U.S. patent number RE41,425 [Application Number 12/081,710] was granted by the patent office on 2010-07-06 for piperazine and piperidine compounds.
This patent grant is currently assigned to Duphar International Research B.V.. Invention is credited to Jacobus A. J. Den Hartog, Roelof Willem Feenstra, Cornelis G. Kruse, Stephen K. Long, Martinus T. M. Tulp.
United States Patent |
RE41,425 |
Feenstra , et al. |
July 6, 2010 |
Piperazine and piperidine compounds
Abstract
A group of new piperazine and piperidine compounds having
interesting advantageous pharmacological properties and have the
formula (a) ##STR00001## wherein A represents a heterocyclic group
having 5-7 ring atoms wherein 1-3 heteroatoms selected from the
group O, N and S are present, R.sub.1 is hydrogen or fluoro,
R.sub.2 is C.sub.1-4-alkyl, C.sub.1-4-alkoxy or an oxo group, and p
is 0, 1 or 2, Z represents carbon or nitrogen, and the dotted line
represents a single bond when Z is nitrogen, and represents a
single or double bond when Z is carbon, R.sub.3 and R.sub.4
independently are hydrogen or C.sub.1-4-alkyl, n has the value 1 or
2, R.sub.5 is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the
meta-position with respect to the methylene bridge with a group Y,
and optionally substituted with (R.sub.6)q, Y is a phenyl, furanyl
or thienyl group, which groups may be substituted with 1-3
substituents from the group hydroxy, halogen, CF.sub.3,
C.sub.1-4-alkoxy, C.sub.1-4-alkyl, cyano aminocarbonyl, mono- or
di-C.sub.1-4-alkylaminocarbonyl, R.sub.6 is halogen, hydroxy,
C.sub.1-4-alkoxy or C.sub.1-4-alkyl, and q is 0, 1, 2 or 3 and
salts thereof, are disclosed.
Inventors: |
Feenstra; Roelof Willem (Weesp,
NL), Den Hartog; Jacobus A. J. (Weesp, NL),
Kruse; Cornelis G. (Weesp, NL), Tulp; Martinus T.
M. (Weesp, NL), Long; Stephen K. (Weesp,
NL) |
Assignee: |
Duphar International Research
B.V. (Weesp, NL)
|
Family
ID: |
8228755 |
Appl.
No.: |
12/081,710 |
Filed: |
April 18, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
09158520 |
Sep 22, 1998 |
06090812 |
Jul 18, 2000 |
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Foreign Application Priority Data
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Sep 24, 1997 [EP] |
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97202950 |
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Current U.S.
Class: |
544/364 |
Current CPC
Class: |
C07D
405/12 (20130101); C07D 413/12 (20130101); C07D
409/14 (20130101); A61P 25/00 (20180101); A61P
25/18 (20180101); A61P 25/22 (20180101); C07D
405/14 (20130101); A61P 43/00 (20180101); A61P
25/24 (20180101); A61P 25/16 (20180101); A61P
1/08 (20180101); A61P 25/28 (20180101); A61P
25/04 (20180101) |
Current International
Class: |
C07D
295/12 (20060101); A61K 31/496 (20060101) |
Field of
Search: |
;544/364 ;514/254 |
References Cited
[Referenced By]
U.S. Patent Documents
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4874770 |
October 1989 |
Van Wijngaarden et al. |
5332732 |
July 1994 |
Scott et al. |
5436246 |
July 1995 |
Bernotas et al. |
5464834 |
November 1995 |
Peglion et al. |
6090807 |
July 2000 |
Hellendahl et al. |
6258813 |
July 2001 |
Arlt et al. |
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19637237 |
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Mar 1998 |
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Mar 1998 |
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WO |
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Other References
Van Steen et al., "Structure-Affinity Relationship Studies on
5-HT.sub.IAReceptor Ligands. 2. Heterobicyclic Phenylpiperazines
with N4-Aralkyl Substituents", J. Med. Chem., 37(17):2761-2773
(1994). cited by other .
Van der Heyden & Bradford, A rapidly acquired one-way
conditioned avoidance procedure in rats as a primary screening test
for antipsychotics: influence of shock intensity on avoidance
performance, Behav. Brain Res., 31:61-67 (1988). cited by other
.
Van Hest et al., Flesinoxan shows antidepressant activity in a DRL
72-s screen, Psychopharmacology, 107:474-479 (1992). cited by other
.
Van der Poel et al., Temporal pattering of ultrasonic distress
calls in the adult rat: effects of morphine and benzodiazepines,
Pschopharmacology, 97:147-148 (1989). cited by other.
|
Primary Examiner: Anderson; Rebecca L
Assistant Examiner: Havlin; Robert
Attorney, Agent or Firm: Finnegan, Henderson, Farabow,
Garrett & Dunner, L.L.P.
Claims
What is claimed is:
1. A compound having the formula (a) ##STR00016## wherein A
represents a heterocyclic group having 5-7 ring atoms wherein 1-3
heteroatoms selected from the group O, N and S are present, R.sub.1
is hydrogen or fluoro, R.sub.2 is C.sub.1-4-alkyl, C.sub.1-4-alkoxy
or an oxo group, and p is 0, 1 or 2, Z represents carbon or
nitrogen, and the dotted line represents a single bond when Z is
nitrogen, and represents a single or double bond when Z is carbon,
R.sub.3 and R.sub.4 independently are hydrogen or C.sub.1-4-alkyl,
n has the value 1 or 2, R.sub.5 is 2-pyridyl, 3-pyridyl or
4-pyridyl substituted at the meta-position with respect to the
methylene bridge with a group Y, and optionally substituted with
(R.sub.6)q, Y is a phenyl, furanyl or thienyl group, which groups
may be substituted with 1-3 substituents selected from the group
hydroxy, halogen, CF.sub.3, C.sub.1-4-alkoxy, C.sub.1-4-alkyl,
cyano, aminocarbonyl, mono- or di-C.sub.1-4-alkylaminocarbonyl,
R.sub.6 is halogen, hydroxy, C.sub.1-4-alkoxy or C.sub.1-4-alkyl,
and q is 0, 1, 2 or 3, or a pharmaceutically acceptable salt
thereof.
2. A compound according to claim 1, wherein A together with the
phenyl group represents a group having the formula b, c, d, e, f or
g ##STR00017## and wherein n is 1, and R.sub.1, .[.(R.sub.2)p,.].
.Iadd.R.sub.2, .Iaddend.R.sub.3, R.sub.4, R.sub.5,
.[.(R.sub.6)q,.]. .Iadd.R.sub.6, p, q, .Iaddend.Y and Z have the
meanings given in claim 1, or a pharmaceutically acceptable salt
thereof.
3. A compound according to claim 2, wherein A together with the
phenyl group represents a group of the formula (c) or (d), wherein
R.sub.5 has the meaning given in claim 1, Y is phenyl, R.sub.3 and
R.sub.4 are hydrogen, R.sub.6 is hydroxy, methoxy or halogen, q is
0 or 1 and Z is nitrogen, or a pharmaceutically acceptable salt
thereof.
4. A compound according to claim 3, wherein A together with the
phenyl group represents a group of the formula (d), wherein
R.sub.1, .[.(R.sub.2)p,.]. R.sub.3 and R.sub.4 are hydrogen,
.Iadd.p is 0, .Iaddend.n is 1, Z is nitrogen, and R.sub.5 is the
group 5-(4-fluorophenyl)-pyrid-3-yl, or a pharmaceutically
acceptable salt thereof.
5. A method for preparing a compound of the formula (a) according
to claim 1, said method comprising a) reacting a compound of
formula ##STR00018## with a compound of the formula
R.sub.5--CH.sub.2--X, wherein X is a leaving group; or b) reacting
a compound of the formula ##STR00019## wherein .[.R.sub.5' has the
same meaning as R.sub.5 as given in claim 1, with the proviso that
the bromine atom is at the meta-position with respect to the
methylene bridge.]. .Iadd.R'.sub.5 is 2-pyridyl, 3-pyridyl or
4-pyridyl substituted at the meta-position with respect to the
methylene bridge with the bromine atom.Iaddend., with a compound of
the formula B(OH).sub.2--Y, in which each substituent has the
meanings given in claim 1.
6. A pharmaceutical composition, said composition comprising a
pharmaceutically effective amount of at least one compound
according to claim 1 and a pharmaceutically acceptable carrier.
7. A method of preparing a pharmaceutical composition for treating
a CNS disorder, said method comprising .[.including in.].
.Iadd.adding to .Iaddend.said composition a pharmaceutically
effective amount of at least one compound of the formula (a)
according to claim 1 and a pharmaceutically acceptable carrier.
8. A method of treating a CNS disorder, said method comprising
administering to a host in need of said treatment an effective
amount of a compound of formula (a) according to claim 1.
9. A compound of the formula ##STR00020## wherein R.sub.1,
(R.sub.2)p, Z, n, R.sub.3 and R.sub.4 have the meanings given in
claim 1, and .[.R.sub.5' has the same meaning as R.sub.5 given in
claim 1, with the proviso that the bromine atom is at the
meta-position with respect to the methylene bridge.].
.Iadd.R'.sub.5 is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at
the meta-position with respect to the methylene bridge with the
bromine atom.Iaddend..
.Iadd.10. A pharmaceutical composition, said composition comprising
a pharmaceutically effective amount of at least one compound
according to claim 4 and a pharmaceutically acceptable
carrier..Iaddend.
.Iadd.11. A method of preparing a pharmaceutical composition for
treating a CNS disorder, said method comprising adding to said
composition a pharmaceutically effective amount of at least one
compound according to claim 4 and a pharmaceutically acceptable
carrier..Iaddend.
.Iadd.12. A method of treating a CNS disorder, said method
comprising administering to a host in need of said treatment an
effective amount of at least one compound according to claim
4..Iaddend.
Description
The invention relates to a group of new piperazine and piperidine
compounds having interesting pharmacological properties. The
inventors have discovered that compounds of the formula (a)
##STR00002## wherein A represents a heterocyclic group having 5-7
ring atoms, wherein 1-3 heteroatoms selected from the group O, N
and S are present, R.sub.1 is hydrogen or fluoro, R.sub.2 is
C.sub.1-4-alkyl, C.sub.1-4-alkoxy or an oxo group, and p is 0, 1 or
2, Z represents carbon or nitrogen, and the dotted line represents
a single bond when Z is nitrogen, and represents a single or double
bond when Z is carbon, R.sub.3 and R.sub.4 independently are
hydrogen or C.sub.1-4-alkyl, n has the value 1 or 2, R.sub.5 is
2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position
with respect to the methylene bridge with a group Y, and optionally
substituted with (R.sub.6)q, Y is a phenyl, furanyl or thienyl
group, which groups may be substituted with 1-3 substituents
selected from the group hydroxy, halogen, CF.sub.3,
C.sub.1-4-alkoxy, C.sub.1-4-alkyl, cyano, aminocarbonyl, mono- or
di-C.sub.1-4-alkylaminocarbonyl, R.sub.6 is halogen, hydroxy,
C.sub.1-4-alkoxy or C.sub.1-4-alkyl, and q is 0, 1, 2 or 3, and the
salts thereof have interesting and advantageous pharmacological
properties.
Preferred compounds according to the invention are the compounds of
formula (a) wherein A together with the phenyl group represents a
group of the formula b, c, d, e, f or g ##STR00003## wherein n is 1
and R.sub.1 and (R.sub.2)p, R.sub.3, R.sub.4, R.sub.5,
(R.sub.6).sub.q, Y and Z have the above meanings, and the salts
thereof.
Particularly preferred are the inventive compounds of formula (a)
wherein A together with the phenyl group represents a group of the
formula (c) or (d), R.sub.5 has the above meaning and Y is phenyl
which may be substituted as mentioned above, and wherein R.sub.2
has the above mentioned meaning, p=0 or 1, n is 1, R.sub.3 and
R.sub.4 are hydrogen, R.sub.6 is hydroxy, methoxy or halogen, q is
0 or 1, Z is nitrogen, and the salts thereof.
Particularly preferred is the compound having formula (a) wherein A
together with the phenyl group represents the group of the formula
(d), wherein R.sub.1, (R.sub.2).sub.p, R.sub.3 and R.sub.4 are
hydrogen, n is 1, Z is nitrogen, and R.sub.5 is the group
5-(4-fluorophenyl)-pyrid-3-yl, and the salts thereof.
It is known from EP 0650964 that compounds of the formula
##STR00004## wherein R.sub.0 is C.sub.1-4-alkyl, which compounds
can be substituted in the phenyl group and/or heterocyclic group
and/or the piperazine group, act on the central nervous system by
binding to 5-HT receptors. In particular these compounds bind to
subtypes of the 5-HT-receptor, i.e. 5-HT.sub.1A and 5-HT.sub.1D
receptors.
It has now surprisingly been found that the compounds according to
the invention show affinities for the dopamine D.sub.2 receptor
(pK.sub.i range 7-9.5) and dopamine D.sub.4 receptor (pK.sub.i
range 6.5-9.5) without significant preference for one of the above
mentioned two receptors. Moreover, the compounds according to the
invention show affinity for serotonin 5-HT.sub.1A receptors
(pK.sub.i range 7-9.5). This combination of affinities for dopamine
and serotonin receptors is useful for the treatment of
schizophrenia and other psychotic disorders and might allow for a
more complete treatment of all disease symptoms, e.g., positive
symptoms, negative symptoms and cognitive deficits.
The inventive compounds also show varying activities as either
partial agonists or antagonists at dopamine D.sub.2-, D.sub.3-, and
D.sub.4- receptors. Some inventive compounds show agonist-like
effects at dopamine receptors, however they potently antagonize
apomorphine-induced climbing behavior in mice (ED.sub.50
values<1 mg/kg p.o). The inventive compounds further show
varying activity as 5-HT.sub.1A receptor agonists and induce
aspects of the serotinin behavioral syndrome to differing
intensities.
The inventive compounds are active in therapeutic models sensitive
to clinically relevant antipsychotics (e.g., the conditioned
avoidance response; Van der Heyden & Bradford, Behav. Brain
Res., 1988, 31:61-67, the disclosure of which is incorporated
herein by reference), antidepressants (e.g., differential
reinforcement of low rate responses; van Hest et al.,
Psychopharmacology, 1992, 107:474-479, the disclosure of which is
incorporated herein by reference), and anxiolytics (e.g.,
suppression of stress-induced vocalization; van der Poel et al.,
Psychopharmacology, 1989, 97:147-148, the disclosure of which is
incorporated herein by reference).
In contrast to clinically relevant dopamine D.sub.2 receptor
antagonists, the described compounds have a low propensity to
induce catalepsy in rodents and as such are likely to induce less
extrapyramidal side effects than existing antipsychotic agents.
The .sup.5-HT.sub.1A receptor agonism inherent in the inventive
compounds may be responsible for the reduced tendency to induce
extrapyramidal effects and the therapeutic effects observed in
behavioral models sensitive to either antidepressants or
anxiolytics.
The inventive compounds are additionally expected to be of value
for the treatment of affective disorders or diseases of the central
nervous system caused by disturbances in either the dopaminergic or
serotinergic systems, for example: Parkinson's disease, aggression,
anxiety disorders, autism, vertigo, depression, disturbances of
cognition or memory, and in particular schizophrenia and other
psychotic disorders.
Suitable acids with which the inventive compounds can form
pharmaceutically acceptable acid addition salts are, for example,
hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid,
and organic acids such as citric acid, fumaric acid, maleic acid,
tartaric acid, acetic acid, benzoic acid, p-toluene sulphonic acid,
methanesulphonic acid and naphtalene-sulphonic acid.
The compounds of the invention can be brought into forms for
administration by means of well known processes using auxiliary
substances such as liquid and solid carrier materials.
The compounds of the invention can be obtained according to methods
(A and B) which are described below. The piperazines used in these
methods are indicated as I-H to III-H, wherein I to III represent
the following groups: ##STR00005##
The synthesis of these piperazines I-H to II-H is described in EP
0189612, the disclosure of which is incorporated herein by
reference.
The H-atom of the N--H moiety of compounds I-H to III-H can be
replaced by group Q in two different chemical ways (A and B),
eventually leading to the compounds of the invention. In FIG. 2,
the meanings of Q1 to Q9 are shown. ##STR00006## Synthesis route
A
The compounds listed in table A (vide infra) were prepared via the
synthesis depicted in scheme A1 (vide infra): a piperazine was
reacted with a compound Q--X (X.dbd.Cl, Br) in e.g., acetonitrile
with Et(i-Pr).sub.2N acting as a base; in some cases Kl (or Nal) be
used instead of Et(i-Pr).sub.2N. ##STR00007## Synthesis route B
The compounds listed in table B (vide infra) were prepared via the
synthesis depicted in scheme Bi (vide infra): a piperazine was
reacted with 3-bromo-5-chloromethylpyridine to yield the
intermediate b1 (scheme B2), which was coupled with a boronic acid
derivative by means of a so-called Suzuki cross-coupling reaction.
##STR00008##
A preferred method for preparing a compound of the formula (a) as
defined above, comprises either reacting a compound of formula
##STR00009## with a compound of the formula R.sub.5--CH.sub.2--X,
wherein X is a leaving group and the remaining substituents
R.sub.1, R.sub.2, R.sub.3, R.sub.4, Z, A, p, n and R.sub.5 are as
defined above for formula (a), or reacting a compound of formula
##STR00010## wherein .[.R.sub.5'.]. .Iadd.R'.sub.5 .Iaddend.has the
same meaning as R.sub.5 given above in formula (a), with the
proviso that the bromine atom is at the meta-position with respect
to the methylene bridge, with a compound of the formula
B(OH).sub.2--Y, wherein .[.B and Y have.]. .Iadd.each substituent
has .Iaddend.the same meanings as given in formula (a) above.
The preparation of the compounds of formula (a) and of a number of
intermediate compounds will now be described in detail in the
following nonlimiting
EXAMPLES
Example 1
Procedure A1 (scheme A1):
To a suspension of 1-(2,3-dihydro-1,4-benzodioxin-5-yl) piperazine
monohydrochloride III-H.HCl (1.1 g, 4.25 mmol) in CH.sub.3CN (40
ml) was added Q4-Cl (1.0 g, 3.87 mmol) and diisopropylethylamine
(2.45 g, 19 mmol). The mixture was stirred at reflux for 3 hrs.
After cooling and evaporation of the solvent in vacuo, the residue
was taken up in CH.sub.2Cl.sub.2, washed with 5% NaHCO.sub.3
solution, saturated NaCl, dried (Na.sub.2SO.sub.4), filtered, and
evaporated in vacuo. The resulting dark oil was purified by flash
chromatography on silica gel (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH,
97.25 /2.5/0.25) to give A8 (0.9 g, 58%) as an oil. The product was
converted to its monohydrochloride salt; the residue was dissolved
in Et.sub.2O and treated with 1 eq. of ethanolic HCl. The product
precipitated as a white solid. The solid A8.HCl was collected by
filtration and dried: mp 233-5.degree. C., dec; .sup.1H NMR (400
MHz, DMSO/CDCl.sub.3, 4/1) .delta. (ppm) 3.1-3.6 (cluster, 8H),
4.24 (m, 4H), 4.58 (s, 2H), 6.49 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8
Hz), 6.74 (t, 1H, J=8 Hz), 7.34 (m, 2H), 7.91 (m, 2H), 8.77 (m,
1H), 8.9 (m, 1H), 9.10 (m, 1H), 11.8 (br s, 1 H, NH.sup.+).
Example 2
Procedure A1 (scheme A1):
A suspension of 2-(p-fluorophenyl)-4-bromomethylpyridine Q5-Br
(0.71 g, 2.67 mmol), and 1-(2-benzoxazolinone-4-yl) piperazine
I-H.HCl (0.58 g, 2.27 mmol) in DMF (20 ml) together with 2.1
equivalents of Et.sub.3N was stirred at room temperature for 2 h.
The resulting clear solution was concentrated to give a red oil
which was purified by flash column chromatography (SiO.sub.2,
eluting with CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH, 92/7.5/0.5) to give
A9 (0.28 g, 26%) as a yellow solid: mp 213-4.degree. C.; .sup.1H
NMR (400 MHz, DMSO/CDCl.sub.3, 4/1) .delta. (ppm) 2.62 (m, 4H),
3.24 (m, 4H), 3.64 (s, 2H), 6.59 (d, 1 H, J=8 Hz), 6.63 (d, 1H, J=8
Hz), 7.01 (t, 1H, J=8 Hz), 7.27 (m, 2H), 7.32 (m, 1H), 7.85 (m,
1H), 8.13 (m, 2H), 8.6 (m, 1H), 11.5 (s, 1H).
According to the syntheses given above, the other compounds A1-A12
were prepared in a similar way.
TABLE-US-00001 TABLE A melting point compound piperazine Q X salt
.degree. C. A1 II 1 Cl fb 105-6 A2 III 1 Cl fb 125-6 A3 II 2 Cl fb
132-3 A4 I 2 Cl fb 233-5 A5 III 3 Cl HCl 208 A6 I 4 Cl fb 214-5 A7
I 3 Cl fb 172-3 A8 III 4 Cl HCl 233-5 d A9 I 5 Br fb 213-4 A10 III
5 Br 2HCl 162 d A11 III 6 Cl 2HCl 223 d A12 I 6 Cl 2HCl 270-5 d fb
= free base, d = decomposition
Example 3
Procedure B1 (scheme B1)
A solution of b1 (1.07 g, 2.75 mmol) and Pd(PPh.sub.3).sub.4 (0.1
g, 0.08 mmol) in DME (5 ml) was stirred at room temperature for 10
minutes under a N.sub.2 atmosphere. Then 2-thiopheneboronic acid
(0.39 g, 3.0 mmol) and an aqueous solution of Na.sub.2CO.sub.3
(2.75 ml of a 2M solution) were consecutively added and the mixture
was allowed to react at reflux temperature for 1 hr. The solution
was cooled, diluted with H.sub.2O, and extracted with
CH.sub.2Cl.sub.2. The organic phase was evaporated to dryness in
vacuo to give the crude product B1, which was purified by flash
chromatography (CH.sub.2Cl.sub.2/MeOH, 98/2) and then converted to
its monohydrochloride salt to obtain B1.HCl (0.8 g, 74%) as a white
solid: mp 160.degree. C., dec., material turned sticky; .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. (ppm) 3.0-3.8 (br b , 8H, NH.sup.+,
H.sub.2O), 4.25 (m, 4H), 4.63 (br s, 2H), 6.54 (d, 1H, J=8 Hz),
6.64 (d, 1H, J=8 Hz), 6.75 (t, 1H, J=8 Hz), 7.14 (m, 1H), 7.43 (d,
1H, J=5 Hz), 7.74 (m, 1H).
According to the synthesis given above, the compounds B2-B3 were
prepared in a similar way.
TABLE-US-00002 TABLE B melting point compound piperazine Q salt
.degree. C. B1 III 7 HCl turns sticky at 160 B2 III 8 HCl 224-5 B3
III 9 HCl 238-9
Intermediates used in route A Intermediates Q--X: Q1-Cl:
This intermediate was synthesized as depicted in scheme A2:
##STR00011## Step i (scheme A2):
This step was carried out analogously to the procedure described in
J. Het. Chem., 12, (1975), 443, the disclosure of which is
incorporated herein by reference.
Step ii (scheme A2):
While stirring at room temperature, 4.8 g *28.5 mmol) of
2-phenyl-6-methyl-pyridine were dissolved in 50 ml of chloroform
after which a solution of 7.8 g of 75% mCPBA (33.9 mmol) in 75 ml
of chloroform were added dropwise. The reaction mixture showed only
a slight rise in temperature. After stirring for 1.5 hr, the
reaction mixture was shaken twice with 5% aqueous NaHCO.sub.3
solution and twice with an aqueous solution of
Na.sub.2S.sub.2O.sub.3 to remove the excess of mCPBA, after which
the reaction mixture proved to be negative on wet Kl/starch paper,
The organic layer was dried on MgSO.sub.4. Removal of the drying
agent by filtration and solvent by evaporation in vacuo yielded an
oil which crystallized upon scratching to give 5.5 g (105%) of
crude of 2-phenyl-6-methyl-pyridine-N-oxide, which was employed in
the next step without further purification.
Step iii (scheme A2):
A stirred solution of the crude 2-phenyl-6-methyl-pyridine-N-oxide
(5.2 g, 28.5 mmol) in Ac.sub.2O (25 ml) was heated at reflux
temperature for 2 hrs. The Ac.sub.2O was removed with the aid of an
oil pump (10 mm) at 40.degree. C. to yield a red oil which was
purified by flash chromatography over silica gel with
Et.sub.2O/petroleum benzine=1/1 as the eluent and yielded
2-phenyl-6-(acetoxymethyl)-pyridine (4.6 g, 70%) as an oil.
Step iv (scheme A2:)
4.5 g of 2-phenyl-6-(acetoxymethyl)-pyridine (20 mmol) was treated
with an aqueous HCl solution (15%, 10 ml) and the mixture was
heated at reflux temperature while stirring. After 30 minutes the
reaction mixture was concentrated with the aid of an oil pump (10
mm) at 40.degree. C., CH.sub.3CN was added, and the mixture was
evaporated to dryness in vacuo and yielded
2-phenyl-6-(hydroxymethyl)-pyridine (3.0 g, 80%) as an oil.
Step v (scheme A2):
To a stirred solution of 2-phenyl-6-(hydroxymethyl)-pyridine (1.0
g, 5.4 mmol) in CHCl.sub.3 (7 ml) at room temperature was added
dropwise SOCl.sub.2 (1.22 g, 10.2 mmol) and the mixture was heated
at 60.degree. C. for 20 minutes. After evaporation of the solvent
in vacuo, the residue was purified by trituration with Et.sub.2O.
The resulting precipitate was collected by filtrition and dried to
give 2-phenyl-6-(chloromethyl)-pyridinium chloride Q1-Cl (1.2 g,
92%) as a white solid.
Q2-Cl:
Q2-Cl was prepared analogously to the synthesis of Q1-Cl.
Q3-Cl
Q3-Cl was prepared analogously to the synthesis of Q4-Cl (vide
infra).
Q4-Cl:
This intermediate was synthesized as depicted in scheme A3:
##STR00012## Step i (scheme A3);
A stirred mixture of 3-bromo-5-pyridine-carboxylic acid (10.1 g, 50
mmol) and H.sub.2SO.sub.4 (1.5 ml) in EtOH (150 ml) was refluxed
for 6 hrs. After cooling, the solvent was removed by evaporation in
vacuo. The residue as diluted with H.sub.2O (100 ml), basified with
5% NaHCO.sub.3 (aq) solution and extracted with ether (4.times.100
ml). The combined organic extracts were washed with saturated NaCl
and dried over Na.sub.2SO.sub.4. Filtration and concentration in
vacuo of the filtrate yielded 3-bromo-5-pyridine-carboxylic acid
ethyl ester as an oil that solidified on standing: (9.8 g,
85%).
Step ii (scheme A3):
To a stirred solution of 3-bromo-5-pyridine-carboxylic acid ethyl
ester (9.5 g, 41.3 mmol) in EtOH (96%, 220 ml), NaBH.sub.4 (14.4 g,
380 mmol) was added slowly at 25.degree. C.
The reaction was mildly endothermic. The mixture was stirred under
an nitrogen atmosphere at room temperature for 6 hrs. The resulting
milky mixture was diluted with H.sub.2O (150 ml), the EtOH was
evaporated in vacuo and the residue was extracted with
CH.sub.2Cl.sub.2 (3.times.). The combined organic layers were dried
on Na.sub.2SO.sub.4. After filtration the filtrate was concentrated
in vacuo to give 9 g of a crude oil which was purified by flash
chromatography on silica gel (eluent: Et.sub.2O) to give
3-bromo-5-hydroxymethyl-pyridine (3.5 g, 45%).
Step iii (scheme A3):
To a solution of 3-bromo-5-hydroxymethyl-pyridine (3.3 g, 17.5
mmol) in toluene (35 ml) was added Pd(PPh.sub.3).sub.4 (0.6 g, 0.52
mmol), an aqueous solution of Na.sub.2CO.sub.3 (17.5 ml of a 2M
solution) and p-fluorphenylboronic acid (2.65 g, 19 mmol, dissolved
in 8.5 ml EtOH). The mixture was heated at 80-90.degree. C. for 1
hr and vigorously stirred. After the reaction was completed, the
biphasic reaction mixture was cooled, the organic layer was
collected and washed with saturated NaCl. The aqueous layer was
washed with EtOAc and the combined organic layers were dried on
Na.sub.2SO.sub.4. The drying agent was removed by filtration and
the solvent was evaporated in vacuo to give a dark oil which was
purified by flash chromatography on silica gel (eluent:
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH, 95/4.5/0.5) and yielded
3-(p-fluorophenyl)-5-hydroxymethyl-pyridine (3.0 g, 84%). The
product was converted into its monohydrochloride salt; the residue
was dissolved in Et.sub.2O and treated with 16.5 eq of ethanolic
HCl. The product 3-(p-fluorophenyl)-5-hydroxymethyl-pyridinium
hydrochloride Q4-OH.HCl precipitated as a white solid which was
collected by filtration and subsequent drying.
Step iv (scheme A3):
3-(p-fluorophenyl)-5-hydroxymethyl-pyridinium hydrochloride
Q4-OH.HCl (3.5 g, 14.7 mmol) was added to an excess of SOCl.sub.2
(20 ml) and the mixture was heated at 60.degree. C. to start the
reaction (generation of HCl). After complete conversion of the
starting material (45 min), the reaction mixture was cooled and
excess SOCl.sub.2 was removed in vacuo to leave a dry residue.
Crystallization from Et.sub.2O provided
3-(p-fluorophenyl)-5-chloromethyl-pyridinium hydrochloride
Q4-Cl.HCl (2.5 g, 66%).
Q5-Br:
The synthesis of Q5-Br is depicted in scheme A4: ##STR00013## Step
i (scheme A4):
A solution of 2-bromo-4-methyl-pyridine (10 g, 58 mmol) and
Pd(PPh.sub.3).sub.4 (1.5 g, 1.3 mmol) in toluene (110 ml) was
stirred at room temperature under a nitrogen atmosphere.
Subsequently an aqueous solution of Na.sub.2 CO.sub.3 (58 ml of a
2M solution) and p-fluorophenylboronic acid (8.93 g, 63.8 mmol)
were added and the resulting mixture was allowed to react at
90-100.degree. C. for 4 hrs. The mixture was cooled, the aqueous
layer was separated and extracted with EtOAc (2.times.). The
combined EtOAc and toluene fractions were dried on MgSO.sub.4.
Filtration of the drying agent and removal of the solvent in vacuo
yielded a pink oil (28 g). Distillation gave pure
2-(p-fluorophenyl)-4-methyl-pyridine (6.10 g, 56%); bp
110-116.degree. C. (6-7 mbar) as a colorless oil.
Step ii (scheme A4):
A mixture of 2-(p-fluorophenyl)-4-methyl-pyridine (0.5 g, 2.67
mmol), N-bromosuccinimide (0.48 g, 2.69 mmol), and a catalytic
amount of benzoylperoxide in CCl.sub.4 (50 ml) was stirred at
reflux temperature and irradiated by means of an ordinary 250-W UV
lamp for 4 hrs. Afterwards, the reaction mixture was cooled and
subsequently triturated with Et.sub.2O/petroleum benzine. The
precipitate was removed by filtration, and the filtrate was
concentrated in vacuo to give
2-(p-fluorophenyl)-4-bromomethyl-pyridine (0.63 g, 88%, unstable)
as a dark yellow oil.
Q6-Cl:
Scheme A5
The intermediate Q6-Cl was synthesized according to the scheme
given below (scheme A5): ##STR00014## Step i (scheme A5):
4-(p-fluorophenyl)pyridine (13 g, 75 mmol) was dissolved in glacial
acetic acid (100%; 50 ml) at 70-80.degree. C. Subsequently
H.sub.2O.sub.2 (35%; 8 ml) was added while stirring. After 4 hrs an
additional portion of H.sub.2O.sub.2 (35%; 5 ml) was added. The
reaction mixture was allowed to cool after which it was evaporated
to dryness in vacuo leaving a yellow solid which was diluted with
H.sub.2O (150 ml), basified with an aqueous solution of NaOH (150
ml of a 2M solution), and extracted with CH.sub.2Cl.sub.2 (100 ml).
The organic layer was separated and dried on Na.sub.2SO.sub.4.
After removal of the drying agent by filtration and evaporation of
the solvent in vacuo, 13 g (91%) of the desired product
4-(p-fluorophenyl)pyridine-N-oxide were isolated.
Step ii (scheme A5):
To 13 g of .sup.4-(p-fluorophenyl)pyridine-N-oxide (68.7 mmol) was
added Me.sub.2SO.sub.4 (8.6 g, 68 mmol) at 80.degree. C. under an
N.sub.2 atmosphere after which the mixture was stirred a
100-110.degree. C. for 2 hrs. The mixture was cooled and 70%
dioxan/water was poured into the reaction mixture. The obtained
dark brown solution was added dropwise to a stirred solution of
NaCN (10 g, 0.20 mol) in H.sub.2O (85 ml) at 15-20.degree. C. The
mixture was stirred at room temperature for 3 hrs. The reaction
mixture was filtered, the residue was washed with CH.sub.2Cl.sub.2,
which was added to the biphasic filtrate. The organic layer of the
filtrate was dried on Na.sub.2SO.sub.4. Removal of the drying agent
by filtration and evaporation of the solvent in vacuo, yielded the
desired compound as a light brown solid which was purified by
crystallization from EtOH (300 ml) to provide
2-cyano-4-(p-fluorophenyl)pyridine (8.6 g, 68%): mp 194-195.degree.
C.
Step iii (scheme A5):
A stirred solution of 2-cyano-4-(p-fluorophenyl)pyridine (8.6 g,
46.7 mmol) in saturated HCl-MeOH (200 ml) was allowed to react at
reflux temperature for 6 hrs. The resulting pink solution was
concentrated in vacuo to a volume of approximately 50 ml, after
which it was diluted with 250 ml of water. The latter solution was
basified with an aqueous solution of NH.sub.4OH (25%), and
extracted with CH.sub.2Cl.sub.2. The organic layer was dried on
Na.sub.2SO.sub.4. Removal of the drying agent by filtration and
evaporation of the solvent in vacuo, yielded the desired product
4-(p-fluorophenyl)pyridine-2-carboxylic acid methyl ester as a pink
solid (5.0 g, 46%): mp 97-8.degree. C.
Step iv (scheme A5):
NaBH.sub.4 (8.2 g, 0.2 mol) was added portionwise to a stirred
solution of 4-(p-fluorophenyl)pyridine-2-carboxylic acid methyl
ester (5.0 g, 21.6 mmol) in EtOH (96%, 100 ml) and the mixture was
stirred at room temperature for 6 hrs. The solvent was removed at
reduced pressure after which water was added. Subsequently
extraction with EtOAc took place. The organic layer was dried on
MgSO.sub.4. Removal of the drying agent and evaporation of the
solvent in vacuo yielded an oil which was dissolved in MeOH and
treated with 1.1 eq. HCl/EtOH to afford
2-hydroxymethyl-4-(p-fluorophenyl)pyridinium hydrochloride
Q6-OH.HCl as a yellow foam (4.47 g, 87%).
Step v (scheme A5):
This reaction was performed analogously to step iv in scheme
A3.
Intermediates used in route B.
Intermediate b1:
This intermediate was synthesized as depicted in scheme B2:
##STR00015## Step i (scheme B2):
To a suspension of 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine
monohydrochloride (5.4g, 21 mmol) in CH.sub.3CN (125 mmol) was
added 3-bromo-5-chloromethyl-pyridine (4.6 g, 19 mmol) and
diisopropylethylamine (12.3 g, 95 mmol). The mixture was stirred at
reflux temperature for 30 min. After cooling of the mixture and
evaporation of the solvent in vacuo, the residue was taken up in
(CH.sub.2Cl.sub.2, washed with 5% NaHCO.sub.3 (aq) solution,
saturated NaCl (aq) solution after which the organic fraction was
dried on Na.sub.2SO.sub.4. After removal of the drying agent by
filtration and solvent by evaporation in vacuo, the residue was
purified by flash chromatography on silica gel
(CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH, 97.25/2.5/0.25) to give b1 (7.2
g, 97%) as an oil.
* * * * *