U.S. patent application number 14/810063 was filed with the patent office on 2016-06-30 for processes for preparing 3-benzazepines.
The applicant listed for this patent is Arena Pharmaceuticals, Inc.. Invention is credited to Shelley Aytes, Scott A. Estrada, Charles A. Gilson, III, Max Rey, Dipanjan Sengupta, Brian Smith, Ulrich Weigl, Beverly L. Wolgast.
Application Number | 20160185729 14/810063 |
Document ID | / |
Family ID | 34221229 |
Filed Date | 2016-06-30 |
United States Patent
Application |
20160185729 |
Kind Code |
A1 |
Wolgast; Beverly L. ; et
al. |
June 30, 2016 |
PROCESSES FOR PREPARING 3-BENZAZEPINES
Abstract
The present invention provides processes and intermediates for
the preparation of 3-benzazepines and salts thereof which can be
useful as serotonin (5-HT) receptor agonists for the treatment of,
for example, central nervous system disorders such as obesity.
Inventors: |
Wolgast; Beverly L.; (San
Diego, CA) ; Gilson, III; Charles A.; (San Diego,
CA) ; Aytes; Shelley; (San Diego, CA) ;
Estrada; Scott A.; (San Diego, CA) ; Sengupta;
Dipanjan; (San Diego, CA) ; Smith; Brian; (San
Diego, CA) ; Rey; Max; (Wallisellen, CH) ;
Weigl; Ulrich; (Hilzingen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Arena Pharmaceuticals, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
34221229 |
Appl. No.: |
14/810063 |
Filed: |
July 27, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13619788 |
Sep 14, 2012 |
9102627 |
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14810063 |
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10560953 |
Apr 26, 2007 |
8367657 |
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PCT/US2004/019279 |
Jun 16, 2004 |
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13619788 |
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60479280 |
Jun 17, 2003 |
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60512967 |
Oct 21, 2003 |
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Current U.S.
Class: |
540/594 ;
564/374 |
Current CPC
Class: |
A61P 25/00 20180101;
C07C 59/255 20130101; C07C 213/02 20130101; A61P 43/00 20180101;
C07C 209/74 20130101; C07C 209/50 20130101; C07C 17/16 20130101;
C07C 25/06 20130101; C07C 231/02 20130101; C07C 209/50 20130101;
C07C 211/27 20130101; C07C 213/02 20130101; A61P 3/00 20180101;
C07C 215/08 20130101; C07C 231/02 20130101; C07C 211/29 20130101;
A61P 3/04 20180101; C07D 223/16 20130101; C07C 211/29 20130101;
C07C 215/08 20130101; C07C 233/13 20130101 |
International
Class: |
C07D 223/16 20060101
C07D223/16; C07C 211/29 20060101 C07C211/29; C07C 59/255 20060101
C07C059/255 |
Claims
1-651. (canceled)
652. A method of resolving a mixture of compounds of Formula Va and
Vb: ##STR00059## wherein: R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
R.sup.2 is C.sub.1-C.sub.8 alkyl, --CH.sub.2--O--(C.sub.1-C.sub.8
alkyl), C(O)O--(C.sub.1-C.sub.8 alkyl), --C(O)NH--(C.sub.1-C.sub.8
alkyl), OH, C.sub.1-C.sub.4 haloalkyl, or CH.sub.2OH; R.sup.3,
R.sup.4, R.sup.5, and R.sup.6 are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
hydroxy, OR.sup.9, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl,
C(O)NH-alkyl, hydroxyalkyl, NR.sup.10R.sup.11, CN, NO.sub.2,
heterocycloalkyl, aryl, or heteroaryl, wherein said aryl and
heteroaryl can be substituted with one or more substituents
selected from C.sub.1-C.sub.8 alkyl, halo, C.sub.1-C.sub.8
haloalkyl, and alkoxy; or R.sup.4 and R.sup.5 together with the
atoms to which they are attached form a 5- or 6-member heterocyclic
ring having one O atom; R.sup.8a and R.sup.8b are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, alkoxyalkyl, hydroxy, C(O)-alkyl,
C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, or R.sup.8a and
R.sup.8b together with the carbon atom to which they are attached
form a C.sub.3-C.sub.7 cycloalkyl group; R.sup.9 is H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl; and R.sup.10
and R.sup.11 are each, independently, H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl, or R.sup.10 and R.sup.11 together with
the N atom to which they are attached form a heterocyclic ring;
comprising: contacting said mixture of compounds with a chiral
resolving acid to form chiral resolving acid salts of said
compounds, wherein said chiral resolving acid comprises
substantially one stereoisomer; and precipitating said chiral
resolving acid salts of said compounds, wherein the resulting
precipitate is enriched in the chiral resolving acid salt of one of
said compounds of Formula Va or Vb.
653. The method of claim 652, wherein said chiral resolving acid is
tartaric acid.
654. The method of claim 652, wherein said chiral resolving acid is
L-(+)-tartaric acid.
655. The method of claim 652, wherein said precipitate is enriched
in the chiral resolving acid salt of said compound of Formula
Vb.
656. The method of claim 652, wherein R.sup.1 is H, R.sup.2 is Me,
R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is H, R.sup.6 is H, R.sup.8a
is H, and R.sup.8b is H.
657. A chiral resolving acid salt of a compound of Formula Va or
Vb: ##STR00060## wherein: R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
R.sup.2 is C.sub.1-C.sub.8 alkyl, --CH.sub.2--O--(C.sub.1-C.sub.8
alkyl), C(O)O--(C.sub.1-C.sub.8 alkyl), --C(O)NH--(C.sub.1-C.sub.8
alkyl), OH, C.sub.1-C.sub.4 haloalkyl, or CH.sub.2OH; R.sup.3,
R.sup.4, R.sup.5, and R.sup.6 are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C haloalkyl, hydroxy,
OR.sup.9, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,
hydroxyalkyl, NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl,
aryl, or heteroaryl, wherein said aryl and heteroaryl can be
substituted with one or more substituents selected from
C.sub.1-C.sub.8 alkyl, halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy;
or R.sup.4 and R.sup.5 together with the atoms to which they are
attached form a 5- or 6-member heterocyclic ring having one O atom;
R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group; R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl; and R.sup.10 and R.sup.11 are each,
independently, H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl, or R.sup.10 and R.sup.11 together with
the N atom to which they are attached form a heterocyclic ring.
658. The salt of claim 657, wherein said salt is a tartaric acid
salt.
659. The salt of claim 657, wherein said tartaric acid is
L-(+)-tartaric acid.
660. The salt of claim 657, having Formula Vb.
661. The salt of claim 660, wherein R.sup.1 is H, R.sup.2 is Me,
R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is H, R.sup.6 is H, R.sup.8a
is H, and R.sup.8b is H.
662. A composition comprising at least one chiral resolving acid
salt of claim 657.
663. The composition of claim 662, wherein said composition
comprises said tartaric acid salt form of a compound of Formula Va
and said tartaric acid salt form of a compound of Formula Vb,
wherein said composition is enriched in one of either of said
tartaric acid salt form of a compound of Formula Va or said
tartaric acid salt form of a compound of Formula Vb.
664. A compound of Formula IX or X: ##STR00061## or salt form
thereof, wherein: R.sup.1 is H or C.sub.1-C.sub.8 alkyl; R.sup.2 is
C.sub.1-C.sub.8 alkyl, --CH.sub.2--O--(C.sub.1-C.sub.8 alkyl),
C(O)O--(C.sub.1-C.sub.8 alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl),
or C.sub.1-C.sub.4 haloalkyl; R.sup.3, R.sup.4, R.sup.5, and
R.sup.6 are each, independently, H, halo, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.1-C.sub.8 haloalkyl, hydroxy, OR.sup.9,
alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom; R.sup.8a and R.sup.8b
are each, independently, H, halo, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.1-C.sub.8 haloalkyl, alkoxyalkyl, hydroxy,
C(O)-alkyl, C(O)O-alkyl, C(O)NH-- alkyl, or hydroxyalkyl, or
R.sup.8a and R.sup.8b together with the carbon atom to which they
are attached form a C.sub.3-C.sub.7 cycloalkyl group; R.sup.9 is H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl; R.sup.10 and
R.sup.11 are each, independently, H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl, or R.sup.10 and R.sup.11 together with
the N atom to which they are attached form a heterocyclic ring;
X.sup.2 is halo or SO.sub.2R''; and R'' is C.sub.1-C.sub.8 alkyl,
aryl, or heteroaryl each optionally substituted by one or more
halo, cyano, nitro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4
haloalkoxy.
665. The compound of claim 665, wherein X.sup.2 is Cl.
666. The compound of claim 665, wherein R.sup.1 is H, R.sup.2 is
Me, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is H, R.sup.6 is H,
R.sup.8a is H, and R.sup.8b is H.
667. The compound of claim 665, wherein X.sup.2 is Cl, R.sup.1 is
H, R.sup.2 is Me, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is H,
R.sup.6 is H, R.sup.8a is H, and R.sup.8b is H.
Description
FIELD OF THE INVENTION
[0001] The present invention generally relates to processes and
intermediates for the preparation of 3-benzazepines and salts
thereof which can be useful as serotonin (5-HT) receptor agonists
for the treatment of, for example, central nervous system disorders
such as obesity.
BACKGROUND OF THE INVENTION
[0002] Serotonin (5-HT) neurotransmission plays an important role
in numerous physiological processes both in health and in
psychiatric disorders. For example, 5-HT has been implicated in the
regulation of feeding behavior. 5-HT is believed to work by
inducing a feeling of fullness or satiety so eating stops earlier
and fewer calories are consumed. It has been shown that a
stimulatory action of 5-HT on the 5HT.sub.2C receptor plays an
important role in the control of eating and in the anti-obesity
effect of d-fenfluramine. As the 5-HT.sub.2C receptor is expressed
in high density in the brain (notably in the limbic structures,
extrapyramidal pathways, thalamus and hypothalamus i.e. PVN and
DMH, and predominantly in the choroid plexus) and is expressed in
low density or is absent in peripheral tissues, a selective
5-HT.sub.2C receptor agonist can be a more effective and safe
anti-obesity agent. Also, 5-HT.sub.2C knockout mice are overweight
with cognitive impairment and susceptibility to seizure. Thus, the
5HT.sub.2C receptor is recognized as a well-accepted receptor
target for the treatment of obesity, psychiatric, and other
disorders.
[0003] 3-Benzazepines have been found to be agonists of the
5HT.sub.2C receptor and show effectiveness at reducing obesity in
animal models (see, e.g., U.S. Ser. No. 60/479,280 and U.S. Ser.
No. 10/410,991, each of which is incorporated herein by reference
in its entirety). Numerous synthetic routes to 3-benzazepines have
been reported and typically involve a phenyl-containing starting
material upon which is built an amine- or amide-containing chain
that is capable of cyclizing to form the fused 7-member ring of the
benzazepine core. Syntheses of 3-benzazepines and intermediates
thereof are reported in U.S. Ser. No. 60/479,280 and U.S. Ser. No.
10/410,991 as well as Nair et al., Indian J. Chem., 1967, 5, 169;
Onto et al., Tetrahedron, 1980, 36, 1017; Wu et al., Organic
Process Research and Development, 1997, 1, 359; Draper et al.,
Organic Process Research and Development, 1998, 2, 175; Draper et
al., Organic Process Research and Development, 1998, 2, 186;
Kuenburg et al., Organic Process Research and Development, 1999, 3,
425; Baindur et al., J. Med. Chem., 1992, 35(1), 67; Neumeyer et
al., J. Med. Chem., 1990, 33, 521; Clark et al., J. Med. Chem.,
1990, 33, 633; Pfeiffer et al., J. Med. Chem., 1982, 25, 352;
Weinstock et al., J. Med. Chem., 1980, 23(9), 973; Weinstock et
al., J. Med. Chem., 1980, 23(9), 975; Chumpradit et al., J. Med.
Chem., 1989, 32, 1431; Heys et al., J. Org. Chem., 1989, 54, 4702;
Bremner et al., Progress in Heterocyclic Chemistry, 2001, 13, 340;
Hasan et al., Indian J. Chem., 1971, 9(9), 1022; Nagle et al.,
Tetrahedron Letters, 2000, 41, 3011; Robert, et al., J. Org. Chem.,
1987, 52, 5594); and Deady et al., J. Chem Soc., Perkin Trans. I,
1973, 782.
[0004] Other routes to 3-benzazepines and related compounds are
reported in Ladd et al., J. Med. Chem., 1986, 29, 1904; EP 204349;
EP 285 919; CH 500194; Tetrahedron Letters, 1986, 27, 2023; Ger.
Offen., 3418270, 21 Nov. 1985; J. Org. Chem., 1985, 50, 743; U.S.
Pat. Nos. 4,957,914 and 5,015,639; Synthetic Commun., 1988, 18,
671; Tetrahedron, 1985, 41, 2557; Hokkaido Daigaku Kogakubu Kenkyu
Hokoku, 1979, 96, 41-4; Chemical & Pharmaceutical Bulletin,
1975, 23, 2584; J. Am. Chem. Soc., 1970, 92, 5686; J. Am. Chem.
Soc., 1968, 90, 6522; J. Am. Chem. Soc., 1968, 90, 776; J. Am.
Chem. Soc., 1967, 89, 1039; and Chang et al., Bioorg. Med. Chem.
Letters, 1992, 2, 399
[0005] In view of the growing demand for compounds for the
treatment of disorders related to the 5-HT.sub.2C receptor, new and
more efficient routes to 3-benzazepines are needed. The processes
and compounds described herein help meet these and other needs.
SUMMARY OF THE INVENTION
[0006] The processes and intermediates of the present invention are
useful in the preparation of therapeutic agents for the treatment
or prophylaxis of 5-HT mediated disorders such as obesity and other
central nervous system diseases.
[0007] The present invention provides, inter alia, a process for
preparing a compound of Formula I:
##STR00001##
or salt form thereof, wherein:
[0008] R.sup.1 is H;
[0009] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0010] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, mercapto, OR.sup.9, SR.sup.9,
alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0011] R.sup.7a and R.sup.7b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.7a and R.sup.7b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0012] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0013] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl;
[0014] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising reacting a compound of Formula II:
##STR00002##
with a reducing agent optionally in the presence of a Lewis acid
for a time and under conditions suitable for forming said compound
of Formula I or salt form thereof.
[0015] The present invention further provides a process for
preparing a compound of Formula II or salt form thereof,
wherein:
[0016] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0017] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0018] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, mercapto, OR.sup.9, SR.sup.9,
alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0019] R.sup.7a and R.sup.7b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.7a and R.sup.7b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0020] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0021] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl;
[0022] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising reacting a compound of Formula III:
##STR00003##
or salt form thereof, wherein:
[0023] L is halo, hydroxy, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
thioalkoxy, C.sub.1-C.sub.8 acyloxy, --OSO.sub.2R, or
--OSi(R').sub.3;
[0024] R is C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each
optionally substituted by one or more halo, cyano, nitro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkoxy;
[0025] R' is C.sub.1-C.sub.8 alkyl;
with a cyclizing reagent for a time and under conditions suitable
for forming said compound of Formula II or salt form thereof.
[0026] The present invention further provides a process for
preparing a compound of Formula I or salt form thereof,
wherein:
[0027] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0028] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0029] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, mercapto, OR.sup.9, SR.sup.9,
alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0030] R.sup.7a and R.sup.7b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.7a and R.sup.7b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0031] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0032] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl; and
[0033] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising:
[0034] (a) reacting a compound of Formula III:
##STR00004##
or salt form thereof, wherein:
[0035] L is halo, hydroxy, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
thioalkoxy, C.sub.1-C.sub.8 acyloxy, --OSO.sub.2R, or
--OSi(R').sub.3;
[0036] R is C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each
optionally substituted by one or more halo, cyano, nitro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkoxy; and
[0037] R' is C.sub.1-C.sub.8 alkyl;
with a cyclizing reagent for a time and under conditions suitable
for forming a compound of Formula II or salt form thereof; and
[0038] (b) reacting said compound of Formula II or salt form
thereof with a reducing agent optionally in the presence of a Lewis
acid for a time and under conditions suitable for forming said
compound of Formula I or salt form thereof.
[0039] The present invention further provides a process for
preparing a compound of Formula I or salt form thereof,
wherein:
[0040] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0041] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0042] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, mercapto, OR.sup.9, SR.sup.9,
alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.16R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0043] R.sup.7a and R.sup.7b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.7a and R.sup.7b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0044] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.2-C.sub.5
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0045] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl; and
[0046] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising:
[0047] (a) reacting a compound of Formula IV:
##STR00005##
or salt form thereof, with a compound of Formula:
##STR00006##
wherein:
[0048] L is halo, hydroxy, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
thioalkoxy, C.sub.1-C.sub.8 acyloxy, --OSO.sub.2R, or
--OSi(R').sub.3;
[0049] R is C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each
optionally substituted by one or more halo, cyano, nitro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkoxy;
[0050] R' is C.sub.1-C.sub.8 alkyl; and
[0051] Q is a leaving group,
for a time and under conditions suitable for forming a compound of
Formula III or salt form thereof;
[0052] (b) reacting said compound of Formula III or salt form
thereof, with a cyclizing reagent for a time and under conditions
suitable for forming a compound of Formula II or salt form thereof;
and
[0053] (c) reacting said compound of Formula II with a reducing
agent optionally in the presence of a Lewis acid for a time and
under conditions suitable for forming said compound of Formula I or
salt form thereof.
[0054] The present invention further provides a process for
preparing a compound of Formula I or salt form thereof,
wherein:
[0055] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0056] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0057] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, mercapto, OR.sup.9, SR.sup.9,
alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl,
[0058] C(O)NH-alkyl, hydroxyalkyl, NR.sup.10R.sup.11, CN, NO.sub.2,
heterocycloalkyl, aryl, or heteroaryl, wherein said aryl and
heteroaryl can be substituted with one or more substituents
selected from C.sub.1-C.sub.8 alkyl, halo, C.sub.1-C.sub.8
haloalkyl, and alkoxy; or R.sup.4 and R.sup.5 together with the
atoms to which they are attached form a 5- or 6-member heterocyclic
ring having one O atom;
[0059] R.sup.7a and R.sup.7b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.7a and R.sup.7b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0060] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0061] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl; and
[0062] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising reacting a compound of Formula IIIa:
##STR00007##
wherein:
[0063] L is halo, hydroxy, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
thioalkoxy, C.sub.1-C.sub.8 acyloxy, --OSO.sub.2R, or
--OSi(R').sub.3;
[0064] R is C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each
optionally substituted by one or more halo, cyano, nitro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkoxy; and
[0065] R' is C.sub.1-C.sub.8 alkyl;
with a cyclizing reagent for a time and under conditions suitable
for forming said compound of Formula I.
[0066] The present invention further provides a process for
preparing a compound of Formula IIIa or salt form thereof,
wherein:
[0067] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0068] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0069] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, mercapto, OR.sup.9, SR.sup.9,
alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0070] R.sup.7a and R.sup.7b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.7a and R.sup.7b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0071] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl,
C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl;
[0072] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
[0073] L is halo, hydroxy, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
thioalkoxy, C.sub.1-C.sub.8 acyloxy, --OSO.sub.2R, or
--OSi(R').sub.3;
[0074] R is C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each
optionally substituted by one or more halo, cyano, nitro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkoxy; and
[0075] R' is C.sub.1-C.sub.8 alkyl;
comprising reacting a compound of Formula III:
##STR00008##
with a reducing agent optionally in the presence of a Lewis acid
for a time and under conditions suitable for forming said compound
of Formula IIIa.
[0076] The present invention further provides a process for
preparing a compound of Formula I or salt form thereof,
wherein:
[0077] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0078] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0079] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, mercapto, OR.sup.9, SR.sup.9,
alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0080] R.sup.7a and R.sup.7b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.7a and R.sup.7b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0081] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0082] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl;
[0083] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising
[0084] a) reacting a compound of Formula III
wherein:
[0085] L is halo, hydroxy, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
thioalkoxy, C.sub.1-C.sub.8 acyloxy, --OSO.sub.2R, or
--OSi(R').sub.3;
[0086] R is C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each
optionally substituted by one or more halo, cyano, nitro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkoxy; and
[0087] R' is C.sub.1-C.sub.8 alkyl;
with a reducing agent optionally in the presence of a Lewis acid
for a time and under conditions suitable for forming a compound of
Formula IIIa; and
[0088] b) reacting said compound of Formula IIIa with a cyclizing
reagent for a time and under conditions suitable for forming said
compound of Formula I.
[0089] The present invention further provides a process for
preparing a compound of Formula I or salt form thereof,
wherein:
[0090] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0091] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0092] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, mercapto, OR.sup.9, SR.sup.9,
alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0093] R.sup.7a and R.sup.7b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.7a and R.sup.7b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0094] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0095] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl;
[0096] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising:
[0097] (a) reacting a compound of Formula IV
or salt form thereof, with a compound of Formula:
##STR00009##
wherein:
[0098] L is halo, hydroxy, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
thioalkoxy, C.sub.1-C.sub.8 acyloxy, --OSO.sub.2R, or
--OSi(R').sub.3;
[0099] R is C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each
optionally substituted by one or more halo, cyano, nitro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkoxy;
[0100] R' is C.sub.1-C.sub.8 alkyl; and
[0101] Q is a leaving group, for a time and under conditions
suitable for forming a compound of Formula III or salt form
thereof;
[0102] (b) reacting said compound of Formula III with a reducing
agent optionally in the presence of a Lewis acid for a time and
under conditions suitable for forming a compound of Formula IIIa;
and
[0103] (c) reacting said compound of Formula IIIa with a cyclizing
reagent for a time and under conditions suitable for forming said
compound of Formula I.
[0104] The present invention further provides a method of resolving
a mixture of compounds of Formulas Ia and Ib:
##STR00010##
wherein:
[0105] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0106] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0107] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, mercapto, OR.sup.9, SR.sup.9,
alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0108] R.sup.7a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.7a and R.sup.7b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0109] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0110] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl;
[0111] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising:
[0112] contacting said mixture of compounds with a chiral resolving
acid to form chiral resolving acid salts of said compounds, wherein
said chiral resolving acid comprises substantially one
stereoisomer; and
[0113] precipitating said chiral resolving acid salts of said
compounds, wherein the resulting precipitate is enriched in the
chiral resolving acid salt of one of said compounds of Formula Ia
or Ib.
[0114] The present invention further provides a compound of Formula
II or Ma or salt form thereof,
wherein:
[0115] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0116] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0117] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, mercapto, OR.sup.9, SR.sup.9,
alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0118] R.sup.7a and R.sup.7b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.7a and R.sup.7b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0119] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0120] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl;
[0121] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
[0122] L is halo, hydroxy, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
thioalkoxy, C.sub.1-C.sub.8 acyloxy, --OSO.sub.2R, or
--OSi(R').sub.3;
[0123] R is C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each
optionally substituted by one or more halo, cyano, nitro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkoxy; and
[0124] R' is C.sub.1-C.sub.8 alkyl.
[0125] The present invention further provides a chiral resolving
acid salt of a compound of Formula Ia or Ib
wherein:
[0126] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0127] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0128] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, mercapto, OR.sup.9, SR.sup.9,
alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0129] R.sup.7a and R.sup.7b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.7a and R.sup.7b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0130] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0131] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl; and
[0132] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring.
[0133] The present invention further provides a process for
preparing a compound of Formula V:
##STR00011##
or salt thereof, wherein:
[0134] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0135] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), or C.sub.1-C.sub.4
haloalkyl;
[0136] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, OR.sup.9, alkoxyalkyl,
C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.16R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0137] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0138] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl; and
[0139] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising reacting a compound of Formula IX:
##STR00012##
or salt thereof, wherein X.sup.2 is halo or SO.sub.2R'' and R'' is
C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each optionally
substituted by one or more halo, cyano, nitro, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, or
C.sub.1-C.sub.4 haloalkoxy, with a cyclizing reagent for a time and
under conditions suitable for forming said compound of Formula
V.
[0140] The present invention further provides a process for
preparing a compound of Formula X:
##STR00013##
or salt thereof, wherein:
[0141] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0142] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), or C.sub.1-C.sub.4
haloalkyl;
[0143] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, OR.sup.9, alkoxyalkyl,
C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0144] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0145] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl; and
[0146] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising reacting a compound of Formula XI:
##STR00014##
wherein X.sup.1 is a leaving group, with a compound of Formula:
##STR00015##
for a time and under conditions suitable for forming said compound
of Formula X.
[0147] The present invention further provides a process for
preparing a compound of Formula V or salt thereof,
wherein:
[0148] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0149] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), or C.sub.1-C.sub.4
haloalkyl;
[0150] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, OR.sup.9, alkoxyalkyl,
C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.16R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0151] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0152] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl; and
[0153] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising:
[0154] a) reacting a compound of Formula X or salt thereof;
with a halogenating/sulfonating reagent for a time and under
conditions suitable for forming a compound of Formula IX or salt
thereof; wherein X.sup.2 is halo or SO.sub.2R'' and R'' is
C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each optionally
substituted by one or more halo, cyano, nitro, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, or
C.sub.1-C.sub.4 haloalkoxy; and
[0155] b) reacting said compound of Formula IX with a cyclizing
reagent for a time and under conditions suitable for forming said
compound of Formula V.
[0156] The present invention further provides a process for
preparing a compound of Formula V or salt thereof,
wherein:
[0157] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0158] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), or C.sub.1-C.sub.4
haloalkyl;
[0159] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, OR.sup.9, alkoxyalkyl,
C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0160] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0161] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl; and
[0162] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising:
[0163] a) reacting a compound of Formula XI:
##STR00016##
wherein X.sup.1 is a leaving group, with a compound of Formula:
##STR00017##
or salt thereof, for a time and under conditions suitable for
forming a compound of Formula X or salt thereof;
[0164] b) reacting said compound of Formula X with a
halogenating/sulfonating reagent for a time and under conditions
suitable for forming a compound of Formula IX or salt thereof;
wherein X.sup.2 is halo or SO.sub.2R'' and R'' is C.sub.1-C.sub.8
alkyl, aryl, or heteroaryl each optionally substituted by one or
more halo, cyano, nitro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4 haloalkoxy;
and
[0165] c) reacting said compound of Formula IX with a cyclizing
reagent for a time and under conditions suitable for forming said
compound of Formula V.
[0166] The present invention further provides a process for
preparing a compound of Formula V or salt thereof,
wherein:
[0167] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0168] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), or C.sub.1-C.sub.4
haloalkyl;
[0169] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, OR.sup.9, alkoxyalkyl,
C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, NO.sub.2, heterocycloalkyl, aryl, or heteroaryl,
wherein said aryl and heteroaryl can be substituted with one or
more substituents selected from C.sub.1-C.sub.8 alkyl, halo,
C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0170] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0171] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl; and
[0172] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising:
[0173] a) reacting a compound of Formula XII:
##STR00018##
with a halogenating/sulfonating reagent for a time and under
conditions suitable for forming a compound of Formula XI wherein
X.sup.1 is a leaving group;
[0174] b) reacting said compound of Formula XI with a compound of
Formula:
##STR00019##
or salt thereof, for a time and under conditions suitable for
forming a compound of Formula X or salt thereof;
[0175] c) reacting said compound of Formula X with a further
halogenating/sulfonating reagent for a time and under conditions
suitable for forming a compound of Formula IX or salt thereof;
[0176] wherein X.sup.2 is halo or SO.sub.2R'' and R'' is
C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each optionally
substituted by one or more halo, cyano, nitro, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, or
C.sub.1-C.sub.4 haloalkoxy; and
[0177] d) reacting said compound of Formula IX with a cyclizing
reagent for a time and under conditions suitable for forming said
compound of Formula V.
[0178] The present invention further provides a compound of Formula
IX or X or salt form thereof,
wherein:
[0179] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0180] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), or C.sub.1-C.sub.4
haloalkyl;
[0181] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, OR.sup.9, alkoxyalkyl,
C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0182] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0183] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl;
[0184] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring; and
[0185] X.sup.2 is halo or SO.sub.2R''; and
[0186] R'' is C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each
optionally substituted by one or more halo, cyano, nitro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkoxy.
[0187] The present invention further provides a method of resolving
a mixture of compounds of Formula Va and Vb:
##STR00020##
wherein:
[0188] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0189] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0190] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, OR.sup.9, alkoxyalkyl,
C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0191] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0192] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl; and
[0193] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
comprising:
[0194] contacting said mixture of compounds with a chiral resolving
acid to form chiral resolving acid salts of said compounds, wherein
said chiral resolving acid comprises substantially one
stereoisomer; and
[0195] precipitating said chiral resolving acid salts of said
compounds, wherein the resulting precipitate is enriched in the
chiral resolving acid salt of one of said compounds of Formula Va
or Vb.
[0196] The present invention further provides a chiral resolving
acid salt of a compound of Formula Va or Vb
wherein:
[0197] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0198] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0199] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, OR.sup.9, alkoxyalkyl,
C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0200] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0201] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl; and
[0202] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0203] The processes and intermediates of the present invention are
useful in the preparation of therapeutic agents for the treatment
or prophylaxis of 5-HT mediated disorders such as obesity and other
central nervous system diseases.
[0204] Example processes and intermediates of the present invention
are provided below in Scheme I, wherein constituent members for the
compounds depicted therein are defined hereinbelow. The symbol "*"
designates optionally chiral centers that can be substantially
retained or inverted over the course of the depicted reactions.
##STR00021##
[0205] In a first aspect of the invention are provided processes,
such as are exemplified by Scheme I, that involve compounds of
Formulas I, Ia, Ib, II, III, Ma, and IV, or salt forms thereof,
wherein:
[0206] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0207] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0208] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, mercapto, OR.sup.9, SR.sup.9,
alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0209] R.sup.7a and R.sup.7b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.7a and R.sup.7b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0210] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0211] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl;
[0212] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.5
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
[0213] L is halo, hydroxy, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
thioalkoxy, C.sub.1-C.sub.8 acyloxy, --OSO.sub.2R, or
--OSi(R').sub.3;
[0214] R is C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each
optionally substituted by one or more halo, cyano, nitro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkoxy; and
[0215] R' is C.sub.1-C.sub.8 alkyl.
[0216] In some embodiments:
[0217] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, or CH.sub.2OH;
[0218] R.sup.3 and R.sup.6 are each H;
[0219] R.sup.4 and R.sup.5 are each, independently, H, halo,
C.sub.1-C.sub.8 haloalkyl, hydroxy, OR.sup.9, SR.sup.9,
alkoxyalkyl, NHR.sup.10, NR.sup.10R.sup.11, aryl, or heteroaryl,
wherein said aryl can be substituted with up to two substituents
selected from C.sub.1-C.sub.8 alkyl, halo, C.sub.1-C.sub.8
haloalkyl, and alkoxy, and said heteroaryl can be optionally
substituted with up to two substituents selected from halogen and
C.sub.1-C.sub.8 alkyl; or R.sup.4 and R.sup.5 together with the
atoms to which they are attached form a 5- or 6-member heterocyclic
ring having one O atom;
[0220] R.sup.7a is H;
[0221] R.sup.7b is H or C.sub.1-C.sub.8 alkyl;
[0222] R.sup.8a and R.sup.8b are each H; and
[0223] R.sup.10 and R.sup.11 are each, independently,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
haloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or
allyl.
[0224] In some embodiments, (A) if R.sup.2 is methyl and R.sup.4 is
H, then R.sup.5 is not thiazole, substituted thiazole or a thiazole
derivative;
[0225] In some embodiments, (B) if R.sup.7a is H and R.sup.b is
other than H, then neither R.sup.4 nor R.sup.5 can be H;
[0226] In some embodiments, (C) if R.sup.1 and R.sup.2 are methyl,
and R.sup.5 is H then R.sup.4 is not NHR.sup.10 or
NR.sup.10R.sup.11;
[0227] In some embodiments, (D) if R.sup.1 and R.sup.2 are methyl
and R.sup.5 is H, then R.sup.4 is not imidazolyl, substituted
imidazolyl, or an imidazole derivative;
[0228] In some embodiments, (E) if R.sup.1 is H or CH.sub.3, and
R.sup.2 is CH.sub.3 or OH, then R.sup.3, R.sup.4, R.sup.5, and
R.sup.6 cannot all be H.
[0229] In some embodiments, (F) if R.sup.1 is H and R.sup.2 is
isopropyl or OH, then R.sup.4 and R.sup.5 cannot both be OCH.sub.3
or OH.
[0230] In some embodiments, (G) if R.sup.1 is CH.sub.3 and R.sup.2
is n-propyl, then R.sup.4 cannot be OH, R.sup.5 cannot Cl, and
R.sup.3 and R.sup.6 cannot both be H.
[0231] In further embodiments, R.sup.1 is H.
[0232] In further embodiments, R.sup.1 is C.sub.1-C.sub.8
alkyl.
[0233] In further embodiments, R.sup.2 is methyl, ethyl, n-propyl,
or isopropyl.
[0234] In further embodiments, R.sup.2 is methyl.
[0235] In further embodiments, R.sup.4 is Cl, Br, haloalkyl,
CF.sub.3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or
imidazolyl.
[0236] In further embodiments, R.sup.4 is Cl.
[0237] In further embodiments, R.sup.5 is methoxy, ethoxy,
n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl,
pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is
optionally substituted by one or more halo or methyl and said
phenyl is optionally substituted with up to two substituents
selected from C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 haloalkyl,
halo, and alkoxy.
[0238] In further embodiments, R.sup.5 is H.
[0239] In some embodiments:
[0240] R.sup.2 is C.sub.1-C.sub.4 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.4 haloalkyl,
or CH.sub.2OH; R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, hydroxy, NH.sub.2, CN, or NO.sub.2; and
[0241] R.sup.7a, R.sup.7b, R.sup.8a, and R.sup.8b are each H.
[0242] In some embodiments, (H) when R.sup.2 is C.sub.1-C.sub.4
alkyl, --CH.sub.2--O--(C.sub.1-C.sub.4 alkyl), or CH.sub.2OH, then
R.sup.3 and R.sup.6 are not both H; and
[0243] In some embodiments, (I) when R.sup.2 is CH.sub.3, then
R.sup.3, R.sup.4, and R.sup.6 are each H and R.sup.5 is not H or
isopropyl.
[0244] In further embodiments, R.sup.1 is H.
[0245] In further embodiments, R.sup.1 is C.sub.1-C.sub.8
alkyl.
[0246] In further embodiments, R.sup.2 is C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 haloalkyl.
[0247] In further embodiments, R.sup.2 is methyl, ethyl, isopropyl,
n-butyl, or CF.sub.3.
[0248] In further embodiments, R.sup.3, R.sup.4, R.sup.5, and
R.sup.6 are each, independently, H, methyl, NH.sub.2, CN, halo,
CF.sub.3, NO.sub.2, or OH.
[0249] In further embodiments of the invention, R.sup.7a, R.sup.7b,
R.sup.8a, and R.sup.8b are each H.
[0250] In further embodiments of the invention, R.sup.3 and R.sup.6
are each H.
[0251] In further embodiments of the invention, R.sup.3, R.sup.5,
and R.sup.6 are each H.
[0252] In further embodiments of the invention, R.sup.4 is
halo.
[0253] In further embodiments of the invention, R.sup.4 is Cl.
[0254] In further embodiments of the invention, R.sup.2 is
C.sub.1-C.sub.4 alkyl.
[0255] In further embodiments of the invention, R.sup.2 is
methyl.
[0256] In further embodiments of the invention, R.sup.1 is H.
[0257] In further embodiments of the invention, R.sup.1 is H or
C.sub.1-C.sub.4 alkyl, R.sup.2 is C.sub.1-C.sub.4 alkyl, R.sup.3 is
H, R.sup.4 is halo, R.sup.5 is H, R.sup.6 is H, R.sup.7a is H,
R.sup.7b is H, R.sup.8a is H, and R.sup.8b is H.
[0258] In further embodiments of the invention, R.sup.1 is H,
R.sup.2 is Me, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is H, R.sup.6
is H, R.sup.7a is H, R.sup.7b is H, R.sup.8a is H, and R.sup.8b is
H.
[0259] In further embodiments of the invention, L is halo.
[0260] In further embodiments of the invention, L is hydroxy.
[0261] In further embodiments of the invention, L is Cl.
[0262] In further embodiments of the invention, L is Br.
[0263] In further embodiments of the invention, L is --OSO.sub.2R
such as sulfonates (e.g., mesylate, triflate, methyl
sulfonate).
[0264] In further embodiments of the invention, L is OSi(R').sub.3
such as trimethylsilyloxy.
[0265] In further embodiments of the invention, the compound of
Formula I has an S configuration at the carbon bearing R.sup.2.
[0266] In further embodiments of the invention, the compound of
Formula I has an R configuration at the carbon bearing R.sup.2.
[0267] The present invention provides a process for preparing a
compound of Formula I:
##STR00022##
or salt form thereof, comprising reacting a compound of Formula
II:
##STR00023##
with a reducing agent optionally in the presence of a Lewis acid
for a time and under conditions suitable for forming the compound
of Formula I or salt form thereof.
[0268] In some embodiments, the reducing agent comprises a borane
such as BH.sub.3. In further embodiments, the reducing agent
comprises a metal hydride such as a borohydride or aluminum
hydride. In some embodiments, the reducing agent is BH.sub.3:THF.
Other reducing agents are suitable and can be selected by one
skilled in the art. Example suitable reducing agents are compounds
that selectively reduce the amide moiety of the compound of Formula
II.
[0269] In further embodiments, a Lewis acid can be present in the
reaction in an amount sufficient to increase reaction rate.
Suitable Lewis acids include boron-containing Lewis acids such as
BF.sub.3 and adducts thereof including BF.sub.3:TBME (t-butyl
methyl ether); BF.sub.3:OEt.sub.2;
BF.sub.3:O(CH.sub.2CH.sub.2CH.sub.2CH.sub.3).sub.2; BF.sub.3:THF;
and the like. Suitable amounts include from about 0.01 eq to about
1 eq relative to amount of compound of Formula II.
[0270] Due to potential sensitivity of the reducing agent to air,
the reaction can be conducted under an inert atmosphere.
[0271] Reacting can be carried out in any inert solvent such as a
dialkylether or cyclic ether (e.g., THF) at any suitable
temperature, such as room temperature. The duration of the
reduction can be carried out for any amount of time determined by
one skilled in the art. In some embodiments, the reaction duration
is sufficient to allow the reaction to go substantially to
completion. For example, reaction durations can range from about 10
minutes to about 48 hours. In some embodiments, the reaction
duration is about 8-12 hours. Reaction completion can be monitored,
for example, by LC/MS.
[0272] The amount of reducing agent provided is typically
sufficient to provide at least enough reducing equivalents to
reduce the compound of Formula II to the desired product. For
example, an excess of reducing agent can be provided such as about
10.times., about 5.times., about 3.times., or about 2.times.
reducing equivalent excess. For boranes and related reducing
agents, the molar ratio of reducing agent to the compound of
Formula II can be, for example, about 2:1, about 3:1, about 5:1, or
about 10:1. In some embodiments, the molar ratio is about 3:1.
[0273] In some embodiments, the yield for the reduction reaction
(based on amount of compound of Formula II), is greater than about
50%, about 60%, about 70%, about 80%, or about 90%.
[0274] The present invention further provides a process for
preparing a compound of Formula II, or salt form thereof,
comprising reacting a compound of Formula III:
##STR00024##
or salt form thereof, with a cyclizing reagent for a time and under
conditions suitable for forming the compound of Formula II or salt
form thereof
[0275] In some embodiments, L of the compound of Formula III is
halo. In further embodiments, L of the compound of Formula III is
Cl.
[0276] In some embodiments, the cyclizing reagent includes a Lewis
acid, such as, for example, a C.sub.1-C.sub.8 alkyl aluminum halide
(e.g., methyl aluminum chloride, ethyl aluminum chloride, etc.), a
C.sub.2-C.sub.16 dialkyl aluminum halide (e.g., dimethyl aluminum
chloride, diethyl aluminum chloride, etc.), trialkylaluminum,
AlCl.sub.3, or AlBr.sub.3. In some embodiments, the cyclizing
reagent is AlCl.sub.3. Other suitable cyclizing reagents include
acids such as sulfuric acid.
[0277] Cyclization can be carried out in the absence of solvent or
in the presence of solvent. Suitable solvents include non-polar or
weakly polar solvents such as decahydronaphthalene or
1,2-dichlorobenzene. Other suitable solvents include haloalkanes
and other halogenated aromatics such as 1,3-dichlorobenzene and
1,4-dichlorobenzene.
[0278] The cyclizing reagent can be provided in an amount suitable
for maximizing the yield of the cyclized product. In some
embodiments, the cyclizing reagent can be provided in molar excess
relative to the amount of compound of Formula III. Example molar
ratios of cyclizing reagent to compound of Formula III include
about 2:1, about 3:1, about 5:1, or about 10:1. In some
embodiments, the molar ratio is about 3:1.
[0279] In further embodiments, cyclization is carried out at
elevated temperature such as at about 80 to about 160.degree. C. In
some embodiments, cyclization is carried out at about 150.degree.
C. The cyclization reaction can be monitored by LC/MS. Duration to
substantial completion can be about 10 minutes to about 24 hours.
In some embodiments, reaction duration is from about 3 hours to
about 15 hours.
[0280] In some embodiments, the yield for the cyclization reaction
(based on amount of compound of Formula III), is greater than about
40%, about 50%, about 60%, about 70%, about 80%, or about 90%.
[0281] The present invention further provides preparing a compound
of Formula III comprising reacting a compound of Formula IV:
##STR00025##
or salt form thereof, with a compound of Formula:
##STR00026##
wherein Q is a leaving group, for a time and under conditions
suitable for forming the compound of
[0282] Formula III or salt form thereof.
[0283] According to some embodiments, Q is hydroxy, alkoxy, halo,
or O(CO)R.sup.Q, wherein R.sup.Q is C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
In some embodiments, Q is halo such as Cl. In other embodiments, Q
is hydroxy. In yet other embodiments, Q is alkoxy, such as methoxy,
ethoxy, or t-butoxy.
[0284] Amide formation can be optionally carried out in the
presence of base such as an amine (e.g., NMe.sub.3, NEt.sub.3,
morpholine, pyridine, diisopropylethylamine, piperidine,
N,N-dimethylaminopiperidine, and the like). Other suitable bases
include inorganic bases such as NaOH, KOH, CsOH, and the like.
[0285] Relative amounts of reagents suitable for carrying out the
reaction include about molar equivalents of each. For example, the
amide formation reaction can be carried out with a molar ratio of
compound of Formula IV to compound of Formula:
##STR00027##
of about 1:1. In further embodiments, an equivalent amount of base
can also be included (e.g., molar ratio of about 1:1:1). In yet
further embodiments, base can be added in excess relative to the
amount of compound of Formula IV.
[0286] In further embodiments, the amide formation reaction can be
carried out in solvent, such a polar solvent. An example of a polar
solvent is acetonitrile. Reaction temperature can vary from about
10 to about 30.degree. C. In some embodiments, the reaction can
start at a temperature below room temperature such as about
0.degree. C., and for the reaction duration, rise to about room
temperature. Reaction progress can be monitored, for example, by
TLC, and time to completion can be from about 10 minutes to about 5
hours, depending on, for example, scale of the reaction.
[0287] In some embodiments, the yield for the amide formation
reaction (based on amount of compound of Formula IV), is greater
than about 40%, about 50%, about 60%, about 70%, about 80%, or
about 90%.
[0288] In an alternate route to compounds of Formula I, the present
invention provides a process for preparing a compound of Formula
I:
##STR00028##
or salt form thereof, comprising reacting a compound of Formula
IIIa:
##STR00029##
with a cyclizing reagent for a time and under conditions suitable
for forming the compound of Formula I.
[0289] In some embodiments, L of the compound of Formula IIIa is
halo. In further embodiments, L of the compound of Formula IIIa is
Br or Cl.
[0290] In some embodiments, the cyclizing reagent includes a Lewis
acid, such as, for example, a C.sub.1-C.sub.8 alkyl aluminum halide
(e.g., methyl aluminum chloride, ethyl aluminum chloride, etc.), a
C.sub.2-C.sub.16 dialkyl aluminum halide (e.g., dimethyl aluminum
chloride, diethyl aluminum chloride, etc.), trialkylaluminum,
AlCl.sub.3, or AlBr.sub.3. Other suitable cyclizing reagents
include acids such as sulfuric acid.
[0291] Cyclization can be carried out in the absence of solvent or
in the presence of solvent. Suitable solvents include non-polar or
weakly polar solvents such as decahydronaphthalene or
1,2-dichlorobenzene. Other suitable solvents include haloalkanes
and other halogenated aromatics such as 1,3-dichlorobenzene and
1,4-dichlorobenzene.
[0292] The cyclizing reagent can be provided in an amount suitable
for maximizing the yield of the cyclized product. In some
embodiments, the cyclizing reagent can be provided in molar excess
relative to the amount of compound of Formula IIIa. Example molar
ratios of cyclizing reagent to compound of Formula IIIa include
about 2:1, about 3:1, about 5:1, or about 10:1. In some
embodiments, the molar ratio is about 3:1.
[0293] In further embodiments, cyclization is carried out at
elevated temperature such as at about 80 to about 160.degree. C. In
some embodiments, cyclization is carried out at about 140.degree.
C. The cyclization reaction can be monitored by LC/MS. Duration to
completion can be about 10 minutes to about 24 hours. In some
embodiments, reaction duration is from about 3 hours to about 15
hours.
[0294] In some embodiments, the yield for the cyclization reaction
(based on amount of compound of Formula IIIa), is greater than
about 40%, about 50%, about 60%, about 70%, about 80%, or about
90%.
[0295] The present invention further provides a process for
preparing a compound of Formula IIIa, or salt form thereof,
comprising reacting a compound of Formula III:
##STR00030##
with a reducing agent optionally in the presence of a Lewis acid
for a time and under conditions suitable for forming said compound
of Formula IIIa.
[0296] In some embodiments, the reduction of III can be carried out
so that the stereochemistry of one or more chiral centers present
in the compound of Formula III is substantially retained in the
reduced product (Formula IIIa). In further embodiments, the
reduction of Ma can be carried out using a substantially pure
stereoisomer of Ma. In yet further embodiments, the reduction of Ma
can be carried out using a substantially pure stereoisomer of Ma
and result in a substantially pure stereoisomer of III. For
example, a compound of Formula III having ee of greater than about
80, about 90, or about 95% can reduced to form a compound of
Formula IIIa having a similar ee.
[0297] In some embodiments, the reducing agent comprises a borane
such as BH.sub.3. In further embodiments, the reducing agent
comprises a metal hydride such as a borohydride or aluminum
hydride. In some embodiments, the reducing agent is BH.sub.3:THF.
Other reducing agents are suitable and can be selected by one
skilled in the art. Example suitable reducing agents are compounds
that selectively reduce the amide moiety of the compound of Formula
II.
[0298] In further embodiments, a Lewis acid can be present in the
reaction in an amount sufficient to increase reaction rate.
Suitable Lewis acids include boron-containing Lewis acids such as
BF.sub.3 and adducts thereof including BF.sub.3:TBME (t-butyl
methyl ether); BF.sub.3:OEt.sub.2;
BF.sub.3:O(CH.sub.2CH.sub.2CH.sub.2CH.sub.3).sub.2; BF.sub.3:THF;
and the like. Suitable amounts include from about 0.01 eq to about
1 eq relative to amount of compound of Formula III.
[0299] Due to potential sensitivity of the reducing agent to air,
the reaction can be conducted under an inert atmosphere.
[0300] The reduction reaction can be carried out in inert solvent
such as a dialkylether or cyclic ether (e.g., THF) at any suitable
temperature, such as room temperature. The duration of the
reduction can be carried out for any amount of time. In some
embodiments, the reaction duration is sufficient to allow the
reaction to go substantially to completion. For example, reaction
durations can range from about 10 minutes to about 72 hours. In
some embodiments, the reaction duration is about 8-12 hours.
Reaction completion can be monitored, for example, by LC/MS.
[0301] The amount of reducing agent provided is typically
sufficient to provide at least enough reducing equivalents to
reduce the compound of Formula II to the desired product. For
example, an excess of reducing agent can be provided such as about
10.times., 5.times., 3.times., or 2.times. reducing equivalent
excess. For boranes and related reducing agents, the molar ratio of
reducing agent to the compound of Formula II can be, for example,
2:1, 3:1, 5:1, or 10:1. In some embodiments, the molar ratio is
3:1.
[0302] In some embodiments, the yield for the reduction reaction
(based on amount of compound of Formula III), is greater than about
50%, about 60%, about 70%, about 80%, or about 90%.
[0303] The present invention further provides processes provided
below in Schemes Ia, Ib and Ic, wherein constituent members of the
structures depicted therein are defined above.
##STR00031##
##STR00032##
##STR00033##
[0304] In further embodiments, the present invention provides a
method of resolving a mixture of compounds of Formulas Ia and
Ib:
##STR00034##
by contacting the mixture of compounds with a chiral resolving acid
enriched in one stereoisomer (e.g., ee greater than about 50%,
about 75%, about 90% or about 95%) to form chiral resolving acid
salts of the compounds of the mixture, and then precipitating the
chiral resolving acid salts. The resulting precipitate is typically
enriched in the chiral resolving acid salt of one of the compounds
of Formulas Ia or Ib (e.g., ee >50%). In some embodiments, the
precipitate is enriched in the chiral resolving acid salt form of
the compound of Formula Ia. In some embodiments, the precipitate is
enriched in the chiral resolving acid salt form of the compound of
Formula Ib. In further embodiments, the chiral resolving acid is a
stereoisomer of toluoyl tartaric acid, camphoric acid, ketogulonic
acid, or tartaric acid. In further embodiments, the chiral
resolving acid is a stereoisomer of tartaric acid such as
L-(+)-tartaric acid.
[0305] Contacting of compounds with a chiral resolving acid can be
carried out in solution. Suitable solvents support dissolution of
both the chiral resolving acid and the compounds of Formulas Ia and
Ib. Some example solvents include polar solvents or water-miscible
solvents such as alcohols (e.g., methanol, ethanol, isopropanol,
t-butanol, and the like), isopropylacetate, water, and mixtures
thereof. In further embodiments, the solvent contains a mixture of
t-butanol and water. Some example mixtures include about 5-25%
water and about 75-95% t-butanol. In some embodiments, the solvent
contains about 8-12% water and about 88-92% of t-butanol.
[0306] Precipitate containing the chiral resolving acid salt forms
can be formed by precipitation from any suitable solvent which
dissolves the salts such as the solvent in which contacting was
carried out. Precipitation can be induced by any method known in
the art such as by heating a solution containing the mixture of
salts followed by cooling. Precipitate can be separated from the
solvent by, for example, filtration. Enrichment of the precipitate
in one chiral salt over the other can be characterized by an
enantiomeric excess (ee) of greater than about 50%, about 60%,
about 70%, about 80%, about 90%, about 95%, about 98%, or about
99%. In some embodiments, ee is greater than about 80%.
Precipitation can be repeated one or more times to increase the
proportion of a chiral salt in the precipitate by re-dissolving and
re-precipitating previously obtained precipitate.
[0307] The present invention further provides a chiral resolving
acid salt of a compound of Formula Ia or Ib:
##STR00035##
wherein constituent members are defined hereinabove. Compositions
of the present invention can contain one or or both the salt form
of a compound of Formula Ia and the salt form of a compound of
Formula Ib. In some embodiments, the salt form of the compound of
Formula Ia is present in the composition in an amount greater than
the salt form of a compound of Formula Ib. In other embodiments,
the salt form of the compound of Formula Ib is present in the
composition in an amount greater than the salt form of a compound
of Formula Ia.
[0308] Further example processes and intermediates of the present
invention are provided below in Scheme II, where constituent
members of compounds depicted therein are defined hereinbelow. The
symbol "*" designates optionally chiral centers that can be
substantially retained or inverted over the course of the depicted
reactions.
##STR00036##
[0309] In a second aspect of the present invention are provided
processes, such as are exemplified by Scheme II, that involve
compounds of Formulas V, Va, Vb, IX, X, XI, and XII, or salt forms
thereof, wherein:
[0310] R.sup.1 is H or C.sub.1-C.sub.8 alkyl;
[0311] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, C.sub.1-C.sub.4
haloalkyl, or CH.sub.2OH;
[0312] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, hydroxy, OR.sup.9, alkoxyalkyl,
C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,
NR.sup.10R.sup.11, CN, NO.sub.2, heterocycloalkyl, aryl, or
heteroaryl, wherein said aryl and heteroaryl can be substituted
with one or more substituents selected from C.sub.1-C.sub.8 alkyl,
halo, C.sub.1-C.sub.8 haloalkyl, and alkoxy; or R.sup.4 and R.sup.5
together with the atoms to which they are attached form a 5- or
6-member heterocyclic ring having one O atom;
[0313] R.sup.8a and R.sup.8b are each, independently, H, halo,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or
hydroxyalkyl, or R.sup.8a and R.sup.8b together with the carbon
atom to which they are attached form a C.sub.3-C.sub.7 cycloalkyl
group;
[0314] R.sup.9 is H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkenyl, C.sub.1-C.sub.8 alkynyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.8 haloalkyl, aralkyl, aryl, heteroaryl,
heteroarylalkyl, or allyl; and
[0315] R.sup.10 and R.sup.11 are each, independently, H,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8 haloalkyl,
aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R.sup.10
and R.sup.11 together with the N atom to which they are attached
form a heterocyclic ring;
[0316] X.sup.1 is a leaving group;
[0317] X.sup.2 is halo or SO.sub.2R''; and
[0318] R'' is C.sub.1-C.sub.8 alkyl, aryl, or heteroaryl each
optionally substituted by one or more halo, cyano, nitro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkoxy.
[0319] In some embodiments of the invention:
[0320] R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), OH, or CH.sub.2OH;
[0321] R.sup.3 and R.sup.6 are each H;
[0322] R.sup.4 and R.sup.5 are each, independently, H, halo,
C.sub.1-C.sub.8 haloalkyl, hydroxy, OR.sup.9, SR.sup.9,
alkoxyalkyl, NHR.sup.10, NR.sup.10R.sup.11, aryl, or heteroaryl,
wherein said aryl can be substituted with up to two substituents
selected from C.sub.1-C.sub.8 alkyl, halo, C.sub.1-C.sub.8
haloalkyl, and alkoxy, and said heteroaryl can be optionally
substituted with up to two substituents selected from halogen and
C.sub.1-C.sub.8 alkyl; or R.sup.4 and R.sup.5 together with the
atoms to which they are attached form a 5- or 6-member heterocyclic
ring having one O atom;
[0323] R.sup.7a is H;
[0324] R.sup.7b is H or C.sub.1-C.sub.8 alkyl;
[0325] R.sup.8a and R.sup.8b are each H; and
[0326] R.sup.10 and R.sup.11 are each, independently,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
haloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or
allyl.
[0327] In some embodiments, (A) if R.sup.2 is methyl and R.sup.4 is
H, then R.sup.5 is not thiazole, substituted thiazole or a thiazole
derivative.
[0328] In some embodiments, (B) if R.sup.7a is H and R.sup.7b is
other than H, then neither R.sup.4 nor R.sup.5 can be H.
[0329] In some embodiments, (C) if R.sup.1 and R.sup.2 are methyl,
and R.sup.5 is H then R.sup.4 is not NHR.sup.16 or
NR.sup.10R.sup.11.
[0330] In some embodiments, (D) if R.sup.1 and R.sup.2 are methyl
and R.sup.5 is H, then R.sup.4 is not imidazolyl, substituted
imidazolyl, or an imidazole derivative.
[0331] In some embodiments, (E) if R.sup.1 is H or CH.sub.3, and
R.sup.2 is CH.sub.3 or OH, then R.sup.3, R.sup.4, R.sup.5, and
R.sup.6 cannot all be H.
[0332] In some embodiments, (F) if R.sup.1 is H and R.sup.2 is
isopropyl or OH, then R.sup.4 and R.sup.5 cannot both be OCH.sub.3
or OH.
[0333] In some embodiments, (G) if R.sup.1 is CH.sub.3 and R.sup.2
is n-propyl, then R.sup.4 cannot be OH, R.sup.5 cannot Cl, and
R.sup.3 and R.sup.6 cannot both be H.
[0334] In further embodiments, R.sup.1 is H.
[0335] In further embodiments, R.sup.1 is C.sub.1-C.sub.8
alkyl.
[0336] In further embodiments, R.sup.2 is methyl, ethyl, n-propyl,
or isopropyl.
[0337] In further embodiments, R.sup.2 is methyl.
[0338] In further embodiments, R.sup.4 is Cl, Br, haloalkyl,
CF.sub.3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or
imidazolyl.
[0339] In further embodiments, R.sup.4 is Cl.
[0340] In further embodiments, R.sup.5 is methoxy, ethoxy,
n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl,
pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is
optionally substituted by one or more halo or methyl and said
phenyl is optionally substituted with up to two substituents
selected from C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 haloalkyl,
halo, and alkoxy.
[0341] In further embodiments, R.sup.5 is H.
[0342] In some embodiments:
[0343] R.sup.2 is C.sub.1-C.sub.4 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.4 haloalkyl,
or CH.sub.2OH;
[0344] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each,
independently, H, halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, hydroxy, NH.sub.2, CN, or NO.sub.2; and
[0345] R.sup.7a, R.sup.7b, R.sup.8a, and R.sup.8b are each H.
[0346] In some embodiments, (H) when R.sup.2 is C.sub.1-C.sub.4
alkyl, --CH.sub.2--O--(C.sub.1-C.sub.4 alkyl), or CH.sub.2OH, then
R.sup.3 and R.sup.6 are not both H.
[0347] In some embodiments, (I) when R.sup.2 is CH.sub.3, then
R.sup.3, R.sup.4, and R.sup.6 are each H and R.sup.5 is not H or
isopropyl.
[0348] In further embodiments, R.sup.1 is H.
[0349] In further embodiments, R.sup.1 is C.sub.1-C.sub.8
alkyl.
[0350] In further embodiments, R.sup.2 is C.sub.1-C.sub.8 alkyl,
--CH.sub.2--O--(C.sub.1-C.sub.8 alkyl), C(O)O--(C.sub.1-C.sub.8
alkyl), --C(O)NH--(C.sub.1-C.sub.8 alkyl), or C.sub.1-C.sub.4
haloalkyl;
[0351] In further embodiments, R.sup.2 is C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 haloalkyl.
[0352] In further embodiments, R.sup.2 is methyl, ethyl, isopropyl,
n-butyl, or CF.sub.3.
[0353] In further embodiments, R.sup.3, R.sup.4, R.sup.5, and
R.sup.6 are each, independently, H, methyl, NH.sub.2, CN, halo,
CF.sub.3, NO.sub.2, or OH.
[0354] In further embodiments of the invention, R.sup.7a, R.sup.7b,
R.sup.8a, and R.sup.8b are each H.
[0355] In further embodiments of the invention, R.sup.3 and R.sup.6
are each H.
[0356] In further embodiments of the invention, R.sup.3, R.sup.5,
and R.sup.6 are each H.
[0357] In further embodiments of the invention, R.sup.4 is
halo.
[0358] In further embodiments of the invention, R.sup.4 is Cl.
[0359] In further embodiments of the invention, R.sup.2 is
C.sub.1-C.sub.4 alkyl.
[0360] In further embodiments of the invention, R.sup.2 is
methyl.
[0361] In further embodiments of the invention, R.sup.1 is H.
[0362] In further embodiments, X.sup.1 is halo.
[0363] In further embodiments, X.sup.1 is Br.
[0364] In further embodiments, X.sup.1 is Cl.
[0365] In further embodiments, X.sup.2 is halo.
[0366] In further embodiments, X.sup.2 is Br.
[0367] In further embodiments, X.sup.2 is Cl.
[0368] In further embodiments of the invention, R.sup.1 is H or
C.sub.1-C.sub.4 alkyl, R.sup.2 is C.sub.1-C.sub.4 alkyl, R.sup.3 is
H, R.sup.4 is halo, R.sup.5 is H, R.sup.6 is H, R.sup.7a is H,
R.sup.7b is H, R.sup.8a is H, and R.sup.8b is H.
[0369] In further embodiments of the invention, R.sup.1 is H,
R.sup.2 is Me, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is H, R.sup.6
is H, lea is H, R.sup.7b is H, R.sup.8a is H, and R.sup.8b is
H.
[0370] In further embodiments of the invention, the compound of
Formula V has an S configuration at the carbon bearing R.sup.2.
[0371] In further embodiments of the invention, the compound of
Formula V has an R configuration at the carbon bearing R.sup.2.
[0372] The present invention provides a process for preparing a
compound of Formula V:
##STR00037##
or salt thereof, by reacting a compound of Formula IX:
##STR00038##
or salt thereof, with a cyclizing reagent for a time and under
conditions suitable for forming the compound of Formula V.
[0373] In some embodiments, the cyclizing reagent includes a Lewis
acid, such as, for example, a C.sub.1-C.sub.8 alkyl aluminum halide
(e.g., methyl aluminum chloride, ethyl aluminum chloride, etc.), a
C.sub.2-C.sub.16 dialkyl aluminum halide (e.g., dimethyl aluminum
chloride, diethyl aluminum chloride, etc.), trialkylaluminum,
AlCl.sub.3, or AlBr.sub.3. Other suitable cyclizing reagents
include acids such as sulfuric acid.
[0374] The cyclizing reagent can be provided in an amount suitable
for maximizing the yield of the cyclized product. In some
embodiments, the cyclizing reagent can be provided in molar excess
relative to the amount of compound of Formula IX. Example molar
ratios of cyclizing reagent to compound of Formula IX include about
1.5:1, about 2:1, about 3:1, about 5:1, or about 10:1. In some
embodiments, the molar ratio is about 1.5:1.
[0375] Reacting can be carried out in the presence of any suitable
solvent (or in the absence of solvent) such as a non-polar or
weakly-polar solvent or a high boiling solvent (boiling point
greater than for water). In some embodiments, reacting can be
carried out in the presence of 1,2-dichlorobenzene. In further
embodiments, reacting can be carried out in the presence of
decalin.
[0376] Reaction temperature can be any suitable temperature such as
temperatures that do not readily degrade the reactants yet maximize
reaction efficiency and/or minimize reaction time. In some
embodiments, reacting is carried out at an elevated temperature
such as, for example, between about 80 and about 170.degree. C. In
some embodiments, elevated temperature is from about 100 to about
150, about 120 to about 150, or about 140.degree. C.
[0377] The cyclization reaction can be monitored by LC/MS. Duration
to completion can be about 10 minutes to about 24 hours. In some
embodiments, reaction duration is from about 3 hours to about 15
hours. In further embodiments, reaction duration is about 2 to 5
hours.
[0378] In some embodiments, the yield for the cyclization reaction
(based on amount of compound of Formula IX), is greater than about
40%, about 50%, about 60%, about 70%, about 80%, or about 90%.
[0379] The present invention further provides a process for
preparing a compound of Formula IX:
##STR00039##
or salt thereof, by reacting a compound of Formula X:
##STR00040##
or salt thereof, with a halogenating/sulfonating reagent for a time
and under conditions suitable for forming the compound of Formula
XI.
[0380] Suitable halogenating/sulfonating reagents are capable of
replacing the OH moiety in the compound of Formula X with a halogen
atom or sulfonate moiety. In some embodiments, the
halogenating/sulfonating reagent is SOBr.sub.2 or SOCl.sub.2.
[0381] The halogenating/sulfonating reagent can be provided in an
amount sufficient to theoretically produce maximum yield. Suitable
molar ratios of halogenating/sulfonating reagent to compound of
Formula X include the ratios of about 10:1, about 5:1, about 3:1,
about 2:1, or about 1.5:1. In some embodiments, the molar ratio is
about 1.06:1 to about 1.4:1.
[0382] Reacting can be carried out in any suitable solvent or in
the absence of solvent, such as solvents capable of dissolving at
least one of the compound of Formula X or the
halogenating/sulfonating reactant. In some embodiments, the solvent
contains DMF (dimethylformamide). In further embodiments, the
solvent contains toluene. In yet further embodiments, the solvent
contains dichloromethane. In some embodiments, the solvent contains
dimethylformamide and toluene, and in further embodiments, the
solvent contains dimethylformamide and dichloromethane.
[0383] Any reaction temperature that does not substantially
decompose the starting materials, solvent, or products is suitable.
In some embodiments, reacting is carried out at temperatures such
as from about -40 to about 80.degree. C., about 10 to about
30.degree. C., or about 0.degree. C. to about room temperature.
[0384] In some embodiments, the compound of Formula XI is isolated,
such as by recrystallization from a suitable solvent. Yield can be
greater than about 20%, greater than about 30%, greater than about
40%, or greater than about 50%. In some embodiments, yield is
greater than about 50%.
[0385] The present invention also provides a process for preparing
a compound of Formula X:
##STR00041##
or salt thereof, comprising reacting a compound of Formula XI:
##STR00042##
with a compound of Formula:
##STR00043##
for a time and under conditions suitable for forming the compound
of Formula X.
[0386] The reacting can be carried out, for example, at elevated
temperature such as from about 80 to about 110.degree. C. or 90 to
about 100.degree. C. In some embodiments, reacting is carried out
at about 95.degree. C.
[0387] Any suitable inert solvent can be used, and in some
embodiments, reacting is carried out in the absence of solvent.
[0388] A sufficient amount of compound of Formula:
##STR00044##
can be provided in the reaction to obtain a theoretical or
empirical maximum yield. Example amounts can range from at least
about 1 molar equivalent to any amount that would be in molar
excess (e.g., about 10.times. or 15.times.) relative to the amount
of compound of Formula XI.
[0389] An example reaction duration can be from about 3 to about 5
hours.
[0390] The present invention further provides a process of
preparing a compound of Formula XI by reacting a compound of
Formula XII:
##STR00045##
with a halogenating/sulfonating reagent for a time and under
conditions suitable for forming the compound of Formula XI.
[0391] The halogenating/sulfonating reagent can be any suitable
reagent capable of replacing the hydroxy moiety of the compound of
Formula XII with a suitable leaving group such as a halogen atom or
sulfonate moiety. In some embodiments, the halogenating/sulfonating
reagent is, for example, PBr.sub.3 or PCl.sub.3.
[0392] Any suitable solvent can be used or the reacting can be
carried out in the absence of solvent.
[0393] Reaction temperature can be readily selected by the art
skilled. In some embodiments, reacting is carried out at lowered
temperatures such as from about 20 to about 15.degree. C., about 10
to about 10.degree. C., or about 0.degree. C. In some embodiments,
the reaction temperature is below about 10.degree. C.
[0394] Halogenating/sulfonating reagent can be provided in an
amount sufficient to produce maximum theoretical yield. For
example, the molar ratio of halogenating/sulfonating reagent to
compound of Formula XII can range from about 20:1 to about 0.2:1.
In some embodiments, halogenating/sulfonating reagent is provided
in slight excess, such as in a ratio of about 1:1 or about
0.5:1.
[0395] Reaction yield can be greater than about 75%, greater than
about 85%, greater than about 90%, greater than about 95, or
greater than about 98%. In some embodiments, yield is from about
95% to about 100%.
[0396] In further embodiments, the present invention provides a
method of resolving a mixture of compounds of Formulas Va and
Vb:
##STR00046##
by contacting the mixture of compounds with a chiral resolving acid
enriched in one stereoisomer (e.g., ee greater than about 50%,
about 75%, about 90% or about 95%) to form chiral resolving acid
salts of the compounds of the mixture, and then precipitating the
chiral resolving acid salts. The resulting precipitate is typically
enriched in the chiral resolving acid salt of one of the compounds
of Formulas Va or Vb (e.g., ee >50%). In some embodiments, the
precipitate is enriched in the chiral resolving acid salt form of
the compound of Formula Va. In some embodiments, the precipitate is
enriched in the chiral resolving acid salt form of the compound of
Formula Vb. In further embodiments, the chiral resolving acid is a
stereoisomer of toluoyl tartaric acid, camphoric acid, ketogulonic
acid, or tartaric acid. In further embodiments, the chiral
resolving acid is tartaric acid such as L-(+)-tartaric acid.
[0397] Contacting of compounds of Formulas Va and Vb with a chiral
resolving acid can be carried out in solution. Suitable solvents
support dissolution of both the chiral resolving acid and the
compounds of Formulas Va and Vb. Some example solvents include
polar solvents or water-miscible solvents such as alcohols (e.g.,
methanol, ethanol, isopropanol, t-butanol, 1-butanol and the like),
isopropylacetate, tetrahydrofuran, acetone, methyl isobutyl ketone,
water, and mixtures thereof. In some embodiments, the solvent
contains a mixture of alcohol and water. In further embodiments,
the solvent contains a mixture of t-butanol and water. Some example
mixtures include about 5-25% water and about 75-95% t-butanol. In
some embodiments, the solvent contains about 8-12% water and about
88-92% of t-butanol. In some embodiments, the solvent contains a
mixture of acetone and water.
[0398] Precipitate containing the chiral resolving acid salt forms
can be formed by precipitation from any suitable solvent which
dissolves the salts such as the solvent in which contacting was
carried out. Precipitation can be induced by any method known in
the art such as by heating a solution containing the mixture of
salts followed by cooling. Precipitate can be separated from the
solvent by, for example, filtration. Enrichment of the precipitate
in one chiral salt over the other can be characterized by an
enantiomeric excess (ee) of greater than about 50%, about 60%,
about 70%, about 80%, about 90%, about 95%, about 98%, or about
99%. In some embodiments, ee is greater than about 80%.
Precipitation can be repeated one or more times to increase the
proportion of a chiral salt in the precipitate by re-dissolving and
re-precipitating previously obtained precipitate.
[0399] The present invention further provides a chiral resolving
acid salt of a compound of Formula Va or Vb:
##STR00047##
wherein constituent members are defined hereinabove. Compositions
of the present invention can contain one or or both the salt form
of a compound of Formula Va and the salt form of a compound of
Formula Vb. In some embodiments, the salt form of the compound of
Formula Va is present in the composition in an amount greater than
the salt form of a compound of Formula Vb. In other embodiments,
the salt form of the compound of Formula Vb is present in the
composition in an amount greater than the salt form of a compound
of Formula Va.
[0400] The present invention further provides a hydrochloric acid
salt of a compound of Formula Va or Vb and compositions
thereof.
[0401] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable
subcombination.
[0402] As used herein, the term "alkyl" is meant to refer to a
saturated hydrocarbon group which is straight-chained or branched.
Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g.,
n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl),
pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An
alkyl group can contain from 1 to about 20, from 2 to about 20,
from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to
about 4, or from 1 to about 3 carbon atoms.
[0403] As used herein, "alkenyl" refers to an alkyl group having
one or more double carbon-carbon bonds. Example alkenyl groups
include ethenyl, propenyl, cyclohexenyl, and the like.
[0404] As used herein, "alkynyl" refers to an alkyl group having
one or more triple carbon-carbon bonds. Example alkynyl groups
include ethynyl, propynyl, and the like.
[0405] As used herein, "haloalkyl" refers to an alkyl group having
one or more halogen substituents. Example haloalkyl groups include
CF.sub.3, C.sub.2F.sub.5, CHF.sub.2, CCl.sub.3, CHCl.sub.2,
C.sub.2Cl.sub.5, and the like. An alkyl group in which all of the
hydrogen atoms are replaced with halogen atoms can be referred to
as "perhaloalkyl."
[0406] As used herein, "aryl" refers to monocyclic or polycyclic
aromatic hydrocarbons such as, for example, phenyl, naphthyl,
anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some
embodiments, aryl groups have from 6 to about 20 carbon atoms.
[0407] As used herein, "cycloalkyl" refers to non-aromatic
hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups.
Cycloalkyl groups can include mono-, bi- or poly-cyclic ring
systems as well as double and triple bonds. Example cycloalkyl
groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,
cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and
the like. Also included in the definition of cycloalkyl are
moieties that have one or more aromatic rings fused (i.e., having a
bond in common with) to the cycloalkyl ring, for example, benzo
derivatives of pentane, hexane, and the like.
[0408] As used herein, "heteroaryl" groups are monocyclic and
polycyclic aromatic hydrocarbons that have at least one heteroatom
ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups
include, without limitation, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl,
imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl,
benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl,
tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,
benzothienyl, purinyl, carbazolyl, benzimidazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide,
benzoxazolin-2-on-yl, indolinyl, benzodioxolanyl, benzodioxane, and
the like. In some embodiments, heteroaryl groups can have from 1 to
about 20 carbon atoms, and in further embodiments from about 3 to
about 20 carbon atoms. In some embodiments, heteroaryl groups have
1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
[0409] As used herein, "heterocycloalkyl" refers to a cycloalkyl
group wherein one or more of the ring-forming carbon atoms is
replaced by a heteroatom such as an O, S, N, or P atom. Also
included in the definition of heterocycloalkyl are moieties that
have one or more aromatic rings fused (i.e., having a bond in
common with) to the nonaromatic heterocyclic ring, for example
phthalimidyl, naphthalimidyl pyromellitic diimidyl, phthalanyl, and
benzo derivatives of saturated heterocycles such as indolene and
isoindolene groups.
[0410] As used herein, "halo" or "halogen" includes fluoro, chloro,
bromo, and iodo.
[0411] As used herein, "alkoxy" refers to an --O-alkyl group.
Example alkoxy groups include methoxy, ethoxy, propoxy (e.g.,
n-propoxy and isopropoxy), t-butoxy, and the like.
[0412] As used herein, "thioalkoxy" refers to an alkoxy group in
which the O atom is replaced by an S atom.
[0413] As used herein, "aryloxy" refers to an --O-aryl group. An
example aryloxy group is phenoxy.
[0414] As used herein, "thioaryloxy" refers to an aryloxy group in
which the O atom is replaced by an S atom.
[0415] As used herein, "aralkyl" refers to an alkyl moiety
substituted by an aryl group. Example aralkyl groups include
benzyl, phenethyl, and naphthylmethyl groups. In some embodiments,
arylalkyl groups have from 7 to 20 or 7 to 11 carbon atoms.
[0416] As used herein, "hydroxyalkyl" refers to an alkyl group
substituted by hydroxy.
[0417] As used herein, "alkoxyalkyl" refers to an alkyl group
substituted by an alkoxy group.
[0418] As used herein, the term "reacting" is used as known in the
art and generally refers to the bringing together of chemical
reagents in such a manner so as to allow their interaction at the
molecular level to achieve a chemical or physical
transformation.
[0419] As used herein, the term "substituted" refers to the
replacement of a hydrogen moiety with a non-hydrogen moiety in a
molecule or group.
[0420] As used herein, the term "thiazole derivative" refers to a
moiety containing a thiazolyl group.
[0421] As used herein, the term "imidazole derivative" refers to a
moiety containing a imidazolyl group.
[0422] As used herein, the term "contacting" refers to the bringing
together of substances so that they can interact at the molecular
level.
[0423] As used herein, the term "reducing agent" is used as known
in the art and refers to any chemical reagent that carries out the
reduction of another chemical reagent. In some embodiments, a
reduction carried out by a reducing agent involves lowering the
number of bonds of an atom (e.g., a C atom) to oxygen or sulfur.
For example, a reducing agent can convert (or reduce) a ketone to
an alcohol. In some embodiments, the reducing agent converts an
amide to an amine Numerous reducing agents are known in the art and
can be identified by comparing redox potentials of the reducing
agent and the substance to be reduced. Typically, a reducing agent
has a lower reducing potential than the substance to be reduced.
Methods for measuring redox potentials are well known in the art.
In other embodiments, the reducing agent can be an oxo acceptor.
Example reducing agents include metal hydrides such as borohydrides
(e.g., NaBH.sub.4, LiBH.sub.4, NaBH.sub.3CN) and aluminum hydrides
(e.g., LiAlH.sub.4) including, for example, C.sub.1-C.sub.8 alkyl
aluminum hydrides, C.sub.2-C.sub.16 dialkyl aluminum hydrides,
alkoxy aluminum hydrides (e.g., mono-, di-, and trialkoxy aluminum
hydrides). Other suitable reducing agents include boranes such as
BH.sub.3 or B.sub.2H.sub.6 and adducts thereof. Example borane
adducts include, for example, dialkylsulfide boranes (e.g.,
BH.sub.3:CH.sub.3SCH.sub.3), amine boranes (e.g.,
BH.sub.3:triethylamine), dialkyl ether boranes (e.g.,
BH.sub.3:diethyl ether), cyclic ether boranes (e.g.,
BH.sub.3:tetrahydrofuran), C.sub.1-C.sub.8 alkyl boranes,
C.sub.2-C.sub.16 dialkyl boranes, C.sub.3-C.sub.24 trialkyl boranes
(e.g., 9-borabicyclo[3.3.1]nonane), cyclic boranes (e.g.,
borolanes), and the like. Further example reducing agents include
Red-Al and H.sub.2 optionally in the presence of catalyst such as
Pd/C.
[0424] As used herein, the term "cyclizing reagent" refers to any
chemical reagent that can be used in a reaction to cyclize a linear
or branched molecule or portion of a molecule. In some embodiments
according to the present invention, cyclization of a linear or
branched moiety attached to an aryl compound can be carried out
using, for example, a Lewis acid. As is known in the art, a Lewis
acid includes a molecule that can accept a lone pair of electrons.
Example Lewis acids include hydrogen ion (a proton), boron
derivatives such as BH.sub.3 and BF.sub.3, and aluminum derivatives
such as AlCl.sub.3. Some example Lewis acids include
C.sub.1-C.sub.8 alkyl aluminum halide (e.g., methyl aluminum
chloride, ethyl aluminum chloride, etc.), a C.sub.2-C.sub.16
dialkyl aluminum halide (e.g., dimethyl aluminum chloride, diethyl
aluminum chloride, etc.), and trialkylaluminum.
[0425] In some embodiments, cyclizing can be carried out according
to Friedel-Crafts alkylation chemistry which is known to follow the
general transformation: ArH+RCH.sub.2Cl.fwdarw.ArCH.sub.2R (Ar is
aryl and R is, for example, any alkyl, amino, or other group) in
the presence of a reagent such as a Lewis acid. Friedel-Crafts
reactions are typically carried out in the presence of AlCl.sub.3
and optionally at elevated temperatures. Suitable Lewis acids
include boron-containing reagents and aluminum containing reagents.
Example boron-containing reagents include BH.sub.3, BF.sub.3 and
adducts thereof (e.g., BF.sub.3:TBME and BF.sub.3:OEt.sub.2).
Example aluminum-containing reagents include alkyl aluminum
halides, dialkyl aluminum halides, trialkyl aluminum, and aluminum
halides (e.g., AlCl.sub.3 and AlBr.sub.3). Other suitable cyclizing
reagents include, for example, acids such as sulfuric acid,
sulfonic acids (e.g., CF.sub.3SO.sub.3H, CH.sub.3SO.sub.3H, pTSA),
phosphoric acids, polyphosphoric acids (e.g.,
H.sub.3PO.sub.4/P.sub.2O.sub.5), and the like. Additional suitable
Friedel-Crafts alkylation catalysts include FeCl.sub.3, TiCl.sub.4,
ZrCl.sub.4, and ZnCl.sub.4.
[0426] As used herein, the term "halogenating/sulfonating reagent"
refers to any chemical reagent that can be used to replace hydrogen
or a chemical substituent on a molecule with a leaving group such
as a halogen moiety or sulfonate moiety (e.g., alkyl sulfonate,
mesylate, tosylate, etc.). In some embodiments, the
halogenating/sulfonating reagent replaces a hydroxyl with a halogen
moiety or sulfonate moiety. Example halogenating/sulfonating
reagents include phosphorous trihalides (e.g., PBr.sub.3),
phosphorous pentahalides, phosphorous oxyhalides, thionyl halides
(e.g., SOBr.sub.2), and the like. Other halogenating/sulfonating
reagents include N-bromosuccinimide (NBS),
1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide
(pyrHBr.sub.3), diethylaminosulfur trifluoride (DAST),
N-fluorobenzenesulfonimide, and the like. Further
halogenating/sulfonating reagents include sulfonyl halides such as
mesyl chloride, tosyl chloride, and the like.
[0427] As used herein, the term "leaving group" refers to a moiety
that can be displaced by another moiety, such as by nucleophilic
attack, during a chemical reaction. Leaving groups are well known
in the art and include, for example, halogen, hydroxy, alkoxy,
--O(CO)R.sup.a, --OSO.sub.2--R.sup.b, and OSi(R.sup.c).sub.3
wherein IV can be C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.7
cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein R.sup.b
can be C.sub.1-C.sub.8 alkyl, aryl (optionally substituted by one
or more halo, cyano, nitro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4 haloalkoxy),
or heteroaryl (optionally substituted by one or more halo, cyano,
nitro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4 haloalkoxy), and wherein
Re can be C.sub.1-C.sub.8 alkyl. Example leaving groups include
chloro, bromo, iodo, mesylate, tosylate, trimethylsilyl, and the
like.
[0428] As used herein, the terms "resolving" and "resolution" are
used as known in the art and generally refer to the separation of a
mixture of isomers such as stereoisomers (e.g., optical isomers
such as enantiomers or diastereomers). Resolving can include
processes that can increase the proportion of one stereoisomer over
another in a mixture of stereoisomers. A mixture of stereoisomers
having a greater proportion of a first stereoisomer over a further
stereoisomer can be said to be "enriched" in the first
stereoisomer.
[0429] As used herein, the term "precipitating" is used as known in
the art and generally refers to the formation of solid (e.g.,
precipitate) from a solution in which the solid is dissolved. The
solid can be amorphous, crystalline, or a mixture thereof. Methods
of precipitation are well known in the art and include, for
example, increasing the proportion of solvent in which a solute is
insoluble, decreasing temperature, chemically transforming the
solute such that it becomes no longer soluble in its solvent, and
the like. Precipitation can be used to increase the proportion of a
stereoisomer in a mixture of stereoisomers.
[0430] The processes described herein can be monitored according to
any suitable method known in the art. For example, product
formation can be monitored by spectroscopic means, such as nuclear
magnetic resonance spectroscopy (e.g., .sup.1H or .sup.13C)
infrared spectroscopy, spectrophotometry (e.g., UV-visible), or
mass spectrometry, or by chromatography such as high performance
liquid chromatography (HPLC) or thin layer chromatography.
[0431] In some embodiments, preparation of compounds can involve
the protection and deprotection of various chemical groups. The
need for protection and deprotection, and the selection of
appropriate protecting groups can be readily determined by one
skilled in the art. The chemistry of protecting groups can be
found, for example, in Green and Wuts, et al., Protective Groups in
Organic Synthesis, 3rd. Ed., Wiley & Sons, 1999, which is
incorporated herein by reference in its entirety.
[0432] The reactions of the processes described herein can be
carried out in suitable solvents which can be readily selected by
one of skill in the art of organic synthesis. Suitable solvents can
be substantially nonreactive with the starting materials
(reactants), the intermediates, or products at the temperatures at
which the reactions are carried out, e.g., temperatures which can
range from the solvent's freezing temperature to the solvent's
boiling temperature. A given reaction can be carried out in one
solvent or a mixture of more than one solvent. Depending on the
particular reaction step, suitable solvents for a particular
reaction step can be selected. In some embodiments, reactions can
be carried out in the absence of solvent, such as when at least one
of the reagents is a liquid or gas.
[0433] Suitable solvents can include halogenated solvents such as
carbon tetrachloride, bromodichloromethane, dibromochloromethane,
bromoform, chloroform, bromochloromethane, dibromomethane, butyl
chloride, dichloromethane, tetrachloroethylene, trichloroethylene,
1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane,
2-chloropropane, .alpha.,.alpha.,.alpha.-trifluorotoluene,
1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene,
1,2,4-trichlorobenzene, o-dichlorobenzene, chlorobenzene,
fluorobenzene, fluorotrichloromethane, chlorotrifluoromethane,
bromotrifluoromethane, carbon tetrafluoride, dichlorofluoromethane,
chlorodifluoromethane, trifluoromethane,
1,2-dichlorotetrafluorethane and hexafluoroethane.
[0434] Suitable ether solvents include: dimethoxymethane,
tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether,
ethylene glycol dimethyl ether, ethylene glycol diethyl ether,
diethylene glycol dimethyl ether, diethylene glycol diethyl ether,
triethylene glycol dimethyl ether, anisole, or t-butyl methyl
ether.
[0435] Suitable protic solvents can include, by way of example and
without limitation, water, methanol, ethanol, 2-nitroethanol,
2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol,
1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol,
i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene
glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl
alcohol, diethylene glycol monomethyl ether, diethylene glycol
monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or
glycerol.
[0436] Suitable aprotic solvents can include, by way of example and
without limitation, tetrahydrofuran (THF), dimethylformamide (DMF),
dimethylacetamide (DMAC),
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),
1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),
formamide, N-methylacetamide, N-methylformamide, acetonitrile,
dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate,
hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,
sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane,
nitrobenzene, or hexamethylphosphoramide.
[0437] Suitable hydrocarbon solvents include benzene, cyclohexane,
pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane,
ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or
naphthalene.
[0438] Supercritical carbon dioxide can also be used as a
solvent.
[0439] The reactions of the processes described herein can be
carried out at appropriate temperatures which can be readily
determined by the skilled artisan. Reaction temperatures will
depend on, for example, the melting and boiling points of the
reagents and solvent, if present; the thermodynamics of the
reaction (e.g., vigorously exothermic reactions may need to be
carried out at reduced temperatures); and the kinetics of the
reaction (e.g., a high activation energy barrier may need elevated
temperatures). "Elevated temperature" refers to temperatures above
room temperature (about 20.degree. C.) and "reduced temperature"
refers to temperatures below room temperature.
[0440] The reactions of the processes described herein can be
carried out in air or under an inert atmosphere. Typically,
reactions containing reagents or products that are substantially
reactive with air can be carried out using air-sensitive synthetic
techniques that are well known to the skilled artisan.
[0441] In some embodiments, preparation of compounds can involve
the addition of acids or bases to effect, for example, catalysis of
a desired reaction or formation of salt forms such as acid addition
salts.
[0442] Example acids can be inorganic or organic acids. Inorganic
acids include hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, and nitric acid. Organic acids include formic
acid, acetic acid, propionic acid, butanoic acid, methanesulfonic
acid, p-toluene sulfonic acid, benzenesulfonic acid,
trifluoroacetic acid, propiolic acid, butyric acid, 2-butynoic
acid, vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic
acid, octanoic acid, nonanoic acid and decanoic acid.
[0443] Example bases include lithium hydroxide, sodium hydroxide,
potassium hydroxide, lithium carbonate, sodium carbonate, and
potassium carbonate. Some example strong bases include, but are not
limited to, hydroxide, alkoxides, metal amides, metal hydrides,
metal dialkylamides and arylamines, wherein; alkoxides include
lithium, sodium and potassium salts of methyl, ethyl and t-butyl
oxides; metal amides include sodium amide, potassium amide and
lithium amide; metal hydrides include sodium hydride, potassium
hydride and lithium hydride; and metal dialkylamides include sodium
and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl,
t-butyl, trimethylsilyl and cyclohexyl substituted amides.
[0444] The compounds described herein can be asymmetric (e.g.,
having one or more stereocenters). All stereoisomers, such as
enantiomers and diastereomers, are intended unless otherwise
indicated. Compounds of the present invention that contain
asymmetrically substituted carbon atoms can be isolated in
optically active or racemic forms. Methods on how to prepare
optically active forms from optically active starting materials are
known in the art, such as by resolution of racemic mixtures or by
stereoselective synthesis.
[0445] The processes described herein can be stereoselective such
that any given reaction starting with one or more chiral reagents
enriched in one stereoisomer forms a product that is also enriched
in one stereoisomer. The reaction can be conducted such that the
product of the reaction substantially retains one or more chiral
centers present in the starting materials. The reaction can also be
conducted such that the product of the reaction contains a chiral
center that is substantially inverted relative to a corresponding
chiral center present in the starting materials.
[0446] Resolution of racemic mixtures of compounds can be carried
out by any of numerous methods known in the art. An example method
includes fractional recrystallizaion using a "chiral resolving
acid" which is an optically active, salt-forming organic acid.
Suitable resolving agents for fractional recrystallization methods
are, for example, optically active acids, such as the D and L forms
of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,
mandelic acid, malic acid, lactic acid or the various optically
active camphorsulfonic acids such as .beta.-camphorsulfonic acid.
Other resolving agents suitable for fractional crystallization
methods include stereoisomerically pure forms of
.alpha.-methylbenzylamine (e.g., S and R forms, or
diastereomerically pure forms), 2-phenylglycinol, norephedrine,
ephedrine, N-methylephedrine, cyclohexylethylamine,
1,2-diaminocyclohexane, camphoric acid,
.alpha.-methoxy-.alpha.-trifluoromethylphenylacetic acid (MTPA or
Mosher's acid), pyrrolidone-5-carboxylic acid,
di-O-isopropylene-keto-glutamic acid, di-toluoyl-tartaric acid, and
the like.
[0447] Resolution of racemic mixtures can also be carried out by
elution on a column packed with an optically active resolving agent
(e.g., dinitrobenzoylphenylglycine). Suitable elution solvent
composition can be determined by one skilled in the art.
[0448] Compounds of the invention can also include all isotopes of
atoms occurring in the intermediates or final compounds. Isotopes
include those atoms having the same atomic number but different
mass numbers. For example, isotopes of hydrogen include tritium and
deuterium.
[0449] Compounds of the invention can also include tautomeric
forms, such as keto-enol tautomers. Tautomeric forms can be in
equilibrium or sterically locked into one form by appropriate
substitution.
[0450] The present invention also includes salt forms of the
compounds described herein. Examples of salts (or salt forms)
include, but are not limited to, mineral or organic acid salts of
basic residues such as amines, alkali or organic salts of acidic
residues such as carboxylic acids, and the like. Generally, the
salt forms can be prepared by reacting the free base or acid with
stoichiometric amounts or with an excess of the desired
salt-forming inorganic or organic acid or base in a suitable
solvent or various combinations of solvents. Lists of suitable
salts are found in Remington's Pharmaceutical Sciences, 17th ed.,
Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure
of which is hereby incorporated by reference in its entirety.
[0451] Upon carrying out preparation of compounds according to the
processes described herein, the usual isolation and purification
operations such as concentration, filtration, extraction,
solid-phase extraction, recrystallization, chromatography, and the
like may be used, to isolate the desired products.
[0452] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner.
[0453] Those of skill in the art will readily recognize a variety
of noncritical parameters which can be changed or modified to yield
essentially the same results.
EXAMPLES
Example 1
Preparation of 2-(4-chlorophenyl)ethyl-N-2-chloropropionamide
##STR00048##
[0455] To a 1-liter, 3-necked round bottom flask under argon
balloon equipped with reflux condenser and addition funnel, were
added sequentially 2-(4-chlorophenyl) ethylamine (30 g, 193 mmol),
400 mL acetonitrile, triethylamine (19.5 g, 193 mmol) and 80 mL
acetonitrile. The clear colorless solution was stirred and cooled
to 0.degree. C. 2-Chloropropionyl chloride (24.5 g, 193 mmol,
distilled) in 5 mL acetonitrile was slowly added over 20 minutes to
evolution of white gas, formation of white precipitate, and color
change of reaction mixture to slight yellow. An additional 10 mL of
acetonitrile was used to rinse the addition funnel. The mixture was
stirred at 0.degree. C. for 30 minutes and then warmed to room
temperature and stirred vigorously for an additional one hour. The
yellow reaction mixture was concentrated on the rotary evaporator
to a solid containing triethylamine hydrochloride (76.36 grams).
This material was taken up in 100 mL ethylacetate and 200 mL water,
and stirred vigorously. The layers were separated and the aqueous
layer was extracted with an additional 100 mL ethylacetate. The
combined organic layers were washed twice with 25 mL of saturated
brine, dried over magnesium sulfate, filtered, and concentrated to
a light tan solid (41.6 grams, 88%). TLC in ethylacetate-hexane,
8:2 showed a major spot two-thirds of the way up the plate and a
small spot at the baseline. Baseline spot was removed as follows:
This material was taken up in 40 mL of ethylacetate and hexane was
added until the solution became cloudy. Cooling to 0.degree. C.
produced a white crystalline solid (40.2 grams, 85% yield). The
product is a known compound (Hasan et al., Indian J. Chem., 1971,
9(9), 1022) with CAS Registry No. 34164-14-2.
[0456] LC/MS gave product 2.45 minute; 246.1 M.sup.++H.sup.+.
[0457] .sup.1H NMR (CDCl.sub.3): .delta. 7.2 (dd, 4H, Ar), 6.7 (br
S, 1H, NH), 4.38 (q, 1H, CHCH.sub.3), 3.5 (q, 2H,
ArCH.sub.2CH.sub.2NH), 2.8 (t, 2H, ArCH.sub.2), 1.7 (d, 3H,
CH.sub.3).
[0458] .sup.13C NMR (CDCl.sub.3): 169 (1C, C.dbd.O), 136 (1C,
Ar--Cl), 132 (1C, Ar), 130 (2C, Ar), 128 (2C, Ar), 56 (1C, CHCl),
40 (1C, CHN), 34 (1C, CHAr), 22 (1C, CH.sub.3).
Example 2
Preparation of
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one
##STR00049##
[0460] 2-(4-Chlorophenyl)ethyl-N-2-chloropropionamide (10 g, 40.6
mmol) of Example 1 and aluminum chloride (16 g, 119.9 mmol) were
added to a clean dry 100 mL round bottom flask equipped with an
argon balloon, stirring apparatus, and heating apparatus. The white
solid melted to a tan oil with bubbling at 91.degree. C. (Note: if
impure starting materials are used, a black tar can result but
clean product can still be isolated). The mixture was heated and
stirred at 150.degree. C. for 12 hours. (Note: The time is
dependent on the reaction scale and can easily be followed by
LC/MS; higher temperatures can be used for shorter time periods.
E.g., a 1 gram sample was complete in 5 hours.) The reaction can be
followed by LC/MS with the starting material at 2.45 minutes (246.1
M.sup.++H.sup.+), the product at 2.24 minutes (209.6
M.sup.++H.sup.+) on a 5 minute reaction time from 5-95% w/0.01% TFA
in water/MeCN (50:50).
[0461] After cooling to room temperature, the reaction mixture was
quenched with slow addition of 10 mL of MeOH followed by 5 mL of 5%
HCl in water and 5 mL of ethyl acetate. After separation of the
resulting layers, the aqueous layer was extracted a second time
with 10 mL of ethyl acetate. The combined organic layers were dried
over magnesium sulfate, filtered, and concentrated to a tan solid
(6.78 grams, 80% yield). LC/MS showed one peak, at 2.2 min and
209.6 MI. This material was taken up in ethyl acetate, filtered
through celite and Kieselgel 60 (0.5 inch plug on a 60 mL Buchner
funnel) and the filtrate was recrystallized from hexane/ethyl
acetate to give final product (4.61 grams, 54% yield).
[0462] .sup.1H NMR (CDCl.sub.3): 7.3-7.1 (m, 3H, Ar), 5.6 (br S,
1H, NH), 4.23 (q, 1H, CHCH.sub.3), 3.8 (m, 1H,
ArCH.sub.2CH.sub.2NH), 3.49 (m, 1H, ArCH.sub.2CH.sub.2NH), 3.48 (m,
1H, ArCH.sub.2CH.sub.2NH), 3.05 (m, 1H, ArCH.sub.2CH.sub.2NH), 1.6
(d, 3H, CH.sub.2).
[0463] .sup.13C NMR (CDCl.sub.3): 178 (1C, C.dbd.O), 139 (1C, Ar),
135 (1C, Ar), 130, 129 (2C, Ar), 126 (2C, Ar), 42 (1C, C), 40 (1C,
CHN), 33 (1C, CHAr), 14 (1C, CH.sub.3).
Example 3
Preparation of
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
##STR00050##
[0464] Procedure A
[0465] HPLC purified
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (150 mg,
0.716 mmol) of Example 2 was added to a 50 mL round bottom flask
with 2M borane-tetrahydrofuran solution (2 mL, 2.15 mmol). The
mixture was stirred 10 hours at room temperature under an argon
balloon. LC/MS showed the desired product as the major peak with
approximately 5% of starting material still present. The reaction
mixture was quenched with 5 mL methanol and the solvents were
removed on the rotary evaporator. This procedure was repeated with
methanol addition and evaporation. The mixture was evaporated on
the rotary evaporator followed by 2 hours in vacuo to give the
product as a white solid (117 mg, 70% yield).
[0466] NMR, LC/MS and other analytical data are provided below.
Procedure B
[0467] Recrystallized
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (137 mg,
0.653 mmol) was added to a 50 mL round bottom flask with stirring
under nitrogen gas. To the flask was slowly added
borane-tetrahydrofuran solution (1M, 10 mL) followed by boron
trifluoride TBME solution (1 mL, 8.85 mmol) with vigorous gas
evolution. The mixture was stirred 6 hours at room temperature
under nitrogen gas. LC/MS showed the desired product. The reaction
mixture was quenched with 5 mL methanol and 3 mL conc. HCl and the
solvents were removed on the rotary evaporator. This procedure was
repeated with methanol and HCl addition and evaporation. The
mixture was evaporated on the rotary evaporator followed by 2 hours
on the pump to dryness to give
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride
(106 mg, 70% yield).
[0468] .sup.1H NMR (CDCl.sub.3): 10.2 (br s, 1H), 9.8 (br s, 1H),
7.14 (dd, 1H, J=2, 8 Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8
Hz), 3.6 (m, 2H), 3.5 (m, 2H), 2.8-3.0 (m, 3H), 1.5 (d, 3H, J=7
Hz).
[0469] LC/MS: 1.41 minute, 196.1 M+H.sup.+ and 139 major fragment.
No impurities were observed.
Example 4
Preparation of L-(+)-tartaric acid salt of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
##STR00051##
[0471] To a clean, dry 50 mL round bottom flask were added 11.5 g
(0.06 mol) of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
from Example 3 to 2.23 g (0.015 mol) of L-(+)-tartaric acid. The
suspension was diluted with 56 g of tert-butanol and 6.5 mL of
H.sub.2O. The mixture was heated to reflux (75-78.degree. C.) and
stirred for 10 min to obtain a colorless solution. The solution was
slowly cooled down to room temperature (during 1 h) and stirred for
3 h at room temperature. The suspension was filtered and the
residue was washed twice with acetone (10 mL). The product was
dried under reduced pressure (50 mbar) at 60.degree. C. to yield
6.3 g of the tartrate salt (ee=80). This tartrate salt was added to
56 g of tert-butanol and 6.5 mL of H.sub.2O. The resulting
suspension was heated to reflux and 1 to 2 g of H.sub.2O was added
to obtain a colorless solution. The solution was slowly cooled down
to room temperature (over the course of 1 h) and stirred for 3 h at
room temperature. The suspension was filtered and the residue was
washed twice with acetone (10 mL). The product was dried under
reduced pressure (50 mbar) at 60.degree. C. to produce 4.9 g (48%
yield) of product (ee >98.9).
[0472] If the ee value of the product obtained is not satisfactory,
an additional recrystallization can be carried out as described.
Either enantiomer can be synthesized in high ee utilizing this
method.
Example 5
Conversion of Salt Form to Free Amine
[0473] The L-tartaric acid salt of
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (300 mg, 0.87
mmol) from Example 4 was added to a 25 mL round bottom flask with
50% sodium hydroxide solution (114 .mu.L, 2.17 mmol) with an added
2 mL of water. The mixture was stirred 3 minutes at room
temperature. The solution was extracted with methylene chloride (5
mL) twice. The combined organic extracts were washed with water (5
mL) and evaporated to dryness on the pump to get free amine (220 mg
crude weight). LC/MS 196 (M+H).
Example 6
Preparation of 2-(4-Chlorophenyl)-N-ethyl-N-2-propylchloride
##STR00052##
[0475] To a dry 100-milliliter, round bottom flask under nitrogen
with stirring was added 2-(4-chlorophenyl)
ethyl-N-2-chloropropionylamide (8.8 g, 35.8 mmol) followed by
borane in THF (1.8 M, 70 mL, 140 mmol) over 10 minutes (gas
evolution and solid becomes solubilized). After the addition was
complete, boron trifluoride in tert-butyl methyl ether (8 mL, 70.8
mmol) was added over 10 minutes with more gas evolution. After 4
hours, LC/MS showed complete reaction. The reaction mixture was
quenched with 20 mL of conc. HCL (37%) with additional of gas
evolution. The reaction mixture was stirred at 40.degree. C. for 2
hours, cooled to room temperature and evaporated. Then, the white
slurry was taken up in 40 mL ethyl acetate and 20 mL of 2.5 M NaOH
to make a yellow solution over a white slurry. The yellow organic
layer was washed with brine, dried over magnesium sulfate, filtered
and evaporated to give 12.2 grams of white to yellow solid. This
solid was recrystallized from ethyl acetate/hexane in two crops to
give 6.7 grams of white solid product (80% yield).
[0476] .sup.1H NMR (DMSO-d6): 9.0 (br s, 2H, NH, HCl), 7.2 (d, 2H,
J=8 Hz), 7.05 (d, 2H, J=8 Hz), 4.5 (m, 1H), 3.2 (m, 2H), 3.1 (m,
2H), 3.0 (m, 2H), 1.5 (d, 3H, J=7 Hz).
[0477] LC/MS: 1.71 minute, 232.1 M+H.sup.+ and 139 major fragment.
Minor impurity observed at 2.46 min with 321 and 139 peaks.
Example 7
Preparation of
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
##STR00053##
[0478] Small Scale
[0479] 2-(4-Chlorophenyl)-N-ethyl-N-2-propylchloride (1 g, 4.3
mmol) of Example 6 was reacted with aluminum chloride (3 g, 22
mmol) in a dry 50 mL round bottom flask under nitrogen gas in an
oil bath at 120.degree. C. with stirring. Analysis by LC/MS showed
complete reaction in two hours. After cooling the resulting black
oil to room temperature, 20 mL ethyl acetate and 20 mL of pH 6
water were added. After 30 min of vigorous stirring the mixture was
solubilized to a clear colorless upper organic layer and a brown
clear lower aqueous layer. After separation of the layers, the
aqueous layer was extracted two additional times with 20 mL ethyl
acetate. The combined organic layers were dried over magnesium
sulfate, filtered and evaporated to give 0.55 grams (55% yield) of
a white to slightly yellow solid containing the HCl salt. This
material was found to be very hygroscopic. The remaining aqueous
layer (pH 6) was brought to pH 15 by addition of 5 grams of NaOH
pellets. The aqueous layer became a thick white emulsion. Three
times 40 mL of ethyl acetate were added to the thick white emulsion
and decanted off. The combined organic layers were dried over
magnesium sulfate, filtered and evaporated to give 0.3 g (36%) of a
brown oil containing free amine. The combined yield was 91%.
[0480] .sup.1H NMR (CDCl.sub.3): 7.2 (d, 1H, J=2.5 Hz), 7.15 (dd,
1H, J=2.5, 8 Hz), 7.05 (d, 1H, J=8 Hz), 3.6 (m, 2H), 3.5 (m, 2H),
3.1 (m, 2H), 2.9 (m, 2H), 1.5 (d, 3H, J=7 Hz).
[0481] .sup.13C NMR (CDCl.sub.3): 144, 136, 133, 131, 127 (2), 51,
45, 32, 30, 17.
[0482] LC/MS: 1.41 minute, 196.1 M+H.sup.+ and 139 major fragment.
No impurities observed.
Large Scale
[0483] 2-(4-Chlorophenyl)-N-ethyl-N-2-propylchloride (49.24 g,
179.92 mmol) and aluminum trichloride (34.79 g, 260.89 mmol) were
added to a flask under a nitrogen atmosphere. To this solid
mixture, 1,2-dichlorobenzene (139.31 g) was added resulting in a
suspension which was then heated to 120.degree. C. which was
associated with evolution of hydrogen chloride gas, which was
neutralized in a sodium hydroxide filled gas scrubber. The reaction
mixture became a yellow to brown solution which was heated at
120.degree. C. for a total of 12 hours. At the end of this time
HPLC analysis indicated that the ratio of product to starting
material was greater than 99:1 The reaction solution was cooled to
20 to 30.degree. C. and added drop-wise to a mixture of sodium
hydroxide solution (176.0 g, 1320 mmol) approx. 30%, water (79.5
g), and cyclohexane (176 g), so that the internal temperature did
not exceed 50.degree. C. The layers were separated and the lower
aqueous layer was extracted with cyclohexane (74 g). The combined
organic layers were extracted with a solution of aq. hydrochloric
acid (22.76 g, 231 mmol) 36/38% and water (68.23 g). The organic
layer was extracted with water (45.47 g). The combined aqueous
layers were washed with cyclohexane (37 g). To the aqueous layer
was added sodium hydroxide (40.08 g, 301 mmol) solution approx. 30%
and cyclohexane (100 g). The aqueous layer was extracted with
cyclohexane (100 g). The combined organic layers were concentrated
at 40.degree. C. to 60.degree. C. and a final vacuum of 30 mbar to
give 36.79 g, of a yellow oil. HPLC analysis indicated that the
product had a purity of 85.45%, thus giving a corrected yield of
89.29%.
Example 8
Preparation of 2-(4-chlorophenyl)ethylbromide
##STR00054##
[0485] 2-(4-Chlorophenyl)ethylbromide was prepared according to
Robert, et al., J. Org. Chem., 1987, 52, 5594).
Small Scale
[0486] To a 100-mililiter, round bottom flask under nitrogen
containing 2-(4-chlorophenyl)ethanol (10 g, 193 mmol) was added
phosphorous tribromide (19 g, 193 mmol) via syringe while cooling
0.degree. C. After the addition was complete, the ice bath was
removed and the mixture was heated to 95.degree. C. for two hours.
The reaction mixture was quenched with slow addition of water in an
ice bath. The material was taken up in 30 mL of methylene chloride,
the layers were separated, and the organic layer was dried over
magnesium sulfate, filtered, and evaporated to dryness to obtain
13.8 grams of clear oil (98% yield). LC/MS and proton NMR were as
expected. .sup.1H-NMR: 3.10 t, 3.51 t, 7.11 d, 7.26 d.
Large Scale
[0487] To 171.05 g (1.092 mol) of 2-(4-chlorophenyl)ethanol was
added dropwise 147.82 g (0.546 mol) of phosphorous tribromide over
3 hours and at a temperature of 0.degree. C. The mixture was
stirred at 0.degree. C. for 15 min, at room temperature for 2 h,
and then at 100.degree. C. for 2 h, cooled to 0.degree. C.,
hydrolyzed by dropwise addition of 400.0 g of water and diluted
with 400.0 g of tert-butyl methyl ether. The organic layer was
separated and washed with 100.0 g of water. The solvent was
distilled off under reduced pressure to yield a colorless liquid.
Yield: 95% (based on purity). Purity: 96%. Volume yield (reaction):
100.0%. Volume yield (extraction): 18.0%. .sup.1H-NMR: 3.10 t, 3.51
t, 7.11 d, 7.26 d.
Example 9
Preparation of 2-(4-chlorophenyl)-N-ethyl-N-2-propanol
##STR00055##
[0488] Small Scale
[0489] To 2-(4-chlorophenyl)ethylbromide (0.5 g, 2.28 mmol, from
Example 8) in a 25 mL round bottom flask were added
1-amino-2-propanol (1.7 g, 22.8 mmol) dropwise via syringe at
95.degree. C. The addition was carried out over one hour and the
reaction mixture was stirred at 95.degree. C. for an additional two
hours. Then, the reaction mixture was cooled to room temperature
and 3 mL of water were added, 10 mL of ethylacetate were added, and
the organic layer was separated, dried over magnesium sulfate,
filtered and concentrated to obtain 0.453 g of yellow solid (93%
yield). LC/MS and proton NMR were as expected.
Large Scale
[0490] To 821.25 g (10.93 mol) of 1-amino-2-propanol was added
dropwise 240.01 g (1.093 mol) of 2-(4-chlorophenyl)ethylbromide
during 3 hours and a temperature of 90-100.degree. C. The mixture
is stirred at 90-100.degree. C. for further 1 h, cooled to room
temperature, and diluted with 859.6 g of water. The water layer was
extracted three times with 150.0 g of tert-butyl methyl ether. The
combined organic phases were washed with 100.0 g of water, the
solvent was distilled off at a temperature of 60.degree. C. and
reduced pressure to yield a colorless solid with a melting point of
68-70.degree. C. Yield: 87% (based on purity). Purity: 99%. Volume
yield (reaction): 21%. Volume yield (extraction): 12%. 1H-NMR: 1.12
d, 2.42 dd, 2.5-2.9 m, 2.62 d, 2.82 t, 3.75 m, 7.11 d, 7.23 d.
Example 10
Preparation of 2-(4-chlorophenyl)-N-ethyl-N-2-propylbromide
##STR00056##
[0492] This preparation was based on Nagle et al., Tetrahedron
Letters, 2000, 41, 3011.
Small Scale
[0493] 2-(4-Chlorophenyl)-N-ethyl-N-2-propanol (453 mg, 2.12 mmol,
see Example 9) was dissolved in 1.5 mL methylene chloride and
dimethyl formamide (0.77 mL) was added to the solution. The
reaction mixture was cooled to at 0.degree. C. and thionyl bromide
(0.23 mL, 3.0 mmol) was added dropwise. The reaction was then
stirred at room temperature for two hours. The product
precipitated. The mixture was cooled to 0.degree. C. and the
precipitate was filtered and washed with cold methylene chloride to
obtain 350 mg of white solid. A second crop was obtained by
concentrating, retaking up in methylene chloride, and cooling to
obtain an additional 72 mg of product (56% yield).
[0494] .sup.1H NMR (DMSO-d6): 8.7 (br s, 1H), 8.6 (br s, 1H), 7.2
(d, 2H, J=8 Hz), 7.1 (d, 2H, J=8 Hz), 4.32 (m, 1H), 3.51 (br m,
1H), 3.28 (br m, 1H), 3.03 (m, 2H), 2.82 (m, 2H), 1.5 (d, 3H, J=7
Hz).
[0495] .sup.13C NMR (DMSO-d6): 136, 131, 130 (2), 128 (2), 53, 47,
44, 30, 23.
[0496] LC/MS: 1.56 min, 278 M+H.sup.+ (--HBr) and 139 major
fragment.
Large Scale
[0497] 194.0 g (0.91 mol) of
2-(4-chlorophenyl)-N-ethyl-N-2-propanol were dissolved in 1000.0 g
of CH.sub.2C.sub.12. Then 31.17 g (0.46 mol) of
N,N-Dimethylformamide were added and the clear solution was cooled
down to 0.degree. C. At this temperature, 264.3 g (1.4 mol) of
thionyl bromide were added within 1 h. After complete addition, the
reaction mixture was allowed to warm up to room temperature and
stirred for further 12 h, while precipitation of the product
occurred. The reaction mixture was cooled to 0.degree. C. and the
precipitate was filtered off and washed with 500.0 g of ice-cold
CH.sub.2C.sub.12, dried at 80.degree. C. under reduced pressure to
obtain an off-white powder with a melting point of 194-197.degree.
C. Yield: 63% (based on purity). Purity: 97%. Volume yield
(reaction): 14%. .sup.1H-NMR: 1.80 d, 3.05 m, 3.15 m, 3.45 m, 4.59
m, 7.15 d, 7.40 d, 8.95 s.
Example 11
Preparation of 2-(4-chlorophenyl)-N-ethyl-N-2-propylchloride
##STR00057##
[0499] 267 g (125 mmol) of 2-(4-chlorophenyl)-N-ethyl-N-2-propanol
was diluted with 364 g of toluene and warmed to 40.degree. C. 19.30
g, 222 mmol dimethylacetamide were added and following this 111.83
g 940 mmol thionyl chloride was added dropwise so that the internal
temperature was kept between 40 and 60.degree. C. The resulting
thick suspension was stirred for 2 to 3 hours at 60 to 65.degree.
C. The suspension was filtered and washed with 335 g of toluene via
the reactor. The resulting 397.1 g of a brown crude product was
suspended in 326 g of isopropanol and 35.2 g of water, and heated
to approx. 80 to 85.degree. C. to reflux forming a clear brown
solution. The solution was then cooled over 3 to 12 h to 0 to
5.degree. C. and stirred for at least 1 hour at 0 to 5.degree. C.,
before being centrifuged. The wet product was washed with 146 g of
isopropanol in several parts via the reactor and with 100 g of
isopropanol directly over the filter cake (when the material is
still colored, the amount of isopropanol can be increased until
colourless material is obtained). About 790 g of mother liquid with
pH=0 was also formed. 157.93 g of a white to lightly beige wet
product was yielded, which was dried at 70.degree. C. in vacuum at
30 mbar. Yield: 113.42 g (99.53 percent by weight).
Example 12
Preparation of
8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
##STR00058##
[0500] Small Scale
[0501] To 2-(4-chlorophenyl)-N-ethyl-N-2-propylbromide (0.343 g,
0.959 mmol, see Example 10) in a 50 mL round bottom flask was added
aluminum chloride (0.192 g, 1.44 mmol). The two solids were heated
at 140.degree. C. for 4 hours and then cooled to 90.degree. C.
Toluene (350 microliters) was added and the reaction mixture was
cooled to room temperature. Water (350 microliters) was added as
well as 1 gram of ice. The mixture was stirred for 15 minutes then
sodium hydroxide solution (350 microliters of a solution made up of
2 g of NaOH in 6 g water) was added. The reaction mixture was
extracted three times with ethyl acetate. The organic layer was
washed with brine, dried over magnesium sulfate and concentrated to
give 218 mg of a dark yellow oil product (90% yield).
[0502] Attempted distillation of the oil product at 115-180.degree.
C. and 0.1 torr caused decomposition and dimerization.
[0503] LC/MS and proton NMR are as expected.
Large Scale
[0504] A 750 mL reaction vessel was charged with
2-(4-chlorophenyl)-N-ethyl-N-2-propylbromide (240 g, 0.67 mol) to
which aluminum chloride (134 g, 1.01 mol) and 1,2-dichlorobenzene
(480 g) were added. The resulting suspension was heated to
138-142.degree. C. (yellow solution) and HBr-gas evolved
(neutralized with sodium hydroxide solution). The reaction was
stirred for 8-12 hours (monitored by HPLC). The reaction was cooled
to 20-30.degree. C. and transferred to a dropping funnel.
Extraction mixture containing water (300 g), 30% sodium hydroxide
solution (670 g), and cyclohexane (670 g) was added to the reaction
vessel. The reaction solution was added portionwise to the
extraction mixture while cooling keeping the temperature below
50.degree. C. The resulting layers were separated and the aqueous
phase was extracted with cyclohexane (144 g). The organic layers
were combined and extracted with a solution of HCl (pH of the water
layer was <2). The organic layer was extracted once more with
water. The combined water layers were washed with cyclohexane. A
30% sodium hydroxide solution (100 g) was then added (pH of the
water layer was >13). The water layer was first extracted with
cyclohexane (720 g) and then with further cyclohexane (144 g). The
combined organic layers were dried over sodium sulfate. The sodium
sulfate was filtered out and the filtrate was evaporated under
reduced pressure at a temperature of 45-50.degree. C. Crude product
was obtained as a glutinous oil (134.42 g).
Example 13
Large Scale Preparation of L-(+)-tartaric acid salt of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
[0505] Crude product (134.32 g) of the large scale synthesis of
Example 12 was dissolved in tert-butanol (480 g). An aqueous
solution of L-(+)-tartaric acid (21 g of acid in 30 g of water) and
seed crystals were added. The solution was stirred at 15-25.degree.
C. overnight until crystals formed. The resulting suspension was
filtered and the precipitate washed with acetone. EE was 68.1%
(HPLC). The precipitate was then refluxed in additional
tert-butanol (480 g) and water (10 g). Water (80 g) was added until
the precipitate dissolved completely and then the solution was
cooled to 15-25.degree. C. and stirred overnight. The resulting
precipitate was filtered out and washed with acetone. EE was 96.8%
(HPLC). The precipitate was again refluxed in additional
tert-butanol (480 g) and stirred for 1 hour at reflux. The
resulting suspension was cooled to 15-25.degree. C. and stirred
overnight. The resulting precipitate was filtered out and washed
with acetone. EE was 98.7% (HPLC) and the product was dried under
vacuum at 60.degree. C. Yield was 34.96 g.
Example 14
Preparation of Hydrochloric Acid Salt of
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
[0506] To a clean, dry 25 mL round bottom flask were added
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free
amine (220 mg), 3 mL methylene chloride, and 1.74 mL of 1M HCl in
ether. The mixture was stirred for 5 minutes at room temperature.
The solvent was removed under reduced pressure to give a white
solid, the HCl salt. The salt was re-dissolved in methylene
chloride (3 mL) and an additional 1.74 mL of 1 M HCl was added and
the solution was again stirred at room temperature for 5 minutes.
The solvent was removed under reduced pressure to give the desired
HCl salt of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(190 mg crude weight, 95% yield). NMR data was consistent with the
desired product.
[0507] .sup.1H NMR (CDCl.sub.3): 10.2 (br s, 1H), 9.8 (br s, 1H),
7.14 (dd, 1H, J=2, 8 Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8
Hz), 3.6 (m, 2H), 3.5 (m, 2H), 2.8-3.0 (m, 3H), 1.5 (d, 3H, J=7
Hz).
[0508] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims. Each reference cited
in the present application is incorporated herein by reference in
its entirety.
* * * * *