U.S. patent application number 13/741498 was filed with the patent office on 2013-05-23 for process for the preparation of chymase modulators.
This patent application is currently assigned to Janssen Pharmaceutica, NV. The applicant listed for this patent is Janssen Pharmaceutica, NV. Invention is credited to Luigi Anzalone, Llias Konstantinos Dorziotis, Penina Feibush, Xun Li, Frank J. Villani.
Application Number | 20130131401 13/741498 |
Document ID | / |
Family ID | 42129268 |
Filed Date | 2013-05-23 |
United States Patent
Application |
20130131401 |
Kind Code |
A1 |
Anzalone; Luigi ; et
al. |
May 23, 2013 |
PROCESS FOR THE PREPARATION OF CHYMASE MODULATORS
Abstract
The present invention is a process for the preparation of
chymase modulators, useful in the treatment of inflammatory and
serine protease mediated disorders.
Inventors: |
Anzalone; Luigi; (West
Chester, PA) ; Feibush; Penina; (Ambler, PA) ;
Dorziotis; Llias Konstantinos; (Somerville, NJ) ; Li;
Xun; (New Hope, PA) ; Villani; Frank J.;
(Perkasie, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Pharmaceutica, NV; |
Beerse |
|
BE |
|
|
Assignee: |
Janssen Pharmaceutica, NV
Beerse
BE
|
Family ID: |
42129268 |
Appl. No.: |
13/741498 |
Filed: |
January 15, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13570545 |
Aug 9, 2012 |
8378122 |
|
|
13741498 |
|
|
|
|
12608585 |
Oct 29, 2009 |
8263785 |
|
|
13570545 |
|
|
|
|
61197815 |
Oct 29, 2008 |
|
|
|
Current U.S.
Class: |
570/144 |
Current CPC
Class: |
C07F 9/5728 20130101;
C07F 9/657181 20130101; C07F 9/4021 20130101; C07F 9/655354
20130101; C07C 17/087 20130101; C07F 9/4075 20130101; C07F 9/4006
20130101 |
Class at
Publication: |
570/144 |
International
Class: |
C07C 17/087 20060101
C07C017/087 |
Claims
1. A process for the preparation of a compound of formula (III)
##STR00119## comprising the step of ##STR00120## (a) reacting a
compound of formula (II) with a brominating agent; in the presence
of a catalyst; in a mixture of water and an organic solvent; to
yield the corresponding compound of formula (III).
2. A process as in claim 1, wherein the compound of formula (II) is
present in an excess of its corresponding trans isomer; wherein the
brominating agent is 1-bromo-pyrrolidine-2,5-dione; wherein the
brominating agent is present in an amount of about 1.1 molar
equivalents; wherein the catalyst is manganese acetate hydrate;
wherein the catalyst is present in an amount of about 0.5 molar
equivalents; wherein the organic solvent is acetonitrile; and
wherein the compound of formula (II) is reacted with brominating
agent at a temperature in the range of from about 25.degree. C. to
about 70.degree. C.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 13/570,545, filed on Aug. 9, 2012, which is a divisional of
nonprovisional U.S. application Ser. No. 12/608,585, filed on Oct.
29, 2009, now U.S. Pat. No. 8,263,785, issued on Sep. 11, 2012,
which claims the benefit of U.S. Provisional Application No.
61/197,815, filed on Oct. 29, 2008, which are all incorporated by
reference herein in their entirety.
FIELD OF THE INVENTION
[0002] The present invention is a process for the preparation of
chymase modulators, useful in the treatment of inflammatory and
serine protease mediated disorders.
SUMMARY OF THE INVENTION
[0003] The present invention is directed to a process for the
preparation of compounds of formula (I)
##STR00001##
[0004] wherein
##STR00002##
is independently selected from the group consisting of aryl,
heteroaryl, and benzo fused heterocyclyl; optionally substituted
with R.sup.2 and R.sup.3;
[0005] R.sup.2 is one to three substituents independently selected
from the group consisting of C.sub.1-4alkyl, methoxy,
C.sub.2-6alkoxy, NH.sub.2, NH(C.sub.1-6alkyl),
--N(C.sub.1-6)dialkyl, aryl, heteroaryl, halogen, hydroxy, and
nitro;
[0006] wherein the C.sub.1-4alkyl and C.sub.2-6 alkoxy substituents
of R.sup.2 are optionally substituted with a substituent
independently selected from the group consisting of
--NR.sup.11R.sup.12, aryl heteroaryl, one to three halogens and
hydroxy; wherein R.sup.11 and R.sup.12 are substituents
independently selected from the group consisting of hydrogen,
C.sub.1-6 alkyl, and aryl; wherein the C.sub.1-6alkyl substituent
of R.sup.11 or R.sup.12 is optionally substituted with a
substituent selected from the group consisting of hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, and --NR.sup.15R.sup.16;
[0007] wherein said R.sup.15 and R.sup.16 are substituents
independently selected from the group consisting of hydrogen,
C.sub.1-6 alkyl, and aryl,
[0008] alternatively, R.sup.15 and R.sup.16 are taken together with
the atoms to which they are attached to form a ring of five to
seven members;
[0009] R.sup.3 is one to three substituents independently selected
from the group consisting of C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.1-6alkoxy, --OCH.sub.2(C.sub.2-6)alkenyl, NH.sub.2,
--NH(C.sub.1-6alkyl), --N(C.sub.1-6)dialkyl, --NHC(.dbd.O)Cy,
--N(C.sub.1-6alkyl)C(.dbd.O)Cy, --C(.dbd.O)C.sub.1-4alkoxy,
--C(.dbd.O)NR.sup.17R.sup.18, --C(.dbd.O)NHcycloalkyl,
--C(.dbd.O)N(C.sub.1-6alkyl)cycloalkyl, --C(.dbd.O)NHCy,
--C(.dbd.O)N(C.sub.1-6alkyl)Cy, --C(.dbd.O)Cy,
--OC(.dbd.O)NR.sup.19R.sup.20, halogen, hydroxy, nitro, cyano,
aryl, and aryloxy;
[0010] wherein alkyl and alkoxy are optionally substituted with one
to three substituents independently selected from the group
consisting of --NR.sup.21R.sup.22, --NHcycloalkyl,
--N(C.sub.1-6alkyl)cycloalkyl, --NHCy, --N(C.sub.1-6alkyl)Cy, aryl,
heteroaryl, halogen, --C(.dbd.O)NR.sup.23R.sup.24,
--OC(.dbd.O)NR.sup.25R.sup.26, --C(.dbd.O)(C.sub.1-4)alkoxy, and
--C(.dbd.O)Cy; wherein alkenyl is optionally substituted on a
terminal carbon with aryl and --C(.dbd.O)NR.sup.27R.sup.28; and,
wherein aryl and cycloalkyl are optionally substituted with one to
three substituents independently selected from R.sup.14;
[0011] each R.sup.14 is independently hydrogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.2-6alkenyl, C.sub.1-6alkylthio, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; wherein any one
of the foregoing Cl.sub.--6alkyl- or C.sub.1-6alkoxy-containing
substituents of R.sup.14 is optionally substituted on a terminal
carbon atom with a substituent selected from --NR.sup.29R.sup.30,
aryl, heteroaryl, one to three halogen atoms, or hydroxy;
[0012] R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22,
R.sup.23, R.sup.24, R.sup.25 and R.sup.26 are substituents
independently selected from the group consisting of hydrogen,
C.sub.1-6alkyl and aryl; wherein the C.sub.1-6alkyl and aryl are
each optionally substituted with hydroxy, aryl, aryloxy,
--C(.dbd.O)-aryl, --C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2,
--NH(C.sub.1-6alkyl), or --N(C.sub.1-6)dialkyl; alternatively,
R.sup.17 and R.sup.18, R.sup.19 and R.sup.20, R.sup.21 and
R.sup.22, R.sup.23 and R.sup.24 or R.sup.25 and R.sup.26 are taken
together with the atoms to which they are attached to form a ring
of five to seven members;
[0013] R.sup.27 and R.sup.28 are independently hydrogen;
C.sub.1-6alkyl optionally substituted with hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2, --NH(C.sub.1-6alkyl) or
--N(C.sub.1-6)dialkyl; or aryl; alternatively, R.sup.27 and
R.sup.28 are taken together with the atoms to which they are
attached to form a ring of five to seven members;
[0014] R.sup.29 and R.sup.30 are independently hydrogen,
C.sub.1-6alkyl optionally substituted with hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2, --NH(C.sub.1-6alkyl), or
--N(C.sub.1-6)dialkyl; or aryl; alternatively, R.sup.29 and
R.sup.30 are taken together with the atoms to which they are
attached to form a ring of five to seven members;
[0015] Cy is a heterocyclyl optionally substituted with a
substituent selected from the group consisting of C.sub.1-6 alkyl,
C.sub.1-6alkylC(.dbd.O)C.sub.1-6alkyl,
--C.sub.1-6alkylC(.dbd.O)C.sub.1-6alkoxy,
C.sub.1-6alkylC(.dbd.O)aryl, --C(.dbd.O)(C.sub.1-6)alkyl,
--C(.dbd.O)(C.sub.1-6)alkoxy, --C(.dbd.O)aryl, --SO.sub.2aryl,
aryl, heteroaryl, and heterocyclyl; wherein aryl and the aryl
portion of the C.sub.1-6alkylC(.dbd.O)aryl, --C(.dbd.O)aryl and
--SO.sub.2aryl are optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen, hydroxy, NH.sub.2,
NH(C.sub.1-6alkyl), or --N(C.sub.1-6)dialkyl; and wherein
heterocyclyl is optionally substituted with aryl, one to three
halogen atoms, or one to three oxo substituents; and, wherein
heterocyclyl is optionally spiro-fused to said Cy;
[0016] R.sup.5 is selected from the group consisting of
hydrogen;
[0017] C.sub.1-3alkyl optionally substituted with NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl,
C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkoxycarbonyloxy,
C.sub.1-6alkylcarbonylthio, (C.sub.1-6)alkylaminocarbonyl,
di(C.sub.1-6)alkylaminocarbonyl, one to three halogens, or
hydroxy;
[0018] and aryl optionally substituted with C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.2-6 alkenyl, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, halogen, hydroxy, or nitro;
[0019] alternatively, when R.sup.6 is C.sub.1-8alkoxy, R.sup.5 and
R.sup.6 are taken together with the atoms to which they are
attached to form a 5-8 membered monocyclic ring;
[0020] and provided that R.sup.5 is other than C.sub.1-3alkyl
substituted with di(C.sub.1-6)alkylamino-carbonyl when ring system
A is 3,4-difluoro-phenyl, R.sup.6 is OH, and Z--R.sup.4 is
5-chloro-benzothiophen-3-yl; and provided that R.sup.5 is other
than C.sub.1-3alkyl substituted with C.sub.1-6alkylcarbonylthio
when ring system A is 3,4-difluoro-phenyl, R.sup.6 is CH.sub.3, and
Z--R.sup.4 is 5-chloro-benzothiophen-3-yl;
[0021] R.sup.6 is selected from the group consisting of
C.sub.1-6alkyl, C.sub.1-8alkoxy, heteroaryl, aryl, and hydroxy;
wherein alkyl and C.sub.1-8alkoxy are optionally substituted on a
terminal carbon atom with a substituent selected from
C.sub.1-3alkoxy, aryl, or hydroxy; and alkoxy is optionally
substituted on a terminal carbon with a substituent independently
selected from the group consisting of C.sub.1-6alkylcarbonyloxy,
and di(C.sub.1-6)alkylaminocarbonyl; and wherein heteroaryl and
aryl are optionally substituted with one to three substituents
independently selected from the group consisting of aryl, hydroxy,
C.sub.1-6alkoxy, and halogen;
[0022] Z is a bicyclic aryl or bicyclic heteroaryl;
[0023] R.sup.4 is one to three substituents selected from the group
consisting of H, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkoxy,
aryl(C.sub.2-6)alkenyl, halogen, --C(.dbd.O)Cy,
--C(.dbd.O)NR.sup.31R.sup.32, aryl, --CO.sub.2H, oxo, and cyano;
wherein the alkyl and alkoxy are optionally substituted with a
substituent independently selected from the group consisting of
--NR.sup.33R.sup.34, aryl, one to three halogen atoms, and hydroxy;
wherein the aryl is optionally substituted with a substituent
independently selected from the group consisting of hydrogen,
C.sub.1-6alkyl, C.sub.1-6alkoxy, aryl, halogen, hydroxy, and
nitro;
[0024] wherein said R.sup.31, R.sup.32, R.sup.33, and R.sup.34 are
substituents independently selected from the group consisting of
hydrogen, C.sub.1-6 alkyl, and aryl, wherein alkyl is optionally
substituted with hydroxy, aryl, --C(.dbd.O)C.sub.1-4alkoxy,
NH.sub.2, NH(C.sub.1-6alkyl), or --N(C.sub.1-6)dialkyl; or R.sup.31
with R.sup.32, or R.sup.33 with R.sup.34 are optionally taken
together with the atoms to which they are attached to form a ring
of five to seven members;
[0025] and pharmaceutically acceptable salts thereof; comprising
the steps of
##STR00003##
[0026] (a) reacting a compound of formula (IV), wherein PG.sup.1 is
an oxygen protecting group; with a source of nitrogen; in the
presence of CO.sub.2 gas; in an organic solvent; to yield the
corresponding compound of formula (IX);
##STR00004##
[0027] (b) reacting the compound of formula (IX) with a compound of
formula (XVI); in the presence of CuI; in the presence of an
inorganic base; in the presence of a ligand; in an organic solvent
or mixture thereof; to yield the corresponding compound of formula
(XVII);
##STR00005##
[0028] (c) de-protecting the compound of formula (XVII); to yield
the corresponding compound of formula (Ia); and
##STR00006##
[0029] (d) optionally reacting the compound of formula (Ia) with a
compound of formula (XVIII), wherein Q.sup.1 is a leaving group and
wherein R.sup.5 is other than hydrogen; in the presence of an
organic base; in an organic solvent; to yield the corresponding
compound of formula (Ib), wherein R.sup.5 is other than
hydrogen.
[0030] The present invention is further directed to processes for
the preparation of compound of formula (I)
##STR00007##
[0031] wherein
##STR00008##
R.sup.2, R.sup.3, Z, R.sup.4, R.sup.5 and R.sup.6 are as described
herein above; and pharmaceutically acceptable salt thereof;
comprising the steps of
##STR00009##
[0032] (a) reacting a compound of formula (IV) with CO.sub.2; in
the presence of a base; in an organic solvent or mixture thereof;
to yield the corresponding compound of formula (V);
##STR00010##
[0033] (b) activating the compound of formula (V); to yield the
corresponding compound of formula (A1); wherein Y.sup.1 is selected
from the group consisting of chloro, --O--C(O)--C.sub.1-4alkyl and
1-imidazolyl;
##STR00011##
[0034] (c) reacting the compound of formula (A1) with a source of
ammonia; in an organic solvent; to yield the corresponding compound
of formula (IX);
##STR00012##
[0035] (d) reacting the compound of formula (IX) with a compound of
formula (XVI); in the presence of CuI; in the presence of an
inorganic base; in the presence of a ligand; in an organic solvent
or mixture thereof; to yield the corresponding compound of formula
(XVII);
##STR00013##
[0036] (e) de-protecting the compound of formula (XVII); to yield
the corresponding compound of formula (Ia); and
##STR00014##
[0037] (f) optionally reacting the compound of formula (Ia) with a
compound of formula (XVIII), wherein Q.sup.1 is a leaving group and
wherein R.sup.5 is other than hydrogen; in the presence of an
organic base; in an organic solvent; to yield the corresponding
compound of formula (Ib), wherein R.sup.5 is other than
hydrogen.
[0038] Step (b) of said process is preferably accomplished by:
[0039] reacting the compound of formula (V) with a source of
chlorine; in an organic solvent; to yield the corresponding
compound of formula (A1) wherein Y.sup.1 is Cl; or
[0040] reacting the compound of formula (V) with a C.sub.1-4alkyl
chloroformate; in an organic solvent; to yield the corresponding
compound of formula (A1), wherein Y is --O--C(O)--C.sub.1-4alkyl;
or
[0041] reacting the compound of formula (V) with CDI; in an organic
solvent; to yield the corresponding compound of formula (A1),
wherein Y.sup.1 is 1-imidazolyl.
[0042] The present invention is further directed to processes for
the preparation of compounds of formula (I)
##STR00015##
[0043] wherein
##STR00016##
R.sup.2, R.sup.3, Z, R.sup.4, R.sup.5 are as described herein above
and R.sup.6 is hydroxy; and pharmaceutically acceptable salts
thereof; comprising the steps of
##STR00017##
[0044] (a) reacting a compound of formula (X), wherein PG.sup.1 is
an oxygen protecting group and PG.sup.2 is an oxygen protecting
group; with a source of nitrogen; in the presence of CO.sub.2 gas;
in an organic solvent; to yield the corresponding compound of
formula (XV);
##STR00018##
[0045] (b) reacting the compound of formula (XV) with a compound of
formula (XVI); in the presence of CuI; in the presence of an
inorganic base; in the presence of a ligand; in an organic solvent
or mixture thereof; to yield the corresponding compound of formula
(XIX);
##STR00019##
[0046] (c) de-protecting the compound of formula (XIX); to yield
the corresponding compound of formula (Ic); and
##STR00020##
[0047] (d) optionally reacting the compound of formula (Ic) with a
compound of formula (XVIII), wherein Q.sup.1 is a leaving group and
wherein R.sup.5 is other than hydrogen; in the presence of an
organic base; in an organic solvent; to yield the corresponding
compound of formula (Id), wherein R.sup.5 is other than
hydrogen.
[0048] The present invention is further directed to a process for
the preparation of compounds of formula (I)
##STR00021##
[0049] wherein
##STR00022##
R.sup.2, R.sup.3, Z, R.sup.4, R.sup.5 are as described herein above
and R.sup.6 is hydroxy; and pharmaceutically acceptable salts
thereof; comprising the steps of
##STR00023##
[0050] (a) reacting a compound of formula (X) with CO.sub.2; in the
presence of a base; in an organic solvent or mixture thereof; to
yield the corresponding compound of formula (XI);
##STR00024##
[0051] (b) activating the compound of formula (XI); to yield the
corresponding compound of formula (A2), wherein Y.sup.1 is selected
from the group consisting of chloro, --O--C(O)--C.sub.1-4alkyl and
1-imidazolyl;
##STR00025##
[0052] (c) reacting the compound of formula (A2) with a source of
ammonia; in an organic solvent; to yield the corresponding compound
of formula (XV);
##STR00026##
[0053] (d) reacting the compound of formula (XV) with a compound of
formula (XVI); in the presence of CuI; in the presence of an
inorganic base; in the presence of a ligand; in an organic solvent
or mixture thereof; to yield the corresponding compound of formula
(XIX);
##STR00027##
[0054] (e) de-protecting the compound of formula (XIX); to yield
the corresponding compound of formula (Ic); and
##STR00028##
[0055] (f) optionally reacting the compound of formula (Ic) with a
compound of formula (XVIII), wherein Q.sup.1 is a leaving group and
wherein R.sup.5 is other than hydrogen; in the presence of an
organic base; in an organic solvent; to yield the corresponding
compound of formula (Id), wherein R.sup.5 is other than
hydrogen.
[0056] Step (b) of said process is preferably accomplished by:
[0057] reacting the compound of formula (V) with a source of
chlorine; in an organic solvent; to yield the corresponding
compound of formula (A1) wherein Y.sup.1 is Cl; or
[0058] reacting the compound of formula (V) with a C.sub.1-4alkyl
chloroformate; in an organic solvent; to yield the corresponding
compound of formula (A1), wherein Y is --O--C(O)--C.sub.1-4alkyl;
or
[0059] reacting the compound of formula (V) with CDI; in an organic
solvent; to yield the corresponding compound of formula (A1),
wherein Y.sup.1 is 1-imidazolyl.
[0060] The present invention is further directed to compounds of
formula (L)
##STR00029##
[0061] wherein
[0062] PG.sup.1 is an oxygen protecting group;
[0063] R.sup.10 is selected from the group consisting of
--O--PG.sup.2 and R.sup.6;
[0064] PG.sup.2 is an oxygen protecting group
[0065] R.sup.6 is selected from the group consisting of
C.sub.1-6alkyl, C.sub.1-8alkoxy, heteroaryl, aryl, and hydroxy;
wherein alkyl and C.sub.1-8alkoxy are optionally substituted on a
terminal carbon atom with a substituent selected from
C.sub.1-3alkoxy, aryl, or hydroxy; and alkoxy is optionally
substituted on a terminal carbon with a substituent independently
selected from the group consisting of C.sub.1-6alkylcarbonyloxy,
and di(C.sub.1-6)alkylaminocarbonyl; and wherein heteroaryl and
aryl are optionally substituted with one to three substituents
independently selected from the group consisting of aryl, hydroxy,
C.sub.1-6alkoxy, and halogen.
[0066] Z is a bicyclic aryl or bicyclic heteroaryl;
[0067] R.sup.4 is one to three substituents selected from the group
consisting of H, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkoxy,
aryl(C.sub.2-6)alkenyl, halogen, --C(.dbd.O)Cy,
--C(.dbd.O)NR.sup.31R.sup.32, aryl, --CO.sub.2H, oxo, and cyano;
wherein the alkyl and alkoxy are optionally substituted with a
substituent independently selected from the group consisting of
--NR.sup.33R.sup.34, aryl, one to three halogen atoms, and hydroxy;
wherein the aryl is optionally substituted with a substituent
independently selected from the group consisting of hydrogen,
C.sub.1-6alkyl, C.sub.1-6alkoxy, aryl, halogen, hydroxy, and
nitro;
[0068] wherein said R.sup.31, R.sup.32, R.sup.33, and R.sup.34 are
substituents independently selected from the group consisting of
hydrogen, C.sub.1-6 alkyl, and aryl, wherein alkyl is optionally
substituted with hydroxy, aryl, --C(.dbd.O)C.sub.1-4alkoxy,
NH.sub.2, NH(C.sub.1-6alkyl), or --N(C.sub.1-6)dialkyl; or R.sup.31
with R.sup.32, or R.sup.33 with R.sup.34 are optionally taken
together with the atoms to which they are attached to form a ring
of five to seven members;
[0069] or a pharmaceutically acceptable salt thereof.
[0070] The present invention is further directed to a process for
the preparation of compounds of formula (IX)
##STR00030##
[0071] wherein PG.sup.1, R.sup.6, Z and R.sup.4 substituents as
described herein above (compounds of formula (L) wherein R.sup.10
is R.sup.6); and pharmaceutically acceptable salts thereof;
comprising the step of
##STR00031##
[0072] (a) reacting a compound of formula (IV), wherein PG.sup.1 is
an oxygen protecting group; with a source of nitrogen; in the
presence of CO.sub.2 gas; in an organic solvent; to yield the
corresponding compound of formula (IX).
[0073] The present invention is further directed to processes for
the preparation of compounds of formula (IX)
##STR00032##
[0074] wherein PG.sup.1, R.sup.6, Z and R.sup.4 are as described
herein above (compounds of formula (L) wherein R.sup.10 is
R.sup.6); and pharmaceutically acceptable salts thereof; comprising
the step of
##STR00033##
[0075] (a) reacting a compound of formula (IV) with CO.sub.2; in
the presence of a base; in an organic solvent or mixture thereof;
to yield the corresponding compound of formula (V);
##STR00034##
[0076] (b) activating the compound of formula (V); to yield the
corresponding compound of formula (A1); wherein Y.sup.1 is selected
from the group consisting of chloro, --O--C(O)--C.sub.1-4alkyl and
1-imidazolyl;
##STR00035##
[0077] (c) reacting the compound of formula (A1) with a source of
ammonia; in an organic solvent; to yield the corresponding compound
of formula (IX).
[0078] Step (b) of said process is preferably accomplished by:
[0079] reacting the compound of formula (V) with a source of
chlorine; in an organic solvent; to yield the corresponding
compound of formula (A1) wherein Y.sup.1 is Cl; or
[0080] reacting the compound of formula (V) with a C.sub.1-4alkyl
chloroformate; in an organic solvent; to yield the corresponding
compound of formula (A1), wherein Y is --O--C(O)--C.sub.1-4alkyl;
or
[0081] reacting the compound of formula (V) with CDI; in an organic
solvent; to yield the corresponding compound of formula (A1),
wherein Y.sup.1 is 1-imidazolyl.
[0082] The present invention is further directed to processes for
the preparation of compounds of formula (XV)
##STR00036##
[0083] wherein PG.sup.1, PG.sup.2, Z and R.sup.4 are as described
herein above (compounds of formula (L) wherein R.sup.10 is
--O--PG.sup.2); and pharmaceutically acceptable salts thereof;
comprising the step of
##STR00037##
[0084] (a) reacting a compound of formula (X), wherein PG.sup.1 is
an oxygen protecting group and PG.sup.2 is an oxygen protecting
group; with a source of nitrogen; in the presence of CO.sub.2 gas;
in an organic solvent; to yield the corresponding compound of
formula (XV).
[0085] The present invention is further directed to processes for
the preparation of compounds of formula (XV)
##STR00038##
[0086] wherein PG.sup.1, PG.sup.2, Z and R.sup.4 are as described
herein above (compounds of formula (L) wherein R.sup.10 is
--O--PG.sup.2); and pharmaceutically acceptable salts thereof;
comprising the step of
##STR00039##
[0087] (a) reacting a compound of formula (X) with CO.sub.2; in the
presence of a base; in an organic solvent or mixture thereof; to
yield the corresponding compound of formula (XI);
##STR00040##
[0088] (b) activating the compound of formula (XI); to yield the
corresponding compound of formula (A2), wherein Y.sup.1 is selected
from the group consisting of chloro, --O--C(O)--C.sub.1-4alkyl and
1-imidazolyl;
##STR00041##
[0089] (c) reacting the compound of formula (A2) with a source of
ammonia; in an organic solvent; to yield the corresponding compound
of formula (XV).
[0090] Step (b) of said process is preferably accomplished by:
[0091] reacting the compound of formula (V) with a source of
chlorine; in an organic solvent; to yield the corresponding
compound of formula (A1) wherein Y.sup.1 is Cl; or
[0092] reacting the compound of formula (V) with a C.sub.1-4alkyl
chloroformate; in an organic solvent; to yield the corresponding
compound of formula (A1), wherein Y is --O--C(O)--C.sub.1-4alkyl;
or
[0093] reacting the compound of formula (V) with CDI; in an organic
solvent; to yield the corresponding compound of formula (A1),
wherein Y.sup.1 is 1-imidazolyl.
[0094] The present invention is further directed to a process for
the preparation of a compound of formula (III)
##STR00042##
[0095] comprising the step of
##STR00043##
[0096] (a) reacting a compound of formula (II) with a brominating
agent; in the presence of a catalyst; in a mixture of water and an
organic solvent; to yield the corresponding compound of formula
(III).
[0097] The present invention is further directed to a product
prepared according to any of the processes described herein.
DETAILED DESCRIPTION OF THE INVENTION
[0098] The present invention is directed to a process for the
preparation of compound of formula (I)
##STR00044##
[0099] wherein Z, R.sup.4, R.sup.5, R.sup.6, R.sup.2, R.sup.3
and
##STR00045##
are as herein defined; and pharmaceutically acceptable salts
thereof. The compounds of formula (I), prepared according to the
processes described herein, are useful in methods for treating or
ameliorating a serine protease-mediated disorder, as disclosed in
U.S. Pat. No. 7,459,444, issued Dec. 2, 2008, which is incorporated
by reference herein in its entirety.
[0100] In particular, the compounds of formula (I) are useful in
treating or ameliorating a chymase mediated disorder such as, but
not limited to, allergic rhinitis, viral rhinitis, asthma, chronic
obstructive pulmonary diseases, bronchitis, pulmonary emphysema,
acute lung injury (e.g. adult (acute) respiratory distress
syndrome), psoriasis, arthritis, reperfusion injury, ischemia,
hypertension, hypercardia, myocardial infarction, heart failure
damage associated with myocardial infarction, cardiac hypertrophy,
arteriosclerosis, saroidosis, vascular stenosis or restenosis
(e.g., associated with vascular injury, angioplasty, vascular
stents or vascular grafts), pulmonary fibrosis, kidney fibrosis
(e.g., associated with glomerulonephritis), liver fibrosis, post
surgical adhesion formation, systemic sclerosis, keloid scars,
rheumatoid arthritis, bullous pemphigiod, and atherosclerosis.
Additionally, the compounds of formula (I) are useful for
modulating wound healing and remodeling (e.g., cardiac hypertrophy)
as well as immune modulation.
[0101] In an embodiment, the present invention is directed to a
process for the preparation of compounds of formula (I-S)
##STR00046##
[0102] wherein
[0103] R.sup.2 and R.sup.3 are each independently selected from
halogen;
[0104] R.sup.5 is selected from the group consisting of hydrogen
and C.sub.1-3alkyl; wherein the C.sub.1-3alkyl is optionally
substituted with C.sub.1-6alkylcarbonyloxy or
C.sub.1-6alkoxycarbonyloxy;
[0105] R.sup.6 is hydroxy;
[0106] and pharmaceutically acceptable salts thereof; as described
in more detail herein.
[0107] In an embodiment, the present invention is directed to
processes for the preparation of compounds of formula (I) wherein
R.sup.6 is other than hydroxy.
[0108] In another embodiment, the present invention is directed to
processes for the preparation of compounds of formula (I) wherein
R.sup.6 is C.sub.1-4alkyl.
[0109] In another embodiment, the present invention is directed to
processes for the preparation of compounds of formula (I) wherein
R.sup.6 is hydroxy.
[0110] In an embodiment, the present invention is directed to
processes for the preparation of compounds of formula (I) wherein
R.sup.5 is hydrogen.
[0111] In another embodiment, the present invention is directed to
processes for the preparation of compounds of formula (I) wherein
R.sup.5 is selected from the group consisting of
--CH.sub.2--O--C(O)-t-butyl and
--CH.sub.2--O--C(O)--O-isopropyl.
[0112] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I-A)
##STR00047##
[0113] also known as
E-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamo-
yl]-methyl)-methyl}-phosphinic acid, and pharmaceutically
acceptable salts thereof.
[0114] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I-B)
##STR00048##
[0115] also known as
E-{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamo-
yl]-methyl}-phosphonic acid, and pharmaceutically acceptable salts
thereof.
[0116] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I-C)
##STR00049##
[0117] also known as
E-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamo-
yl]-methyl}-hydroxy-phosphinoyloxymethyl ester
2,2-dimethyl-propionic acid, and pharmaceutically acceptable salts
thereof.
[0118] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I-D)
##STR00050##
[0119] also known as
E-{(5-Chloro-benzo[b]thiophen-3-yl)-[2-3,4-difluoro-phenyl)-vinylcarbamoy-
l]-methyl}-phosphonic acid monoisopropoxycarbonyloxymethyl ester,
and pharmaceutically acceptable salts thereof; as described in more
detail herein.
[0120] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I-E)
##STR00051##
[0121] also known as
E-{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-vinylcarbamo-
yl]-methyl}-methyl-phosphinic acid, and pharmaceutically acceptable
salts thereof.
[0122] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I-F)
##STR00052##
[0123] also known as
E-{(5-Chloro-benzo[b]thiophen-3-yl)-[2-3,5-dichloro-phenyl)-vinylcarbamoy-
l]-methyl}-phosphonic acid, and pharmaceutically acceptable salts
thereof.
[0124] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I-G)
##STR00053##
[0125] also known as
E-{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-vinylcarbamo-
yl]-methyl}-hydroxy-phosphinoyloxymethyl ester
2,2-dimethyl-propionic acid, and pharmaceutically acceptable salts
thereof.
[0126] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I-H)
##STR00054##
[0127] also known as
E-{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,5-dichloro-phenyl)-vinylcarbamo-
yl]-methyl}-phosphonic acid monoisopropoxycarbonyloxymethyl ester,
and pharmaceutically acceptable salts thereof; as described in more
detail hereinafter.
[0128] The present invention is further directed to compounds of
formula (L)
##STR00055##
[0129] wherein PG.sup.1, R.sup.10, Z and R.sup.4 are as described
herein above; and pharmaceutically acceptable salts thereof.
[0130] In an embodiment, the present invention is further directed
to compounds of formula (L) wherein R.sup.10 is R.sup.6; herein
referred to as compounds of formula (IX)
##STR00056##
[0131] In an embodiment, the present invention is further directed
to compounds of formula (L) wherein R.sup.10 is O--PG.sup.2; herein
referred to as compounds of formula (XV)
##STR00057##
[0132] The present invention is further directed to processes for
the preparation of compounds of formula (L), as described in more
detail herein.
[0133] In an embodiment, the present invention is directed to
processes for the preparation of the compounds of formula (IX), as
described in more detail herein. The compounds of formula (IX) are
useful as intermediates in the synthesis of the compounds of
formula (I).
[0134] In another embodiment, the present invention is directed
processes for the preparation of compounds of formula (XV), as
described in more detail herein. The compounds of formula (XV) are
useful as intermediates in the synthesis of the compounds of
formula (I), more particularly compounds of formula (I) wherein
R.sup.6 is hydroxy.
[0135] In another embodiment, the present invention is directed to
processes for the preparation of a compound of formula (IX-S)
##STR00058##
[0136] wherein PG.sup.1 is an oxygen protecting group (preferably
PG.sup.1 is selected from the group consisting of
C.sub.1-4alkyl);
[0137] R.sup.6 is selected from the group consisting of
C.sub.1-6alkyl, C.sub.1-8alkoxy, heteroaryl, aryl, and hydroxy;
wherein alkyl and C.sub.1-8alkoxy are optionally substituted on a
terminal carbon atom with a substituent selected from
C.sub.1-3alkoxy, aryl, or hydroxy; and alkoxy is optionally
substituted on a terminal carbon with a substituent independently
selected from the group consisting of C.sub.1-6alkylcarbonyloxy,
and di(C.sub.1-6)alkylaminocarbonyl; and wherein heteroaryl and
aryl are optionally substituted with one to three substituents
independently selected from the group consisting of aryl, hydroxy,
C.sub.1-6alkoxy, and halogen; as described in more detail
herein.
[0138] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (IX-S)
wherein R.sup.6 is methyl.
[0139] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (IX-S)
wherein R.sup.6 is hydroxy.
[0140] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (IX-S)
wherein PG.sup.1 is ethyl; and wherein R.sup.6 is selected from the
group consisting of methyl and hydroxy.
[0141] In another embodiment, the present invention is directed to
processes for the preparation of a compound of formula (XV-S)
##STR00059##
[0142] wherein PG.sup.1 is an oxygen protecting group and PG.sup.2
is an oxygen protecting group; as described in more detail
herein.
[0143] In an embodiment of the present invention, PG.sup.1 and
PG.sup.2 are the same oxygen protecting group.
[0144] In another embodiment of the present invention, PG.sup.1 and
PG.sup.2 are different oxygen protecting groups.
[0145] In another embodiment of the present invention, PG.sup.1 and
PG.sup.2 are each independently selected from C.sub.1-4alkyl.
[0146] In another embodiment of the present invention, PG.sup.1 and
PG.sup.2 are the same and are selected from the group consisting of
methyl and ethyl.
[0147] The present invention is directed to a process for the
preparation of a compound selected from the group consisting of a
compound of formula (III)
##STR00060##
[0148] as described in more detail herein.
[0149] In an embodiment of the present invention, the compound of
formula (III) is present in an excess of its trans isomer of
greater than or equal to about 90%, preferably greater than or
equal to about 95%, more preferably greater than or equal to about
98%, more preferably greater than or equal to about 99%.
[0150] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I)
wherein
##STR00061##
is selected from group consisting of naphthyl, benzothiazolyl,
benzothiophenyl, quinolinyl, isoquinolinyl, dihydronaphthyl,
indanyl, tetralinyl and benzodioxolyl when n is equal to zero; and
A is selected from phenyl, pyridin-2-yl, or pyridin-3-yl when n is
equal to one.
[0151] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I)
wherein
##STR00062##
is selected from phenyl, pyridin-2-yl, or pyridin-3-yl when n is
equal to one.
[0152] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein
R.sup.2 is a substituent independently selected from the group
consisting of C.sub.1-4alkyl, methoxy, C.sub.2-4alkoxy, hydroxy,
halogen, and --NH.sub.2.
[0153] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein
R.sup.3 is one to three substituents independently selected from
the group consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy,
--NR.sup.19R.sup.20, --NHC(.dbd.O)Cy, --C(.dbd.O)NR.sup.17R.sup.18,
--C(.dbd.O)NHcycloalkyl, --C(.dbd.O)N(C.sub.1-6alkyl)cycloalkyl,
halogen, and aryl; wherein alkyl and alkoxy are optionally
substituted on a terminal carbon atom with one to three fluorine
atoms, --NH.sub.2, --NHCy, or --N(C.sub.1-4alkyl)Cy; and wherein
aryl and cycloalkyl are optionally substituted with a group
independently selected from R.sup.14.
[0154] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein
R.sup.5 is hydrogen or C.sub.1-3alkyl optionally substituted with
C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkoxycarbonyloxy,
C.sub.1-6alkylcarbonylthio, (C.sub.1-6)alkylaminocarbonyl, or
di(C.sub.1-6)alkylaminocarbonyl; and alternatively, when R.sup.6 is
C.sub.1-8alkoxy, R.sup.5 and R.sup.6 are taken together with the
atoms to which they are attached to form a 6-membered monocyclic
ring; and provided that R.sup.5 is other than C.sub.1-3alkyl
substituted with di(C.sub.1-6)alkylamino-carbonyl when ring system
A is 3,4-difluoro-phenyl, R.sup.6 is OH, and Z--R.sup.4 is
5-chloro-benzothiophen-3-yl; and provided that R.sup.5 is other
than C.sub.1-3alkyl substituted with C.sub.1-6alkylcarbonylthio
when ring system A is 3,4-difluoro-phenyl, R.sup.6 is CH.sub.3, and
Z--R.sup.4 is 5-chloro-benzothiophen-3-yl.
[0155] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein
R.sup.6 is selected from the group consisting of methyl, ethyl,
methoxypropyl, phenethyl, benzo[1,3]dioxol-5-yl-propyl, hydroxy,
and C.sub.1-3alkoxy optionally substituted with
C.sub.1-6alkylcarbonyloxy, and
di(C.sub.1-6)alkylamino-carbonyl.
[0156] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein Z
is independently selected from the group consisting of indolyl,
benzothiophenyl, naphthalenyl, quinolinyl, isoquinolinyl and
benzothiazolonyl.
[0157] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein
R.sup.4 is one to three substituents selected from the group
consisting of C.sub.1-6alkyl, C.sub.1-6alkenyl,
aryl(C.sub.2-6)alkenyl, halogen, and --C(.dbd.O)Cy; wherein aryl is
optionally substituted with a substituent selected from halogen or
C.sub.1-4alkoxy.
[0158] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I)
wherein
##STR00063##
is a ring system of the formula:
##STR00064##
[0159] wherein the a.sup.1 portion of said a.sup.1a.sup.2 is
optionally substituted with R.sup.2; and the a.sup.2 portion is
optionally substituted with R.sup.3 and n is 0. In another
embodiment, the present invention is directed to a process for the
preparation of a compound of formula (I) wherein
##STR00065##
is a ring system of the formula:
##STR00066##
[0160] and wherein the a.sup.2 portion is aromatic and
##STR00067##
[0161] is selected from group consisting of naphthyl,
benzothiazolyl, benzothiophenyl, quinolinyl, isoquinolinyl,
dihydronaphthyl, indanyl, tetralinyl and benzodioxolyl.
[0162] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein
R.sup.2 is a substituent independently selected from the group
consisting of C.sub.1-4alkyl, methoxy, C.sub.2-4alkoxy, hydroxy,
halogen, and --NH.sub.2.
[0163] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein
R.sup.3 is one to three substituents independently selected from
the group consisting of C.sub.1-6alkyl, Cl.sub.1-6alkoxy,
--NR.sup.19R.sup.20, --NHC(.dbd.O)Cy, --C(.dbd.O)NR.sup.17R.sup.18,
--C(.dbd.O)NHcycloalkyl, --C(.dbd.O)N(C.sub.1-6alkyl)cycloalkyl,
halogen, and aryl; wherein alkyl and alkoxy are optionally
substituted on a terminal carbon atom with one to three fluorine
atoms, --NH.sub.2, --NHCy, or --N(C.sub.1-4alkyl)Cy; and wherein
aryl and cycloalkyl are optionally substituted with a group
independently selected from R.sup.14.
[0164] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein
R.sup.5 is hydrogen or C.sub.1-3alkyl optionally substituted with
C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkoxycarbonyloxy,
C.sub.1-6alkylcarbonylthio, (C.sub.1-6)alkylaminocarbonyl, or
di(C.sub.1-6)alkylaminocarbonyl; and alternatively, when R.sup.6 is
C.sub.1-8alkoxy, R.sup.5 and R.sup.6 are taken together with the
atoms to which they are attached to form a 6-membered monocyclic
ring; provided that R.sup.5 is other than C.sub.1-3alkyl
substituted with di(C.sub.1-6)alkylaminocarbonyl when ring system A
is 3,4-difluoro-phenyl, R.sup.6 is OH, and Z--R.sup.4 is
5-chloro-benzothiophen-3-yl; and provided that R.sup.5 is other
than C.sub.1-3alkyl substituted with C.sub.1-6alkylcarbonylthio
when ring system A is 3,4-difluoro-phenyl, R.sup.6 is CH.sub.3, and
Z--R.sup.4 is 5-chloro-benzothiophen-3-yl.
[0165] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein
R.sup.6 is selected from the group consisting of methyl, ethyl,
methoxypropyl, phenethyl, benzo[1,3]dioxol-5-yl-propyl, hydroxy,
and C.sub.1-3alkoxy optionally substituted with
C.sub.1-6alkylcarbonyloxy, and
di(C.sub.1-6)alkylamino-carbonyl.
[0166] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein Z
is independently selected from the group consisting of indolyl,
benzothiophenyl, naphthalenyl, quinolinyl, isoquinolinyl, and
benzothiazolone.
[0167] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein
R.sup.4 is one to three substituents selected from the group
consisting of C.sub.1-6alkyl, C.sub.1-6alkenyl,
aryl(C.sub.2-6)alkenyl, halogen, and --C(.dbd.O)Cy; wherein aryl is
optionally substituted with a substituent selected from halogen or
C.sub.1-4alkoxy.
[0168] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein
R.sup.1, ring A, R.sup.2, R.sup.3, R.sup.5, R.sup.6, Z, and R.sup.4
are selected from the group consisting of
TABLE-US-00001 ##STR00068## R.sup.5 R.sup.6 Z--R.sup.4
3,4-difluoro-phenyl H OH 5-Cl-benzothiophen-3-yl 4-fluoro-phenyl H
OH 5-Cl-N-methyl-indol-3-yl 3-fluoro-phenyl H CH.sub.3
5-Cl-N-methyl-indol-3-yl 3,4-difluoro-phenyl H CH.sub.3
5-Cl-N-methyl-indol-3-yl 4-amino-phenyl H OH
5-Cl-benzothiophen-3-yl Phenyl H CH.sub.3 5-Cl-benzothiophen-3-yl
3-fluoro-phenyl H CH.sub.3 5-Cl-benzothiophen-3-yl 3,4,5-trifluoro-
H CH.sub.3 5-Cl-benzothiophen-3-yl phenyl 3,4-difluoro-phenyl H
CH.sub.3 5-Cl-benzothiophen-3-yl phenyl H OH
5-Cl-benzothiophen-2-yl 4-fluoro-phenyl H OH
5-Cl-benzothiophen-3-yl 2-fluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 4-fluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl pyridin-3-yl H OH 5-Cl-benzothiophen-3-yl
3,4-difluoro-phenyl H CH.sub.2CH.sub.3 5-Cl-benzothiophen-3-yl
phenyl H OH naphthalen-1-yl 4-methoxy-phenyl H OH
5-Cl-benzothiophen-3-yl 4-methyl-phenyl H OH
5-Cl-benzothiophen-2-yl 3,4-dimethoxy- H OH 5-Cl-benzothiophen-3-yl
phenyl 4-hydroxy-phenyl H OH 5-Cl-benzothiophen-3-yl
4-chloro-phenyl H CH.sub.3 5-Cl-benzothiophen-3-yl
4-trifluoromethyl- H OH 5-Cl-benzothiophen-3-yl phenyl
2-methoxy-phenyl H CH.sub.3 5-Cl-benzothiophen-3-yl 2-nitro-phenyl
H CH.sub.3 5-Cl-benzothiophen-3-yl 2- H CH.sub.3
5-Cl-benzothiophen-3-yl methylcarbonyloxy- phenyl 2-hydroxy-phenyl
H CH.sub.3 5-Cl-benzothiophen-3-yl pyridin-2-yl H CH.sub.3
5-Cl-benzothiophen-3-yl 2-amino-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 3-trifluoromethyl- H CH.sub.3
5-Cl-benzothiophen-3-yl phenyl 3-trifluoromethoxy- H CH.sub.3
5-Cl-benzothiophen-3-yl phenyl 3-methoxy-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 2-methyl-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 2,6-difluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 4-cyano-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 2-ureido-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 2- H CH.sub.3 5-Cl-benzothiophen-3-yl
(NHC.dbd.O)).sub.2NH.sub.2- phenyl 2-chloro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 3-chloro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 3,5-difluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 2,3-difluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 2-bromo-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 2,3-dimethoxy- H CH.sub.3
5-Cl-benzothiophen-3-yl phenyl 3-nitro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 3-bromo-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 3,5-dimethoxy- H CH.sub.3
5-Cl-benzothiophen-3-yl phenyl 2,5-difluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 3,5-dichloro- H CH.sub.3
5-Cl-benzothiophen-3-yl phenyl 2,4-difluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 3-amino-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl phenyl --CH.sub.2C(Me).sub.2CH.sub.2O--
naphthalen-1-yl phenyl 3-methoxy- OH naphthalen-1-yl prop-1-yl
phenyl 3-methoxy- 3-methoxy- naphthalen-1-yl prop-1-yl
prop-1-yl-oxy phenyl 2-(1,3-dioxolan- OH naphthalen-1-yl
2-yl)-eth-1-yl phenyl --CH.sub.2OC(.dbd.O) OH naphthalen-1-yl
t-butyl phenyl --CH.sub.2CH.sub.2CH.sub.2O-- naphthalen-1-yl phenyl
(2-dimethyl- 2-dimethyl- naphthalen-1-yl amino)- amino-ethoxy
eth-1-yl phenyl --CH.sub.2C(.dbd.O) --OCH.sub.2C(.dbd.O)
naphthalen-1-yl NEt.sub.2 NEt.sub.2 phenyl
--(CH.sub.2).sub.2SC(.dbd.O) --O(CH.sub.2).sub.2SC(.dbd.O)
naphthalen-1-yl t-butyl t-butyl 3,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl
3,4-difluoro-phenyl (2-dimethyl CH.sub.3 5-Cl-benzothiophen-3-yl
amino)- eth-1-yl 3,4-difluoro-phenyl (2-amino)- CH.sub.3
5-Cl-benzothiophen-3-yl eth-1-yl 3,4-difluoro-phenyl
--CH.sub.2C(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl NEt.sub.2
3,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O)
5-Cl-benzothiophen-3-yl t-butyl t-butyl 3,4-difluoro-
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl phenyl t-butyl
3,4-difluoro-phenyl --CH.sub.2C(.dbd.O) --OCH.sub.2C(.dbd.O)
5-Cl-benzothiophen-3-yl NEt.sub.2 NEt.sub.2 3,4-difluoro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl
3,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
methyl 3,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy 2-methoxy-phenyl H OH
5-Cl-benzothiophen-3-yl pyridin-2-yl H OH 5-Cl-benzothiophen-3-yl
3-trifluoromethoxy- H OH 5-Cl-benzothiophen-3-yl phenyl
3-methoxy-phenyl H OH 5-Cl-benzothiophen-3-yl 2,6-difluoro-phenyl H
OH 5-Cl-benzothiophen-3-yl 2-chloro-phenyl H OH
5-Cl-benzothiophen-3-yl 3-chloro-phenyl H OH
5-Cl-benzothiophen-3-yl 3,5-difluoro-phenyl H OH
5-Cl-benzothiophen-3-yl 2,3-difluoro-phenyl H OH
5-Cl-benzothiophen-3-yl 2-bromo-phenyl H OH 5-Cl-benzothiophen-3-yl
2,3-dimethoxy- H OH 5-Cl-benzothiophen-3-yl phenyl 3-nitro-phenyl H
OH 5-Cl-benzothiophen-3-yl 3-bromo-phenyl H OH
5-Cl-benzothiophen-3-yl 3,5-dimethoxy- H OH 5-Cl-benzothiophen-3-yl
phenyl 2,5-difluoro-phenyl H OH 5-Cl-benzothiophen-3-yl
3,5-dichloro- H OH 5-Cl-benzothiophen-3-yl phenyl
2,4-difluoro-phenyl H OH 5-Cl-benzothiophen-3-yl 3-amino-phenyl H
OH 5-Cl-benzothiophen-3-yl 2-methoxy-phenyl --CH.sub.2OC(.dbd.O)
CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl pyridin-2-yl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl
3-trifluoromethoxy- --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl phenyl t-butyl 3-methoxy-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl
2,6-difluoro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl t-butyl 2-chloro-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl
3-chloro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl t-butyl 3,5-difluoro-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl
2,3-difluoro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl t-butyl 2-bromo-phenyl --CH.sub.2OC(.dbd.O)
CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl 2,3-dimethoxy-
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl phenyl
t-butyl 3-nitro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl t-butyl 3-bromo-phenyl --CH.sub.2OC(.dbd.O)
CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl 3,5-dimethoxy-
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl phenyl
t-butyl 2,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl t-butyl 3,5-dichloro- --CH.sub.2OC(.dbd.O)
CH.sub.3 5-Cl-benzothiophen-3-yl phenyl t-butyl 2,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl
3-amino-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl t-butyl 2-methoxy-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl
t-butyl t-butyl pyridin-2-yl --CH.sub.2OC(.dbd.O)
--OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl t-butyl t-butyl
3-trifluoromethoxy- --CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O)
5-Cl-benzothiophen-3-yl phenyl t-butyl t-butyl 3-methoxy-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl
t-butyl t-butyl 2,6-difluoro-phenyl --CH.sub.2OC(.dbd.O)
--OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl t-butyl t-butyl
2-chloro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O)
5-Cl-benzothiophen-3-yl t-butyl t-butyl 3-chloro-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl
t-butyl t-butyl 3,5-difluoro-phenyl --CH.sub.2OC(.dbd.O)
--OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl t-butyl t-butyl
2,3-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O)
5-Cl-benzothiophen-3-yl t-butyl t-butyl 2-bromo-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl
t-butyl t-butyl 2,3-dimethoxy- --CH.sub.2OC(.dbd.O)
--OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl phenyl t-butyl
t-butyl 3-nitro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O)
5-Cl-benzothiophen-3-yl t-butyl t-butyl 3-bromo-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl
t-butyl t-butyl 3,5-dimethoxy- --CH.sub.2OC(.dbd.O)
--OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl phenyl t-butyl
t-butyl 2,5-difluoro-phenyl --CH.sub.2OC(.dbd.O)
--OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl t-butyl t-butyl
3,5-dichloro- --CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O)
5-Cl-benzothiophen-3-yl phenyl t-butyl t-butyl 2,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl
t-butyl t-butyl 3-amino-phenyl --CH.sub.2OC(.dbd.O)
--OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl t-butyl t-butyl
2-methoxy-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl pyridin-2-yl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl 3-trifluoromethoxy-
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl phenyl t-butyl
3-methoxy-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl 2,6-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl 2-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl t-butyl
3-chloro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl 3,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl 2,3-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl t-butyl
2-bromo-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl 2,3-dimethoxy- --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl phenyl t-butyl 3-nitro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl t-butyl
3-bromo-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl 3,5-dimethoxy- --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl phenyl t-butyl 2,5-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl t-butyl
3,5-dichloro- --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
phenyl t-butyl 2,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl
t-butyl 3-amino-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl 2-methoxy-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl pyridin-2-yl
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl
3-trifluoromethoxy- --CH.sub.2CH.sub.2CH.sub.2O--
5-Cl-benzothiophen-3-yl phenyl 3-methoxy-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl
2,6-difluoro-phenyl --CH.sub.2CH.sub.2CH.sub.2O--
5-Cl-benzothiophen-3-yl 2-chloro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl
3-chloro-phenyl --CH.sub.2CH.sub.2CH.sub.2O--
5-Cl-benzothiophen-3-yl 3,5-difluoro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl
2,3-difluoro-phenyl --CH.sub.2CH.sub.2CH.sub.2O--
5-Cl-benzothiophen-3-yl 2-bromo-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl
2,3-dimethoxy- --CH.sub.2CH.sub.2CH.sub.2O--
5-Cl-benzothiophen-3-yl phenyl 3-nitro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl
3-bromo-phenyl --CH.sub.2CH.sub.2CH.sub.2O--
5-Cl-benzothiophen-3-yl 3,5-dimethoxy-
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl phenyl
2,5-difluoro-phenyl --CH.sub.2CH.sub.2CH.sub.2O--
5-Cl-benzothiophen-3-yl 3,5-dichloro- --CH.sub.2CH.sub.2CH.sub.2O--
5-Cl-benzothiophen-3-yl phenyl 2,4-difluoro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl
3-amino-phenyl --CH.sub.2CH.sub.2CH.sub.2O--
5-Cl-benzothiophen-3-yl 2-methoxy-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy pyridin-2-yl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl isopropyloxy
3-trifluoromethoxy- --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
phenyl isopropyloxy 3-methoxy-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy 2,6-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl isopropyloxy
2-chloro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
isopropyloxy 3-chloro-phenyl --CH.sub.2 OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy 3,5-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl isopropyloxy
2,3-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
isopropyloxy 2-bromo-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy 2,3-dimethoxy-
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl phenyl isopropyloxy
3-nitro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
isopropyloxy 3-bromo-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy 3,5-dimethoxy-
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl phenyl isopropyloxy
2,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
isopropyloxy 3,5-dichloro- --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl phenyl isopropyloxy 2,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl isopropyloxy
3-amino-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
isopropyloxy 3-fluoro-5-chloro- H CH.sub.3 5-Cl-benzothiophen-3-yl
phenyl 2-fluoro-3-chloro- H CH.sub.3 5-Cl-benzothiophen-3-yl phenyl
4-fluoro-3-chloro- H CH.sub.3 5-Cl-benzothiophen-3-yl phenyl
2-fluoro-5-chloro- H CH.sub.3 5-Cl-benzothiophen-3-yl phenyl
3,5-dibromo- H CH.sub.3 5-Cl-benzothiophen-3-yl phenyl
3-cyano-phenyl H CH.sub.3 5-Cl-benzothiophen-3-yl 2-cyano-phenyl H
CH.sub.3 5-Cl-benzothiophen-3-yl 3-fluoro-5- H CH.sub.3
5-Cl-benzothiophen-3-yl trifluoromethyl- phenyl 3-fluoro-5-chloro-
H OH 5-Cl-benzothiophen-3-yl phenyl 2-fluoro-3-chloro- H OH
5-Cl-benzothiophen-3-yl phenyl 4-fluoro-3-chloro- H OH
5-Cl-benzothiophen-3-yl phenyl 2-fluoro-5-chloro- H OH
5-Cl-benzothiophen-3-yl phenyl 3,5-dibromo- H OH
5-Cl-benzothiophen-3-yl phenyl 3-cyano-phenyl H OH
5-Cl-benzothiophen-3-yl 2-cyano-phenyl H OH 5-Cl-benzothiophen-3-yl
3-fluoro-5- H OH 5-Cl-benzothiophen-3-yl trifluoromethyl- phenyl
3-fluoro-5-chloro- --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl phenyl t-butyl 2-fluoro-3-chloro-
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl phenyl
t-butyl 4-fluoro-3-chloro- --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl phenyl t-butyl 2-fluoro-5-chloro-
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl phenyl
t-butyl 3,5-dibromo- --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl phenyl t-butyl 3-cyano-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl
2-cyano-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl t-butyl 3-fluoro-5- --CH.sub.2OC(.dbd.O)
CH.sub.3 5-Cl-benzothiophen-3-yl trifluoromethyl- t-butyl phenyl
3-fluoro-5-chloro- --CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O)
5-Cl-benzothiophen-3-yl phenyl t-butyl t-butyl 2-fluoro-3-chloro-
--CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl
phenyl t-butyl t-butyl 4-fluoro-3-chloro- --CH.sub.2OC(.dbd.O)
--OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl phenyl t-butyl
t-butyl 2-fluoro-5-chloro- --CH.sub.2OC(.dbd.O)
--OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl phenyl t-butyl
t-butyl 3,5-dibromo- --CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O)
5-Cl-benzothiophen-3-yl phenyl t-butyl t-butyl 3-cyano-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl
t-butyl t-butyl 2-cyano-phenyl --CH.sub.2OC(.dbd.O)
--OCH.sub.2OC(.dbd.O) 5-Cl-benzothiophen-3-yl t-butyl t-butyl
3-fluoro-5- --CH.sub.2OC(.dbd.O) --OCH.sub.2OC(.dbd.O)
5-Cl-benzothiophen-3-yl trifluoromethyl- t-butyl t-butyl phenyl
3-fluoro-5-chloro- --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
phenyl t-butyl 2-fluoro-3-chloro- --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl phenyl t-butyl 4-fluoro-3-chloro-
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl phenyl t-butyl
2-fluoro-5-chloro- --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
phenyl t-butyl 3,5-dibromo- --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl phenyl t-butyl 3-cyano-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl t-butyl
2-cyano-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl 3-fluoro-5- --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
trifluoromethyl- t-butyl phenyl 3-fluoro-5-chloro-
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl phenyl
2-fluoro-3-chloro- --CH.sub.2CH.sub.2CH.sub.2O--
5-Cl-benzothiophen-3-yl phenyl 4-fluoro-3-chloro-
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl phenyl
2-fluoro-5-chloro- --CH.sub.2CH.sub.2CH.sub.2O--
5-Cl-benzothiophen-3-yl phenyl 3,5-dibromo-
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl phenyl
3-cyano-phenyl --CH.sub.2CH.sub.2CH.sub.2O--
5-Cl-benzothiophen-3-yl 2-cyano-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl 3-fluoro-5-
--CH.sub.2CH.sub.2CH.sub.2O-- 5-Cl-benzothiophen-3-yl
trifluoromethyl- phenyl 3-fluoro-5-chloro- --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl phenyl isopropyloxy 2-fluoro-3-chloro-
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl phenyl isopropyloxy
4-fluoro-3-chloro- --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
phenyl isopropyloxy 2-fluoro-5-chloro- --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl phenyl isopropyloxy 3,5-dibromo-
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl phenyl isopropyloxy
3-cyano-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
isopropyloxy 2-cyano-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy 3-fluoro-5-
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl. trifluoromethyl-
isopropyloxy phenyl
[0169] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) selected
from the group consisting of:
##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073##
##STR00074## ##STR00075##
[0170] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I) selected
from the group consisting of:
##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080##
##STR00081## ##STR00082##
[0171] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I) wherein
ring A, R.sup.2, R.sup.3, R.sup.5, R.sup.6, Z, and R.sup.4 are
selected from the group consisting of:
TABLE-US-00002 Formula ##STR00083## R.sup.5 R.sup.6 Z--R.sup.4
(I-A) 3,4-difluoro- H CH.sub.3 5-chloro-benzo- phenyl thiophen-3-yl
(I-B) 3,4-difluoro- H OH 5-chloro-benzo- phenyl thiophen-3-yl (I-C)
3,4-difluoro- --CH.sub.2OC(O)-t-butyl OH 5-chloro-benzo- phenyl
thiophen-3-yl (I-D) 3,4-difluoro- --CH.sub.2OC(O)- OH
5-chloro-benzo- phenyl isopropyloxy thiophen-3-yl (I-E)
3,5-dichloro- H CH.sub.3 5-chloro-benzo- phenyl thiophen-3-yl (I-F)
3,5-dichloro- H OH 5-chloro-benzo- phenyl thiophen-3-yl (I-G)
3,5-dichloro- --CH.sub.2OC(O)-t-butyl OH 5-chloro-benzo- phenyl
thiophen-3-yl (I-H) 3,5-dichloro- --CH.sub.2OC(O)- 5-chloro-benzo-
phenyl isopropyloxy OH thiophen-3-yl.
[0172] In yet another embodiment, the present invention is directed
to a process for the preparation of a compound of formula (I)
selected from the group consisting of
##STR00084## ##STR00085##
[0173] As used herein, unless otherwise noted, "alkyl" whether used
alone or as part of a substituent group refers to straight and
branched carbon chains having 1 to 8 carbon atoms or any number
within this range. The term "alkoxy" refers to an --Oalkyl
substituent group, wherein alkyl is as defined supra. Similarly,
the terms "alkenyl" and "alkynyl" refer to straight and branched
carbon chains having 2 to 8 carbon atoms or any number within this
range, wherein an alkenyl chain has at least one double bond in the
chain and an alkynyl chain has at least one triple bond in the
chain. An alkyl and alkoxy chain may be substituted on a terminal
carbon atom or, when acting as a linking group, within the carbon
chain.
[0174] The term "cycloalkyl" refers to saturated or partially
unsaturated, moncyclic or polycyclic hydrocarbon rings of from 3 to
20 carbon atom members (preferably from 3 to 14 carbon atom
members). Further, a cycloalkyl ring may optionally be fused to one
or more cycloalkyl rings. Examples of such rings include, and are
not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and adamantyl.
[0175] The term "heterocyclyl" refers to a nonaromatic cyclic ring
of 5 to 10 members in which 1 to 4 members are nitrogen or a
nonaromatic cyclic ring of 5 to 10 members in which zero, one or
two members are nitrogen and up to two members is oxygen or sulfur;
wherein, optionally, the ring contains zero, one or two unsaturated
bonds. Alternatively, the heterocyclyl ring may be fused to a
benzene ring (benzo fused heterocyclyl), a 5 or 6 membered
heteroaryl ring (containing one of O, S or N and, optionally, one
additional nitrogen), a 5 to 7 membered cycloalkyl or cycloalkenyl
ring, a 5 to 7 membered heterocyclyl ring (of the same definition
as above but absent the option of a further fused ring) or fused
with the carbon of attachment of a cycloalkyl, cycloalkenyl or
heterocyclyl ring to form a spiro moiety. For instant compounds of
the invention, the carbon atom ring members that form the
heterocyclyl ring are fully saturated. Other compounds of the
invention may have a partially saturated heterocyclyl ring.
Additionally, the heterocyclyl can be bridged to form bicyclic
rings. Preferred partially saturated heterocyclyl rings may have
from one to two double bonds. Such compounds are not considered to
be fully aromatic and are not referred to as heteroaryl compounds.
Examples of heterocyclyl groups include, and are not limited to,
pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl),
pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl,
pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and
piperazinyl.
[0176] The term "aryl" refers to an unsaturated, aromatic
monocyclic ring of 6 carbon members or to an unsaturated, aromatic
polycyclic ring of from 10 to 20 carbon members. Examples of such
aryl rings include, and are not limited to, phenyl, naphthalenyl
and anthracenyl. Preferred aryl groups for the practice of this
invention are phenyl and naphthalenyl.
[0177] The term "benzo fused cycloalkyl" refers to a bicyclic or
tricyclic ring structure wherein at least one of the ring
substituents is phenyl or naphthalenyl and at least one of the
other substituents is a cycloalkyl ring (as cycloalkyl was
previously defined). For the purpose of these definitions, the
cycloalkyl rings may be fused to an additional benzene ring (to
provide fused multiple ring systems such as fluorene). Example of
such benzo fused cycloalkyls include, but are not limited to,
indanyl, 1,2,3,4-tetrahydronaphthalenyl and fluorenyl.
[0178] The term "heteroaryl" refers to an aromatic ring of 5 or 6
members wherein the ring consists of carbon atoms and has at least
one heteroatom member. Suitable heteroatoms include nitrogen,
oxygen or sulfur. In the case of 5 membered rings, the heteroaryl
ring contains one member of nitrogen, oxygen or sulfur and, in
addition, may contain up to three additional nitrogens. In the case
of 6 membered rings, the heteroaryl ring may contain from one to
three nitrogen atoms. For the case wherein the 6 membered ring has
three nitrogens, at most two nitrogen atoms are adjacent.
Optionally, the heteroaryl ring is fused to a benzene ring (benzo
fused heteroaryl), a 5 or 6 membered heteroaryl ring (containing
one of O, S or N and, optionally, one additional nitrogen), a 5 to
7 membered cycloalkyl ring or a 5 to 7 membered heterocyclo ring
(as defined supra but absent the option of a further fused ring).
Examples of heteroaryl groups include, and are not limited to,
furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl;
fused heteroaryl groups include indolyl, isoindolyl, indolinyl,
benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl,
benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl,
quinolizinyl, quinolinyl, isoquinolinyl, and quinazolinyl.
[0179] The term "arylalkyl" means an alkyl group substituted with
an aryl group (e.g., benzyl and phenethyl). Similarly, the term
"arylalkoxy" indicates an alkoxy group substituted with an aryl
group (e.g., benzyloxy).
[0180] The term "halogen" refers to fluorine, chlorine, bromine,
and iodine. Substituents that are substituted with multiple
halogens are substituted in a manner that provides compounds which
are stable.
[0181] Whenever the term "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g., arylalkyl and
alkylamino), it shall be interpreted as including those limitations
given above for "alkyl" and "aryl." Designated numbers of carbon
atoms (e.g., C.sub.1-C.sub.6) shall refer independently to the
number of carbon atoms in an alkyl moiety or to the alkyl portion
of a larger substituent in which alkyl appears as its prefix root.
For alkyl, and alkoxy substituents the designated number of carbon
atoms includes all of the independent member included in the range
specified individually and all the combination of ranges within in
the range specified. For example C.sub.1-6 alkyl would include
methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well
as sub-combinations thereof (e.g., C.sub.1-2, C.sub.1-3, C.sub.1-4,
C.sub.1-5, C.sub.2-6, C.sub.3-6, C.sub.4-6, C.sub.5-6, C.sub.2-5,
etc.). However, for clarity in the terms "C.sub.9-C.sub.14 benzo
fused cycloalkyl", "C.sub.9-C.sub.14 benzo fused cycloalkenyl",
"C.sub.9-C.sub.14 benzo fused aryl"; C.sub.9-C.sub.14 refers to the
number of carbon atoms both in the benzene ring (6) and the number
of atoms in the ring fused to the benzene ring, but does not
include carbon atoms that may be pendent from these multiple ring
systems. The amount of substituents attached to a moiety
"optionally substituted with one to five substituents" is limited
to that amount of open valences on the moiety available for
substitution.
[0182] When a particular group is "substituted" (e.g., alkkyl,
cycloalkyl, aryl, heteroaryl, heterocycloalkyl, etc.), that group
may have one or more substituents, preferably from one to five
substituents, more preferably from one to three substituents, most
preferably from one to two substituents, independently selected
from the list of substituents.
[0183] With reference to substituents, the term "independently"
means that when more than one of such substituents is possible,
such substituents may be the same or different from each other.
[0184] As used herein, the notation "*" shall denote the presence
of a stereogenic center.
[0185] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention. Preferably, wherein the compound is
present as an enantiomer, the enantiomer is present at an
enantiomeric excess of greater than or equal to about 80%, more
preferably, at an enantiomeric excess of greater than or equal to
about 90%, more preferably still, at an enantiomeric excess of
greater than or equal to about 95%, more preferably still, at an
enantiomeric excess of greater than or equal to about 98%, most
preferably, at an enantiomeric excess of greater than or equal to
about 99%. Similarly, wherein the compound is present as a
diastereomer, the diastereomer is present at an diastereomeric
excess of greater than or equal to about 80%, more preferably, at
an diastereomeric excess of greater than or equal to about 90%,
more preferably still, at an diastereomeric excess of greater than
or equal to about 95%, more preferably still, at an diastereomeric
excess of greater than or equal to about 98%, most preferably, at
an diastereomeric excess of greater than or equal to about 99%.
[0186] Similarly, wherein a compound of the present invention
comprises one or more double bonds, said double bond(s) may each be
independently present in a cis or trans configuration (also
sometimes referred to as in an "Z" or "E" configurations,
respectively). It is to be understood that cis and trans geometric
isomers and all mixtures thereof are encompassed within the scope
of the present invention. Wherein a compound comprising a single
double bound is present in an excess of one of its corresponding
geometric isomers (for example, in an excess of its corresponding
trans isomer), said compound is preferably present such that the
desired geometric isomer is present in amount of greater than about
50%, Further, more preferably, greater than about 75%, more
preferably, greater than about 90%, more preferably, greater than
about 95%, most preferably, greater than about 99%.
[0187] Furthermore, some of the crystalline forms for the compounds
of the present invention may exist as polymorphs and as such are
intended to be included in the present invention. In addition, some
of the compounds of the present invention may form solvates with
water (i.e., hydrates) or common organic solvents, and such
solvates are also intended to be encompassed within the scope of
this invention.
[0188] Under standard nomenclature used throughout this disclosure,
the terminal portion of the designated side chain is described
first, followed by the adjacent functionality toward the point of
attachment. Thus, for example, a
"phenylC.sub.1-C.sub.6alkylaminocarbonylC.sub.1-C.sub.6alkyl"
substituent refers to a group of the formula
##STR00086##
[0189] Abbreviations used in the specification, particularly the
Schemes and Examples, are as follows
[0190] DCE=Dichloroethane
[0191] DCM=Dichloromethane
[0192] DIPEA or DIEA=Diisopropylethylamine
[0193] DMA or DMAc=N,N-Dimethylacetamide
[0194] DME=1,2-Dimethoxyethane
[0195] DMF=N,N-Dimethylformamide
[0196] EtOAc=Ethyl acetate
[0197] HPLC=High Pressure Liquid Chromatography
[0198] LiHMDS=Lithium bis(trimethylsilyl)amide
[0199] Mn(OAc).sub.2=Manganese Acetate
[0200] MTBE=Methyl t-Butyl Ether
[0201] NaHMDS=Sodium bis(trimethylsilyl)amide
[0202] NBS=N-bromosuccinimide
[0203] NMP=N-methyl-2-pyrrolidinone
[0204] NH.sub.4OAc=Ammonium Acetate
[0205] TEA=Triethylamine
[0206] THF=Tetrahydrofuran
[0207] TLC=Thin Layer Chromatography
[0208] TMS-Br=Bromotrimethylsilane
[0209] TMS-Cl=Chlorotrimethylsilane
[0210] TMS-I=Iodotrimethylsilane
[0211] As used herein, unless otherwise noted, the term "isolated
form" shall mean that the compound is present in a form which is
separate from any solid mixture with another compound(s), solvent
system or biological environment. In an embodiment of the present
invention, the compound of formula (I) is prepared as an isolated
form. In additional embodiments of the present invention, the
compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G)
and/or (I-H) is prepared as an isolated form.
[0212] As used herein, unless otherwise noted, the term
"substantially pure form" shall mean that the mole percent of
impurities in the isolated compound is less than about 5 mole
percent, preferably less than about 2 mole percent, more
preferably, less than about 0.5 mole percent, most preferably, less
than about 0.1 mole percent. In an embodiment of the present
invention, the compound of formula (I) is prepared as a
substantially pure form. In additional embodiments of the present
invention, the compounds of formula (I-A), (I-B), (I-C), (I-D),
(I-E), (I-F), (I-G) and/or (I-H) is prepared as a substantially
pure form.
[0213] As used herein, unless otherwise noted, the term
"substantially free of a corresponding salt form(s)" when used to
described the compound of formula (I) shall mean that mole percent
of the corresponding salt form(s) in the isolated base of formula
(I) is less than about 5 mole percent, preferably less than about 2
mole percent, more preferably, less than about 0.5 mole percent,
most preferably less than about 0.1 mole percent. In an embodiment
of the present invention, the compound of formula (I) is prepared
in a form which is substantially free of corresponding salt
form(s). In additional embodiments of the present invention, the
compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G)
and/or (I-H) is prepared in a form which is substantially free of
corresponding salt form(s).
[0214] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, who has been the
object of treatment, observation or experiment. Preferably, the
subject has experienced and/or exhibited at least one symptom of
the disease or disorder to be treated and/or prevented.
[0215] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation of
the symptoms of the disease or disorder being treated.
[0216] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0217] The compounds of formula (I) (disclosed as in U.S. Pat. No.
7,459,444, issued Dec. 2, 2008, which is incorporated by reference
herein in its entirety), prepared according to the process of the
present invention, are useful serine protease inhibitors (in
particular, inhibitors of chymase) useful for treating
inflammatory, and serine protease mediated disorders. Serine
proteases such as chymase produced by mast cells have been
recognized to be involved in a variety of inflammatory and wound
healing events (e.g., angiogenesis, collagen deposition and cell
proliferation). Chymase plays these roles by activating a variety
of pre-existing factors present in the microenvironment surrounding
the mast cells. For example, just to name a few of these
interactions chymase activates SCF, angiotensin I to angiotensin
II, endothelin 1, type 1 procollagen, metalloprotienases, IL-1B,
TGF-.beta., as well as, degrades the extracellular matrix (de
Paulis et al. Int Arch Allerg Immunol 118 (1999) 422-425; Longley
et al. Proc Natl Acad Sci USA 94 (1997) 9017-9021). Consequently,
the release of chymase plays significant role in a variety of
pathological conditions associated with vascular proliferation,
fibrosis, tissue remodeling, inflammation, and the like.
[0218] Some of these, inflammatory and serine protease mediated
disorders include, and are not limited to, allergic rhinitis, viral
rhinitis, asthma, chronic obstructive pulmonary diseases,
bronchitis, pulmonary emphysema, acute lung injury (e.g. adult
(acute) respiratory distress syndrome), psoriasis, arthritis,
reperfusion injury, ischemia, hypertension, hypercardia, myocardial
infarction, heart failure damage associated with myocardial
infarction, cardiac hypertrophy, arteriosclerosis, saroidosis,
vascular stenosis or restenosis (e.g., associated with vascular
injury, angioplasty, vascular stents or vascular grafts), pulmonary
fibrosis, kidney fibrosis (e.g., associated with
glomerulonephritis), liver fibrosis, post surgical adhesion
formation, systemic sclerosis, keloid scars rheumatoid arthritis,
bullous pemphigiod and atherosclerosis. Additionally, these
compounds can be used for modulating wound healing and remodeling
(e.g., cardiac hypertrophy) as well as immune modulation.
[0219] One skilled in the art will recognize that, where not
otherwise specified, the reaction step(s) is performed under
suitable conditions, according to known methods, to provide the
desired product.
[0220] One skilled in the art will recognize that, in the
specification and claims as presented herein, wherein a substituent
group (e.g. protecting group such as PG.sup.1 or PG.sup.2;
activating group such as Y.sup.1; leaving group such as Q.sup.1;
alkyl substituent such as A.sup.1; etc.) or reagent or reagent
class/type (e.g. base, solvent, etc.) is recited in more than one
step of a process, or in more than one process, the individual
substituent groups and reagents are independently selected for each
reaction step and may be the same of different from each other. For
example wherein two steps of a process recite an organic or
inorganic base as a reagent, the organic or inorganic base selected
for the first step may be the same or different than the organic or
inorganic base of the second step.
[0221] To provide a more concise description, some of the
quantitative expressions herein are recited as a range from about
amount X to about amount Y. It is understood that wherein a range
is recited, the range is not limited to the recited upper and lower
bounds, but rather includes the full range from about amount X
through about amount Y, or any range therein.
[0222] To provide a more concise description, some of the
quantitative expressions given herein are not qualified with the
term "about". It is understood that whether the term "about" is
used explicitly or not, every quantity given herein is meant to
refer to the actual given value, and it is also meant to refer to
the approximation to such given value that would reasonably be
inferred based on the ordinary skill in the art, including
approximations due to the experimental and/or measurement
conditions for such given value.
[0223] As used herein, unless otherwise noted, the term "aprotic
solvent" shall mean any solvent that does not yield a proton.
Suitable examples include, but are not limited to DMF, 1,4-dioxane,
THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE,
toluene, acetone, and the like.
[0224] As used herein, unless otherwise noted, the term "leaving
group" shall mean a charged or uncharged atom or group which
departs during a substitution or displacement reaction. Suitable
examples include, but are not limited to, Br, Cl, I, mesylate,
tosylate, and the like.
[0225] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991. The protecting groups may be removed
at a convenient subsequent stage using methods known from the
art.
[0226] One skilled in the art will recognize that in the processes
as described herein it may be advantageous and/or desirable to
protected terminal substituent groups such as hydroxy, alkoxy,
alkylcarbonyloxy, alkoxycarbonyloxy, and the like.
[0227] As used herein, unless otherwise noted, the term "nitrogen
protecting group" shall mean a group which may be attached to a
nitrogen atom to protect said nitrogen atom from participating in a
reaction and which may be readily removed following the reaction.
Suitable nitrogen protecting groups include, but are not limited to
carbamates--groups of the formula --C(O)O--R wherein R is for
example methyl, ethyl, t-butyl, benzyl, phenylethyl,
CH.sub.2.dbd.CH--CH.sub.2--, and the like; amides--groups of the
formula --C(O)--R' wherein R' is for example methyl, phenyl,
trifluoromethyl, and the like; N-sulfonyl derivatives-groups of the
formula --SO.sub.2--R'' wherein R'' is for example tolyl, phenyl,
trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,
2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable
nitrogen protecting groups may be found in texts such as T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991.
[0228] As used herein, unless otherwise noted, the term "oxygen
protecting group" shall mean a group which may be attached to a
oxygen atom to protect said oxygen atom from participating in a
reaction and which may be readily removed following the reaction.
Suitable oxygen protecting groups include, but are not limited to,
acetyl, benzoyl, t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM,
THP, and the like. Other suitable oxygen protecting groups may be
found in texts such as T. W. Greene & P. G. M. Wuts, Protective
Groups in Organic Synthesis, John Wiley & Sons, 1991.
[0229] One skilled in the art will recognize that wherein a
reaction step of the present invention may be carried out in a
variety of solvents or solvent systems, said reaction step may also
be carried out in a mixture of the suitable solvents or solvent
systems.
[0230] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography. The compounds may be prepared in
racemic form, or individual enantiomers may be prepared either by
enantiospecific synthesis or by resolution. The compounds may, for
example, be resolved into their component enantiomers by standard
techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as
(-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric
acid followed by fractional crystallization and regeneration of the
free base. The compounds may also be resolved by formation of
diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved using a chiral HPLC column.
[0231] The processes of the present invention may be used in the
preparation of compounds which act as prodrugs of the compounds of
formula (I). In general, such prodrugs will be functional
derivatives of the compounds which are readily convertible in vivo
into the required pharmaceutically active compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified pharmaceutically active compound in vivo
after administration to the patient. Conventional procedures for
the selection and preparation of suitable prodrug derivatives are
described, for example, in "Design of Prodrugs", ed. H. Bundgaard,
Elsevier, 1985.
[0232] For use in medicine, the salts of the compounds of this
invention refer to non-toxic "pharmaceutically acceptable salts."
Other salts may, however, be useful in the preparation of compounds
according to this invention or of their pharmaceutically acceptable
salts. Suitable pharmaceutically acceptable salts of the compounds
include acid addition salts which may, for example, be formed by
mixing a solution of the compound with a solution of a
pharmaceutically acceptable acid such as hydrochloric acid,
sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic
acid, benzoic acid, citric acid, tartaric acid, carbonic acid or
phosphoric acid. Furthermore, where the compounds of the invention
carry an acidic moiety, suitable pharmaceutically acceptable salts
thereof may include alkali metal salts, e.g., sodium or potassium
salts; alkaline earth metal salts, e.g., calcium or magnesium
salts; and salts formed with suitable organic ligands, e.g.,
quaternary ammonium salts. Thus, representative pharmaceutically
acceptable salts include, but are not limited to, the following:
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,
chloride, clavulanate, citrate, dihydrochloride, edetate,
edisylate, estolate, esylate, fumarate, gluceptate, gluconate,
glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,
hydrobromide, hydrochloride, hydroxynaphthoate, iodide,
isothionate, lactate, lactobionate, laurate, malate, maleate,
mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,
mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
oleate, pamoate (embonate), palmitate, pantothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate,
sulfate, subacetate, succinate, tannate, tartrate, teoclate,
tosylate, triethiodide and valerate.
[0233] Representative acids which may be used in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
the following: acids including acetic acid, 2,2-dichloroacetic
acid, acylated amino acids, adipic acid, alginic acid, ascorbic
acid, L-aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic
acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucoronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hipuric acid, hydrobromic acid, hydrochloric
acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid, lactobionic acid,
maleic acid, (-)-L-malic acid, malonic acid, (.+-.)-DL-mandelic
acid, methanesulfonic acid, naphthalene-2-sulfonic acid,
naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid,
nicotinc acid, nitric acid, oleic acid, orotic acid, oxalic acid,
palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid,
salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid,
succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid,
thiocyanic acid, p-toluenesulfonic acid and undecylenic acid.
[0234] Representative bases which may be used in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
the following: bases including ammonia, L-arginine, benethamine,
benzathine, calcium hydroxide, choline, deanol, diethanolamine,
diethylamine, 2-(diethylamino)-ethanol, ethanolamine,
ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole,
L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine,
piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine,
secondary amine, sodium hydroxide, triethanolamine, tromethamine
and zinc hydroxide.
[0235] The present invention is directed to a process for the
preparation of a compound of formula (III), as outlined in more
detail in Scheme 1, which follows herein. The compound of formula
(III) is useful as an intermediate in the synthesis of, for
example, a compound of formula (I-A), a compound of formula (I-B),
a compound of formula (I-C) and/or a compound of formula (I-D).
[0236] In some embodiments, the present invention is directed to
processes for the preparation of compounds of formula (L), more
particularly to process for the preparation of compounds of formula
(IX) and compounds of formula (XV), as described in more detail in
Schemes 2 through 5, which follow herein. The compounds of formula
(L), and more particularly the compounds of formula (IX) and the
compounds of formula (XV), are useful as intermediates in the
synthesis of compounds of formula (I).
[0237] In some embodiments, the present invention is directed to
processes for the preparation of the compounds of formula (I), as
described in more detail in Schemes 6 through 9, which follow
herein. The compounds of formula (I) are useful as chymase
modulators, as described in more detail herein. In additional
embodiments, the present invention is directed to processes for the
preparation of the compounds of formula (I-A), (I-B), (I-C), (I-D),
(I-E), (I-F), (I-G) and (I-H), as described in more detail in
Schemes 10 through 17, which follow herein.
[0238] The present invention is directed to a process for the
preparation of a compound of formula (III), as outlined in Scheme
1, below.
##STR00087##
[0239] Accordingly, a suitably substituted compound of formula
(II), a known compound or compound prepared by known methods,
wherein the compound of formula (II) is preferably present in an
excess of its corresponding trans form, more preferably present as
its corresponding trans form; is reacted with a suitably selected
brominating agent such as 1-bromo-pyrrolidine-2,5-dione, bromine
gas, dibromohydantoin, and the like, preferably,
1-bromo-pyrrolidine-2,5-dione; wherein the brominating agent is
preferably present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents (relative to the moles of the compound
of formula (II), more preferably in an amount in the range of from
about 0.8 to about 1.2 molar equivalents, more preferably still in
an amount of about 1.1 molar equivalents;
[0240] in the presence of a suitably selected catalyst such as
lithium acetate, manganese acetate hydrate, magnesium acetate, and
the like, preferably manganese acetate hydrate; wherein the
catalyst is preferably present in an amount in the range of from
about 0.2 to about 1.0 molar equivalents (relative to the moles of
the compound of formula (II), more preferably in an amount in the
range of from about 0.3 to about 0.8 molar equivalents, more
preferably still in an amount of about 0.5 molar equivalents;
[0241] in a mixture of water and an organic solvent such as
acetonitrile, THF, and the like, preferably acetonitrile;
preferably at a temperature in the range of from about 25.degree.
C. to about 70.degree. C.; to yield the corresponding compound of
formula (III).
[0242] The present invention is further directed to processes for
the preparation of compounds of formula (IX) as outlined in Scheme
2, below.
##STR00088##
[0243] Accordingly, a suitably substituted compound of formula
(IV), a known compound or compound prepared by known methods,
wherein PG.sup.1 is a suitably selected oxygen protecting group
such as C.sub.1-4alkyl, and the like, preferably PG.sup.1 is
methyl, ethyl or t-butyl, more preferably, PG.sup.1 is ethyl, is
reacted with a suitably selected source of nitrogen such as LiHMDS,
NaHMDS, and the like, preferably LiHMDS; wherein the source of
nitrogen is preferably present in an amount in the range of from
about 3.0 to about 6.0 molar equivalents, preferably about 3.0
molar equivalents;
[0244] in the presence of CO.sub.2 gas; wherein the CO.sub.2 gas is
preferably bubbled into the reaction mixture in an excess amount;
in an organic solvent such as THF, MTBE, DME, glyme, and the like;
preferably THF; preferably at a temperature in the range of from
about -10.degree. C. to about 20.degree. C., more preferably at a
temperature in the range of from about 0.degree. C. to about
20.degree. C.; to yield the corresponding compound of formula
(IX).
[0245] One skilled in the art will recognize that in the process as
described above, the compound of formula (IX) is prepared in a
mixture with the corresponding acid (a compound of formula (V)).
Preferably, the compound of formula (IX) is isolated and/or further
purified according to known methods, for example, the compound of
formula (IX) may be further purified by acid/base workup.
[0246] Alternatively, a suitably substituted compound of formula
(IV), a known compound or compound prepared by known methods is
reacted with carbon dioxide; wherein the carbon dioxide is
preferably bubbled into the reaction mixture in an excess amount,
for example in an amount in the range of from about 10 to about 20
molar equivalents;
[0247] in the presence of a base such as n-butyl lithium,
hexyl-lithium, and the like, preferably n-butyl lithium, wherein
the base is preferably present in an amount in the range of from
about 2.0 to bout 6.0 molar equivalents, more preferably about 3.0
molar equivalents; in an organic solvent or mixture thereof such as
THF, THF/toluene, MTBE, and the like, preferably THF; preferably at
a temperature in the range of from about -78.degree. C. to about
-40.degree. C.; to yield the corresponding compound of formula
(V).
[0248] The compound of formula (V) is reacted according to any of
Methods A through C as outlined in more detail below, to yield the
corresponding compound of formula (X). More particularly, as shown
briefly below
##STR00089##
[0249] the compound of formula (V) is activated to yield the
corresponding compound of formula (A1), wherein Y.sup.1 is chloro
(Method A), --O--C(O)--C.sub.1-4alkyl (Method B) of 1-imidazole
(Method C); which compound of formula (A1) is then reacted with a
source of ammonia, to yield the corresponding compound of formula
(IX).
Method A:
[0250] The compound of formula (V) is reacted with a suitably
selected source of chlorine such as SOCl.sub.2, oxalyl chloride,
and the like, preferably SOCl.sub.2; wherein the source of chlorine
is preferably present in an amount in the range of from about 1.0
to about 1.5 molar equivalents; in an organic solvent such as DCE,
DCM, acetonitrile, and the like, preferably DCM; preferably at a
temperature in the range of from about 10.degree. C. to about
40.degree. C.; to yield the corresponding compound of formula
(VI).
[0251] The compound of formula (VI) is reacted with a source of
ammonia such as NH.sub.3, NH.sub.4OH, NH.sub.4OAc, NH.sub.4Cl, and
the like, preferably NH.sub.3; wherein the source of ammonia is
preferably present in an amount in the range of form about 5 to
about 10 molar equivalents; in an organic solvent such as toluene,
DCM, THF, MTBE, and the like, preferably THF; preferably at a
temperature in the range of from about 0.degree. C. to about
50.degree. C.; to yield the corresponding compound of formula
(IX).
Method B:
[0252] The compound of formula (V) is reacted with an alkyl
chloroformate, such as n-butyl chloroformate, isobutyl
chloroformate, ethylchloroformate, and the like, preferably
isobutyl chloroformate; wherein the alkylchloroformate is
preferably present in an amount in the range of from about 2.0 to
about 5.0 molar equivalents; in an organic solvent such as MTBE,
toluene, THF, DCM, and the like, preferably THF; preferably at a
temperature in the range of from about -10.degree. C. to about
50.degree. C.; to yield the corresponding compound of formula
(VII), wherein A.sup.2 is the corresponding alkyl. For example,
wherein the compound of formula (V) is reacted with isobutyl
chloroformate, the product is the corresponding compound of formula
(VII), wherein A.sup.1 is isobutyl.
[0253] The compound of formula (VII) is reacted with a source of
ammonia such as NH.sub.3, NH.sub.4OH, NH.sub.4OAc, NH.sub.4Cl, and
the like, preferably NH.sub.4Cl; wherein the source of ammonia is
preferably present in an amount of from about 3.0 to about 10.0
molar equivalents; in an organic solvent such as acetone,
acetonitrile, THF, and the like, preferably acetone; preferably at
a temperature in the range of from about 0.degree. C. to about
50.degree. C.; to yield the corresponding compound of formula
(IX).
Method C:
[0254] The compound of formula (V) is reacted with CDI, a known
compound; wherein the CDI is preferably present in an amount in the
range of from about 1.0 to about 1.5 molar equivalent; in an
organic solvent such as DMF, DMAc, NMP, and the like, preferably
DMF; preferably at a temperature in the range of from about
0.degree. C. to about 50.degree. C.; to yield the corresponding
compound of formula (VIII).
[0255] The compound of formula (VIII) is reacted with a source of
ammonia such as NH.sub.3, NH.sub.4OH, NH.sub.4OAc, NH.sub.4Cl, and
the like, preferably NH.sub.4Cl; wherein the source of ammonia is
preferably present in an amount in the range of from about 2.0 to
about 6.0 molar equivalents; in an organic solvent such as DMF,
acetonitrile, NMP, and the like; preferably at a temperature in the
range of from about 0.degree. C. to about 50.degree. C.; to yield
the corresponding compound of formula (IX).
[0256] The present invention is further directed to processes for
the preparation of compounds of formula (XV) as outlined in Scheme
3, below.
##STR00090##
[0257] Accordingly, a suitably substituted compound of formula (X),
a known compound or compound prepared by known methods, wherein
PG.sup.1 is a suitably selected oxygen protecting group such as
C.sub.1-4alkyl, and the like, preferably PG.sup.1 is methyl, ethyl
or t-butyl, more preferably, PG.sup.1 is ethyl, is reacted with a
suitably selected source of nitrogen such as LiHMDS, NaHMDS, and
the like, preferably LiHMDS; wherein the source of nitrogen is
preferably present in an amount in the range of from about 3.0 to
about 6.0 molar equivalents, preferably about 3.0 molar
equivalents;
[0258] in the presence of CO.sub.2 gas; wherein the CO.sub.2 gas is
preferably bubbled into the reaction mixture in an excess amount;
in an organic solvent such as THF, MTBE, DME, glyme, and the like;
preferably THF; preferably at a temperature in the range of from
about -10.degree. C. to about 20.degree. C., more preferably at a
temperature in the range of from about 0.degree. C. to about
20.degree. C.; to yield the corresponding compound of formula
(XV).
[0259] One skilled in the art will recognize that in the process as
described above, the compound of formula (XV) is prepared in a
mixture with the corresponding acid (a compound of formula (XI)).
Preferably, the compound of formula (XV) is isolated and/or further
purified according to known methods, for example, the compound of
formula (XV) may be further purified by acid/base workup.
[0260] Alternatively, a suitably substituted compound of formula
(X), a known compound or compound prepared by known methods is
reacted with carbon dioxide; wherein the carbon dioxide is
preferably bubbled into the reaction mixture in an excess amount,
for example in an amount in the range of from about 10 to about 20
molar equivalents;
[0261] in the presence of a base such as n-butyl lithium,
hexyl-lithium, and the like, preferably n-butyl lithium, wherein
the base is preferably present in an amount in the range of from
about 2.0 to bout 6.0 molar equivalents, more preferably about 3.0
molar equivalents; in an organic solvent or mixture thereof such as
THF, THF/toluene, MTBE, and the like, preferably THF; preferably at
a temperature in the range of from about -78.degree. C. to about
-40.degree. C.; to yield the corresponding compound of formula
(XI).
[0262] The compound of formula (XI) is reacted according to any of
Methods A through C as outlined in more detail below, to yield the
corresponding compound of formula (XV). More particularly, as shown
briefly below
##STR00091##
[0263] the compound of formula (XI) is activated to yield the
corresponding compound of formula (A2), wherein Y.sup.1 is chloro
(Method A), --O--C(O)--C.sub.1-4alkyl (Method B) of 1-imidazole
(Method C); which compound of formula (A2) is then reacted with a
source of ammonia, to yield the corresponding compound of formula
(XV).
Method A:
[0264] The compound of formula (XI) is reacted with a suitably
selected source of chlorine such as SOCl.sub.2, oxalyl chloride,
and the like, preferably SOCl.sub.2; wherein the source of chlorine
is preferably present in an amount in the range of from about 1.0
to about 1.5 molar equivalents; in an organic solvent such as DCE,
DCM, acetonitrile, and the like, preferably DCM; preferably at a
temperature in the range of from about 10.degree. C. to about
40.degree. C.; to yield the corresponding compound of formula
(XII).
[0265] The compound of formula (XII) is reacted with a source of
ammonia such as NH.sub.3, NH.sub.4OH, NH.sub.4OAc, NH.sub.4Cl, and
the like, preferably NH.sub.3; wherein the source of ammonia is
preferably present in an amount in the range of form about 5 to
about 10 molar equivalents; in an organic solvent such as toluene,
DCM, THF, MTBE, and the like, preferably THF; preferably at a
temperature in the range of from about 0.degree. C. to about
50.degree. C.; to yield the corresponding compound of formula
(XV).
Method B:
[0266] The compound of formula (XI) is reacted with an alkyl
chloroformate, such as n-butyl chloroformate, isobutyl
chloroformate, ethylchloroformate, and the like, preferably
isobutyl chloroformate; wherein the alkylchloroformate is
preferably present in an amount in the range of from about 2.0 to
about 5.0 molar equivalents; in an organic solvent such as MTBE,
toluene, THF, DCM, and the like, preferably THF; preferably at a
temperature in the range of from about -10.degree. C. to about
50.degree. C.; to yield the corresponding compound of formula
(XIII), wherein A.sup.1 is the corresponding alkyl. For example,
wherein the compound of formula (XI) is reacted with isobutyl
chloroformate, the product is the corresponding compound of formula
(XIII), wherein A.sup.1 is isobutyl.
[0267] The compound of formula (XIII) is reacted with a source of
ammonia such as NH.sub.3, NH.sub.4OH, NH.sub.4OAc, NH.sub.4Cl, and
the like, preferably NH.sub.4Cl; wherein the source of ammonia is
preferably present in an amount of from about 3.0 to about 10.0
molar equivalents; in an organic solvent such as acetone,
acetonitrile, THF, and the like, preferably acetone; preferably at
a temperature in the range of from about 0.degree. C. to about
50.degree. C.; to yield the corresponding compound of formula
(XV).
Method C:
[0268] The compound of formula (XI) is reacted with CDI, a known
compound; wherein the CDI is preferably present in an amount in the
range of from about 1.0 to about 1.5 molar equivalent; in an
organic solvent such as DMF, DMAc, NMP, and the like, preferably
DMF; preferably at a temperature in the range of from about
0.degree. C. to about 50.degree. C.; to yield the corresponding
compound of formula (XIV).
[0269] The compound of formula (XIV) is reacted with a source of
ammonia such as NH.sub.3, NH.sub.4OH, NH.sub.4OAc, NH.sub.4Cl, and
the like, preferably NH.sub.4Cl; wherein the source of ammonia is
preferably present in an amount in the range of from about 2.0 to
about 6.0 molar equivalents; in an organic solvent such as DMF,
acetonitrile, NMP, and the like; preferably at a temperature in the
range of from about 0.degree. C. to about 50.degree. C.; to yield
the corresponding compound of formula (XV).
[0270] In an embodiment, the present invention is directed to
processes for the preparation of a compound of formula (IX-S), as
outlined in Scheme 4 below.
##STR00092##
[0271] Accordingly, a suitably substituted compound of formula
(IV-S), a known compound or compound prepared by known methods,
wherein PG.sup.1 is a suitably selected oxygen protecting group
such as C.sub.1-4alkyl, and the like, preferably PG.sup.1 is
methyl, ethyl or t-butyl, more preferably, PG.sup.1 is ethyl, is
reacted with a suitably selected source of nitrogen such as LiHMDS,
NaHMDS, and the like, preferably LiHMDS; wherein the source of
nitrogen is preferably present in an amount in the range of from
about 3.0 to about 6.0 molar equivalents, preferably about 3.0
molar equivalents;
[0272] in the presence of CO.sub.2 gas; wherein the CO.sub.2 gas is
preferably bubbled into the reaction mixture in an excess amount;
in an organic solvent such as THF, MTBE, DME, glyme, and the like;
preferably THF; preferably at a temperature in the range of from
about -10.degree. C. to about 20.degree. C., more preferably at a
temperature in the range of from about 0.degree. C. to about
20.degree. C.; to yield the corresponding compound of formula
(IX-S).
[0273] One skilled in the art will recognize that in the process as
described above, the compound of formula (IX-S) is prepared in a
mixture with the corresponding acid (a compound of formula (V-S)).
Preferably, the compound of formula (IX-S) is isolated and/or
further purified according to known methods, for example, the
compound of formula (IX-S) may be further purified by acid/base
workup.
[0274] Alternatively, a suitably substituted compound of formula
(IV-S), a known compound or compound prepared by known methods is
reacted with carbon dioxide; wherein the carbon dioxide is
preferably bubbled into the reaction mixture in an excess amount,
for example in an amount in the range of from about 10 to about 20
molar equivalents;
[0275] in the presence of a base such as n-butyl lithium,
hexyl-lithium, and the like, preferably n-butyl lithium, wherein
the base is preferably present in an amount in the range of from
about 2.0 to bout 6.0 molar equivalents, more preferably about 3.0
molar equivalents; in an organic solvent or mixture thereof such as
THF, THF/toluene, MTBE, and the like, preferably THF; preferably at
a temperature in the range of from about -78.degree. C. to about
-40.degree. C.; to yield the corresponding compound of formula
(V-S).
[0276] The compound of formula (V-S) is reacted according to any of
Methods A through C as outlined in more detail below, to yield the
corresponding compound of formula (IX-S). More particularly, as
shown briefly below
##STR00093##
[0277] the compound of formula (V-S) is activated to yield the
corresponding compound of formula (A3), wherein Y.sup.1 is chloro
(Method A), --O--C(O)--C.sub.1-4alkyl (Method B) of 1-imidazole
(Method C); which compound of formula (A3) is then reacted with a
source of ammonia, to yield the corresponding compound of formula
(IX-S).
Method A:
[0278] The compound of formula (V-S) is reacted with a suitably
selected source of chlorine such as SOCl.sub.2, oxalyl chloride,
and the like, preferably SOCl.sub.2; wherein the source of chlorine
is preferably present in an amount in the range of from about 1.0
to about 1.5 molar equivalents; in an organic solvent such as DCE,
DCM, acetonitrile, and the like, preferably DCM; preferably at a
temperature in the range of from about 10.degree. C. to about
40.degree. C.; to yield the corresponding compound of formula
(VI-S).
[0279] The compound of formula (VI-S) is reacted with a source of
ammonia such as NH.sub.3, NH.sub.4OH, NH.sub.4OAc, NH.sub.4Cl, and
the like, preferably NH.sub.3; wherein the source of ammonia is
preferably present in an amount in the range of form about 5 to
about 10 molar equivalents; in an organic solvent such as toluene,
DCM, THF, MTBE, and the like, preferably THF; preferably at a
temperature in the range of from about 0.degree. C. to about
50.degree. C.; to yield the corresponding compound of formula
(IX-S).
Method B:
[0280] The compound of formula (V-S) is reacted with an alkyl
chloroformate, such as n-butyl chloroformate, isobutyl
chloroformate, ethylchloroformate, and the like, preferably
isobutyl chloroformate; wherein the alkylchloroformate is
preferably present in an amount in the range of from about 2.0 to
about 5.0 molar equivalents; in an organic solvent such as MTBE,
toluene, THF, DCM, and the like, preferably THF; preferably at a
temperature in the range of from about -10.degree. C. to about
50.degree. C.; to yield the corresponding compound of formula
(VII-S), wherein A.sup.1 is the corresponding alkyl. For example,
wherein the compound of formula (V-S) is reacted with isobutyl
chloroformate, the product is the corresponding compound of formula
(VII-S), wherein A.sup.1 is isobutyl.
[0281] The compound of formula (VII-S) is reacted with a source of
ammonia such as NH.sub.3, NH.sub.4OH, NH.sub.4OAc, NH.sub.4Cl, and
the like, preferably NH.sub.4Cl; wherein the source of ammonia is
preferably present in an amount of from about 3.0 to about 10.0
molar equivalents; in an organic solvent such as acetone,
acetonitrile, THF, and the like, preferably acetone; preferably at
a temperature in the range of from about 0.degree. C. to about
50.degree. C.; to yield the corresponding compound of formula
(IX-S).
Method C:
[0282] The compound of formula (V-S) is reacted with CDI, a known
compound; wherein the CDI is preferably present in an amount in the
range of from about 1.0 to about 1.5 molar equivalent; in an
organic solvent such as DMF, DMAc, NMP, and the like, preferably
DMF; preferably at a temperature in the range of from about
0.degree. C. to about 50.degree. C.; to yield the corresponding
compound of formula (VIII-S).
[0283] The compound of formula (VIII-S) is reacted with a source of
ammonia such as NH.sub.3, NH.sub.4OH, NH.sub.4OAc, NH.sub.4Cl, and
the like, preferably NH.sub.4Cl; wherein the source of ammonia is
preferably present in an amount in the range of from about 2.0 to
about 6.0 molar equivalents; in an organic solvent such as DMF,
acetonitrile, NMP, and the like; preferably at a temperature in the
range of from about 0.degree. C. to about 50.degree. C.; to yield
the corresponding compound of formula (IX-S).
[0284] In another embodiment, the present invention is directed to
processes for the preparation of a compound of formula (XV-S), as
outlined in Scheme 5 below.
##STR00094##
[0285] Accordingly, a suitably substituted compound of formula
(X-S), a known compound or compound prepared by known methods,
wherein PG.sup.1 is a suitably selected oxygen protecting group
such as C.sub.1-4alkyl, and the like, preferably PG.sup.1 is
methyl, ethyl or t-butyl, more preferably, PG.sup.1 is ethyl, and
wherein PG.sup.2 is a suitably selected oxygen protecting group
such as C.sub.1-4alkyl, and the like, preferably PG.sup.2 is
methyl, ethyl or t-butyl, more preferably, PG.sup.2 is ethyl,
wherein PG.sup.1 and PG.sup.2 are preferably the same; is reacted
with a suitably selected source of nitrogen such as LiHMDS, NaHMDS,
and the like, preferably LiHMDS; wherein the source of nitrogen is
preferably present in an amount in the range of from about 3.0 to
about 6.0 molar equivalents, preferably about 3.0 molar
equivalents;
[0286] in the presence of CO.sub.2 gas; wherein the CO.sub.2 gas is
preferably bubbled into the reaction mixture in an excess amount;
in an organic solvent such as THF, MTBE, DME, glyme, and the like;
preferably THF; preferably at a temperature in the range of from
about -10.degree. C. to about 20.degree. C., more preferably at a
temperature in the range of from about 0.degree. C. to about
20.degree. C.; to yield the corresponding compound of formula
(XV-S).
[0287] One skilled in the art will recognize that in the process as
described above, the compound of formula (XV-S) is prepared in a
mixture with the corresponding acid (a compound of formula (XI-S)).
Preferably, the compound of formula (XV-S) is isolated and/or
further purified according to known methods, for example, the
compound of formula (XV-S) may be further purified by acid/base
workup.
[0288] Alternatively, a suitably substituted compound of formula
(X-S), a known compound or compound prepared by known methods is
reacted with carbon dioxide; wherein the carbon dioxide is
preferably bubbled into the reaction mixture in an excess amount,
for example in an amount in the range of from about 10 to about 20
molar equivalents;
[0289] in the presence of a base such as n-butyl lithium,
hexyl-lithium, and the like, preferably n-butyl lithium, wherein
the base is preferably present in an amount in the range of from
about 2.0 to bout 6.0 molar equivalents, more preferably about 3.0
molar equivalents; in an organic solvent or mixture thereof such as
THF, THF/toluene, MTBE, and the like, preferably THF; preferably at
a temperature in the range of from about -78.degree. C. to about
-40.degree. C.; to yield the corresponding compound of formula
(XI-S).
[0290] The compound of formula (XI-S) is reacted according to any
of Methods A through C as outlined in more detail below, to yield
the corresponding compound of formula (XV-S). More particularly, as
shown briefly below
##STR00095##
[0291] the compound of formula (XI-S) is activated to yield the
corresponding compound of formula (A4), wherein Y.sup.1 is chloro
(Method A), --O--C(O)--C.sub.1-4alkyl (Method B) of 1-imidazole
(Method C); which compound of formula (A4) is then reacted with a
source of ammonia, to yield the corresponding compound of formula
(XV-S).
Method A:
[0292] The compound of formula (XI-S) is reacted with a suitably
selected source of chlorine such as SOCl.sub.2, oxalyl chloride,
and the like, preferably SOCl.sub.2; wherein the source of chlorine
is preferably present in an amount in the range of from about 1.0
to about 1.5 molar equivalents; in an organic solvent such as DCE,
DCM, acetonitrile, and the like, preferably DCM; preferably at a
temperature in the range of from about 10.degree. C. to about
40.degree. C.; to yield the corresponding compound of formula
(XII-S).
[0293] The compound of formula (XII-S) is reacted with a source of
ammonia such as NH.sub.3, NH.sub.4OH, NH.sub.4OAc, NH.sub.4Cl, and
the like, preferably NH.sub.3; wherein the source of ammonia is
preferably present in an amount in the range of form about 5 to
about 10 molar equivalents; in an organic solvent such as toluene,
DCM, THF, MTBE, and the like, preferably THF; preferably at a
temperature in the range of from about 0.degree. C. to about
50.degree. C.; to yield the corresponding compound of formula
(XV-S).
Method B:
[0294] The compound of formula (XI-S) is reacted with an alkyl
chloroformate, such as n-butyl chloroformate, isobutyl
chloroformate, ethylchloroformate, and the like, preferably
isobutyl chloroformate; wherein the alkylchloroformate is
preferably present in an amount in the range of from about 2.0 to
about 5.0 molar equivalents; in an organic solvent such as MTBE,
toluene, THF, DCM, and the like, preferably THF; preferably at a
temperature in the range of from about -10.degree. C. to about
50.degree. C.; to yield the corresponding compound of formula
(XIII-S), wherein A.sup.1 is the corresponding alkyl. For example,
wherein the compound of formula (XI-S) is reacted with isobutyl
chloroformate, the product is the corresponding compound of formula
(XIII-S), wherein A.sup.1 is isobutyl.
[0295] The compound of formula (XIII-S) is reacted with a source of
ammonia such as NH.sub.3, NH.sub.4OH, NH.sub.4OAc, NH.sub.4Cl, and
the like, preferably NH.sub.4Cl; wherein the source of ammonia is
preferably present in an amount of from about 3.0 to about 10.0
molar equivalents; in an organic solvent such as acetone,
acetonitrile, THF, and the like, preferably acetone; preferably at
a temperature in the range of from about 0.degree. C. to about
50.degree. C.; to yield the corresponding compound of formula
(XV-S).
Method C:
[0296] The compound of formula (XI-S) is reacted with CDI, a known
compound; wherein the CDI is preferably present in an amount in the
range of from about 1.0 to about 1.5 molar equivalent; in an
organic solvent such as DMF, DMAc, NMP, and the like, preferably
DMF; preferably at a temperature in the range of from about
0.degree. C. to about 50.degree. C.; to yield the corresponding
compound of formula (XIV-S).
[0297] The compound of formula (XIV-S) is reacted with a source of
ammonia such as NH.sub.3, NH.sub.4OH, NH.sub.4OAc, NH.sub.4Cl, and
the like, preferably NH.sub.4Cl; wherein the source of ammonia is
preferably present in an amount in the range of from about 2.0 to
about 6.0 molar equivalents; in an organic solvent such as DMF,
acetonitrile, NMP, and the like; preferably at a temperature in the
range of from about 0.degree. C. to about 50.degree. C.; to yield
the corresponding compound of formula (XV-S).
[0298] The present invention is directed to a process for the
preparation of compounds of formula (I), preferably compounds of
formula (I) wherein R.sup.6 is other than hydroxy, as described in
more detail in Scheme 6 below.
##STR00096##
[0299] Accordingly, a suitably substituted compound of formula
(IV), wherein PG.sup.1 is a suitably substituted oxygen protecting
group such as C.sub.1-4alkyl, phenyl, benzyl, and the like,
preferably, PG.sup.1 is methyl, ethyl or t-butyl, more preferably,
PG.sup.1 is ethyl; is reacted according to any of the methods as
described in Scheme 2 above; to yield the corresponding compound of
formula (IX).
[0300] The compound of formula (IX) is reacted with a suitably
substituted compound of formula (XVI); wherein the compound of
formula (XVI) is preferably present in an excess of the
corresponding trans orientation, more preferably, the compound of
formula (XVI) is present in the corresponding trans orientation;
wherein the compound of formula (XVI) is preferably present in an
amount in the range of from about 1.0 to about 2.0 molar
equivalents (relative to the moles of the compound of formula
(IX)), more preferably in an amount in the range of from about 1.0
to about 1.5 molar equivalents, more preferably still in an amount
of about 1.1 to about 1.2 molar equivalents;
[0301] in the presence of CuI, and the like, wherein the CuI is
preferably present in an amount in the range of from about 0.1 to
about 1.0 molar equivalents, more preferably, in an amount in the
range of from about 0.1 to about 0.5 molar equivalents, more
preferably in an amount of about 0.2 molar equivalents;
[0302] in the presence of an inorganic base, such as
Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like,
preferably Cs.sub.2CO.sub.3; wherein the inorganic base is
preferably present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents, more preferably, in an amount in the
range of from about 0.5 to about 3.0 molar equivalents, more
preferably, in an amount of about 1.0 molar equivalents;
[0303] in the presence of a suitably selected ligand such as
N,N-dimethylethylenediamine, N,N-dimethylglycine,
dicyclohexyldiamine, and the like, preferably,
N,N-dimethylethylenediamine; wherein the ligand is preferably
present in an amount in the range of from about 0.2 to about 2.0
molar equivalents, more preferably, in an amount in the range of
from about 0.2 to about 1.0 molar equivalents, more preferably, in
an amount of about 0.4 molar equivalents;
[0304] in an organic solvent or mixtures thereof, such as DMA,
N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and the
like, preferably DMA; preferably, at a temperature in the range of
from about 50.degree. C. to about 100.degree. C., preferably at
about 75.degree. C.; to yield the corresponding compound of formula
(XVII).
[0305] Preferably, the compound of formula (IX) is reacted with the
compound of formula (XVI) under an inert atmosphere, for example
under nitrogen or argon. Preferably, a mixture of the compound of
formula (IX), the CuI, the ligand, the inorganic base and the
organic solvent is heated to a temperature in the range of from
about 50.degree. C. to about 100, to yield a homogeneous mixture;
prior to addition of the compound of formula (XVI).
[0306] Preferably, in the reaction of the compound of formula (IX)
with the compound of formula (XVI), the compound of formula (XVI)
is present in an excess of its geometrical isomer, more
particularly, its corresponding trans isomer, to yield the compound
of formula (XVII) in its corresponding trans isomer.
[0307] When the compound of formula (IX) is reacted with a compound
of formula (XVI), wherein the compound of formula (XVI) is present
in either its corresponding cis configuration or as a mixture of
its corresponding cis and trans configurations, then the reaction
proceeds to yield the compound of formula (XVII) as a mixture of
its corresponding cis and trans configurations.
[0308] The compound of formula (XVII) is de-protected according to
known methods, to yield the corresponding compound of formula (Ia).
For example, the compound of formula (XVII) may be reacted with a
suitably selected de-alkylating agent such as TMS-Br, TMS-I,
Br.sub.3, and the like; wherein the de-alkylating agent is
preferably present in an amount of about 2.0 molar equivalents; in
the presence of a proton scavenger such as pyridine,
N-methylmorpholine, proton sponge (i.e.
N,N,N',N'-tetramethyl-1,8-diaminonaphthalene), and the like,
preferably pyridine;
[0309] in an organic solvent such as acetonitrile, DCM, DCE, and
the like, preferably acetonitrile; preferably at a temperature in
the range of from about 10.degree. C. to about 30.degree. C., more
preferably at about 10.degree. C.; to yield the corresponding
compound of formula (Ia), a compound of formula (I) wherein R.sup.5
is hydrogen.
[0310] Alternatively, the compound of formula (XVII) may be reacted
with a suitably selected de-alkylating agent such as TMS-Cl, and
the like; in the presence of NaI, and the like; in an organic
solvent such as acetonitrile, and the like; to yield the
corresponding compound of formula (Ia), a compound of formula (I)
wherein R.sup.5 is hydrogen.
[0311] The compound of formula (Ia) may be optionally further
reacted with a suitably substituted compound of formula (XVIII),
wherein Q.sup.1 is a suitably selected leaving group such as Br,
Cl, I, and the like, preferably Cl, a known compound or compound
prepared by known methods; wherein the compound of formula (XVIII)
is preferably present in an amount in the range of from about 1.0
to about 3.0 molar equivalents, more preferably about 1.7 molar
equivalents; in the presence of an organic base such as DIPEA, TEA,
pyridine, and the like, preferably DIPEA; wherein the organic base
is preferably present in an amount in the range of from about 1.5
to about 5.0 molar equivalents; more preferably about 2.0 molar
equivalents; in an organic solvent such DMF and the like;
preferably at a temperature in the range of from about 50.degree.
C. to about 120.degree. C., more preferably at about 73.degree. C.;
to yield the corresponding compound of formula (Ib), a compound of
formula (I) wherein R.sup.5 is other than hydrogen.
[0312] Compounds of formula (I) wherein R.sup.6 is hydroxy may be
prepared according to the process outlined in Scheme 7 below.
##STR00097##
[0313] Accordingly, a suitably substituted compound of formula (X),
wherein PG.sup.1 is a suitably substituted oxygen protecting group
such as C.sub.1-4alkyl, phenyl, benzyl, and the like, and wherein
PG.sup.2 is a suitably selected oxygen protecting group such as
C.sub.1-4alkyl, phenyl, benzyl, and the like, and wherein PG.sup.1
and PG.sup.2 are the same or different oxygen protecting groups,
preferably PG.sup.1 and PG.sup.2 are different oxygen protecting
groups; is reacted according to any of the methods as described in
Scheme 3 above; to yield the corresponding compound of formula
(XV).
[0314] The compound of formula (XV) is reacted with a suitably
substituted compound of formula (XVI); wherein the compound of
formula (XVI) is preferably present in an excess of the
corresponding trans orientation, more preferably, the compound of
formula (XVI) is present in the corresponding trans orientation;
wherein the compound of formula (XVI) is preferably present in an
amount in the range of from about 1.0 to about 2.0 molar
equivalents (relative to the moles of the compound of formula
(XV)), more preferably in an amount in the range of from about 1.0
to about 1.5 molar equivalents, more preferably still in an amount
of about 1.1 to about 1.2 molar equivalents;
[0315] in the presence of CuI, and the like, wherein the CuI is
preferably present in an amount in the range of from about 0.1 to
about 1.0 molar equivalents, more preferably, in an amount in the
range of from about 0.1 to about 0.5 molar equivalents, more
preferably in an amount of about 0.2 molar equivalents;
[0316] in the presence of an inorganic base, such as
Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like,
preferably Cs.sub.2CO.sub.3; wherein the inorganic base is
preferably present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents, more preferably, in an amount in the
range of from about 0.5 to about 3.0 molar equivalents, more
preferably, in an amount of about 1.0 molar equivalents;
[0317] in the presence of a suitably selected ligand such as
N,N-dimethylethylenediamine, N,N-dimethylglycine,
dicyclohexyldiamine, and the like, preferably,
N,N-dimethylethylenediamine; wherein the ligand is preferably
present in an amount in the range of from about 0.2 to about 2.0
molar equivalents, more preferably, in an amount in the range of
from about 0.2 to about 1.0 molar equivalents, more preferably, in
an amount of about 0.4 molar equivalents;
[0318] in an organic solvent or mixtures thereof, such as DMA,
N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and the
like, preferably DMA; at a temperature in the range of from about
50.degree. C. to about 100.degree. C., preferably at about
75.degree. C.; to yield the corresponding compound of formula
(XIX).
[0319] Preferably, the compound of formula (XV) is reacted with the
compound of formula (XVI) under an inert atmosphere, for example
under nitrogen or argon. Preferably, a mixture of the compound of
formula (XV), the CuI, the ligand, the inorganic base and the
organic solvent is heated to a temperature in the range of from
about 50.degree. C. to about 100, to yield a homogeneous mixture;
prior to addition of the compound of formula (XVI).
[0320] Preferably, in the reaction of the compound of formula (XV)
with the compound of formula (XVI), the compound of formula (XVI)
is present in an excess of its geometrical isomer, more
particularly, its corresponding trans isomer, to yield the compound
of formula (XIX) in its corresponding trans isomer. When the
compound of formula (XV) is reacted with a compound of formula
(XVI), wherein the compound of formula (XVI) is present in either
its corresponding cis configuration or as a mixture of its
corresponding cis and trans configurations, then the reaction
proceeds to yield the compound of formula (XIX) as a mixture of its
corresponding cis and trans configurations.
[0321] The compound of formula (XIX) is de-protected at both the
PG.sup.1 and PG.sup.2 according to known methods, to yield the
corresponding compound of formula (Ic). For example, the compound
of formula (XIX) is reacted with a suitably selected de-alkylating
agent such as TMS-Br, TMS-I, Br.sub.3, and the like; wherein the
de-alkylating agent is preferably present in an amount of about 2.0
molar equivalents; in the presence of a proton scavenger such as
pyridine, N-methylmorpholine, proton sponge (i.e.
N,N,N',N'-tetramethyl-1,8-diaminonaphthalene), and the like,
preferably pyridine; in an organic solvent such as acetonitrile,
DCM, DCE, and the like, preferably acetonitrile; preferably at a
temperature in the range of from about 10.degree. C. to about
30.degree. C., more preferably at about 10.degree. C.; to yield the
corresponding compound of formula (Ic).
[0322] Alternatively, the compound of formula (XIX) may be reacted
with a suitably selected de-alkylating agent such as TMS-Cl, and
the like; in the presence of NaI, and the like; in an organic
solvent such as acetonitrile, and the like; to yield the
corresponding compound of formula (Ic).
[0323] The compound of formula (Ic) may be optionally further
reacted with a suitably substituted compound of formula (XVIII),
wherein Q.sup.1 is a suitably selected leaving group such as Br,
Cl, I, and the like, preferably Cl, a known compound or compound
prepared by known methods; wherein the compound of formula (XVIII)
is preferably present in an amount in the range of from about 1.0
to about 3.0 molar equivalents, more preferably about 1.7 molar
equivalents; in the presence of an organic base such as DIPEA, TEA,
pyridine, and the like, preferably DIPEA; wherein the organic base
is preferably present in an amount in the range of from about 1.5
to about 5.0 molar equivalents; more preferably about 2.0 molar
equivalents; in an organic solvent such DMF and the like;
preferably at a temperature in the range of from about 50.degree.
C. to about 120.degree. C., more preferably at about 73.degree. C.;
to yield the corresponding compound of formula (Id).
[0324] Alternatively, the compound of formula (XIX) is de-protected
at either PG.sup.1 or PG.sup.2, according to known methods, to
yield the corresponding compound of formula (XX), wherein PG.sup.0
is the un-protected PG group. For example, wherein the compound of
formula (XIX) is de-protected to remove PG.sup.1, then in the
resulting compound of formula (XX), PG.sup.0 is PG.sup.2.
Alternatively, wherein the compound of formula (XIX) is
de-protected to remove PG.sup.2, then in the resulting compound of
formula (XX), PG.sup.0 is PG.sup.1.
[0325] The compound of formula (XX) is reacted with a suitably
substituted compound of formula (XVIII), wherein Q.sup.1 is a
suitably selected leaving group such as Br, Cl, I, and the like,
preferably Cl, a known compound or compound prepared by known
methods; wherein the compound of formula (XVIII) is preferably
present in an amount in the range of from about 1.0 to about 3.0
molar equivalents, more preferably about 1.7 molar equivalents; in
the presence of an organic base such as DIPEA, TEA, pyridine, and
the like, preferably DIPEA; wherein the organic base is preferably
present in an amount in the range of from about 1.5 to about 5.0
molar equivalents; more preferably about 2.0 molar equivalents; in
an organic solvent such DMF and the like; preferably at a
temperature in the range of from about 50.degree. C. to about
120.degree. C., more preferably at about 73.degree. C.; to yield
the corresponding compound of formula (XXI).
[0326] The compound of formula (XXI) is then de-protected according
to known methods, as described herein, to yield the corresponding
compound of formula (Id).
[0327] In an embodiment, the present invention is directed to a
process for the preparation of compounds of formula (I-S), as
outlined in Scheme 8 below.
##STR00098##
[0328] Accordingly, a suitably substituted compound of formula
(IV-S), wherein PG.sup.1 is a suitably substituted oxygen
protecting group such as C.sub.1-4alkyl, phenyl, benzyl, and the
like, preferably, PG.sup.1 is methyl, ethyl or t-butyl, more
preferably, PG.sup.1 is ethyl; is reacted according to any of the
methods as described in Schemes 2 and 4 above; to yield the
corresponding compound of formula (IX-S).
[0329] The compound of formula (IX-S) is reacted with a suitably
substituted compound of formula (XVI-S); wherein the compound of
formula (XVI-S) is preferably present in an excess of the
corresponding trans orientation, more preferably, the compound of
formula (XVI-S) is present in the corresponding trans orientation;
wherein the compound of formula (XVI-S) is preferably present in an
amount in the range of from about 1.0 to about 2.0 molar
equivalents (relative to the moles of the compound of formula
(IX-S)), more preferably in an amount in the range of from about
1.0 to about 1.5 molar equivalents, more preferably still in an
amount of about 1.1 to about 1.2 molar equivalents;
[0330] in the presence of CuI, and the like, wherein the CuI is
preferably present in an amount in the range of from about 0.1 to
about 1.0 molar equivalents, more preferably, in an amount in the
range of from about 0.1 to about 0.5 molar equivalents, more
preferably in an amount of about 0.2 molar equivalents;
[0331] in the presence of an inorganic base, such as
Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like,
preferably Cs.sub.2CO.sub.3; wherein the inorganic base is
preferably present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents, more preferably, in an amount in the
range of from about 0.5 to about 3.0 molar equivalents, more
preferably, in an amount of about 1.0 molar equivalents;
[0332] in the presence of a suitably selected ligand such as
N,N-dimethylethylenediamine, N,N-dimethylglycine,
dicyclohexyldiamine, and the like, preferably,
N,N-dimethylethylenediamine; wherein the ligand is preferably
present in an amount in the range of from about 0.2 to about 2.0
molar equivalents, more preferably, in an amount in the range of
from about 0.2 to about 1.0 molar equivalents, more preferably, in
an amount of about 0.4 molar equivalents;
[0333] in an organic solvent or mixtures thereof, such as DMA,
N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and the
like, preferably DMA; preferably, at a temperature in the range of
from about 50.degree. C. to about 100.degree. C., preferably at
about 75.degree. C.; to yield the corresponding compound of formula
(XVII-S).
[0334] Preferably, the compound of formula (IX-S) is reacted with
the compound of formula (XVI-S) under an inert atmosphere, for
example under nitrogen or argon. Preferably, a mixture of the
compound of formula (IX-S), the CuI, the ligand, the inorganic base
and the organic solvent is heated to a temperature in the range of
from about 50.degree. C. to about 100, to yield a homogeneous
mixture; prior to addition of the compound of formula (XVI-S).
[0335] Preferably, in the reaction of the compound of formula
(IX-S) with the compound of formula (XVI-S), the compound of
formula (XVI-S) is present in an excess of its geometrical isomer,
more particularly, its corresponding trans isomer, to yield the
compound of formula (XVII-S) in its corresponding trans isomer.
When the compound of formula (IX-S) is reacted with a compound of
formula (XVI-S), wherein the compound of formula (XVI-S) is present
in either its corresponding cis configuration or as a mixture of
its corresponding cis and trans configurations, then the reaction
proceeds to yield the compound of formula (XVII-S) as a mixture of
its corresponding cis and trans configurations.
[0336] The compound of formula (XVII-S) is de-protected according
to known methods, to yield the corresponding compound of formula
(Ie). For example, the compound of formula (XVII-S) may be reacted
with a suitably selected de-alkylating agent such as TMS-Br, TMS-I,
Br.sub.3, and the like; wherein the de-alkylating agent is
preferably present in an amount of about 2.0 molar equivalents; in
the presence of a proton scavenger such as pyridine,
N-methylmorpholine, proton sponge (i.e.
N,N,N',N'-tetramethyl-1,8-diaminonaphthalene), and the like,
preferably pyridine;
[0337] in an organic solvent such as acetonitrile, DCM, DCE, and
the like, preferably acetonitrile; preferably at a temperature in
the range of from about 10.degree. C. to about 30.degree. C., more
preferably at about 10.degree. C.; to yield the corresponding
compound of formula (I-Sa), a compound of formula (I-S) wherein
R.sup.5 is hydrogen.
[0338] Alternatively, the compound of formula (XVII-S) may be
reacted with a suitably selected de-alkylating agent such as
TMS-Cl, and the like; in the presence of NaI, and the like; in an
organic solvent such as acetonitrile, and the like; to yield the
corresponding compound of formula (I-Sa), a compound of formula
(I-S) wherein R.sup.5 is hydrogen.
[0339] The compound of formula (I-Sa) may be optionally further
reacted with a suitably substituted compound of formula (XVIII),
wherein Q.sup.1 is a suitably selected leaving group such as Br,
Cl, I, and the like, preferably Cl, a known compound or compound
prepared by known methods; wherein the compound of formula (XVIII)
is preferably present in an amount in the range of from about 1.0
to about 3.0 molar equivalents, more preferably about 1.7 molar
equivalents; in the presence of an organic base such as DIPEA, TEA,
pyridine, and the like, preferably DIPEA; wherein the organic base
is preferably present in an amount in the range of from about 1.5
to about 5.0 molar equivalents; more preferably about 2.0 molar
equivalents; in an organic solvent such DMF and the like;
preferably at a temperature in the range of from about 50.degree.
C. to about 120.degree. C., more preferably at about 73.degree. C.;
to yield the corresponding compound of formula (I-Sb), a compound
of formula (I-S) wherein R.sup.5 is other than hydrogen.
[0340] In additional embodiments, the present invention is further
directed to processes for the preparation of compounds of formula
(I-S) wherein R.sup.6 is hydroxy as outlined in Scheme 9 below.
##STR00099##
[0341] Accordingly, a suitably substituted compound of formula
(X-S), wherein PG.sup.1 is a suitably substituted oxygen protecting
group such as C.sub.1-4alkyl, phenyl, benzyl, and the like, and
wherein PG.sup.2 is a suitably selected oxygen protecting group
such as C.sub.1-4alkyl, phenyl, benzyl, and the like, and wherein
PG.sup.1 and PG.sup.2 are the same or different oxygen protecting
groups, preferably PG.sup.1 and PG.sup.2 are different oxygen
protecting groups; is reacted according to any of the methods as
described in Scheme 3 and 5 above; to yield the corresponding
compound of formula (XV-S).
[0342] The compound of formula (XV-S) is reacted with a suitably
substituted compound of formula (XVI-S); wherein the compound of
formula (XVI-S) is preferably present in an excess of the
corresponding trans orientation, more preferably, the compound of
formula (XVI-S) is present in the corresponding trans orientation;
wherein the compound of formula (XVI-S) is preferably present in an
amount in the range of from about 1.0 to about 2.0 molar
equivalents (relative to the moles of the compound of formula
(XV-S)), more preferably in an amount in the range of from about
1.0 to about 1.5 molar equivalents, more preferably still in an
amount of about 1.1 to about 1.2 molar equivalents;
[0343] in the presence of CuI, and the like, wherein the CuI is
preferably present in an amount in the range of from about 0.1 to
about 1.0 molar equivalents, more preferably, in an amount in the
range of from about 0.1 to about 0.5 molar equivalents, more
preferably in an amount of about 0.2 molar equivalents;
[0344] in the presence of an inorganic base, such as
Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like,
preferably Cs.sub.2CO.sub.3; wherein the inorganic base is
preferably present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents, more preferably, in an amount in the
range of from about 0.5 to about 3.0 molar equivalents, more
preferably, in an amount of about 1.0 molar equivalents;
[0345] in the presence of a suitably selected ligand such as
N,N-dimethylethylenediamine, N,N-dimethylglycine,
dicyclohexyldiamine, and the like, preferably,
N,N-dimethylethylenediamine; wherein the ligand is preferably
present in an amount in the range of from about 0.2 to about 2.0
molar equivalents, more preferably, in an amount in the range of
from about 0.2 to about 1.0 molar equivalents, more preferably, in
an amount of about 0.4 molar equivalents;
[0346] in an organic solvent or mixtures thereof, such as DMA,
N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and the
like, preferably DMA; at a temperature in the range of from about
50.degree. C. to about 100.degree. C., preferably at about
75.degree. C.; to yield the corresponding compound of formula
(XIX-S).
[0347] Preferably, the compound of formula (XV-S) is reacted with
the compound of formula (XVI-S) under an inert atmosphere, for
example under nitrogen or argon. Preferably, a mixture of the
compound of formula (XV-S), the CuI, the ligand, the inorganic base
and the organic solvent is heated to a temperature in the range of
from about 50.degree. C. to about 100, to yield a homogeneous
mixture; prior to addition of the compound of formula (XVI-S).
[0348] Preferably, in the reaction of the compound of formula
(XV-S) with the compound of formula (XVI-S), the compound of
formula (XVI-S) is present in an excess of its geometrical isomer,
more particularly, its corresponding trans isomer, to yield the
compound of formula (XIX-S) in its corresponding trans isomer. When
the compound of formula (XV-S) is reacted with a compound of
formula (XVI-S), wherein the compound of formula (XVI-S) is present
in either its corresponding cis configuration or as a mixture of
its corresponding cis and trans configurations, then the reaction
proceeds to yield the compound of formula (XIX) as a mixture of its
corresponding cis and trans configurations.
[0349] The compound of formula (XIX-S) is de-protected at both the
PG.sup.1 and PG.sup.2 according to known methods, to yield the
corresponding compound of formula (I-Sc). For example, the compound
of formula (XIX-S) is reacted with a suitably selected
de-alkylating agent such as TMS-Br, TMS-I, Br.sub.3, and the like;
wherein the de-alkylating agent is preferably present in an amount
of about 2.0 molar equivalents; in the presence of a proton
scavenger such as pyridine, N-methylmorpholine, proton sponge (i.e.
N,N,N',N'-tetramethyl-1,8-diaminonaphthalene), and the like,
preferably pyridine; in an organic solvent such as acetonitrile,
DCM, DCE, and the like, preferably acetonitrile; preferably at a
temperature in the range of from about 10.degree. C. to about
30.degree. C., more preferably at about 10.degree. C.; to yield the
corresponding compound of formula (I-Sc).
[0350] Alternatively, the compound of formula (XIX-S) may be
reacted with a suitably selected de-alkylating agent such as
TMS-Cl, and the like; in the presence of NaI, and the like; in an
organic solvent such as acetonitrile, and the like; to yield the
corresponding compound of formula (I-Sc).
[0351] The compound of formula (I-Sc) may be optionally further
reacted with a suitably substituted compound of formula (XVIII),
wherein Q.sup.1 is a suitably selected leaving group such as Br,
Cl, I, and the like, preferably Cl, a known compound or compound
prepared by known methods; wherein the compound of formula (XVIII)
is preferably present in an amount in the range of from about 1.0
to about 3.0 molar equivalents, more preferably about 1.7 molar
equivalents; in the presence of an organic base such as DIPEA, TEA,
pyridine, and the like, preferably DIPEA; wherein the organic base
is preferably present in an amount in the range of from about 1.5
to about 5.0 molar equivalents; more preferably about 2.0 molar
equivalents; in an organic solvent such DMF and the like;
preferably at a temperature in the range of from about 50.degree.
C. to about 120.degree. C., more preferably at about 73.degree. C.;
to yield the corresponding compound of formula (I-Sd).
[0352] Alternatively, the compound of formula (XIX-S) is
de-protected at either PG.sup.1 or PG.sup.2, according to known
methods, to yield the corresponding compound of formula (XX-S),
wherein PG.sup.0 is the un-protected PG group. For example, wherein
the compound of formula (XIX-S) is de-protected to remove PG.sup.1,
then in the resulting compound of formula (XX-S), PG.sup.0 is
PG.sup.2. Alternatively, wherein the compound of formula (XIX-S) is
de-protected to remove PG.sup.2, then in the resulting compound of
formula (XX-S), PG.sup.0 is PG.sup.1.
[0353] The compound of formula (XX-S) is reacted with a suitably
substituted compound of formula (XVIII), wherein Q.sup.1 is a
suitably selected leaving group such as Br, Cl, I, and the like,
preferably Cl, a known compound or compound prepared by known
methods; wherein the compound of formula (XVIII) is preferably
present in an amount in the range of from about 1.0 to about 3.0
molar equivalents, more preferably about 1.7 molar equivalents; in
the presence of an organic base such as DIPEA, TEA, pyridine, and
the like, preferably DIPEA; wherein the organic base is preferably
present in an amount in the range of from about 1.5 to about 5.0
molar equivalents; more preferably about 2.0 molar equivalents; in
an organic solvent such DMF and the like; preferably at a
temperature in the range of from about 50.degree. C. to about
120.degree. C., more preferably at about 73.degree. C.; to yield
the corresponding compound of formula (XXI-S).
[0354] The compound of formula (XXI-S) is then de-protected
according to known methods, as described herein, to yield the
corresponding compound of formula (I-Sd).
[0355] The present invention is further directed to a process for
the preparation of a compound of formula (I-A), as outlined in
Scheme 10 below.
##STR00100##
[0356] Accordingly, a suitably substituted compound of formula
(IV-S), wherein PG.sup.1 is a suitably substituted oxygen
protecting group such as C.sub.1-4alkyl, phenyl, benzyl, and the
like, preferably, PG.sup.1 is methyl, ethyl or t-butyl, more
preferably, PG.sup.1 is ethyl; is reacted according to any of the
methods as described in Schemes 2 and 4 above; to yield the
corresponding compound of formula (IX-S).
[0357] The compound of formula (IX-S) is reacted with a suitably
substituted compound of formula (XVI-S); wherein the compound of
formula (XVI-A) is preferably present in an excess of the
corresponding trans orientation, more preferably, the compound of
formula (XVI-A) is present in the corresponding trans orientation;
wherein the compound of formula (XVI-A) is preferably present in an
amount in the range of from about 1.0 to about 2.0 molar
equivalents (relative to the moles of the compound of formula
(IV-S)), more preferably in an amount in the range of from about
1.0 to about 1.5 molar equivalents, more preferably still in an
amount of about 1.1 to about 1.2 molar equivalents;
[0358] in the presence of CuI, and the like, wherein the CuI is
preferably present in an amount in the range of from about 0.1 to
about 1.0 molar equivalents, more preferably, in an amount in the
range of from about 0.1 to about 0.5 molar equivalents, more
preferably in an amount of about 0.2 molar equivalents;
[0359] in the presence of an inorganic base, such as
Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like,
preferably Cs.sub.2CO.sub.3; wherein the inorganic base is
preferably present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents, more preferably, in an amount in the
range of from about 0.5 to about 3.0 molar equivalents, more
preferably, in an amount of about 1.0 molar equivalents;
[0360] in the presence of a suitably selected ligand such as
N,N-dimethylethylenediamine, N,N-dimethylglycine,
dicyclohexyldiamine, and the like, preferably,
N,N-dimethylethylenediamine; wherein the ligand is preferably
present in an amount in the range of from about 0.2 to about 2.0
molar equivalents, more preferably, in an amount in the range of
from about 0.2 to about 1.0 molar equivalents, more preferably, in
an amount of about 0.4 molar equivalents;
[0361] in an organic solvent or mixtures thereof, such as DMA,
N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and the
like, preferably DMA; preferably at a temperature in the range of
from about 50.degree. C. to about 100.degree. C., preferably at
about 75.degree. C.; to yield the corresponding compound of formula
(IX-S).
[0362] Preferably, the compound of formula (IX-S) is reacted with
the compound of formula (XVI-A) under an inert atmosphere, for
example under nitrogen or argon. Preferably, a mixture of the
compound of formula (IX-S), the CuI, the ligand, the inorganic base
and the organic solvent is heated to a temperature in the range of
from about 50.degree. C. to about 100, to yield a homogeneous
mixture; prior to addition of the compound of formula (XVI-A).
[0363] Preferably, in the reaction of the compound of formula
(IX-S) with the compound of formula (XVI-A), the compound of
formula (XVI-A) is present in an excess of its geometrical isomer,
more particularly, its corresponding trans isomer, to yield the
compound of formula (XVII-A) in its corresponding trans isomer.
When the compound of formula (IX-S) is reacted with a compound of
formula (XVI-A), wherein the compound of formula (XVI-A) is present
in either its corresponding cis configuration or as a mixture of
its corresponding cis and trans configurations, then the reaction
proceeds to yield the compound of formula (XVII-A) as a mixture of
its corresponding cis and trans configurations.
[0364] The compound of formula (XVII-A) is de-protected according
to known methods, to yield the corresponding compound of formula
(I-A). For example, the compound of formula (XVII-A) may be reacted
with a suitably selected de-alkylating agent such as TMS-Br, TMS-I,
Br.sub.3, and the like; wherein the de-alkylating agent is
preferably present in an amount of about 2.0 molar equivalents; in
the presence of a proton scavenger such as pyridine,
N-methylmorpholine, proton sponge (i.e.
N,N,N',N'-tetramethyl-1,8-diaminonaphthalene), and the like,
preferably pyridine; in an organic solvent such as acetonitrile,
DCM, DCE, and the like, preferably acetonitrile; preferably at a
temperature in the range of from about 10.degree. C. to about
30.degree. C., more preferably at about 10.degree. C.; to yield the
corresponding compound of formula (I-A).
[0365] Alternatively, the compound of formula (XVII-A) may be
reacted with a suitably selected de-alkylating agent such as
TMS-Cl, and the like; in the presence of NaI, and the like; in an
organic solvent such as acetonitrile, and the like; to yield the
corresponding compound of formula (I-A).
[0366] The present invention is further directed to a process for
the preparation of a compound of formula (I-B), as outlined in
Scheme 11 below.
##STR00101##
[0367] Accordingly, a suitably substituted compound of formula
(X-S), wherein PG.sup.1 is a suitably substituted oxygen protecting
group such as C.sub.1-4alkyl, phenyl, benzyl, and the like,
preferably, PG.sup.1 is methyl, ethyl or t-butyl, more preferably,
PG.sup.1 is ethyl; is reacted according to any of the methods as
described in Schemes 3 and 5 above; to yield the corresponding
compound of formula (XV-S).
[0368] The compound of formula (XV-S) is reacted with a suitably
substituted compound of formula (XVI-A); wherein the compound of
formula (XVI-A) is preferably present in an excess of the
corresponding trans orientation, more preferably, the compound of
formula (XVI-A) is present in the corresponding trans orientation;
wherein the compound of formula (XVI-A) is preferably present in an
amount in the range of from about 1.0 to about 2.0 molar
equivalents (relative to the moles of the compound of formula
(XV-S)), more preferably in an amount in the range of from about
1.0 to about 1.5 molar equivalents, more preferably still in an
amount of about 1.1 to about 1.2 molar equivalents;
[0369] in the presence of CuI, and the like, wherein the CuI is
preferably present in an amount in the range of from about 0.1 to
about 1.0 molar equivalents, more preferably, in an amount in the
range of from about 0.1 to about 0.5 molar equivalents, more
preferably in an amount of about 0.2 molar equivalents;
[0370] in the presence of an inorganic base, such as
Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like,
preferably Cs.sub.2CO.sub.3; wherein the inorganic base is
preferably present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents, more preferably, in an amount in the
range of from about 0.5 to about 3.0 molar equivalents, more
preferably, in an amount of about 1.0 molar equivalents;
[0371] in the presence of a suitably selected ligand such as
N,N-dimethylethylenediamine, N,N-dimethylglycine,
dicyclohexyldiamine, and the like, preferably,
N,N-dimethylethylenediamine; wherein the ligand is preferably
present in an amount in the range of from about 0.2 to about 2.0
molar equivalents, more preferably, in an amount in the range of
from about 0.2 to about 1.0 molar equivalents, more preferably, in
an amount of about 0.4 molar equivalents;
[0372] in an organic solvent or mixtures thereof, such as DMA,
N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and the
like, preferably DMA; preferably at a temperature in the range of
from about 50.degree. C. to about 100.degree. C., preferably at
about 75.degree. C.; to yield the corresponding compound of formula
(XIX-A).
[0373] Preferably, the compound of formula (XV-S) is reacted with
the compound of formula (XVI-A) under an inert atmosphere, for
example under nitrogen or argon. Preferably, a mixture of the
compound of formula (XV-S), the CuI, the ligand, the inorganic base
and the organic solvent is heated to a temperature in the range of
from about 50.degree. C. to about 100, to yield a homogeneous
mixture; prior to addition of the compound of formula (XVI-A).
[0374] Preferably, in the reaction of the compound of formula
(XV-S) with the compound of formula (XVI-A), the compound of
formula (XVI-A) is present in an excess of its geometrical isomer,
more particularly, its corresponding trans isomer, to yield the
compound of formula (XIX-A) in its corresponding trans isomer. When
the compound of formula (XV-S) is reacted with a compound of
formula (XVI-A), wherein the compound of formula (XVI-A) is present
in either its corresponding cis configuration or as a mixture of
its corresponding cis and trans configurations, then the reaction
proceeds to yield the compound of formula (XIX-A) as a mixture of
its corresponding cis and trans configurations.
[0375] The compound of formula (XIX-A) is de-protected according to
known methods, to yield the corresponding compound of formula
(I-B). For example, the compound of formula (XIX-A) may be reacted
with a suitably selected de-alkylating agent such as TMS-Br, TMS-I,
Br.sub.3, and the like; wherein the de-alkylating agent is
preferably present in an amount of about 2.0 molar equivalents; in
the presence of a proton scavenger such as pyridine,
N-methylmorpholine, proton sponge (i.e.
N,N,N',N'-tetramethyl-1,8-diaminonaphthalene), and the like,
preferably pyridine; in an organic solvent such as acetonitrile,
DCM, DCE, and the like, preferably acetonitrile; preferably at a
temperature in the range of from about 10.degree. C. to about
30.degree. C., more preferably at about 10.degree. C.; to yield the
corresponding compound of formula (I-B).
[0376] Alternatively, the compound of formula (XIX-A) may be
reacted with a suitably selected de-alkylating agent such as
TMS-Cl, and the like; in the presence of NaI, and the like; in an
organic solvent such as acetonitrile, and the like; to yield the
corresponding compound of formula (I-B).
[0377] The present invention is further directed to a process for
the preparation of a compound of formula (I-C), as outlined in
Scheme 12 below.
##STR00102##
[0378] Accordingly, a suitably substituted compound of formula
(X-S), wherein PG.sup.1 is a suitably substituted oxygen protecting
group such as C.sub.1-4alkyl, phenyl, benzyl, and the like,
preferably, PG.sup.1 is methyl, ethyl or t-butyl, more preferably,
PG.sup.1 is ethyl; is reacted according to any of the methods as
described in Schemes 3 and 5 above; to yield the corresponding
compound of formula (XV-S).
[0379] The compound of formula (XV-S) is reacted with a suitably
substituted compound of formula (XVI-A); wherein the compound of
formula (XVI-A) is preferably present in an excess of the
corresponding trans orientation, more preferably, the compound of
formula (XVI-A) is present in the corresponding trans orientation;
wherein the compound of formula (XVI-A) is preferably present in an
amount in the range of from about 1.0 to about 2.0 molar
equivalents (relative to the moles of the compound of formula
(XV-S)), more preferably in an amount in the range of from about
1.0 to about 1.5 molar equivalents, more preferably still in an
amount of about 1.1 to about 1.2 molar equivalents;
[0380] in the presence of CuI, and the like, wherein the CuI is
preferably present in an amount in the range of from about 0.1 to
about 1.0 molar equivalents, more preferably, in an amount in the
range of from about 0.1 to about 0.5 molar equivalents, more
preferably in an amount of about 0.2 molar equivalents;
[0381] in the presence of an inorganic base, such as
Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like,
preferably Cs.sub.2CO.sub.3; wherein the inorganic base is
preferably present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents, more preferably, in an amount in the
range of from about 0.5 to about 3.0 molar equivalents, more
preferably, in an amount of about 1.0 molar equivalents;
[0382] in the presence of a suitably selected ligand such as
N,N-dimethylethylenediamine, N,N-dimethylglycine,
dicyclohexyldiamine, and the like, preferably,
N,N-dimethylethylenediamine; wherein the ligand is preferably
present in an amount in the range of from about 0.2 to about 2.0
molar equivalents, more preferably, in an amount in the range of
from about 0.2 to about 1.0 molar equivalents, more preferably, in
an amount of about 0.4 molar equivalents;
[0383] in an organic solvent or mixtures thereof, such as DMA,
N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and the
like, preferably DMA; preferably at a temperature in the range of
from about 50.degree. C. to about 100.degree. C., preferably at
about 75.degree. C.; to yield the corresponding compound of formula
(XIX-A).
[0384] Preferably, the compound of formula (XV-S) is reacted with
the compound of formula (XVI-A) under an inert atmosphere, for
example under nitrogen or argon. Preferably, a mixture of the
compound of formula (XV-S), the CuI, the ligand, the inorganic base
and the organic solvent is heated to a temperature in the range of
from about 50.degree. C. to about 100, to yield a homogeneous
mixture; prior to addition of the compound of formula (XVI-A).
[0385] Preferably, in the reaction of the compound of formula
(XV-S) with the compound of formula (XVI-A), the compound of
formula (XVI-A) is present in an excess of its geometrical isomer,
more particularly, its corresponding trans isomer, to yield the
compound of formula (XIX-A) in its corresponding trans isomer. When
the compound of formula (XV-S) is reacted with a compound of
formula (XVI-A), wherein the compound of formula (XVI-A) is present
in either its corresponding cis configuration or as a mixture of
its corresponding cis and trans configurations, then the reaction
proceeds to yield the compound of formula (XIX-A) as a mixture of
its corresponding cis and trans configurations.
[0386] The compound of formula (XIX-A) is de-protected according to
known methods, to yield the corresponding compound of formula
(I-B). For example, the compound of formula (XIX-A) may be reacted
with a suitably selected de-alkylating agent such as TMS-Br, TMS-I,
Br.sub.3, and the like; wherein the de-alkylating agent is
preferably present in an amount of about 2.0 molar equivalents; in
the presence of a proton scavenger such as pyridine,
N-methylmorpholine, proton sponge (i.e.
N,N,N',N'-tetramethyl-1,8-diaminonaphthalene), and the like,
preferably pyridine; in an organic solvent such as acetonitrile,
DCM, DCE, and the like, preferably acetonitrile; preferably at a
temperature in the range of from about 10.degree. C. to about
30.degree. C., more preferably at about 10.degree. C.; to yield the
corresponding compound of formula (I-B).
[0387] Alternatively, the compound of formula (XIX-A) may be
reacted with a suitably selected de-alkylating agent such as
TMS-Cl, and the like; in the presence of NaI, and the like; in an
organic solvent such as acetonitrile, and the like; to yield the
corresponding compound of formula (I-B).
[0388] The compound of formula (I-B) is reacted with a suitably
substituted compound of formula (XVIII-A), wherein Q.sup.1 is a
suitably selected leaving group such as Br, Cl, I, and the like,
preferably Cl, a known compound or compound prepared by known
methods; wherein the compound of formula (XVIII-A) is preferably
present in an amount in the range of from about 1.0 to about 3.0
molar equivalents, more preferably about 1.7 molar equivalents; in
the presence of an organic base such as DIPEA, TEA, pyridine, and
the like, preferably DIPEA; wherein the organic base is preferably
present in an amount in the range of from about 1.5 to about 5.0
molar equivalents; more preferably about 2.0 molar equivalents; in
an organic solvent such DMF and the like; preferably at a
temperature in the range of from about 50.degree. C. to about
120.degree. C., more preferably at about 73.degree. C.; to yield
the corresponding compound of formula (I-C).
[0389] The present invention is further directed to a process for
the preparation of a compound of formula (I-D) as outlined in
Scheme 13 below.
##STR00103##
[0390] Accordingly, a suitably substituted compound of formula
(X-S), wherein PG.sup.1 is a suitably substituted oxygen protecting
group such as C.sub.1-4alkyl, phenyl, benzyl, and the like,
preferably, PG.sup.1 is methyl, ethyl or t-butyl, more preferably,
PG.sup.1 is ethyl; is reacted according to any of the methods as
described in Schemes 3 and 5, above; to yield the corresponding
compound of formula (XV-S).
[0391] The compound of formula (XV-S) is reacted with a suitably
substituted compound of formula (XVI-A); wherein the compound of
formula (XVI-A) is preferably present in an excess of the
corresponding trans orientation, more preferably, the compound of
formula (XVI-A) is present in the corresponding trans orientation;
wherein the compound of formula (XVI-A) is preferably present in an
amount in the range of from about 1.0 to about 2.0 molar
equivalents (relative to the moles of the compound of formula
(XV-S)), more preferably in an amount in the range of from about
1.0 to about 1.5 molar equivalents, more preferably still in an
amount of about 1.1 to about 1.2 molar equivalents;
[0392] in the presence of CuI, and the like, wherein the CuI is
preferably present in an amount in the range of from about 0.1 to
about 1.0 molar equivalents, more preferably, in an amount in the
range of from about 0.1 to about 0.5 molar equivalents, more
preferably in an amount of about 0.2 molar equivalents;
[0393] in the presence of an inorganic base, such as
Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like,
preferably Cs.sub.2CO.sub.3; wherein the inorganic base is
preferably present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents, more preferably, in an amount in the
range of from about 0.5 to about 3.0 molar equivalents, more
preferably, in an amount of about 1.0 molar equivalents;
[0394] in the presence of a suitably selected ligand such as
N,N-dimethylethylenediamine, N,N-dimethylglycine,
dicyclohexyldiamine, and the like, preferably,
N,N-dimethylethylenediamine; wherein the ligand is preferably
present in an amount in the range of from about 0.2 to about 2.0
molar equivalents, more preferably, in an amount in the range of
from about 0.2 to about 1.0 molar equivalents, more preferably, in
an amount of about 0.4 molar equivalents;
[0395] in an organic solvent or mixtures thereof, such as DMA,
N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and the
like, preferably DMA; preferably at a temperature in the range of
from about 50.degree. C. to about 100.degree. C., preferably at
about 75.degree. C.; to yield the corresponding compound of formula
(XIX-A).
[0396] Preferably, the compound of formula (XV-S) is reacted with
the compound of formula (XVI-A) under an inert atmosphere, for
example under nitrogen or argon. Preferably, a mixture of the
compound of formula (XV-S), the CuI, the ligand, the inorganic base
and the organic solvent is heated to a temperature in the range of
from about 50.degree. C. to about 100, to yield a homogeneous
mixture; prior to addition of the compound of formula (XVI-A).
[0397] Preferably, in the reaction of the compound of formula
(XV-S) with the compound of formula (XVI-A), the compound of
formula (XVI-A) is present in an excess of its geometrical isomer,
more particularly, its corresponding trans isomer, to yield the
compound of formula (XIX-A) in its corresponding trans isomer. When
the compound of formula (XV-S) is reacted with a compound of
formula (XVI-A), wherein the compound of formula (XVI-A) is present
in either its corresponding cis configuration or as a mixture of
its corresponding cis and trans configurations, then the reaction
proceeds to yield the compound of formula (XIX-A) as a mixture of
its corresponding cis and trans configurations.
[0398] The compound of formula (XIX-A) is de-protected according to
known methods, to yield the corresponding compound of formula
(I-B). For example, the compound of formula (XIX-A) may be reacted
with a suitably selected de-alkylating agent such as TMS-Br, TMS-I,
Br.sub.3, and the like; wherein the de-alkylating agent is
preferably present in an amount of about 2.0 molar equivalents; in
the presence of a proton scavenger such as pyridine,
N-methylmorpholine, proton sponge (i.e.
N,N,N',N'-tetramethyl-1,8-diaminonaphthalene), and the like,
preferably pyridine; in an organic solvent such as acetonitrile,
DCM, DCE, and the like, preferably acetonitrile; preferably at a
temperature in the range of from about 10.degree. C. to about
30.degree. C., more preferably at about 10.degree. C.; to yield the
corresponding compound of formula (I-B).
[0399] Alternatively, the compound of formula (XIX-A) may be
reacted with a suitably selected de-alkylating agent such as
TMS-Cl, and the like; in the presence of NaI, and the like; in an
organic solvent such as acetonitrile, and the like; to yield the
corresponding compound of formula (I-B).
[0400] The compound of formula (I-B) is reacted with a suitably
substituted compound of formula (XVIII-B), wherein Q.sup.1 is a
suitably selected leaving group such as Br, Cl, I, and the like,
preferably Cl, a known compound or compound prepared by known
methods; wherein the compound of formula (XVIII-B) is preferably
present in an amount in the range of from about 1.0 to about 3.0
molar equivalents, more preferably about 1.7 molar equivalents; in
the presence of an organic base such as DIPEA, TEA, pyridine, and
the like, preferably DIPEA; wherein the organic base is preferably
present in an amount in the range of from about 1.5 to about 5.0
molar equivalents; more preferably about 2.0 molar equivalents; in
an organic solvent such DMF and the like; preferably at a
temperature in the range of from about 50.degree. C. to about
120.degree. C., more preferably at about 73.degree. C.; to yield
the corresponding compound of formula (I-D).
[0401] The present invention is further directed to a process for
the preparation of a compound of formula (I-E), as outlined in
Scheme 14 below.
##STR00104##
[0402] Accordingly, a suitably substituted compound of formula
(IV-S), wherein PG.sup.1 is a suitably substituted oxygen
protecting group such as C.sub.1-4alkyl, phenyl, benzyl, and the
like, preferably, PG.sup.1 is methyl, ethyl or t-butyl, more
preferably, PG.sup.1 is ethyl; is reacted according to any of the
methods as described in Scheme 2 and 4 above; to yield the
corresponding compound of formula (IX-S).
[0403] The compound of formula (IX-S) is reacted with a suitably
substituted compound of formula (XVI-B); wherein the compound of
formula (XVI-B) is preferably present in an excess of the
corresponding trans orientation, more preferably, the compound of
formula (XVI-B) is present in the corresponding trans orientation;
wherein the compound of formula (XVI-B) is preferably present in an
amount in the range of from about 1.0 to about 2.0 molar
equivalents (relative to the moles of the compound of formula
(IX-S)), more preferably in an amount in the range of from about
1.0 to about 1.5 molar equivalents, more preferably still in an
amount of about 1.1 to about 1.2 molar equivalents;
[0404] in the presence of CuI, and the like, wherein the CuI is
preferably present in an amount in the range of from about 0.1 to
about 1.0 molar equivalents, more preferably, in an amount in the
range of from about 0.1 to about 0.5 molar equivalents, more
preferably in an amount of about 0.2 molar equivalents;
[0405] in the presence of an inorganic base, such as
Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like,
preferably Cs.sub.2CO.sub.3; wherein the inorganic base is
preferably present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents, more preferably, in an amount in the
range of from about 0.5 to about 3.0 molar equivalents, more
preferably, in an amount of about 1.0 molar equivalents;
[0406] in the presence of a suitably selected ligand such as
N,N-dimethylethylenediamine, N,N-dimethylglycine,
dicyclohexyldiamine, and the like, preferably,
N,N-dimethylethylenediamine; wherein the ligand is preferably
present in an amount in the range of from about 0.2 to about 2.0
molar equivalents, more preferably, in an amount in the range of
from about 0.2 to about 1.0 molar equivalents, more preferably, in
an amount of about 0.4 molar equivalents;
[0407] in an organic solvent or mixtures thereof, such as DMA,
N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and the
like, preferably DMA; preferably at a temperature in the range of
from about 50.degree. C. to about 100.degree. C., preferably at
about 75.degree. C.; to yield the corresponding compound of formula
(XVII-B).
[0408] Preferably, the compound of formula (IX-S) is reacted with
the compound of formula (XVI-B) under an inert atmosphere, for
example under nitrogen or argon. Preferably, a mixture of the
compound of formula (IX-S), the CuI, the ligand, the inorganic base
and the organic solvent is heated to a temperature in the range of
from about 50.degree. C. to about 100, to yield a homogeneous
mixture; prior to addition of the compound of formula (XVI-B).
[0409] Preferably, in the reaction of the compound of formula
(IX-S) with the compound of formula (XVI-B), the compound of
formula (XVI-B) is present in an excess of its geometrical isomer,
more particularly, its corresponding trans isomer, to yield the
compound of formula (XVII-B) in its corresponding trans isomer.
When the compound of formula (IX-S) is reacted with a compound of
formula (XVI-B), wherein the compound of formula (XVI-B) is present
in either its corresponding cis configuration or as a mixture of
its corresponding cis and trans configurations, then the reaction
proceeds to yield the compound of formula (XVII-B) as a mixture of
its corresponding cis and trans configurations.
[0410] The compound of formula (XVII-B) is de-protected according
to known methods, to yield the corresponding compound of formula
(I-E). For example, the compound of formula (XVII-B) may be reacted
with a suitably selected de-alkylating agent such as TMS-Br, TMS-1,
Br.sub.3, and the like; wherein the de-alkylating agent is
preferably present in an amount of about 2.0 molar equivalents; in
the presence of a proton scavenger such as pyridine,
N-methylmorpholine, proton sponge (i.e.
N,N,N',N'-tetramethyl-1,8-diaminonaphthalene), and the like,
preferably pyridine; in an organic solvent such as acetonitrile,
DCM, DCE, and the like, preferably acetonitrile; preferably at a
temperature in the range of from about 10.degree. C. to about
30.degree. C., more preferably at about 10.degree. C.; to yield the
corresponding compound of formula (I-E).
[0411] Alternatively, the compound of formula (XVII-B) may be
reacted with a suitably selected de-alkylating agent such as
TMS-Cl, and the like; in the presence of NaI, and the like; in an
organic solvent such as acetonitrile, and the like; to yield the
corresponding compound of formula (I-E).
[0412] The present invention is further directed to a process for
the preparation of a compound of formula (I-F), as outlined in
Scheme 15 below.
##STR00105##
[0413] Accordingly, a suitably substituted compound of formula
(X-S), wherein PG.sup.1 is a suitably substituted oxygen protecting
group such as C.sub.1-4alkyl, phenyl, benzyl, and the like,
preferably, PG.sup.1 is methyl, ethyl or t-butyl, more preferably,
PG.sup.1 is ethyl; is reacted according to any of the methods as
described in Schemes 3 and 5 above; to yield the corresponding
compound of formula (XV-S).
[0414] The compound of formula (XV-S) is reacted with a suitably
substituted compound of formula (XVI-B); wherein the compound of
formula (XVI-B) is preferably present in an excess of the
corresponding trans orientation, more preferably, the compound of
formula (XVI-B) is present in the corresponding trans orientation;
wherein the compound of formula (XVI-B) is preferably present in an
amount in the range of from about 1.0 to about 2.0 molar
equivalents (relative to the moles of the compound of formula
(X-B)), more preferably in an amount in the range of from about 1.0
to about 1.5 molar equivalents, more preferably still in an amount
of about 1.1 to about 1.2 molar equivalents;
[0415] in the presence of CuI, and the like, wherein the CuI is
preferably present in an amount in the range of from about 0.1 to
about 1.0 molar equivalents, more preferably, in an amount in the
range of from about 0.1 to about 0.5 molar equivalents, more
preferably in an amount of about 0.2 molar equivalents;
[0416] in the presence of an inorganic base, such as
Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like,
preferably Cs.sub.2CO.sub.3; wherein the inorganic base is
preferably present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents, more preferably, in an amount in the
range of from about 0.5 to about 3.0 molar equivalents, more
preferably, in an amount of about 1.0 molar equivalents;
[0417] in the presence of a suitably selected ligand such as
N,N-dimethylethylenediamine, N,N-dimethylglycine,
dicyclohexyldiamine, and the like, preferably,
N,N-dimethylethylenediamine; wherein the ligand is preferably
present in an amount in the range of from about 0.2 to about 2.0
molar equivalents, more preferably, in an amount in the range of
from about 0.2 to about 1.0 molar equivalents, more preferably, in
an amount of about 0.4 molar equivalents;
[0418] in an organic solvent or mixtures thereof, such as DMA,
N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and the
like, preferably DMA; preferably at a temperature in the range of
from about 50.degree. C. to about 100.degree. C., preferably at
about 75.degree. C.; to yield the corresponding compound of formula
(XIX-B).
[0419] Preferably, the compound of formula (XV-S) is reacted with
the compound of formula (XVI-B) under an inert atmosphere, for
example under nitrogen or argon. Preferably, a mixture of the
compound of formula (XV-S), the CuI, the ligand, the inorganic base
and the organic solvent is heated to a temperature in the range of
from about 50.degree. C. to about 100, to yield a homogeneous
mixture; prior to addition of the compound of formula (XVI-B).
[0420] Preferably, in the reaction of the compound of formula
(XV-S) with the compound of formula (XVI-B), the compound of
formula (XVI-B) is present in an excess of its geometrical isomer,
more particularly, its corresponding trans isomer, to yield the
compound of formula (XIX-B) in its corresponding trans isomer. When
the compound of formula (XV-S) is reacted with a compound of
formula (XVI-B), wherein the compound of formula (XVI-B) is present
in either its corresponding cis configuration or as a mixture of
its corresponding cis and trans configurations, then the reaction
proceeds to yield the compound of formula (XIX-B) as a mixture of
its corresponding cis and trans configurations.
[0421] The compound of formula (XIX-B) is de-protected according to
known methods, to yield the corresponding compound of formula
(I-F). For example, the compound of formula (XIX-B) may be reacted
with a suitably selected de-alkylating agent such as TMS-Br, TMS-I,
Br.sub.3, and the like; wherein the de-alkylating agent is
preferably present in an amount of about 2.0 molar equivalents; in
the presence of a proton scavenger such as pyridine,
N-methylmorpholine, proton sponge (i.e.
N,N,N',N'-tetramethyl-1,8-diaminonaphthalene), and the like,
preferably pyridine; in an organic solvent such as acetonitrile,
DCM, DCE, and the like, preferably acetonitrile; preferably at a
temperature in the range of from about 10.degree. C. to about
30.degree. C., more preferably at about 10.degree. C.; to yield the
corresponding compound of formula (I-F).
[0422] Alternatively, the compound of formula (XIX-B) may be
reacted with a suitably selected de-alkylating agent such as
TMS-Cl, and the like; in the presence of NaI, and the like; in an
organic solvent such as acetonitrile, and the like; to yield the
corresponding compound of formula (I-F).
[0423] The present invention is further directed to a process for
the preparation of a compound of formula (I-G), as outlined in
Scheme 16 below.
##STR00106##
[0424] Accordingly, a suitably substituted compound of formula
(X-S), wherein PG.sup.1 is a suitably substituted oxygen protecting
group such as C.sub.1-4alkyl, phenyl, benzyl, and the like,
preferably, PG.sup.1 is methyl, ethyl or t-butyl, more preferably,
PG.sup.1 is ethyl; is reacted according to any of the methods as
described in Schemes 3 and 5 above; to yield the corresponding
compound of formula (XV-S).
[0425] The compound of formula (XV-S) is reacted with a suitably
substituted compound of formula (XVI-B); wherein the compound of
formula (XVI-B) is preferably present in an excess of the
corresponding trans orientation, more preferably, the compound of
formula (XVI-B) is present in the corresponding trans orientation;
wherein the compound of formula (XVI-B) is preferably present in an
amount in the range of from about 1.0 to about 2.0 molar
equivalents (relative to the moles of the compound of formula
(X-B)), more preferably in an amount in the range of from about 1.0
to about 1.5 molar equivalents, more preferably still in an amount
of about 1.1 to about 1.2 molar equivalents;
[0426] in the presence of CuI, and the like, wherein the CuI is
preferably present in an amount in the range of from about 0.1 to
about 1.0 molar equivalents, more preferably, in an amount in the
range of from about 0.1 to about 0.5 molar equivalents, more
preferably in an amount of about 0.2 molar equivalents;
[0427] in the presence of an inorganic base, such as
Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like,
preferably Cs.sub.2CO.sub.3; wherein the inorganic base is
preferably present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents, more preferably, in an amount in the
range of from about 0.5 to about 3.0 molar equivalents, more
preferably, in an amount of about 1.0 molar equivalents;
[0428] in the presence of a suitably selected ligand such as
N,N-dimethylethylenediamine, N,N-dimethylglycine,
dicyclohexyldiamine, and the like, preferably,
N,N-dimethylethylenediamine; wherein the ligand is preferably
present in an amount in the range of from about 0.2 to about 2.0
molar equivalents, more preferably, in an amount in the range of
from about 0.2 to about 1.0 molar equivalents, more preferably, in
an amount of about 0.4 molar equivalents;
[0429] in an organic solvent or mixtures thereof, such as DMA,
N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and the
like, preferably DMA; preferably at a temperature in the range of
from about 50.degree. C. to about 100.degree. C., preferably at
about 75.degree. C.; to yield the corresponding compound of formula
(XIX-B).
[0430] Preferably, the compound of formula (XV-S) is reacted with
the compound of formula (XVI-B) under an inert atmosphere, for
example under nitrogen or argon. Preferably, a mixture of the
compound of formula (XV-S), the CuI, the ligand, the inorganic base
and the organic solvent is heated to a temperature in the range of
from about 50.degree. C. to about 100, to yield a homogeneous
mixture; prior to addition of the compound of formula (XVI-B).
[0431] Preferably, in the reaction of the compound of formula
(XV-S) with the compound of formula (XVI-B), the compound of
formula (XVI-B) is present in an excess of its geometrical isomer,
more particularly, its corresponding trans isomer, to yield the
compound of formula (XIX-B) in its corresponding trans isomer. When
the compound of formula (XV-S) is reacted with a compound of
formula (XVI-B), wherein the compound of formula (XVI-B) is present
in either its corresponding cis configuration or as a mixture of
its corresponding cis and trans configurations, then the reaction
proceeds to yield the compound of formula (XIX-B) as a mixture of
its corresponding cis and trans configurations.
[0432] The compound of formula (XIX-B) is de-protected according to
known methods, to yield the corresponding compound of formula
(I-F). For example, the compound of formula (XIX-B) may be reacted
with a suitably selected de-alkylating agent such as TMS-Br, TMS-I,
Br.sub.3, and the like; wherein the de-alkylating agent is
preferably present in an amount of about 2.0 molar equivalents; in
the presence of a proton scavenger such as pyridine,
N-methylmorpholine, proton sponge (i.e.
N,N,N',N'-tetramethyl-1,8-diaminonaphthalene), and the like,
preferably pyridine; in an organic solvent such as acetonitrile,
DCM, DCE, and the like, preferably acetonitrile; preferably at a
temperature in the range of from about 10.degree. C. to about
30.degree. C., more preferably at about 10.degree. C.; to yield the
corresponding compound of formula (I-F).
[0433] Alternatively, the compound of formula (XIX-B) may be
reacted with a suitably selected de-alkylating agent such as
TMS-Cl, and the like; in the presence of NaI, and the like; in an
organic solvent such as acetonitrile, and the like; to yield the
corresponding compound of formula (I-F).
[0434] The compound of formula (I-F) is reacted with a suitably
substituted compound of formula (XVIII-A), wherein Q.sup.1 is a
suitably selected leaving group such as Br, Cl, I, and the like,
preferably Cl, a known compound or compound prepared by known
methods; wherein the compound of formula (XVIII-A) is preferably
present in an amount in the range of from about 1.0 to about 3.0
molar equivalents, more preferably about 1.7 molar equivalents; in
the presence of an organic base such as DIPEA, TEA, pyridine, and
the like, preferably DIPEA; wherein the organic base is preferably
present in an amount in the range of from about 1.5 to about 5.0
molar equivalents; more preferably about 2.0 molar equivalents; in
an organic solvent such DMF and the like; preferably at a
temperature in the range of from about 50.degree. C. to about
120.degree. C., more preferably at about 73.degree. C.; to yield
the corresponding compound of formula (I-G).
[0435] The present invention is further directed to a process for
the preparation of a compound of formula (I-H), as outlined in
Scheme 17 below.
##STR00107##
[0436] Accordingly, a suitably substituted compound of formula
(X-S), wherein PG.sup.1 is a suitably substituted oxygen protecting
group such as C.sub.1-4alkyl, phenyl, benzyl, and the like,
preferably, PG.sup.1 is methyl, ethyl or t-butyl, more preferably,
PG.sup.1 is ethyl; is reacted according to any of the methods as
described in Schemes 3 and 5 above; to yield the corresponding
compound of formula (XV-S).
[0437] The compound of formula (XV-S) is reacted with a suitably
substituted compound of formula (XVI-B); wherein the compound of
formula (XVI-B) is preferably present in an excess of the
corresponding trans orientation, more preferably, the compound of
formula (XVI-B) is present in the corresponding trans orientation;
wherein the compound of formula (XVI-B) is preferably present in an
amount in the range of from about 1.0 to about 2.0 molar
equivalents (relative to the moles of the compound of formula
(X-B)), more preferably in an amount in the range of from about 1.0
to about 1.5 molar equivalents, more preferably still in an amount
of about 1.1 to about 1.2 molar equivalents;
[0438] in the presence of CuI, and the like, wherein the CuI is
preferably present in an amount in the range of from about 0.1 to
about 1.0 molar equivalents, more preferably, in an amount in the
range of from about 0.1 to about 0.5 molar equivalents, more
preferably in an amount of about 0.2 molar equivalents;
[0439] in the presence of an inorganic base, such as
Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like,
preferably Cs.sub.2CO.sub.3; wherein the inorganic base is
preferably present in an amount in the range of from about 0.5 to
about 2.0 molar equivalents, more preferably, in an amount in the
range of from about 0.5 to about 3.0 molar equivalents, more
preferably, in an amount of about 1.0 molar equivalents;
[0440] in the presence of a suitably selected ligand such as
N,N-dimethylethylenediamine, N,N-dimethylglycine,
dicyclohexyldiamine, and the like, preferably,
N,N-dimethylethylenediamine; wherein the ligand is preferably
present in an amount in the range of from about 0.2 to about 2.0
molar equivalents, more preferably, in an amount in the range of
from about 0.2 to about 1.0 molar equivalents, more preferably, in
an amount of about 0.4 molar equivalents;
[0441] in an organic solvent or mixtures thereof, such as DMA,
N-methyl-pyrrolidinone, DMA/acetonitrile mixture, DMF, THF, and the
like, preferably DMA; preferably at a temperature in the range of
from about 50.degree. C. to about 100.degree. C., preferably at
about 75.degree. C.; to yield the corresponding compound of formula
(XIX-B).
[0442] Preferably, the compound of formula (XV-S) is reacted with
the compound of formula (XVI-B) under an inert atmosphere, for
example under nitrogen or argon. Preferably, a mixture of the
compound of formula (XV-S), the CuI, the ligand, the inorganic base
and the organic solvent is heated to a temperature in the range of
from about 50.degree. C. to about 100, to yield a homogeneous
mixture; prior to addition of the compound of formula (XVI-B).
[0443] Preferably, in the reaction of the compound of formula
(XV-S) with the compound of formula (XVI-B), the compound of
formula (XVI-B) is present in an excess of its geometrical isomer,
more particularly, its corresponding trans isomer, to yield the
compound of formula (XIX-B) in its corresponding trans isomer. When
the compound of formula (XV-S) is reacted with a compound of
formula (XVI-B), wherein the compound of formula (XVI-B) is present
in either its corresponding cis configuration or as a mixture of
its corresponding cis and trans configurations, then the reaction
proceeds to yield the compound of formula (XIX-B) as a mixture of
its corresponding cis and trans configurations.
[0444] The compound of formula (XIX-B) is de-protected according to
known methods, to yield the corresponding compound of formula
(I-F). For example, the compound of formula (XIX-B) may be reacted
with a suitably selected de-alkylating agent such as TMS-Br, TMS-I,
Br.sub.3, and the like; wherein the de-alkylating agent is
preferably present in an amount of about 2.0 molar equivalents; in
the presence of a proton scavenger such as pyridine,
N-methylmorpholine, proton sponge (i.e.
N,N,N',N'-tetramethyl-1,8-diaminonaphthalene), and the like,
preferably pyridine; in an organic solvent such as acetonitrile,
DCM, DCE, and the like, preferably acetonitrile; preferably at a
temperature in the range of from about 10.degree. C. to about
30.degree. C., more preferably at about 10.degree. C.; to yield the
corresponding compound of formula (I-F).
[0445] Alternatively, the compound of formula (XIX-B) may be
reacted with a suitably selected de-alkylating agent such as
TMS-Cl, and the like; in the presence of NaI, and the like; in an
organic solvent such as acetonitrile, and the like; to yield the
corresponding compound of formula (I-F).
[0446] The compound of formula (I-F) is reacted with a suitably
substituted compound of formula (XVIII-B), wherein Q.sup.1 is a
suitably selected leaving group such as Br, Cl, I, and the like,
preferably Cl, a known compound or compound prepared by known
methods; wherein the compound of formula (XVIII-B) is preferably
present in an amount in the range of from about 1.0 to about 3.0
molar equivalents, more preferably about 1.7 molar equivalents; in
the presence of an organic base such as DIPEA, TEA, pyridine, and
the like, preferably DIPEA; wherein the organic base is preferably
present in an amount in the range of from about 1.5 to about 5.0
molar equivalents; more preferably about 2.0 molar equivalents; in
an organic solvent such DMF and the like; preferably at a
temperature in the range of from about 50.degree. C. to about
120.degree. C., more preferably at about 73.degree. C.; to yield
the corresponding compound of formula (I-H).
[0447] The following Examples are set forth to aid in the
understanding of the invention, and are not intended and should not
be construed to limit in any way the invention set forth in the
claims which follow thereafter.
[0448] In the Examples which follow, some synthesis products are
listed as having been isolated as a residue. It will be understood
by one of ordinary skill in the art that the term "residue" does
not limit the physical state in which the product was isolated and
may include, for example, a solid, an oil, a foam, a gum, a syrup,
and the like.
Example 1
{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-
-methyl}-methyl-phosphinic acid ethyl ester
##STR00108##
[0449] Cesium Carbonate Method:
[0450] A 3 L 4-necked round-bottomed flask equipped with addition
funnel, mechanical stirrer, nitrogen inlet, heating mantle and
thermocouple was charged with
[carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinic
acid ethyl ester (100 g, 0.3 mol), Cs.sub.2CO.sub.3 (58.6 g, 0.18
mol), N,N-dimethylacetamide (DMA) (300 mL, anhydrous 99.8%),
N,N'-dimethyl-ethylenediamine (10.6 g, 0.12 mol) and copper (I)
iodide (11.4 g, 0.06 mol) and the resulting mixture heated to about
80.degree. C., under nitrogen. To the resulting mixture was then
added a solution of 4-(2-bromo-vinyl)-1,2-difluoro-benzene (78.8 g,
0.36 mol) in DMA (30 mL), slowly over a period of about 20 min and
the resulting mixture stirred at this temperature for 5 hours. The
resulting mixture was then quenched while hot with H.sub.2O (600
mL), and diluted with EtOAc (700 mL), added slowly through an
addition funnel. The resulting biphasic mixture was cooled to
50-55.degree. C. and at this temperature the layers were separated.
The organic layer was washed with H.sub.2O (500 mL), 0.5N HCl
aqueous solution (500 mL) and brine (500 mL), then filtered and
concentrated under reduced pressure to approximately half the
original volume (350-400 mL). The concentrated solution was heated
to slow reflux. Heptane (250 mL) was then added slowly at this
temperature. The resulting suspension was cooled to 5-10.degree. C.
over a period of 1 hr, diluted with additional heptane (100 mL) and
aged at this temperature for a period of about 2 hrs. The resulting
solid precipitate was filtered, rinsed with cold heptane/EtOAc
(4/1) solvent mixture (100 ml), and dried at 55.degree. C. in a
vacuum oven overnight, to yield the title compound as a white
solid.
[0451] HPLC on a sample of the isolated product indicated 95%
purity.
Example 2
{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-
-methyl}-methyl-phosphinic acid ethyl ester
##STR00109##
[0452] Potassium Carbonate Method:
[0453] A 3 L 4-necked round-bottomed flask equipped with addition
funnel, mechanical stirrer, nitrogen inlet, heating mantle and
thermocouple was charged with
[carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinic
acid ethyl ester (10.5 g, 0.03 mol), K.sub.2CO.sub.3 (8.0 g, 0.03
mol), N,N-dimethylacetamide (DMA) (40 mL, anhydrous 99.8%),
N,N'-dimethyl-ethylenediamine (1.6 g, 0.018 mol) and copper (I)
iodide (1.14 g, 0.006 mol) and the resulting mixture heated to
about 80.degree. C. under nitrogen. To the resulting mixture was
then added 4-(2-bromo-vinyl)-1,2-difluoro-benzene (7.9 g, 0.036
mol) slowly, over a about 20 minutes, at 80.degree. C. and the
resulting mixture stirred at this temperature for about 5 hours.
The resulting mixture was then quenched while hot with H.sub.2O (60
mL), and diluted with EtOAc (70 mL), added slowly through an
addition funnel. The resulting biphasic mixture was cooled to
50-55.degree. C. and at this temperature the layers were separated.
The organic layer was washed with H.sub.2O (50 mL), 0.5N HCl
aq.solution (50 mL) and brine (50 mL), then filtered and
concentrated under reduced pressure to about half the original
volume (35-40 mL). The concentrated solution was heated to slow
reflux and then heptane (25 mL) was added slowly at this
temperature. The resulting suspension was cooled to 5-10.degree. C.
over a period of 1 hr, diluted with additional heptane (10 mL) and
aged at this temperature for about 2 hrs. The resulting solid
precipitate was filtered, rinsed with cold heptane/EtOAc (4/1)
solvent mixture (10 ml), and dried 55.degree. C. in a vacuum oven
overnight, to yield the title compound as a white solid.
[0454] HPLC on a sample of the isolated product indicated 95%
purity.
Example 3
{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-
-methyl}-methyl-phosphinic acid
##STR00110##
[0456] A 1 L four-necked round-bottomed flask equipped with
mechanical stirrer, addition funnel, condenser, and a thermocouple
was charged with
{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl-
]-methyl}-methyl-phosphinic acid ethyl ester (26.4 g, 0.056 mol),
acetonitrile (200 mL) and pyridine (11.0 mL, 0.136 mol). To the
resulting mixture was then added bromotrimethylsilane (15.5 mL,
0.117 mol), 15 minutes, while maintaining the temperature of the
resulting mixture below about 30.degree. C. The mixture was then
stirred for an additional 15 minutes to yield a clear yellow
solution, which was aged for about 2 hours. The resulting mixture
was then cooled to about 0-5.degree. C. To the mixture was then
added concentrated sulfuric acid (5.4 mL) in water (90 mL), using
vigorous agitation. To the resulting mixture was then added MTBE
(150 mL) and the mixture aged with stirring until two homogeneous
layers were obtained. The layers were separated and the organic
layer was washed twice with water (45 mL) and then concentrated to
yield a residue. The residue was digested with methanol (180 mL)
under vigorous stirring. then concentrated to about 50% of its
original volume under reduced pressure. The resulting slurry was
cooled to about 0-5.degree. C., then aged at this temperature for
about 1 hours. The resulting solids were filtered, washed twice
with cold methanol (18 mL), dried in a vacuum oven at 50.degree.
C., overnight, to yield the title compound as a white crystalline
solid
Example 4
{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-
-methyl}-methyl-phosphinic acid Choline Salt
##STR00111##
[0458] A 250 mL three-necked round-bottomed flask was charged with
{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl-
]-methyl}-methyl-phosphinic acid (20.0 g, 42.2 mol) and methanol
(150 mL), under nitrogen. To the resulting slurry was then added
45% by wt. of choline hydroxide in methanol (12.8 mL, 45.3 mol), in
one portion. Shortly after the addition, a homogeneous clear
solution was obtained. The solution was aged at room temperature
for about 1 hour, then clarified by filtration through a medium
sintered glass filter. The resulting filtered solution was
concentrated by distillation (at a temperature of about
63-65.degree. C.) to a residual volume of about 55-60 mL. While at
the elevated temperature, EtOAc (140-150 mL) was added by an
addition funnel over a period of about 40 minutes, while
maintaining a temperature of about 63-65.degree. C. The resulting
clear solution was seeded, then cooled slowly under moderate
agitation to ambient temperature. The resulting slurry was then
aged overnight, cooled to about 5-10.degree. C. and aged at this
temperature for about 2 hours. The resulting solid was collected by
filtration, rinsed with cold EtOAc (40 mL, 2 C) and dried in a
vacuum oven at 50.degree. C., overnight to yield the title compound
as a white crystalline solid.
Example 5
4-(2-Bromo-vinyl)-1,2-difluoro-benzene
##STR00112##
[0459] Method 1: (Adapted from the Chemistry Described in J. Org.
Chem. 1997, 62, pp 199-200)
[0460] 3,4-Difluorocinnamic acid (1.8 g, 10 mmol) was combined with
acetonitrile (18.6 mL) and water (1.4 mL) and the resulting mixture
treated with lithium acetate (0.12 g) and then N-bromosuccinimide
(1.9 g). The resulting solution was then heated to about 70.degree.
C. and stirred at that temperature for about 2 hours. The resulting
mixture was then cooled to 25.degree. C. and quenched with 5%
sodium thiosulfate solution (about 5 mL). The resulting mixture was
extracted with heptane (2.times.30 mL) and the combined heptane
layers were rinsed with water, dried over magnesium sulfate and the
solvent evaporated to dryness to yield the title compound as a
residue.
[0461] The .sup.1H NMR was measured for a sample of the residue,
which was determined to be a mixture of about 9:1 trans:cis
isomers.
[0462] .sup.1H NMR (CDCl.sub.3): .delta. 7.21 (m, 3H), 6.60 (d, 1H,
J=11.5 Hz), 6.39 (d, 1H, J=11.5 Hz)
Example 6
4-(2-Bromo-vinyl)-1,2-difluoro-benzene
##STR00113##
[0463] Method 2: (Adapted from the Chemistry Described in Synlett
2000, 10 pp 1439)
[0464] 3,4-Difluorocinnamic acid (0.9 g, 5 mmol), lithium acetate
(0.60 mg), N-bromosuccinimide (0.95 g), acetonitrile (9.3 mL) and
water (0.7 mL) were placed in a microwave test tube and the
resulting mixture was heated under microwave radiation for about 2
minutes. The resulting mixture was then cooled to ambient
temperature and quenched with 5% sodium thiosulfate solution (about
2 mL). The resulting mixture was then extracted with heptane
(2.times.10 mL), the combined organics dried over magnesium
sulfate, and then concentrated under reduced pressure to yield the
title compound as a residue.
[0465] The .sup.1H NMR was measured for a sample of the residue,
which was determined to be a mixture of about 9:1 trans:cis
isomers.
[0466] .sup.1H NMR (CDCl.sub.3): .delta. 7.21 (m, 3H), 6.60 (d, 1H,
J=11.5 Hz), 6.39 (d, 1H, J=11.5 Hz)
Example 7
4-(2-Bromo-vinyl)-1,2-difluoro-benzene
##STR00114##
[0467] Method 3: (Adapted from the Chemistry Described in Tet.
Lett. 1996, 37, pp 2623-2624)
[0468] 3,4-Difluorocinnamic acid (1.8 g, 10 mmol) was combined with
acetonitrile (8 mL0 and water (8 mL) and the resulting mixture was
treated first with Mn(OAc).sub.2 hydrate (0.49 g) and then with NBS
(1.9 g). the resulting mixture was then heated to about 50.degree.
C. and stirred at this temperature for about 16 hours. The
resulting mixture was then cooled to about 25.degree. C. and then
quenched with 5% sodium thiosulfate solution (about 5 mL). The
resulting mixture was extracted with heptane (2.times.30 mL) and
the combined heptane layers were rinsed with water, dried over
magnesium sulfate and the solvent evaporated to dryness to yield
the title compound a residue.
[0469] The .sup.1H NMR was measured for a sample of the residue,
which was determined to be a mixture of about 20:1 trans:cis
isomers.
[0470] .sup.1H NMR (CDCl.sub.3): .delta. 7.21 (m, 3H), 6.60 (d, 1H,
J=11.5 Hz), 6.39 (d, 1H, J=11.5 Hz)
Example 8
[Carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinic
acid ethyl ester
##STR00115##
[0471] STEP A:
Ethyl-1-(5-chlorobenzo[b]thiophen-3-yl)-2-oxoethyl-(methyl)-phosphinate-2-
-carboxylic acid
[0472] To a dry 4N 3000 ml flask equipped with mechanical stirrer,
nitrogen inlet, temperature probe and addition port was added ethyl
(5-chlorobenzo[b]thiophen-3-yl)methyl(methyl)phosphinate (95.0 g,
329 mmol) and THF (100 mL), under nitrogen and the resulting
solution cooled to -20.degree. C. To the resulting mixture was then
added 20% 1.06M LiHMDS solution in THF (500 ml), while maintaining
the temperature below 10.degree. C. Into the resulting mixture,
while maintaining the mixture temperature under 15.degree. C., was
continuously bubbled CO.sub.2 until no exotherm was observed. The
resulting mixture was then aged for 1 hour. Following the age, the
resulting mixture was cooled to -10.degree. C. and additional
LiHMDS solution (100 ml) was added, followed by additional bubbled
CO.sub.2. The resulting mixture again cooled to -10.degree. C.,
additional LiHMDS solution (100 ml) was added, followed by
additional bubbled CO.sub.2. The resulting mixture was allowed to
warm to room temperature, aged at room temperature for 2 hours,
then cooled to 4.degree. C. 2N HCl was added (500 ml) slowly to
maintain the cold temperature and the resulting precipitate was
aged for 1 hour, at which time it was filtered and washed with
water (100 mL). Filtration took approximately 1 hour. The resulting
gelatinous solid was allowed to air dry for about 24 hours over
which time the material slowly turned to a compact white solid. The
solid was treated with 1N HCl (500 mL) and MTBE (500 mL) and the
resulting slurry digested for 2 hours. The resulting easily
filterable dense solid was isolated, washed with 1:1=1N HCl:MTBE
(100 ml) and the solid dried for 72 hours at 50.degree. C. under
vacuum and nitrogen purge, to yield
ethyl-1-(5-chlorobenzo[b]thiophen-3-yl)-2-oxoethyl(methyl)phosphinate-2-c-
arboxylic acid as a solid.
STEP B:
[Carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphi-
nic acid ethyl ester
[0473] A 2 L RBF with mechanical stirrer, addition port,
temperature probe and nitrogen inlet was charged with
ethyl-1-(5-chlorobenzo[b]thiophen-3-yl)-2-oxoethyl(methyl)phosphinate-2-c-
arboxylic acid (80 g, 0.24 mole) and DMF (400 mL). To the resulting
light suspension was added NaHCO.sub.3 (40 g, 0.476 mole), the
suspension cooled to 4.degree. C. and 1,1'-carbonyldiimidazole (60
g, 0.37 mole) were added. The resulting mixture was aged for 1 hour
while stirring, over which time off-gassing was observed to stop
and the temperature observed to rise to 15.degree. C. The resulting
mixture was then cooled to 0.degree. C. and ammonia added until no
exotherm was observed. The resulting mixture was cooled to
0.degree. C. and 5% NaHCO.sub.3 (1200 mL) was added over 30 min.
The resulting slurry was stirred and aged at room temperature
overnight, then filtered, washed 2 times with 5% NaHCO.sub.3 (500
mL) and 2 times with water (250 m). The filtercake was air dried,
then slurried with ethyl acetate (400 m) overnight at room
temperature. The resulting mixture was filtered and the filtercake
washed with ethyl acetate (2.times.50 mL), then dried overnight at
45.degree. C. to yield the title compound as a solid.
Example 9
(5-Chloro-benzo[b]thiophen-3-yl)-(ethoxy-methyl-phosphinoyl)-acetic
acid
##STR00116##
[0475] To a dry 4N 300 ml flask equipped with magnetic stirrer,
nitrogen inlet, temperature probe and addition port was added ethyl
(5-chlorobenzo[b]thiophen-3-yl)methyl(methyl)phosphinate (12.7,
43.99 mmol) and dry THF (15 mL) under nitrogen. The resulting
solution was cooled to -20.degree. C. To the mixture was then added
a 40% (2.2 M) NaHMDS solution in THF (25 mL), maintaining the
temperature below 10.degree. C. Following the base addition,
CO.sub.2 was bubbled cautiously until no exotherm was observed,
while maintaining the temperature of the reaction mixture below
15.degree. C. The resulting mixture was then degassed with nitrogen
and NaHMDS (10 mL) was added, followed by additional CO.sub.2
bubbling. The addition of NaHMDS ad CO.sub.2 was repeated 3 more
times. The resulting solution was cooled to 0.degree. C. and MTBE
(80 mL) was added. To the resulting mixture was then added, slowly,
2N HCl (20 mL), followed by 6N HCl (40 mL), at which point the pH
of the mixture was measured to be about 2. Throughout the addition
of the acid, the temperature of the mixture was maintained between
0 and 15.degree. C. Initial precipitation was observed upon
acidification, while on completion of the acid addition, the
mixture resolved in two clear layers. The layers were split, and
the organic layer evaporated to yield an oil. The oil was digested
overnight with MTBE (20 mL) to yield the title compound as a
filterable solid.
Example 10
[Carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinic
acid ethyl ester
##STR00117##
[0477]
(5-Chloro-benzo[b]thiophen-3-yl)-(ethoxy-methyl-phosphinoyl)-acetic
acid (9.0 g, 0.027 mol) was suspended in THF (250 mL), TEA (4.46
mL, 0.032 mol), and isobutylchloroformate (3.5 mL, 0.0027 mol) were
slowly added and the resulting suspension cooled to -5.degree. C.
The resulting mixture was stirred for 1 hour at -2.degree. C. and
then ammonium acetate (2.1 g, 0.027 mol) was added in two portions.
The cooling ice bath was then roomed and the resulting mixture was
left overnight. To the resulting mixture was then added THF (100
mL) and additional isobutylchloroformate (0.5 ml) and the resulting
mixture stirred for 30 minutes. To the resulting mixture was then
added ammonium acetate (3.8 mmol) and the resulting mixture again
stirred for 30 minutes.
[0478] To the resulting mixture was then added water (200 mL). Most
of the THF was then evaporated and ethyl acetate (250 mL) added. To
the resulting mixture was then added water (100 mL; for a total
water amount of 300 mL) and ethyl acetate (150 mL; for a total
ethyl acetate amount of 400 mL). The resulting mixture was heated
to 40.degree. C., the resulting layers were separated. The organic
layer was washed with NaOH (0.1%, 200 mL) and brine (200 mL). The
solvent was removed by evaporation to dryness to yield the title
compound as a residue, as a white solid.
[0479] To the white solid was added acetonitrile (300 mL) and the
resulting mixture heated on a steam bath to dissolve the solid. The
heated mixture was then polish filtered through filter paper. The
crystallized title compound was then isolated as a white solid.
[0480] The procedure described in Example 11 below represents a
recipe for the preparation of the title compound. The
recipe/procedure was applied to the preparation of 4 individual
batches of the title compound.
Example 11
{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-
-methyl}-methyl-phosphinic acid ethyl ester
##STR00118##
[0482]
[Carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphin-
ic acid ethyl ester (60.0 g, 181 mmol) was placed in a reactor
under nitrogen, followed by addition of cesium carbonate (35.3 g,
108 mmol) and copper iodide (6.90 g, 36.2 mmol) and the resulting
mixture was stirred at ambient temperature. DMA (123 g) and
N,N'-dimethylethylenediame (6.36 g, 72.1 mmol) (with the addition
flask washed with DMA (30 g)) were added and the resulting mixture
heated to 70-75.degree. C. with about 30-60 minutes, over which
time a thin blue suspension was observed to form. To the resulting
mixture was then added 4-(2-bromo-vinyl)-1,2-difluoro-benzene (47.6
g, 217 mmol) over about 10-30 minutes (with the addition flask
washed with DMA (30 g)), then stirred for 5 to 7 hours at
75-85.degree. C., with the progress of the reaction monitored by
HPLC. When the reaction was deemed complete, the reaction mixture
was cooled to 60-78.degree. C., ethyl acetate (345 g) was added
followed by addition of water (303 g), and the mixture stirred for
10-30 minutes. The resulting phases were separated. To the organic
phase was added a solution of NaCl (30 g in 270 g H.sub.2O),
followed by stirring for 10-30 min at a temperature of
55-65.degree. C. The resulting phases were separated, to the
organic phase was added again a solution of NaCl (30 g in 270 g
H.sub.2O), followed by stirring for 10-30 min at a temperature of
55-65.degree. C. The resulting phases were separated and treated a
third time with addition of a solution of NaCl (30 g in 270 g
H.sub.2O), followed by stirring for 10-30 min at a temperature of
55-65.degree. C. The resulting phases were separated, the organic
phase heated to distill off 107-139 g of solvent (at 50-65.degree.
C.). To the resulting residue, cyclohexane (280 g) was added over
20-40 minutes and the resulting mixture cooled to 10-15.degree. C.,
then stirred at this temperature for 2-3 hours, over which time a
thick suspension was observed to form. The resulting suspension was
filtered, the filtercake washed with a mixture of cyclohexane (135
g) and ethyl acetate (45 g), then dried at 55-60.degree. C., under
vacuum to yield the title compound as a solid.
Example 12
Oral Formulation
Prophetic Example
[0483] As a specific embodiment of an oral composition, 100 mg of
the compound prepared as in Example 1, 2, 3 or 4 is formulated with
sufficient finely divided lactose to provide a total amount of 580
to 590 mg to fill a size 0 hard gel capsule.
[0484] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *