbonyl-N-2-(3-chlorophenyl)ethyl-3-hydroxybenzylamine
(46.7 mg, 0.129 mmol), n-propyl iodide (0.17 gm. 1.00 mmol), and
tetrabutylammonium bromide (18 mg, 0.057 mmol) in toluene (1 mL).
Stir the mixture at 1200 rpm and heat at 50-54.degree. C. After
64.5 hour pour the mixture into 5 mL of water, separate the phases
and extract the aqueous phase twice with dichloromethane. Combine
the organic phases and wash with saturated sodium bicarbonate
solution, and then saturated brine, dry (MgSO.sub.4), and
concentrate to give a residue. Chromatograph the residue on silica
gel to give the title compound: MS (ES+): m/e (M+1) 404. TLC (20%
EtOAc in hexanes, R.sub.f 0.54).
EXAMPLE 652
N-(2-(3-Chlorophenyl)ethyl)-3-propoxybenzylamine
[0628] ##STR81##
[0629] Add methanesulfonic acid (70 uL) to a solution of
N-t-Butoxycarbonyl-N-2-(3-chlorophenyl)ethyl-3-propoxybenzylamine
in dichloromethane (4 mL) and agitate the mixture for 3 hours at
room temperature. Add 10% aqueous Na.sub.2CO.sub.3 (2 mL), separate
the layers, and concentrate the organic layer in a nitrogen stream
to give a residue. Dissolve the residue in 4 mL of 5% acetic acid
in methanol and pass through a 1 gm SCX column, eluting with 1 M
ammonia in methanol to give the title compound: MS (ES+): m/e
(M+1). HPLC (10-90% water/acetonitrile over 7.5 min, Tr=4.490
min).
[0630] The following compounds were prepared by a similar procedure
to Examples 651 and 652: TABLE-US-00033 ##STR82## No. R.sub.4 Data
654 ethyl Method 1: LCMS Rf 4.223 min at 254/220 nm; m/e 298.9 (M +
1) 655 butyl Method 1: LCMS Rf 4.715 min at 254/220 nm; m/e 317.9
(M + 1) 656 hexyl Method 1: LCMS Rf 5.137 min at 254/220 nm; m/e
345.9 (M + 1) 658 allyl Method 1: LCMS Rf 4.373 min at 254/220 nm;
m/e 301.9 (M + 1) 660 pyridin-2- Method 1: LCMS Rf 3.547 min at
254/220 nm; m/e ylmethyl 352.9 (M + 1) 661 pyridin-3- Method 1:
LCMS Rf 3.487 min at 254/220 nm; m/e ylmethyl 352.9 (M + 1) 662
pyridin-4- Method 1: LCMS Rf 3.455 min at 254/220 nm; m/e ylmethyl
352.9 (M + 1)
EXAMPLE 665
N-(2-(5-Methoxy-1-ethyl-1H-indol-3-yl
ethyl-N-ethyl-3-phenyoxybenzylamine
[0631] ##STR83##
[0632] Add acetaldehyde (0.080 mL; 0.77 mmol) to a solution of
N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-3-phenyoxybenzylamine (free
base, 55.5 mg, 0.149 mmol) in dichloromethane (1 mL) followed by a
suspension of sodium triacetoxyborobydride (64 mg; 0.30 mmol) in
dichloromethane (1 mL). After 44 hours, quench by the addition of
methanol (0.5 mL) and concentrate in a stream of nitrogen to give a
residue. Dissolve the residue in 4 mL of 5% acetic acid in methanol
and partially purify by passage through a 1 gm SCX column, eluting
with 1 M ammonia in methanol to give a residue. Chromatograph the
residue by preparative HPLC (C-18 column, flow rate of 20 ml/min,
5-90% water/acetonitrile over 12 min) to give the title compound:
MS (ES+): m/e (+1); HPLC: (10-90% water/acetonitrile over 10 min,
Tr=5.25 min).
[0633] The following compounds were prepared following a similar
procedure in Example 665: TABLE-US-00034 ##STR84## No. R.sub.2 Data
666 methyl LC Method 2: Rf 5.12 min at 254/220 nm; m/e 351.9 (M +
1) 667 ethyl LC Method 2: Rf 5.25 min at 254/220 nm; m/e 365.9 (M +
1)
[0634] TABLE-US-00035 ##STR85## No. R.sub.2 Data 668 ethyl LC
Method 2: Rf 4.98 min at 254/220 nm; m/e 401.09 (M + 1)
EXAMPLE 670
3-Propoxybenzaldehyde
[0635] Combine 3-hydroxybenzaldehyde (7.50 gm; 61.4 mmol), n-propyl
iodide (17.3 gm; 102 mmol), and potassium carbonate (16.90 gm; 122
mmol) in 2-butanone (100 mL) and reflux. After 17 h, allow the
mixture to cool to room temperature, decant the solution and
concentrate by rotary evaporation. Partition the residue between
diethyl ether (150 mL) and water (150 mL), separate the layers and
extract the aqueous layer with diethyl ether (2.times.100 mL).
Combine organic layers and wash with water, 1 N NaOH, and then
water, dry over MgSO.sub.4, and concentrate to give a residue.
Distill the residue to give the title compound: bp: 122-125.degree.
C. (15 mm); TLC (10% Et.sub.2O/hexanes; R.sub.f 0.35).
EXAMPLE 671
3-(3,3,3-Trifluoropropoxy)benzaldehyde
[0636] Cool a mixture of toluenesulfonyl chloride (7.43 gm; 39.0
mmol) and pyridine (50 mL) to 0.degree. C., add
3,3,3-3,3,3-trifluoropropanol (2.23 gm; 19.5 mmol) and store the
mixture at 3.degree. C. After 48 hour pour the reaction mixture
into 350 mL of ice water and extract with diethyl ether
(3.times.125 mL). Combine the organic layers and wash with 5 N HCl,
water, saturated sodium bicarbonate solution, and brine, dry over
MgSO.sub.4, and concentrate to give 3,3,3-trifluoropropyl tosylate.
The material was carried into the next step without
purification.
[0637] Combine 3,3,3-trifluoropropyl tosylate (4.057 gm; 15.12
mmol), 3-hydroxybenzaldehyde (1.85 gm; 15.12 mmol), and
K.sub.2CO.sub.3 (4.15 gm; 30.0 mmol) in DMF (80 mL) and heat at
100.degree. C. After 18 hours, cool to room temperature, dilute
with water (200 mL) and extract with dichloromethane (2.times.200
mL). Combine organic extracts and wash sequentially with water (100
mL), 0.1 M NaOH (2.times.100 mL), saturated sodium bicarbonate (100
mL) and saturated brine (100 mL), dry (MgSO.sub.4), and
concentrate. Chromatography on silica gel (0-20% ethyl acetate in
hexane) to give the title product.
EXAMPLE 672
3-(2-Fluoroethoxy)benzaldehyde
[0638] Combine 1-bromo-2-fluoroethane (4.575 g; 36.0 mmol),
3-hydroxybenzaldehyde (4.103 gm; 33.60 mmol), and K.sub.2CO.sub.3
(7.05 gm; 51.0 mmol) in 2-butanone (100 mL) and reflux. After 18
hour cool the mixture to ambient temperature, concentrate, and
partition between 100 mL of water and 100 mL of dichloromethane.
Separate the layers and extract the aqueous layer with
dichloromethane (2.times.75 mL). Combine the organic layers and
wash sequentially with brine (2.times.150 mL), 1 M NaOH
(2.times.100 mL), NaHCO.sub.3 (saturated, 100 mL), and brine (150
mL), dried (MgSO.sub.4), concentrate, and chromatograph on silica
gel (0-25% diethyl ether in hexanes) to give the title
compound.
EXAMPLE 673
N-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-3-propoxybenzylamine
[0639] ##STR86##
[0640] Combine 3-propoxybenzaldehyde (29.6 mg; 0.18 mmol) and
5-fluorotryptamine (14.2 mg; 0.080 mmol) in methanol (2 mL). Add a
solution of sodium borohydride in diglyme (1 ml of a 0.5 M
solution; 0.50 mmol) and agitate. After 63 h at room temperature
concentrate in a stream of nitrogen. Dissolve the residue in
methanol and add to a 1 gm SCX column previously rinsed with 5%
acetic acid in methanol. Elute the product from the SCX column with
1 M ammonia in methanol to give the title compound: MS (ES+): m/e
(M+1); HPLC (10-90% water/acetonitrile over 10 min, Tr=4.08
min.
General LC Methods:
[0641] Method 1: (Shimadzu Class VP HPLC and Micromass Platform LC
with HP1100 LC system) 10-90 in 7.5 min. Solvent A: water 0.1%
trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic
acid. Column: C18 Metachem, monochrom 3 micron, 2.5.times.2.5.
[0642] Method 2: (Shimadzu Class VP HPLC and Micromass Platform LC
with HP1100 LC system) 10-90 in 10 min. Solvent A: water 0.1%
trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic
acid. Column: C18 Metachem, monochrom 3 micron, 2.5.times.2.5.
[0643] Method 3: (Waters Millennium HPLC and Micromass Platform LC
with HP1100 LC system) 10-100 in 10 min. Solvent A: 0.1%
trifluoroacetic acid, Solvent B: acetonitrile 0.08% trifluoroacetic
acid. Column: YMC, 5 micron, 2.5.times.25.
[0644] Method 4: (Shimadzu QP8000) 10-90 in 4.5 min. Solvent A:
water 0.1% trifluoroacetic acid, Solvent B: acetonitrile 0.1%
trifluoroacetic acid. Column: C18 Metachem, monochrom 3 micron,
2.5.times.25.
[0645] The following compounds were prepared following a procedure
following Example 673: TABLE-US-00036 ##STR87## No. Z' Data 675
2-fluoro LC Method 3: Rf 4.18 min at 254/220 nm; m/e 322.0 (M + 1)
676 3-fluoro LC Method 3: Rf 4.23 min at 254/220 nm; m/e 322.0 (M +
1) 677 4-chloro LC Method 3: Rf 4.48 min at 254/220 nm; m/e 337.9
(M + 1) 678 4-hydroxy LC Method 3: Rf 3.62 min at 254/220 nm; m/e
320.0 (M + 1) 679 2-methoxy LC Method 3: Rf 4.30 min at 254/220 nm;
m/e 334.0 (M + 1) 680 4-bromo 3-methoxy LC Method 3: Rf 4.50 min at
254/220 nm; m/e 411.9 (M + 1) 681 4-fluoro LC Method 3: Rf 4.22 min
at 254/220 nm; m/e 322.0 (M + 1) 682 2-chloro LC Method 3: Rf 4.36
min at 254/220 nm; m/e 338.0 (M + 1) 683 4-bromo LC Method 3: Rf
4.55 min at 254/220 nm; m/e 383.91 (M + 1) 684 4-methyl LC Method
3: Rf 4.42 min at 254/220 nm; m/e 318.0 (M + 1) 685 3-methoxy LC
Method 3: Rf 4.19 min at 254/220 nm; m/e 334.0 (M + 1) 686
4-methoxy LC Method 3: Rf 4.15 min at 254/220 nm; m/e 334.0 (M + 1)
687 2-ethoxy LC Method 3: Rf 4.55 min at 254/220 nm; m/e 348.0 (M +
1) 688 4-ethoxy LC Method 3: Rf 4.43 min at 254/220 nm; m/e 348.0
(M + 1) 689 4-phenoxy LC Method 3: Rf 5.00 min at 254/220 nm; m/e
396.0 (M + 1) 690 4-sulfonamide LC Method 3: Rf 3.46 min at 254/220
nm; m/e 383.0 (M + 1) 691 3,4-dichloro LC Method 3: Rf 4.74 min at
254/220 nm; m/e 372.0 (M + 1) 692 2,5-dichloro LC Method 3: Rf 4.74
min at 254/220 nm; m/e 372.0 (M + 1) 693 2,6-dichloro LC Method 3:
Rf 4.51 min at 254/220 nm; m/e 372.0 (M + 1) 694 2,5-dimethoxy LC
Method 3: Rf 4.31 min at 254/220 nm; m/e 364.0 (M + 1) 695
2,3-dimethoxy LC Method 3: Rf 4.24 min at 254/220 nm; m/e 364.0 (M
+ 1) 696 3,5-dimethoxy LC Method 3: Rf 4.26 min at 254/220 nm; m/e
364.0 (M + 1) 697 3-ethoxy-4-methoxy LC Method 3: Rf 4.14 min at
254/220 nm; m/e 378.0 (M + 1)
[0646] The following compounds were prepared following a procedure
following Example 673: TABLE-US-00037 ##STR88## No. Z' Data 698
5-methyl LC Method 4: Rf 2.852 min at 254/220 nm; m/e 357 (M + 1)
699 5-chloro LC Method 4: Rf 2.893 min at 254/220 nm; m/e 377 (M +
1)
[0647] TABLE-US-00038 ##STR89## No. Z' Data 700 2-fluoro LC Method
3: Rf 3.90 min at 254/220 nm; m/e 288.0 (M + 1) 701 3-fluoro LC
Method 3: Rf 3.95 min at 254/220 nm; m/e 288.0 (M + 1) 702 4-fluoro
LC Method 3: Rf 3.96 min at 254/220 nm; m/e 288.0 (M + 1) 703
2-chloro LC Method 3: Rf 4.23 min at 254/220 nm; m/e 303.9 (M + 1)
704 4-chloro LC Method 3: Rf 4.12 min at 254/220 nm; m/e 303.9 (M +
1) 705 4-bromo LC Method 3: Rf 4.33 min at 254/220 nm; m/e 347.9 (M
+ 1) 706 4-methyl LC Method 3: Rf 4.17 min at 254/220 nm; m/e 284.0
(M + 1) 707 4-hydroxy LC Method 3: Rf 3.26 min at 254/220 nm; m/e
286.0 (M + 1) 708 2-methoxy LC Method 3: Rf 4.03 min at 254/220 nm;
m/e 300.0 (M + 1) 709 3-methoxy LC Method 3: Rf 3.91 min at 254/220
nm; m/e 300.0 (M + 1) 710 4-methoxy LC Method 3: Rf 3.91 min at
254/220 nm; m/e 300.0 (M + 1) 711 3-ethoxy LC Method 3: Rf 4.31 min
at 254/220 nm; m/e 314.0 (M + 1) 712 4-ethoxy LC Method 3: Rf 4.14
min at 254/220 nm; m/e 314.0 (M + 1) 713 4-phenoxy LC Method 3: Rf
4.77 min at 254/220 nm; m/e 362.0 (M + 1) 714 4-sulfonamide LC
Method 3: Rf 3.06 min at 254/220 nm; m/e 349.0 (M + 1) 715
3,4-dichloro LC Method 3: Rf 4.52 min at 254/220 nm; m/e 337.9 (M +
1) 716 2,5-dichloro LC Method 3: Rf 4.51 min at 254/220 nm; m/e
337.9 (M + 1) 717 2,6-dichloro LC Method 3: Rf 4.28 min at 254/220
nm; m/e 337.9 (M + 1) 718 3,4-dimethoxy LC Method 3: Rf 3.59 min at
254/220 nm; m/e 330.0 (M + 1) 719 2,5-dimethoxy LC Method 3: Rf
4.04 min at 254/220 nm; m/e 330.0 (M + 1) 720 2,3-dimethoxy LC
Method 3: Rf 3.96 min at 254/220 nm; m/e 330.0 (M + 1) 721
3,5-dimethoxy LC Method 3: Rf 3.99 min at 254/220 nm; m/e 330.0 (M
+ 1) 722 3-bromo 4-methoxy LC Method 3: Rf 4.22 min at 254/220 nm;
m/e 379.9 (M + 1) 723 4-ethoxy-3-methoxy LC Method 3: Rf 3.88 min
at 254/220 nm; m/e 344.0 (M + 1) 724 3-ethoxy-4-methoxy LC Method
3: Rf 3.84 min at 254/220 nm; m/e 344.0 (M + 1)
[0648] The following compounds were prepared following a procedure
following Example 673: TABLE-US-00039 ##STR90## No. R.sub.1 Data
725 pyridine-2-yl LC Method 3: Rf 2.38 min at 254/220 nm; m/e 271.0
(M + 1) 726 pyridin-3-yl LC Method 3: Rf 2.25 min at 254/220 nm;
m/e 271.0 (M + 1) 727 pyridin-4-yl LC Method 3: Rf 2.21 min at
254/220 nm; m/e 271.0 (M + 1) 729 7-methyl-1H-indol-3-yl LC Method
3: Rf 4.19 min at 254/220 nm; m/e 323.0 (M + 1) 730
6-methoxy-1H-indol-3-yl LC Method 3: Rf 3.90 min at 254/220 nm; m/e
339.0 (M + 1) 731 thiophen-3-yl LC Method 3: Rf 3.70 min at 254/220
nm; m/e 275.9 (M + 1) 732 5-methyl-1H-indol-3-yl LC Method 4: Rf
2.680 min at 254/220 nm; m/e 323 (M + 1) 733 5-chloro-1H-indol-3-yl
LC Method 4: Rf 4.019 min at 254/220 nm; m/e 344 (M + 1)
[0649] The following compounds were prepared following a procedure
following Example 673: TABLE-US-00040 ##STR91## No. Z' R.sub.4 Data
734 5-methyl 2-fluoroethyl LC Method 4: Rf 2.381 min at 254/220 nm;
m/e 327 (M + 1) 735 5-fluoro 2-fluoroethyl LC Method 4: Rf 2.300
min at 254/220 nm; m/e 331 (M + 1) 736 5-methyl 2,2-difluoroethyl
LC Method 4: Rf 2.520 min at 254/220 nm; m/e 345 (M + 1) 737
5-fluoro 2,2difluoroethyl LC Method 4: Rf 2.445 min at 254/220 nm;
m/e 349 (M + 1) 738 5-chloro 2,2-difluoroethyl LC Method 4: Rf
2.598 min at 254/220 nm; m/e 365 (M + 1) 739 5-fluoro
4,4,4-trifluorobutyl LC Method 4: Rf 3.017 min at 254/220 nm; m/e
395 (M + 1) 740 5-fluoro 2,2,2-trifluoroethyl LC Method 4: Rf 2.787
min at 254/220 nm; m/e 367 (M + 1) 741 5-methoxy
2,2,2-trifluoroethyl LC Method 4: Rf 2.681 min at 254/220 nm; m/e
379 (M + 1) 742 5-chloro 4,4,4-trifluorobutyl LC Method 4: Rf 3.151
min at 254/220 nm; m/e 411 (M + 1) 743 5-fluoro 3-fluoropropyl LC
Method 4: Rf 2.475 min at 254/220 nm; m/e 345 (M + 1) 744 5-methoxy
3,3,3-trifluoropropyl LC Method 4: Rf 2.889 min at 254/220 nm; m/e
393 (M + 1) 745 5-chloro 3-fluoropropyl LC Method 4: Rf 2.628 min
at 254/220 nm; m/e 361 (M + ) 746 5-fluoro 2,2,3,3- LC Method 4: Rf
2.680 min at tetrafluoropropyl 254/220 nm; m/e 399 (M + 1) 747
5-methyl 2,2,3,3- LC Method 4: Rf 2.756 min at tetrafluoropropyl
254/220 nm; m/e 397 (M + 1) 748 5-chloro 2,2,3,3- LC Method 4: Rf
2.820 min at tetrafluoropropyl 254/220 nm; m/e 417 (M + 1) 750
5-fluoro 2,2,3,3,3- LC Method 4: Rf 2.833 min at pentafluoropropyl
254/220 nm; m/e 417 (M + 1) 751 5-methyl 2,2,3,3,3- LC Method 4: Rf
2.908 min at pentafluoropropyl 254/220 nm; m/e 415 (M + 1) 752
5-chloro 2,2,3,3,3- LC Method 4: Rf 2.784 min at pentafluoropropyl
254/220 nm; m/e 433 (M + 1) 754 5-methyl 3-fluoropropyl LC Method
4: Rf 2.457 min at 254/220 nm; m/e 341 (M + 1) 755 5-methoxy
4,4,4-trifluorobutyl LC Method 4: Rf 2.931 min at 254/220 nm; m/e
406 (M + 1) 756 5-methoxy 2,2,3,3- LC Method 4: Rf 2.795 min at
tetrafluoropropyl 254/220 nm; m/e 411 (M + 1) 757 5-chloro
2-fluoroethyl LC Method 4: Rf 2.477 min at 254/220 nm; m/e 347 (M +
1)
[0650] The following compounds were prepared following a procedure
following Example 673: TABLE-US-00041 ##STR92## No. Z' R.sub.4 Data
758 3-trifluoro 2,2,3,3- LC Method 4: Rf 2.650 min at methyl
tetrafluoro propyl 254/220 nm; m/e 410 (M + 1) 759 3-trifluoro
4,4,4-trifluoro LC Method 4: Rf 2.761 min at methyl butyl 254/220
nm; m/e 406 (M + 1)
EXAMPLE 760
3-Trifluoromethoxyphenethylamine
[0651] Combine nitromethane (1.8 g, 30 mmol), ethanol (4 mL) and 10
N NaOH (0.1 mL). Add 3-trifluoromethoxybenzaldehyde (5.0 g, 28.6
mmol) and stir. After 20 hours, pour into ethyl acetate, wash with
water, dried over Na.sub.2SO.sub.4, filter, and concentrate to give
a residue. Chromatograph the residue on silica gel to give
2-nitro-1-(3-trifluoroethoxyphenyl)ethanol: MS (M-1) 250; .sup.1H
NMR (CDCl.sub.3) 7.45 (1H, t, J=8.4 Hz), 7.36-7.30 (2 h, m),
7.24-7.20 (1 h, m), 5.51 (1 h, dt, J=8.8 and 4.0 Hz), 4.62-4.51
(2H, m).
[0652] Combine 2-nitro-1-(3-trifluoroethoxyphenyl)ethanol (6.1 g,
24.2 mmol) and methanesulfonyl chloride (2.02 mL) in
dichloromethane (50 mL) and cool in an ice-bath. Add dropwise,
triethylamine (7.28 mL) while maintaining the temperature near
0.degree. C. After 2 hours, pour into ethyl acetate, wash with
water, dry with Na.sub.2SO.sub.4, filter, and then concentrate to
residue. Chromatograph the residue on silica gel to give
3-(2-nitrovinyl)-1-trifluoroethoxybenzene: MS (MH.sup.+) 234;
.sup.1H NMR (CDCl.sub.3) 7.97 (1H, d, J=13.6 Hz), 7.57 (1H, d,
J=13.6 Hz), 7.53-7.48 (2H, m), 7.40-7.35 (2H, m).
[0653] Combine 3-(2-nitrovinyl)-1-trifluoroethoxybenzene (3.0 g,
12.88 mmol) and methanol (50 mL) and concentrated HCl (5 mL) and
hydrogenate at ambient temperature and 50 psi (340 kPa) in the
presence of PtO.sub.2 (0.6 g). After 5 hours, filter to the
catalyst, dilute the filtrate with 1N HCl (50 mL) and wash with
ethyl acetate. Separate the aqueous layer, neutralize with 2N NaOH
(100 mL), extract with ether, dry with Na.sub.2SO.sub.4, filter and
then concentrated to give the title compound which can be used
without further purification. MS (MH.sup.+) 206; .sup.1H NMR
(CDCl.sub.3) 7.32 (1H, t, J=7.6 Hz), 7.18-7.06 (3H, m), 2.98 (2H,
t, J=7.2 Hz), 2.77 (2H, t, J=7.2 Hz).
EXAMPLE 761
N-(2-(3-Trifluoromethoxyphenyl)ethyl)-3-(2,2,2-trifluoroethyl)benzylamine
[0654] ##STR93##
[0655] Combine trifluoromethoxyphenethylamine (400 mg, 1.95 mmol),
and 3-(2-trifluoroethoxy)benzaldehyde (596 mg, 2.92 mmol), and 4
.ANG. molecular sieve (4.0 g) in ethanol (30 mL) and reflux. after
4.5 hours, decant and treat of NaBH.sub.4 (221 mg, 5.85 mmol).
After 1 hour, evaporate and partition between 5N NaOH and
dichloromethane. Separate the organic layer, dry over
Na.sub.2SO.sub.4, filter, and concentrate to give a residue.
Chromatograph the residue by HPLC to give the title compound. The
HCl salt of the title compound gives a white solid: MS (MH.sup.+)
394; .sup.1H (DMSO-d.sub.6) 9.48 (2H, br s), 7.48 (I H, t, J=7.6
Hz), 7.40 (1H, t, J=8.0 Hz), 7.34 (1H, s), 7.32-7.21 (4H, m), 7.11
(1H, dd, J=8.4 and 2.8 Hz), 4.79 (2H, q, J=8.8 Hz), 4.15 (2H, s),
3.22-3.12 (2H, m), 3.11-3.04 (2H, m).
EXAMPLE 762
N-(2-(3-Trifluoromethoxyphenyl)ethyl)-3-(2,2,3,3-tetrafluoropropyl)benzyla-
mine
[0656] ##STR94##
[0657] The method of Example 761 gives the title compound. The HCl
salt of the title compound gives a white solid: MS (MH.sup.+) 426;
.sup.1H (DMSO-d6) 9.42 (2H, br s), 7.48 (1H, t, J=7.6 Hz), 7.40
(1H, t, J=7.6 Hz), 7.32-7.26 (3H, m), 7.20 (1H, d, J=7.2 Hz), 7.11
(1H, dd, J=8.4 and 2.8 Hz), 6.70 (1H, tt, J=52 and 5.2 Hz), 4.62
(2H, t, J=13.6 Hz), 4.15 (2H, s), 3.22-3.12 (2H, m), 3.10-3.02 (2H,
M).
EXAMPLE 763
N-(2-(4,7-Difluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylami-
ne
[0658] ##STR95##
[0659] Combine 2-(4,7-difluoro-1H-indol-3-yl)ethylamine (483 mg,
2.46 mmol) and ethanol (45 mL) and stir. After 10 minutes treat
with 3-(2,2,2-trifluoroethoxy)benzaldehyde (502 mg, 2.46 mmol) and
anhydrous sodium sulfate (3.5 g) and stir under nitrogen and heat
at 70.degree. C. After 2 h, cool the reaction vacuum filter to
remove the sodium sulfate and treat with sodium borohydride (279
mg, 7.38 mmol) in a 500 mL round bottom flask equipped with
magnetic stirring. Allow the solution to stir for 2 hours at room
temperature and then carefully treat with three drops of glacial
acetic acid to quench the excess hydride. Remove the solvent in
vacuo and re-dissolve the crude material in methanol. Purify by a
10 g SCX column by washing thoroughly with methanol, eluting with
2N ammonia in methanol, and concentrating in vacuo to give the
title compound as a straw colored oil. Prepare the hydrochloride
salt by dissolving the free base (800 mg, 2.08 mmol) in methanol
(15 mL) and treating with a solution of ammonium chloride (111 mg,
2.08 mmol) in methanol (5 mL). Sonicate the mixture for 10 minutes
before concentrating in vacuo to give a white solid. Recrystallize
from ethyl acetate to obtain the hydrochloride salt of the title
compound: mp 208.5-210.0.degree. C.; .sup.1H NMR (400 MHz,
dmso-d6): 11.79 (br s, 1H), 9.21 (br s, 2H), 7.39 (t, 1H, J=7.8
Hz), 7.32 (d, 1H, J=2.0 Hz) 7.30 (s, 1H), 7.18 (d, 1H, J=8.0 Hz),
7.11 (dd, 1H, J=2.6, 8.2 Hz), 6.85-6.91 (m, 1H), 6.67-6.73 (m, 1H),
4.77 (q, 2H, J=8.8 Hz), 4.16 (s, 4H), 3.12-3.16 (m, 4H); MS (APCI):
in/e 385.1 (M+1); CHN (for C.sub.19H.sub.17F.sub.5NO.HCl) calcd: C,
54.23; H, 4.31; N, 6.66; found: C, 54.20; H, 4.30; N, 6.66.
EXAMPLE 764
N-(2-(4,5,6,7-Tetrafluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)be-
nzylamine
[0660] ##STR96##
[0661] By a method similar to Example 763, using
2-(4,5,6,7-tetrafluoro-1H-indol-3-yl)ethylamine (484 mg, 2.08
mmol), ethanol (45 mL), 3-(2,2,2-trifluoroethoxy)benzaldehyde (425
mg, 2.08 mmol), anhydrous sodium sulfate (3.5 g) sodium borohydride
(236 mg, 6.24 mmol) to give the free base of the title compound as
a straw colored solid. Recrystallize from methylene chloride to
obtain the title compound: mp 107.2-108.2.degree. C. .sup.1H NMR
(400 MHz, dmso-d6): 11.92 (br s, 1H), 7.32 (s, 2H), 6.95-6.99 (m,
2H), 6.87 (dd, 1H, J=2.4, 8.0 Hz) 4.68 (q, 2H, J=8.8 Hz), 3.70 (s,
2H), 2.88 (t, 2H, J=7.2 Hz) 2.75 (t, 2H, J=7.2 Hz). MS (ES+): m/e
421.1 (M+1). CHN (for
C.sub.19H.sub.15F.sub.7N.sub.2O.HCl.0.20H.sub.2O) calcd: C, 53.83;
H, 3.66; N, 6.61; found: C, 53.75; H, 3.33; N, 6.
EXAMPLE 765
5-Trifluoromethyltryptamine
[0662] Combine 4-trifluoromethylaniline (32.2 g, 199.8 mmol) and
dichloromethane (600 ml) in a 2 L round bottomed flask under
nitrogen and cool to -70.degree. C. Add tert-butylhypochlorite
(protected from the light) (22.8 g, 210 mmol) in dichloromethane
(150 ml) stir for a total of 45 min at about -65 to -70.degree. C.
At 35 min, add a solution of methylthioacetaldehyde dimethylacetal
(30 g, 220.2 mmol) in dichloromethane (150 ml) is added. At 45 min
at -70.degree. C., add a solution of triethylamine (31.2 ml, 22.78
g, 225.1 mmol) in dichloromethane (80 ml). Bring the reaction
mixture to room temperature. Wash with water and evaporate to
dryness to give 72 g an oil.
[0663] Dissolve the oil in toluene (600 ml) and add triethylamine
(60 ml). Heat to reflux. After 24 hours, evaporate the solvent and
dry the residue under vacuum to yield 7a residue. Combine the
residue, diethyl ether (600 ml), and 2N HCl (500 ml) and stir 24
hours at room temperature. Separate the aqueous layer and wash the
organic layer successively with water and saturated NaHCO.sub.3,
dry over MgSO.sub.4, filter, and evaporate to give a residue.
Chromatograph on silica gel by eluting with cyclohexane-ethyl
acetate (8/2, v/v), and pool the fractions containing the expected
and evaporate to give 33.8 g of
2-methylthio-5-trifluoromethyl-1H-indole.
[0664] Combine moist Raney nickel (330 g),
2-methylthio-5-trifluoromethyl-1H-indole (33.8 g, 146.2 mmol) and
absolute ethanol (850 ml) and stir. After 1.5 hours, filter the
mixture through celite and wash the celite with ethanol (500 ml).
Evaporate the filtrate to dryness, add toluene (20 ml) and
evaporate and dry to give 5-trifluoromethylindole: mp=55-60.degree.
C.
[0665] Dissolve 5-trifluoromethylindole (24 g, 130 mmol) in
anhydrous diethyl ether (288 ml) and cool to 10.degree. C. and add
dropwise oxalyl chloride (12 ml) over 10 min. (exothermic reaction)
and stir at room temperature for 4 h. Add and additional amount of
oxalyl chloride (3 ml) and stir overnight at room temperature to
give a solid. Collect the solid, wash with anhydrous diethyl ether
(20 ml), and dry to give
2-(5-(trifluoromethyl-1H-indol-3-yl)-2-oxo-acetyl chloride.
[0666] Combine 2-(5-(trifluoromethyl-1H-indol-3-yl)-2-oxo-acetyl
chloride an NH.sub.4OH 1N (700 ml) and stir the suspension
intensely. After 3 hours, collect the
2-(5-(trifluoromethyl)-1H-indol-3-yl)-2-oxo-acetamide.
[0667] Add LiAlH.sub.4 (37.95 g, 1.00 mol) to THF (650 mL) under
ice-bath cooling. Prepare a solution of AlCl.sub.3 (50 g, 375 mmol)
in THF (600 ml) and add dropwise to the LiAlH.sub.4 solution over
45 min at 5-10.degree. C. While maintaining the temperature at
about 5.degree. C., add a solution of
2-(5-(trifluoromethyl)-1H-indol-3-yl)-2-oxo-acetamide (21.4 g, 83.5
mmol) in THF (600 ml) and stir overnight with warming to ambient
temperature. Cool the mixture with ice water and treat with 30%
NaOH (100 ml) while maintaining the temperature at less than about
30.degree. C. After stirring for about 30 minutes, filter, wash
with THF (2 L), and evaporate the filtrate to give the title
compound. Form of the HCl salt by dissolving the title compound in
diethyl ether and adding of a solution of HCl in diethyl ether
(until acidic). Collect the solid by filtration, wash with diethyl
ether, and dry under reduced pressure to give the hydrochloride
salt of the title compound.
[0668] The title compound can be further purified by basic
extraction of the hydrochloride salt into ethyl acetate, drying
over MgSO.sub.4, filter, and evaporate to dryness followed by
hydrochloride salt formation in diethyl ether.
EXAMPLE 766
3-Propoxybenzaldehyde
[0669] Combine 3-hydroxybenzaldehyde (790 g), K.sub.2CO.sub.3,
(1627 g) and DMF (8 L). Add 1-iodopropane (1000 g) and heat to
105.degree. C. and stir for 4 h. Cool to about 50.degree. C. and
add water (15 L), continue cooling to about room temperature and
add toluene (10 L). Separate the organic layer and extract the
aqueous phase with toluene (2.times.10 L), combine organic phases
and wash with NaOH 1N (2.times.5.8 L), concentrate the combined
organic layers in vacuo to afford the title compound.
EXAMPLE 777
N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)-3-propoxybenzylamine
[0670] Combine 3-propoxybenzaldehyde (14.05 g, 0.0856 mole) and
5-methoxytryptamine (13.64 g, 0.0717 mole) in 390 mL absolute EtOH.
Add molecular sieves (19.2 g) and heat the suspension to reflux.
After 4 hours, cool to room temperature and add NaBH.sub.4 (37.32
g, 0.2146 mole) in 3 portions. Stir the mixture for 1 hour at room
temperature, filter, evaporate the filtrate to a mass of about 100
g, add water and dichloromethane. After separation, wash the
aqueous phase with dichloromethane, combine the organic layers, dry
over MgSO.sub.4, filter, evaporate the solvent in vacuo to afford
the title compound.
[0671] Combine the title compound and isopropanol (250 mL) and
slowly add a solution of HCl in EtOH (33 ml, 2.5N). Heat to reflux
and stir for 30 min. Cool to room temperature and stir for 2 h to
give a solid. collect the solid by filtration, wash isopropanol,
and dry to give the hydrochloride salt of the title compound.
EXAMPLE 778
2,2,3,3,3-Pentafluoropropyl tosylate
[0672] Combine 2,2,3,3,3-pentafluoropropan-1-ol (9.7 ml) and
pyridine. Cool to between 0.degree. C. and 10.degree. C. and add
portion-wise the p-toluenesulfonylchloride (6.2 g) and stir with
warming to room temperature. After 3 hours at room temperature,
pour the reaction mixture into ice water and stir for 30 min to
give a solid. Filter the solid, wash with water, and dry to give of
the title compound.
EXAMPLE 779
3,3,3-Trifluoro-propyl tosylate
[0673] Add 3,3,3-trifluoropropan-1-ol (61.8 ml) and pyridine (224
ml). Cool to between 0.degree. C. and 10.degree. C. and add
portion-wise p-toluenesulfonylchloride (147 g). Allow to warm to
ambient temperature and stir overnight. Add HCl 0.5N (1.6 L),
extract with ethyl acetate, combine the organic layers, dry over
MgSO.sub.4, filter, and evaporate to give the title compound.
EXAMPLE 780
6-Fluorotryptamine
[0674] Add dropwise 422 mL of glacial acetic acid to 40% aqueous
dimethylamine (408 mL) over 40 minutes while maintaining the
temperature below about 15.degree. C. Cool to 0.degree. C. After
stirring for 20 minutes at 0.degree. C., slowly add 37% aqueous
formaldehyde (289 mL, 1.3 eq.) over about 15 minutes. Add
6-fluoroindole (400 g, 2.96 mol, 1 eq.) in four portions over about
15 minutes. After 30 minutes, divide the reaction mixture into two
portions. To one portion, slowly 1149 g (75% of total mass) over 30
minutes to 3 L of 10% NaOH and stir at room temperature. After 18
hours, collect the solid that forms, wash three times with 200 mL
of water, dry by suction to give wet
3-(N,N-dimethylaminomethyl)-6-fluoroindole.
[0675] Dilute another portion of the reaction mixture (383 g, 25%
of total mass) with aqueous NaOH till pH 12-13 to give a solid.
After 30 minutes, collect the solid by filtration, wash with water,
dry at 50.degree. C. overnight to give
3-(N,N-dimethylaminomethyl)-6-fluoroindole.
[0676] Combine KCN (50.8 g, 0.78 mol),
3-(N,N-dimethylaminomethyl)-6-fluoroindole (100 g, 0.52 mol), DMF
(400 mL) and water (200 mL). Heat to reflux. Evolution of gas
begins at about 70.degree. C. Maintain the reflux for 4 hours. Cool
the reaction mixture to room temperature, dilute with water and
toluene and stir for 10 minutes. Decant the organic layer and wash
successively with of saturated aqueous sodium bicarbonate and of 2M
aqueous hydrochloric acid. Concentrate to dryness the organic layer
to give 2-(6-fluoro-1H-indol-3-yl)acetonitrile.
[0677] Combine 2-(6-fluoro-1H-indol-3-yl)acetonitrile (165 g, 0.925
mol) and THF (1.32 L). Slowly add 1M solution of BH.sub.3 (2.042 L,
1,832 Kg, 0.131 mol) in THF over about 40 minutes. When the
addition is complete, heat to reflux within 1 hour. After 1 hour at
reflux, cool to room temperature and the reaction mixture, over
about 25 minutes, to a well-stirred 15% aqueous solution of NaOH
(1.9 L, 9.5 mol). After addition, slowly and gradually heat to
50.degree. C. After 1 hour, heat 60.degree. C. After 30 minutes,
heat to reflux for 1 hour. Cool to room temperature and stir
overnight, decant the alkaline aqueous layer and replace by water.
Heat to 30.degree. C. under a pressure of 200 mbars in order to
distill the THF until about 2.5 kg of distilate is removed. Extract
the mixture with dichloromethane. Slowly add to the combined
organic layers over a 25 minutes a mixture of 37% aqueous HCl (143
g) and water (220 g) and stir to give a solid. After 1 hour,
collect the solid by filtration, wash with of dichloromethane, and
dry overnight to afford of the hydrochloride salt of the title
compound.
[0678] Combine 6-fluorotryptamine hydrochloride (100 g, 0.437 mol),
2% w/w NaOH (2.5 kg), and dichloromethane (1.5 L) and stir. After
15 minutes, decant the organic layer, extract the aqueous layer
with dichloromethane, combine organic layers, and concentrate to
give a residue. Combine the residue and isopropanol and evaporate
in vacuo to give the title compound.
EXAMPLE 782
N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropyl)benzylami-
ne
[0679] ##STR97##
[0680] Combine isopropanol (500 g),
2,2,3,3-tetrafluoropropylbenzaldehyde (116.8 g), and
6-fluorotryptamine (1.15 equiv.). Heat to reflux over about 1.5
hour. After 30 minutes at the reflux, distill and over 30 minutes
collect about 380 g of distillate. Cool the reaction mixture to
50.degree. C. and add NaBH.sub.4 (19.71 g) in one portion. After 1
hour at 50.degree. C., slowly add water over 15 minutes and allow
the resulting solution to cool to room temperature overnight.
Distill the isopropanol under reduced pressure to give a residue
and extract with dichloromethane, combine organic layers, and treat
with 1N aqueous HCl (650 mL) to give a solid. Stir the heavy
suspension for 2 hours at 20-25.degree. C. Collect the solid by
filtration, wash with dichloromethane and dry at 50.degree. C.
under vacuum overnight to afford title compound.
EXAMPLE 783A
3-(2,2,2-Trifluoroethoxy)benzaldehyde
[0681] Combine 3-hydroxybenzaldehyde (134.3 g), potassium carbonate
(304.0 g), 2,2,2-trifluoroethyl p-toluenesulfonate (293.6 g) and
dimethylformamide (2 L). Heat the mixture at 90.degree. C. After 15
hours, cool to room temperature, pour on ice-water, and extract
with dichloromethane. Combine the organic layers, wash with 1N
sodium hydroxide, and then with water. Dry the organic phase over
magnesium sulfate, filter, and concentrate to a residue. Dissolve
residue in toluene (200 ml), Chromatograph on silica gel eluting
sequentially with toluene and then ethyl acetate to give a residue.
Distill the reside under reduced pressure using a Claisen flask
equipped with a Vigreux column gives title compound: bp 0.8 mm Hg,
84-85.degree. C. Redistilling some fractions using a Claisen flask
equipped with a Vigreux column and subsequently an adiabatic column
filled with Rasching rings gives title compound: bp 0.9-1.0 mm Hg,
74-76.degree. C.
EXAMPLE 783B
3-(2,2,3,3-Tetrafluoropropoxy)benzaldehyde
[0682] Combine 3-(2,2,3,3-tetrafluoropropoxy)tosylate (200 g, 0.664
mol), 3-hydroxybenzaldehyde (101.7 g, 0.833 mol), dimethylformamide
(1.5 L) and powdered potassium carbonate (192 g). Heat under
stirring at 92.degree. C. for about 22 h. Cool the reaction mixture
to 40.degree. C., pour over ice-water and extract with ethyl
acetate. Combine organic phases, wash with 1 N sodium hydroxide (1
L and 0.5 L) and then a solution of saturated sodium hydrogen
carbonate, dry over magnesium sulfate, filter, evaporate to dryness
to provide a oily residue. Distill the oily residue under reduced
pressure in a Claisen flask to give a first fraction of the title
compound: bp 108-110.degree. C. under 0.4-0.5 mmHg and a second
fraction at 110-111.degree. C. under 0.4-0.5 mmHg.
EXAMPLE 784
3-(2,2,3,3-Tetrafluoropropoxy)benzaldehyde
[0683] Combine 3-(2,2,3,3-tetrafluoropropoxy)tosylate (5.72 g, 17.2
mmol), 3-hydroxybenzaldehyde (2.44 g, 20.0 mmol), dimethylformamide
(36 ml) and powdered potassium carbonate (3.03 g) and heat at
110.degree. C. for 10 h. Cool to 20.degree. C. Pass through a bed
of aluminium-oxide-90 (57.2 g, 70-230 mesh, grade II-III,
Brockmann: Merck #1.01097) and elute with toluene (120 ml). Wash
the eluted organic phase with 1N HCl (36 ml) and then water.
Evaporate the organic layer under reduced pressure to give the
title compound.
EXAMPLE 785
2-(5-Chloro-1H-Indol-3-yl)-2-oxo-acetyl chloride
[0684] Combine 5-chloroindole (20 g, 0.13 mole) and dibutyl ether
(230 mL) and cool to 5.degree. C. and slowly add the oxalyl
chloride (20.08 g, 0.16 mole) over 15 min while maintaining the
temperature between 5.degree. C. and 10.degree. C. Warm to room
temperature and stir for 1 hour to give a solid. Cool to 5.degree.
C. and stir for 15 minutes, collect the solid by filtration, wash
with dibutyl ether, and dry under vacuum to give the title
compound.
EXAMPLE 786
(2-(5-Chloro-1H-Indol-3-yl)-2-oxoacetamide
[0685] Combine 2-(5-chloro-1H-indol-3-yl)-oxo-acetyl chloride (28.9
g, 0.12 mole) and NH.sub.4OH 1N solution (720 ml) to give a
suspension. After 18 hours, filter, wash with water, and dry under
vacuum to give the title compound.
EXAMPLE 787
5-Chlorotryptamine
[0686] Cool to 5.degree. C., a suspension of LiAlH.sub.4 (40.97 g)
in THF (700 ml). Add a solution of AlCl.sub.3 (53.9 g, 0.40 mole)
to THF (645 ml) over about 30 minutes while maintaining the
temperature at about 5.degree. C. and 10.degree. C. Add
(2-(5-chloro-1H-Indol-3-yl)-2-oxo-acetamide (20 g, 0.09 mole) in
THF (900 ml) while maintaining the temperature at between 5.degree.
C. and 7.5.degree. C. When the addition is complete warm to room
temperature. Stir overnight and then cool to 7.degree. C. and
slowly add a solution of NaOH 50% (342 g, 4.28 mol). After stirring
for about 1 hour, add anhydrous Na.sub.2SO.sub.4 (30 g) and filter
the suspension on a celite bed. Evaporate the filtrate to dryness
to give an oil. Combine the and Et.sub.2O (500 mL) and add a
solution of Et.sub.2O/HCl 4.5N (15 mL) at room temperature to give
a solid. Stir the suspension at room temperature for 1 hour,
filter, and wash with 50 mL Et.sub.2O, dry under vacuum at
50.degree. C. to give the hydrochloride of the title compound.
[0687] Add 5-chlorotryptamine hydrochloride (15 g, 0.06 mole) water
(150 ml), NaOH 1N (75 ml), and dichloromethane (350 mL). Stir the
mixture at room temperature for 30 minutes, and separate the
phases. Wash the aqueous phase with dichloromethane, combine the
organic phases, dry over MgSO.sub.4, filter, and evaporate to
dryness under vacuum to give the title compound.
EXAMPLE 789
N-(5-Chloro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoro-propoxy)benzylamin-
e
[0688] ##STR98##
[0689] Combine 5-chlorotryptamine (12.1 g, 0.0621 mol) and
3-(2,2,3,3-tetrafluoropropoxybenzaldehyde (17.6 g, 0.0621 mole) in
EtOH (340 mL). Add molecular sieves and heat to reflux and stir for
4 h. Cool the mixture to room temperature and add NaBH.sub.4 (7 g,
0.1876 mol) in 3 portions. Stir the for 1 h at room temperature.
Filter the solid and evaporate the filtrate to a weight of about 90
g, add water, and extract with dichloromethane. Dry the combined
organic layers over MgSO.sub.4, filter, and remove the solvent
under reduced pressure to afford the title compound.
[0690] Combine the title compound (27.6 g) and isopropanol (300
mL). Add a solution of oxalic acid (6 g) in isopropanol (60 mL) to
give a suspension. Heat the suspension to reflux and stir for 30
min and then cool to room temperature. Stir for 1 hour at room
temperature. collect the solid by filtration, wash with
isopropanol, and dry under vacuum to afford the oxalate of the
title compound.
EXAMPLE 790
N-2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(2,2,3,3,-tetrafluoro-propoxy)benzyla-
mine L-tartaric salt
[0691] Combine
N-2-(5-chloro-1H-indol-3-yl)ethyl)-(3-(2,2,3,3-tetrafluoropropoxy)benzyla-
mine oxalic acid salt and dichloromethane (700 mL) and add NaOH
1N(150 mL), water (450 mL) and MeOH (190 mL). Stir the mixture for
1 h at room temperature. Separate the layers. Add water (200 mL) to
the aqueous phase and extract with dichloromethane, combine the
organic layers, dry over MgSO.sub.4, filter, and evaporate under
vacuum to afford 19.4 g of
N-2-(5-chloro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylam-
ine.
[0692] Combine
N-2-(5-chloro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylam-
ine (19.4 g) in isopropanol (125 mL) and warm to dissolve. Add a
solution of L-tartaric acid (7.02 g) in isopropanol (70 HL). Add
seeding crystals and stir to give a solid. After 2.5 hours, collect
the solid by filtration, wash with isopropanol, and dry under
vacuum at 45.degree. C. to afford the title compound.
[0693] By the method of Example 221 the following compounds were
prepared, isolated as the maleate except where noted:
TABLE-US-00042 ##STR99## No. Z' R.sub.4 Data 791 6-bromo 2,2,3,3-
mp 162-164.degree. C. Analysis for
C.sub.24H.sub.23BrF.sub.4N.sub.2O.sub.5: tetrafluoro Calcd: C,
50.10; H, 4.03; N, 4.87; found: C, propyl 50.24; H, 4.02; N, 4.87.
792 6-bromo 2,2,2-trifluoro mp 168-171.degree. C. Analysis for
C.sub.23H.sub.22BrF.sub.3N.sub.2O.sub.5: ethyl Calcd: C, 50.84; H,
4.08; N, 5.16; found: C, 51.02; H, 4.13; N, 5.21. 793 6-methane
2,2,3,3- mp 233-235.degree. C. MS (ACPI): m/e 459.1 (M + 1).
sulfonyl tetrafluoro Analysis for
C.sub.21H.sub.23ClF.sub.4N.sub.2O.sub.3S: Calcd: C, 50.96; propyl
H, 4.68; N, 5.66; found: C, 50.87; H, 4.65; N, 5.64. (isolated as
the hydrochloride) 794 6-methane 2,2,2-trifluoro mp 234-236.degree.
C. MS (ACPI): m/e 427.0 (M + 1). sulfonyl ethyl Analysis for
C.sub.20H.sub.22ClF.sub.3N.sub.2O.sub.3S: Calcd: C, 51.89; H, 4.79;
N, 6.05; found: C, 51.84; H, 4.79; N, 6.10. (isolated as the
hydrochloride) 795 6-benzene 2,2,3,3- mp 213-215.degree. C. MS
(ACPI): m/e 521.0 (M + 1). sulfonyl tetrafluoro Analysis for
C.sub.26H.sub.25ClF.sub.4N.sub.2O.sub.3S: Calcd: C, 56.07; propyl
H, 4.52; N, 5.03; found: C, 55.81; H, 4.66; N, 4.96. (isolated as
the hydrochloride) 796 6-benzene 2,2,2-trifluoro mp
231-233.5.degree. C. MS (ACPI): m/e 489.0 (M + 1). sulfonyl ethyl
Analysis for C.sub.25H.sub.24ClF.sub.3N.sub.2O.sub.3S: Calcd: C,
57.20; H, 4.61; N, 5.34; found: C, 56.98; H, 4.63; N, 5.21.
(isolated as the hydrochloride)
EXAMPLE 799
6-Methanesulfonyl-1H-indole
[0694] Dissolve 6-Methanesulfonyl-indol-1-ol (5.0 g, 23.7 mmol) in
triethyl phosphite (35 ml) and heat at 1600 for 5 hours. Cool the
solution to ambient temperature and dilute with diethyl ether. Wash
the ether solution with brine and water followed by drying (sodium
sulfate) and reducing to residue. Crystallize the residue from warm
ethyl acetate to give the title compound as colorless cubes: mp
149-152.degree. C. MS (ACPI): m/e 196.0 (M+1). Analysis for
C.sub.9H.sub.9NO.sub.2S: Calcd: C, 55.37; H, 4.65; N, 7.17; found:
C, 55.14; H, 4.71; N, 7.20.
EXAMPLE 800
6-Benzenesulfonyl-1H-indole
[0695] Dissolve 6-Bromoindole (6.0 g, 30.6 mmol) in T-F (100 ml)
and cool the mixture to -10.degree.. Slowly add 60% NaH in mineral
oil (3.67 g). After 1 hour, add triisopropylsilyltrifluoromethane
sulfonate (9.9 ml, 36.7 mmol) slowly, remove the cooling bath, and
stir for 24 hours. Quench excess NaH with ice and remove the THF
under vacuum. Dilute the remaining residue with water and extract
with dichloromethane. Combine, wash (brine), dry (sodium sulfate),
and reduce the extracts to residue. Purify the residue on silica
gel using 60% hexanes/dichloromethane to give a yellow oil.
[0696] Cool a solution of 6-bromo-1-triisopropylsilanyl-1H-indole
(5.5 g, 15.7 mmol) in 100 mL anhydrous THF to -78.degree. C. under
nitrogen and treat with 1.7 M t-butyl lithium (20.5 mL, 34.5 mmol)
while keeping the temperature at -78.degree. C. After the addition,
slowly add phenylsulfonyl fluoride (2.1 ml, 17.3 mmol) and stir for
30 minutes at -78.degree. C. Warm the mixture to ambient
temperature and stir for 1 hour. Quench excess t-butyl lithium with
ice and dilute the mixture with water followed by extraction with
ethyl acetate. Combine, wash (brine), dry (sodium sulfate), and
reduce the extracts to residue. Purify the residue on silica gel
using 50% hexanes/dichloromethane to give the product as a white
solid.
[0697] Dissolve the resulting white solid in THF (50 ml) and treat
the solution with 1 M tetrabutylammonium fluoride (18.1 mL) and 1 M
boric acid (18.1 ml). After stirring for 1.5 hours at ambient
temperature, dilute the mixture with water and extract with ethyl
acetate. Combine, wash (brine), dry (sodium sulfate), and reduce
the extracts to residue. Purify the residue on silica gel using 1%
methanol/dichloromethane to give the title compound as a white
solid: mp 141-144.degree. C. MS (ACPI): m/e 258.0 (M+1). Analysis
for C.sub.14H.sub.11NO.sub.2S: Calcd: C, 65.35; H, 4.31; N, 5.44;
found: C, 64.99; H, 4.31; N, 5.39.
[0698] By the method of Example 440 the following compounds were
prepared and isolated as the hydrochloride except where noted:
TABLE-US-00043 ##STR100## No. Z' R.sub.4 Data 802 7-Chloro 2,2,3,3-
ISMS 415 (M + 1); .sup.1H NMR (DMSO-d6-HCl salt) 11.3 (bs, 1H),
tetrafluoro 9.4 (bs, 2H), 7.6-7.5 (m, 1H), 7.45-7.3 (m, 3H),
7.25-6.95 (m, propyl 4H), 6.9-6.5 (m, 1H), 4.7-4.5 (m, 2H), 4.2
(bs, 2H), 3.25 (bs, 4H) 803 6-Methoxy 2,2,3,3- .sup.1H NMR
(CDCl.sub.3-freebase) 7.99 (bs, 1H), 7.47-7.44 (d, 1H), tetrafluoro
7.23-7.19 (m, 1H), 6.94-6.92 (d, 1H), 6.89-6.88 (m, 1H), propyl
6.83-6.82 (m, 2H), 6.79-6.75 (m, 2H), 6.19-5.90 (m, 1H), 4.29-4.22
(m, 2H), 3.82 (s, 3H), 3.78 (m, 2H), 2.95 (s, 4H), no N--H
observed
[0699] By the method of Example 270 the following compounds were
prepared, isolated as the maleate except where noted:
TABLE-US-00044 ##STR101## 809 5-(4- phenyl ISMS 437 (M + 1);
C.sub.29H.sub.26FClN.sub.2O.cndot.0.2 H2O: fluoro calcd: C, 73.08;
H, 5.58; N, 5.88; found: C, phenyl) 72.99; H, 5.38; N, 5.83
EXAMPLE 811
N-(2-(5-Methoxy-1H-indol-3-yl)-ethyl)-(3-(3,3,3-trifluoropropoxy)benzyl)am-
ine
[0700] ##STR102##
[0701] Combine 350 mg (1.8 mmol) 5-methoxytryptamine, 401 mg
3-trifluoropropoxybenzaldehyde (1.8 mmol) and 4 g 4A molecular
sieves in 35 mL EtOH and reflux overnight. Decant the liquid into a
separate flask and treat with 209 mg (5.5 mmol) NaBH.sub.4. Stir
the reaction at ambient temperature for 1 hour. Concentrate under
vacuum, and partition between 50 mL 1 N NaOH and 25 mL
dichloromethane. Extract the aqueous layer with 25 ml
dichloromethane and combine the organic layers and concentrate to
dryness. Purify the resulting oil by radial chromatography
(SiO.sub.2; 1% MeOH in CHCl.sub.3 mixed with conc. NH.sub.4OH) to
afford 705 mg (1.8 mmol; 100%) of the desired compound as an oil.
Conversion to it's HCl salt by stirring a solution of the compound
in 50 mL 50/50 THF/EtOH with 1 g polyvinyl pyridine hydrochloride
overnight, filtering and concentrating to a solid. Recrystallize
the product from EtOAc: Analysis for
C.sub.21H.sub.23F.sub.3N.sub.2O.sub.2.HCl: calcd: C, 58.81; H,
5.64; N, 6.53; found: C, 58.42; H, 5.44; N, 6.51; ISMS 393
(M+1).
[0702] By the method of Example 811 the following compounds were
prepared, isolated as the hydrochloride except where noted:
TABLE-US-00045 ##STR103## No. Z' R.sub.4 Data 812 5-fluoro
3,3,3-trifluoro Analysis for
C.sub.20H.sub.20F.sub.4N.sub.2O.cndot.HCl: propyl calcd: C, 57.63;
H, 5.08; N, 6.72; found: C, 57.49; H, 5.04; N, 6.76; ISMS 381 (M +
1) 814 5-bromo phenyl Analysis for calcd:
C.sub.23H.sub.21BrN.sub.2O.cndot.HCl.cndot.0.5H.sub.2O: found: C,
59.18; H, 4.97; N, 6.00; C, 59.18; H, 4.80; N, 5.92 ISMS 422 (M +
1) 815 5-bromo 2,2,3,3- Analysis for
C.sub.20H.sub.19BrF.sub.4N.sub.2O.cndot.HCl: tetrafluoro calcd: C,
48.46; H, 4.07; N, 5.65; propyl found: C, 48.39; H, 3.95; N, 5.55;
ISMS 459 (M + 1) 816 5-bromo 2,2,3,3,3- Analysis for
C.sub.20H.sub.18BrF.sub.5N.sub.2O.cndot.HCl: pentafluoro calcd: C,
46.76; H, 3.73; N, 5.45; propyl found: C, 46.47; H, 3.67; N, 5.46;
ISMS 478 (M + 1) 817 5-SO.sub.2CH.sub.3 phenyl Analysis for
C.sub.20H.sub.18BrF.sub.5N.sub.2O.cndot.
HCl.cndot.0.5H.sub.2O.cndot.0.4C.sub.7H.sub.8: calcd: C, 64.01; H,
5.85; N, 5.57; found: C, 64.09; H, 5.64; N, 5.48 ISMS 421 (M + 1)
818 5-cyano phenyl Analysis for
C.sub.24H.sub.21N.sub.3O.cndot.HCl.cndot.0.3H.sub.2O: calcd: C,
70.42; H, 5.57; N, 10.27; found: C, 70.55; H, 5.41; N, 10.25 ISMS
368 (M + 1) 819 5- phenyl Analysis for carboxylic
C.sub.25H.sub.24N.sub.2O.sub.3.cndot.HCl.cndot.0.3H.sub.2O: acid
methyl calcd: C, 68.04; H, 5.62; N, 6.35; ester found: C, 68.06; H,
5.64; N, 6.43 ISMS 401 (M + 1) 820 5- 2,2,2- Analysis for
carboxylic trifluoroethyl
C.sub.21H.sub.21F.sub.3N.sub.2O.sub.3.cndot.HCl.cndot.0.1H.sub.2O:
acid methyl calcd: C, 56.72; H, 5.03; N, 6.30; ester found: C,
56.46; H, 4.77; N, 6.04 ISMS 407 (M + 1) 821 5- phenyl ISMS 385 (M
+ 1); carboxylic Analysis for C.sub.24H.sub.23N.sub.3O.sub.2.cndot.
acid amide HCl.cndot.0.9H.sub.2O.cndot.0.1C.sub.7H.sub.8: calcd: C,
66.32; H, 5.99; N, 9.39; found: C, 66.07; H, 5.68; N, 9.01; .sup.1H
NMR (Free base CDCl.sub.3) .delta. 8.56 (s, 1H), 8.13 (s, 1H),
7.64-7.62 (m, 1H), 7.33-7.22 (m, 4H), 7.10-6.94 (m, 6H), 6.87-6.84
(m, 1H), 6.2 (bs, 1H), 5.8 (bs, 1H), 3.77 (s, 2H), 2.99-2.94 (m,
4H), 1.7 (bs, 1H)
EXAMPLE 825
N-2-(5-Nitro-1H-indol-3-yl)-ethyl)-3-phenoxybenzylamine
[0703] ##STR104##
[0704] Combine 5-nitrotryptamine (500 mg, 2.4 mmol),
3-phenoxybenzaldehyde (480 mg, 2.4 mmol) and 4 g 4A molecular
sieves in 30 mL EtOH and reflux overnight. Decant the liquid into a
separate flask and treat with NaBH.sub.4 (280 mg, 7.2 mmol) at
ambient temperature. After 1 hour concentrate under vacuum and
partition the residue between 25 mL 1 N NaOH and 25 mL
dichloromethane. Extract the aqueous layer with 25 ml
dichloromethane and dry the combined organic layers over MgSO.sub.4
and concentrate to dryness. Purify the resulting oil by radial
chromatography (SiO.sub.2; 2% MeOH in CHCl.sub.3) to afford the
desired compound as an oil. Convert to the HCl salt by treating a
solution of the compound in 10 mL EtOH with 0.25 mL 5 N HCl and 40
mL toluene then concentrating to a solid. Analysis for
C.sub.23H.sub.21N.sub.3O.sub.3.HCl.0.2 EtOH: calcd: C, 64.62; H,
5.17; N, 9.75; found: C, 64.89; H, 5.40; N, 9.75; ISMS 388
(M+1).
[0705] By the method of Example 825 the following compounds were
prepared, isolated as the hydrochloride except where noted:
TABLE-US-00046 ##STR105## No. Z' R.sub.4 Data 826 5-butoxy phenyl
Analysis for
C.sub.27H.sub.30N.sub.2O.sub.2.cndot.HCl.cndot.0.4H.sub.2O: calcd:
C, 70.77; H, 7.00; N, 6.11; found: C, 70.87; H, 6.84; N, 6.14; ISMS
415 (M + 1) 827 5-benzamide phenyl Analysis for
C.sub.30H.sub.27N.sub.3O.sub.2.cndot.HCl.cndot.0.2H.sub.2O: calcd:
C, 71.83; H, 5.71; N, 8.38; found: C, 71.63; H, 5.35; N, 8.09; ISMS
462 (M + 1) 828 5-benzamide 2,2,2- Analysis for
C.sub.26H.sub.24F.sub.3N.sub.3O.sub.2.cndot.HCl: trifluoroethyl
calcd: C, 61.97; H, 5.00; N, 8.33; found: C, 61.78; H, 5.16; N,
7.97; ISMS 468 (M + 1) 829 5-benzamide 2,2,3,3- Analysis for
C.sub.27H.sub.25F.sub.4N.sub.3O.sub.2.cndot.HCl: tetrafluoropropyl
calcd: C, 60.51; H, 4.89; N, 7.84; found: C, 60.47; H, 4.95; N,
7.49; ISMS 500 (M + 1) 830 5-methane phenyl Analysis for
C.sub.24H.sub.25N.sub.3O.sub.3S.cndot.HCl.cndot.0.5H.sub.2O.cndot.0.5C.su-
b.7H.sub.8: sulfonamide calcd: C, 63.53; H, 5.86; N, 8.08; found:
C, 63.57; H, 5.77; N, 7.81; ISMS 436 (M + 1) 831 5-methane 2,2,2-
Analysis for
C.sub.20H.sub.22F.sub.3N.sub.3O.sub.3S.cndot.HCl.cndot.0.1H.sub.2O.cndot.-
0.5C.sub.7H.sub.8: sulfonamide trifluoroethyl calcd: C, 53.68; H,
5.21; N, 7.99; found: C, 53.48; H, 5.19; N, 7.72; ISMS 442 (M + 1)
832 5-methane 2,2,3,3- Analysis for
C.sub.21H.sub.23F.sub.4N.sub.3O.sub.3S.cndot.HCl.cndot.0.1EtOH.cndot.0.8C-
.sub.7H.sub.8: sulfonamide tetrafluoropropyl calcd: C, 54.72; H,
5.31; N, 7.14; found: C, 54.63; H, 5.25; N, 6.99; ISMS 474 (M + 1)
833 5-isopropoxy phenyl Analysis for
C.sub.26H.sub.28N.sub.2O.sub.2.cndot.1.1HCl.cndot.0.1H.sub.2O:
calcd: C, 70.58; H, 6.68; N, 6.33; found: C, 70.37; H, 6.31; N,
6.35; ISMS 401 (M + 1) 834 5-isopropoxy 2,2,2- Analysis for
C.sub.22H.sub.25F.sub.3N.sub.2O.sub.2.cndot.HCl.cndot.0.3H.sub.2O:
trifluoroethyl calcd: C, 58.94; H, 5.98; N, 6.25; found: C, 59.08;
H, 5.78; N, 6.25; ISMS 407 (M + 1) 835 5-isopropoxy 2,2,3,3-
Analysis for
C.sub.23H.sub.26F.sub.4N.sub.2O.sub.2.cndot.HCl.cndot.0.3H.sub.2O:
tetrafluoropropyl calcd: C, 57.51; H, 5.79; N, 5.83; found: C,
57.66; H, 5.55; N, 5.80; ISMS 439 (M + 1) 836 5-ethoxy phenyl
Analysis for
C.sub.25H.sub.26N.sub.2O.sub.2.cndot.HCl.cndot.0.2H.sub.2O: calcd:
C, 70.39; H, 6.47; N, 6.57; found: C, 70.40; H, 6.32; N, 6.68; ISMS
387 (M + 1) 837 5-ethoxy 2,2,2- Analysis for
C.sub.21H.sub.23F.sub.3N.sub.2O.sub.2.cndot.HCl: trifluoroethyl
calcd: C, 58.81; H, 5.64; N, 6.53; found: C, 58.61; H, 5.61; N,
6.52; ISMS 393 (M + 1) 838 5-ethoxy 2,2,3,3- Analysis for
C.sub.22H.sub.24F.sub.4N.sub.2O.sub.2.cndot.HCl: tetrafluoropropyl
calcd: C, 57.33; H, 5.47; N, 6.08; found: C, 57.01; H, 5.35; N,
6.03; ISMS 425 (M + 1) 839 2,2,2- phenyl Analysis for
C.sub.25H.sub.23F.sub.3N.sub.2O.sub.2.cndot.HCl: trifluoro- calcd:
C, 62.96; H, 5.07; N, 5.87; ethoxy found: C, 62.76; H, 4.93; N,
5.88; ISMS 441 (M + 1) 840 2,2,2- 2,2,2- Analysis for
C.sub.21H.sub.20F.sub.6N.sub.2O.sub.2.cndot.HCl: trifluoro-
trifluoroethyl calcd: C, 52.24; H, 4.38; N, 5.80; ethoxy found: C,
52.21; H, 4.28; N, 6.18; ISMS 447 (M + 1) 841 2,2,2- 2,2,3,3-
Analysis for
C.sub.22H.sub.21F.sub.7N.sub.2O.sub.2.cndot.HCl.cndot.0.2H.sub.2O.cndot.0-
.2C.sub.7H.sub.8: trifluoro- tetrafluoropropyl calcd: C, 52.35; H,
4.51; N, 5.22; ethoxy found: C, 52.15; H, 4.30; N, 5.58; ISMS 479
(M + 1) 842 5-butyloxy pyridin-2-yl Analysis for
C.sub.26H.sub.29N.sub.3O.sub.2.cndot.2HCl.cndot.0.5EtOH.cndot.0.3C.sub.7H-
.sub.8: calcd: C, 64.83; H, 6.81; N, 7.79; found: C, 64.99; H,
6.48; N, 7.47; ISMS 416 (M + 1) 843 5-isopropyl 2,2,2- Analysis for
C.sub.22H.sub.25F.sub.3N.sub.2O.cndot.HCl: trifluoroethyl calcd: C,
61.90; H, 6.14; N, 6.56; found: C, 61.72; H, 6.14; N, 6.42; ISMS
391 (M + 1) 844 5-isopropyl phenyl Analysis for
C.sub.26H.sub.28N.sub.2O.cndot.HCl: calcd: C, 74.18; H, 6.94; N,
6.65; found: C, 73.82; H, 6.79; N, 6.65; ISMS 385 (M + 1) 845
5-benzene phenyl Analysis for
C.sub.29H.sub.26N.sub.2O.sub.3S.cndot.2HCl: sulfonyl calcd: C,
67.11; H, 5.24; N, 5.40; found: C, 67.46; H, 5.37; N, 5.09; ISMS
483 (M + 1) 846 5-benzene 2,2,3,3- Analysis for
C.sub.26H.sub.24F.sub.4N.sub.2O.sub.3S.cndot.HCl.cndot.0.3EtOH.cndot.0.2C-
.sub.7H.sub.8: sulfonyl tetrafluoropropyl calcd: C, 57.07; H, 4.86;
N, 4.75; found: C, 56.95; H, 4.68; N, 4.77 ISMS 521 (M + 1) 847
5-benzene 2,2,2- Analysis for
C.sub.26H.sub.29N.sub.3O.sub.2.cndot.HCl.cndot.0.6H.sub.2O:
sulfonyl trifluoroethyl calcd: C, 56.04; H, 4.74; N, 5.23; found:
C, 56.05; H, 4.71; N, 5.12; ISMS 489 (M + 1) 848 5-carboxylic
2,2,2- Analysis for
C.sub.22H.sub.23F.sub.3N.sub.2O.sub.3.cndot.HCl: acid ethyl
trifluoroethyl calcd: C, 57.84; H, 5.30; N, 6.13; ester found: C,
57.85; H, 5.17; N, 6.09; ISMS 421 (M + 1) 849 5-carboxylic 2,2,3,3-
Analysis for
C.sub.23H.sub.26F.sub.3N.sub.3O.sub.2.cndot.HCl.cndot.0.6H.sub.2O.cndot.0-
.1C.sub.7H.sub.8: acid tetrafluoropropyl calcd: C, 56.84; H, 5.79;
N, 8.05; propylamide found: C, 56.65; H, 5.63; N, 7.71; ISMS 466 (M
+ 1) 850 5-carboxylic phenyl Analysis for
C.sub.27H.sub.29N.sub.3O.sub.2.cndot.HCl.cndot.0.4H.sub.2O.cndot.0.2C.sub-
.7H.sub.8: acid calcd: C, 69.66; H, 6.67; N, 8.58; propylamide
found: C, 69.75; H, 6.57; N, 8.38; ISMS 428 (M + 1) 851
5-carboxylic 2,2,2- Analysis for
C.sub.23H.sub.26F.sub.3N.sub.3O.sub.2.cndot.HCl.cndot.0.8H.sub.2O.cndot.0-
.1C.sub.7H.sub.8: acid trifluoroethyl calcd: C, 57.67; H, 6.00; N,
8.51; propylamide found: C, 57.55; H, 5.77; N, 8.43; ISMS 434 (M +
1) 852 5-carboxylic phenyl Analysis for
C.sub.28H.sub.31N.sub.3O.sub.2.cndot.HCl.cndot.0.7H.sub.2O: acid
calcd: C, 68.54; H, 6.86; N, 8.56; butylamide found: C, 68.41; H,
6.60; N, 8.37; ISMS 442 (M + 1) 853 5-carboxylic 2,2,3,3- Analysis
for C.sub.25H.sub.29F.sub.4N.sub.3O.sub.2.cndot.HCl.cndot.H.sub.2O:
acid tetrafluoropropyl calcd: C, 56.23; H, 6.04; N, 7.87;
butylamide found: C, 56.23; H, 5.79; N, 7.84; ISMS 480 (M + 1) 854
H 2,2,3,3- Analysis for
C.sub.20H.sub.20F.sub.4N.sub.2O.cndot.HCl.cndot.0.5H.sub.2O:
tetrafluoropropyl calcd: C, 56.41; H, 5.21; N, 6.58; found: C,
56.98; H, 4.93; N, 6.53; ISMS 381 (M + 1) 855 5-benzyloxy 2,2,2-
Analysis for C.sub.26H.sub.25F.sub.3N.sub.2O.sub.2.cndot.HCl:
trifluoroethyl calcd: C, 63.61; H, 5.34; N, 5.71; found: C, 63.46;
H, 5.53; N, 5.72; ISMS 455 (M + 1) 856 5-benzyloxy 2,2,3,3 Analysis
for C.sub.27H.sub.26F.sub.4N.sub.2O.sub.2.cndot.HCl:
tetrafluoropropyl calcd: C, 62.01; H, 5.20; N, 5.36; found: C,
62.04; H, 5.16; N, 5.36; ISMS 487 (M + 1) 857 6-phenoxy phenoxy
ISMS 435 (M + 1);
C.sub.29H.sub.27ClN.sub.2O.sub.2.cndot.0.1H.sub.2O: calcd: C,
73.67; H, 5.80; N, 5.93; found: C, 73.49; H, 5.49; N, 5.82 858
6-Phenoxy 2,2,3,3- ISMS 473 (M + 1); tetrafluoropropyl
C.sub.26H.sub.25F.sub.4ClN.sub.2O.sub.2: calcd: C, 61.36; H, 4.95;
N, 5.50; found: C, 61.02; H, 4.67; N, 5.42 859 6-Phenoxy 2,2,2-
ISMS 441 (M + 1); trifluoroethyl
C.sub.26H.sub.25F.sub.4ClN.sub.2O.sub.2.cndot.0.2H.sub.2O: calcd:
C, 62.49; H, 5.12; N, 5.83; found: C, 62.27; H, 4.78; N, 5.74 860
5(3- 2,2,3,3- ISMS 474 (M + 1); pyridyloxy) tetrafluoropropyl
C.sub.25H.sub.25F.sub.4Cl.sub.2N.sub.3O.sub.2.cndot.0.5 H.sub.2O:
calcd: C, 54.06; H, 4.72; N, 7.57; found: C, 53.97; H, 4.76; N,
7.29 861 5-(Pyridinyl- 2,2,2- ISMS 442 (M + 1); 3-oxy)
trifluoroethyl .sup.1H NMR (CDCl.sub.3) 8.37-8.36 (m, 1H),
8.27-8.26 (m, 1H), 8.01 (bs, 1H), 7.35-7.32 (m, 1H), 7.26-7.24 (m,
3H), 7.22-7.18 (m, 2H), 7.08-7.07 (m, 1H), 6.93-6.91 (m, 2H),
6.9-6.86 (m, 1H), 6.79-6.76 (m, 1H), 4.31-4.25 (m, 2H), 3.77 (s,
2H), 3.77 (s, 4H). Isolated as dihydrochloride salt
EXAMPLE 863
6-Phenoxytryptamine
[0706] By using a method similar to Example 422, the title compound
was prepared: ISMS 253 (M+1); .sup.1H NMR (CDCl.sub.3) 8.1 (bs,
1H), 7.56-7.54 (m, 1H), 7.32-7.28 (m, 3H), 7.07-6.98 (m, 4H),
6.89-6.86 (m, 1H), 3.06-3.02 (m, 2H), 2.92-2.88 (m, 2H), 1.68 (bs,
2H).
EXAMPLE 864
2-(5-(Pyridin-3-yloxy)-1H-indol-3-yl)-ethylamine
[0707] By using a method similar to Example 422, the title compound
was prepared: ISMS 254 (M+1); C.sub.15H.sub.15N.sub.3O.1.1
C.sub.2H.sub.2O.sub.4.0.2H.sub.2O: calcd: C, 58.04; H, 4.98; N,
11.81; found: C, 58.17; H, 4.62; N, 11.45.
EXAMPLE 865
6-Phenoxy-1H-indole-3-carbaldehyde
[0708] By using a method similar to Example 414, the title compound
was prepared: ISMS 238 (M+1); .sup.1H NMR (CDCl.sub.3) 10.78 (bs,
1H), 9.95 (s, 1H), 8.20-8.18 (m, 1H), 7.76-7.75 (m, 1H), 7.30-7.26
(m, 2H), 7.06-7.02 (m, 2H), 7.00-6.95 (m, 3H).
EXAMPLE 866
5-(Pyridin-3-yloxy)-1H-indole-3-carbaldehyde
[0709] By using a method similar to Example 414, the title compound
was prepared: ISMS 239 (M+1);
C.sub.14H.sub.10N.sub.2O.sub.2.0.3H.sub.2O: calcd: C, 69.01; H,
4.39; N, 11.50; found: C, 68.91; H, 4.16; N, 11.39.
EXAMPLE 867
3-(3-Methyl-4-nitro henoxy)pyridine
[0710] Rinse 35% oil dispersion of KH (12 g, 11 mmol) with 100 mL
hexanes twice and dry under vacuum before cooling in an ice bath.
Add 100 mL dry DMF then a solution of 3-hydroxypyridine (10 g, 105
mmol) in 100 mL DMF dropwise. Treat with a solution of
5-fluoro-2-nitrotoluene (16.3 g, 105 mmol) in 50 mL DMF to obtain a
dark solution. Stir at ambient temperature for 1 hour, pour the
mixture into 1 liter of brine and extract twice with 200 mL of
EtOAc. Combine the extracts and wash twice with 500 mL brine, dry
over MgSO.sub.4 and concentrate to 24 g of a dark oil. Purification
by chromatography 20% EtOAc in hexanes give the title compound as
an oil: ISMS 231 (M+1); C.sub.12H.sub.10N.sub.2O.sub.3: calcd: C,
62.61; H, 4.38; N, 12.17; found: C, 62.63; H, 4.58; N, 12.06.
EXAMPLE 869
3-Ethoxybenzaldehyde
[0711] Combine 5.6 g of 3-hydroxybenzaldehyde (46 mmol) and 10.7 g
of 1-iodoethane (69 mmol) in DMSO (25 mL) and warm to 80.degree. C.
and treat with 22.4 g of cesium carbonate (69 mmol) portionwise and
stir. After 1 hour, pour into 200 mL brine and extract twice with
150 mL diethyl ether. Combine the extracts and wash twice with 200
mL brine, dry over MgSO.sub.4 and concentrate under vacuum to give
an oil. Purification by chromatography (SiO.sub.2; 2.5% EtOAc in
Hexanes) affords 5.73 g (38 mmol; 83%) of the desired compound as
an oil: .sup.1H NMR (CDCl.sub.3) 9.94 (s, 1H), 7.42-7.41 (m, 2H),
7.36-7.35 (m, 1H), 7.16-7.13 (m, 1H), 4.10-4.04 (q, 214), 1.64-1.40
(t, 3H).
EXAMPLE 870
3-Propoxybenzaldehyde
[0712] By using a method similar to Example 869, the title compound
was prepared: .sup.1H NMR (CDCl.sub.3) 9.95 (s, 1H), 7.43-7.41 (m,
2H), 7.37-7.36 (m, 1H), 7.17-7.14 (m, 1H), 9.98-3.95 (t, 2H),
1.84-1.79 (m, 2H), 1.05-1.02 (t, 3H).
EXAMPLE 872
4-Phenoxy-1-methyl-2-nitrobenzene
[0713] Combine phenyl boronic acid (7.32 g, 60 mmol),
4-methyl-3-nitrophenol (4.5 g, 30 mmol), and
Cu(oAC).sub.2--H.sub.2O (6 g, 30 mmol) in 30 mL CH.sub.2Cl.sub.2
and treat with 6 g 4A molecular sieves powder. Add Et.sub.3N (15.18
g, 150 mmol) dropwise, and stir the reaction at ambient temperature
for 8 days. Dilute with 100 mL CH.sub.2Cl.sub.2 and filter through
celite and concentrate to dryness. Purification by chromatography
using 2% EtOAc in hexanes gave the desired product as a yellow
oil.
EXAMPLE 873
6-Phenoxy-1H-indole
[0714] Combine 4-phenoxy-1-methyl-2-nitro-benzene (6 g, 26.2 mmol)
and DMF dimethylacetal (15.6 g, 131 mmol) in 60 mL dry DMF and heat
at 170.degree. C. for 16 hours. Cool to room temperature and
concentrate to dryness. Dissolve residue in 50 mL EtOAc and
hydrogenate with 2 g 5% Pd/C and hydrogen for 3 hours at
atmospheric pressure. Filter through celite and concentrate to an
oil. Purify by chromatography using Hex/EtoAC to obtain a tan
solid: ISMS 210 (M+1)
[0715] .sup.1H NMR (CDCl.sub.3) 8.08 (bs, 1H), 7.61-7.59 (m, 1H),
7.34-7.29 (m, 2H), 7.18-7.17 (m, 1H), 7.18-7.0 (m, 4H), 6.92-6.89
(m, 1H), 6.56-6.54 (m, 1H).
EXAMPLE 874
5-Pyridin-3-yl-1-methyl-2-nitro-benzene
[0716] By a method similar to Example 872, the title compound was
prepared.
EXAMPLE 875
5-Pyridin-3-yloxy)-1H-indole
[0717] By a method similar to Example 873, the title compound was
prepared: ISMS 211 (M+1); C.sub.13H.sub.10N.sub.2O.0.1H.sub.2O:
calcd: C, 73.64; H, 4.85; N, 13.21; found: C, 73.76; H, 4.80; N,
13.09.
EXAMPLE 877
N-2-(5-Phenoxy-1H-indol-3-yl)-ethyl)-3-phenoxybenzylamine
[0718] ##STR106##
[0719] Combine 2-(5-phenoxy-1H-indol-3-yl)ethylamine (0.400 g, 1,59
mmol), 3-phenoxybenzaldehyde (0.377 g, 1.90 mmol) and molecular
sieves 4A (0.40 g) and stir in methanol (15 mL) After 4 h, filter
the molecular sieves and wash several times with MeOH. To this MeOH
solution, add portionwise NaBH.sub.4 (61.5 mg, 1.59 mmol), stir the
resulting mixture at room temperature for 1 h. Remove MeOH under
vacuum, dilute the residue with CH.sub.2Cl.sub.2/water, extract
with CH.sub.2Cl.sub.2, the combine the organic layers and dry over
Na.sub.2SO.sub.4. Concentrate in vacuo the solvent, purification on
silica gel (CH.sub.2Cl.sub.2/MeOH) to give the free base of the
title compound. React free base with oxalic acid to form the salt:
m.p. 196-198.degree. C.; .sup.1H NMR (300 MHz, DMSO-d6) 2.95-3.15
(m, 4H), 4.15 (s, 2H), 6.85-7.46 (m, 18H), 11.06 (br, 1H); MS
(ELECTROSPRAY) Mn/e: 435.3 (M+1); HRMS (ES+) calcd for
C.sub.29H.sub.27N.sub.2O.sub.2 (M+H) 435.2084 found 435.2073.
EXAMPLE 878
(3-Phenoxybenzyl)-(2-(5-phenoxy-1H-indol-3-yl)-ethyl)-carbamic acid
tert butyl ester
[0720] Combine
(3-phenoxy-benzyl)-(2-(5-phenoxy-1H-indol-3-yl)-ethyl)-amine (0.96
g, 2.2 mmol) and NaOH (87.7 mg, 2.2 mmol) and dissolve in THF (10
mL), stir at room temperature for 15 min. Add di-tert-butyl
dicarbonate (0.58 g, 2.64 mmol) in THF (10 mL) and stir. After 2 h,
dilute the reaction with water, extract with EtOAc (3.times.15 mL),
dry over Na.sub.2SO.sub.4. Concentrate the organic solvent on
vacuum to give the title compound as an oil: .sup.1H NMR (300 MHz,
CDCl.sub.3) 1.36 (s, 9H), 2.85-2.91 (m, 2H), 3.89-3.65 (m, 2H),
4.26 (s, 1H), 4.39 (s, 1H) 6.83-7.13 (m, 10H), 7.21-7.33 (m, 7H),
8.00 (s, 1H); MS (ELECTROSPRAY) m/e 534.9 (M+1).
EXAMPLE 879
N-Methyl-N-2-(5-Phenoxy-1H-indol-3-yl)-ethyl)-3-phenoxybenzylamine
[0721] ##STR107##
[0722] Add slowly 1.0 M solution of LiAlH.sub.4-THF (5.5 mL, 5.5
mmol) to a solution of
(3-phenoxy-benzyl)-(2-(5-phenoxy-1H-indol-3-yl)-ethyl)-carbamic
acid tert butyl ester (0.60 g, 1.12 mmol) in 10 mL dry THF. After
addition, heat to reflux the reaction mixture. After 2 h, cool to
room temperature, quench the reaction by adding water 1.5 mL
cautiously, followed by 2N NaOH (1.0 mL). Filter the suspension and
wash repeatedly with ether, dry the organic solution over
Na.sub.2SO.sub.4 and concentrate in vacuo. Purification on silica
gel using CH.sub.2Cl.sub.2/MeOH as eluent gives the free base of
the title compound and further reaction with oxalic acid to form
the salt: m.p. 174-175.degree. C.; .sup.1H NMR (250 MHz, DMSO-d6)
2.51(s, 3H), 3.00-3.13 (m, 4H), 4.15 (s, 2H), 6.81-7.03 (m, 7H),
7.11-7.42 (m, 11H), 11.05 (br, 1H); MS (ELECTROSPRAY) m/e: 449.1
(M+1-C.sub.2H.sub.2O.sub.4).
EXAMPLE 880
N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-(3-(2,2-difluoro
ethoxy)benzyl)amine
[0723] ##STR108##
[0724] Combine 2-(6-chloro-1H-indol-3-yl)ethylamine hydrochloride
(1.0 g, 4.3 mmol) and ethyldiisopropylamine (900 .mu.L, 5.2 mmol)
in ethanol (150 mL) and stir at room temperature and treat with
3-(2,2-difluoroethoxy)benzaldehyde (856 mg, 4.6 mmol) and anhydrous
sodium sulfate (12 g) and heat at 78.degree. C. overnight. Cool to
room temperature and filter. Treat the resulting filtrate with
sodium borohydride (488 mg, 12.9 mmol) and stir the milky-white
mixture at room temperature overnight. Remove in vacuo the solvent,
and purification of the crude on silica gel eluting with 10%
methanol in dichloromethane gives the free base of the title
compound as a light yellow oil. Dissolve a portion of the oil (651
mg, 1.78 mmol) in methanol (15 mL) and treat with a homogenous
solution of ammonium chloride (95 mg, 1.78 mmol) in methanol (3
mL). Sonicate the resulting solution for 10 minutes before removal
of the solvent in vacuo to provide an off-white solid. Triturate
with diethyl ether containing a few drops of acetonitrile.
Filtration and drying of the precipitate afforded the title
hydrochloride as a white solid: mp 131.6-133.degree. C.; .sup.1H
NMR (400 MHz, dmso-d.sub.6): 11.15 (br s, 1H), 9.50 (br s, 2H),
7.57 (d, 1H, J=8.8 Hz), 7.39 (d, 1H, J=2.0 Hz), 7.36 (t, 1H, J=8.2
Hz), 7.32 (br s, 1H), 7.26 (d, 1H, J=2.0 Hz), 7.17 (d, 1H, J=7.6
Hz), 7.04 (dd, 1H, J=7.8, 2.2 Hz), 7.01 (dd, 1H, J=8.4, 2.0 Hz),
6.41 (tt, 1H, J=54.4, 3.4 Hz), 4.32 (td, 2H, J=14.8, 3.6 Hz), 4.14
(br s, 2H), 3.11 (br s, 4H); MS (ES+): m/e 365.3 (M+1); CHN (for
C.sub.19H.sub.19F.sub.2ClN.sub.2O.HCl.0.3H.sub.2O) calcd: C, 56.11;
H, 5.11; N, 6.89; found: C, 56.03; H, 4.95; N, 7.18.
EXAMPLE 881
N-Methyl-N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-3-(2,2-difluoroethoxy)benzyla-
mine
[0725] ##STR109##
[0726] Combine
(2-(6-chloro-1H-indol-3-yl)ethyl)-(3-(2,2-difluoroethoxy)benzyl)amine
(276 mg, 0.76 mmol) and formaldehyde (55.5 .mu.L of a 38% aqueous
solution, 0.76 mmol) in dichloroethane (15 mL) and stir at room
temperature for 10 minutes; add in two portions sodium
triacetoxyborohydride (321 mg, 1.51 mmol) over 10 minutes and stir
at room temperature overnight before diluting with methanol (10 mL)
and quenching with one drop of glacial acetic acid. Remove in vacuo
the solvent, and redissolve the crude residue in methanol and
directly load onto a 10 g SCX column. After washing thoroughly with
methanol, elute the column with 2 N ammonia in methanol.
Concentrate in vacuo the eluant to give the free base of the title
compound as a straw-colored oil. Dissolve the free base (239 mg,
0.64 mmol) in methanol (20 mL) and treat with a solution of
ammonium chloride (36 mg, 0.67 mmol) in methanol (5 mL). Sonicate
the mixture for 10 minutes before removal of the solvent in vacuo
to give the hydrochloride salt as a tacky yellow oil. Dissolve the
oil in 10 mL of 1:1 acetonitrile-water and lyophilize overnight,
providing a fluffy white solid and triturate with diethyl ether (10
mL) and acetonitrile (2 drops). Filtration and drying of the
resulting precipitate afforded the desired hydrochloride as a white
amorphous solid: mp: 63.8-65.8.degree. C.; .sup.1H NMR (400 MHz,
dmso-d.sub.6): 11.10 (br s, 1H), 7.52 (d, 1H, J=8.4 Hz) 7.36 (d,
1H, J=2.0 Hz), 7.40-7.26 (m, 2H), 7.22 (d, 1H, J=2.4 Hz), 7.20-7.11
(m, 1H), 7.04 (br d, 1H, J=7.6 Hz), 6.96 (dd, 1H, J=8.6, 1.4 Hz),
6.38 (tt, 1H, J=54.4, 3.6, Hz), 4.50-4.02 (br m, 2H), 4.30 (td, 2H,
J=14.4, 3.2 Hz), 3.15 (br s, 4H), 2.68 (br s, 3H); MS (ES+): m/e
378.9 (M+1); CHN (for
C.sub.20H.sub.21ClF.sub.2N.sub.2O.HCl.0.7H.sub.2O) calcd: C, 56.14;
H, 5.51; N, 6.55; found: C, 55.72; H, 5.32; N, 7.07.
[0727] By the method of Example 319 the following compounds were
prepared, isolated as the oxalate except where noted:
TABLE-US-00047 ##STR110## No. Z' R.sub.4 Data 883 4,7-difluoro
2,2,2-trifluoro mp 208.5-210.0.degree. C.; .sup.1H NMR (400 MHz,
dmso-d.sub.6): 11.79 (br s, 1H), 9.21 (br s, 2H), 7.39 (t, 1H,
J=7.8 Hz), ethyl 7.32 (d, 1H, J=2.0 Hz) 7.30 (s, 1H), 7.18 (d, 1H,
J=8.0 Hz), 7.11 (dd, 1H, J=2.6, 8.2 Hz), 6.85-6.91 (m, 1H),
6.67-6.73 (m, 1H), 4.77 (q, 2H, J=8.8 Hz), 4.16 (s, 4H), 3.12-3.16
(m, 4H). MS (APCI): m/e 385.1 (M + 1). CHN (for
C.sub.19H.sub.17F.sub.5N.sub.2O.cndot.1HCl) calcd: C 54.23, H 4.31,
N 6.66; found: C 54.20, H 4.30, N 6.66. 884 4,5,6,7-
2,2,2-trifluoro mp 107.2-108.20.degree. C.; .sup.1H NMR (400 MHz,
dmso-d.sub.6): 11.92 (br s, 1H), 7.32 (s, 2H), 6.95-6.99 (m, 2H),
6.87 tetrafluoro ethyl (dd, 1H, J=2.4, 8.0 Hz) 4.68 (q, 2H, J=8.8
Hz), 3.70 (s, 2H), 2.88 (t, 2H, J=7.2 Hz) 2.75 (t, 2H, J=7.2 Hz).
MS (ES+): m/e 421.1 (M + 1). CHN (for
C.sub.19H.sub.15F.sub.7N.sub.2O.cndot.1HCl.cndot.0.20H.sub.2O)
calcd: C 53.83, H 3.66, N 6.61; found: C 53.75, H 3.33, N 6.54. 885
4,7-difluoro 2,2,3,3 mp 171.8-173.0.degree. C.; .sup.1H NMR (400
MHz, dmso-d.sub.6): 11.80 (br s, 1H), 9.21 (s, 2H), 7.39 (t, 1H,
J=8.0 Hz), tetrafluoro 7.30-7.33 (m, 2H), 7.18 (d, 1H, J=7.6 Hz),
7.10 (dd, 1H, J=2.4, 8.0 Hz), 6.85-6.91 (m, 1H), 6.54-6.83 (m, 2H),
propyl 4.60 (t, 2H, J=13.6 Hz), 4.16 (s, 2H), 3.16 (s, 4H). MS
(APCI): m/e 417.1 (M + 1). CHN (for
C.sub.20H.sub.18F.sub.6N.sub.2O.cndot.1HCl.cndot.0.25H.sub.2O)
calcd: C 52.53, H 4.30, N 6.13; found: C 52.75, H 4.24, N 5.76. 886
4,5,6,7- 2,2,3,3-tetra mp 262.5-263.8.degree. C.; .sup.1H NMR (400
MHz, dmso-d.sub.6): 12.16 (br s, 1H), 9.43 (s, 2H), 7.44 (d, 1H,
J=2.0 Hz), tetrafluoro fluoropropyl 7.34-7.40 (m, 2H) 7.19-7.21 (d,
1H, J=3.6 Hz), 7.08-7.10 (dd, 1H, J=2.0, 8.0 Hz), 6.69 (tt, 1H,
J=5.2, 52.0 Hz) 4.59 (t, 2H, J=13.4 Hz), 4.15 (s, 2H), 3.16 (s,
4H). MS (APCI): m/e 453.1 (M + 1). CHN (for
C.sub.20H.sub.16F.sub.8N.sub.2O.cndot.1HCl.cndot.0.10H.sub.2O)
calcd: C 48.96, H 3.53, N 5.71; found: C 48.74, H 3.33, N 5.61. 887
7-trifluoro 2,2,2- mp 173.8-175.6.degree. C. .sup.1H NMR (400 MHz,
dmso-d.sub.6): 11.36 (br s, 1H), 9.07 (br s, 1H), 7.87 (d, 1H,
J=7.6 Hz), methyl trifluoroethyl 7.45 (d, 1H, J=7.6 Hz) 7.38-7.42
(m, 1H), 7.36 (d, 1H, J=2.4 Hz), 7.28-7.29 (m, 2H), 7.16-7.29 (m,
2H) 7.11 (dd, 1H, J=2.0, 8.0 Hz), 4.77 (q, 2H, J=8.8 Hz), 4.15 (s,
2H), 3.12-3.16 (m, 4H). MS (APCI): m/e 417.1 (M + 1). CHN (for
C.sub.20H.sub.18F.sub.6N.sub.2O.cndot.1HCl.cndot.0.20H.sub.2O)
calcd: C 52.63, H 4.28, N 6.14; found: C 52.56, H 4.05, N 5.79. 888
7-trifluoro 2,2,3,3-tetra mp 154.0-155.8.degree. C.; .sup.1H NMR
(400 MHz, dmso-d.sub.6): 11.35 (br s, 1H), 9.51 (br s, 2H), 7.91
(d, 1H, J=8.0 Hz), methyl fluoropropyl 7.36-7.45 (m, 4H) 7.22 (d,
1H, J=8.0 Hz) 7.17 (t, 1H, J=7.6 Hz), 7.09 (dd, 1H, J=2.2, 8.0 Hz),
6.69 (tt, 1H, J=5.2, 52.0 Hz), 4.60 (t, 2H, J=13.6 Hz), 4.15 (s,
2H), 3.13-3.20 (m, 4H). MS (ES+): m/e 449.0 (M + 1). CHN (for
C.sub.21H.sub.19F.sub.7N.sub.2O.cndot.1HCl.cndot.0.10H.sub.2O)
calcd: C 51.83, H 4.18, N 5.76; found: C 51.54, H 3.97, N 5.68. 889
7-nitro 2,2,2- mp 133.0-134.8.degree. C.; .sup.1H NMR (400 MHz,
dmso-d.sub.6): 11.81 (s, 1H), 9.46 (br s, 2H) 8.14 (d, 1H, J=8.0
Hz), 8.11 trifluoroethyl (d, 1H, J=8.0 Hz) 7.45 (d, 1H, J=2.0 Hz)
7.39 (t, 1H, J=8.0 Hz), 7.36-7.37 (m, 1H), 7.25 (t, 1H, J=8.0 Hz),
7.21 (d, 1H, J=8.0 Hz), ) 7.10 (dd, 1H, J=2.0, 8.0 Hz), 4.78 (q,
2H, J=8.8 Hz), 4.15 (s, 2H), 3.12-3.24 (m, 4H). MS (APCI): m/e
394.1 (M + 1). CHN (for
C.sub.19H.sub.18F.sub.3N.sub.3O.sub.3.cndot.1HCl.cndot.0.80H.sub.2O)
calcd: C 51.37, H 4.67, N 9.46; found: C 51.02, H 4.43, N 10.19.
890 7-nitro 2,2,3,3-tetra mp 175.0-176.8.degree. C.; .sup.1H NMR
(400 MHz, dmso-d.sub.6): 11.81 (br s, 1H), 9.32 (br s, 2H), 8.13
(d, 1H, J=8.0 Hz), fluoropropyl 8.11 (d, 1H, J=8.0 Hz) 7.45 (d, 1H,
J=2.0 Hz) 7.39 (t, 1H, J=8.0 Hz), 7.31-7.32 (m, 1H), 7.25 (t, 1H,
J=8.0 Hz), 7.20 (d, 1H, J=7.6 Hz), ) 7.10 (dd, 1H, J=2.4, 8.4 Hz),
6.69 (tt, 1H, J=5.2, 52.0 Hz), 4.60 (t, 2H, J=13.2 Hz), 4.16 (s,
2H), 3.18 (s, 4H). MS (APCI): m/e 426.1 (M + 1). CHN (for
C.sub.20H.sub.19F.sub.4N.sub.3O.sub.3.cndot.1HCl.cndot.0.90H.sub.2O)
calcd: C 50.25, H 4.60, N 8.79; found: C 49.98, H 4.38, N 9.47.
EXAMPLE 892
2-(7-Trifluoromethyl-1H-indol-3-yl)-ethylamine
[0728] Combine in a 500 mL round bottom flask equipped with
magnetic stirring, (2-trifluoromethyl-phenyl)-hydrazine (5.0 g,
28.4 mmol) and 4-aminobutyraldehyde dimethyl acetal (4.54 g, 34.1
mmol) and stir. After 5 minutes, slowly add 1N HCl (200 mL) and
heat the reaction to 85.degree. C. for 2 hours forming an
orange-red colored solution. Increase the temperature to
100.degree. C. for 10 minutes and cool to room temperature. Pour
the reaction mixture over ice and stir for 10 minutes followed by
adjustment to pH .about.10 with ammonium hydroxide. Extract the
mixture with methylene chloride, pool the organic phases, dry over
sodium sulfate, and concentrate in vacuo to give a dark
orange-brown oil. Purification on a pre-packed, HMDS treated silica
column using a step gradient of 9% to 17% methanol in methylene
chloride gives the pure title compound as an orange oil: .sup.1H
NMR (400 MHz, dmso-d.sub.6): 11.18 (br s, 1H), 7.82 (d, 1H, J=7.6
Hz), 7.40 (d, 1H, J=7.2 Hz), 7.24 (d, 1H, J=2.0 Hz), 7.13 (t, 1H,
J=7.6 Hz) 2.76-2.83 (m, 4H). MS (APCI): m/e 229.0 (M+1), 212.0
(M-NH.sub.2).
EXAMPLE 893
(7-Nitro-1H-indol-3-yl)-acetonitrile
[0729] Dissolve in a 500 mL round bottom flask equipped with
magnetic stirring, 7-nitro indole (4.55 g, 28.1 mmol) in 130 mL of
glacial acetic acid and heat to 70.degree. C. Add
di-methyl-methylene ammonium iodide (Eschenmoser's salt) and stir
the mixture at 70.degree. C. After 45 minutes, cool the reaction
mixture and remove the solvent in vacuo to give a crude yellow
solid. Treat the crude material with 200 mL ammonium hydroxide and
extract with ethyl acetate. Pool the organic phases and dry over
magnesium sulphate and concentrate in vacuo to give the amine
intermediate as a yellow crystalline solid. Immediately dissolve
the intermediate in 200 mL of dimethyl sulphoxide, treat with
methyl iodide (4.55 mL, 56.2 mmole), and stir overnight at room
temperature. Add potassium cyanide (18.30 g, 281 mmol), and
18-crown-6 (226 mg) and stir the mixture at 50.degree. C. for 25
minutes. Pour the resulting brown-yellow suspension over ice, stir
for 10 minutes, saturate with sodium chloride, and extract with
ethyl acetate. Wash the pooled extracts once with water, twice with
brine, dry over sodium sulfate, and concentrate in vacuo to give
the title compound as a yellow-brown solid. No further purification
was necessary. .sup.1H NMR (400 MHz, dmso-d.sub.6): 11.92 (br s,
1H) 8.14 (d, 1H, J=8.0 Hz), 8.12 (d, 1H, J=8.0 Hz) 7.53 (d, 1H,
J=2.0 Hz) 7.31 (t, 1H, J=8.0 Hz), 4.16 (s, 2H), MS (ES-):m/e 200.0
(M-1).
EXAMPLE 894
2-(7-Nitro-1H-indol-3-yl)ethylamine
[0730] Dissolve in a 500 mL round bottom flask equipped with
magnetic stirring, and a nitrogen inlet,
(7-nitro-1H-indol-3-yl)-acetonitrile (5.27 g, 26 mmol) in dry
tetrahydrofuran (150 mL). Treat the solution with 1M B.sub.3:THF
(55 mL, 55 mmol) and stir at room temperature. After 20 hours,
quench the reaction by the cautious dropwise addition of water (9
mL) and stir until foaming and gas evolution has stopped.
Concentrate the mixture to dryness in vacuo, redissolve in 1 N HCl
(300 ml) and extracte with ethyl acetate. Basify the aqueous phase
5 N NaOH and extract with ethyl acetate. Pool the ethyl acetate
extracts and dry over sodium sulfate and concentrate in vacuo to
give the title compound as an orange-brown solid: .sup.1H NMR (400
MHz, dmso-d.sub.6): 11.66 (br s, 1H) 8.07 (t, 2H, J=7.6 Hz), 7.32
(s, 1H), 7.20 (t, 1H, J=8.0 Hz) 2.79-2.83 (m, 4H), MS (APCI):m/e
189.0 (M-NH.sub.2).
EXAMPLE 895
N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-4-fluoro-3-phenoxy-benzylamine
[0731] ##STR111##
[0732] The method of Example 340 gives the hydrochloride of the
title compound: mp 173-175.degree. C.; MS(n/e): 379 (M+1), 377
(M-1); Calculated for C.sub.23H.sub.20F.sub.2N.sub.2O.HCl: Calcd:
C, 66.59; H, 5.10; N, 6.75. Found: C, 66.39; H, 5.05; N, 6.57.
EXAMPLE 896
N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine
[0733] ##STR112##
[0734] The method of Example 340 gives the hydrochloride of the
title compound: mp 196-199.degree. C.; MS(m/e): 361 (M+1), 359
(M-1); Calculated for C.sub.23H.sub.21FN.sub.2O.HCl: Calcd: C,
69.60; H, 5.59; N, 7.06. Found: C, 69.23; H, 5.58; N, 7.00.
EXAMPLE 897
4-Fluoro-1-methyl-3-phenoxybenzene
[0735] Add triethylamine (28.6 mL, 205 mmol) dropwise to a mixture
of 2-fluoro-5-methylphenol (5.18 g, 41.1 mmol), copper(II) acetate
(7.46 g, 41.1 mmol), phenylboronic acid (10.0 g, 82.1 mmol),
powdered 4 .ANG. sieves (7 g), and methylene chloride (400 mL).
Stir at ambient temperature. After 22 h, filter and concentrate the
filtrate. Purify the residue by silica gel chromatography (50%
methylene chloride/hexanes), concentrate and purify again by silica
gel chromatography (100% hexanes) to give 2.4 g (29%) of the title
compound: MS(m/e): 202 (M.sup.+).
EXAMPLE 898
4-Fluoro-3-phenoxybenzaldehyde
[0736] Combine 4-fluoro-1-methyl-3-phenoxybenzenze (2.43 g, 12.0
mmol), N-bromosuccinimide (4.92 g, 27.6 mmol), benzoyl peroxide
(408 mg, 1.68 mmol), and carbon tetrachloride (55 mL). Heat the
mixture at reflux temperature for 6.5 h and cool to 0.degree. C.
for 64 h. Filter the solids and concentrate the filtrate. Dissolve
the residue in chloroform and wash with ice cold sodium carbonate
solution. Dry the chloroform solution over sodium sulfate, filter
and concentrate under reduced pressure. Dissolve the residue in
acetonitrile (50 mL) and add 4-methylmorpholine-4-oxide (4.6 g,
39.1 mmol) and powdered 4 .ANG. sieves (200 mg). Stir at ambient
temperature for 20 h, filter and concentrate. Purify by silica gel
chromatography (5%, 30% ethyl acetate/hexanes) to give 220 mg (8%)
of the title compound: MS(m/e): 216 (M.sup.+).
EXAMPLE 899
7-Fluorotryptamine
[0737] Combine lithium aluminum hydride (12.8 g; 336.1 mmol) and
0.degree. C. anhydrous tetrahydrofuran (160 mL). Cool resulting
exotherm to 0.degree. C. Add 7-fluoro-3-(2-nitrovinyl)-1H-indole
(11.55 g, 56.0 mmol) in anhydrous THF (200 mL) dropwise. After 30
min, warm to ambient temperature. After 4 hours, cool to 0.degree.
C. and add saturated sodium sulfate solution (35 mL) dropwise.
Filter the solids and wash with THF and ethyl acetate. Concentrate
the filtrate and dissolve the residue in methylene chloride. Filter
the precipitate to give 1.26 g of product as brown crystals.
Concentrate the filtrate and chromatograph on silica gel eluting
with 5%, 7%, 10% 2N ammonia in methanol/methylene chloride to give
product: MS(m/e): 179 (M+1), 177 (M-1); Calculated for
C.sub.10H.sub.11FN.sub.2: Calcd: C, 67.40; H, 6.22; N, 15.72.
Found: C, 67.06; H, 6.11; N, 15.48.
EXAMPLE 900
3-(2-Nitrovinyl)-6-methanesulfonyl-1H-indole
[0738] Combine 1-dimethylamino-2-nitroethylene (892.1 mg, 7.68
mmol) and TFA (9.0 ml) and stir until dissolved. Add
6-methanesulfonyl-1H-indole (1.5 g, 7.68 mmol) and stir at ambient
temperature. After 24 hours, pour the reaction mixture into
ice/water, extract with ethyl acetate, then wash ethyl acetate with
brine and saturated sodium bicarbonate. Filter, wash, and dry the
precipitate to give the title compound as a yellow powder:
mp>250.degree. C. MS (ACPI): m/e 267.0 (M+1). Analysis for
C.sub.11H.sub.10N.sub.2O.sub.4S: Calcd: C, 49.62; H, 3.79; N,
10.52; found: C, 49.86; H, 3.97; N, 10.25.
EXAMPLE 901
3-(2-Nitrovinyl)-6-benzenesulfonyl-1H-indole
[0739] Combine 1-dimethylamino-2-nitroethylene (676.9 mg, 5.83
mmol) and TFA (9.0 ml) and stir until dissolved. Add
6-benzenesulfonyl-1H-indole (1.5 g, 5.83 mmol) and stir at ambient
temperature. After 24 hours, pour the reaction mixture into
ice/water and adjust to pH 8. After stirring, filter the
precipitate, wash with water, and dry to give the title compound as
a yellow powder: mp 110.degree. C., dec. MS (ACPI): m/e 329.0
(M+1). Analysis for C.sub.16H.sub.12N.sub.2O.sub.4S: Calcd: C,
58.53; H, 3.68; N, 8.53; found: C, 58.54; H, 3.83; N, 7.85.
EXAMPLE 902
(3-Phenoxybenzyl)-(2-pyridin-2-yl-ethyl)amine oxalic acid salt
[0740] Combine 2-pyridin-2-yl-ethylamine (Aldrich, 0.36 mL, 3.0
mmol), 3-phenoxybenzaldehyde (Aldrich, 0.58 mL, 3.66 mmol), 3A
molecular sieves (0.5 g), and methanol (30 mL) and heat to reflux
for 4 hours. Remove the molecular sieves by filtration. Add sodium
borohydride (0.35 g, 9.0 mmol) slowly and stir the reaction at room
temperature. After 1 hour, concentrate the reaction and dissolve
the residue in a mixture of 1 N NaOH solution and methylene
chloride and extract the mixture with methylene chloride. Wash the
organic extract with water, dry (Na.sub.2SO.sub.4) and concentrated
to give a pale yellow oil. Form the salt with oxalic acid and
crystallize from ethyl acetate to give a white solid:
mp=183-185.degree. C.; ms: ion at 305.2.
EXAMPLE 903
(3-[1,3]Dioxolan-2-yl-phenyl)-pyridin-2-ylamine
[0741] Combine 2-aminopyridine (8.25 g, 95 mmol),
2-(3-bromo-phenyl)-[1,3]dioxolane (13.8 mL, 90 mmol), sodium
t-butoxide (12.2 g, 126 mmol), BINAP (210 mg, 0.62 mmol),
Pd2(dbu).sub.3 (630 mg, 0.21 mmol) and toluene (100 mL) and heat to
reflux for 48 hours. Cool the reaction to room temperature,
dissolve in ether and filter and concentrate the resulting
solution. Purification by flash chromatography (hexanes/EtOAc
(8.5:1.5) and then hexanes/EtOAc (7:3)) provides the title compound
as a yellow oil.
EXAMPLE 904
3-(Pyridin-2-ylamino)-benzaldehyde
[0742] Dissolve (3-[1,3]dioxolan-2-yl-phenyl)-pyridin-2-yl-anine
(10.32 g, 42.6 mmol) in THF (150 mL). Add concentrated HCl solution
(37.5 mL) and stir the solution at room temperature overnight.
Concentrate the reaction, treat with water, and extract with
CH.sub.2Cl.sub.2. Wash the organic extract with water, dry
(Na.sub.2SO.sub.4) and concentrate to give the crude product.
Purification by flash chromatography (hexanes/EtOAc (7:3)) provides
the title compound as a yellow solid.
EXAMPLE 905
N-(3-(2-(6-Chloro-1H-indol-3-yl)ethyl)-3-(pyrid-2-ylamino)benzylamine
[0743] ##STR113##
[0744] Combine 6-chlorotryptamine (0.22 g, 1.1 mmol),
3-(pyridin-2-ylamino)benzaldehyde (0.22 g, 1.1 mmol), 3A molecular
sieves (0.5 g), and methanol (25 mL) are and heat to reflux for 4
hours. Remove the molecular sieves by filtration. Add sodium
borohydride (0.16 g, 3.3 mmol) slowly and stir the reaction at room
temperature. After 1 hour, concentrate the reaction and dissolve
the residue in a mixture of 1N NaOH solution and methylene chloride
and extract the mixture with methylene chloride. Wash the organic
extract with water, dry (Na.sub.2SO.sub.4) and concentrate to give
the crude product. Purification by flash chromatography (EtOAc/MeOH
(9:1) with 2% concentrated NH.sub.4OH solution) provides the
desired product as a colorless oil. Form the dihydrochloride salt
and crystallize from EtOAc to give the desired product:
mp=164-166.degree. C.; ms: ion at 377.1.
[0745] The following compounds were prepared following a procedure
following Example 673: TABLE-US-00048 ##STR114## No: R.sub.1
R.sub.4 Data 906 pyrid-2-yl phenyl LC Method 3: Rf 2.83 min at
54/220 nm; m/e 305.0 (M + 1) 907 thien-2-yl phenyl LC Method 3: Rf
4.00 min at 254/220 nm; m/e 3309.9 (M + 1)
[0746] The following compounds were prepared following a procedure
following Example 673: TABLE-US-00049 ##STR115## No.: Z' R.sub.4
Data 908 3-Br propyl LC Method 3: Rf 4.48 min at 254/220 nm; m/e
349.9 (M + 1) 908a 3-COOCH.sub.3 phenyl MS = 362 (m + 1), IR;
1718.51, 1584.26, 1489.84, 1445.78, 1285.67, 1253.07, 1199.51
cm.sup.-1
[0747] The following compounds were prepared following a similar
procedure in Example 665: TABLE-US-00050 ##STR116## No.: Z' R.sub.2
Data 909 H isopropyl LC Method 3: Rf 5.43 min at 254/220 nm; m/e
385.0 (M + 1) 910 methoxy methyl LC Method 2: Rf 4.86 min at
254/220 nm; m/e 385.0 (M + 1)
[0748] By the method of Example 221 the following compounds were
prepared, isolated as the maleate except where noted:
TABLE-US-00051 ##STR117## No. Z'' R.sub.4 Data 911 3-chloro
2-fluoro- LC Method 3: Rf 4.61 min at 254/220 nm; benzyl m/e 369.9
(M + 1) 912 3-chloro 4-fluoro- LC Method 3: Rf 4.62 min at 254/220
nm; benzyl m/e 369.9 (M + 1) 913 3-chloro 2,3-difluoro- LC Method
3: Rf 4.76 min at 254/220 nm; benzyl m/e 387.9 (M + 1)
EXAMPLE 914
3-Propoxybenzonitrile
[0749] Combine 3-hydroxybenzonitrile (11.052 gm; 92.8 mmol),
n-propyl bromide (24.4 gm; 198 mmol), and potassium carbonate
(38.65 gm; 280 mmol) in 2-butanone (175 mL) and heat and reflux.
After 17 h, cool the mixture to room temperature, and decant the
solution and concentrate by rotary evaporation. Partition the
residue between diethyl ether (150 mL) and water (150 mL), separate
the layers and extract the aqueous layer with diethyl ether
(2.times.100 mL). Combine the organic layers and wash with water, 1
N NaOH, and water, dry over MgSO.sub.4, and concentrate. Distill
the residue to give the title compound.
EXAMPLE 915
3-Propoxybenzylamine hydrochloride
[0750] Combine 100 mL of lithium aluminum hydride (1 M in THF) and
50 mL of THF and add sulfuric acid (100%) dropwise at 10.degree. C.
Allow the mixture to warm to room temperature and stir. After a 1 h
period, remove the solids by filtration through diatomaceous earth
using nitrogen pressure, and to the clear solution add dropwise a
solution of nitrile in 50 mL of THF at 0.degree. C. Allow the
reaction to stir. After 1 h at 0.degree. C., allow to warm to
ambient temperature and stir over a 2.5 h period. Cool the reaction
to 0.degree. C. and add dropwise 16 mL of a 1:1 solution of
water/THF, and add dropwise addition of 2 M NaOH (60 mL). Filter
the resulting mixture, wash the solids with THF (2.times.100 mL),
combine the organic layers dry over sodium sulfate and concentrate.
Dissolve the residue in dry ether (250 mL) and acidify with
HCl/dioxane solution (20 mL of 4 M solution). Wash the resulting
solid with ether to yield the title compound as a white solid.
EXAMPLE 916
2-(3-Bromophenyl)-N-(3-propoxybenzyl)acetamide
[0751] Combine 3-propoxy-benzylamine in 50 mL of dichloromethane
and add dropwise to a mixture of 3-bromophenylacetyl chloride (4.90
gm; 21.0 mmol) and triethylamine (3.60 gm; 35.9 mmol) in 250 mL of
dichloromethane at 0.degree. C. Allow the reaction to warm to room
temperature and stir for 18 h. Pour the reaction into 100 mL of
saturated brine, separate the layers and extract the aqueous layer
with 100 mL of dichloromethane. Combine organic layers, wash with
brine, dry (MgSO.sub.4), and concentrate. Purification by
chromatography on silica gel with 40% EtOAc in hexanes gives the
title compound.
EXAMPLE 917
2-(4'-Fluorobiphenyl-3-yl)-N-(3-propoxybenzyl)acetamide
[0752] Combine bromoamide (0.365 gm; 1.008 mmol),
4-fluorophenylboronic acid (0.175 gm; 1.25 mmol), cesium fluoride
(0.360 gm; 2.37 mmol), and
dichloro(bistriphenylphosphine)palladium(II) (0.062 gm; 0.088 mmol)
in NMP (3 mL) and heat at 104.degree. C. After 13.3 h. cool to
ambient temperature and dilute with 40 mL each of dichloromethane
and water. Separate the layers and extract the aqueous layer with
dichloromethane (2.times.20 mL). Combine the organic layers, wash
four times with 10 mL portions of saturated brine, dry (MgSO.sub.4)
and concentrate. Purification by chromatography on silica gel with
40% EtOAc in hexanes gives the title compound.
EXAMPLE 918
N-(2-(3-(4-Fluorophenyl)phenyl)ethyl)-3-propoxybenzylamine
[0753] ##STR118##
[0754] Combine
2-(4'-fluorobiphenyl-3-yl)-N-(3-propoxybenzylacetamide in 15 mL of
THF and add a solution of BH.sub.3--SMe.sub.2 (2 M in THF) dropwise
at 0.degree. C. Allow the reaction to warm to ambient temperature
and stir. After 5 h. Cautiously add ethanol (1 mL), and concentrate
the mixture. Dissolve the residue in ethanol (2 mL), heat to reflux
for 2 h, and concentrate. Purification using gives the title
compound as a tan solid. Dissolve the amine in 10 mL of 1:1
dichloromethane/methanol and add 600 mg of polyvinylpyridine
hydrochloride. Shake the mixture for 4 h, removed by filtration the
polymer and concentrate the residue and wash with ether to give the
title compound as the hydrochloride: MS (ES+): m/e 364 (M+1).
EXAMPLE 919
N-(2-(5-Benzyloxy-1H-indol-3-yl)-ethyl)-3-phenoxybenzylamine
[0755] ##STR119##
[0756] Combine 5-benzyloxy tryptamine (1.23 g, 4.6 mmol),
3-phenoxybenzaldehyde (97%, 1.09 g, 5.53 mmol) and molecular sieves
4A (1.0 g) and stir in methanol (15 mL) for 4 h. Filter the
molecular sieves and wash several times with MeOH. To this MeOH
solution, add portionwise NaBH.sub.4 (174 mg, 4.60 mmol), stir the
resulting mixture at room temperature for 1 h. Remove MeOH under
vacuum, dilute the residue with CH.sub.2CL.sub.2/water, extract
with CH.sub.2Cl.sub.2, combine organic layers, dry over
Na.sub.2SO.sub.4 and concentrate the solvent in vacuo. Purification
by silica gel chromatography (CH.sub.2Cl.sub.2/MeOH) to give the
free base. Combine the free base with oxalic acid to form the salt:
(300 MHz, DMSO-d.sub.6) 2.95-3.15 (m, 4H), 3.93 (s, 2H), 4.10 (br,
1H), 5.05 (s, 2H), 6.85-7.46 (m, 18H), 10.67 (br, 1H); ms
(ELECTROSPRAY) m/e: 449.2 (M+1).
EXAMPLE 921
N-(2-(5-Benzyloxy-1H-indol-3-yl)ethyl)-N-methyl-3-phenoxy-benzylamine
[0757] ##STR120##
[0758] Combine
N-(2-(5-benzyloxy-1H-indol-3-yl)ethyl)-3-phenoxy-benzylamine (1.61
g, 3.59 mmol) and NaOH (143.6 mg, 3.59-1.75 mmol) and dissolve in
THF (25 mL) and stir at room temperature. After 15 min., add
di-tert-butyl dicarbonate (1.57 g, 7.18 mmol) in THF (20 mL) and
heat to reflux for 4 h. Remove the solvent, dilute with water,
extract with CH.sub.2Cl.sub.2, (3.times.15 mL), dry over
Na.sub.2SO.sub.4 and concentrate in vacuo to give a brown oil. The
crude product was used directly in the next step without
purification.
[0759] Combine 1.0 M solution of LiAlH.sub.4-THF (13.4 mL, 13.4
mmol) and
(3-phenoxy-benzyl)-(2-(5-benzyloxy-1H-indol-3-yl)-ethyl)-carbamic
acid tert-butyl ester (1.83 g, 3.34 mmol) and slowly add 15 mL dry
THF. After addition, heat the reaction mixture to reflux. After 4.5
h, cool down to room temperature. Quench the reaction by adding
water (1.5 mL) cautiously, followed by 10% NaOH. Filter off the
suspension and wash repeatedly with ether. Dry the organic solution
over Na.sub.2SO.sub.4 and concentrate the solvent in vacuo.
Purification by silica gel chromatography using
CH.sub.2Cl.sub.2/MeOH as eluent to give the free base: .sup.1H NMR
(300 MHz, CDCl.sub.3) 2.35 (s, 3H), 2.69-2.74 (m, 2H), 2.91-2.96
9m, 2H), 3.65 (s, 2H), 5.07 (s, 2H), 6.90-7.53 (m, 18H), 7.80 (s,
1H). This compound reacted further with oxalic acid to form the
salt.
EXAMPLE 922
N-(2-(6,7-Difluoro-1H-indol-3-yl)-ethyl)-3-(pyridin-4-yloxy)benzylamine
[0760] ##STR121##
[0761] Combine 6,7-difluoro tryptamine (0.285 g, 1.450 mmol),
3-pyridin-4-yloxybenzaldehyde (0.303 g, 1.52 mmol, 1.05 eq.) and
molecular sieves 4A (0.30 g) and stir in methanol (12 mL). After 4
h. filter the molecular sieves and wash several times with MeOH. To
this MeOH solution, add portionwise NaBH.sub.4 (55.0 mg, 1.45
mmol), and stir at room temperature for 1 h. Remove MeOH in vacuo,
dilute the residue with CH.sub.2Cl.sub.2/water, extract with
CH.sub.2Cl.sub.2, combine organic layers, dry over Na.sub.2SO.sub.4
and concentrate in vacuo. Purification by flash chromatography on
silica gel (CH.sub.2Cl.sub.2/MeOH) to give the free base which is
converted to the hydrochloride salt: .sup.1H NMR (300 MHz,
DMSO-d.sub.6) 3.13 (s, 4H), 4.20 (s, 2H), 6.85-7.55 (m, 10H),
8.47-8.50 (m, 1H), 9.58 (br, 1H), 11.57 (br, 1H): MS (electrospray)
m/e: 380.2 (M+1-HCl), 378.3 (M-1-HCl).
[0762] The present invention also provides novel intermediates of
the compounds of formula I. The present invention provides
intermediates of formula III: ##STR122##
[0763] wherein
[0764] R.sub.3 is selected from the group consisting of hydrogen,
fluoro, and methyl;
[0765] R.sub.4' is fluorinated C.sub.2-C.sub.4 alkyl.
[0766] The present invention also provides novel crystalline forms
of the compounds of formula I. Thus, for example,
N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzyla-
mine hydrochloride may be prepared by crystallization under
controlled conditions to give novel crystalline forms.
Crystallization from a solution and slurrying techniques are
contemplated to be within the scope of the present process. In
practice, a number of factors can influence the form of
(N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzyl-
amine hydrochloride obtained, including temperature and solvent
composition. While the precise conditions under which crystalline
(N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzyl-
amine hydrochloride is formed may be empirically determined it is
only possible to give a number of methods which have been found to
be suitable in practice. A preferred polymorphic form of
N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzyla-
mine hydrochloride can be prepared by crystallization or slurry
from diethyl ether. Another preferred polymorphic form of
N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzyla-
mine hydrochloride can be prepared by crystallization from aqueous
dichloromethane, aqueous acetone, ethyl acetate, ethyl
acetate/cyclohexane, ethyl acetate/hexane, ethyl acetate/heptane,
acetone/cyclohexane, isopropanol/hexanes, acetonitrile,
acetonitrile/toluene, n-propanol/isoamylacetate/hexane, isopropyl
acetate/diethyl ether, methyl t-butyl ether/acetone, water,
water/acetone, water/diethyl ether.
[0767] Crystalline
(N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzyl-
amine may be prepared by direct crystallization under controlled
conditions. The novel crystalline forms of the present invention
may also be prepared by dissolving
(N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzyl-
amine in a solvent and then forming the hydrochloride salt by the
addition of a solution containing hydrochloric acid and then
allowing crystallization while controlling the temperature.
[0768] A number of methods are available to characterize
crystalline forms of organic compounds. For example methods include
differential scanning calorimetry, solid state NMR spectrometry,
infra-red spectroscopy, and X-ray powder diffraction. Among these
X-ray powder diffraction and solid state NMR spectroscopy are very
useful for identifying and distinguishing between crystalline
forms.
[0769] X-ray powder diffraction analysis are performed by a variety
of methods known to the skilled person. These methods can be varied
to increase sensitivity by sample preparation techniques and by
using more intense radiation, smaller scan steps, and slower scan
rates. One method is as follows. Either with or without lightly
grinding the sample with an agate mortar and pestle, the sample is
loaded into a sample holder for the X-ray powder diffraction
measurement. The X-ray powder diffraction patterns are measured
using a Siemens D5000 X-ray powder diffractometer equipped with a
CuK.sub..alpha. source (.lamda.=1.54056 .ANG.) operated at 50 kV
and 40 mA using divergence slit size of 1 mm, receiving slit of 1
mm, and detector slit of 0.1 mm. Samples can be scanned between
4.degree. and 35.degree. (2.theta.) with a step size of 0.020 and a
maximum scan rate of 3 sec/step. Data is collected using a Kevex
solid-state silicon lithium detector. Optimally, a silicon standard
is run routinely to check the instrument alignment.
[0770] It is well known in the crystallography art that, for any
given crystal form, the relative intensities and peak widths of the
diffraction peaks may vary due to a number of factors, including
the effects of preferred orientation and/or particle size. Where
the effects of preferred orientation and/or particle size are
present, peak intensities may be altered, but the characteristic
peak positions of the polymorph are unchanged. See, e.g., The
United States Pharmacopoeia #24, National Formulary #19, pages
1843-1844, 2000.
[0771] Grinding may be used to minimize peak intensity. However, if
grinding significantly alters the diffractogram or alters the
crystalline state of the sample, then the diffractogram of the
unground sample should be used. Grinding is done in a small agate
mortar and pestle. The mortar is held during the grinding and light
pressure was applied to the pestle.
[0772] Thus, a properly prepared sample crystalline compound of
formula I may be characterized by one or more 2.theta. values in an
X-ray diffraction pattern obtained as described above.
[0773] Crystalline compounds of formula I may also be characterized
by solid state NMR spectroscopy. Solid state .sup.13C chemical
shifts reflect not only the molecular structure of but also the
electronic environment of the molecule in the crystal.
[0774] Solid state NMR (.sup.13C) analysis can be carried out using
.sup.13C Cross polarization/magic angle spinning (CP/MAS). NMR
(solid-state NMR or SSNMR) spectra are obtained using a Varian
Unity 400 MHz spectrometer operating at a carbon frequency of
100.580 MHz, equipped with a complete solids accessory and Varian 7
mm VT CP/MAS probe. Acquisition parameters are readily determined
and typically are 90.degree. proton r.f. pulse width 4.0 Vs,
contact time 1.0 ms, pulse repetition time 5 s, MAS frequency 7.0
kHz, spectral width 50 kHz, and acquisition time 50 ms. Chemical
shifts are generally reported by referenced to the methyl group of
external hexamethylbenzene, that is, by sample replacement with
hexamethylbenzene.
[0775] Thus, crystalline compounds of formula I may be
characterized one or more resonances in the solid state .sup.13C
nuclear magnetic spectra obtained as described above.
[0776] The compounds of the present invention can be administered
alone or in the form of a pharmaceutical composition, that is,
combined with pharmaceutically acceptable carriers or excipients.
The compounds of the present invention, while effective themselves,
may be formulated and administered in the form of their
pharmaceutically acceptable salts, for purposes of stability,
convenience, solubility, and the like. In practice, the compounds
of formula I and II are usually administered in the form of
pharmaceutical compositions, that is, in admixture with
pharmaceutically acceptable carriers or diluents.
[0777] Thus, the present invention provides pharmaceutical
compositions comprising a compound of the formula I or II and a
pharmaceutically acceptable diluent.
[0778] The compounds of formula I and II can be administered by a
variety of routes. In effecting treatment of a patient afflicted
with disorders described herein, a compound of formula I and II can
be administered in any form or mode which makes the compound
bioavailable in an effective amount, including oral and parenteral
routes. For example, compounds of formula I and II can be
administered orally, by inhalation, subcutaneously,
intramuscularly, intravenously, transdermally, intranasally,
rectally, occularly, topically, sublingually, buccally, and the
like. Oral administration is generally preferred for treatment of
the disorders described herein.
[0779] One skilled in the art of preparing formulations can readily
select the proper form and mode of administration depending upon
the particular characteristics of the compound selected, the
disorder or condition to be treated, the stage of the disorder or
condition, the solubility and chemical properties of the compound
selected, the chosen route of administration, and other relevant
circumstances considered in standard pharmaceutical practice.
(Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing
Co. (1990)).
[0780] The pharmaceutical compositions are prepared in a manner
well known in the pharmaceutical art. The carrier or excipient may
be a solid, semi-solid, or liquid material which can serve as a
vehicle or medium for the active ingredient. Suitable carriers or
excipients are well known in the art. The pharmaceutical
composition may be adapted for oral, inhalation, parenteral, or
topical use and may be administered to the patient in the form of
tablets, capsules, aerosols, inhalants, suppositories, solutions,
suspensions, or the like.
[0781] The compounds of the present invention may be administered
orally, for example, with an inert diluent or capsules or
compressed into tablets. For the purpose of oral therapeutic
administration, the compounds may be incorporated with excipients
and used in the form of tablets, troches, capsules, elixirs,
suspensions, syrups, wafers, chewing gums and the like. These
preparations should contain at least 4% of the compound of the
present invention, the active ingredient, but may be varied
depending upon the particular form and may conveniently be between
4% to about 70% of the weight of the unit. The amount of the
compound present in compositions is such that a suitable dosage
will be obtained. Preferred compositions and preparations according
to the present invention may be determined by a person skilled in
the art.
[0782] The tablets, pills, capsules, troches, and the like may also
contain one or more of the following adjuvants: binders such as
microcrystalline cellulose, gum tragacanth or gelatin; excipients
such as starch or lactose, disintegrating agents such as alginic
acid, Primogel, corn starch and the like; lubricants such as
magnesium stearate or Sterotex; glidants such as colloidal silicon
dioxide; and sweetening agents such as sucrose or saccharin may be
added or a flavoring agent such as peppermint, methyl salicylate or
orange flavoring. When the dosage unit form is a capsule, it may
contain, in addition to materials of the above type, a liquid
carrier such as polyethylene glycol or a fatty oil. Other dosage
unit forms may contain other various materials which modify the
physical form of the dosage unit, for example, as coatings. Thus,
tablets or pills may be coated with sugar, shellac, or other
coating agents. A syrup may contain, in addition to the present
compounds, sucrose as a sweetening agent and certain preservatives,
dyes and colorings and flavors. Materials used in preparing these
various compositions should be pharmaceutically pure and non-toxic
in the amounts used.
[0783] For the purpose of parenteral therapeutic administration,
the compounds of the present invention may be incorporated into a
solution or suspension. These preparations typically contain at
least 0.1% of a compound of the invention, but may be varied to be
between 0.1 and about 90% of the weight thereof. The amount of the
compound of formula I and II present in such compositions is such
that a suitable dosage will be obtained. The solutions or
suspensions may also include one or more of the following
adjuvants: sterile diluents such as water for injection, saline
solution, fixed oils, polyethylene glycols, glycerine, propylene
glycol or other synthetic solvents; antibacterial agents such as
benzyl alcohol or methyl paraben; antioxidants such as ascorbic
acid or sodium bisulfite; chelating agents such as ethylene
diaminetetraacetic acid; buffers such as acetates, citrates or
phosphates and agents for the adjustment of tonicity such as sodium
chloride or dextrose. The parenteral preparation can be enclosed in
ampoules, disposable syringes or multiple dose vials made of glass
or plastic. Preferred compositions and preparations are able to be
determined by one skilled in the art.
[0784] The compounds of the present invention may also be
administered topically, and when done so the carrier may suitably
comprise a solution, ointment, or gel base. The base, for example,
may comprise one or more of the following: petrolatum, lanolin,
polyethylene glycols, bees wax, mineral oil, diluents such as water
and alcohol, and emulsifiers, and stabilizers. Topical formulations
may contain a concentration of the formula I and II or its
pharmaceutical salt from about 0.1 to about 10% w/v (weight per
unit volume).
[0785] The compounds of formula I and II are antagonists of
5-HT.sub.6 receptors. Such antagonism can be identified by the
methods below.
EXAMPLE A
Assay for 5HT.sub.6 binding
[0786] The assay buffer used is 50 mM Tris-HCl pH 7.4, 120 mM NaCl,
5 mM KCl, 5 mM MgCl2, 1 mM EDTA. The radioligand used is 3H-LSD
from New England Nuclear Cat. #NET 638-75.9 Ci/mmol. The membranes
used are from Receptor Biology, Cat. No. RB-HS6. These are
membranes from HEK-293 cells expressing the Human 5HT.sub.6
receptor.
[0787] Test compounds are obtained as 10 mM stocks in 100% DMSO.
They are diluted to 1 mM in 100% DMSO by adding 180 .mu.l DMSO to
20 .mu.l of stock in 96 well plates using a multidrop. The 1 mM
stocks are then diluted to make an 11 point concentration range
from 125 .mu.M down to 1.25 nM in half log increments using 10%
DMSO as diluent. This is done using a TECAN robot. The final DMSO
at this stage is 21.25%.
[0788] Radioligand is diluted in assay buffer to make a 125 nM
solution and each vial of membranes is diluted up to 92 mL in assay
buffer. The final assay volume is 250 .mu.l consisting of 210 .mu.l
of diluted membranes, 20 .mu.l of compound or 21.25% DMSO for total
binding, and 20 .mu.l of diluted radioligand. The compounds are
transferred from drug dilution plates into corning 96 well assay
plates using a 96 well Multimek pipettor. Radioligand and membranes
are added to assay plates using multidrop pipettors. Non-specific
binding is determined in wells containing a final serotonin
concentration of 10 .mu.M. In the final assay volume the
radioligand is 10 nM and the membrane protein is approximately 25
.mu.g/well. The final drug concentration range in half logs is from
10 .mu.M down to 0.1 nM. The final DMSO in the assay is 1.7%.
[0789] After addition of drug, membrane, and ligand, the plates are
incubated for one hour at room temperature. During this time 96
well Millipore filter plates (MAFBNOB50) are soaked for a least 30
minutes with 200 .mu.l per well of 0.5% polyethyleneimine.
[0790] The 0.5% PEI is removed from filterplate wells using a
TiterTek MAP aspirator and 200 .mu.l of the incubation mixture is
transferred from the incubation plate to the filterplate after
mixing. This transfer is done using the 96 tip Mutimek pipettor.
After transfer to the filterplate filterplates are extracted and
washed twice with 220 .mu.l per well of cold buffer on the MAP
aspirator. The peel away bottoms are removed from the filterplates
and 100 .mu.l per well of microscint 20 scintillation fluid is
added per well using a multidrop. Plates are placed into suitable
holders and are left at room temperature for three hours and are
counted for .sup.3H in either a Wallac Microbeta counter or on a
Packard Topcount.
[0791] In one embodiment, the present invention provides methods of
treating disorders associated with the 5-HT.sub.6 receptor,
comprising: administering to a patient in need thereof an effective
amount of a compound of formula I. Thus, the present invention
contemplates the various disorders described to be treated herein
and others which can be treated by such antagonists as are
appreciated by those skilled in the art.
[0792] In particular, because of their ability to antagonize the
5-HT.sub.6 receptor, it is recognized that the compounds of the
present invention are useful for treating cognitive disorders, that
is, disorders involving cognitive deficits. A number of the
disorders which can be treated by 5-HT.sub.6 antagonists are known
according to established and accepted classifications, while others
are not.
[0793] Some of the disorders to be treated according to the present
invention are not well categorized and classified because cognition
is a complicated and sometimes poorly defined phenomenon. It is,
however, widely recognized that cognition includes various
"domains." These domains include short term memory, long term
memory, working memory, executive function, and attention.
[0794] While many of the disorders which can be treated according
to the present invention are not uniformly described and classified
in the art, it is understood that the compounds of the present
invention are useful for treatment of disorders characterized by a
deficit in any of the cognitive domains listed above or in other
aspects of cognition. Thus the term "cognitive disorders" is meant
to encompass any disorder characterized by a deficit in one or more
cognitive domain, including but not limited to short term memory,
long term memory, working memory, executive function, and
attention.
[0795] One cognitive disorder to be treated by the present
invention is age-related cognitive decline. This disorder is not
well defined, but includes decline in the cognitive domains,
particularly the memory and attention domains, which accompany
aging. Another is mild cognitive impairment. Again, this disorder
is not well defined in the art, but involves decline in the
cognitive domains, and is believed to represent a group of patients
the majority of which have incipient Alzheimer's disease. Also, a
wide variety of insults, including stroke, ischemia, hypoxia,
inflammation, and infectious processes can result in cognitive
deficits as a sequella which can be treated according to the
present invention.
[0796] Where the disorders which can be treated by 5-HT.sub.6
antagonists are, at present, known according to established and
accepted classifications, these classifications can be found in
various sources. For example, at present, the fourth edition of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV.TM.)
(1994, American Psychiatric Association, Washington, D.C.),
provides a diagnostic tool for identifying many of the disorders
described herein. Also, the International Classification of
Diseases, Tenth Revision, (ICD-10) provides classifications for
many of the disorders described herein. The skilled artisan will
recognize that there are alternative nomenclatures, nosologies, and
classification systems for disorders described herein, including
those not well characterized by the art and those described in the
DMS-IV and ICD-10, and that terminology and classification systems
evolve with medical scientific progress.
[0797] In one embodiment, the present invention provides methods of
treating disorders selected from the group consisting of:
age-related cognitive disorder, mild cognitive impairment, mood
disorders (including depression, mania, bipolar disorders),
psychosis (in particular schizophrenia), anxiety (particularly
including generalized anxiety disorder, panic disorder, and
obsessive compulsive disorder), idiopathic and drug-induced
Parkinson's disease, epilepsy, convulsions, migraine (including
migraine headache), substance withdrawal (including, substances
such as opiates, nicotine, tobacco products, alcohol,
benzodiazepines, cocaine, sedatives, hypnotics, etc.), sleep
disorders (including narcolepsy), attention deficit/hyperactivity
disorder, conduct disorder, learning disorders, dementia (including
Alzheimer's disease and AIDS-induced dementia), Huntington's
Chorea, cognitive deficits subsequent to cardiac bypass surgery and
grafting, stroke, cerebral ischemia, spinal cord trauma, head
trauma, perinatal hypoxia, cardiac arrest, and hypoglycemic
neuronal damage, vascular dementia, multi-infarct dementia,
amylotrophic lateral sclerosis, and multiple sclerosis, comprising:
administering to a patient in need thereof an effective amount of a
compound of formula I or II. That is, the present invention
provides for the use of a compound of formula I and II or
pharmaceutical composition thereof for the treatment disorders
associated with the 5-HT.sub.6 receptor.
[0798] It is recognized that the terms "treatment" and "treating"
are intended to include improvement of the cognitive deficit
associated with each of the disorders associated with the
5-HT.sub.6 receptor described herein. Also, it is also recognized
that one skilled in the art may affect the disorders by treating a
patient presently afflicted with the disorders or by
prophylactically treating a patient believed to be susceptible to
such disorders with an effective amount of the compound of formula
I. Thus, the terms "treatment" and "treating" are intended to refer
to all processes wherein there may be a slowing, interrupting,
arresting, controlling, or stopping of the progression of the
disorders described herein, but does not necessarily indicate a
total elimination of all symptoms, and is intended to include
prophylactic treatment of such disorders. For example, the present
invention specifically encompasses the treatment of the cognitive
deficits associated with schizophrenia, stroke, Alzheimer's
disease, and the other disorders described herein. Thus, it is
understood that the present invention includes adjunctive treatment
of the disorders described herein. More specifically, the compounds
of formula I and II are useful to treat cognition disorders in
combination with a wide variety of therapeutic agents, in
particular, in combination with AMPA potentiators; with typical and
atypical antipsychotics, including olanzapine; with a variety of
agents such as mGluR agonists, with NMDA antagonists, with IL 1-6
inhibitors, and the like; with cholinergics, including
cholinesterase inhibitors, such as tacrine and donepezil, and
compounds that inhibit amyloid protein processing, including
inhibitors of amyloid precursor protein processing and antibodies
directed against amyloid proteins; with antidepressants, including
SSRIs; and with anxiolytic agents; etc. It is believed that the
combinations above are synergistically beneficial providing
efficacy at doses that are a small fraction of those required to
produce the same effect with the individual components.
[0799] As used herein, the term "patient" refers to a warm blooded
animal such as a mammal which is afflicted with one or more
disorders associated with the 5-HT.sub.6 receptor. It is understood
that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep,
pigs, and humans are examples of animals within the scope of the
meaning of the term.
[0800] As used herein, the term "effective amount" of a compound of
formula I or II refers to an amount, that is, the dosage which is
effective in treating the disorders described herein.
[0801] An effective amount can be readily determined by the
attending diagnostician, as one skilled in the art, by the use of
conventional techniques and by observing results obtained under
analogous circumstances. In determining an effective amount, the
dose of a compound of formula I, a number of factors are considered
by the attending diagnostician, including, but not limited to: the
compound of formula I or II to be administered; the
co-administration of other therapies, if used; the species of
mammal; its size, age, and general health; the specific disorder
involved; the degree of involvement or the severity of the
disorder; the response of the individual patient; the mode of
administration; the bioavailability characteristics of the
preparation administered; the dose regimen selected; the use of
other concomitant medication; and other relevant circumstances.
[0802] An effective amount of a compound of formula I and II is
expected to vary from about 0.1 milligram per kilogram of body
weight per day (mg/kg/day) to about 100 mg/kg/day. Preferred
amounts are able to be determined by one skilled in the art.
[0803] Of the disorders to be treated according to the present
invention a number are particularly preferred.
[0804] In a preferred embodiment the present invention provides a
method of treating cognitive disorders, comprising: administering
to a patient in need thereof an effective amount of a compound of
claim 1.
[0805] In another preferred embodiment the present invention
provides a method for treating Alzheimer's disease, comprising:
administering to a patient in need thereof an effective amount of a
compound of formula I.
[0806] In a preferred embodiment the present invention provides a
method for treating schizophrenia, comprising: administering to a
patient in need thereof an effective amount of a compound of
formula I.
[0807] The fourth edition of the Diagnostic and Statistical Manual
of Mental Disorders (DSM-IV.TM.) (1994, American Psychiatric
Association, Washington, D.C.), provides a diagnostic tool
including schizophrenia and related disorders, all of which are
understood to be specifically included in the scope of this
invention.
[0808] In a preferred embodiment the present invention provides a
method for treating migraine, comprising: administering to a
patient in need thereof an effective amount of a compound of
formula I or II or a pharmaceutical composition thereof.
[0809] In one of the available sources of diagnostic tools,
Dorland's Medical Dictionary (23.sup.rd Ed., 1982, W. B. Saunders
Company, Philadelphia, Pa.), migraine is defined as a symptom
complex of periodic headaches, usually temporal and unilateral,
often with irritability, nausea, vomiting, constipation or
diarrhea, and photophobia. As used herein the term "migraine"
includes to these periodic headaches, both temporal and unilateral,
the associated irritability, nausea, vomiting, constipation or
diarrhea, photophobia, and other associated symptoms. The skilled
artisan will recognize that there are alternative nomenclatures,
nosologies, and classification systems for neurological and
psychiatric disorders, including migraine, and that these systems
evolve with medical scientific progress.
[0810] In a preferred embodiment the present invention provides a
method for treating anxiety disorders, including generalized
anxiety disorder, panic disorder, and obsessive compulsive
disorder, comprising: administering to a patient in need thereof an
effective amount of a compound of formula I.
[0811] At present, the fourth edition of the Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV.TM.) (1994, American
Psychiatric Association, Washington, D.C.), provides a diagnostic
tool including anxiety and related disorders. These include: panic
disorder with or without agoraphobia, agoraphobia without history
of panic disorder, specific phobia, social phobia,
obsessive-compulsive disorder, post-traumatic stress disorder,
acute stress disorder, generalized anxiety disorder, anxiety
disorder due to a general medical condition, substance-induced
anxiety disorder and anxiety disorder not otherwise specified. As
used herein the term "anxiety" includes treatment of those anxiety
disorders and related disorders as specifically described in the
DSM-IV and the term "anxiety" is intended to include like disorders
that are described in other diagnostic sources.
[0812] A number of preclinical laboratory animal models have been
described for the disorders described herein.
EXAMPLE B
Fear Potentiated Startle Paradigm
[0813] Male Sprague-Dawley rats weighing 325-400 g were purchased
from Harlan Sprague-Dawley, Inc. (Cumberland, Ind.) and given a one
week acclimation period before testing. Rats were individually
housed with food and water ad libitum in an animal room on a
12-hour light/dark cycle with lights on between 6:00 A.M. and 6:00
P.M. The compound of Example 16 was prepared in a suspension of 5%
ethanol, 0.5% CMC, 0.5% Tween 80 and 99% water.
2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)propionic
acid was prepared in sterile water. Control rats were given the
respective vehicle.
[0814] The fear potentiated startle paradigm is conducted over
three consecutive days. All three days begin with a 5-minute
adaptation period before the trial starts. On day one (baseline
startle) after the adaptation period, the animal receives 30 trials
of 120 dB auditory noise. The mean startle amplitude (V.sub.max) is
used to assign animals to groups with similar means before
conditioning begins. Day two consists of conditioning the animals.
Each animal receives 0.5 mA of shock for 500 msec preceded by a 5
second presentation of light which remains on for the duration of
the shock. Ten presentations of the light and shock are
administered. Day three is the testing trial where drug
administration occurs prior to testing. Twenty-four hours after
conditioning, startle testing sessions are conducted. Ten trials of
acoustic startle (120 dB), non-light paired, are presented at the
beginning of the session. This is followed by 20 random trials of
the noise alone and 20 random trials of noise preceded by light.
Excluding the first 10 trials, the startle response amplitudes for
each trial type are averaged for each animal. Data is presented as
the difference between light+noise and noise-alone. Differences in
startle response amplitudes were analyzed by Jmp statistical
software using a One-way Anova (analysis of variance, t-test).
Group differences were considered to be significant at
p<0.05.
[0815] The radial arm maze model can be used as a model of
cognition and can be used to evaluate the present compounds.
EXAMPLE C
Radial Arm Maze
[0816] The delayed non-match to sample task has been used to study
the effect of drugs on memory retention (Pussinen, R. and Sirvio,
J. J of Psychopharm 13: 171-179(1999); Staubli, U., et al. Proc
Natl Acad Sci 91: 777-781(1994)) in the eight arm radial maze.
[0817] Well-trained rats were allowed to retrieve food rewards from
four randomly selected arms of the maze (sampling phase). Some time
later, the rats were exposed to eight open arms and were tested for
their ability to remember and avoid the arms they had previously
entered to obtain food. Re-entry into an arm that was baited during
the sampling session was counted as a reference error, whereas
entry into the same arm more than once during the retention session
was counted as working error. The total (reference+working number
of errors made during the retention test increases with increasing
delay periods. For example, young male rats made 0.66 (+0.4) errors
at a 1 minute delay, 2 (+0.5) errors at a one hour delay, and 3.95
(+0.2) errors at a seven hour delay (observations of this lab).
[0818] Male Sprague-Dawley rats were individually housed and
maintained on a 12 h light-dark cycle (lights on at 6 am). The rats
were given free access to water and maintained at 85% of their
free-feeding weight by supplemental feedings of Purina Lab
Chow.
[0819] The rats were initially trained to search for food at the
end of each of the eight arms. Once the rats had reached the
criteria of no more than two errors (i.e. entering the same arm
more than once during a session) on three consecutive days, a delay
of one minute was imposed between the fourth and the fifth arm
choices. This training ensured that the rats were thoroughly
familiar with the procedural aspects of the task before any drugs
were administered. Once stable performance had been obtained on the
delay task (i.e. no more than one error was made on three
consecutive days), drug and vehicle tests commenced using a seven
hour delay period. A novel set of arms was baited each day for each
rat and the maze was thoroughly cleaned during the delay
period.
[0820] During the sampling session, each rat was placed on the
center platform with access to all eight arms of the maze blocked.
Four of the eight arms were randomly selected and baited with food.
The gates of the baited arms were raised and the rat was allowed
five minutes to obtain the food at the end of each of the four
arms. As soon as the rat had obtained the food, it was removed,
administered vehicle or various doses of compounds, and placed back
in its home cage. Seven hours later (retention session), the rat
was placed back onto the center platform with access to all eight
arms blocked. The four arms that were previously baited during the
sampling session, were baited and the gates to all eight arms were
raised. The rat was allowed five minutes to obtain the remaining
four pieces of food. An entry into a non-baited arm or a re-entry
into a previously visited arm was counted as an error. Significance
(p<0.05) was determined using a repeated measure ANOVA followed
by a Dunnett's test for comparison with control.
[0821] In order to compare test compounds with standards,
scopolamine and tacrine were administered s.c. immediately after
the sampling phase. The effects of scopolamine, a known amnesic,
were tested after a three-hour delay, whereas the effect of
tacrine, a cholinesterase inhibitor used in the treatment of
Alzheimer's disease was tested after a six-hour delay. Scopolamine
disrupted retention after a three-hour delay in a dose-related
fashion. Tacrine significantly improved retention after a six-hour
delay at 10, but not at 3 mg/kg.
EXAMPLE D
Acquisition in the Radial Maze 8-Arm Radial Maze Acquisition
[0822] A prominent early feature of Alzheimer's disease (AD)
symptomology is a pronounced deficit in declarative memory (R. W.
Parks, R. F. Zec & R. S. Wilson (Eds.), Neuropsychology of
Alzheimer's disease and other dementias. NY: Oxford University
Press pp. 3-80 (1993).
[0823] As the disease progresses, other domains of cognition become
severely affected as well. Among the brain regions affected early
in the progression of AD is the hippocampus, which is a critical
neural substrate for declarative memory (West M. J., Coleman P. D.,
Flood D. G. & Troncoso J. C. Differences in the pattern of
hippocampal neuronal loss in normal aging and Alzheimer's disease.
Lancet, 344: 769-772(1994). One behavioral test that is often used
to assess hippocampal function in animal models is the 8-arm radial
maze (Olton D. S. The radial arm maze as a tool in behavioral
pharmacology. Physiology & Behavior, 40: 793-797 (1986)).
[0824] Lesions or pharmacological blockade of the hippocampus
disrupt performance of this task. Moreover, aged animals generally
show deficits in this task (Porsolt R. D., Roux S. & Wettstein
J. G. Animal models of dementia. Drug Development Research, 35:
214-229(1995)).
[0825] In this test of spatial learning and memory, a hungry rat is
placed in the center of the maze and allowed to traverse the maze
in search of food located at the end of each runway arm. In this
version of the maze, the rat learns a win-shift strategy in which a
visited arm is not replaced. Therefore, the most efficient foraging
strategy is to visit each arm once. The version of the maze also
taps into general learning processes as the rat is naive to the
maze on day one of the four day experiment.
[0826] Upon arrival, male Sprague Dawley.RTM., rats were
individually housed in a regular light-cycle colony room and
allowed to acclimate for at least 4 days prior to testing. Each rat
was reduced to and maintained at 85% of their target body weight
throughout the experiment. Proper body weight was maintained by
adjusting the allotment of lab chow based on a combination of age
and the rat's daily bodyweight reading.
[0827] A session began with an individual rat being placed into the
hub of the maze and then all guillotine doors were raised, allowing
free access to all areas of the maze. A food hopper was located at
the end of each of the 8 runway arms and a single food pellet was
placed in each food hopper. Each daily session terminated when
either all 8 food-hoppers had been visited or when the rat timed
out (15 min on Day 1: 5 min on Days 2-4). The number of arm entries
was recorded. Errors were counted as repeat arm entries or failures
to visit an arm in the session period. An animal was excluded from
the study if it failed to visit at least one arm on Day 1, 2 arms
on Day 2, and at least 4 arms on Days 3 & 4.
[0828] Each rat was pseudo-randomly assigned to either a vehicle or
drug group and received the same treatment throughout the
experimental period. Vehicle consisted of 5% acacia within sterile
water. Injections were administered subcutaneously 20-30 minutes
prior to each daily session.
[0829] In this acquisition task, vehicle-treated animals do not
consistently show significant acquisition of maze learning as
compared to the number of errors committed on Day 1. We have found
that in compounds that facilitate acquisition of maze learning, the
effects are often not observed until the fourth day of training.
Therefore, results consisted of total Day 4 errors across treatment
groups.
* * * * *