U.S. patent application number 14/740954 was filed with the patent office on 2015-12-24 for synthesis of polycyclic-carbamoylpyridone compounds.
The applicant listed for this patent is Gilead Sciences, Inc.. Invention is credited to Anna Chiu, John Enquist, JR., Nolan Griggs, Christopher Hale, Jochem Van Herpt, Norihiro Ikemoto, Katie Ann Keaton, Matt Kraft, Scott E. Lazerwith, Michel Leeman, Zhihui Peng, Kate Schrier, Jonathan Trinidad, Andrew W. Waltman.
Application Number | 20150368264 14/740954 |
Document ID | / |
Family ID | 53674256 |
Filed Date | 2015-12-24 |
United States Patent
Application |
20150368264 |
Kind Code |
A1 |
Chiu; Anna ; et al. |
December 24, 2015 |
SYNTHESIS OF POLYCYCLIC-CARBAMOYLPYRIDONE COMPOUNDS
Abstract
Methods of making compounds of Formula I are disclosed:
##STR00001##
Inventors: |
Chiu; Anna; (Burlingame,
CA) ; Enquist, JR.; John; (San Mateo, CA) ;
Griggs; Nolan; (San Mateo, CA) ; Hale;
Christopher; (Foster City, CA) ; Ikemoto;
Norihiro; (South Plainfield, NJ) ; Keaton; Katie
Ann; (Burlingame, CA) ; Kraft; Matt; (Foster
City, CA) ; Lazerwith; Scott E.; (San Francisco,
CA) ; Leeman; Michel; (Fairfield, NJ) ; Peng;
Zhihui; (Foster City, CA) ; Schrier; Kate;
(Redwood City, CA) ; Trinidad; Jonathan; (Foster
City, CA) ; Herpt; Jochem Van; (Fairfield, NJ)
; Waltman; Andrew W.; (San Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gilead Sciences, Inc. |
Foster City |
CA |
US |
|
|
Family ID: |
53674256 |
Appl. No.: |
14/740954 |
Filed: |
June 16, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62015081 |
Jun 20, 2014 |
|
|
|
Current U.S.
Class: |
544/95 ; 546/296;
549/274; 549/417; 564/194; 564/200 |
Current CPC
Class: |
C07D 319/06 20130101;
C07C 231/02 20130101; C07D 213/82 20130101; C07D 498/22 20130101;
C07C 231/12 20130101; C07C 237/20 20130101; C07D 309/40 20130101;
C07D 498/14 20130101; C07C 235/80 20130101; C07C 231/02 20130101;
C07C 235/80 20130101; C07C 231/12 20130101; C07C 237/16
20130101 |
International
Class: |
C07D 498/14 20060101
C07D498/14; C07D 309/40 20060101 C07D309/40; C07C 237/20 20060101
C07C237/20; C07D 213/82 20060101 C07D213/82; C07D 319/06 20060101
C07D319/06; C07C 235/78 20060101 C07C235/78 |
Claims
1-153. (canceled)
154. A process to prepare a compound of Formula I: ##STR00125##
according to the following General Scheme VI ##STR00126##
##STR00127## wherein the process comprises the following steps:
reacting B-1.J-1 under conditions suitable to yield C-1; reacting
C-1 with an alkylated formamide acetal to yield D-1; reacting D-1
with K-1 to yield E-1; reacting E-1 with M-1 in the presence of a
base to yield F-1; reacting F-1 with at least one acid to yield
FF-1; reacting FF-1 with N-1, or salts or co-crystals thereof, in
the presence of an additive to yield G-1; reacting G-1 under
conditions suitable to yield a compound of Formula I; wherein Hal
is halogen, which may be the same or different, n is 1, 2, or 3, L
is --C(R.sup.c).sub.2--, --C(R.sup.c).sub.2C(R.sup.c).sub.2--,
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--, or
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--,
each R.sup.c is, independently, hydrogen, halo, hydroxyl or
C.sub.1-C.sub.4alkyl, each R.sup.a, R.sup.1, and R.sup.2 is,
independently, (C.sub.1-C.sub.4)alkyl, (C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl (C.sub.1-C.sub.4)alkyl; each R.sup.h is
independently (C.sub.1-C.sub.4)alkyl.
155. The process of claim 154 wherein B-1.J-1 is reacted in the
presence of an acid.
156. The process of claim 155 wherein the acid is selected from the
group consisting of an inorganic acid, an organic acid, a
halogenated organic acid, a Lewis acid and mixtures thereof.
157. (canceled)
158. The process of claim 155 wherein the acid is trifluoroacetic
acid.
159. (canceled)
160. The process of claim 154 wherein the alkylated formamide
acetal is N,N-dimethylformamide dimethyl acetal.
161. The process of claim 154 wherein C-1 is reacted with an
alkylated formamide acetal in the presence of an acid.
162. (canceled)
163. The process of claim 161, wherein the acid is trifluoroacetic
acid.
164. (canceled)
165. The process of claim 154 wherein K-1 is aminoacetaldehyde
dimethylacetal.
166. (canceled)
167. The process of claim 154 wherein M-1 is dimethyl oxalate.
168. The process of claim 154 wherein E-1 is reacted with M-1 in
the presence of a base selected from the group consisting of a
metal hydride, an alkoxide, an inorganic carbonate, a
bis(triaklylsilyl)amide base, and a mixture thereof.
169. (canceled)
170. The process of claim 168, wherein the base is sodium
methoxide.
171. The process of claim 154 wherein F-1 is reacted with at least
one acid selected from the group consisting of an organic acid, an
inorganic acid, an organic carboxylic acids, and mixtures
thereof.
172. (canceled)
173. The process of claim 171 wherein the at least one acid is
p-toluenesulfonic acid.
174. The process of claim 154 wherein L is
--CH.sub.2--CH.sub.2--.
175. The process of claim 154 wherein N-1 is ##STR00128##
176. The process of claim 154 wherein N-1 is in the form of a salt
or co-crystal.
177. The process of claim 176 wherein N-1 is ##STR00129##
178. (canceled)
179. The process of claim 154 wherein the additive is selected from
the group consisting of a carboxylate salt, an inorganic carbonate,
a metal hydride, an alkoxide, a water scavenger and a mixture
thereof.
180. (canceled)
181. The process of claim 154 wherein the additive is potassium
acetate.
182. The process of claim 154 wherein G-1 is reacted with at least
one reagent selected from the group consisting of metal salts,
Lewis acids, sodium ethanethiolate, sodium hexamethyldisiloxane,
trifluoroacetic acid, and combinations thereof.
183. (canceled)
184. The process of claim 182 wherein the at least one reagent is
magnesium bromide.
185. The process of claim 154 wherein each R.sup.a, R.sup.b,
R.sup.1, and R.sup.2 is, independently C.sub.1-C.sub.4alkyl.
186-192. (canceled)
193. The process of claim 154 wherein J-1 is ##STR00130##
194-240. (canceled)
241. A compound having the structure: ##STR00131## ##STR00132## or
a salt, or co-crystal thereof, wherein Hal is halogen, which may be
the same or different, n is 1, 2, or 3, L is --C(R.sup.c).sub.2--,
--C(R.sup.c).sub.2C(R.sup.c).sub.2--,
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--, or
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--,
each R.sup.c is, independently, hydrogen, halo, hydroxyl or
C.sub.1-C.sub.4alkyl, and each R.sup.b, R.sup.d, R.sup.1, and
R.sup.2 is, independently, (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.30)aryl, or
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.4)alkyl.
242. A compound having the structure: ##STR00133## or a salt, or
co-crystal thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and the benefit of U.S.
Provisional Application No. 62/015,081, filed Jun. 20, 2014, which
is hereby incorporated by reference in its entirety.
BACKGROUND
[0002] 1. Field
[0003] Novel methods of synthesis of polycyclic carbamoylpyridone
compounds are disclosed. Intermediates in the synthetic pathway of
polycyclic carbamoylpyridone compound are also disclosed.
[0004] 2. Description of the Related Art
[0005] Human immunodeficiency virus infection and related diseases
are a major public health problem worldwide. Human immunodeficiency
virus type 1 (HIV-1) encodes three enzymes which are required for
viral replication: reverse transcriptase, protease, and integrase.
Although drugs targeting reverse transcriptase and protease are in
wide use and have shown effectiveness, particularly when employed
in combination, toxicity and development of resistant strains have
limited their usefulness (Palella, et al. N. Engl. J Med. (1998)
338:853-860; Richman, D. D. Nature (2001) 410:995-1001).
Accordingly, there is a need for new agents that inhibit the
replication of HIV and that minimize PXR activation when
co-administered with other drugs.
[0006] Certain polycyclic carbamoylpyridone compounds have been
found to have antiviral activity, as disclosed in
PCT/US2013/076367. Accordingly, there is a need for synthetic
routes for such compounds.
SUMMARY
[0007] The present invention is directed to a novel synthetic
process for preparing the polycyclic carbamoylpyridone compounds of
Formula I using the synthetic steps described herein. The present
invention is also directed to particular individual steps of this
process and particular individual intermediates used in this
process. One embodiment of the present invention provides a process
to prepare a Compound of Formula I:
##STR00002##
[0008] A further embodiment provides a process to prepare a
Compound of Formula I
##STR00003##
according to the following General Scheme I:
##STR00004## [0009] wherein the process comprises the following
steps: [0010] reacting C-1 with an alkylated formamide acetal to
yield D-1; [0011] reacting D-1 with K-1 to yield E-1; [0012]
reacting E-1 with M-1 in the presence of a base to yield F-1;
[0013] reacting F-1 with at least one acid and N-1, or salts or
co-crystals thereof, in the presence of a base to yield G-1; [0014]
reacting G-1 under conditions suitable to yield a compound of
Formula I; wherein [0015] Hal is halogen, which may be the same or
different, [0016] n is 1, 2, or 3, [0017] L is
--C(R.sup.c).sub.2--, --C(R.sup.c).sub.2C(R.sup.c).sub.2--,
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--, or
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--,
[0018] each R.sup.c is, independently, hydrogen, halo, hydroxyl or
C.sub.1-C.sub.4alkyl, [0019] each R.sup.a, R.sup.1, and R.sup.2 is,
independently, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.10)aryl, or
(C.sub.2-C.sub.10)aryl (C.sub.1-C.sub.4)alkyl.
[0020] In some embodiments, each R.sup.b is independently
(C.sub.1-C.sub.4)alkyl.
[0021] In some embodiments, each R.sup.a, R.sup.1, and R.sup.2 is,
independently, (C.sub.1-C.sub.4)alkyl, (C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl (C.sub.1-C.sub.4)alkyl.
[0022] Another embodiment provides a process to prepare a compound
of Formula I
##STR00005##
according to the following General Scheme II:
##STR00006## ##STR00007##
wherein the process comprises the following steps: [0023] reacting
A-1 with H-1 in the presence of a catalyst, a base, and an
acylating reagent to yield B-1; [0024] reacting B-1 with J-1 in the
presence of an acid to yield C-1; [0025] reacting C-1 with an
alkylated formamide acetal to yield D-1; [0026] reacting D-1 with
K-1 to yield E-1; [0027] reacting E-1 with M-1 in the presence of a
base to yield F-1; [0028] reacting F-1 with at least one acid and
N-1, in the presence of a base to yield G-1; [0029] reacting G-1
under conditions suitable to yield a compound of Formula I; wherein
[0030] Hal is halogen, [0031] n is 1, 2, or 3, [0032] L is
--C(R.sup.c).sub.2--, --C(R.sup.c).sub.2C(R.sup.c).sub.2--,
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--, or
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--,
[0033] each R.sup.c is, independently, hydrogen, halo, hydroxyl or
C.sub.1-C.sub.4alkyl, [0034] each R.sup.a, R.sup.b, R.sup.1, and
R.sup.2 is, independently (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.10)aryl, or (C.sub.2-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl.
[0035] In some embodiments, Hal is halogen, which may be the same
or different.
[0036] In some embodiments, each R.sup.a, R.sup.b, R.sup.1, and
R.sup.2 is, independently, (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or (C.sub.6-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl.
[0037] In some embodiments, J-1 is in the form of a salt or a
co-crystal.
[0038] In some embodiments, N-1 is in the form of a salt or a
co-crystal.
[0039] Another embodiment provides a process to prepare a Compound
of Formula I
##STR00008##
according to the following General Scheme III:
##STR00009## ##STR00010##
wherein the process comprises the following steps: [0040] reacting
B-1 with Q-1 to yield BB-1 [0041] reacting BB-1 with J-1 to yield
C-1; [0042] reacting C-1 with an alkylated formamide acetal to
yield D-1; [0043] reacting D-1 with K-1 to yield E-1; [0044]
reacting E-1 with M-1 in the presence of a base to yield F-1;
[0045] reacting F-1 with at least one acid and N-1, or salts or
co-crystals thereof, in the presence of a base to yield G-1; [0046]
reacting G-1 under conditions suitable to yield a compound of
Formula I; wherein [0047] Hal is halogen, [0048] n is 1, 2, or 3,
[0049] L is --C(R.sup.c).sub.2--,
--C(R.sup.c).sub.2C(R.sup.c).sub.2--,
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--, or
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--,
[0050] each R.sup.c is, independently, hydrogen, halo, hydroxyl or
C.sub.1-C.sub.4alkyl, [0051] each R.sup.a, R.sup.b, R.sup.d,
R.sup.1, and R.sup.2 is, independently, (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.10)aryl, or (C.sub.2-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl.
[0052] In some embodiments, Hal is halogen, which may be the same
or different.
[0053] In some embodiments, each R.sup.a, R.sup.b, R.sup.d,
R.sup.1, and R.sup.2 is, independently, (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or (C.sub.6-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl.
[0054] In some embodiments, J-1 is in the form of a salt or a
co-crystal.
[0055] Another embodiment provides a process to prepare a Compound
of Formula I
##STR00011##
according to the following General Scheme IV:
##STR00012##
wherein the process comprises the following steps: [0056] reacting
C-1 with an alkylated formamide acetal to yield D-1; [0057]
reacting D-1 with M-1 to yield EE-1; [0058] reacting EE-1 with K-1
to yield F-1; [0059] reacting F-1 with at least one acid and N-1,
in the presence of a base to yield G-1; [0060] reacting G-1 under
conditions suitable yield a compound of Formula I; wherein [0061]
Hal is halogen, [0062] n is 1, 2, or 3, [0063] L is
--C(R.sup.c).sub.2--, --C(R.sup.c).sub.2C(R.sup.c).sub.2--,
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--, or
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--,
[0064] each R.sup.c is, independently, hydrogen, halo, hydroxyl or
C.sub.1-C.sub.4alkyl, [0065] each R.sup.a, R.sup.b, R.sup.1, and
R.sup.2 is, independently, (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.10)aryl, or (C.sub.2-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl.
[0066] In some embodiments, Hal is halogen, which may be the same
or different.
[0067] In some embodiments, each R.sup.a, R.sup.b, R.sup.1, and
R.sup.2 is, independently, (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or (C.sub.6-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl.
[0068] In some embodiments, N-1 is in the form of a salt or a
co-crystal.
[0069] Another embodiment provides a process to prepare a compound
of Formula II:
##STR00013##
according to the following General Scheme V:
##STR00014##
wherein the process comprises the following steps: [0070] reacting
C-1 with an alkylated formamide acetal to yield D-1; [0071]
reacting D-1 with K-1 to yield E-1; [0072] reacting E-1 with M-1 in
the presence of a base to yield F-1; [0073] reacting F-1 with a
base to yield a compound of Formula II, wherein [0074] Hal is
halogen, [0075] n is 1, 2, or 3, [0076] each R.sup.a, R.sup.b,
R.sup.1, and R.sup.2 is, independently, (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.10)aryl, or (C.sub.2-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl.
[0077] In some embodiments, Hal is halogen, which may be the same
or different.
[0078] In some embodiments, each R.sup.a, R.sup.b, R.sup.1, and
R.sup.2 is, independently, (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or (C.sub.6-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl.
[0079] Another embodiment provides a process to prepare a Compound
of Formula I:
##STR00015##
according to the following General Scheme VI
##STR00016## ##STR00017##
wherein the process comprises the following steps: [0080] reacting
B-1.J-1 under conditions suitable to yield C-1; [0081] reacting C-1
with an alkylated formamide acetal to yield D-1; [0082] reacting
D-1 with K-1 to yield E-1; [0083] reacting E-1 with M-1 in the
presence of a base to yield F-1; [0084] reacting F-1 with at least
one acid to yield FF-1; [0085] reacting FF-1 with N-1, or salts or
co-crystals thereof, in the presence of an additive to yield G-1;
[0086] reacting G-1 under conditions suitable to yield a compound
of Formula I; wherein [0087] Hal is halogen, which may be the same
or different, [0088] n is 1, 2, or 3, [0089] L is
--C(R.sup.c).sub.2--, --C(R.sup.c).sub.2C(R.sup.c).sub.2--,
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--, or
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--,
[0090] each R.sup.c is, independently, hydrogen, halo, hydroxyl or
C.sub.1-C.sub.4alkyl, [0091] each R.sup.b is, independently
C.sub.1-C.sub.4alkyl, [0092] each R.sup.a, R.sup.1, and R.sup.2 is,
independently, (C.sub.1-C.sub.4)alkyl, (C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl (C.sub.1-C.sub.4)alkyl.
[0093] Other embodiments and features will be set forth in the
detailed description of the embodiments that follows, and in part
will be apparent from the description, or may be learned by
practice, of the claimed invention. The foregoing summary has been
made with the understanding that it is to be considered as a brief
and general synopsis of some of the embodiments disclosed herein,
is provided solely for the benefit and convenience of the reader,
and is not intended to limit in any manner the scope, or range of
equivalents, to which the appended claims are lawfully
entitled.
DETAILED DESCRIPTION
[0094] In the following description, certain specific details are
set forth in order to provide a thorough understanding of various
embodiments. However, one skilled in the art will understand that
the invention may be practiced without these details. The
description below of several embodiments is made with the
understanding that the present disclosure is to be considered as an
exemplification of the claimed subject matter, and is not intended
to limit the appended claims to the specific embodiments
illustrated. The headings used throughout this disclosure are
provided for convenience only and are not to be construed to limit
the claims in any way. Embodiments illustrated under any heading
may be combined with embodiments illustrated under any other
heading.
DEFINITIONS
[0095] Unless the context requires otherwise, throughout the
present specification and claims, the word "comprise" and
variations thereof, such as, "comprises" and "comprising" are to be
construed in an open, inclusive sense, that is as "including, but
not limited to".
[0096] A prefix such as "C.sub.u-v" or (C.sub.u-C.sub.v) indicates
that the following group has from u to v carbon atoms. For example,
"(C.sub.1-C.sub.6)alkyl" indicates that the alkyl group has from 1
to 6 carbon atoms and (C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl
indicates that the aryl portion of the group has from 6 to 10
carbon atoms and the alkyl portion of the group has from one to six
carbon atoms.
[0097] Reference throughout this specification to "one embodiment"
or "an embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment of the present invention. Thus,
the appearances of the phrases "in one embodiment" or "in an
embodiment" in various places throughout this specification are not
necessarily all referring to the same embodiment. Furthermore, the
particular features, structures, or characteristics may be combined
in any suitable manner in one or more embodiments.
[0098] "Amino" refers to the --NH.sub.2 radical.
[0099] "Cyano" refers to the --CN radical.
[0100] "Hydroxy" or "hydroxyl" refers to the --OH radical.
[0101] "Imino" refers to the .dbd.NH substituent.
[0102] "Nitro" refers to the --NO.sub.2 radical.
[0103] "Oxo" refers to the .dbd.O substituent.
[0104] "Thioxo" refers to the .dbd.S substituent.
[0105] "BzOH" refers to benzoic acid or
##STR00018##
[0106] "Alkyl" refers to a straight or branched saturated
hydrocarbon chain radical consisting solely of carbon and hydrogen
atoms, having from one to twelve carbon atoms (C.sub.1-C.sub.12
alkyl), or one to eight carbon atoms (C.sub.1-C.sub.8 alkyl), or
one to six carbon atoms (C.sub.1-C.sub.6 alkyl), or one to 4 carbon
atoms (C.sub.1-C.sub.4 alkyl) and which is attached to the rest of
the molecule by a single bond, e.g., methyl, ethyl, n-propyl,
1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl
(t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-1-enyl,
but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethynyl, propynyl,
butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise
specifically in the specification, an alkyl group may be optionally
substituted.
[0107] In some embodiments, "Alkyl" refers to a straight or
branched saturated hydrocarbon chain radical consisting solely of
carbon and hydrogen atoms, having from one to twelve carbon atoms
(C.sub.1-C.sub.12 alkyl), or one to eight carbon atoms
(C.sub.1-C.sub.8 alkyl), or one to six carbon atoms
(C.sub.1-C.sub.6 alkyl), or one to 4 carbon atoms (C.sub.1-C.sub.4
alkyl) and which is attached to the rest of the molecule by a
single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl
(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),
3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise
specifically in the specification, an alkyl group may be optionally
substituted.
[0108] "Alkenyl" refers to any group derived from a straight or
branched hydrocarbon with at least one carbon-carbon double bond.
Alkenyl groups include, but are not limited to, ethenyl (vinyl),
propenyl (allyl), 1-butenyl, 1,3-butadienyl, and the like. Unless
otherwise specified, an alkenyl group has from 2 to about 10 carbon
atoms, for example from 2 to 10 carbon atoms, for example from 2 to
6 carbon atoms, for example from 2 to 4 carbon atoms.
[0109] "Alkynyl" refers to any group derived from a straight or
branched hydrocarbon with at least one carbon-carbon triple bond
and includes those groups having one triple bond and one double
bond. Examples of alkynyl groups include, but are not limited to,
ethynyl (--C.ident.CH), propargyl (--CH.sub.2C.ident.CH),
(E)-pent-3-en-1-ynyl, and the like. Unless otherwise specified, an
alkynyl group has from 2 to about 10 carbon atoms, for example from
2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for
example from 2 to 4 carbon atoms.
[0110] "Alkoxy" refers to a radical of the formula --OR.sup.A where
R.sup.A is an alkyl radical as defined above containing one to
twelve carbon atoms, or one to eight carbon atoms, or one to six
carbon atoms, or one to four carbon atoms. Unless stated otherwise
specifically in the specification, an alkoxy group may be
optionally substituted.
[0111] "Alkylamino" refers to a radical of the formula --NHR.sup.A
or --NR.sup.AR.sup.A where each R.sub.A is, independently, an alkyl
radical as defined above containing one to twelve carbon atoms, or
one to eight carbon atoms, or one to six carbon atoms, or one to
four carbon atoms. Unless stated otherwise specifically in the
specification, an alkylamino group may be optionally
substituted.
[0112] "Thioalkyl" refers to a radical of the formula --SR.sup.A
where R.sup.A is an alkyl radical as defined above containing one
to twelve carbon atoms, or one to eight carbon atoms, or one to six
carbon atoms, or one to four carbon atoms. Unless stated otherwise
specifically in the specification, a thioalkyl group may be
optionally substituted.
[0113] "Aryl" refers to a monocyclic hydrocarbon ring system
radical comprising hydrogen and 6 to 18 carbon atoms, or 6 to 10
carbon atoms or 6 to 8 carbon atoms. Aryl radicals include, but are
not limited to, aryl radicals derived from benzene. Unless stated
otherwise specifically in the specification, the term "aryl" or the
prefix "ar-" (such as in "aralkyl") is meant to include aryl
radicals that are optionally substituted.
[0114] "Arylalkyl" (also "aralkyl") refers to a radical of the
formula --R.sup.B--R.sup.C where R.sup.B is an alkyl group as
defined above and R.sub.C is one or more aryl radicals as defined
above, for example, benzyl. Arylalkyl groups include, but are not
limited to, those groups derived from benzyl, tolyl,
dimethylphenyl, 2-phenylethan-1-yl, 2-naphthylmethyl,
phenylmethylbenzyl, 1,2,3,4-tetrahydronapthyl, and the like. An
arylalkyl group comprises from 6 to about 30 carbon atoms, for
example the alkyl group can comprise from 1 to about 10 carbon
atoms and the aryl group can comprise from 5 to about 20 carbon
atoms. Unless stated otherwise specifically in the specification,
an aralkyl group may be optionally substituted.
[0115] In some embodiments, "Arylalkyl" (also "aralkyl") refers to
a radical of the formula --R.sup.B--R.sup.C where R.sup.B is an
alkyl group as defined above and R.sub.C is one or more aryl
radicals as defined above, for example, benzyl. Arylalkyl groups
include, but are not limited to, those groups derived from benzyl,
tolyl, dimethylphenyl, 2-phenylethan-1-yl, 2-naphthylmethyl,
phenylmethylbenzyl, 1,2,3,4-tetrahydronapthyl, and the like. An
arylalkyl group comprises from 6 to about 30 carbon atoms, for
example the alkyl group can comprise from 1 to about 10 carbon
atoms and the aryl group can comprise from 6 to about 20 carbon
atoms. Unless stated otherwise specifically in the specification,
an aralkyl group may be optionally substituted.
[0116] "Cycloalkyl" refers to a cyclic alkyl group. A cycloalkyl
group can have one or more cyclic rings and includes fused and
bridged groups. Examples include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and
the like. Unless otherwise stated specifically in the
specification, a carbocyclic group may be optionally
substituted.
[0117] "Carbocyclic ring" or "carbocycle" refers to a stable
non-aromatic monocyclic hydrocarbon radical consisting solely of
carbon and hydrogen atoms, having from three to fifteen carbon
atoms, preferably having from three to ten carbon atoms, and which
is saturated or unsaturated and attached to the rest of the
molecule by a single bond. Monocyclic radicals include, for
example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and cyclooctyl. Unless otherwise stated specifically
in the specification, a carbocyclic group may be optionally
substituted.
[0118] "Cycloalkylalkyl" refers to a radical of the formula
--R.sub.BR.sub.D where R.sub.B is an alkyl group as defined above
and R.sup.D is a carbocyclic radical as defined above. Unless
stated otherwise specifically in the specification, a
cycloalkylalkyl group may be optionally substituted.
[0119] In some embodiments, "Cycloalkylalkyl" refers to a radical
of the formula --R.sub.BR.sub.D where R.sub.B is an alkyl group as
defined above and R.sub.D is a carbocyclic radical as defined
above. Unless stated otherwise specifically in the specification, a
cycloalkylalkyl group may be optionally substituted.
[0120] "Halo" or "halogen" refers to bromo, chloro, fluoro or
iodo.
[0121] "Haloalkyl" refers to an alkyl radical, as defined above,
that is substituted by one or more halo radicals, as defined above,
e.g., trifluoromethyl, difluoromethyl, trichloromethyl,
2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,
1,2-dibromoethyl, and the like. Unless stated otherwise
specifically in the specification, a haloalkyl group may be
optionally substituted.
[0122] "Heterocyclyl" or "heterocyclic ring" refers to a stable 3-
to 18-membered non-aromatic ring radical which consists of two to
twelve carbon atoms and from one to six heteroatoms selected from
the group consisting of nitrogen, oxygen and sulfur. In some
embodiments, the heterocyclyl radical is a 3 to 12 membered
non-aromatic ring, or a 3 to 8 membered non-aromatic ring, or a 3
to 6 membered non-aromatic ring. In some embodiments, the
heterocyclyl radical contains one to four heteroatoms, or one to
three heteroatoms, or one to two heteroatoms, or one heteroatom. In
the embodiments disclosed herein, the heterocyclyl radical is a
monocyclic ring system; and the heterocyclyl radical may be
partially or fully saturated. Examples of such heterocyclyl
radicals include, but are not limited to, dioxolanyl, thienyl,
[1,3]dithianyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,
isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,
4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl,
tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,
thiamorpholinyl, 1-oxo-thiomorpholinyl, and
1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in
the specification, a heterocyclyl group may be optionally
substituted.
[0123] In some embodiments, "Heterocyclyl" or "heterocyclic ring"
refers to a stable 4- to 18-membered non-aromatic ring radical
which consists of 3 to 17 carbon atoms and from one to six
heteroatoms selected from the group consisting of nitrogen, oxygen
and sulfur. In some embodiments, the heterocyclyl radical is a 4 to
12 membered non-aromatic ring, or a 4 to 8 membered non-aromatic
ring, or a 4 to 6 membered non-aromatic ring. In some embodiments,
the heterocyclyl radical contains one to four heteroatoms, or one
to three heteroatoms, or one to two heteroatoms, or one heteroatom.
Unless stated otherwise specifically in the specification, a
heterocyclyl group may be optionally substituted.
[0124] "N-heterocyclyl" refers to a heterocyclyl radical as defined
above containing at least one nitrogen and where the point of
attachment of the heterocyclyl radical to the rest of the molecule
is through a nitrogen atom in the heterocyclyl radical. Unless
stated otherwise specifically in the specification, an
N-heterocyclyl group may be optionally substituted.
[0125] "Heterocyclylalkyl" refers to a radical of the formula
--R.sub.BR.sub.E where R.sub.B is an alkyl group as defined above
and R.sub.E is a heterocyclyl radical as defined above, and if the
heterocyclyl is a nitrogen-containing heterocyclyl, the
heterocyclyl may be attached to the alkyl radical at the nitrogen
atom. Unless stated otherwise specifically in the specification, a
heterocyclylalkyl group may be optionally substituted.
[0126] "Heteroaryl" refers to an aryl group in which one or more of
the carbon atoms (and any associated hydrogen atoms) are each
independently replaced with the the same or different heteroatom
selected from the group consisting of nitrogen, oxygen and sulfur.
Unless otherwise specified, an heteroaryl group has from 5 to about
20 carbon atoms, for example from 5 to 18 carbon atoms, for example
from 5 to 14 carbon atoms, for example from 5 to 10 carbon atoms.
Heteroaryl groups have from one to six heteroatoms, from one to
four heteroatoms, from one to three heteroatoms, from one to two
heteroatoms or one heteroatom. Unless stated otherwise specifically
in the specification, a heteroaryl group may be optionally
substituted.
[0127] In some, embodiments, "Heteroaryl" refers to an aryl group
in which one or more of the carbon atoms (and any associated
hydrogen atoms) are each independently replaced with the same or
different heteroatom selected from the group consisting of
nitrogen, oxygen and sulfur. Heteroaryl groups include, but are not
limited to, groups derived from furan, imidazole, isothiazole,
isoxazole, oxadiazole, oxazole, pyrazine, pyrazole, pyridazine,
pyridine, pyrimidine, pyrrole, tetrazole, thiadiazole, thiazole,
thiophene, triazole, and the like. Unless otherwise specified, an
heteroaryl group has from 5 to about 20 carbon atoms, for example
from 5 to 18 carbon atoms, for example from 5 to 14 carbon atoms,
for example from 5 to 10 carbon atoms. Heteroaryl groups have from
one to six heteroatoms, from one to four heteroatoms, from one to
three heteroatoms, from one to two heteroatoms or one heteroatom.
Unless stated otherwise specifically in the specification, a
heteroaryl group may be optionally substituted.
[0128] "N-heteroaryl" refers to a heteroaryl radical as defined
above containing at least one nitrogen and where the point of
attachment of the heteroaryl radical to the rest of the molecule is
through a nitrogen atom in the heteroaryl radical. Unless stated
otherwise specifically in the specification, an N-heteroaryl group
may be optionally substituted.
[0129] "Heteroarylalkyl" refers to a radical of the formula
--R.sub.BR.sub.F where R.sub.B is an alkyl group as defined above
and R.sub.F is a heteroaryl radical as defined above. Unless stated
otherwise specifically in the specification, a heteroarylalkyl
group may be optionally substituted.
[0130] The term "substituted" used herein means any of the above
groups (i.e., alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl,
aralkyl, carbocycle, cycloalkylalkyl, haloalkyl, heterocyclyl,
N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or
heteroarylalkyl) wherein at least one hydrogen atom is replaced by
a bond to a non-hydrogen atoms such as, but not limited to: a
halogen atom such as F, Cl, Br, and I; an oxygen atom in groups
such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur
atom in groups such as thiol groups, thioalkyl groups, sulfone
groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in
groups such as amines, amides, alkylamines, dialkylamines,
arylamines, alkylarylamines, diarylamines, N-oxides, imides, and
enamines; a silicon atom in groups such as trialkylsilyl groups,
dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl
groups; and other heteroatoms in various other groups.
"Substituted" also means any of the above groups in which one or
more hydrogen atoms are replaced by a higher-order bond (e.g., a
double- or triple-bond) to a heteroatom such as oxygen in oxo,
carbonyl, carboxyl, and ester groups; and nitrogen in groups such
as imines, oximes, hydrazones, and nitriles. For example,
"substituted" includes any of the above groups in which one or more
hydrogen atoms are replaced with NR.sub.GR.sub.H,
--NR.sub.GC(.dbd.O)R.sub.H, --NR.sub.GC(.dbd.O)NR.sub.GR.sub.H,
--NR.sub.GC(.dbd.O)OR.sub.H,
--NR.sub.GC(.dbd.NR.sub.g)NR.sub.GR.sub.H,
--NR.sub.GSO.sub.2R.sub.H, --OC(.dbd.O)NR.sub.GR.sub.H, --OR.sub.G,
--SR.sub.G, --SOR.sub.G, --SO.sub.2R.sub.G, --OSO.sub.2R.sub.G,
--SO.sub.2OR.sub.G, .dbd.NSO.sub.2R.sub.G, and
--SO.sub.2NR.sub.GR.sub.H. "Substituted also means any of the above
groups in which one or more hydrogen atoms are replaced with
--C(.dbd.O)R.sub.G, --C(.dbd.O)OR.sub.G,
--C(.dbd.O)NR.sub.GR.sub.H, --CH.sub.2SO.sub.2R.sub.G,
--CH.sub.2SO.sub.2NR.sub.GR.sub.H. In the foregoing, R.sub.G and
R.sub.H are the same or different and independently hydrogen,
alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocycle,
cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,
heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
"Substituted" further means any of the above groups in which one or
more hydrogen atoms are replaced by a bond to an amino, cyano,
hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy,
alkylamino, thioalkyl, aryl, aralkyl, carbocycle, cycloalkylalkyl,
haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl,
heteroaryl, N-heteroaryl and/or heteroarylalkyl group. In addition,
each of the foregoing substituents may also be optionally
substituted with one or more of the above substituents.
[0131] The term "alkylated formamide acetal" as used herein, refers
to a compound of Formula:
##STR00019##
wherein each R.sup.b is independently (C.sub.1-C.sub.4)alkyl,
R.sup.v1 and R.sup.v2 are independently (C.sub.1-C.sub.6)alkyl or
R.sup.v1 and R.sup.v2 together with the atoms to which they are
attached form a 5 to 10 membered heterocyclyl.
[0132] "Alkylated formamide acetal" includes, but is not limited to
N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide
diethyl acetal, N,N-dimethylformamide diisopropyl acetal,
N,N-diethylformamide dimethyl acetal, and N,N-diisopropylformamide
dimethyl acetal.
[0133] The term "acyl donor" as used herein, refers to a reactive
compound which transfers a group --CO--R.sup.x onto another
molecule, wherein R.sup.x is (C.sub.1-C.sub.6)alkyl-R.sup.y and
R.sup.y is selected from the group consisting of H, CN,
--NR.sup.z1R.sup.z2, --C(O)R.sup.z1, --C(O)OR.sup.z1,
--C(O)NR.sup.z1R.sup.z2, --OC(O)NR.sup.z1R.sup.z2,
--NR.sup.z1C(O)R.sup.z2, --NR.sup.z1C(O)NR.sup.z2,
--NR.sup.z1C(O)OR.sup.z2, --SR.sup.z1, --S(O).sub.1-2R.sup.z1,
--S(O).sub.2NR.sup.z1R.sup.z2, --NR.sup.z1S(O).sub.2R.sup.z2,
--NR.sup.z1S(O).sub.2R.sup.z2, and OR.sup.z1. R.sup.z1 and R.sup.z2
are independently selected from the group consisting of H,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6heteroalkyl, C.sub.3-10cycloalkyl, 3 to 12 membered
heterocyclyl, C.sub.6-10aryl and 5 to 10 membered heteroaryl. In
certain embodiments, R.sup.y is H. In certain embodiments, R.sup.z1
and R.sup.z2 are independently selected from the group consisting
of H and C.sub.1-6alkyl. Acyl donors include but are not limited to
anhydrides, esters and acid chlorides such as succinic anhydride,
glutaric anhydride, acetic anhydride, vinyl acetate, isopropenyl
acetate, 4-chlorophenyl acetate, ethyl methoxy acetate, acetyl
chloride and benzoyl chloride.
[0134] A person skilled in the art will understand that throughout
this application, and more specifically in Schemes I, II, III, V
and VI, compound E-1 may exist in an E or in a Z configuration or
as a mixture of an E and Z configuration. Accordingly, in certain
embodiments, compound E-1 is in an E or a Z configuration, or a
mixture thereof. In certain embodiments, compound E-1 is in an E
configuration. In certain embodiments, compound E-1 is in an Z
configuration. In certain embodiments, compound E-1 is in a mixture
of Z and E configurations.
##STR00020##
[0135] A person skilled in the art will understand that throughout
this application, compound B-1.J-1 is a salt:
##STR00021##
[0136] The term "protecting group," as used herein, refers to a
labile chemical moiety which is known in the art to protect
reactive groups including without limitation, hydroxyl and amino
groups, against undesired reactions during synthetic procedures.
Hydroxyl and amino groups protected with a protecting group are
referred to herein as "protected hydroxyl groups" and "protected
amino groups", respectively. Protecting groups are typically used
selectively and/or orthogonally to protect sites during reactions
at other reactive sites and can then be removed to leave the
unprotected group as is or available for further reactions.
Protecting groups as known in the art are described generally in
Greene and Wuts, Protective Groups in Organic Synthesis, 3rd
edition, John Wiley & Sons, New York (1999). Generally, groups
are protected or present as a precursor that will be inert to
reactions that modify other areas of the parent molecule for
conversion into their final groups at an appropriate time. Further
representative protecting or precursor groups are discussed in
Agrawal, et al., Protocols for Oligonucleotide Conjugates, Eds,
Humana Press; New Jersey, 1994; Vol. 26 pp. 1-72. Examples of
"hydroxyl protecting groups" include, but are not limited to,
t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl,
1-ethoxyethyl, 1-(2-chloroethoxyl)ethyl, 2-trimethylsilylethyl,
p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl,
diphenylmethyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl,
triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl (TBDPS),
triphenylsilyl, benzoylformate, acetate, chloroacetate,
trichloroacetate, trifluoroacetate, pivaloate, benzoate,
p-phenylbenzoate, 9-fluorenylmethyl carbonate, mesylate and
tosylate. Examples of "amino protecting groups" include, but are
not limited to, carbamate-protecting groups, such as
2-trimethylsilylethoxycarbonyl (Teoc),
1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), t-butoxycarbonyl
(BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl
(Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups, such
as formyl, acetyl, trihaloacetyl, benzoyl, and nitrophenylacetyl;
sulfonamide-protecting groups, such as 2-nitrobenzenesulfonyl; and
imine and cyclic imide protecting groups, such as phthalimido and
dithiasuccinoyl.
[0137] The invention disclosed herein is also meant to encompass
all pharmaceutically acceptable compounds of Formula I and
compounds of Formula II being isotopically-labeled by having one or
more atoms replaced by an atom having a different atomic mass or
mass number. Examples of isotopes that can be incorporated into the
disclosed compounds include isotopes of hydrogen, carbon, nitrogen,
oxygen, phosphorous, fluorine, chlorine, and iodine, such as
.sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N,
.sup.15O, .sup.17O, .sup.18O, .sup.31P, .sup.32P, .sup.35S,
.sup.18F, .sup.36Cl, .sup.123I, and .sup.125I, respectively. These
radiolabeled compounds could be useful to help determine or measure
the effectiveness of the compounds, by characterizing, for example,
the site or mode of action, or binding affinity to
pharmacologically important site of action. Certain
isotopically-labeled compounds of Formula I and compounds of
Formula II, for example, those incorporating a radioactive isotope,
are useful in drug and/or substrate tissue distribution studies.
The radioactive isotopes tritium, i.e. .sup.3H, and carbon-14, i.e.
.sup.14C, are particularly useful for this purpose in view of their
ease of incorporation and ready means of detection.
[0138] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability. For example, in vivo half-life may
increase or dosage requirements may be reduced. Thus, heavier
isotopes may be preferred in some circumstances.
[0139] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy. Isotopically-labeled compounds of Formula I and
compounds of Formula II can generally be prepared by conventional
techniques known to those skilled in the art or by processes
analogous to those described in the Examples as set out below using
an appropriate isotopically-labeled reagent in place of the
non-labeled reagent previously employed.
[0140] The invention disclosed herein is also meant to encompass
the in vivo metabolic products of the disclosed compounds. Such
products may result from, for example, the oxidation, reduction,
hydrolysis, amidation, esterification, and the like of the
administered compound, primarily due to enzymatic processes.
Accordingly, the invention includes compounds produced by a process
comprising administering a compound of this invention to a mammal
for a period of time sufficient to yield a metabolic product
thereof. Such products are typically identified by administering a
radiolabeled compound described in the embodiments herein in a
detectable dose to an animal, such as rat, mouse, guinea pig,
monkey, or to human, allowing sufficient time for metabolism to
occur, and isolating its conversion products from the urine, blood
or other biological samples.
[0141] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0142] "Lewis acid" refers to a group that can accept a nonbonding
pair of electrons, i.e., an electron-pair acceptor. Lewis acids are
able to react with a Lewis base to form a Lewis adduct, by sharing
the electron pair supplied by the Lewis base.
[0143] "Mammal" includes humans and both domestic animals such as
laboratory animals and household pets (e.g., cats, dogs, swine,
cattle, sheep, goats, horses, rabbits), and non-domestic animals
such as wildlife and the like.
[0144] "Optional" or "optionally" means that the subsequently
described event of circumstances may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not. For example, "optionally
substituted aryl" means that the aryl radical may or may not be
substituted and that the description includes both substituted aryl
radicals and aryl radicals having no substitution.
[0145] "Pharmaceutically acceptable carrier, diluent or excipient"
includes without limitation any adjuvant, carrier, excipient,
glidant, sweetening agent, diluent, preservative, dye/colorant,
flavor enhancer, surfactant, wetting agent, dispersing agent,
suspending agent, stabilizer, isotonic agent, solvent, or
emulsifier which has been approved by the United States Food and
Drug Administration as being acceptable for use in humans or
domestic animals.
[0146] "Pharmaceutically acceptable salt" refers to a salt of a
compound that is pharmaceutically acceptable and that possesses (or
can be converted to a form that possesses) the desired
pharmacological activity of the parent compound. Examples of
"pharmaceutically acceptable salts" of the compounds disclosed
herein include salts derived from an appropriate base, such as an
alkali metal (for example, sodium), an alkaline earth metal (for
example, magnesium), ammonium and NX.sub.4.sup.+ (wherein X is
C.sub.1-C.sub.4 alkyl). Pharmaceutically acceptable salts of a
nitrogen atom or an amino group include for example salts of
organic carboxylic acids such as acetic, benzoic, camphorsulfonic,
citric, glucoheptonic, gluconic, lactic, fumaric, tartaric, maleic,
malonic, malic, mandelic, isethionic, lactobionic, succinic,
2-napththalenesulfonic, oleic, palmitic, propionic, stearic, and
trimethylacetic acids; organic sulfonic acids, such as
methanesulfonic, ethanesulfonic, benzenesulfonic and
p-toluenesulfonic acids; and inorganic acids, such as hydrochloric,
hydrobromic, sulfuric, nitric, phosphoric and sulfamic acids.
Pharmaceutically acceptable salts of a compound of a hydroxy group
include the anion of said compound in combination with a suitable
cation such as Na.sup.+ and NX.sub.4.sup.+ (wherein X is
independently selected from H or a C.sub.1-C.sub.4 alkyl group).
Pharmaceutically acceptable salts also include salts formed when an
acidic proton present in the parent compound is replaced by either
a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or
an aluminum ion; or coordinates with an organic base such as
diethanolamine, triethanolamine, N-methylglucamine and the like.
Also included in this definition are ammonium and substituted or
quaternized ammonium salts. Representative non-limiting lists of
pharmaceutically acceptable salts can be found in S. M. Berge et
al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science
and Practice of Pharmacy, R. Hendrickson, ed., 21st edition,
Lippincott, Williams & Wilkins, Philadelphia, Pa., (2005), at
p. 732, Table 38-5, both of which are hereby incorporated by
reference herein.
[0147] For therapeutic use, salts of active ingredients of the
compounds disclosed herein will typically be pharmaceutically
acceptable, i.e. they will be salts derived from a physiologically
acceptable acid or base. However, salts of acids or bases which are
not pharmaceutically acceptable may also find use, for example, in
the preparation or purification of a compound of Formula I, a
compound of Formula II or another compound described herein. All
salts, whether or not derived from a physiologically acceptable
acid or base, are within the scope of the present invention.
[0148] Metal salts refer to salts wherein the cation is a metal,
such as those formed when an acidic proton present in a compound is
replaced by either a metal ion, e.g., an alkali metal ion, an
alkaline earth ion, or an aluminium ion; or a metal ion coordinates
with an organic base such as diethanolamine, triethanolamine,
N-methylglucamine and the like.
[0149] The metal can be an alkali metal, alkaline earth metal,
transition metal, or main group metal. Non-limiting examples of
suitable metals include lithium, sodium, potassium, cesium, cerium,
magnesium, manganese, iron, calcium, strontium, cobalt, titanium,
aluminum, copper, cadmium, and zinc.
[0150] Non-limiting examples of suitable metal salts include a
lithium salt, a sodium salt, a potassium salt, a cesium salt, a
cerium salt, a magnesium salt, a manganese salt, an iron salt, a
calcium salt, a strontium salt, a cobalt salt, a titanium salt, a
aluminum salt, a copper salt, a cadmium salt, and a zinc salt.
[0151] In addition, salts may be formed from acid addition of
certain organic and inorganic acids, e.g., HCl, HBr,
H.sub.2SO.sub.4, H.sub.3PO.sub.4 or organic sulfonic acids, to
basic centers, typically amines.
[0152] Finally, it is to be understood that the compositions herein
comprise compounds disclosed herein in their un-ionized, as well as
zwitterionic form, and combinations with stoichiometric amounts of
water as in hydrates.
[0153] Often crystallizations produce a solvate of the compound
described in the embodiments disclosed herein. As used herein, the
term "solvate" refers to an aggregate that comprises one or more
molecules of a compound described herein with one or more molecules
of solvent. The solvent may be water, in which case the solvate may
be a hydrate. Alternatively, the solvent may be an organic solvent.
Thus, the compounds of the present invention may exist as a
hydrate, including a monohydrate, dihydrate, hemihydrate,
sesquihydrate, trihydrate, tetrahydrate and the like, as well as
the corresponding solvated forms. The compounds described herein
may be true solvates, while in other cases, the compound described
herein may merely retain adventitious water or be a mixture of
water plus some adventitious solvent.
[0154] A "pharmaceutical composition" refers to a formulation of a
compound described herein and a medium generally accepted in the
art for the delivery of the biologically active compound to
mammals, e.g., humans. Such a medium includes all pharmaceutically
acceptable carriers, diluents or excipients therefor.
[0155] "Effective amount" or "therapeutically effective amount"
refers to an amount of a compound according to the invention, which
when administered to a patient in need thereof, is sufficient to
effect treatment for disease-states, conditions, or disorders for
which the compounds have utility. Such an amount would be
sufficient to elicit the biological or medical response of a tissue
system, or patient that is sought by a researcher or clinician. The
amount of a compound according to the invention which constitutes a
therapeutically effective amount will vary depending on such
factors as the compound and its biological activity, the
composition used for administration, the time of administration,
the route of administration, the rate of excretion of the compound,
the duration of the treatment, the type of disease-state or
disorder being treated and its severity, drugs used in combination
with or coincidentally with the compounds described herein, and the
age, body weight, general health, sex and diet of the patient. Such
a therapeutically effective amount can be determined routinely by
one of ordinary skill in the art having regard to their own
knowledge, the state of the art, and this disclosure.
[0156] The term "treatment" as used herein is intended to mean the
administration of a compound or composition according to the
present invention to alleviate or eliminate symptoms of HIV
infection and/or to reduce viral load in a patient. The term
"treatment" also encompasses the administration of a compound or
composition according to the present invention post-exposure of the
individual to the virus but before the appearance of symptoms of
the disease, and/or prior to the detection of the virus in the
blood, to prevent the appearance of symptoms of the disease and/or
to prevent the virus from reaching detectible levels in the blood,
and the administration of a compound or composition according to
the present invention to prevent perinatal transmission of HIV from
mother to baby, by administration to the mother before giving birth
and to the child within the first days of life.
[0157] The term "antiviral agent" as used herein is intended to
mean an agent (compound or biological) that is effective to inhibit
the formation and/or replication of a virus in a human being,
including but not limited to agents that interfere with either host
or viral mechanisms necessary for the formation and/or replication
of a virus in a human being.
[0158] The term "inhibitor of HIV replication" as used herein is
intended to mean an agent capable of reducing or eliminating the
ability of HIV to replicate in a host cell, whether in vitro, ex
vivo or in vivo.
[0159] The compounds described herein, or their pharmaceutically
acceptable salts may contain one or more asymmetric centers and may
thus give rise to enantiomers, diastereomers, and other
stereoisomeric forms that may be defined, in terms of absolute
stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino
acids. The present invention is meant to include all such possible
isomers, as well as their racemic and optically pure forms.
Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-
isomers may be prepared using chiral synthons or chiral reagents,
or resolved using conventional techniques, for example,
chromatography and fractional crystallization. Conventional
techniques for the preparation/isolation of individual enantiomers
include chiral synthesis from a suitable optically pure precursor
or resolution of the racemate (or the racemate of a salt or
derivative) using, for example, chiral high pressure liquid
chromatography (HPLC). When the compounds described herein contain
olefinic double bonds or other centers of geometric asymmetry, and
unless specified otherwise, it is intended that the compounds
include both E and Z geometric isomers. Likewise, all tautomeric
forms are also intended to be included.
[0160] A "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. The
present invention contemplates various stereoisomers and mixtures
thereof and includes "enantiomers", which refers to two
stereoisomers whose molecules are nonsuperimposeable mirror images
of one another.
[0161] A "tautomer" refers to a proton shift from one atom of a
molecule to another atom of the same molecule. The present
invention includes tautomers of any said compounds.
[0162] An "enantioenriched" compound refers to a compound which
contains more than 50% of one of a pair of enantiomers. An
"enantioenriched" compound may have an enantiomeric excess (% ee)
of over 5%, over 10%, over 20%, over 30%, over 40%, over 50%, over
60%, over 70%, over 80%, over 90%, over 95%, over 99%, or over
99.9%.
[0163] Reference to "about" a value or parameter herein includes
(and describes) embodiments that are directed to that value or
parameter per se. For example, description referring to "about X"
includes description of "X". Also, the singular forms "a" and "the"
include plural references unless the context clearly dictates
otherwise. Thus, e.g., reference to "the compound" includes a
plurality of such compounds and reference to "the assay" includes
reference to one or more assays and equivalents thereof known to
those skilled in the art.
General Schemes
[0164] Certain embodiments are directed to the multistep general
synthetic methods described below, namely General Schemes I-VI. All
substituent groups in the steps described below are as defined as
follows: [0165] Hal is halogen, [0166] n is 1, 2, or 3, [0167] L is
--C(R.sup.c).sub.2--, --C(R.sup.c).sub.2C(R.sup.c).sub.2--,
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--, or
--C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2C(R.sup.c).sub.2--,
[0168] each R.sup.c is, independently, hydrogen, halo, hydroxyl or
C.sub.1-C.sub.4alkyl, [0169] each R.sup.a, R.sup.b, R.sup.d,
R.sup.1, and R.sup.2 is, independently, alkyl, aryl, or
aralkyl.
[0170] In some embodiments, Hal is halogen, which may be the same
or different.
[0171] In certain embodiments, each R.sup.a, and R.sup.2 is,
independently, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.10)aryl, or
(C.sub.2-C.sub.10)aryl (C.sub.1-C.sub.4)alkyl.
[0172] In some embodiments, each R.sup.a, R.sup.b, R.sup.1, and
R.sup.2 is, independently, (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or (C.sub.6-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl.
[0173] In certain embodiments, each R.sup.b is, independently,
(C.sub.1-C.sub.4)alkyl.
[0174] In certain embodiments, each Re is, independently, hydrogen,
--F, --Cl, hydroxyl, or methyl. In certain embodiments, each
R.sup.c is, independently, hydrogen, --F, or --Cl. In certain
embodiments, each Re is hydrogen.
[0175] In certain embodiments, each R.sup.a, R.sup.b, R.sup.d,
R.sup.1, and R.sup.2 is, independently, methyl, ethyl, phenyl, or
benzyl. In certain embodiments, each R.sup.a, R.sup.b, R.sup.1, and
R.sup.2 is methyl. In particular embodiments, R.sup.d is ethyl.
[0176] In certain embodiments, each R.sup.1 is C.sub.1-C.sub.4alkyl
and each R.sup.1, together along with the atoms to which they are
bonded, forms a heterocycle. In certain embodiments, each R.sup.1
is methyl or ethyl, and each R.sup.1, together along with the atoms
to which they are bonded, forms a heterocycle. In certain
embodiments, each R.sup.1 is methyl, and each R.sup.1, together
along with the atoms to which they are bonded, forms a
heterocycle
General Scheme I:
[0177] In certain embodiments, a process according to general
scheme I is provided:
##STR00022## [0178] wherein the process comprises the following
steps: [0179] reacting C-1 with an alkylated formamide acetal to
yield D-1; [0180] reacting D-1 with K-1 to yield E-1; [0181]
reacting E-1 with M-1 in the presence of a base to yield F-1;
[0182] reacting F-1 with at least one acid and N-1, or salts or
co-crystals thereof, in the presence of a base to yield G-1; [0183]
reacting G-1 under conditions suitable to yield a compound of
Formula I.
[0184] In some embodiments, N-1 is in the form of a salt or a
co-crystal.
General Scheme II:
[0185] In certain embodiments, a process according to general
scheme I is provided:
##STR00023## ##STR00024##
wherein the process comprises the following steps: [0186] reacting
A-1 with H-1 in the presence of a catalyst, a base, and an
acylating reagent to yield B-1; [0187] reacting B-1 with J-1 in the
presence of an acid to yield C-1; [0188] reacting C-1 with an
alkylated formamide acetal to yield D-1; [0189] reacting D-1 with
K-1 to yield E-1; [0190] reacting E-1 with M-1 in the presence of a
base to yield F-1; [0191] reacting F-1 with at least one acid and
N-1 in the presence of a base to yield G-1; [0192] reacting G-1
under conditions suitable yield a compound of Formula I.
[0193] In some embodiments, J-1 is in the form of a salt or a
co-crystal.
[0194] In some embodiments, N-1 is in the form of a salt or a
co-crystal.
General Scheme III:
[0195] In certain embodiments, a process according to general
scheme I is provided:
##STR00025## ##STR00026##
wherein the process comprises the following steps: [0196] reacting
B-1 with Q-lto yield BB-1 [0197] reacting BB-1 with J-1 to yield
C-1; [0198] reacting C-1 with an alkylated formamide acetal to
yield D-1; [0199] reacting D-1 with K-1 to yield E-1; [0200]
reacting E-1 with M-1 in the presence of a base to yield F-1;
[0201] reacting F-1 with at least one acid and N-1, or salts or
co-crystals thereof, in the presence of a base to yield G-1; [0202]
reacting G-1 under conditions suitable to yield a compound of
Formula I.
[0203] In some embodiments, J-1 is in the form of a salt or a
co-crystal.
General Scheme IV:
[0204] In certain embodiments, a process according to general
scheme I is provided:
##STR00027##
wherein the process comprises the following steps: [0205] reacting
C-1 with an alkylated formamide acetal to yield D-1; [0206]
reacting D-1 with M-1 to yield EE-1; [0207] reacting EE-1 with K-1
to yield F-1; [0208] reacting F-1 with at least one acid and N-1,
in the presence of a base to yield G-1; [0209] reacting G-1 under
conditions suitable to yield a compound of Formula I.
[0210] In some embodiments, N-1 is in the form of a salt or a
co-crystal.
General Scheme V
[0211] In certain embodiments, a process according to general
scheme I is provided:
##STR00028##
wherein the process comprises the following steps: [0212] reacting
C-1 with an alkylated formamide acetal to yield D-1; [0213]
reacting D-1 with K-1 to yield E-1; [0214] reacting E-1 with M-1 in
the presence of a base to yield F-1; [0215] reacting F-1 with a
base to yield a compound of Formula II.
General Scheme VI
[0216] In certain embodiments, a process according to general
scheme I is provided:
##STR00029## ##STR00030##
wherein the process comprises the following steps: [0217] reacting
B-1.J-1 under conditions suitable to yield C-1; [0218] reacting C-1
with an alkylated formamide acetal to yield D-1; [0219] reacting
D-1 with K-1 to yield E-1; [0220] reacting E-1 with M-1 in the
presence of a base to yield F-1; [0221] reacting F-1 with at least
one acid to yield FF-1; [0222] reacting FF-1 with N-1, or salts or
co-crystals thereof, in the presence of an additive to yield G-1;
[0223] reacting G-1 under conditions suitable to yield a compound
of Formula I.
[0224] In some embodiments reacting F-1 with at least one acid
yields the following aldehyde:
##STR00031## [0225] which is hydrated to give FF-1.
General Scheme VII
[0226] Certain embodiments are directed to the multistep synthetic
method described below, namely General Scheme VII:
##STR00032##
wherein the process comprises the following steps: [0227]
hydrogenating (-)-Vince lactam and protecting the reduced product
to yield a-1; [0228] reacting a-1 with R.sup.3-M to yield b-1;
[0229] oxidizing b-1 and hydrolyzing the product of the oxidation
to yield c-1.
[0230] In General Scheme VII: [0231] PG is a protecting group; and
[0232] R.sup.3M is a n-alkyl Grignard reagent or an alkyl
organolithium reagent.
[0233] In certain embodiments, the protecting group (PG) is
selected from the group consisting of Boc, phtalimide, benzyl,
FMoc, acetyl, triphenylmethyl, trifluoroacetyl, benzylidene,
p-Toluenesulfonamide, p-Methoxybenzyl carbonyl, benzoyl,
p-methoxybenzyl, carbamates, 3,4-Dimethoxybenzyl, p-methoxyphenyl,
sulfonamides and carbobenzyloxy. In particular embodiments, the
protecting group is Boc.
[0234] In certain embodiments, R.sup.3M is an ethylmagnesium
halide, an n-propylmagnesium halide, and n-butylmagnesium halide,
methyl lithium, n-butyllithium, or n-hexyllithium. In particular
embodiments, R.sup.3M is methyl magnesium bromide.
Scheme VIII
[0235] Certain embodiments are directed to the multistep synthetic
method described below, namely Scheme VIII:
##STR00033##
wherein the process comprises the following steps: reacting g-1x
under conditions effective to yield h-1x; and reacting h-1x under
conditions effective to yield N-1x.
[0236] In some embodiments, the process further comprises the
following step:
##STR00034##
reacting f-1x under conditions effective to yield g-1x.
[0237] In some embodiments, g-1x is hydrogenated in the presence of
a catalyst and a source of hydrogen to yield h-1x.
[0238] In some embodiments, the catalyst is selected form the group
consisting of palladium (Pd) based catalysts, PtO.sub.2, Raney
Nickel, RhCl(PPh.sub.3).sub.3, Nyori's catalyst, and Crabtree's
catalyst. Exemplary palladium catalyst include Pd/C. In some
embodiments, the catalyst is selected form the group consisting of
Pd/C, PtO.sub.2, Raney Nickel, RhCl(PPh.sub.3).sub.3, Nyori's
catalyst, and Crabtree's catalyst. In some embodiments, the
catalyst is PtO.sub.2.
[0239] In certain embodiments, the source of hydrogen is formic
acid, hydrazine, dihydronapthalene, dihydroanthracene, H.sub.2 gas
or Hantzch ester and isopropanol. In particular embodiments, the
source of hydrogen is H.sub.2 gas. In particular embodiments, the
source of hydrogen is H.sub.2 gas under an atmosphere of
hydrogen.
[0240] In some embodiments, h-1x is reacted with an acid to yield
N-1x. In some embodiments, the acid is a sulfonic acid, including
but not limited to methanesulfonic acid, p-toluenesulfonic acid and
camphorsulfonic acid; an inorganic acid, including but not limited
to phosphoric acid, hydrochloric acid and sulfuric acid; a
carboxylic acid including but not limited to trifluoroacetic acid,
oxalic acid and benzoic acid. In certain embodiments, the acid is
an inorganic acid. In particular embodiments, the acid is
hydrochloric acid. In particular embodiments, the acid is anhydrous
hydrochloric acid.
[0241] In some embodiments, g-1x is
##STR00035##
and N-1x is
##STR00036##
[0243] In some embodiments, f-1x is
##STR00037##
Scheme IX
[0244] Certain embodiments are directed to the multistep synthetic
method described below, namely General Scheme IX:
##STR00038##
wherein the process comprises the following steps: reacting racemic
c-1a (which is a mixture of cc-1b and cc-1a) with an acyl donor and
an enzyme to yield cc-1b and e-1; isolating e-1 from cc-1b; and
hydrolyzing e-1 to yield enantioenriched cc-1a.
[0245] In certain embodiments, R.sup.x is
(C.sub.1-C.sub.6)alkyl-R.sup.y and R.sup.y is selected from the
group consisting of H, CN, --NR.sup.z1R.sup.z2, C(O)OR.sup.z1,
--C(O)NR.sup.z1R.sup.z2, --OC(O)NR.sup.z1R.sup.z2,
--NR.sup.z1C(O)NR.sup.z2, --NR.sup.z1C(O)OR.sup.z2,
--SR.sup.z1C(O)OR.sup.z2, --SR.sup.z1, --S(O).sub.1-2R.sup.z1,
--S(O).sub.2NR.sup.z1R.sup.z2, --NR.sup.z1S(O).sub.2R.sup.z2,
NR.sup.z1S(O).sub.2R.sup.z2, and OR.sup.z1.
[0246] In certain embodiments, R.sup.z1 and R.sup.z2 are
independently selected from the group consisting of H,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6heteroalkyl, C.sub.3-10cycloalkyl, 3 to 12 membered
heterocyclyl, C.sub.6-10aryl and 5 to 10 membered heteroaryl.
[0247] In certain embodiments, R.sup.x is
(C.sub.1-C.sub.6)alkyl-R.sup.y and R.sup.y is selected from the
group consisting of H, --C(O)OR.sup.z1 and R.sup.z1 is selected
from the group consisting of H, C.sub.1-6alkyl,
C.sub.3-10cycloalkyl, and 3 to 12 membered heterocyclyl.
[0248] In certain embodiments, R.sup.x is
(C.sub.1-C.sub.6)alkyl-R.sup.y and R.sup.y is selected from the
group consisting of H, --C(O)OR.sup.z1 and R.sup.z1 is selected
from the group consisting of H and C.sub.1-6alkyl.
[0249] In certain embodiments, R.sup.x is
(C.sub.1-C.sub.4)alkyl-R.sup.y and R.sup.y is selected from the
group consisting of H and CO.sub.2H.
[0250] In certain embodiments, R.sup.x is methyl or
(CH.sub.2).sub.3--CO.sub.2H. In certain embodiments, R.sup.x is
(CH.sub.2).sub.3--CO.sub.2H.
[0251] In certain embodiments, the acyl donor is an anhydride or an
ester. In certain embodiments, the anhydride includes but is not
limited to glutaric anhydride and acetic anhydride. In certain
embodiments, the ester includes but is not limited to vinyl
acetate, isopropenyl acetate, 4-chlorophenyl acetate and ethyl
methoxy acetate. In particular embodiments, the acyl donor is
glutaric anhydride.
[0252] In certain embodiments, the enzyme is a lipase. In certain
embodiments, the lipase includes but is not limited to Novozyme
435, CAL-A, CAL-B, PPL, PSL-C, PSL, CRL and MML. In certain
embodiments, the lipase includes but is not limited to CAL-A,
CAL-B, PPL, PSL-C, PSL, CRL and MML. In certain embodiments, the
enzyme is CAL-B. In certain embodiments, the enzyme is Novozyme
435.
[0253] Novozyme 435 is a CAL-B lipase immobilized on an hydrophobic
carrier (acrylin resin).
[0254] CAL-B is Candida antartica B lipase.
[0255] CAL-A is Candida antartica A lipase.
[0256] PPL is Porcine Pancreas Lipase.
[0257] PSL is Pseudomonas cepacia lipase.
[0258] PSL-C is an immobilized lipase from Pseudomonas cepacia.
[0259] CRL is Candida rugosa lipase.
[0260] MML is Mucor miehei lipase.
[0261] Scheme X
[0262] Certain embodiments are directed to the multistep synthetic
method described below, namely General Scheme X:
##STR00039##
wherein the process comprises the following steps: reacting racemic
c-1a (which is a mixture of cc-1b and cc-1a) with an acyl donor to
yield racemic ee-1; reacting racemic ee-1 (which is a mixture of
e-1 and e-2) with an enzyme to yield e-2 and cc-1a; and isolating
enantioenriched cc-1a.
[0263] In certain embodiments, R.sup.x is
(C.sub.1-C.sub.6)alkyl-R.sup.y and R.sup.y is selected from the
group consisting of H, CN, --NR.sup.z1R.sup.z2, C(O)R.sup.z1,
--C(O)OR.sup.z1, --C(O)NR.sup.z1R.sup.z2, --OC(O)NR.sup.z1R.sup.z2,
--NR.sup.z1C(O)R.sup.z2, --NR.sup.z1C(O)NR.sup.z2,
--NR.sup.z1C(O)OR.sup.z2, --SR.sup.z1, --S(O).sub.1-2R.sup.z1,
--S(O).sub.2NR.sup.z1R.sup.z2, NR.sup.z1S(O).sub.2R.sup.z2,
NR.sup.z1S(O).sub.2R.sup.z2, and OR.sup.z1.
[0264] In certain embodiments, each R.sup.z1 and R.sup.z2 is
independently selected from the group consisting of H,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6heteroalkyl,
C.sub.3-10cycloalkyl, 3 to 12 membered heterocyclyl, C.sub.6-10aryl
and 5 to 10 membered heteroaryl.
[0265] In certain embodiments, R.sup.x is
(C.sub.1-C.sub.6)alkyl-R.sup.y and R.sup.y is selected from the
group consisting of H, --C(O)OR.sup.z1 and R.sup.z1 is selected
from the group consisting of H, C.sub.3-10cycloalkyl, and 3 to 12
membered heterocyclyl.
[0266] In certain embodiments, R.sup.x is
(C.sub.1-C.sub.6)alkyl-R.sup.y and R.sup.y is selected from the
group consisting of H, --C(O)OR.sup.z1 and R.sup.z1 is selected
from the group consisting of H and C.sub.1-6alkyl.
[0267] In certain embodiments, R.sup.x is
(C.sub.1-C.sub.4)alkyl-R.sup.y and R.sup.y is selected from the
group consisting of H and CO.sub.2H.
[0268] In certain embodiments, R.sup.x is methyl or
(CH.sub.2).sub.3--CO.sub.2H. In certain embodiments, R.sup.x is
(CH.sub.2).sub.3--CO.sub.2H.
[0269] In certain embodiments, the acyl donor includes but is not
limited to an anhydride or an acid chloride. In certain
embodiments, the anhydride includes but is not limited to succinic
anhydride and acetic anhydride. In certain embodiments, the acid
chloride include but is not limited to acetyl chloride and benzoyl
chloride. In particular embodiments, the acyl donor is Glutaric
anhydride.
[0270] In certain embodiments, the enzyme is a lipase such as but
are not limited to CAL-A, CAL-B, PPL, PSL-C, PSL, CRL, and MML. In
particular embodiments, the enzyme is CAL-B.
Scheme XI
[0271] Certain embodiments are directed to the multistep synthetic
method described below, namely Scheme XI:
##STR00040##
wherein the process comprises the following steps: reacting racemic
c-1a (which is a mixture of cc-1b and cc-1a) with a chiral acid to
yield dd-1 and dd-2; and isolating enantioenriched dd-1.
[0272] In certain embodiments, the chiral acid is selected from the
group consisting of: [0273] single enantiomers of carboxylic acids
including but not limited to: naproxen, phenyl succinic acid, malic
acid, 2-phenylpropionic acid, alpha-methoxy-phenyl acetic acid,
tartranilic acid, 3-phenyllactic acid, .alpha.-hydroxyisovaleric
acid, 2'-methoxy-tartranilic acid, (alpha-methylbenzyl)phthalamic
acid, 2'-chloro-tartranilic acid, pyroglutamic acid; [0274] single
enantiomers of mandelic acid derivatives including but not limited
to: mandelic acid, 2-chloromandelic acid, 4-bromo-mandelic acid,
O-acetyl mandelic acid, 4-methyl-mandelic acid; [0275] single
enantiomers of sulfonic acids including but not limited to: camphor
sulfonic acid; [0276] single enantiomers of tartaric acid
derivatives including but not limited to: tartaric acid, dibenzoyl
tartaric acid hydrate, di-p-anisoyltartaric acid, di-toluyltartaric
acid, dibenzoyl tartaric acid hydrate; [0277] single enantiomers of
phosphoric acid derivatives including but not limited to:
phencyphos hydrate, chlocyphos, anisyphos, BINAP phosphate; and
[0278] single enantiomers of amino acids including but not limited
tos: N-acetyl-phenylalanine, N-acetyl-leucine, N-acetyl-proline,
boc-phenylalanine, and boc-homophenylalanine.
[0279] In certain embodiments, the chiral acid is a single
enantiomers of a carboxylic acid.
[0280] In particular embodiments, the acid is (R)-Naproxen. In
particular embodiments, the acid is R-(+)-mandelic acid.
[0281] In particular embodiments, the acid is (S)-Naproxen. In
particular embodiments, the acid is S-(+)-mandelic acid.
[0282] In certain embodiments, the reaction with the chiral acid
occurs in a solvent selected from the group consisting of water,
acetonitrile, ethanol, isopropanol, methyl ethyl ketone, isopropyl
acetate, dioxane, a mixture of water and a water-miscible organic
solvents such as ethanol and isopropanol, an halogenated solvent
such as dichloromethane and chloroform. In particular embodiments,
the solvent is water or isopropanol or a mixture thereof. In
particular embodiments, the solvent is water. In particular
embodiments, the solvent is isopropanol.
[0283] In certain embodiments, the reaction with the chiral acid is
stirred at 0 to 120.degree. C., 20 to 120.degree. C., 50 to
120.degree. C., 80 to 120.degree. C., or about 100.degree. C. In
certain embodiments, the reaction is stirred at about 20.degree.
C.
[0284] In certain embodiments, isolating dd-1 comprises selectively
recrystallizing dd-1. In certain embodiments, the recrystallization
occurs in water, acetonitrile, ethanol, isopropanol, methyl ethyl
ketone, isopropyl acetate, dioxane; a mixture of water and
water-miscible organic solvents such as ethanol and isopropanol, or
a halogenated solvent such as dichloromethane or chloroform. In
certain embodiments, the recrystallization occurs in a mixture of
methyl ethyl ketone and water.
[0285] In certain embodiments, dd-1 precipitates out of solution
and is filtered.
[0286] Schemes VII-XI disclose steps and intermediates which are
useful for the the preparation of N-1 and/or a compound of Formula
I.
General Schemes--Individual Steps
[0287] Additional embodiments are directed to the individual steps
of the multistep general synthetic methods described above, namely
General Schemes I-V and VI to XI. These individual steps and
intermediates of the present invention are described in detail
below. All substituent groups in the steps described below are as
defined in the multi-step method above.
[0288] A. Acylation and Amidation of Meldrum's Acid to Provide
C-1:
##STR00041##
[0289] 1. Conversion of A-1 to B-1
[0290] In particular embodiments, one equivalent of Meldrum's acid
(A-1) and a suitable catalyst are suspended in a suitable solvent,
and the resulting solution is treated with about 1.2 equivalents of
H-1. About 2 equivalents of a suitable base are slowly added to the
resulting solution, followed by the addition of about 1.1
equivalents of a suitable acylating reagent. The reaction occurs at
about 20 to 80.degree. C. and is allowed to continue until
consumption of Meldrum's acid is complete, as monitored by any
suitable method known in the art.
[0291] In certain embodiments, the catalyst is a nucleophilic
amine-containing compound, such as, but is not limited to,
4-dimethylaminopyridine, imidazole, 1,4-diazabicyclo[2.2.2]octane,
1,8-diazabicyclo[5.4.0]undec-7-ene, or pyridine. In further
embodiments, the catalyst is a nucleophilic phosphine containing
compound, such as, but not limited to, triphenylphosphine. In a
particular embodiment, the catalyst is 4-dimethylaminopyridine.
[0292] In certain embodiments, the solvent for the above reaction
is a polar non-protic solvent or an aromatic solvent. In certain
embodiments, the solvent for the above reaction is a polar
non-protic solvent. In certain embodiments, the solvent for the
above reaction is an aromatic solvent. Exemplary polar non-protic
solvents include, but are not limited to, acetonitrile,
N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or
N-methyl-2-pyrrolidinone. Exemplary aromatic solvents for the above
reaction include, but not limited to, pyridine, toluene, xylene,
benzene, or chlorobenzene. In still further embodiments, the
solvent is a mixture comprising at least one of the forgoing
solvents. For example, in certain embodiments, the solvent is a
mixture of up to three, or up to two, polar non-protic solvents
selected from the group consisting of acetonitrile,
N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and
N-methyl-2-pyrrolidinone. In other embodiments, the solvent is a
mixture of up to three, or up to two, aromatic solvents selected
from the group consisting of pyridine, toluene, xylene, benzene,
and chlorobenzene. In one embodiment the solvent is a mixture of up
to three, or up to two, solvents selected from the group consisting
of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,
1,4-dioxane, N-methyl-2-pyrrolidinone, pyridine, toluene, xylene,
benzene, and chlorobenzene. In a further embodiment, the solvent is
acetonitrile.
[0293] In certain embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.10)aryl, or (C.sub.2-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.a is
(C.sub.1-C.sub.4)alkyl, (C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl. In certain
embodiments R.sup.a is --CH.sub.3, that is H-1 is methoxyacetic
acid.
[0294] In certain embodiments, the base is an amine base, an
aromatic base, inorganic carbonate, a metal hydride, an alkoxide,
or mixtures thereof. In certain embodiments, the base is an amine
base. In certain embodiments, the base is an aromatic base. In
certain embodiments, the base is an inorganic carbonate. In certain
embodiments, the base is a metal hydride. In certain embodiments,
the base is an alkoxide. Exemplary amine bases include, but are not
limited to, triethylamine, N,N-diisopropylethylamine, quinuclidine,
1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene,
tripropylamine, and tributylamine. Exemplary aromatic amine bases
include, but are not limited to, pyridine. Exemplary inorganic
carbonates include, but are not limited to, lithium carbonate,
sodium carbonate, potassium carbonate, or cesium carbonate.
Exemplary metal hydrides, include, but are not limited to, sodium
hydride or potassium hydride. Exemplary alkoxides include, but are
not limited to, sodium methoxide, sodium tert-butoxide or lithium
tert-butoxide. In still further embodiments, the base is a mixture
comprising at least one of the preceding bases. For example, in
certain embodiments, the base is a mixture of up to three, or up to
two, amine bases. In certain embodiments, the base is a mixture of
up to three, or up to two, aromatic bases. In certain embodiments,
the base is a mixture of up to three, or up to two, inorganic
carbonates. In certain embodiments, the base is a mixture of up to
three, or up to two, metal hydrides. In certain embodiments, the
base is a mixture of up to three, or up to two, alkoxides. In
certain embodiments, the base is a mixture of up to three, or up to
two, bases from the group consisting of triethylamine,
N,N-diisopropylethylamine, quinuclidine,
1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene,
tripropylamine, tributylamine, pyridine, lithium carbonate, sodium
carbonate, potassium carbonate, cesium carbonate, sodium hydride,
potassium hydride, sodium methoxide, sodium tert-butoxide and
lithium tert-butoxide. In a particular embodiment, the base is
triethylamine.
[0295] In certain embodiments, the acylating reagent is a
carboxylic acid activating reagent, a carbodiimide derivative, or a
mixture thereof. In certain embodiments, the acylating reagent is a
carboxylic acid activating reagent. In certain embodiments, the
acylating reagent is a carbodiimide derivative. In certain
embodiments, the acylating reagent is a mixture of a carboxylic
acid activating reagent and a carbodiimide derivative. Exemplary
carboxylic acid activating reagents include, without limitation,
pivaloyl chloride, carbonyldiimidazole, thionyl chloride, and
oxalyl chloride. Exemplary carbodiimide derivatives include,
without limitation, carbonyldiimidazole and
N,N'-dicyclohexylcarbodiimide. In certain embodiments, the
acylating reagent is pivaloyl chloride, carbonyldiimidazole,
thionyl chloride, oxalyl chloride, or
N,N'-dicyclohexylcarbodiimide. In certain embodiments, the
acylating reagent is a mixture of up to three, or up to two,
reagents from the groups consisting of pivaloyl chloride,
carbonyldiimidazole, thionyl chloride, oxalyl chloride, or
N,N'-dicyclohexylcarbodiimide. In certain embodiments, the
acylating reagent is pivaloyl chloride. In certain embodiments, the
reaction occurs at about 20 to 70.degree. C., about 20 to
60.degree. C., about 20 to 50.degree. C., about 20 to 40.degree.
C., about 20 to 30.degree. C., about 30 to 80.degree. C., about 30
to 70.degree. C., about 30 to 60.degree. C., about 30 to 50.degree.
C., about 30 to 40.degree. C., about 40 to 80.degree. C., about 40
to 70.degree. C., about 40 to 60.degree. C., about 40 to 50.degree.
C., about 50 to 80.degree. C., about 50 to 70.degree. C., about 50
to 60.degree. C., about 60 to 80.degree. C., about 60 to 70.degree.
C., about 70 to 80.degree. C., or any subrange therebetween. In
particular embodiments, the reaction occurs at about 35 to
40.degree. C., about 40 to 45.degree. C., about 45 to 50.degree.
C., or any subrange therebetween.
[0296] In particular embodiments, the catalyst is
4-dimethylaminopyridine, the solvent is acetonitrile, R.sup.a is
--CH.sub.3, the base is triethylamine, the acylating reagent is
pivaloyl chloride and the reaction occurs at about 45 to 50.degree.
C.
[0297] 2. Conversion of B-1 to C-1
[0298] In a separate vessel, about 1.2 equivalents of J-1 is
suspended in a suitable solvent. The resulting solution is treated
with about 1.5 equivalents of a suitable acid, and then this acidic
solution is added to the above acylation reaction in progress. The
reaction is allowed to continue for about 12 to about 24 hours at
about 20 to 80.degree. C., after which time the solvent is removed
and C-1 is recovered and purified from the residue using any
suitable technique known in the art, such as, but not limited to
solvent extraction, silica gel chromatography and
crystallization.
[0299] In certain embodiments, J-1 is suspended in a polar
non-protic solvent or an aromatic solvent. In certain embodiments,
J-1 is suspended in a polar non-protic solvent. In certain
embodiments, J-1 is suspended in an aromatic solvent. Exemplary
polar non-protic solvent include, but are not limited to,
acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,
1,4-dioxane, and N-methyl-2-pyrrolidinone. Exemplary aromatic
solvents include, but are not limited to, pyridine, toluene,
xylene, benzene, and chlorobenzene. In still further embodiments,
J-1 is suspended in a solvent mixture comprising one or more polar
non-protic solvents and/or one or more aromatic solvents. In
certain embodiments, J-1 is suspended in a solvent mixture
comprising up to three, or up to two, polar non-protic solvents. In
certain embodiments, J-1 is suspended in a solvent mixture
comprising up to three, or up to two, aromatic solvents. In certain
embodiments, J-1 is suspended in a solvent mixture comprising up to
three, or up to two, solvents from the group consisting of
acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,
1,4-dioxane, N-methyl-2-pyrrolidinone, pyridine, toluene, xylene,
benzene, and chlorobenzene. In a further embodiment, J-1 is
suspended in acetonitrile.
[0300] In particular embodiments, the acid is an inorganic acid, an
organic acid, or a halogenated organic acid. In certain
embodiments, the acid is an inorganic acid. In certain embodiments,
the acid is an organic acid. Exemplary inorganic acids, include,
but are not limited to hydrochloric acid, hydrobromic acid, and
hydroiodic acid. Exemplary organic acids, include, but are not
limited to, formic acid and acetic acid. In yet other embodiments
the organic acid is a halogenated organic acid. Exemplary
halogenated organic acids include, but are not limited to,
trifluoromethanesulfonic acid, trifluoroacetic acid,
trichloroacetic acid, and perfluoropropionic acid. In still further
embodiments, the acid is a mixture comprising one or more organic
acids and one or more inorganic acids. In certain embodiments, the
acid is a mixture comprising up to three, or up to two, organic
acids. In certain embodiments, the acid is a mixture comprising up
to three, or up to two, halogenated organic acids. In certain
embodiments, the acid is a mixture comprising up to three, or up to
two, inorganic acids. In a certain embodiment, the acid is a
mixture of up to three, or up to two, acids selected from the group
consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid,
formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid,
trichloroacetic acid, and perfluoropropionic acid. In a particular
embodiment, the acid is trifluoroacetic acid.
[0301] In particular embodiments, each Hal is independently --F or
--Cl. In a particular embodiment, Hal is --F In certain
embodiments, n=1-3. In certain embodiments, n=2. In certain
embodiments, n=3. In further embodiments, J-1 is
##STR00042##
In certain embodiments, J-1 is
##STR00043##
In further embodiments, J-1 is
##STR00044##
[0302] In still further embodiments, J-1 is in the form of a salt
or co-crystal, such as, but not limited to a salt or co-crystal of
hydrochloric acid or trifluoroacetic acid. In certain embodiments,
J-1 is a salt or co-crystal of methane sulfonic acid.
[0303] For example, in certain embodiments, J-1 is:
##STR00045##
[0304] In a particular embodiment, J-1 is
##STR00046##
[0305] In a particular embodiment, J-1 is
##STR00047##
[0306] For example, in certain embodiments, J-1 is:
##STR00048##
[0307] In a particular embodiment, J-1 is
##STR00049##
[0308] In a particular embodiment, J-1 is
##STR00050##
[0309] In certain embodiments, the reaction occurs at about 20 to
70.degree. C., about 20 to 60.degree. C., about 20 to 50.degree.
C., about 20 to 40.degree. C., about 20 to 30.degree. C., about 30
to 80.degree. C., about 30 to 70.degree. C., about 30 to 60.degree.
C., about 30 to 50.degree. C., about 30 to 40.degree. C., about 40
to 80.degree. C., about 40 to 70.degree. C., about 40 to 60.degree.
C., about 40 to 50.degree. C., about 50 to 80.degree. C., about 50
to 70.degree. C., about 50 to 60.degree. C., about 60 to 80.degree.
C., about 60 to 70.degree. C., about 70 to 80.degree. C., or any
subrange therebetween. In particular embodiments, the reaction
occurs at about 35 to 40.degree. C., about 40 to 45.degree. C.,
about 45 to 50.degree. C., or any subrange therebetween.
[0310] In certain embodiments, the solvent is removed under reduced
pressure. In particular embodiments, C-1 is extracted from the
crude residue by solvent extraction. In a particular embodiment,
the crude residue is dissolved in an organic solvent, such as ethyl
acetate, and the organic layer is washed with water. The combined
aqueous layers are extracted with an organic solvent, such as ethyl
acetate. The combined organic layers are washed with saturated
sodium bicarbonate solution, and the combined bicarbonate washes
are back extracted with an organic solvent such as ethyl acetate.
Total combined organic layers are dried over a drying agent, such
as magnesium sulfate, filtered, and concentrated under reduced
pressure. The resulting crude material is purified using any
suitable technique, such as silica gel chromatography to yield
C-1.
[0311] In particular embodiments, J-1 is suspended in acetonitrile,
the acid is trifluoroacetic acid, J-1 is
##STR00051##
and the reaction occurs at about 45 to 50.degree. C.
[0312] 3. Formation of C-1 Through B-1.J-1 Salt
[0313] Alternatively, in certain embodiments, C-1 is formed via
formation of a B-1.J-1 salt following the procedure below.
[0314] a. Formation of B-1.J-1 Salt by Addition of J-1 to B-1
##STR00052##
[0315] The free acid of B-1 (about 1 equivalent) is dissolved in a
solvent, followed by addition of J-1 (about 1 to about 5
equivalents). In certain embodiments, the salt is aged for up to 12
hours, up to 10 hours, up to 8 hours, up to 6 hours, up to 4 hours,
or up to 3 hours. The salt is obtained by any suitable methods
known in the art, including but not limited to solvent filtration,
extraction, crystallization, and silica gel chromatography.
[0316] In certain embodiments, the solvent for the above reaction
is a polar non-protic solvent or an aromatic solvent. In certain
embodiments, the solvent for the above reaction is a polar
non-protic solvent. In certain embodiments, the solvent for the
above reaction is an aromatic solvent. Exemplary polar non-protic
solvents include, but are not limited to, acetonitrile,
N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or
N-methyl-2-pyrrolidinone. Exemplary aromatic solvents for the above
reaction include, but not limited to, pyridine, toluene, xylene,
benzene, or chlorobenzene. In still further embodiments, the
solvent is a mixture comprising at least one of the forgoing
solvents. For example, in certain embodiments, the solvent is a
mixture of up to three, or up to two, polar non-protic solvents
selected from the group consisting of acetonitrile,
N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and
N-methyl-2-pyrrolidinone. In other embodiments, the solvent is a
mixture of up to three, or up to two, aromatic solvents selected
from the group consisting of pyridine, toluene, xylene, benzene,
and chlorobenzene. In one embodiment the solvent is a mixture of up
to three, or up to two, solvents selected from the group consisting
of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,
1,4-dioxane, N-methyl-2-pyrrolidinone, pyridine, toluene, xylene,
benzene, and chlorobenzene. In a further embodiment, the solvent is
acetonitrile.
[0317] In some embodiments, B-1.J-1 is:
##STR00053##
[0318] In certain embodiments, the reaction is stirred to about 15
to 30.degree. C., about 20 to 70.degree. C., about 20 to 60.degree.
C., about 20 to 50.degree. C., about 20 to 40.degree. C., about 20
to 30.degree. C., about 30 to 80.degree. C., about 30 to 70.degree.
C., about 30 to 60.degree. C., about 30 to 50.degree. C., about 30
to 40.degree. C., about 40 to 80.degree. C., about 40 to 70.degree.
C., about 40 to 60.degree. C., about 40 to 50.degree. C., about 50
to 80.degree. C., about 50 to 70.degree. C., about 50 to 60.degree.
C., about 60 to 80.degree. C., about 60 to 70.degree. C., about 70
to 80.degree. C., or any subrange therebetween. In further
embodiments, the reaction proceeds at about 15 to about 25.degree.
C.
[0319] In certain embodiments, the solvent is acetonitrile and the
reaction proceeds at about 18 to about 25.degree. C.
[0320] b. Formation of C-1 from salt B-1.J-1
##STR00054##
[0321] The salt B-1.J-1 (about 1 equivalent) is suspended in a
suitable solvent. The resulting solution is treated with about 0.1
to 1 equivalents of a suitable acid. The reaction is allowed to
continue for about 12 to about 24 hours at about 20 to 80.degree.
C., after which time the solvent is removed and C-1 is recovered
and purified from the residue using any suitable technique known in
the art, such as, but not limited to solvent extraction, silica gel
chromatography, crystallization, and filtration.
[0322] In certain embodiments, the solvent for the above reaction
is a polar non-protic solvent or an aromatic solvent. In certain
embodiments, the solvent for the above reaction is a polar
non-protic solvent. In certain embodiments, the solvent for the
above reaction is an aromatic solvent. Exemplary polar non-protic
solvents include, but are not limited to, acetonitrile,
N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or
N-methyl-2-pyrrolidinone. Exemplary aromatic solvents for the above
reaction include, but not limited to, pyridine, toluene, xylene,
benzene, or chlorobenzene. In still further embodiments, the
solvent is a mixture comprising at least one of the forgoing
solvents. For example, in certain embodiments, the solvent is a
mixture of up to three, or up to two, polar non-protic solvents
selected from the group consisting of acetonitrile,
N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and
N-methyl-2-pyrrolidinone. In other embodiments, the solvent is a
mixture of up to three, or up to two, aromatic solvents selected
from the group consisting of pyridine, toluene, xylene, benzene,
and chlorobenzene. In one embodiment the solvent is a mixture of up
to three, or up to two, solvents selected from the group consisting
of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,
1,4-dioxane, N-methyl-2-pyrrolidinone, pyridine, toluene, xylene,
benzene, and chlorobenzene. In a further embodiment, the solvent is
acetonitrile.
[0323] In particular embodiments, the acid is an inorganic acid, an
organic acid, or a halogenated organic acid. In certain
embodiments, the acid is an inorganic acid. In certain embodiments,
the acid is an organic acid. Exemplary inorganic acids, include,
but are not limited to hydrochloric acid, hydrobromic acid,
hydroiodic acid. Exemplary organic acids, include, but are not
limited to, formic acid and acetic acid. In yet other embodiments
the organic acid is a halogenated organic acid. Exemplary
halogenated organic acids include, but are not limited to,
trifluoromethanesulfonic acid, trifluoroacetic acid,
trichloroacetic acid, and perfluoropropionic acid. In certain
embodiments, the acid is trifluoroacetic acid. In still further
embodiments, the acid is a mixture comprising one or more organic
acids and one or more inorganic acids. In certain embodiments, the
acid is a mixture comprising up to three, or up to two, organic
acids. In certain embodiments, the acid is a mixture comprising up
to three, or up to two, halogenated organic acids. In certain
embodiments, the acid is a mixture comprising up to three, or up to
two, inorganic acids. In a certain embodiment, the acid is a
mixture of up to three, or up to two, acids selected from the group
consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid,
formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid,
trichloroacetic acid, and perfluoropropionic acid. In a particular
embodiment, the acid is trifluoroacetic acid.
[0324] In certain embodiments, after the addition is complete the
reaction is heated to about 20 to 70.degree. C., about 20 to
60.degree. C., about 20 to 50.degree. C., about 20 to 40.degree.
C., about 20 to 30.degree. C., about 30 to 80.degree. C., about 30
to 70.degree. C., about 30 to 60.degree. C., about 30 to 50.degree.
C., about 30 to 40.degree. C., about 40 to 80.degree. C., about 40
to 70.degree. C., about 40 to 60.degree. C., about 40 to 50.degree.
C., about 50 to 80.degree. C., about 50 to 70.degree. C., about 50
to 60.degree. C., about 60 to 80.degree. C., about 60 to 70.degree.
C., about 70 to 80.degree. C., or any subrange therebetween. In
further embodiments, the reaction proceeds at about 60.degree.
C.
[0325] In particular embodiments, the solvent is acetonitrile, the
acid is trifluoroacetic acid and the reaction proceeds at about
60.degree. C.
[0326] B. Alkylation of C-1 to Form E-1:
##STR00055##
[0327] A solution of about one equivalent of C-1 in a suitable
solvent is treated with about one to one and a half equivalents of
an alkylated formamide acetal and is stirred at about 0 to
60.degree. C. for about 10 hours to about 18 hours. The reaction is
treated with about one equivalent of K-1, and is allowed to
continue for about one to about four hours, and is then quenched
via the addition of an acid. E-1 is then extracted and purified by
any suitable methods known in the art, including but not limited to
solvent extraction, crystallization, and silica gel
chromatography.
[0328] In a particular embodiment, the solvent is a non-protic
polar organic solvent such as, but not limited to, 2-methyl
tetrahydrofuran, tetrahydrofuran, acetonitrile, diisopropyl ether,
methyl tert-butyl ether, N,N-dimethylformamide,
N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidinone, or
mixtures thereof. In a further embodiment, the solvent is 2-methyl
tetrahydrofuran.
[0329] In certain embodiments, the alkylated formamide acetal is
selected from the group consisting of N,N-dimethylformamide
dimethyl acetal, N,N-dimethylformamide diethyl acetal,
N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide
dimethyl acetal, and N,N-diisopropylformamide dimethyl acetal. In a
particular embodiment, the alkylated formamide acetal is
N,N-dimethylformamide dimethyl acetal.
[0330] In particular embodiments, one equivalent of C-1 is treated
with about 1.1 equivalents of the alkylated formamide acetal.
[0331] In certain embodiments, R.sup.1 is (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.10)aryl, or (C.sub.2-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.1 is
(C.sub.1-C.sub.4)alkyl, (C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.1 is C.sub.1-C.sub.4alkyl. In further
embodiments R.sup.1 is --CH.sub.3, that is, K-1 is
aminoacetaldehyde dimethyl acetal.
[0332] In certain embodiments, the reaction is quenched with an
inorganic acid, an organic acid, or a halogenated organic acid. In
certain embodiments, the acid is an inorganic acid. In certain
embodiments, the acid is an organic acid. In certain embodiments,
the acid is a halogenated organic acid. Exemplary inorganic acids,
include, but are not limited to hydrochloric acid, hydrobromic
acid, hydroiodic acid. Exemplary organic acids, include, but are
not limited to, formic acid and acetic acid. Exemplary halogenated
organic acids include, but are not limited to,
trifluoromethanesulfonic acid, trifluoroacetic acid,
trichloroacetic acid, and perfluoropropionic acid. In still further
embodiments, the acid is a mixture comprising one or more organic
acids, one or more inorganic acids, and/or one or more halogenated
organic acids. In certain embodiments, the acid is a mixture
comprising up to three, or up to two, organic acids. In certain
embodiments, the acid is a mixture comprising up to three, or up to
two, halogenated organic acids. In certain embodiments, the acid is
a mixture comprising up to three, or up to two, inorganic acids. In
a certain embodiment, the acid is a mixture of up to three, or up
to two, acids selected from the group consisting of hydrochloric
acid, hydrobromic acid, hydroiodic acid, formic acid,
trifluoromethanesulfonic acid, trifluoroacetic acid,
trichloroacetic acid, and perfluoropropionic acid. In a particular
embodiment, the acid is trifluoroacetic acid. In particular
embodiments, the reaction is quenched with hydrochloric acid. In
particular embodiments, the reaction is quenched with 2 N HCl. In
certain embodiments, the reaction is not quenched.
[0333] In certain embodiments, the reaction proceeds at about 10 to
60.degree. C., about 10 to 50.degree. C., about 10 to 40.degree.
C., about 10 to 30.degree. C., about 10 to 20.degree. C., 20 to
60.degree. C., about 20 to 50.degree. C., about 20 to 40.degree.
C., about 20 to 30.degree. C., about 30 to 60.degree. C., about 30
to 50.degree. C., about 30 to 40.degree. C., about 40 to 60.degree.
C., about 40 to 50.degree. C., about 50 to 60.degree. C., or any
subrange therebetween. In particular embodiments, the reaction
proceeds at room temperature. In further embodiments, the reaction
proceeds at about 15 to about 25.degree. C.
[0334] In particular embodiments, the solvent is 2-methyl
tetrahydrofuran, the alkylated formamide acetal is
N,N-dimethylformamide dimethyl acetal, R.sup.1 is --CH.sub.3, and
the reaction proceeds at about 18 to about 23.degree. C.
[0335] C. Cyclization of E-1 to Form F-1:
##STR00056##
[0336] In particular embodiments, a solution of about one
equivalent of E-1 and about one to five equivalents of M-1 in a
first suitable solvent is combined and cooled to about 0 to
5.degree. C. In certain embodiments, the base is slowly introduced
to the reaction mixture while the internal temperature of the
reaction is kept cool throughout the addition (e.g., below room
temperature, or below about 25.degree. C., or below about
20.degree. C., or below about 15.degree. C.). After the addition is
complete the reaction is heated to about 20 to 80.degree. C. for at
least about 14 hours.
[0337] After this time has elapsed, the reaction may be diluted
with an aqueous acidic solution and a further suitable organic
solvent and the product extracted and purified by any suitable
methods known in the art, including but not limited to solvent
extraction, crystallization, and silica gel chromatography. In
certain embodiments, the aqueous acidic solution is hydrochloric
acid and acetic acid. For example, in certain embodiments, the
aqueous acidic solution is glacial acetic acid.
[0338] In particular embodiments, the first solvent is one or more
alcohols, one or more polar organic solvents, or a mixture of or
more alcohols and one or more polar organic solvents. In certain
embodiments, the first solvent is up to three alcohols, up to three
polar organic solvents, or a mixture thereof (i.e., a mixture of up
to three, or up to two, alcohols and up to three, or up to two,
polar organic solvents). In certain embodiments, the first solvent
is one or two alcohols, one or two polar organic solvents, or a
mixture thereof (i.e., a mixture of one or two alcohols and one or
two polar organic solvents). In certain embodiments, the first
solvent is an alcohol. In certain embodiments, the first solvent is
a polar organic solvent. Exemplary alcohols include, but are not
limited to, methanol, ethanol, n-propanol, 2-propanol, butanol, and
tert-butanol. Exemplary polar organic solvents include, but are not
limited to, acetone, acetonitrile, N,N-dimethylformamide,
N,N-dimethylacetamide, 1,4-dioxane, and N-methyl-2-pyrrolidinone.
In certain embodiments, the first solvent is methanol, ethanol,
n-propanol, 2-propanol, butanol, tert-butanol acetone,
acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,
1,4-dioxane, or N-methyl-2-pyrrolidinone. In a certain embodiment,
the first solvent is methanol.
[0339] In particular embodiments, the base is a metal hydride, an
alkoxide, or a bis(trialkylsilyl)amide. In certain embodiments, the
base is a metal hydride. In certain embodiments, the base is an
alkoxide. In certain embodiments, the base is a
bis(trialkylsilyl)amide. Exemplary metal hydrides include, but are
not limited to lithium hydride, sodium hydride, and potassium
hydride. Exemplary alkoxides include, but are not limited to,
sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium
tert-butoxide, potassium ethoxide, sodium tert-pentoxide, and
lithium tert-butoxide. Exemplary bis(trialkylsilyl)amide bases
include, but are not limited to lithium bis(trimethylsilyl)amide,
sodium bis(trimethylsilyl)amide, and potassium
bis(trimethylsilyl)amide. In still further embodiments, the base is
a mixture of at least one of the foregoing bases. In certain
embodiments, the base is a mixture of up to three, or up to two,
metal hydrides. In certain embodiments, the base is a mixture of up
to three, or up to two, alkoxides. In certain embodiments, the base
is a mixture of up to three, or up to two, metal
bis(trialkylsilyl)amides. In certain embodiments, the base is a
mixture of up to three, or up to two, of the following bases:
lithium hydride, sodium hydride, potassium hydride, sodium
methoxide, sodium tert-butoxide, sodium ethoxide, potassium
tert-butoxide, potassium ethoxide, sodium tert-pentoxide, lithium
tert-butoxide, lithium bis(trimethylsilyl)amide, sodium
bis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide. In
particular embodiments, the base is sodium methoxide.
[0340] In certain embodiments, R.sup.2 is (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.10)aryl, or (C.sub.2-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.2 is
(C.sub.1-C.sub.4)alkyl, (C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.2 is C.sub.1-C.sub.4alkyl. In certain
embodiments, R.sup.2 is --CH.sub.3.
[0341] In certain embodiments, after the addition is complete the
reaction is heated to about 20 to 70.degree. C., about 20 to
60.degree. C., about 20 to 50.degree. C., about 20 to 40.degree.
C., about 20 to 30.degree. C., about 30 to 80.degree. C., about 30
to 70.degree. C., about 30 to 60.degree. C., about 30 to 50.degree.
C., about 30 to 40.degree. C., about 40 to 80.degree. C., about 40
to 70.degree. C., about 40 to 60.degree. C., about 40 to 50.degree.
C., about 50 to 80.degree. C., about 50 to 70.degree. C., about 50
to 60.degree. C., about 60 to 80.degree. C., about 60 to 70.degree.
C., about 70 to 80.degree. C., or any subrange therebetween.
[0342] In particular embodiments, the first solvent is an alcohol,
the base is an alkoxide, after the addition is complete the
reaction is heated to about 40 to about 50.degree. C. and R.sup.2
is (C.sub.1-C.sub.4)alkyl.
[0343] In particular embodiments, the first solvent is methanol,
the base is sodium methoxide, after the addition is complete the
reaction is heated to about 40 to about 50.degree. C. and R.sup.2
is --CH.sub.3.
[0344] D. Alkylation and Cyclization of C-1 to Form F-1:
##STR00057##
[0345] In certain embodiments, about one equivalent of C-1 and
about 1 to about 5 equivalents of an alkylated formamide acetal are
combined in a reaction vessel, and reaction mixture is agitated for
approximately 30 minutes. In certain embodiments, about one
equivalent of C-1 and about 1 to about 3 equivalents of an
alkylated formamide acetal are combined in a reaction vessel. A
first suitable solvent and about one equivalent of K-1 are added to
the mixture, and the reaction is allowed to proceed for several
hours, after which the first solvent is removed by any suitable
means known in the art.
[0346] The resulting material is dissolved in a second suitable
solvent and about 1 to about 5 equivalents of M-1 is added. The
reaction mixture is cooled to about 0.degree. C. to about 5.degree.
C., and then about one and a half to two equivalents of a base is
slowly added to the reaction mixture. The internal temperature of
the reaction is kept cool throughout the addition (e.g., below room
temperature, or below about 25.degree. C., or below about
20.degree. C., or below about 15.degree. C.). After the addition is
complete the reaction is heated to about 20 to 80.degree. C. for
about 8 to about 16 hours.
[0347] After this time has elapsed, the reaction is cooled to room
temperature, quenched via the addition of an acid and diluted with
the addition of an organic solvent. The product, F-1, may then be
extracted and purified by any suitable methods known in the art,
including but not limited to solvent extraction, crystallization
and silica gel chromatography.
[0348] In certain embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.10)aryl, or (C.sub.2-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.a is
(C.sub.1-C.sub.4)alkyl, (C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.a is C.sub.1-C.sub.4alkyl. In certain
embodiments, R.sup.a is --CH.sub.3.
[0349] In a particular embodiment, the first solvent is a
non-protic polar organic solvent such as, but not limited to,
2-methyl tetrahydrofuran, tetrahydrofuran, acetonitrile,
diisopropyl ether, methyl tert-butyl ether, N,N-dimethylformamide,
N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidinone, or
mixtures thereof. In a further embodiment, the first solvent is
2-methyl tetrahydrofuran.
[0350] In certain embodiments, the alkylated formamide acetal is
selected from the group consisting of N,N-dimethylformamide
dimethyl acetal, N,N-dimethylformamide diethyl acetal,
N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide
dimethyl acetal, and N,N-diisopropylformamide dimethyl acetal. In a
particular embodiment, the alkylated formamide acetal is
N,N-dimethylformamide dimethyl acetal.
[0351] In certain embodiments, R.sup.1 is (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.10)aryl, or (C.sub.2-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.1 is
(C.sub.1-C.sub.4)alkyl, (C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.1 is C.sub.1-C.sub.4alkyl. In further
embodiments R.sup.1 is --CH.sub.3, that is K-1 is aminoacetaldehyde
dimethyl acetal.
[0352] In particular embodiments, the base is a metal hydride, a
bis(trialkylsilyl) amide base, or an alkoxide. In certain
embodiments, the base is a metal hydride. In particular
embodiments, the base is a bis(trialkylsilyl)amide base. In
particular embodiments, the base is an alkoxide. Exemplary metal
hydrides include, but are not limited to lithium hydride, sodium
hydride, and potassium hydride. Exemplary bis(trialkylsilyl)amide
bases include, but are not limited to lithium
bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and
potassium bis(trimethylsilyl)amide. Exemplary alkoxides include,
but are not limited to, sodium methoxide, sodium tert-butoxide,
sodium ethoxide, potassium tert-butoxide, potassium ethoxide,
sodium tert-pentoxide, and lithium tert-butoxide. In still further
embodiments, the base is a mixture of at least one of the foregoing
bases. In certain embodiments, the base is a mixture of up to
three, or up to two, metal hydrides. In certain embodiments, the
base is a mixture of up to three, or up to two, bis(trialkylsilyl)
amide base. In certain embodiments, the base is a mixture of up to
three, or up to two, alkoxides. In certain embodiments, the base is
a mixture of up to three, or up to two, bases selected from the
group consisting of lithium hydride, sodium hydride, potassium
hydride, lithium bis(trimethylsilyl)amide, sodium
bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide,
sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium
tert-butoxide, potassium ethoxide, sodium tert-pentoxide, and
lithium tert-butoxide. In particular embodiments, the base is
sodium methoxide. In particular embodiments, a solution of base in
alcohol is added to the reaction. A suitable alcohol includes but
is not limited to, methanol, ethanol, n-propanol, 2-propanol,
butanol, or tert-butanol. In a certain embodiment, the base is
sodium methoxide. In a certain embodiment, the base is added as 30%
solution of sodium methoxide in methanol.
[0353] In particular embodiments, the second solvent is an alcohol
or a polar solvent. In certain embodiments, the second solvent is
an alcohol. In certain embodiments, the second solvent is a polar
solvent. Exemplary alcohols include, but are not limited to,
methanol, ethanol, n-propanol, 2-propanol, butanol, and
tert-butanol. Exemplary polar organic solvents include, but are not
limited to, acetone, acetonitrile, N,N-dimethylformamide,
N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidinone. In
a certain embodiment, the second solvent is methanol.
[0354] In certain embodiments, R.sup.2 is (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.10)aryl, or (C.sub.2-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.2 is
(C.sub.1-C.sub.4)alkyl, (C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.2 is C.sub.1-C.sub.4alkyl. In certain
embodiments, R.sup.2 is --CH.sub.3.
[0355] In certain embodiments, after the addition is complete the
reaction is heated to about 20 to 70.degree. C., about 20 to
60.degree. C., about 20 to 50.degree. C., about 20 to 40.degree.
C., about 20 to 30.degree. C., about 30 to 80.degree. C., about 30
to 70.degree. C., about 30 to 60.degree. C., about 30 to 50.degree.
C., about 30 to 40.degree. C., about 40 to 80.degree. C., about 40
to 70.degree. C., about 40 to 60.degree. C., about 40 to 50.degree.
C., about 50 to 80.degree. C., about 50 to 70.degree. C., about 50
to 60.degree. C., about 60 to 80.degree. C., about 60 to 70.degree.
C., about 70 to 80.degree. C., or any subrange therebetween.
[0356] In particular embodiments, R.sup.a is
(C.sub.1-C.sub.4)alkyl, the first solvent is 2-methyl
tetrahydrofuran, the alkylated formamide acetal is
N,N-dimethylformamide dimethyl acetal, R.sup.1 is
(C.sub.1-C.sub.4)alkyl, the base is an alkoxide, the second solvent
is an alcohol, after the addition is complete the reaction is
heated to about 40 to about 50.degree. C., and R.sup.2 is
(C.sub.1-C.sub.4)alkyl.
[0357] In particular embodiments, R.sup.a is --CH.sub.3, the first
solvent is 2-methyl tetrahydrofuran, the alkylated formamide acetal
is N,N-dimethylformamide dimethyl acetal, R.sup.1 is --CH.sub.3,
the base is sodium methoxide, the second solvent is methanol, after
the addition is complete the reaction is heated to about 40 to
about 50.degree. C., and R.sup.2 is --CH.sub.3.
[0358] E. Preparation of EE-1 from D-1
##STR00058##
[0359] D-1 is reacted with M-1 to yield EE-1. For example. D-1 is
dissolved in a suitable solvent and about 1 to about 5 equivalents
of M-1 is added. The reaction mixture is cooled to about 0.degree.
C. to about 5.degree. C., and then about one and a half to two
equivalents of a base is slowly added to the reaction mixture. The
internal temperature of the reaction is kept cool throughout the
addition (e.g., below room temperature, or below about 25.degree.
C., or below about 20.degree. C., or below about 15.degree. C.).
After the addition is complete the reaction is heated to about 20
to 80.degree. C. for about 8 to about 16 hours.
[0360] After this time has elapsed, the reaction is cooled to room
temperature, quenched via the addition of an acid and diluted with
the addition of an organic solvent. The product, EE-1, may then be
extracted and purified by any suitable methods known in the art,
including but not limited to solvent extraction, crystallization
and silica gel chromatography.
[0361] In certain embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.10)aryl, or (C.sub.2-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.a is
(C.sub.1-C.sub.4)alkyl, (C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.a is C.sub.1-C.sub.4alkyl. In particular
embodiments, R.sup.a is --CH.sub.3.
[0362] In certain embodiments, R.sup.b is (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.10)aryl, or (C.sub.2-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, In certain
embodiments, each R.sup.b is, independently (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or (C.sub.6-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.b is
C.sub.1-C.sub.4alkyl. In further embodiments R.sup.b is --CH.sub.3.
In certain embodiments, In certain embodiments, each R.sup.b is
--CH.sub.3.
[0363] In particular embodiments, the base is an inorganic
carbonate, a metal hydride, or an alkoxide, or a mixture thereof.
In particular embodiments, the base is an inorganic carbonate. In
particular embodiments, the base is a metal hydride. In particular
embodiments, the base is an alkoxide. Exemplary inorganic
carbonates include, without limitation, lithium carbonate, sodium
carbonate, potassium carbonate and cesium carbonate. Exemplary
metal hydrides include, without limitation, sodium hydride and
potassium hydride. Exemplary alkoxides include, without limitation,
sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium
tert-butoxide, potassium ethoxide, sodium tert-pentoxide, and
lithium tert-butoxide. In certain embodiments, the base is a
mixture of up to three, or in other embodiments, up to two,
inorganic carbonates. In certain embodiments, the base is a mixture
of up to three, or in other embodiments, up to two, metal hydrides.
In certain embodiments, the base is a mixture of up to three, or in
other embodiments, up to two, alkoxides. In certain embodiments,
the base is a mixture of up to three, or in other embodiments, up
to two, bases selected from the group consisting of lithium
carbonate, sodium carbonate, potassium carbonate, cesium carbonate,
sodium hydride, potassium hydride, sodium tert-butoxide, sodium
ethoxide, potassium tert-butoxide, potassium ethoxide, sodium
tert-pentoxide, and lithium tert-butoxide. In particular
embodiments, the base is sodium methoxide.
[0364] In particular embodiments, the solvent is an alcohol or a
polar solvent. In certain embodiments, the solvent is an alcohol.
In certain embodiments, the solvent is a polar solvent. Exemplary
alcohols include, but are not limited to, methanol, ethanol,
n-propanol, 2-propanol, butanol, and tert-butanol. Exemplary polar
organic solvents include, but are not limited to, acetone,
acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,
1,4-dioxane, or N-methyl-2-pyrrolidinone. In a certain embodiment,
the solvent is N-methyl-2-pyrrolidinone.
[0365] In certain embodiments, the reaction is quenched with an
inorganic acid, an organic acid, or a halogenated organic acid. In
certain embodiments, the acid is an inorganic acid. In certain
embodiments, the acid is an organic acid. In certain embodiments,
the acid is a halogenated organic acid. Exemplary inorganic acids,
include, but are not limited to hydrochloric acid, hydrobromic
acid, hydroiodic acid. Exemplary organic acids, include, but are
not limited to, formic acid and acetic acid. Exemplary halogenated
organic acids include, but are not limited to,
trifluoromethanesulfonic acid, trifluoroacetic acid,
trichloroacetic acid, and perfluoropropionic acid. In still further
embodiments, the acid is a mixture comprising one or more organic
acids, one or more inorganic acids, and/or one or more halogenated
organic acids. In certain embodiments, the acid is a mixture
comprising up to three, or up to two, organic acids. In certain
embodiments, the acid is a mixture comprising up to three, or up to
two, halogenated organic acids. In certain embodiments, the acid is
a mixture comprising up to three, or up to two, inorganic acids. In
a certain embodiment, the acid is a mixture of up to three, or up
to two, acids selected from the group consisting of hydrochloric
acid, hydrobromic acid, hydroiodic acid, formic acid,
trifluoromethanesulfonic acid, trifluoroacetic acid,
trichloroacetic acid, and perfluoropropionic acid. In a particular
embodiment, the acid is trifluoroacetic acid. In particular
embodiments, the reaction is quenched with hydrochloric acid. In
particular embodiments, the reaction is quenched with 2 N HCl. In
certain embodiments, the reaction is not quenched.
[0366] In certain embodiments, R.sup.2 is (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.10)aryl, or (C.sub.2-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.2 is
(C.sub.1-C.sub.4)alkyl, (C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.2 is C.sub.1-C.sub.4alkyl. In certain
embodiments, R.sup.2 is --CH.sub.3.
[0367] In certain embodiments, after the addition is complete the
reaction is heated to about 20 to 80.degree. C., about 20 to
80.degree. C., about 20 to 60.degree. C., about 20 to 50.degree.
C., about 20 to 40.degree. C., about 20 to 30.degree. C., about 30
to 80.degree. C., about 30 to 70.degree. C., about 30 to 60.degree.
C., about 30 to 50.degree. C., about 30 to 40.degree. C., about 40
to 80.degree. C., about 40 to 70.degree. C., about 40 to 60.degree.
C., about 40 to 50.degree. C., about 50 to 80.degree. C., about 50
to 70.degree. C., about 50 to 60.degree. C., about 60 to 80.degree.
C., about 60 to 70.degree. C., about 70 to 80.degree. C., or any
subrange therebetween.
[0368] In particular embodiments, R.sup.2 is
(C.sub.1-C.sub.4)alkyl, each R.sup.b is (C.sub.1-C.sub.4)alkyl
which are the same or different, R.sup.a is (C.sub.1-C.sub.4)alkyl,
the base is an alkoxide, and the solvent is an organic solvent.
[0369] In particular embodiments, R.sup.2 is --CH.sub.3, each
R.sup.b is --CH.sub.3, R.sup.a is --CH.sub.3, the base is sodium
methoxide, and the solvent is N-methyl-2-pyrrolidinone.
[0370] F. Condensation of F-1 with N-1 to Form G-1:
##STR00059##
[0371] One equivalent of F-1 and a suitable solvent are combined in
a reaction vessel, about 5 to 8 equivalents of a first acid and
about 0.2 to about 0.5 equivalent of a second acid are added. The
reaction may take place between about 20 to about 100.degree.
C.
[0372] The reaction is allowed to continue for about 2 to about 5
hours, after which about 1.5 equivalents of N-1 and about 2 to
about 3 equivalents of a base are slowly introduced to the reaction
vessel. After the addition is completed, the reaction is allowed to
progress for at least about 1 hour.
[0373] Water and additional solvent are added to the reaction
vessel and G-1 is extracted and purified by any suitable method
known in the art, including but not limited to solvent extraction,
silica gel chromatography and crystallization.
[0374] In particular embodiments, the solvent is a non-protic polar
organic solvent, such as, but not limited to, tetrahydrofuran,
acetonitrile, diisopropyl ether, methyl tert-butyl ether,
N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or
N-methyl-2-pyrrolidinone, or mixtures thereof. In certain
embodiments, the solvent is a mixture of one, two or three, or in
certain embodiments, a mixture of one or two of the following
solvents: tetrahydrofuran, acetonitrile, diisopropyl ether, methyl
tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide,
1,4-dioxane, or N-methyl-2-pyrrolidinone. In further embodiments,
the solvent is acetonitrile.
[0375] In certain embodiments, the first acid is an organic acid,
an organic carboxylic acid, or an inorganic acid. In certain
embodiments, the first acid is an organic acid. In certain
embodiments, the first acid is an organic carboxylic acid. In
certain embodiments, the first acid is an inorganic acid. Exemplary
organic acids include, but are not limited to methane sulfonic
acid, trifluoromethanesulfonic acid and trifluoroacetic acid.
Exemplary organic carboxylic acids include, but are not limited to
acetic acid, formic acid, butyric acid, propionic acid, and benzoic
acid. Exemplary inorganic acids include, but are not limited to,
hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid,
or sulfuric acid. In yet further embodiments, the first acid is
acetic acid.
[0376] In certain embodiments, the second acid is an organic acid,
an organic carboxylic acid, or an inorganic acid. In certain
embodiments, the second acid is an organic acid. In certain
embodiments, the second acid is an organic carboxylic acid. In
certain embodiments, the first acid is an inorganic acid. Exemplary
organic acids include, but are not limited to methanesulfonic acid,
trifluoromethanesulfonic acid and trifluoroacetic acid. Exemplary
inorganic acids include, but are not limited to, hydrochloric acid,
hydrobromic acid, and sulfuric acid. Exemplary organic carboxylic
acids include, but are not limited to acetic acid, formic acid,
butyric acid, propionic acid, or benzoic acid. In particular
embodiments, the second acid is methanesulfonic acid or formic
acid.
[0377] In certain embodiments, the first acid is acetic acid and
the second acid is methanesulfonic acid.
[0378] In certain embodiments, the first acid and the second acid
are the same acid. In yet other embodiments, the first acid and the
second acid are formic acid or acetic acid.
[0379] In certain embodiments, N-1 is in solution when added to the
reaction mixture.
[0380] In further embodiments, L is --CH.sub.2--CH.sub.2--, that
is, N-1 is (1R,3S)-3-aminocyclopentan-1-ol:
##STR00060##
In some embodiments, N-1 is
##STR00061##
[0381] In particular embodiments, N-1 is a salt or co-crystal.
Suitable salts or co-crystals of N-1 include, but are not limited
to, oxalic acid, hydrochloric acid, mandelic acid, R-mandelic acid,
and S-mandelic acid. Suitable salts or co-crystals of N-1 include,
but are not limited to, benzoic acid, naproxen, S-naproxen and
R-naproxen.
[0382] In still further embodiments, N-1 is
##STR00062## ##STR00063##
[0383] In still further embodiments, N-1 is;
##STR00064##
[0384] In certain embodiments, after the addition of the acid(s)
the reaction is kept at about 20 to about 90.degree. C., about 20
to about 80.degree. C., about 20 to about 70.degree. C., about 20
to about 60.degree. C., about 20 to about 50.degree. C., about 20
to about 40.degree. C., about 20 to about 30.degree. C., about 30
to about 100.degree. C., about 30 to about 90.degree. C., about 30
to about 80.degree. C., about 30 to about 70.degree. C., about 30
to about 60.degree. C., about 30 to about 50.degree. C., about 30
to about 40.degree. C., about 40 to about 100.degree. C., about 40
to about 90.degree. C., about 40 to about 80.degree. C., about 40
to about 70.degree. C., about 40 to about 60.degree. C., about 40
to about 50.degree. C., about 50 to about 100.degree. C., about 50
to about 90.degree. C., about 50 to about 80.degree. C., about 50
to about 70.degree. C., about 50 to about 60.degree. C., about 60
to about 100.degree. C., about 60 to about 90.degree. C., about 60
to about 80.degree. C., about 60 to about 70.degree. C., about 70
to about 80.degree. C., or any subrange therebetween. In still
further embodiments, after the addition of the acid(s) the reaction
is kept at about 65 to about 70.degree. C., about 70 to about
75.degree. C., about 75 to about 80.degree. C., or any subrange
therebetween.
[0385] In particular embodiments, the solvent is acetonitrile, the
first acid is an organic carboxylic acid, the second acid is an
organic carboxylic acid, and after the addition of the acids the
reaction is kept at about 70 to about 75.degree. C.
[0386] In particular embodiments, the solvent is acetonitrile, the
first acid is acetic acid, the second acid is methanesulfonic acid,
after the addition of the acids the reaction is kept at about 70 to
about 75.degree. C., and N-1 is
##STR00065##
[0387] G. Deprotection of G-1 to Form a Compound of Formula I:
##STR00066##
[0388] A reaction vessel is charged with approximately one
equivalent of G-1 and a suitable solvent. About two to three
equivalents of a metal salt, a Lewis acid, or other reagent is
added to the solution. The resulting suspension is stirred at about
40 to about 100.degree. C. for about ten minutes to about three
hours. The reaction is quenched by the addition of an acid and a
compound of Formula I is then extracted and purified by any
suitable technique known in the art, such as, but not limited to,
solvent extraction, preparative HPLC and crystallization.
[0389] In a particular embodiment, the solvent is a non-protic
polar organic solvent such as, but not limited to, 2-methyl
tetrahydrofuran, tetrahydrofuran, acetonitrile, diisopropyl ether,
methyl tert-butyl ether, N,N-dimethylformamide,
N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidinone, or
mixtures thereof. In a further embodiment, the solvent is
acetonitrile.
[0390] In certain embodiments, G-1 is reacted with at least one
reagent selected from the group consisting of metal salts, Lewis
acids, sodium ethanethiolate, sodium hexamethyldisiloxane,
trifluoroacetic acid, and combinations thereof.
[0391] In further embodiments, the metal salt is selected from the
group consisting of magnesium bromide, lithium chloride, lithium
bromide, and lithium iodide. In still further embodiments, the
metal salt is lithium chloride.
[0392] In particular embodiments, the Lewis acid is selected from
the group consisting of boron trifluoride methyl etherate, boron
trifluoride diethyl etherate, boron trifluoride dibutyl etherate,
aluminium chloride, aluminum bromide, boron trichloride, boron
tribromide, chlorotrimethylsilane, iodotrimethylsilane, palladium,
and boron trifluoride diethyl etherate. In certain embodiments, the
Lewis acid is selected from the group consisting of
chlorotrimethylsilane, iodotrimethylsilane, sodium ethanethiolate,
sodium hexamethyldisiloxane, palladium, boron trifluoride diethyl
etherate, and trifluoroacetic acid.
[0393] In particular embodiments, other reagents suitable to
facilitate the conversion are sodium ethanethiolate, sodium
hexamethyldisiloxane, and trifluoroacetic acid
[0394] In particular embodiments, the deprotection of G-1 to form a
compound of Formula I takes place in the presence of about two to
about three equivalents of a reagent selected from the group
consisting of: magnesium bromide, lithium chloride, lithium
bromide, lithium iodide, boron trifluoride methyl etherate, boron
trifluoride diethyl etherate, boron trifluoride dibutyl etherate,
aluminium chloride, aluminum bromide, boron trichloride, boron
tribromide, chlorotrimethylsilane, iodotrimethylsilane, palladium,
boron trifluoride diethyl etherate, chlorotrimethylsilane,
iodotrimethylsilane, sodium ethanethiolate, sodium
hexamethyldisiloxane, palladium, boron trifluoride diethyl
etherate, and trifluoroacetic acid.
[0395] In certain embodiments, the reaction proceeds at about 40 to
about 50.degree. C., about 40 to about 60.degree. C., about 40 to
about 70.degree. C., about 50 to about 60.degree. C., about 50 to
about 70.degree. C., about 50 to about 80.degree. C., about 60 to
about 70.degree. C., about 60 to about 80.degree. C., or any
subrange therebetween. In particular embodiments, the reaction
proceeds at about 50.degree. C.
[0396] In particular embodiments, the solvent is acetonitrile, the
metal salt is magnesium bromide, and the reaction proceeds at about
50.degree. C.
[0397] H. Hydrolysis of F-1 to Yield a Compound of Formula II:
##STR00067##
[0398] A reaction vessel is charged with approximately one
equivalent of F-1 and a solution of about ten to fifteen parts of a
first organic solvent and about 3 to 8 parts water is prepared.
About two equivalents of a base are added to the solution. The
resulting suspension is stirred at about 0 to about 50.degree. C.
for about 14 to about 17 hours. Conversion may be monitored by any
suitable method known in the art, such as, but not limited to
HPLC.
[0399] Water and a second organic solvent are added to the
suspension and the pH adjusted to about pH 3 by the dropwise
addition of a suitable acid. The product, a compound of Formula II,
can then be extracted and optionally purified by any suitable
technique known in the art, such as, but not limited to, solvent
extraction, silica gel chromatography and crystallization.
[0400] In certain embodiments, the first organic solvent is an
alcoholic solvent or a polar organic solvent. In certain
embodiments, the first organic solvent is an alcoholic solvent. In
certain embodiments, the first organic solvent is a polar organic
solvent. Exemplary alcoholic solvents include, without limitation,
methanol, ethanol, n-propanol, 2-propanol, butanol, and
tert-butanol. Exemplary polar organic solvents include, but are not
limited to, N,N-dimethylformamide, N,N-dimethylacetamide,
1,4-dioxane, and N-methyl-2-pyrrolidinone. In particular
embodiments, the first organic solvent is methanol.
[0401] In further embodiments, the base is selected from the group
consisting of lithium hydroxide, sodium hydroxide, potassium
hydroxide, lithium carbonate, sodium carbonate and potassium
carbonate. In still further embodiments, the base is lithium
hydroxide monohydrate.
[0402] In certain embodiments, the reaction proceeds at about 10 to
about 50.degree. C., about 10 to about 40.degree. C., about 10 to
about 30.degree. C., about 10 to about 20.degree. C., about 20 to
about 50.degree. C., about 20 to about 40.degree. C., about 20 to
about 30.degree. C., about 30 to about 50.degree. C., about 30 to
about 40.degree. C., about 40 to about 50.degree. C., or any
subrange therebetween. In particular embodiments, the reaction
proceeds at room temperature. In further embodiments, the reaction
proceeds at about 18 to about 23.degree. C.
[0403] In particular embodiments, the base is lithium hydroxide
monohydrate, the reaction proceeds at about 10 to about 50.degree.
C. and the first organic solvent is methanol.
[0404] In particular embodiments, the base is lithium hydroxide
monohydrate, the reaction proceeds at about 18 to about 23.degree.
C. and the first organic solvent is methanol.
[0405] I. Preparation of BB-1 from B-1 and Q-1:
##STR00068##
[0406] About one equivalent of B-1 and eight to twelve equivalents
of Q-1 are added to a reaction vessel and dissolved in a suitable
organic solvent. The solution is then heated to about 85 to about
115.degree. C. and allowed to proceed for about two to six hours,
after which time the reaction is cooled to room temperature. BB-1
is then purified using techniques known in the art, such as, but
not limited to silica gel chromatography.
[0407] In certain embodiments, the solvent is a non-polar aromatic
solvent or a polar aprotic solvent. In certain embodiments, the
solvent is a non-polar aromatic solvent. In certain embodiments,
the solvent is a polar aprotic solvent. Exemplary non-polar
aromatic include, but are not limited to, toluene, xylene,
chlorobenzene, and dichlorobenzene. Exemplary polar aprotic
solvents include, but are not limited to, N,N-dimethylformamide,
N,N-dimethylacetamide, 1,4-dioxane, and N-methylpyrrolidinone. In
still further embodiments, the reaction can occur without
additional solvent. In particular embodiments, the solvent is
toluene.
[0408] In certain embodiments, the reaction proceeds at about 85 to
about 105.degree. C., about 85 to about 95.degree. C., about 95 to
about 105.degree. C., about 95 to about 115.degree. C., about 105
to about 115.degree. C., about 100 to about 105.degree. C., about
105 to about 110.degree. C., about 110 to about 115.degree. C., or
any subrange therebetween.
[0409] In particular embodiments, the reaction proceeds at about 95
to about 115.degree. C., and the solvent is toluene.
[0410] In particular embodiments, the reaction proceeds at about
110 to about 115.degree. C., and the solvent is toluene.
[0411] J. Preparation of C-1 from BB-1:
##STR00069##
[0412] About 1 equivalent of BB-1 and about 1 to about 3
equivalents of J-1 are combined in a reaction vessel. The compounds
are dissolved in a polar non-protic solvent or an aromatic solvent.
In certain embodiments, the compounds are dissolved is suspended in
a polar non-protic solvent. In certain embodiments, the compounds
are dissolved in an aromatic solvent. Exemplary polar non-protic
solvent include, but are not limited to, acetonitrile,
N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and
N-methyl-2-pyrrolidinone. Exemplary aromatic solvents include, but
are not limited to, pyridine, toluene, xylene, benzene, and
chlorobenzene. In still further embodiments, the compounds are
dissolved in a solvent mixture comprising one or more polar
non-protic solvents and/or one or more aromatic solvents. In
certain embodiments, the compounds are dissolved in a solvent
mixture comprising up to three, or up to two, polar non-protic
solvents. In certain embodiments, the compounds are dissolved in a
solvent mixture comprising up to three, or up to two, aromatic
solvents. In certain embodiments, the compounds are dissolved in a
solvent mixture comprising up to three, or up to two, solvents from
the group consisting of acetonitrile, N,N-dimethylformamide,
N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidinone,
pyridine, toluene, xylene, benzene, and chlorobenzene. In a further
embodiment the compounds are dissolved in toluene.
[0413] In particular embodiments, each Hal is independently --F or
--Cl. In a particular embodiment, Hal is --F In certain
embodiments, n=1-3. In certain embodiments, n=2. In certain
embodiments, n=3. In further embodiments, J-1 is
##STR00070##
In certain embodiments, J-1 is
##STR00071##
In further embodiments, J-1 is
##STR00072##
[0414] In still further embodiments, J-1 is in the form of a salt
or co-crystal, such as, but not limited to a salt or co-crystal of
hydrochloric acid or trifluoroacetic acid. In certain embodiments,
J-1 is a salt or co-crystal of methane sulfonic acid.
[0415] In certain embodiments, the reaction proceeds at about 65 to
about 115.degree. C., about 75 to about 115.degree. C., about 85 to
about 115.degree. C., about 95 to about 115.degree. C., about 105
to about 115.degree. C., about 65 to about 70.degree. C., about 70
to about 80.degree. C., about 80 to about 90.degree. C., about 90
to about 100.degree. C., about 100 to about 110.degree. C., about
110 to about 115.degree. C., or any subrange therebetween.
[0416] In certain embodiments, the solvent is removed under reduced
pressure. In particular embodiments, C-1 is extracted from the
crude residue by solvent extraction. The resulting crude material
is purified using any suitable technique, such as silica gel
chromatography or crystallization to yield C-1.
[0417] In particular embodiments, the compounds are dissolved in an
aromatic solvent, J-1 is
##STR00073##
and the reaction proceeds at about 65 to about 115.degree. C.
[0418] In particular embodiments, the compounds are dissolved in
toluene, J-1 is
##STR00074##
and the reaction proceeds at about 100 to about 110.degree. C.
[0419] K. Preparation of C-1 from B-1.J-1
##STR00075##
[0420] B-1.J-1, a solvent and an acid are combined in a reactor
under conditions effective to produce C-1.
[0421] In certain embodiments, the acid is absent. In certain
embodiments, the acid is a protic acid or a Lewis acid. In certain
embodiments, protic acids include but are not limited to
trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid,
chloroacetic acid, acetic acid, formic acid, hydrochloric acid,
hydrobromic acid, para-toluenesulfonic acid and methane sulfonic
acid. In certain embodiments, Lewis acids include but are not
limited to zinc chloride, magnesium bromide, magnesium triflate,
copper triflate, and scandium triflate. In particular embodiments,
the acid is trifluoroacetic acid.
[0422] In certain embodiments, about 10 equivalents, about 5
equivalents, about 1 equivalents, or about 0.1 equivalent of acid
is used in the reaction of B-1.J-1 to form C-1.
[0423] In certain embodiments, the solvent is toluene, heptane,
water, 2-methyltetrahydrofuran, iso-propylacetate,
N,N-dimethylformamide, N-methyl-2-pyrrolidinone, methyl-tert-butyl
ether, dimethylsulfoxide, n-butanol, acetonitrile, acetone, or a
mixture thereof. In a particular embodiment, the solvent is
acetonitrile.
[0424] In certain embodiments, B-1.J-1 is at a concentration
ranging from about 2 to 40 mL/g, about 2 to 20 mL/g, about 5 to 15
mL/g. In a particular embodiment, B-1.J-1 is at a concentration of
about 10 mL/g.
[0425] In certain embodiments, the reaction mixture is heated to a
temperature between about 20 and 110.degree. C., about 30 and
90.degree. C., about 40 and 80.degree. C., about 50 and 70.degree.
C., about 55 and 65.degree. C., or about 58 and 61.degree. C. In a
particular embodiment, the reaction mixture is heated to about
60.degree. C.
[0426] In certain embodiments, other additives are added to the
reaction. In certain embodiments, the additives include but are not
limited to lithium chloride, sodium chloride, and potassium
chloride.
[0427] In certain embodiments, B-1.J-1 is charged to the reactor in
a single portion at about 20.degree. C. followed by heating. In
certain embodiments, B-1.J-1 is charged to the reactor in portions
over 1 hour during heating.
[0428] In certain embodiments, the reaction is heated for about 1
to 24 hours, for about 2 to 12 hours, or for about 3 to 6 hours. In
a particular embodiment, the reaction is heated for about 2.5
hours.
[0429] In certain embodiments, the product formed is extracted and
optionally purified by any suitable technique known in the art,
such as, but not limited to solvent extraction, chromatography,
crystallization or a combination thereof.
[0430] In certain embodiments, the reaction is cooled down and the
reactor contents are partially distilled.
[0431] In certain embodiments, the organic phase is washed at least
once with an aqueous solution. In certain embodiments, the aqueous
solution contains about 23% NaCl, about 1.5% H.sub.2SO.sub.4, and
about 76% water. In certain embodiments, the aqueous solution
contains about 20% NaCl.
[0432] In certain embodiments, a solution of the product is seeded
with seeds of C-1 which had been previously isolated. In certain
embodiments, solid C-1 is isolated by filtration.
[0433] In particular embodiments, each Hal is independently --F or
--Cl. In a particular embodiment, each Hal is --F In certain
embodiments, n=1-3. In certain embodiments, n=2. In certain
embodiments, n=3. In further embodiments, J-1 is
##STR00076##
In certain embodiments, J-1 is
##STR00077##
In further embodiments, J-1 is
##STR00078##
[0434] In certain embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl(C.sub.1C.sub.4)alkyl. In certain
embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.a is methyl.
[0435] In particular embodiments, R.sup.a is
(C.sub.1-C.sub.4)alkyl, the solvent is acetonitrile, the reaction
mixture is heated to about 60.degree. C., and J-1 is
##STR00079##
[0436] In particular embodiments, R.sup.a is methyl, the solvent is
acetonitrile, the reaction mixture is heated to about 60.degree.
C., and J-1 is
##STR00080##
[0437] L. Enamine Formation from C-1 to Provide D-1
##STR00081##
[0438] To a solution of C-1 and an acid in a solvent, about 0.5 to
about 1.5 equivalent of an alkylated formamide acetal is added
under conditions effective to produce D-1.
[0439] In particular embodiments, one equivalent of C-1 is combined
with about 1.1 equivalents of the alkylated formamide acetal.
[0440] In certain embodiments, the alkylated formamide acetal is
selected from the group consisting of N,N-dimethylformamide
dimethyl acetal, N,N-dimethylformamide diethyl acetal,
N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide
dimethyl acetal, and N,N-diisopropylformamide dimethyl acetal. In a
particular embodiment, the alkylated formamide acetal is
N,N-dimethylformamide dimethyl acetal.
[0441] In certain embodiments, the solvent is dichloromethane,
tetrahydrofuran, acetone, acetonitrile, ethyl acetate, isopropyl
acetate, toluene, N,N-dimethylformamide, N,N-dimethylacetamide,
2-methyltetrahydrofuran or N-methyl-2-pyrrolidone. In a particular
embodiment, the solvent is 2-methyltetrahydrofuran.
[0442] In certain embodiments, the acid is an organic acid. In
certain embodiments, the organic acid includes, but is not limited
to trifluoroacetic acid, formic acid, acetic acid, sulfuric acid,
trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic
acid. In certain embodiments, the acid is a mixture comprising up
to three, or up to two, organic acids. In a particular embodiment,
the acid is trifluoroacetic acid.
[0443] In certain embodiments, the reaction mixture is heated to an
internal temperature of about 40.degree. C. before adding the
alkylated formamide acetal.
[0444] In certain embodiments, the reaction proceeds at about 0 to
75.degree. C., about 10 to 60.degree. C., about 20 to 50.degree.
C., about 40 to 50.degree. C., or about 30 to 40.degree. C. In
particular embodiments, the reaction proceeds at room temperature.
In further embodiments, the reaction proceeds at about 40.degree.
C.
[0445] In certain embodiments, the reaction proceeds for about 0.1
hours to about 12 hours, for about 0.1 hours to about 6 hours, for
about 0.1 hour to about 3 hours, for about 0.1 hour to about 1
hour, or for about 0.2 hour to about 0.5 hour.
[0446] In certain embodiments, D-1 is extracted and purified by any
suitable methods known in the art, including but not limited to
solvent extraction, crystallization, and chromatography.
[0447] In certain embodiments, seeds of D-1 are added and the
mixture is stirred. In certain embodiments, the mixture is stirred
at about 40.degree. C. for at least 1 hour.
[0448] In certain embodiments, about 0.2 to 0.6 equivalent of
alkylated formamide acetal is added and the reaction mixture is
agitated for at least about 25 minutes. The reaction mixture is
cooled to room temperature and allowed to stir for about 12
hours.
[0449] In certain embodiments, the contents of the reactor are
filtered, and the filter cake is rinsed with a solvent and dried to
yield D-1. In certain embodiments, the solvent is a combination of
2-methyltetrahydrofuran and heptanes.
[0450] In particular embodiments, each Hal is independently --F or
--Cl. In a particular embodiment, each Hal is --F In certain
embodiments, n=1-3. In certain embodiments, n=2. In certain
embodiments, n=3.
[0451] In certain embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl(C.sub.1C.sub.4)alkyl. In certain
embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.a is methyl.
[0452] In certain embodiments, each R.sup.b is independently
(C.sub.1-C.sub.4)alkyl, (C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10aryl(C.sub.1C.sub.4)alkyl. In certain embodiments,
each R.sup.b is independently (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.b is methyl.
[0453] In particular embodiments, R.sup.b is
(C.sub.1-C.sub.4)alkyl, R.sup.a is (C.sub.1-C.sub.4)alkyl, the
alkylated formamide acetal is N,N-dimethylformamide dimethyl
acetal, the solvent is 2-methyltetrahydrofuran, the reaction
proceeds at about 10 to about 60.degree. C., the acid is
trifluoroacetic acid, each Hal is --F and n=3.
[0454] In particular embodiments, R.sup.b is methyl, R.sup.a is
methyl, the alkylated formamide acetal is N,N-dimethylformamide
dimethyl acetal, the solvent is 2-methyltetrahydrofuran, the
reaction proceeds at about 40.degree. C., the acid is
trifluoroacetic acid, Hal is --F and n=3.
[0455] M. Formation of F-1 from D-1 Through E-1
##STR00082##
[0456] To a solution of D-1 in a solvent, is added about 1.1
equivalent of K-1 under conditions effective to produce E-1.
[0457] In certain embodiments, the solvent is an alcoholic solvent
such as, but not limited to ethanol, n-propanol, 2-propanol,
butanol, methanol and tert-butanol, or an aprotic polar organic
solvents such as, but not limited to 2-methyl tetrahydrofuran,
tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide,
N,N-dimethylacetamide, 1,4-dioxane, and N-methyl-2-pyrrolidinone.
In particular embodiments, the solvent is methanol.
[0458] In certain embodiments, K-1 is an aminoacetaldehyde acetal
such as, but not limited to, aminoacetaldehyde diethylacetal,
aminoacetaldehyde dipropylacetal, Aminoacetaldehyde dimethylacetal,
and aminoacetaldehyde dibutalacetal. In certain embodiments, K-1 is
aminoacetaldehyde dimethylacetal.
[0459] In certain embodiments, the reaction proceeds at about 10 to
60.degree. C., about 10 to 50.degree. C., about 10 to 40.degree.
C., about 10 to 30.degree. C., about 10 to 20.degree. C., 20 to
60.degree. C., about 20 to 50.degree. C., about 20 to 40.degree.
C., about 20 to 30.degree. C., about 30 to 60.degree. C., about 30
to 50.degree. C., about 30 to 40.degree. C., about 40 to 60.degree.
C., about 40 to 50.degree. C., about 50 to 60.degree. C., or any
subrange therebetween. In particular embodiments, the reaction
proceeds at room temperature. In further embodiments, the reaction
proceeds at about 16.degree. C. to about 23.degree. C.
[0460] In certain embodiments, the reaction is stirred for about
0.1 to about 12 hours, about 0.5 to about 4 hours, about 1 to about
2 hours.
[0461] Once the reaction has progressed sufficiently to produce
E-1, M-1 is added to the reaction mixture.
[0462] In certain embodiments, about 1 to about 10 or about 1 to
about 5 equivalents of M-1 is added. In a particular embodiment,
about 5 equivalents of M-1 is added.
[0463] In certain embodiments, M-1 is dimethyl oxalate, diethyl
oxalate, dipropyl oxalate, or dibutyl oxalate. In a particular
embodiment, M-1 is dimethyl oxalate.
[0464] The reaction mixture is stirred at a temperature sufficient
to achieve dissolution of M-1. In certain embodiments, the reaction
mixture is stirred at about 20-80.degree. C., at about
20-70.degree. C., at about 20-60.degree. C., at about 30-60.degree.
C., at about 40-50.degree. C. or at about 45.degree. C.
[0465] In certain embodiments, a base is added to the reaction
mixture following the addition of M-1.
[0466] In certain embodiments, the base is a metal hydride, an
alkoxide, an inorganic carbonate, or a bis(trialkylsilyl)amide. In
certain embodiments, the base is a metal hydride. In certain
embodiments, the base is an alkoxide. In certain embodiments, the
base is an inorganic carbonate. In certain embodiments, the base is
a bis(trialkylsilyl)amide. Exemplary metal hydrides include, but
are not limited to lithium hydride, sodium hydride, and potassium
hydride. Exemplary alkoxides include, but are not limited to,
sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium
tert-butoxide, potassium ethoxide, sodium tert-pentoxide, and
lithium tert-butoxide. Exemplary bis(trialkylsilyl)amide bases
include, but are not limited to lithium bis(trimethylsilyl)amide,
sodium bis(trimethylsilyl)amide, and potassium
bis(trimethylsilyl)amide. Exemplary carbonates include, but are not
limited to lithium, sodium, potassium, and cesium carbonate.
[0467] In still further embodiments, the base is a mixture of at
least one of the foregoing bases. In certain embodiments, the base
is a mixture of up to three, or up to two, metal hydrides. In
certain embodiments, the base is a mixture of up to three, or up to
two, alkoxides. In certain embodiments, the base is a mixture of up
to three, or up to two, metal bis(trialkylsilyl)amides. In certain
embodiments, the base is a mixture of up to three, or up to two, of
the following bases: lithium hydride, sodium hydride, potassium
hydride, sodium methoxide, sodium tert-butoxide, sodium ethoxide,
potassium tert-butoxide, potassium ethoxide, sodium tert-pentoxide,
lithium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium
bis(trimethylsilyl)amide, and potassium
bis(trimethylsilyl)amide.
[0468] In particular embodiments, the base is sodium methoxide. In
particular embodiments, the base is sodium methoxide in solution in
methanol.
[0469] In certain embodiments, after the addition of the base, the
reaction is heated to about 20 to 80.degree. C., 20 to 70.degree.
C., about 20 to 60.degree. C., about 20 to 50.degree. C., about 20
to 40.degree. C., about 20 to 30.degree. C., about 30 to 80.degree.
C., about 30 to 70.degree. C., about 30 to 60.degree. C., about 30
to 50.degree. C., about 30 to 40.degree. C., about 40 to 80.degree.
C., about 40 to 70.degree. C., about 40 to 60.degree. C., about 40
to 50.degree. C., about 50 to 80.degree. C., about 50 to 70.degree.
C., about 50 to 60.degree. C., about 60 to 80.degree. C., about 60
to 70.degree. C., about 70 to 80.degree. C., or any subrange
therebetween. In a particular embodiment, the reaction is heated to
about 42 to 48.degree. C. In a particular embodiment, the reaction
is heated to about 45.degree. C.
[0470] In certain embodiments, the reaction is stirred for about 1
to about 24 hours, about 6 to about 24 hours, about 12 to about 20
hours, about 14 to about 18 hours.
[0471] In certain embodiments, the reaction is diluted with an
aqueous solution and F-1 is extracted and purified by any suitable
methods known in the art, including but not limited to solvent
extraction, crystallization, and silica gel chromatography.
[0472] In certain embodiments, the temperature is reduced to about
34-37.degree. C. over the course of about 1 hour, optionally
charged with F-1 seed crystals and allowed to age for about 1-2
hours. At this point, water is added and temperature is reduced to
about 18-22.degree. C. over 1 hour. The resulting slurry is
filtered.
[0473] In certain embodiments, liquors are recycled to displace
solids remaining in the reactor. The collected solids on the filter
are then washed with a 1:1 mixture of water and methanol, followed
by water. The collected wet cake is dried in a vacuum oven at about
36-42.degree. C. for about 16 hours, providing F-1.
[0474] In certain embodiments, R.sup.1 is (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or (C.sub.6-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.1 is
C.sub.1-C.sub.4alkyl. In further embodiments R.sup.1 is --CH.sub.3,
that is, K-1 is aminoacetaldehyde dimethyl acetal.
[0475] In certain embodiments, R.sup.2 is (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or (C.sub.6-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.2 is
C.sub.1-C.sub.4alkyl. In certain embodiments, R.sup.2 is
--CH.sub.3.
[0476] In particular embodiments, each Hal is independently --F or
In a particular embodiment, Hal is --F In certain embodiments,
n=1-3. In certain embodiments, n=2. In certain embodiments,
n=3.
[0477] In certain embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl(C.sub.1C.sub.4)alkyl. In certain
embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.a is methyl.
[0478] In certain embodiments, each R.sup.b is independently
(C.sub.1-C.sub.4)alkyl, (C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl(C.sub.1C.sub.4)alkyl. In certain
embodiments, each R.sup.b is independently (C.sub.1-C.sub.4)alkyl.
In certain embodiments, R.sup.b is methyl.
[0479] In particular embodiments, R.sup.b is methyl, R.sup.a is
(C.sub.1-C.sub.4)alkyl, each Hal is --F, n=3, R.sup.2 is
(C.sub.1-C.sub.4)alkyl, R.sup.1 is (C.sub.1-C.sub.4)alkyl, the
solvent is an alcoholic solvent, K-1 is aminoacetaldehyde
dimethylacetal, the first reaction proceeds at about 2 to about
40.degree. C., the second reaction is heated to about 20 to about
80.degree. C., the base is n alkoxide, and M-1 is dimethyl
oxalate
[0480] In particular embodiments, R.sup.b is methyl, R.sup.a is
methyl, Hal is --F, n=3, R.sup.2 is --CH.sub.3, R.sup.1 is
--CH.sub.3, the solvent is methanol, K-1 is aminoacetaldehyde
dimethylacetal, the first reaction proceeds at about 16 to about
23.degree. C., the second reaction is heated to about 45.degree.
C., the base is sodium methoxide, and M-1 is dimethyl oxalate
[0481] N. Acetal Hydrolysis of F-1 to Form FF-1
##STR00083##
[0482] To a solution of F-1 in a solvent, is added about 0.1 to 1
equivalent of a first acid and about 2 to 20 equivalents of a
second acid under conditions effective to produce FF-1.
[0483] In some embodiments, about 0.1 to 0.5 equivalent of the
first acid is added. In particular embodiments, about 0.1
equivalent of the first acid is added.
[0484] In some embodiments, the solvent is a polar organic solvent
or a weak protic acid. In some embodiments, the polar organic
solvent include, but is not limited to propionitrile,
tetrahydroduran, 1,4-dioxane, acetonitrile and ethyl acetate. In
some embodiments, the weak protic acid include, but is not limited
to formic acid, propionic acid and butyric acid. In a particular
embodiment, the solvent is acetonitrile.
[0485] In some embodiments, the first acid is a strong protic acid
including, but not limited to methanesulfonic acid, sulfuric acid,
hydrochloric acid, trifluoroacetic acid, p-Toluenesulfonic acid and
camphorsulfonic acid.
[0486] In a particular embodiment, the first acid is
p-Toluenesulfonic acid. In a particular embodiment, the first acid
is p-Toluenesulfonic acid monohydrate.
[0487] In some embodiments, the second acid is a weak protic acid
including, but not limited to acetic acid, formic acid, propionic
acid and butyric acid. In a particular embodiment, the second acid
is acetic acid.
[0488] The reaction is then heated to about 20 to 120.degree. C.,
about 40 to 100.degree. C., about 60 to 80.degree. C., or about 70
to 80.degree. C. In a particular embodiment, the reaction is heated
to about 75.degree. C.
[0489] In certain embodiments, the reaction is stirred for about 1
to about 24 hours, for about 4 to about 14 hours, for about 8 to
about 10 hours.
[0490] In certain embodiments, water is added to the reaction
mixture.
[0491] In certain embodiments, the product formed is extracted and
optionally purified by any suitable technique known in the art,
such as, but not limited to solvent extraction, chromatography,
crystallization or a combination thereof.
[0492] In certain embodiments, the mixture is concentrated under
reduced pressure to remove the solvent. The resultant slurry is
then aged at room temperature for about 2 hours, filtered and
washed with water. The cake is dried in a vacuum oven at 50.degree.
C. for at least 10 hours to give FF-1.
[0493] In certain embodiments, R.sup.1 is (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or (C.sub.6-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.1 is
C.sub.1-C.sub.4alkyl. In further embodiments R.sup.1 is
--CH.sub.3.
[0494] In certain embodiments, R.sup.2 is (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or (C.sub.6-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.2 is
C.sub.1-C.sub.4alkyl. In certain embodiments, R.sup.2 is
--CH.sub.3.
[0495] In particular embodiments, each Hal is independently --F or
In a particular embodiment, Hal is --F In certain embodiments,
n=1-3. In certain embodiments, n=2. In certain embodiments,
n=3.
[0496] In certain embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl(C.sub.1C.sub.4)alkyl. In certain
embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.a is methyl.
[0497] In particular embodiments, R.sup.a is
(C.sub.1-C.sub.4)alkyl, each Hal is --F, n=3, R.sup.2 is
(C.sub.1-C.sub.4)alkyl, R.sup.1 is (C.sub.1-C.sub.4)alkyl, the
reaction is heated to about 20 to about 120.degree. C., the first
acid is p-Toluenesulfonic acid, the second acid is acetic acid, and
the solvent is acetonitrile.
[0498] In particular embodiments, R.sup.a is methyl, Hal is --F,
n=3, R.sup.2 is --CH.sub.3, R.sup.1 is --CH.sub.3, the reaction is
heated to about 75.degree. C., the first acid is p-Toluenesulfonic
acid, the second acid is acetic acid, and the solvent is
acetonitrile.
[0499] O. Cyclization of FF-1 and N-1 to Form G-1
##STR00084##
[0500] The starting material FF-1, N-1, or a salt or co-crystal
thereof, and an additive are combined with a solvent under
conditions effective to produce G-1.
[0501] In certain embodiments, the additive is a carboxylate salt
such as, but not limited to sodium acetate, potassium acetate,
lithium acetate, sodium propionate, and potassium propionate. In
certain embodiments, the additive is a carbonate such as, but not
limited to sodium carbonate, potassium carbonate, lithium
carbonate, and cesium carbonate. In certain embodiments, the
additive is a water scavenger such as but not limited to molecular
sieves, trimethyl orthoacetate, and trimethyl orthoformate. In
particular embodiments, the additive is potassium acetate.
[0502] In certain embodiments, about 1 to about 2 or about 1 to
about 1.5 equivalents of N-1 or a salt or co-crystal thereof, is
used.
[0503] In certain embodiments, about 1 to about 5 equivalents of
additive are used. In particular embodiments, about 2.5 equivalents
of additive is added.
[0504] In certain embodiments, the solvent is acetonitrile, ethyl
acetate, toluene, 2-methyl tetrahydrofuran, isopropyl acetate,
dichloromethane, or a mixture thereof. In particular embodiments,
the solvent is dichloromethane.
[0505] In certain embodiments, the reaction is stirred at about 0
to about 40.degree. C., about 10 to about 30.degree. C., about 15
to about 25.degree. C., about 20.degree. C.
[0506] In certain embodiments, G-1 is extracted and optionally
purified by any suitable technique known in the art, such as, but
not limited to solvent extraction, chromatography, crystallization
or a combination thereof.
[0507] In particular embodiments, the reaction mixture is washed
with an aqueous solution and evaporated to dryness. In particular
embodiments, the residue is dissolved in dimethylformamide and the
resulting solution is added to water over about 2 hours, while
agitating. The product slurry is aged at about 20.degree. C. for
about 12 hours and filtered. The product cake is washed with water
and dried to afford G-1.
[0508] In certain embodiments, N-1 is in solution when added to the
reaction mixture.
[0509] In further embodiments, L is --CH.sub.2--CH.sub.2--.
[0510] In particular embodiments, N-1 is
(1R,3S)-3-aminocyclopentan-1-ol:
##STR00085##
[0511] In particular embodiments, N-1 is a free base or is
synthesized and used without isolation.
[0512] In particular embodiments, N-1 is a salt or co-crystal.
Suitable salts or co-crystals of N-1 include, but are not limited
to, benzoic acid, acetic acid, fumaric acid, methanesulfonic acid,
p-toluenesulfonic acid, oxalic acid, hydrochloric acid, naproxen,
S-naproxen, R-naproxen, mandelic acid, R-mandelic acid, and
S-mandelic acid.
[0513] In still further embodiments, N-1 is
##STR00086## ##STR00087##
[0514] In particular embodiments, N-1 is a salt or co-crystal with
benzoic acid.
[0515] In particular embodiments, N-1 is
##STR00088##
[0516] In particular embodiments, each Hal is independently --F or
--Cl. In a particular embodiment, each Hal is --F In certain
embodiments, n=1-3. In certain embodiments, n=2. In certain
embodiments, n=3.
[0517] In certain embodiments, R.sup.2 is (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or (C.sub.6-C.sub.10)aryl
(C.sub.1-C.sub.4)alkyl. In certain embodiments, R.sup.2 is
C.sub.1-C.sub.4alkyl. In certain embodiments, R.sup.2 is
--CH.sub.3.
[0518] In certain embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl,
(C.sub.6-C.sub.10)aryl, or
(C.sub.6-C.sub.10)aryl(C.sub.1C.sub.4)alkyl. In certain
embodiments, R.sup.a is (C.sub.1-C.sub.4)alkyl. In certain
embodiments, R.sup.a is methyl.
[0519] In particular embodiments, R.sup.a is
(C.sub.1-C.sub.4)alkyl, each Hal is --F, n=3, R.sup.2 is
--CH.sub.3, N-1 is
##STR00089##
the solvent is dichloromethane, the reaction is stirred at about 0
to about 40.degree. C. and the additive is potassium acetate.
[0520] In particular embodiments, R.sup.a is methyl, Hal is --F,
n=3, R.sup.2 is --CH.sub.3, N-1 is
##STR00090##
the solvent is dichloromethane, the reaction is stirred at about
20.degree. C. and the additive is potassium acetate.
[0521] P. Conversion of (-)-Vince Lactam to b-1 Through a-1
##STR00091##
[0522] A catalyst, a solvent and (-)-Vince lactam are stirred in a
reactor, which is purged with an inert gas. A source of hydrogen is
added.
[0523] In certain embodiments, the hydrogen source is formic acid,
hydrazine, dihydronapthalene, dihydroanthracene, hydrogen gas, or
Hantzch ester and isopropanol. In particular embodiments, the
hydrogen source is hydrogen gas.
[0524] In certain embodiments, the catalyst is a platinum catalyst
such as PtO.sub.2, a nickel catalyst such as Raney Nickel, a
rhodium catalyst such as RhCl(PPh.sub.3).sub.3, a palladium
catalyst, a ruthenium catalyst such as Nyori's catalyst or an
iridium catalyst such as Crabtree's catalyst. In some embodiments,
the catalyst is selected form the group consisting of Pd/C,
PtO.sub.2, Raney Nickel, RhCl(PPh.sub.3).sub.3, Nyori's catalyst,
and Crabtree's catalyst. In particular embodiments, the catalyst is
Pd/C.
[0525] In certain embodiments, the solvent is a polar aprotic
solvent such as THF, 2-MeTHF, dioxane, diethyl ether, diisopropyl
ether, DME, MTBE, CPME, EtOAc, and DCM. In certain embodiments, the
solvent is a polar protic solvent such as methanol, ethanol,
n-butanol, and isopropanol. In particular embodiments, the solvent
is 2-methyltetrahydrofuran.
[0526] In certain embodiments, the reaction is stirred at about 0
to 65.degree. C., about 10 to 55.degree. C., about 15 to 45.degree.
C., about 20 to 40.degree. C., about 25 to 35.degree. C.
[0527] In certain embodiments, the reactor is maintained at about
0.30 to about 0.35 MPa.
[0528] In certain embodiments, the reaction takes place over about
1 to about 24 hours, about 1 to about 12 hours, about 3 to about 9
hours, about 6.5 hours.
[0529] In certain embodiments, the product formed is extracted and
optionally purified by any suitable technique known in the art,
such as, but not limited to solvent extraction, chromatography,
crystallization or a combination thereof.
[0530] In certain embodiments, the reaction is filtered through
celite washed with 2-MeTHF to yield the hydrogenated product in
solution.
[0531] In certain embodiments, to a solution of the hydrogenated
product, a second catalyst is added, as well as an activated source
for a protecting group.
[0532] In certain embodiments, the second catalyst is a
nucleophilic amine-containing compound such as imidazole,
derivatives of 4-dimethylaminopyridine,
1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene,
and pyridine, or a nucleophilic phosphine containing compound such
as triphenylphosphine. In particular embodiments, the second
catalyst is 4-dimethylaminopyridine (DMAP).
[0533] In certain embodiments, the activated source of protecting
group is Boc.sub.2O. In particular embodiments, Boc.sub.2O is
prepared in solution in 2-MeTHF.
[0534] In certain embodiments, the protecting group is Boc.
[0535] In certain embodiments, the reaction occurs in a polar
aprotic solvent such as THF, EtOAc, DCM, acetonitrile or 2-MeTHF.
In particular embodiments, the reaction occurs in 2-MeTHF.
[0536] In certain embodiments, the reaction occurs at temperatures
in the range from about 20 to 80.degree. C., about 25 to 70.degree.
C., about 35 to 60.degree. C., about 45 to 50.degree. C.
[0537] In certain embodiments, the reaction occurs for about 0.5 to
about 12 hours, about 1 to about 6 hours, about 1 to about 3 hours,
about 2 hours.
[0538] In certain embodiments, the product formed is extracted and
optionally purified by any suitable technique known in the art,
such as, but not limited to solvent extraction, chromatography,
crystallization or a combination thereof.
[0539] In certain embodiments, the solution is concentrated and a
second solvent is added.
[0540] In certain embodiments, the second solvent is a polar
aprotic solvent such as THF, Dioxane, DME, diisopropyl ether,
diethyl ether, MTBE, CPME, 2-MeTHF and toluene. In particular
embodiments, the second solvent is 2-MeTHF.
[0541] In certain embodiments, the solution is maintained at about
-50 to 30.degree. C., about -50 to 30.degree. C., about -30 to
20.degree. C., about -20 to 10.degree. C., about -10 to 0.degree.
C.
[0542] Following hydrogenation and addition of the protecting group
PG, a nucleophile R.sup.3M is added to the reaction mixture.
[0543] In certain embodiments, nucleophile R.sup.3M is a n-alkyl
Grignard reagent such as ethylmagnesium halides, n-propylmagnesium
halides, and n-butylmagnesium halides or an organolithium reagent
such as methyl lithium, n-butyllithium, and n-hexyllithium. In
particular embodiments, the nucleophile is methyl magnesium
bromide.
[0544] In certain embodiments, nucleophile R.sup.3M is added, while
maintaining the reaction within the desired temperature range, over
about 1 to about 12 hours, about 3 to about 9 hours, about 5 to
about 7 hours, about 6 hours. After the addition is complete, the
mixture is stirred for an additional about 0.5 to about 12 hours,
about 0.5 to about 6 hours, about 0.5 to about 4 hours, about 1 to
about 2 hours.
[0545] In certain embodiments, the product formed is extracted and
optionally purified by any suitable technique known in the art,
such as, but not limited to solvent extraction, chromatography,
crystallization or a combination thereof.
[0546] In certain embodiments, following addition of nucleophile
R.sup.3M, 15% aqueous AcOH is added while maintaining the
temperature at about 0 to 5.degree. C. to adjust the pH to
approximately 7. The layers are separated and the organic layer is
washed with water twice. The organic layer is concentrated to 4 to
5 Volumes under reduced pressure at about .ltoreq.45.degree. C. The
solution is azeotroped with 2-MeTHF. The final solution is
concentrated under reduced pressure to about 2.5 to 3 Volumes and
n-Heptane is slowly added while maintaining the temperature at 30
to 35.degree. C. In certain embodiments, b-1 seeds are added and
the mixture is stirred at about 30 to 35.degree. C. for about 5 to
10 hours.
[0547] In certain embodiments, additional n-heptane is added while
maintaining the temperature at 30 to 35.degree. C. over
approximately 5 h. The contents are cooled to -5 to 0.degree. C.
and held for approximately 1 to 2 hours. The product is collected
by filtration, washed with n-heptane at -5 to 0.degree. C., and
dried under reduced pressure at 40 to 45.degree. C. to afford
b-1.
[0548] In particular embodiments, the hydrogen source is hydrogen
gas, the catalyst is a palladium catalyst, the solvent for the
hydrogenation is 2-methyltetrahydrofuran, the hydrogenation
reaction is stirred at about 0 to about 65.degree. C., the second
catalyst is a nucleophilic amine-containing compound, the activated
source of protecting group is Boc.sub.2O, the protection reaction
occurs in 2-MeTHF at about 25 to 70.degree. C., the second solvent
is 2-MeTHF, and the nucleophile is methyl magnesium bromide.
[0549] In particular embodiments, the hydrogen source is hydrogen
gas, the catalyst is Pd/C, the solvent for the hydrogenation is
2-methyltetrahydrofuran, the hydrogenation reaction is stirred at
about 25 to 35.degree. C., the second catalyst is
4-Dimethylaminopyridine, the activated source of protecting group
is Boc.sub.2O, the protection reaction occurs in 2-MeTHF at about
45 to 50.degree. C., the second solvent is 2-MeTHF, and the
nucleophile is methyl magnesium bromide.
[0550] Q. Conversion of b-1 to c-1
##STR00092##
[0551] To a solution of b-1 in a solvent, an oxidant is added and
the reaction is stirred.
[0552] In certain embodiments, PG is a protecting group. In certain
embodiments, the protecting group PG is Boc.
[0553] In certain embodiments, the solvent is a polar aprotic
solvent such as DCM, 1,2-dichloroethane, toluene, chlorobenzene,
dichlorobenzene, chloroform, carbon tetrachloride and DMF, or a
polar protic solvent such as water, acetic acid, methanol, and
ethanol. In particular embodiments, the solvent is toluene.
[0554] In certain embodiments, the oxidant is hydrogen peroxide,
ozone, t-butyl hydrogen peroxide, trifluoroperacetic acid (TFPAA),
nitroperbenzoic acid, monopermaleic acid (MPMA), monoperphthalic
acid, monoperphthalic acid magnesium salt, persulfuric acid,
performic acid, peracetic acid, perbenzoic acid, a silylated
peracid, benzeneperoxyseleninic acid, sodium perborate,
meta-chloroperoxybenzoic acid, or a resin-bound peracid. In
particular embodiments, the oxidant is meta-chloroperoxybenzoic
acid (mCPBA).
[0555] In certain embodiments, mCPBA is added in several portions
every 4 to 6 h.
[0556] In certain embodiments, the reaction is stirred within the
temperature range of -10 to 50.degree. C., 0 to 40.degree. C., 10
to 45.degree. C., 15 to 40.degree. C., 20 to 35.degree. C., 25 to
30.degree. C.
[0557] In certain embodiments, the reaction is stirred for 1 to 48
h, 6 to 36 h, 10 to 20 h.
[0558] In certain embodiments, the product formed is extracted and
optionally purified by any suitable technique known in the art,
such as, but not limited to solvent extraction, chromatography,
crystallization or a combination thereof.
[0559] In particular embodiments, 20% NaHSO.sub.3 is added, then
10% NaOH is added. The organic layer is washed with water and
concentrated to afford the oxidized product in solution.
[0560] To a solution of the oxidized product, is added water, a
solvent and a base or an acid.
[0561] In certain embodiments, the solvent is a polar protic
solvent such as methanol, ethanol, isopropanol or water, or a
combination of at least one polar aprotic solvent with a polar
aprotic solvent such as THF, Dioxane, DME, disopropylether, diethyl
ether, MTBE, CPME, or toluene. In particular embodiments, the
solvent is a combination of toluene, methanol, and water.
[0562] In certain embodiments, the base is an hydroxide base such
as lithium hydroxide, sodium hydroxide and potassium hydroxide or a
silanolate base such as sodium trimethylsilanolate and potassium
trimethylsilanolate. In particular embodiments, the base is lithium
hydroxide.
[0563] In certain embodiments, the acid is a concentrated strong
acid such as sulfuric and hydrochloric acid.
[0564] In certain embodiments, the reaction is stirred at about 0
to 80.degree. C., about 5 to 70.degree. C., about 10 to 60.degree.
C., about 15 to 50.degree. C., about 20 to 40.degree. C., about 25
to 30.degree. C.
[0565] In certain embodiments, the product formed is extracted and
optionally purified by any suitable technique known in the art,
such as, but not limited to solvent extraction, chromatography,
crystallization or a combination thereof.
[0566] In particular embodiments, toluene and 25% NaCl are added
and the layers separated. The organic layer is washed with a
solution of 20% NaCl adjusted to about pH 7 to about pH 8 with 1 N
HCl. The organic layer is filtered and concentrated. Toluene is
added and the distillation continued. Toluene and active carbon are
added. The mixture is warmed to about 30 to about 40.degree. C. and
stirred for about 2 to 6 h. The contents are cooled, filtered
through celite and washed with toluene. The filtrate is
concentrated. n-heptane is added over about 1 to 2 hours and the
mixture is optionally seeded with c-1 and stirred for an additional
approximately 2 to 3 hours. n-heptane is added and the mixture is
stirred for about 2 to 3 h. The mixture is cooled to about 10 to
15.degree. C. and stirred for an additional approximately 3 to 5 h.
The product is collected by filtration and washed with n-heptane at
about 10 to 15.degree. C. The product is dried to afford c-1.
[0567] In particular embodiments, the protecting group PG is Boc,
the solvent is a polar aprotic solvent, the oxidant is mCPBA, the
reaction is stirred at 10 to 45.degree. C., the hydrolysis occurs
in a combination of toluene, methanol, and water at about 10 to
60.degree. C., and the base is an hydroxide base.
[0568] In particular embodiments, the protecting group PG is Boc,
the solvent is toluene, the oxidant is mCPBA, the reaction is
stirred at 25 to 30.degree. C., the hydrolysis occurs in a
combination of toluene, methanol, and water at about 25 to
30.degree. C., and the base is lithium hydroxide.
[0569] R. Resolution of c-1a--Selective Acylation
##STR00093##
[0570] In certain embodiments, enantioenriched cc-1a is obtained
through enzymatically catalyzed selective acylation.
[0571] In this process, the racemic starting material c-1a is a
mixture of cc-1b and cc-1a (i.e., c-1a (+/-) and is dissolved in a
solvent.
[0572] In certain embodiments, the solvent is a polar aprotic
solvent, a non-polar solvent, a polar protic solvent, a mixture of
organic solvents with aqueous buffers or a mixture thereof.
Exemplary polar aprotic solvents include but are not limited to
diethyl ether, diisopropyl ether, methyl t-butyl ether,
2-methyltetrahydrofuran, tetrahydrofuran, dichloromethane and
chloroform. Exemplary non-polar solvents include but are not
limited to toluene, hexane and heptane. Exemplary polar protic
solvents include but are not limited to t-butanol. In particular
embodiments, the solvent used is toluene.
[0573] Once the racemic starting material c-1a is dissolved in the
solvent, about 1 equivalent of an acyl donor is added. In certain
embodiments, the acyl donor is an anhydride or an ester. In certain
embodiments, the anhydride include but is not limited to glutaric
anhydride and acetic anhydride. In certain embodiments, the ester
include but is not limited to vinyl acetate, isopropenyl acetate,
4-chlorophenyl acetate and ethyl methoxy acetate. In particular
embodiments, the acyl donor is glutaric anhydride.
[0574] In certain embodiments, R.sup.x is
(C.sub.1-C.sub.6)alkyl-R.sup.y and R.sup.y is selected from the
group consisting of H, CN, --NR.sup.z1R.sup.z2, C(O)R.sup.z1,
--C(O)OR.sup.z1, --C(O)NR.sup.z1R.sup.z2, --OC(O)NR.sup.z1R.sup.z2,
--NR.sup.z1C(O)R.sup.z2, --NR.sup.z1C(O)NR.sup.z2,
--NR.sup.z1C(O)OR.sup.z2, --SR.sup.z1, --S(O).sub.1-2R.sup.z1,
--S(O).sub.2NR.sup.z1R.sup.z2, NR.sup.z1S(O).sub.2R.sup.z2,
NR.sup.z1S(O).sub.2R.sup.z2, and OR.sup.z1.
[0575] In certain embodiments, R.sup.z1 and R.sup.z2 are
independently selected from the group consisting of H,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6heteroalkyl, C.sub.3-10cycloalkyl, 3 to 12 membered
heterocyclyl, C.sub.6-10aryl and 5 to 10 membered heteroaryl.
[0576] In certain embodiments, R.sup.x is
(C.sub.1-C.sub.4)alkyl-R.sup.y and R.sup.y is selected from the
group consisting of H and CO.sub.2H.
[0577] In certain embodiments, R.sup.x is methyl or
(CH.sub.2).sub.3--CO.sub.2H. In certain embodiments, R.sup.x is
(CH.sub.2).sub.3--CO.sub.2H.
[0578] About 15% by weight of an enzyme is added. In certain
embodiments, the enzyme is a lipase. In certain embodiments, the
lipase includes but is not limited to Novozyme 435, CAL-A, CAL-B,
PPL, PSL-C, PSL, CRL and MML. In certain embodiments, the lipase
includes but is not limited to CAL-A, CAL-B, PPL, PSL-C, PSL, CRL
and MML. In particular embodiments, the enzyme used is Novozyme
435.
[0579] In certain embodiments, the reaction is allowed to stir for
about 1 to 48 h for about 6 to 48 h, for about 12 to 30 h, for
about 20 to 26 h, for about 23 h.
[0580] In certain embodiments, the reaction is allowed to stir at
about 0 to 60.degree. C. at about 5 to 30.degree. C., at about 10
to 15.degree. C.
[0581] In certain embodiments, additional enzyme is added and the
reaction is allowed to proceed for about 1 to 48 h at about 0 to
60.degree. C. In certain embodiments, about 5% by weight of
additional enzyme is added and the reaction is allowed to proceed
for about 6 to 24 h at about 5 to 30.degree. C. In particular
embodiments, additional enzyme is added and the reaction is allowed
to proceed for about 12 h at about 10 to 15.degree. C.
[0582] In certain embodiments, the ester formed e-1 is extracted
and optionally purified by any suitable technique known in the art,
such as, but not limited to solvent extraction, chromatography,
crystallization or a combination thereof.
[0583] In certain embodiments, precipitated enzyme solids are
removed by filtration and rinsed with solvent. The desired e-1 is
extracted into a basic aqueous layer such as aqueous
Na.sub.2CO.sub.3. The aqueous is washed with an organic solvent
(such as MTBE) to remove undesired material. A solvent (such as
THF) is then added to the aqueous layer, which contains e-1,
followed by hydroxide.
[0584] In certain embodiments, the solvent is a polar aprotic
solvent. Exemplary polar aprotic solvent include but are not
limited to diethyl ether, diisopropyl ether, methyl t-butyl ether,
2-methyltetrahydrofuran, tetrahydrofuran, dichloromethane and
chloroform. In particular embodiments, the solvent is THF.
[0585] Exemplary sources of hydroxide include but are not limited
to sodium hydroxide, potassium hydroxide and lithium hydroxide. In
particular embodiments, the source of hydroxide is sodium
hydroxide.
[0586] In certain embodiments, the mixture is allowed to stir for
about 1 to 24 h at about 0 to 60.degree. C. In certain embodiments,
the mixture is allowed to stir for about 1 to 12 h at about 5 to
30.degree. C. In particular embodiments, the mixture is allowed to
stir for about 4 h at about 15 to 20.degree. C.
[0587] In certain embodiments, the product cc-1a is extracted and
optionally purified by any suitable technique known in the art,
such as, but not limited to solvent extraction, chromatography,
crystallization or a combination thereof.
[0588] In particular embodiments, the layers are separated, and the
organic layer is concentrated.
[0589] In certain embodiments, the organic phase is concentrated
and cc-1a is recrystallized in a solvent with the addition of seeds
of cc-1a. In certain embodiments, the solvent is a mixture of THF,
dichloromethane and water, and the recrystallization is conducted
at about 40 to 50.degree. C.
[0590] In certain embodiments, the enantiomeric excess (% ee) of
the product is about 50 to 100, about 75 to 100, about 90 to 100,
about 95 to 100, about 98 to 100, about 98.5 to 100, about 98.5 to
99, about 99 to 100, about 99.5 to 100, about 99.9 to 100.
[0591] In particular embodiments, c-1a is dissolved in a nonpolar
solvent, the acyl donor is glutaric anhydride, R.sup.x is
(CH.sub.2).sub.3--CO.sub.2H, the enzyme used is a lipase, the
reaction is stirred at about 10 to 15.degree. C., cc-1b is removed
by filtration, the hydrolysis occurs in THF at about 5 to
30.degree. C., and the source of hydroxide is sodium hydroxide.
[0592] In particular embodiments, c-1a is dissolved in toluene, the
acyl donor is glutaric anhydride, R.sup.x is
(CH.sub.2).sub.3--CO.sub.2H, the enzyme used is Novozyme 435, the
reaction is stirred at about 10 to 15.degree. C., cc-1b is removed
by filtration, the hydrolysis occurs in THF at about 15 to
20.degree. C., and the source of hydroxide is sodium hydroxide.
[0593] S. Resolution of c-1a--Selective Hydrolysis
##STR00094##
[0594] In certain embodiments, enantioenriched cc-1a is obtained
through enzymatically catalyzed selective hydrolysis.
[0595] A mixture of the starting material, c-1a, an acyl donor, a
base and a catalyst in a solvent, is stirred.
[0596] In certain embodiments, the acyl donor includes but is not
limited to an anhydride or an acid chloride. In certain
embodiments, the anhydride includes but is not limited to succinic
anhydride and acetic anhydride. In certain embodiments, the acid
chloride include but is not limited to acetyl chloride and benzoyl
chloride. In particular embodiments, the acyl donor is glutaric
anhydride.
[0597] In certain embodiments, R.sup.x is
(C.sub.1-C.sub.6)alkyl-R.sup.y and R.sup.y is selected from the
group consisting of H, CN, --NR.sup.z1R.sup.z2, C(O)R.sup.z1,
--C(O)OR.sup.z1, --C(O)NR.sup.z1R.sup.z2, --OC(O)NR.sup.z1R.sup.z2,
--NR.sup.z1C(O)R.sup.z2, --NR.sup.z1C(O)NR.sup.z2,
--NR.sup.z1C(O)OR.sup.z2, --SR.sup.z1, --S(O).sub.1-2R.sup.z1,
--S(O).sub.2NR.sup.z1R.sup.z2,
NR.sup.z1S(O).sub.2R.sup.z2NR.sup.z1S(O).sub.2R.sup.z2, and
OR.sup.z1.
[0598] In certain embodiments, R.sup.z1 and R.sup.z2 are
independently selected from the group consisting of H,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6heteroalkyl,
C.sub.3-10cycloalkyl, 3 to 12 membered heterocyclyl, C.sub.6-10aryl
and 5 to 10 membered heteroaryl.
[0599] In certain embodiments, R.sup.x is
(C.sub.1-C.sub.4)alkyl-R.sup.y and R.sup.y is selected from the
group consisting of H and CO.sub.2H.
[0600] In certain embodiments, R.sup.x is methyl or
(CH.sub.2).sub.3--CO.sub.2H. In certain embodiments, R.sup.x is
(CH.sub.2).sub.3--CO.sub.2H.
[0601] In certain embodiments, the catalyst includes but is not
limited to nucleophilic amine-containing compounds and nucleophilic
phosphine containing compounds. In certain embodiments, the
nucleophilic amine-containing compounds include but are not limited
to imidazole, derivatives of 4-dimethylaminopyridine,
1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene,
and pyridine. In certain embodiments, the nucleophilic phosphine
containing compounds include but are not limited to
triphenylphosphine. In particular embodiments, the catalyst is
4-dimethylaminopyridine.
[0602] In certain embodiments, the base includes but is not limited
to amine bases, aromatic amine bases, inorganic carbonates, metal
hydrides and alkoxides. In certain embodiments, the amine bases
include but are not limited to N,N-diisopropylethylamine,
quinuclidine, 1,4-diazabicyclo[2.2.2]octane,
1,8-diazabicyclo[5.4.0]undec-7-ene, tripropylamine, and
tributylamine. In certain embodiments, the aromatic amine bases
include but are not limited to pyridine. In certain embodiments,
the inorganic carbonate bases include but are not limited to
lithium carbonate, sodium carbonate, potassium carbonate, and
cesium carbonate. In certain embodiments, the metal hydride bases
include but are not limited to sodium hydride, and potassium
hydride. In certain embodiments, the alkoxide bases include but are
not limited to sodium methoxide, sodium tert-butoxide and lithium
tert-butoxide. In particular embodiments, the base is pyridine.
[0603] In certain embodiments, the solvent is an aromatic solvent
or a polar non-protic solvent. In certain embodiments, the aromatic
solvent includes but is not limited to pyridine, toluene, xylene,
benzene, and chlorobenzene. In certain embodiments, the polar
non-protic solvent includes but is not limited to
N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane,
N-methyl-2-pyrrolidinone, and dichloromethane. In particular
embodiments, the solvent is Pyridine.
[0604] In certain embodiments, the reaction mixture is stirred for
about 1 to 48 h, for about 6 to 24 h, for about 12 h.
[0605] In certain embodiments, the reaction mixture is stirred at
about 0 to 120.degree. C., at about 20 to 100.degree. C., at about
40 to 80.degree. C., or at about 60.degree. C.
[0606] In certain embodiments, the product ee-1 is extracted and
optionally purified by any suitable technique known in the art,
such as, but not limited to solvent extraction, chromatography,
crystallization or a combination thereof.
[0607] In particular embodiments, the reaction mixture is
evaporated to dryness, dissolved in DCM and washed with a 0.2 M HCl
aqueous solution. The organic layer is evaporated to dryness. The
residue is stirred with water and the pH adjusted to about 7.8 with
a 2 M NaOH solution. The water layer is washed with DCM. The water
layer is then acidified to pH 4 with 3 N HCl aqueous solution and
extracted DCM. The combined organic layers are dried over
Na.sub.2SO.sub.4, filtered and evaporated. Trituration with pentane
followed by filtration and drying under vacuum yields ee-1.
[0608] ee-1 is suspended in a solvent, an enzyme is added.
[0609] In certain embodiments, the solvent is a polar aprotic
solvent, a non-polar solvent or a mixtures of organic solvents with
aqueous buffers. In certain embodiments, the polar aprotic solvent
includes but is not limited to diethyl ether, diisopropyl ether,
methyl t-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran,
dichloromethane, and chloroform. In certain embodiments, non-polar
solvents include but are not limited to hexane and heptane. In
particular embodiments, the solvent is diisopropyl ether:phosphate
buffer 1:2.
[0610] In certain embodiments, the enzyme is a lipase such as but
are not limited to CAL-A, CAL-B, PPL, PSL-C, PSL, CRL, and MML. In
particular embodiments, the enzyme is CAL-B.
[0611] In certain embodiments, the reaction is stirred at 0 to
60.degree. C., at 10 to 50.degree. C., at 20 to 40.degree. C., at
about 30.degree. C.
[0612] In certain embodiments, the reaction is stirred for 24 to
200 h, 50 to 150 h, about 100 h.
[0613] In certain embodiments, the product cc-1a is extracted and
optionally purified by any suitable technique known in the art,
such as, but not limited to solvent extraction, chromatography,
crystallization or a combination thereof.
[0614] In certain embodiments, e-2 is removed by extraction with an
aqueous layer. In certain embodiments, the product e-2 is removed
by extraction in a basic aqueous layer.
[0615] In particular embodiments, the reaction mixture is filtered
and the layers of the filtrate are separated. The solid is washed
with DCM and the filtrate is used to extract the aqueous layer. The
combined organic layers are washed with 5% Na.sub.2CO.sub.3, brine
and dried. Filtration and evaporation of the volatiles under
reduced pressure affords cc-1a.
[0616] In particular embodiments, the acyl donor is an anhydride,
R.sup.x is (C.sub.1-C.sub.4)alkyl-R.sup.y, R.sup.y is selected from
the group consisting of H and CO.sub.2H, the catalyst is
4-dimethylaminopyridine, the base for the first step is pyridine,
the solvent for the first step is an aromatic solvent, the reaction
mixture in the first step is stirred at about 0 to about 60.degree.
C., the solvent for the hydrolysis is diisopropyl ether:phosphate
buffer 1:2, the enzyme is CAL-B, and hydrolysis reaction is stirred
at about 0 to about 30.degree. C.
[0617] In particular embodiments, the acyl donor is glutaric
anhydride, R.sup.x is (CH.sub.2).sub.3--CO.sub.2H, the catalyst is
4-dimethylaminopyridine, the base for the first step is pyridine,
the solvent for the first step is pyridine, the reaction mixture in
the first step is stirred at about 60.degree. C., the solvent for
the hydrolysis is diisopropyl ether:phosphate buffer 1:2, the
enzyme is CAL-B, the hydrolysis reaction is stirred at about
30.degree. C., and e-2 is removed by extraction in a basic aqueous
layer.
[0618] In certain embodiments, the enantiomeric excess (% ee) of
the product is about 50 to 100, about 75 to 100, about 90 to 100,
about 95 to 100, about 98 to 100, about 98.5 to 100, about 98.5 to
99, about 99 to 100, about 99.5 to 100, about 99.9 to 100.
[0619] T. Classical Resolution of c-1a
##STR00095##
[0620] In certain embodiments, c-1a is resolved via a classical
resolution process. In this process, c-1a, an acid, and a solvent
are combined.
[0621] In certain embodiments, the acid is selected from the group
consisting of: [0622] single enantiomers of carboxylic acids
including but not limited to: naproxen, phenyl succinic acid, malic
acid, 2-phenylpropionic acid, alpha-methoxy-phenyl acetic acid,
tartranilic acid, 3-phenyllactic acid, .alpha.-hydroxyisovaleric
acid, 2'-methoxy-tartranilic acid, (alpha-methylbenzyl)phthalamic
acid, 2'-chloro-tartranilic acid, pyroglutamic acid; [0623] single
enantiomers of mandelic acid derivatives including but not limited
to: mandelic acid, 2-chloromandelic acid, 4-bromo-mandelic acid,
O-acetyl mandelic acid, 4-methyl-mandelic acid; [0624] single
enantiomers of sulfonic acids including but not limited to: camphor
sulfonic acid; [0625] single enantiomers of tartaric acid
derivatives including but not limited to: tartaric acid, dibenzoyl
tartaric acid hydrate, di-p-anisoyltartaric acid, di-toluyltartaric
acid, dibenzoyl tartaric acid hydrate; [0626] single enantiomers of
phosphoric acid derivatives including but not limited to:
phencyphos hydrate, chlocyphos, anisyphos, BINAP phosphate; and
[0627] single enantiomers of amino acids including but not limited
to: N-acetyl-phenylalanine, N-acetyl-leucine, N-acetyl-proline,
boc-phenylalanine, and boc-homophenylalanine.
[0628] In some embodiments, the acid is (S)-Naproxen or
S-(+)-mandelic acid. In particular embodiments, the acid is
(S)-Naproxen. In particular embodiments, the acid is S-(+)-mandelic
acid.
[0629] In certain embodiments, the solvent is water, acetonitrile,
ethanol, isopropanol, methyl ethyl ketone, isopropyl acetate,
dioxane, a mixture of water and a water-miscible organic solvents
such as ethanol and isopropanol, an halogenated solvent such as
dichloromethane and chloroform. In particular embodiments, the
solvent is water or isopropanol or a mixture thereof. In particular
embodiments, the solvent is water. In particular embodiments, the
solvent is isopropanol.
[0630] In certain embodiments, the reaction is stirred at 0 to
120.degree. C., 2 to 120.degree. C., 50 to 120.degree. C., 80 to
120.degree. C., about 100.degree. C. In certain embodiments, the
reaction is stirred at about 20.degree. C.
[0631] In certain embodiments, the product is extracted and
optionally purified by any suitable technique known in the art,
such as, but not limited to solvent extraction, chromatography,
crystallization or a combination thereof.
[0632] In certain embodiments, dd-1 precipitates out of solution
and is filtered. The solid may be further recrystallized in a
solvent such as isopropanol.
[0633] In particular embodiments, removal of the solvent by
evaporation yields a mixture of dd-1 and dd-2. The mixture is
suspended in a solvent.
[0634] In certain embodiments, dd-1 is selectively
recrystallized.
[0635] In certain embodiments, the solvent is water, acetonitrile,
ethanol, isopropanol, methyl ethyl ketone, isopropyl acetate,
dioxane; a mixture of water and water-miscible organic solvents
such as ethanol and isopropanol, or a halogenated solvent such as
dichloromethane or chloroform. In particular embodiments, the
solvent is a mixture of methyl ethyl ketone and water.
[0636] In certain embodiments, the mixture is stirred at about 0 to
100.degree. C., about 20 to 80.degree. C., about 40 to 60.degree.
C.
[0637] In certain embodiments, the mixture is allowed to cool to
room temperature and the solid is isolated by filtration, dried and
recrystallized from 10% water in methyl ethyl ketone to provide
enantioenriched dd-1.
[0638] In particular embodiments, the acid is S-(+)-mandelic acid
or (S)-Naproxen, the solvent is water or isopropanol, the reaction
is stirred at about 0 to about 20.degree. C., and dd-1 the product
is isolated by solvent extraction, chromatography, crystallization
or a combination thereof.
[0639] In particular embodiments, the acid is S-(+)-mandelic acid,
the solvent is isopropanol, the reaction is stirred at about
20.degree. C., and dd-1 precipitates out of solution.
[0640] In particular embodiments, the acid is the acid is
(S)-Naproxen, the solvent is water, the reaction is stirred at
about 20.degree. C., and dd-1 is selectively recrystallized in a
mixture of methyl ethyl ketone and water.
[0641] In certain embodiments, the enantiomeric excess (% ee) of
the product is about 50 to 100, about 75 to 100, about 90 to 100,
about 95 to 100, about 98 to 100, about 98.5 to 100, about 98.5 to
99, about 99 to 100, about 99.5 to 100, about 99.9 to 100.
[0642] U. Allylic Amination
##STR00096##
[0643] In certain embodiments, an allylic amination process for
obtaining g-1x is provided. In this process, a ligand and a
catalyst are mixed in degassed solvent, followed by addition of
f-1x, a base and a nucleophile.
[0644] In certain embodiments, the ligand is absent,
tricyclohexylphosphine, 1,3-bis(diphenylphosphino)propane;
1,2-bis(diphenylphosphino)ethane, triphenylphosphine or
1,1'-bis(diphenylphosphino)fenocene. In particular embodiments, the
ligand is triphenylphosphine.
[0645] In certain embodiments, the catalyst is a Palladium catalyst
such as Pd(OAc).sub.2, PdCl.sub.2(PPh.sub.3),
Pd(tBu.sub.2Ph).sub.2Cl.sub.2,
Tris(dibenzylideneacetone)dipalladium (0) and
Pd(amphos).sub.2Cl.sub.2. In particular embodiments, the catalyst
is Tris(dibenzylideneacetone)dipalladium (0).
[0646] In certain embodiments, the solvent is an ether such as
dimethoxyethane, THF or MeTHF, an aromatic solvent such as toluene
and benzene. In particular embodiments, the solvent is THF.
[0647] In certain embodiments, the base is potassium isopropoxide,
cesium hydroxide, Hunig's base or a carbonate base such as cesium
carbonate, potassium carbonate and sodium carbonate. In particular
embodiments, the base is cesium carbonate.
[0648] In certain embodiments, the nucleophile is a phthalamide
such as potassium phthalamide, an azide such as sodium azide or
TMS-azide, an amine such as benzylamine or dibenzylamine, a
carboxylate such as di-tert-butyl iminodicarboxylate. In particular
embodiments, the nucleophile is di-tert-butyl
iminodicarboxylate.
[0649] In certain embodiments, about 1 equivalent of nucleophile is
added.
[0650] In certain embodiments, the reaction is stirred at about 20
to 80.degree. C., about 30 to 70.degree. C., about 40 to 60.degree.
C., about 50.degree. C.
[0651] In certain embodiments, the mixture is heated to about
50.degree. C. for approximately 18 h.
[0652] In certain embodiments, the product formed is extracted and
optionally purified by any suitable technique known in the art,
such as, but not limited to solvent extraction, chromatography,
crystallization or a combination thereof.
[0653] In certain embodiments, the mixture is cooled and water and
ethyl acetate are added. The layers are separated and the organic
phase is washed with ethyl acetate. The combined organics are
concentrated to dryness. The residue is purified by silica gel
column chromatography (0 to 40% ethyl acetate in hexane). The
isolated material is dissolved in MeTHF, washed with 5% aq. KOH,
concentrated, and purified by silica gel column chromatography (0
to 10% methanol in dichloromethane) to provide g-1x.
[0654] In particular embodiments, the ligand is triphenylphosphine,
the catalyst is a palladium cataloyst, the solvent is an ether, the
base is a carbonate base, the nucleophile is di-tert-butyl
iminodicarboxylate, and the reaction is stirred at about 20 to
about 80.degree. C.
[0655] In particular embodiments, the ligand is triphenylphosphine,
the catalyst is Tris(dibenzylideneacetone)dipalladium (0), the
solvent is THF, the base is cesium carbonate, the nucleophile is
di-tert-butyl iminodicarboxylate, and the reaction is stirred at
about 50.degree. C.
[0656] V. Hydrogenation
##STR00097##
[0657] In certain embodiments, a hydrogenation process for
obtaining h-1x is provided. In this process, g-1x and a catalyst
are combined in a solvent, followed by addition of a source of
hydrogen.
[0658] In certain embodiments, the catalyst is a platinum catalyst
such as PtO.sub.2, a palladium catalyst, a nickel catalyst such as
Raney Nickel, a rhodium catalyst such as RhCl(PPh.sub.3).sub.3, a
ruthenium catalyst such as Nyori's catalyst, or an iridium catalyst
such as Crabtree's catalyst. In some embodiments, the catalyst is
selected form the group consisting of Pd/C, PtO.sub.2, Raney
Nickel, RhCl(PPh.sub.3).sub.3, Nyori's catalyst, and Crabtree's
catalyst. In particular embodiments, the catalyst is PtO.sub.2.
[0659] In certain embodiments, the solvent is a polar aprotic
solvent such as THF, 2-MeTHF, dioxane, diethyl ether, diisopropyl
ether, DME, MTBE, CPME, EtOAc and DCM or a polar protic solvent
such as methanol, isopropanol, ethanol, and n-butanol. In
particular embodiments, the solvent is isopropanol.
[0660] In certain embodiments, the reaction is stirred at about 0
to 65.degree. C., about 5 to 55.degree. C., about 10 to 45.degree.
C., about 10 to 35.degree. C., or about 15 to 25.degree. C.
[0661] In certain embodiments, the source of hydrogen is formic
acid, hydrazine, dihydronapthalene, dihydroanthracene, H.sub.2 gas
or Hantzch ester and isopropanol. In particular embodiments, the
source of hydrogen is H.sub.2 gas. In particular embodiments, the
source of hydrogen is an atmosphere of hydrogen.
[0662] In certain embodiments, the reaction is stirred for 1 to 48
h, 6 to 24 h, 10 to 20 h, 16 to 20 h, or about 18 h.
[0663] In certain embodiments, h-1x is extracted and optionally
purified by any suitable technique known in the art, such as, but
not limited to solvent extraction, chromatography, crystallization
or a combination thereof.
[0664] In certain embodiments, the mixture is filtered through
celite and used without further purification in the subsequent
deprotection.
[0665] In particular embodiments, the catalyst is a platinum
catalyst, the solvent is a polar protic solvent, the reaction is
stirred at about 5 to 55.degree. C., and the source of hydrogen is
H.sub.2 gas.
[0666] In particular embodiments, the catalyst is PtO.sub.2, the
solvent is isopropanol, the reaction is stirred at about 15 to
25.degree. C., and the source of hydrogen is H.sub.2 gas.
[0667] W. Deprotection
##STR00098##
[0668] In certain embodiments, a deprotection process for obtaining
N-1x is provided. In this process, h-1x is added to an acid in a
solvent.
[0669] In certain embodiments, the acid is a sulfonic acid such as
methanesulfonic acid, p-toluenesulfonic acid and camphorsulfonic
acid, an inorganic acid such as phosphoric acid, hydrochloric acid
and sulfuric acid, a carboxylic acid such as trifluoroacetic acid,
oxalic acid and benzoic acid. In particular embodiments, the acid
is anhydrous hydrochloric acid.
[0670] In certain embodiments, the solvent is an alcoholic solvent
such as methanol, isopropanol and ethanol, or a polar aprotic
solvent such as dioxane, acetonitrile and dichloromethane, or
water. In certain embodiments, the solvent is an alcoholic solvent.
In certain embodiments, the solvent is a polar aprotic solvent. In
certain embodiments, the solvent is water. In certain embodiments,
the solvent is methanol, isopropanol, ethanol, dioxane,
acetonitrile, dichloromethane, or water. In particular embodiments,
the solvent is isopropanol.
[0671] In certain embodiments, the reaction is stirred at about 0
to 80.degree. C., about 0 to 60.degree. C., about 5 to 45.degree.
C., about 10 to 35.degree. C., or about 15 to 25.degree. C.
[0672] In certain embodiments, about 1 to 10 equivalents, about 5
to 10 equivalents, or about 7 equivalents of acid is used.
[0673] In certain embodiments, the reaction is stirred for about 1
to 48 h, about 6 to 24 h, about 12 to 24 h, or about 18 h.
[0674] In certain embodiments, the product formed, N-1x, is
extracted and optionally purified by any suitable technique known
in the art, such as, but not limited to solvent extraction,
chromatography, crystallization or a combination thereof.
[0675] In particular embodiments, the reaction is cooled to
approximately 0.degree. C. and the product N-1x is collected by
filtration.
[0676] In particular embodiments, the acid is an inorganic acid,
the solvent is an alcoholic solvent, and the reaction is stirred at
5 to 45.degree. C.
[0677] In particular embodiments, the acid is anhydrous
hydrochloric acid, the solvent is isopropanol, and the reaction is
stirred at 15 to 25.degree. C.
EXAMPLES
[0678] In order for this invention to be more fully understood, the
following examples are set forth. These examples are for the
purpose of illustrating embodiments, and are not to be construed as
limiting the scope of this disclosure in any way. The reactants
used in the examples below may be obtained either as described
herein, or if not described herein, are themselves either
commercially available or may be prepared from commercially
available materials by methods known in the art.
[0679] In one embodiment, a multi-step synthetic method for
preparing a compound of Formula I is provided, as set forth below.
In certain embodiments, each of the individual steps of the Schemes
set forth below is provided. Examples and any combination of two or
more successive steps of the below Examples are provided.
[0680] A. Acylation and Amidation of Meldrum's Acid to Form
C-1a:
##STR00099##
[0681] In a reaction vessel, Meldrum's acid (101 g, 1.0 equivalent)
and 4-dimethylaminopyridine (1.8 g, 0.2 equivalents) were combined
with acetonitrile (300 mL). The resulting solution was treated with
methoxyacetic acid (6.2 mL, 1.2 equivalents). Triethylamine (19.4
mL, 2.0 equivalents) was added slowly to the resulting solution,
followed by pivaloyl chloride (9.4 mL, 1.1 equivalents). The
reaction was then heated to about 45 to about 50.degree. C. and
aged until consumption of Meldrum's acid was deemed complete.
[0682] A separate reaction vessel was charged with acetonitrile (50
mL) and J-1a (13.4 g, 1.2 equivalents). The resulting solution was
treated with trifluoroacetic acid (8.0 mL, 1.5 equivalents), and
then this acidic solution was added to the acylation reaction in
progress at about 45 to about 50.degree. C.
[0683] The reaction was allowed to age for at least 18 hours at
about 45 to about 50.degree. C., after which time the solvent was
removed under reduced pressure. The crude residue was dissolved in
ethyl acetate (150 mL), and the organic layer was washed with
water. The combined aqueous layers were extracted with ethyl
acetate. The combined organic layers were washed with saturated
sodium bicarbonate solution, and the combined bicarbonate washes
were back extracted with ethyl acetate. The combined organic layers
were dried over magnesium sulfate, filtered, and concentrated under
reduced pressure. The resulting crude material was purified twice
via silica gel chromatography to yield C-1a.
[0684] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.12 (br, 1H),
6.66 (app t, J=8.1 Hz, 2H), 4.50 (app d, J=5.7 Hz, 2H), 4.08 (s,
2H), 3.44 (s, 2H), 3.40 (s, 3H). .sup.13C NMR (100 MHz,
CDCl.sub.3): .delta. 203.96, 164.90, 162.37 (ddd, J=250.0, 15.7,
15.7 Hz), 161.71 (ddd, J=250.3, 14.9, 10.9 Hz), 110.05 (ddd,
J=19.7, 19.7, 4.7 Hz), 100.42 (m), 77.58, 59.41, 45.71, 31.17 (t,
J=3.5 Hz). LCMS, Calculated: 275.23. Found: 275.97 (M).
[0685] B. Alkylation of C-1a to Form E-1a:
##STR00100##
[0686] A solution of C-1a (248 mg, 1.0 equivalent) and 2-methyl
tetrahydrofuran (1.3 mL) was treated with N,N-dimethylformamide
dimethylacetal (0.1 mL, 1.1 equivalent) and stirred at room
temperature overnight (.about.14 hours). The reaction was treated
with aminoacetaldehyde dimethyl acetal (0.1 mL, 1.0 equivalents),
and was allowed to age for about 2 hours, and then was quenched via
the addition of 2 N HCl (1.5 mL).
[0687] The reaction was diluted via the addition of ethyl acetate,
and phases were separated. The aqueous layer was extracted with
ethyl acetate. The combined organic layers were washed with brine,
dried over magnesium sulfate, filtered, and concentrated under
reduced pressure. The crude residue was purified via silica gel
chromatography to yield E-1a.
[0688] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 10.85 (s, 1H),
9.86 (s, 1H), 8.02 (d, J=13.1 Hz, 1H), 6.65 (dd, J=8.7, 7.7 Hz,
2H), 4.53 (d, J=3.9 Hz, 2H), 4.40 (t, J=5.1 Hz, 1H), 4.18 (s, 2H),
3.42 (s, 6H), 3.39 (m, 2H), 3.37 (s, 3H). .sup.13C NMR (100 MHz,
CDCl.sub.3): .delta. 193.30, 169.15, 162.10 (ddd, J=248.9, 15.5,
15.5 Hz), 161.7 (ddd, J=250.0, 14.9, 11.1 Hz), 161.66, 111.08 (ddd
J=19.9, 19.9, 4.7 Hz) 103.12, 100.29 (ddd, J=28.1, 17.7, 2.3 Hz),
76.30, 58.83, 54.98, 53.53, 51.57, 29.89 (t, J=3.3 Hz). LCMS,
Calculated: 390.36. Found: 390.92 (M).
[0689] C. Cyclization of E-1a to Form F-1a:
##STR00101##
[0690] E-1a (0.2 g, 1.0 equivalent), dimethyl oxalate (0.1 g, 2.5
equivalents) and methanol (1.5 mL) were combined and cooled to
about 0 to about 5.degree. C. Sodium methoxide (0.2 mL, 30%
solution in methanol, 1.75 equivalents) was introduced to the
reaction slowly while keeping the internal temperature of the
reaction below about 10.degree. C. throughout the addition. After
the addition was completed the reaction was heated to about 40 to
about 50.degree. C. for at least 18 hours.
[0691] After this time had elapsed, the reaction was diluted with 2
N HCl (1.5 mL) and ethyl acetate (2 mL). The phases were separated,
and the aqueous phase was extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over
magnesium sulfate, filtered, and solvent was removed under reduced
pressure. The resulting crude oil was purified via silica gel
chromatography to afford F-1a.
[0692] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 10.28 (t, J=5.5
Hz, 1H), 8.38 (s, 1H), 6.66-6.53 (m, 2H), 4.58 (d, J=5.6 Hz, 2H),
4.43 (t, J=4.7 Hz, 1H), 4.00 (d, J=4.7 Hz, 2H), 3.92 (s, 3H), 3.88
(s, 3H), 3.32 (s, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3): .delta.
173.08, 163.81, 162.17, 162.14 (ddd, J=249.2, 15.6, 15.6 Hz),
161.72 (ddd, J=250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98,
119.21, 110.53 (ddd, J=19.8, 4.7, 4.7 Hz), 102.70, 100.22 (m),
60.68, 56.75, 55.61, 53.35, 30.64. LCMS, Calculated: 458.39. Found:
459.15 (M+H).
[0693] D. Alkylation and Cyclization of C-1a to Form F-1a:
##STR00102##
[0694] To a reaction vessel were added C-1a (245 mg, 1.0
equivalent) and N,N-dimethylformamide dimethylacetal (0.5 mL, 4.3
equivalent). The reaction mixture was agitated for approximately 30
minutes. The reaction was then treated with 2-methyl
tetrahydrofuran (2.0 mL) and aminoacetaldehyde dimethyl acetal (0.1
mL, 1.0 equivalent). The reaction was allowed to age for several
hours and then solvent was removed under reduced pressure.
[0695] The resulting material was dissolved in methanol and
dimethyl oxalate was added (0.3 g, 2.5 equivalents). The reaction
mixture was cooled to about 0 to about 5.degree. C., and then
sodium methoxide (0.4 mL, 30% solution in methanol, 1.75
equivalents) was introduced to the reaction slowly. After the
addition was completed the reaction was heated to about 40 to about
50.degree. C.
[0696] After this time had elapsed, the reaction was cooled to room
temperature and quenched via the addition of 2 N HCl (1.5 mL). The
reaction was then diluted with ethyl acetate, and the resulting
phases were separated. The aqueous layer was extracted with ethyl
acetate. The combined organic layers were dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. The
crude residue was purified via silica gel chromatography to yield
F-1a.
[0697] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 10.28 (t, J=5.5
Hz, 1H), 8.38 (s, 1H), 6.66-6.53 (m, 2H), 4.58 (d, J=5.6 Hz, 2H),
4.43 (t, J=4.7 Hz, 1H), 4.00 (d, J=4.7 Hz, 2H), 3.92 (s, 3H), 3.88
(s, 3H), 3.32 (s, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3): .delta.
173.08, 163.81, 162.17, 162.14 (ddd, J=249.2, 15.6, 15.6 Hz),
161.72 (ddd, J=250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98,
119.21, 110.53 (ddd, J=19.8, 4.7, 4.7 Hz), 102.70, 100.22 (m),
60.68, 56.75, 55.61, 53.35, 30.64. LCMS, Calculated: 458.39. Found:
459.15 (M+H).
[0698] E. Condensation of F-1a with N-1a to Form G-1a:
##STR00103##
[0699] To a reaction vessel were added F-1a (202 mg, 1.0
equivalent) and acetonitrile (1.4 mL). The resulting solution was
treated with glacial acetic acid (0.2 mL, 6.0 equivalents) and
methane sulfonic acid (0.01 mL, 0.3 equivalents). The reaction was
then heated to about 70 to about 75.degree. C.
[0700] After 3 hours, a solid mixture of N-1a (0.128 g, 1.5
equivalents) and potassium carbonate (0.2 g, 2.7 equivalents) was
introduced to the reaction at about 70 to about 75.degree. C. After
the addition was completed, the reaction was allowed to progress
for at least about 1 hour.
[0701] After this time had elapsed, water (1.4 mL) and
dichloromethane (1.4 mL) were introduced to the reaction. The
phases were separated, and the aqueous layer was extracted with
dichloromethane. The combined organic layers were dried over
magnesium sulfate, then were filtered and concentrated under
reduced pressure. The resulting crude material was purified via
silica gel chromatography to obtain G-1a.
[0702] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 10.23 (t, J=5.5
Hz, 1H), 8.39 (s, 1H), 6.60 (t, J=8.1 Hz, 2H), 5.29 (dd, J=9.5, 3.7
Hz, 2H), 4.57 (d, J=5.4 Hz, 3H), 4.33 (dd, J=12.8, 3.8 Hz, 1H),
4.02-3.87 (m, 1H), 3.94 (s, 3H), 2.06-1.88 (m, 4H), 1.78 (dd,
J=17.2, 7.5 Hz, 1H), 1.55-1.46 (m, 1H). .sup.13C NMR (100 MHz,
CDCl.sub.3): .delta. 174.53, 163.75, 162.33 (dd, J=249.4, 15.7,
15.7 Hz), 161.86 (ddd, J=250.4, 14.9, 10.9 Hz), 154.18, 154.15,
142.44, 129.75, 118.88, 110.58 (ddd, J=19.8, 4.7, 4.7 Hz), 100.42
(m), 77.64, 74.40, 61.23, 54.79, 51.13, 38.31, 30.73, 29.55, 28.04.
LCMS, Calculated: 463.14. Found: 464.15 (M+H).
[0703] F. Deprotection of G-1a to Form a Compound of Formula
Ia:
##STR00104##
[0704] G-1a (14 g) was suspended in acetonitrile (150 mL) and
dichloromethane (150 mL). MgBr.sub.2 (12 g) was added. The reaction
was heated to 40 to 50.degree. C. for approximately 10 min before
being cooled to room temperature. The reaction was poured into 0.5M
HCl (140 mL) and the layers separated. The organic layer was washed
with water (70 mL), and the organic layer was then concentrated.
The crude product was purified by silica gel chromatography (100%
dichloromethane up to 6% ethanol/dichloromethane) to afford Ia.
[0705] G. Hydrolysis of F-1a to Form II-a:
##STR00105##
[0706] To a reaction vessel were added F-1a (480 mg, 1.0 equiv.),
methanol (5.8 mL) and water (2.4 mL). To the resulting homogeneous
solution, lithium hydroxide monohydrate (88 mg, 2.0 equiv.) is
added. The resulting suspension was stirred at room temperature for
about 17 hours.
[0707] Water (15 mL) and ethyl acetate were added, then 1N HCl was
added dropwise until the pH was about 3. The layers were mixed and
separated, the aqueous layer extracted with ethyl acetate (15 mL),
and the combined organic layers dried over Na.sub.2SO.sub.4. The
organic layer was removed by evaporation. The aqueous layer was
then brought to pH <2, and extracted twice with ethyl acetate
(2.times.15 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, mixed with the residue from the previous
extraction and the solvent was removed by evaporation. The residue
was taken up in MTBE (2.4 mL), to form a slurry, which was filtered
and washed with MTBE to provide 1002.
[0708] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 10.43 (t, J=5.2
Hz, 1H), 9.65 (bs, 1H), 8.52 (s, 1H), 6.67 (t, J=8.0 Hz, 2H), 4.67
(d, J=6.0 Hz, 2H), 4.58 (t, J=4.8 Hz, 1H), 4.16 (d, J=4.8 Hz, 1H),
3.91 (s, 3H), 3.37 (s, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3):
.delta. 173.04, 164.15, 162.10, 148.63, 145.28, 137.25, 118.66,
102.46, 100.35 (t, J=30.7 Hz), 87.42, 61.30, 57.09, 55.55,
30.94.
[0709] H. Preparation of BB-1a from B-1a:
##STR00106##
[0710] To a reaction vessel was added B-1a (0.2 g, 1.0 equivalent)
and 3-pentanone (1.0 mL, 10.0 equivalents). These compounds were
then dissolved in toluene (1.0 mL) and heated to about 110 to about
115.degree. C. The reaction was maintained at this temperature for
about 4 hours, after which time the reaction was cooled to room
temperature and solvent was removed. The resulting crude material
was purified over silica gel to afford BB-1a.
[0711] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 5.46 (t, J=1.1
Hz, 1H), 3.97 (d, J=1.0 Hz, 2H), 3.42 (s, 3H), 1.99 (m, 4H), 0.98
(t, J=7.5 Hz, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3): .delta.
167.63, 160.94, 111.05, 93.04, 70.07, 59.27, 28.08, 7.40. LCMS,
Calculated: 200.10. Found 200.79 (M.sup.+).
[0712] I. Preparation of C-1a from BB-1a:
##STR00107##
[0713] To a reaction vessel was added BB-1a (0.08 g, 1.0
equivalent) and N-1a (0.08 g, 1.1 equivalents). These compounds
were then dissolved in toluene (1.5 mL) and heated to about
115.degree. C. After about 1 h, the reaction was cooled and solvent
was removed. The resulting crude material was purified via silica
gel chromatography to obtain C-1a.
[0714] All spectral data collected for C-1a matched that provided
above.
[0715] J. Formation of B-1a.J-1a Salt:
##STR00108##
[0716] The free acid of B-1a (4.4 g) was dissolved in 50 mL
acetonitrile and J-1a (3.3 g, 1.0 equivalent) in 30 mL acetonitrile
was added. The desired salt was obtained and was aged for about one
hour at room temperature. The solids were filtered and the cake was
rinsed with 2.times.10 mL acetonitrile to afford the product.
[0717] .sup.1H NMR (400 MHz, DMSO-d.sup.6) .delta. 7.40 (bs, 3H),
6.11 (t, J=7.7 Hz, 2H), 3.12 (s, 2H), 2.92 (s, 2H), 2.08 (s, 3H),
0.35 (s, 6H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) .delta. 191.98,
164.66, 163.06 (dt, J=248.6, 16.2 Hz), 161.82 (ddd, J=250.4, 15.8,
10.4 Hz), 107.39 (td, J=20.0, 4.7 Hz), 101.16 (m), 100.01, 87.01,
77.71, 58.39, 30.45, 26.37.
[0718] K. Formation of B-1a.J-1a Salt:
##STR00109##
[0719] Meldrum's acid (10.1 g, 1.1 equivalents) and DMAP (0.6 g,
0.08 equivalents) were dissolved in 300 mL acetonitrile.
Methoxyacetic acid (5.8 g, 1 equivalents) and 17.6 g (2.1
equivalents) Hunig's base were added. The solution was warmed to
about 45.degree. C. and 8.4 g (1.1 equivalents) of pivaloyl
chloride in 30 mL of acetonitrile was added over about 1 hour.
[0720] After about 2.5 hours at about 45.degree. C., the solution
was cooled to room temperature and was concentrated under vacuum.
The resulting oil was dissolved in 110 mL dichloromethane, cooled
over ice bath, and extracted with 50 mL 1N HCl. The layers were
separated, and the aqueous layer was extracted with 40 mL
dichloromethane. The combined organic layer was concentrated and
diluted in acetonitrile and evaporated again. The material was
dissolved in 220 mL acetonitrile.
[0721] After cooling over an ice bath, trifluorobenzylamine (11.4
g, 1.1 equivalents) and the mixture at about 9.degree. C. was
allowed to warm up to room temperature and agitated as the slurry
thickened. After about 2 hours, 220 mL MTBE was added slowly and
the slurry was aged overnight. The slurry was cooled over ice bath
for about 3 hours and was filtered, rinsed with 50 mL cold 1:1
acetonitrile/MTBE, and dried overnight in a vacuum oven to afford
the product.
[0722] L. Amidation Using the B-1a.J-1a Salt to Form C-1a
##STR00110##
[0723] The salt B-1a.J-1a (3.7 g, 1.0 equivalent) was suspended in
50 mL of acetonitrile, and then was treated with trifluoroacetic
acid (0.1 mL, 0.1 equivalent). The reaction was heated to about 40
to about 50.degree. C. for approximately 18 hours, and then cooled
to room temperature. Solvent was removed under reduced pressure,
and the resulting residue was suspended in 5 volumes of 2-methyl
tetrahydrofuran and 5 volumes of hexanes were added dropwise over 1
h. The resulting mixture was allowed to stir for at least 24 hours,
and then the resulting slurry was filtered to afford the
product.
[0724] M. Amidation of B-1a.J-1a to C-1a:
##STR00111##
[0725] B-1a.J-1a (75.077 g, 198.97 mmol, 1.0 equivalent),
acetonitrile (750 mL), and trifluoroacetic acid (1.5 mL, 20 mmol,
0.1 equiv) were combined in a reactor. The reactor was heated until
the internal temperature reached about 58.degree. C., and the
reactor contents were aged between about 58-61.degree. C. for about
3.5 hours. The jacket temperature was then adjusted to about
45.degree. C. and vacuum was applied. The reactor contents were
distilled until about 150 mL remained. iso-Propylacetate (300 mL)
was then charged to the reactor, and distillation was continued
until the volume reached about 150 mL. iso-Propylacetate (150 mL)
was then charged to the reactor, the jacket temperature was
adjusted to about 20.degree. C., and contents were allowed to reach
an internal temperature of <25.degree. C. A wash solution (22.8%
NaCl, 1.5% H.sub.2SO.sub.4, 75.7% water, 300 mL) was charged to the
reactor, and the contents were agitated for about 30 minutes. The
bottom phase was separated, and a second wash solution (22.8% NaCl,
1.5% H.sub.2SO.sub.4, 75.7% water, 300 mL) was charged to the
reactor. After agitating for about 15 minutes, the bottom phase was
separated, and 20% aqueous NaCl (300 mL) was charged to the reactor
and agitated for about 15 minutes. The bottom phase was separated.
Heptane (150 mL) was charged to the reactor, followed by seed (51
mg, 0.1 wt %). The mixture was aged for about 30 minutes, during
which a slurry formed. Additional heptane (450 mL) was then charged
over no less than 30 minutes. The jacket temperature was then
adjusted to about 29.degree. C., and solvent was distilled under
vacuum until the reactor contents reached a volume of about 450 mL.
The slurry was then cooled to an internal temperature of about
5.degree. C. over no less than 1 hour. The reactor contents were
discharged and solids were collected by filtration. The mother
liquors were recycled twice in order to displace solids from the
reactor, each time allowing the internal temperature to reach about
<6.degree. C. before discharging. A solution of
heptane/iso-propylacetate (75% v/v, 225 mL) was then charged to the
reactor, and when the internal temperature reached <6.degree.
C., the slurry was rinsed forward through the filter cake. The wet
cake was then dried under vacuum at about 40.degree. C. for about
18 hours, providing C-1a.
[0726] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.12 (br, 1H),
6.66 (app t, J=8.1 Hz, 2H), 4.50 (app d, J=5.7 Hz, 2H), 4.08 (s,
2H), 3.44 (s, 2H), 3.40 (s, 3H). .sup.13C NMR (100 MHz,
CDCl.sub.3): .delta. 203.96, 164.90, 162.37 (ddd, J=250.0, 15.7,
15.7 Hz), 161.71 (ddd, J=250.3, 14.9, 10.9 Hz), 110.05 (ddd,
J=19.7, 19.7, 4.7 Hz), 100.42 (m), 77.58, 59.41, 45.71, 31.17 (t,
J=3.5 Hz). LCMS, Calculated: 275.23. Found: 275.97 (M).
[0727] N. Enamine Formation of D-1a from C-1a
##STR00112##
[0728] C-1a (8.4 g, 1.0 equiv) was charged to a reactor, followed
by the addition of 2-methyltetrahydrofuran (166.7 mL, 20 volumes,
0.18 M) and trifluoroacetic acid (231.9 uL, 0.1 equiv). The
reaction mixture was heated to an internal temperature of about
40.degree. C., and DMF-DMA (3.0 mL, 0.75 equiv) was quickly added.
The reaction mixture is agitated for a few minutes, followed by the
addition of D-1a seeds (20 mgs, 0.002 equivalent) at about
40.degree. C. The heterogenous mixture was aged at 40.degree. C.
for about one hour. An additional portion of DMF-DMA was added (1.5
mL, 0.37 equivalent), and the reaction mixture was agitated for
about 25 minutes. One final portion of DMF-DMA (1.5 mL, 0.37 equiv)
was added, and the reaction mixture was cooled from about
40.degree. C. to room temperature and allowed to agitate
overnight.
[0729] The contents of the reactor were filtered, and the filter
cake was rinsed with a solvent combination of
2-methyltetrahydrofuran and heptanes (67.1 mL, 8 volumes) to
provide D-1a. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.34 (br,
1H), 7.83 (s, 1H), 6.63 (m, 2H), 4.53 (s, 2H), 4.12 (s, 2H), 3.34
(s, 3H), 3.10 (s, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3): .delta.
192.33, 165.85, 163.03, 160.54, 158.00, 110.89, 103.50, 100.05,
76.11, 58.77, 44.74, 30.61. LCMS, Calculated: 330.12. Found: 330.91
(M).
[0730] O. Condensation and Cyclization of D-1a to Form F-1a Via
E-1a
##STR00113##
[0731] D-1a (70.0 g, 212 mmol, 1.0 equivalent) was charged to an
inerted 1 L reactor. To this reactor was then charged methanol (420
mL, 6 volumes) and aminoacetaldehyde dimethylacetal (1, 28.8 mL,
233 mmol, 1.1 equivalent). The reactor jacket temperature was
maintained between about 16 and 23.degree. C.
[0732] After aging the reaction for about 1-2 hours, dimethyl
oxalate (2, 125 g, 1.06 mol, 5.0 equivalents) was charged to the
reactor and the reactor jacket temperature was increased to between
about 42-48.degree. C. Upon achieving complete dissolution of
dimethyl oxalate, the reactor was charged with sodium methoxide as
a solution in methanol (84.7 g, 25 wt %, 197 mmol, 1.85
equivalents). The reactor jacket temperature was maintained between
about 42-48.degree. C. for about 14-18 h.
[0733] Reactor jacket temperature was reduced to about
34-37.degree. C. over the course of about 1 h. Upon reaching a
stable temperature in this range, the reactor was charged with F-1a
seed crystals (0.350 g, ca. 0.5 wt %) and allowed to age for about
1-2 h. At this point, water (420 mL, 6 volumes) was charged to the
reactor over the course of about 2-3 hours. The reactor jacket
temperature was reduced to about 18-22.degree. C. over about 1
h.
[0734] The resulting slurry was discharged from the reactor, and
the solids collected by filtration. Liquors were recycled to
displace solids remaining in the reactor. The collected solids on
the filter were then washed with a 1:1 mixture of water and
methanol (420 mL, 6 volumes), followed by water (420 mL, 6 V). The
collected wet cake was dried in a vacuum oven at about
36-42.degree. C. for about 16 h, providing F-1a.
[0735] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 10.28 (t, J=5.5
Hz, 1H), 8.38 (s, 1H), 6.66-6.53 (m, 2H), 4.58 (d, J=5.6 Hz, 2H),
4.43 (t, J=4.7 Hz, 1H), 4.00 (d, J=4.7 Hz, 2H), 3.92 (s, 3H), 3.88
(s, 3H), 3.32 (s, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3): .delta.
173.08, 163.81, 162.17, 162.14 (ddd, J=249.2, 15.6, 15.6 Hz),
161.72 (ddd, J=250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98,
119.21, 110.53 (ddd, J=19.8, 4.7, 4.7 Hz), 102.70, 100.22 (m),
60.68, 56.75, 55.61, 53.35, 30.64. LCMS, Calculated: 458.39. Found:
459.15 (M+H).
[0736] P. Acetal hydrolysis of F-1a to form FF-1a:
##STR00114##
[0737] To a solution of F-1a (10.0 g, 1.0 equivalent) and
acetonitrile (50 mL) was added p-Toluenesulfonic acid monohydrate
(0.414 g, 0.10 equivalent) and acetic acid (16.3 mL, 12
equivalent). The reaction was then heated to about 75.degree. C.
and aged for about 8-10 hours. Once the reaction completion was
confirmed by HPLC, the reaction was cooled to room temperature and
water (60 mL) was added. The mixture was then concentrated under
reduced pressure to remove acetonitrile. The resultant slurry was
then aged at room temperature for about 2 hours, filtered, washed
with water (2.times.30 mL). The cake was dried in vacuum oven at
about 50.degree. C. for about 10 hours to give FF-1a.
[0738] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.34 (t, J=8.0
Hz, 1H), 8.45 (s, 1H), 7.19 (m, 2H), 6.37 (m, 2H), 4.96 (m, 1H),
4.55 (d, J=4.0 Hz, 2H), 3.95 (m, 2H), 3.93 (s, 3H). 3.79 (s, 3H).
.sup.13C NMR (100 MHz, DMSO-d.sub.6): .delta. 172.32, 163.47,
162.10, 161.93 (dt, J=246, 15.0 Hz), 161.41 (ddd, J=247, 15.0, 11.0
Hz), 148.01, 145.57, 135.84, 118.32, 111.48 (td, J=20.0, 5.0 Hz),
101.17 (m), 87.99, 60.55, 60.50, 53.98, 30.37. LCMS, Calculated:
431.1061. Found: 431.1062 (M+H).
[0739] Q. Cyclization of FF-1a and N-1a.BzOH to Form G-1a
##STR00115##
[0740] FF-1a (90.0 g, 1.0 equiv), N-1a.BzOH (60.7 g, 1.3 equiv),
and potassium acetate (51.3 g, 2.5 equiv) were charged to a
reactor. Dichloromethane (DCM, 1.1 L) was charged and the mixture
was agitated at about 20.degree. C. until the reaction is complete.
A 5% aqueous NaHCO.sub.3 solution (540 mL) was charged to the
reactor and the mixture was agitated until the solids completely
dissolve. The phases were separated and the bottom organic phase
was charged back to the reactor. Water (450 mL) was charged to the
reactor and the mixture was agitated for about 15 minutes. The
phases were separated and the organic phase was distilled to
dryness.
[0741] The crude G-1a was dissolved in dimethylformamide (DMF, 180
mL) and the resulting solution was charged to a reactor containing
water (1.1 L) over about 2 hours, while agitating the water. The
product slurry was aged at about 20.degree. C. for about 12 hours
and then filtered. The product cake was washed with water (360 mL)
and dried to afford G-1a.
[0742] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 10.23 (t, J=5.5
Hz, 1H), 8.39 (s, 1H), 6.60 (t, J=8.1 Hz, 2H), 5.29 (dd, J=9.5, 3.7
Hz, 2H), 4.57 (d, J=5.4 Hz, 3H), 4.33 (dd, J=12.8, 3.8 Hz, 1H),
4.02-3.87 (m, 1H), 3.94 (s, 3H), 2.06-1.88 (m, 4H), 1.78 (dd,
J=17.2, 7.5 Hz, 1H), 1.55-1.46 (m, 1H). .sup.13C NMR (100 MHz,
CDCl.sub.3): .delta. 174.53, 163.75, 162.33 (dd, J=249.4, 15.7,
15.7 Hz), 161.86 (ddd, J=250.4, 14.9, 10.9 Hz), 154.18, 154.15,
142.44, 129.75, 118.88, 110.58 (ddd, J=19.8, 4.7, 4.7 Hz), 100.42
(m), 77.64, 74.40, 61.23, 54.79, 51.13, 38.31, 30.73, 29.55, 28.04.
LCMS, Calculated: 463.14. Found: 464.15 (M+H).
[0743] R. Conversion of (-)-Vince Lactam to b-1a
##STR00116##
[0744] Wet Pd/C (0.138 kg) was charged to a reactor followed by
2-MeTHF (421 kg) and (-)-Vince lactam (55 kg). The vessel was
purged with nitrogen followed by hydrogen. The contents were
adjusted to about 25 to 35.degree. C. and the hydrogen maintained
at about 0.30 to 0.35 MPa. After about 6.5 h, the reaction was
deemed complete by HPLC. The contents were filtered through celite
(11 kg) and washed with 2-MeTHF (102 kg). The product was obtained
in solution.
[0745] A solution of Boc.sub.2O in 2-MeTHF was prepared as follows:
Boc.sub.2O (123 kg) was charged to a reactor followed by 2-MeTHF
(60 kg). After a solution was achieved, it was discharged into a
container and rinsed forward with 2-MeTHF (44.6 kg) and held until
further use.
[0746] The solution of the product of the hydrogenation was charged
to a reactor and concentrated under reduced pressure to about 5 to
6 V at .ltoreq.45.degree. C. DMAP (0.34 kg) was charged and the
mixture warmed to about 45 to 50.degree. C. The solution of
Boc.sub.2O was added over approximately 2 h and the mixture allowed
to stir for an additional 2 h at the target temperature. After this
time, the reaction was deemed complete by HPLC. 2-MeTHF was charged
(480 kg) and the solution concentrated under reduced pressure to
about 4 to 5 V at about .ltoreq.45.degree. C. This process was
repeated twice more to remove t-BuOH. 2-MeTHF was charged (278.8
kg) to afford a-1a in solution.
[0747] The solution of a-1a was diluted with 2-MeTHF (405.8 kg) and
cooled to -10 to 0.degree. C. MeMgBr (35% in 2-MeTHF, 201.3 kg) was
added over approximately 6 h to maintain the temperature at about
-10 to 0.degree. C. After the addition was complete, the mixture
was stirred for an additional approximately 1 to 2 h at which time
the reaction was complete as determined by HPLC. 15% aqueous AcOH
(350 kg) was added maintaining the temperature at about 0 to
5.degree. C. to adjust the pH to approximately 7. The layers were
separated and the organic layer was washed with water twice (726 kg
total water used). The organic layer was concentrated to about 4 to
5 V under reduced pressure at about .ltoreq.45.degree. C. The
solution was azeotroped with 2-MeTHF three times to about 4 to 5 V
each time (2810 kg 2-MeTHF used). The final solution was
concentrated under reduced pressure to about 2.5 to 3 V. n-Heptane
(126 kg) was slowly added maintaining the temperature at 30 to
35.degree. C. b-1a seeds were added (0.7 kg) and the mixture
stirred at about 30 to 35.degree. C. for 5 to 10 h. Additional
n-heptane was added (200.4 kg) maintaining the temperature at about
30 to 35.degree. C. over approximately 5 h. The contents were
distilled under reduced pressure at about .ltoreq.45.degree. C. to
about 6 to 7 V. Additional n-heptane was added (243.2 kg)
maintaining the temperature at about 30 to 35.degree. C. over
approximately 1 to 2 h. The contents were distilled under reduced
pressure at about .ltoreq.45.degree. C. to about 6 to 7 V.
Additional n-heptane was added (241.4 kg) maintaining the
temperature at about 30 to 35.degree. C. over approximately 1 to 2
h. The contents were distilled under reduced pressure at about
.ltoreq.45.degree. C. to about 6 to 7 V. Additional n-heptane was
added (253.6 kg) maintaining the temperature at about 30 to
35.degree. C. over approximately 1 to 2 h. The contents were cooled
to about -5 to 0.degree. C. and held for approximately 1 to 2 h.
Product was collected by filtration, washed with n-heptane (187 kg)
at about -5 to 0.degree. C., and dried under reduced pressure at
about 40 to 45.degree. C. to afford single enantiomer b-1a.
[0748] S. Conversion of b-1a to cc-1a
##STR00117##
[0749] b-1a (90.9 kg) and toluene (822 kg) were charged to a
reactor and stirred at 25 to 30.degree. C. to achieve a solution.
m-CPBA (174 kg) was charged into the reactor in 5 portions (4 to 6
h between additions). The reaction was allowed to stir at about 25
to 30.degree. C. until the reaction was deemed complete by HPLC
(approximately 10 to 20 h). 20% NaHSO.sub.3 (428 kg) was added
maintaining the temperature about below 30.degree. C. and the
mixture stirred until negative with starch potassium iodide paper.
10% NaOH (698 kg) was added maintaining the temperature about below
30.degree. C. The mixture was stirred for approximately 30 to 60
min. The organic layer was washed with water (500 kg) and the
organic layer concentrated under reduced pressure at about
.ltoreq.45.degree. C. to 5 to 6 V. The temperature was adjusted to
15 to 25.degree. C. to afford the oxidized product in solution.
[0750] Water (90 kg), methanol (70 kg), and LiOH.H.sub.2O (29.5 kg)
were added to the solution of the oxidized product and the mixture
stirred at 25 to 30.degree. C. for 3 to 6 h at which time the
reaction was deemed complete by HPLC. Toluene (390 kg) and 25% NaCl
(278 kg) were added to the mixture and stirred for about 30 to 60
min. The layers were separated and 20% NaCl (259 kg) were added to
the organic layer. The pH of the solution was adjusted to about 7
to 8 with 1 N HCl (7.6 kg) and the layers separated. The organic
layer was washed with 20% NaCl (259.4 kg). The organic layer was
filtered and concentrated under reduced pressure at about
.ltoreq.45.degree. C. to about 4.5 to 5.5 V. Toluene (385.6 kg) was
charged and the distillation/toluene addition were repeated until
KF.ltoreq.0.05%. Toluene (385.3 kg) was charged followed by active
carbon (6.5 kg). The mixture was warmed to about 30 to 40.degree.
C. and stirred for about 2 to 6 h. The contents were cooled,
filtered through celite (6.3 kg), and washed with toluene (146 kg).
The filtrate was concentrated under reduced pressure at about
.ltoreq.45.degree. C. to about 1.5 to 1.6 V. The mixture was
stirred for about 30 to 60 min at about 30 to 35.degree. C.
n-Heptane (87 kg) was charged over about 1 to 2 h and the mixture
seeded with cc-1a (0.516 kg) and stirred for an additional 2 to 3
h. n-Heptane (286.4 kg) was slowly charged and stirred for about 2
to 3 h. The mixture was cooled to about 10 to 15.degree. C. and
stirred for an additional about 3 to 5 h. The product was collected
by filtration and washed with n-heptane (40 kg) at about 10 to
15.degree. C. The product was dried under reduced pressure at about
35 to 45.degree. C. to afford single enantiomer cc-1a.
[0751] T. Classical Resolution of c-1a
##STR00118##
[0752] A vessel was charged with c-1a (10.0 g, 1 equivalent),
(S)-Naproxen (11.5 g, 1.03 mmol) and water (200 mL). The mixture
was refluxed overnight, after which the mixture had turned dark.
Removal of the solvent by rotary evaporation yielded the desired
salt as a brown solid. The mixture of dd-2a and dd-1a (3.0 g) was
suspended in MEK (50 mL) and the mixture was heated to reflux.
Water was added (4 mL). The mixture was allowed to cool to room
temperature. The solid was isolated by filtration, dried and
recrystallized from 10% water in MEK (30 mL) to afford dd-1a which
showed an optical purity >90% ee.
[0753] U. Classical Resolution of c-1a
##STR00119##
[0754] To a solution of c-1a (89.7 mgs, 1.0 equiv) in IPA (0.9 mL)
was quickly added a solution of S-(+)-mandelic acid (134.9 mgs, 1.0
equiv) in IPA (0.9 mL). The mixture was stirred at approximately
room temperature and solid precipitate was observed after
approximately 20 minutes. The slurry was stirred for an additional
15 minutes, and the solids were filtered and collected. The solids
obtained from the initial salt formation were recrystallized in IPA
and was slowly cooled from approximately 80.degree. C. to
approximately 0.degree. C. to provide the enantioenriched product
dd-1b.
[0755] V. Enzymatic Resolution of c-1a--Selective Acylation
##STR00120##
[0756] Toluene (500 mL) was added to a reaction vessel followed by
c-1a (50 g, 1 eq.). Glutaric anhydride (28.4 g, 1 eq.) was added
followed by Novozyme 435 (7.5 g, 15 wt %). The reaction was allowed
to stir for approximately 23 h at approximately 10 to 15.degree. C.
Additional Novozyme (2.5 g, 5 wt %) was charged and the reaction
allowed to proceed for approximately 12 h at approximately 10 to
15.degree. C. Solids were removed by filtration and rinsed with
toluene (100 mL). The organic phase was washed with 10%
Na.sub.2CO.sub.3 (250 mL) followed by 5% Na.sub.2CO.sub.3 (250 mL).
The combined aqueous phases were washed with MTBE (2.times.500 mL).
THF (150 mL) was added to the resulting aqueous phase followed by
sodium hydroxide (14.9 g, 3 equivalents). The mixture was allowed
to stir for approximately 4 h at approximately 15 to 20.degree. C.
The layers were separated, and the THF layer was concentrated. The
aqueous layer was extracted with dichloromethane (2.times.250 mL).
The residue from the THF layer was dissolved in the combined
dichloromethane, and the mixture washed with water (250 mL). The
organic phase was concentrated to approximately 100 mL and water
(300 mL) was added. The mixture was further concentrated to
approximately 250 mL at approximately 55 to 60.degree. C. The
mixture was cooled to approximately 47.degree. C. over
approximately 1 h, seeds of the product (200 mg) were added and the
mixture aged for approximately 1 h at approximately 45 to
47.degree. C. The mixture was cooled to approximately 25.degree. C.
over approximately 2 h and aged approximately 0.5 h. The solids
were collected by filtration and washed with water (50 mL). The
product was dried at approximately 35 to 40.degree. C. under vacuum
to afford the desired product cc-1a (>95% ee).
[0757] W. Enzymatic Resolution of c-1a--Selective Hydrolysis
##STR00121##
[0758] A mixture of compound c-1a (50 g, 1 eq.), glutaric anhydride
(42.5 g, 1.5 eq.) and DMAP (50 mg, 0.001 eq.) in 300 mL pyridine
was stirred overnight at approximately 60.degree. C. The reaction
mixture was evaporated to dryness. Subsequently the residue was
dissolved in DCM (250 mL) and washed with 3.times.250 mL 0.2 M HCl
(aq.). The organic layer was evaporated to dryness. The residue was
stirred with 300 mL water and the pH was adjusted to 7.8 with
approximately 300 mL 2 M NaOH solution. The water layer was washed
with DCM (3.times.70 mL). The water layer was then acidified to pH
4 with 3 N HCl (aq) and extracted with DCM (4.times.150 mL and
2.times.100 mL). The combined organic layers were dried over
Na.sub.2SO4, filtered and evaporated, yielding a colorless oil
which crystalized upon standing. Trituration with pentane
(.about.100 mL) followed by filtration and drying under vacuum
yielded racemic ee-1a.
[0759] Racemic ee-1a (1.008 g) was suspended in diisopropyl ether
(10 mL). To the suspension was added 200 mM sodium phosphate buffer
pH 7 (20 mL) and Cal-B (0.2 g). The reaction mixture was shaken at
250 rpm, 30.degree. C. for .about.100 h (>80% ee observed after
91.5 h). The reaction mixture was filtered and the layers of the
filtrate were separated. The solid was washed with DCM (2.times.10
mL). The filtrate was used to extract the aqueous layer. The
aqueous layer was extracted a second time with DCM (10 mL). The
combined organic layers were washed with 5% Na.sub.2CO.sub.3
(2.times.20 mL), brine (10 mL) and dried over Na.sub.2SO.sub.4.
Filtration and evaporation of the volatiles under reduced pressure
afforded the desired product cc-1a.
[0760] X. Allylic Amination of f-1a to Form g-1a
##STR00122##
[0761] Triphenylphosphine (0.37 g, 0.02 eq) and Pd.sub.2(dba).sub.3
(0.32 g, 0.005 eq) were mixed in degassed THF (200 mL) at
approximately room temperature for approximately 20 min. f-1a (10
g, 1 eq, single enantiomer), Cs.sub.2CO.sub.3 (46 g, 2 eq) and
di-tert-butyl iminodicarboxylate (16.05 g, 1.05 eq) were added and
the mixture heated to 50.degree. C. for approximately 18 h. The
mixture was cooled and water (100 mL) and ethyl acetate (50 mL)
were added. The layers were separated and the organic phase was
washed 2.times. ethyl acetate. The combined organics were dried
over sodium sulfate and concentrated to dryness. The residue was
purified by silica gel column chromatography (0 to 40% ethyl
acetate in hexane). The isolated material was dissolved in MeTHF,
washed with 5% aq. KOH, concentrated, and purified by silica gel
column chromatography (0 to 10% methanol in dichloromethane) to
provide the desired product g-1a.
[0762] Y. Hydrogenation of g-1a to Form h-1a
##STR00123##
[0763] g-1a (1.0 g) and PtO.sub.2 (0.008 g) were combined in
isopropanol (10 mL). The vessel was flushed with H.sub.2 gas and
stirred under an atmosphere of hydrogen at approximately room
temperature for approximately 18 h. The mixture was filtered
through celite and used without further purification in the
subsequent deprotection.
[0764] Z. Deprotection of h-1a to Form N-1a
##STR00124##
[0765] Acetyl chloride (1.7 mL, 7 eq) was combined with isopropanol
(5 mL) and stirred at approximately room temperature for
approximately 15 min to generate HCl in isopropanol. Crude starting
material h-1a in isopropanol (2.5 mL) was added and rinsed forward
with isopropanol (2.5 mL). After approximately 18 h, the slurry was
cooled to approximately 0.degree. C. and N-1a was collected by
filtration. .sup.1H NMR (CD.sub.3OD) confirmed the desired product
was isolated.
[0766] Each of the references including all patents, patent
applications and publications cited in the present application is
incorporated herein by reference in its entirety, as if each of
them is individually incorporated. Further, it would be appreciated
that, in the above teaching of invention, the skilled in the art
could make certain changes or modifications to the invention, and
these equivalents would still be within the scope of the disclosure
defined by the appended claims of the application.
* * * * *