U.S. patent application number 11/762274 was filed with the patent office on 2008-07-10 for processes for preparing pyrroles.
Invention is credited to Michael Wallace.
Application Number | 20080167480 11/762274 |
Document ID | / |
Family ID | 34549387 |
Filed Date | 2008-07-10 |
United States Patent
Application |
20080167480 |
Kind Code |
A1 |
Wallace; Michael |
July 10, 2008 |
PROCESSES FOR PREPARING PYRROLES
Abstract
The present invention relates to an improved synthesis of
pyrrole capping group precursors.
Inventors: |
Wallace; Michael; (West
Chester, PA) |
Correspondence
Address: |
VERTEX PHARMACEUTICALS INC.
130 WAVERLY STREET
CAMBRIDGE
MA
02139-4242
US
|
Family ID: |
34549387 |
Appl. No.: |
11/762274 |
Filed: |
June 13, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10978301 |
Oct 28, 2004 |
7250520 |
|
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11762274 |
|
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60515283 |
Oct 28, 2003 |
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Current U.S.
Class: |
548/562 |
Current CPC
Class: |
C07D 207/416 20130101;
A61P 43/00 20180101; C07D 207/34 20130101; A61P 31/16 20180101 |
Class at
Publication: |
548/562 |
International
Class: |
C07D 207/30 20060101
C07D207/30 |
Claims
1. A process for preparing a compound of formula I-a: ##STR00030##
comprising: combining an aqueous solution of the compound of
formula IV-a: ##STR00031## wherein R.sup.3 is C.sub.1-12 aliphatic,
C.sub.3-12 alkyl-cycloaliphatic, C.sub.3-12 alkyl-aryl, C.sub.3-12
alkyl-heteroaryl, or C.sub.3-12 alkyl-cycloaliphatic; with a
compound of formula V-a ##STR00032## wherein R.sup.1 and R.sup.2
are each independently C.sub.1-6 aliphatic; in the presence of
zinc, water, and optionally an additional suitable solvent to form
a compound of formula VI ##STR00033##
2. A process for preparing a compound of formula VI-a: ##STR00034##
comprising, combining an aqueous solution of compound of formula
IV-a: ##STR00035## wherein R.sup.3 is C.sub.1-12 aliphatic,
C.sub.3-12 alkyl-cycloaliphatic, C.sub.3-12 alkyl-aryl, C.sub.3-12
alkyl-heteroaryl, or C.sub.3-12 alkyl-cycloaliphatic; with a
compound of formula V-a ##STR00036## wherein R.sup.1 and R.sup.2
are each independently C.sub.1-6 aliphatic in the presence of zinc
and a suitable solvent to form the compound of formula VI.
3. A process for preparing a compound of formula I-a: ##STR00037##
comprising, D) combining an aqueous solution of the compound of
formula IV-a: ##STR00038## wherein R.sup.3 is C.sub.1-12 aliphatic,
C.sub.3-12 alkyl-cycloaliphatic, C.sub.3-12 alkyl-aryl, C.sub.3-12
alkyl-heteroaryl, or C.sub.3-12 alkyl-cycloaliphatic; with a
compound of formula V-a ##STR00039## wherein R.sup.1 and R.sup.2
are each independently C.sub.1-6 aliphatic; in the presence of zinc
and a solvent comprising of water and optionally another suitable
solvent to form the compound of formula VI: ##STR00040## E)
Acylating the compound of formula VI with a suitable acylating
agent to form the compound of formula VII: ##STR00041## F)
Hydrolyzing the compound of formula VII under suitable hydrolysis
conditions to form the compound of formula I: ##STR00042##
4. The process according to any one of claims 1-2 further
comprising reacting the compound of formula VI under suitable
acylation conditions to provide a compound of formula IX
##STR00043##
5. The process according to claim 4 wherein the compound of formula
VI is reacted with R.sup.5--X or
R.sup.5C(.dbd.O)--O--C(.dbd.O)R.sup.5 to form the compound of
formula IX wherein X is a suitable leaving group; R.sup.5 is
C.sub.1-12 aliphatic, aryl, heteroaryl, C.sub.1-12
aliphatic-cycloaliphatic, C.sub.1-12 aliphatic-aryl, C.sub.1-12
aliphatic-heteroaryl, or C.sub.1-12 aliphatic-cycloaliphatic.
6. The process according to claim 5, wherein the acylation
conditions comprise: heating the compound with AlCl.sub.3 and
R.sup.5C(.dbd.O)--O--C(.dbd.O)R.sup.5 to form the compound of
formula IX.
7. The process according to claim 6, wherein the acylation
conditions comprise: heating the compound with AlCl.sub.3 and
Ac.sub.2O in refluxing dichloromethane to form the compound of
formula IX wherein R.sup.5 is methyl.
8. The process according to claim 7 further comprising reacting the
compound of formula IX under suitable hydrolysis conditions to
provide a compound of formula I.
9. The process according to claim 8 wherein the hydrolysis
conditions comprise: a suitable base, a suitable solvent, and a
reaction temperature between 20-100.degree. C.
10. The process according to claim 9 wherein the base is
M(OH).sub.n, wherein M is a metal selected from lithium, sodium,
potassium, cesium, magnesium, and calcium and n is 1-2.
11. The process according to claim 10 wherein the solvent is an
alcoholic solvent.
12. The process according to claim 11 wherein the base is KOH, the
solvent is EtOH, and the temperature is that of refluxing
ethanol.
13. The process according to any one of claims 1-12 wherein the
compound of formula IV, the compound of formula V, and a suitable
acid are reacted in water and a suitable volume of an organic
solvent to keep the reaction mixture in solution.
14. The process according to any one of claims 1-13 wherein the
compound of formula IV, the compound of formula V, and acetic acid
are reacted in a suitable volume of water and dioxane to maintain
the internal temperature of the reaction between about 50.degree.
C. to about 80.degree. C.
15. The process according to any one of claims 1-14 wherein the
compound of formula IV, the compound of formula V, water, dioxane,
and acetic acid are stirred at about 50.degree. C. to about
65.degree. C.
16. The process according to claim 15 wherein the reaction mixture
is stirred at about 58.degree. C. to about 60.degree. C.
17. The process according to any one of claims 1-16 further
comprising the step of adding zinc.
18. The process according to claim 17 further comprising stirring
the mixture at about 75.degree. C. to about 85.degree. C.
19. The process according to claim 18 wherein the mixture is
stirred at about 80.degree. C. to about 85.degree. C.
20. The process according to claim 19 wherein the mixture is
stirred at about 80.degree. C. to about 82.degree. C.
21. The process according to any one of claims 1-20 wherein the
zinc is added portionwise.
22. The process according to any one of claims 1-21 wherein each
R.sup.3 is independently C.sub.1-6 alkyl.
23. The process according to claim 22 wherein each R.sup.3 is
independently C.sub.1-3 alkyl.
24. The process according to claim 23 wherein each R.sup.3 is
independently methyl.
25. The process according to any one of claims 1-24 wherein each
R.sup.2 and R.sup.3 is independently methyl and R.sup.1 is
ethyl.
26. The process according to any one of claims 1-21, wherein
R.sup.5 is C.sub.1-6 alkyl.
27. The process according to claim 26 wherein R.sup.5 is
methyl.
28. The process according to any one of claims 1-27 wherein each
R.sup.3 and R.sup.5 is independently methyl.
29. The process according to claim 28 wherein each R.sup.2,
R.sup.3, and R.sup.5 is independently methyl and R.sup.1 is ethyl.
Description
RELATED APPLICATIONS PARAGRAPH
[0001] This application is a continuation application of U.S. Ser.
No. 10/978,301 filed Oct. 28, 2004, which claims the benefit, under
35 U.S.C. .sctn. 119, of U.S. Provisional patent application No.
60/515,283, filed Oct. 28, 2003, and the entire contents of these
applications are hereby incorporated by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to processes for preparing
compounds useful in the synthesis of biologically active compounds,
particularly protease inhibitors.
BACKGROUND OF THE INVENTION
[0003] Infection by hepatitis C virus ("HCV") is a compelling human
medical problem. HCV is recognized as the causative agent for most
cases of non-A, non-B hepatitis, with an estimated human
sero-prevalence of 3% globally [A. Alberti et al., "Natural History
of Hepatitis C," J. Hepatology, 31., (Suppl. 1), pp. 17-24 (1999)].
Nearly four million individuals may be infected in the United
States alone [M. J. Alter et al., "The Epidemiology of Viral
Hepatitis in the United States, Gastroenterol. Clin. North Am., 23,
pp. 437-455 (1994); M. J. Alter "Hepatitis C Virus Infection in the
United States," J. Hepatology, 31., (Suppl. 1), pp. 88-91 (1999)].
Unfortunately, there are no broadly effective treatments for the
debilitating progression of chronic HCV.
[0004] There are not currently any satisfactory anti-HCV agents or
treatments. Until recently, the only established therapy for HCV
disease was interferon treatment. However, interferons have
significant side effects [M. A. Wlaker et al., "Hepatitis C Virus:
An Overview of Current Approaches and Progress," DDT, 4, pp. 518-29
(1999); D. Moradpour et al., "Current and Evolving Therapies for
Hepatitis C," Eur. J. Gastroenterol. Hepatol., 11, pp. 1199-1202
(1999); H. L. A. Janssen et al. "Suicide Associated with
Alfa-Interferon Therapy for Chronic Viral Hepatitis," J. Hepatol.,
21, pp. 241-243 (1994); P. F. Renault et al., "Side Effects of
Alpha Interferon," Seminars in Liver Disease, 9, pp. 273-277.
(1989)] and induce long term remission in only a fraction
(.about.25%) of cases [O. Weiland, "Interferon Therapy in Chronic
Hepatitis C Virus Infection", FEMS Microbiol. Rev., 14, pp. 279-288
(1994)]. Recent introductions of the pegylated forms of interferon
(PEG-INTRON.RTM. and PEGASYS.RTM.) and the combination therapy of
ribavirin and pegylated interferon (REBETROL.RTM.) have resulted in
only modest improvements in remission rates and only partial
reductions in side effects. Moreover, the prospects for effective
anti-HCV vaccines remain uncertain.
[0005] The HCV nonstructural (NS) proteins are presumed to provide
the essential catalytic machinery for viral replication. The HCV
NS3 serine protease and its associated cofactor, NS4A, helps
process all of the viral enzymes, and is thus considered essential
for viral replication. This processing appears to be analogous to
that carried out by the human immunodeficiency virus aspartyl
protease, which is also involved in viral enzyme processing HIV
protease inhibitors, which inhibit viral protein processing are
potent antiviral agents in man, indicating that interrupting this
stage of the viral life cycle results in therapeutically active
agents. Consequently it is an attractive target for drug
discovery.
[0006] Protease inhibitors and many other compounds comprise
N-terminal capping groups. Such N-terminal capping, or protecting,
groups are not limited to HCV protease inhibitors. Any peptidyl
biologically active compound may have an N-terminal capping group.
Similarly, many non-peptidyl (particularly peptidyl mimetic)
compounds comprise the equivalent of an N-terminal capping group.
Furthermore, a primary or secondary amine in any compound could be
derivatized with a capping group. Accordingly, N-terminal capping
groups are widely used. There is therefore a need for N-terminal
capping groups (sometimes referred to as protecting or protective
groups) and methods for making such groups.
[0007] A pyrrole-based capping group that is particularly useful
has been described (WO 03/087092). This capping group is relatively
complex. A disadvantage of relatively complex capping groups is
that they may not be readily available commercially and/or may be
difficult to synthesize. As is known, carboxylic acids are
convenient precursors for such capping groups. Unfortunately, there
are no safe, efficient, and/or large-scale methods for synthesizing
the carboxylic acid precursors corresponding to these particularly
useful capping groups (see, D. T. Kozhich et al., Zh. Organ.
Khimii, 16 pp. 849-855-750 (1980); UDC 547, 745:312; A. J. Robinson
et al., J. Org. Chem. 66, pp. 4148-4152 (2001); H. Falk et al.
Monatsh. Chemie, 104, pp. 925-923 (1973)).
[0008] Thus, there is a need for efficient synthetic routes to
these carboxylic acid precursors of pyrrole-based capping
groups.
SUMMARY OF THE INVENTION
[0009] The present invention relates to an improved synthesis of a
pyrrole capping group.
DETAILED DESCRIPTION OF THE INVENTION
[0010] This invention provides an improved synthesis of a
carboxylic acid substituted pyrrole. Advantageously, this synthesis
is amenable to large scale synthesis. Applicants' invention allows
for the capping group to be more readily available.
[0011] Accordingly to a one embodiment (A), this invention provides
a process for preparing a compound:
##STR00001##
[0012] wherein:
[0013] each R is independently selected from an alkyl group;
comprising;
[0014] a) reacting a compound of formula II-B:
##STR00002## [0015] wherein each R is independently selected from
an alkyl group, with a compound of formula III-B,
[0015] ##STR00003## [0016] in the presence of NaOt-Bu (sodium
t-butoxide), an appropriate solvent (such as THF) at an appropriate
temperature to provide a compound of formula IV-B:
##STR00004##
[0017] An appropriate reaction temperature in any embodiment of the
above reaction is about 20.degree. C. or less. In one embodiment a
solution of butanone and an appropriate solvent (such as THF) is
cooled to about -5.degree. C. to about 15.degree. C. (preferably
about 0.degree. C. to about 10.degree. C.; alternatively about
5.degree. C. to about 10.degree. C.). In one embodiment the
reaction is stirred overnight at about 20.degree. C. to about
28.degree. C. (preferably about 22.degree. C. to about 26.degree.
C.).
[0018] Accordingly to another embodiment, this invention provides a
process for preparing a compound:
##STR00005##
[0019] wherein each R is independently an alkyl group,
comprising:
reacting a compound of formula IV-B:
##STR00006##
[0020] wherein each R is independently an alkyl group, and a
compound of formula VI-B:
##STR00007##
[0021] wherein R.sup.2 and R.sup.3 are each independently an alkyl
group; in the presence of zinc, acetic acid, water, and dioxane (or
another appropriate solvent); to provide a compound of formula
VI-B:
##STR00008##
[0022] In a specific embodiment, R.sup.2 is methyl.
[0023] In another specific embodiment, R.sup.3 is methyl.
[0024] In one embodiment, the compound of formula IV-B, the
compound of formula VI-B, water, dioxane (or other appropriate
solvent), and acetic acid are reacted at about 50.degree. C. to
about 65.degree. C. In a more specific embodiment the reaction
mixture is stirred at about 58.degree. C. to about 60.degree.
C.
[0025] In one embodiment, zinc is added (preferably portionwise)
subsequent to the above heating step. This reaction mixture is then
stirred at about 75.degree. C. to about 85.degree. C. In a more
specific embodiment, the mixture is stirred at about 80.degree. C.
to about 85.degree. C., more specifically at about 80.degree. C. to
about 82.degree. C.
[0026] In one embodiment, the reaction mixture is extracted with
t-butyl methyl ether (at about 25.degree. C. to about 28.degree.
C.).
[0027] Advantageously, in this embodiment, no base (such as sodium
acetate) is added.
[0028] In the embodiments of this invention, R is preferably a C-1
to C-6 alkyl group (including any integers therein). In a more
specific embodiment each R is independently, a C-1, C2-, or C-3
alkyl group.
[0029] Accordingly to another embodiment (B), this invention
provides a process for preparing a compound of formula I-a:
##STR00009##
[0030] comprising:
[0031] combining an aqueous solution of the compound of formula
IV-a:
##STR00010## [0032] wherein R.sup.3 is C.sub.1-12 aliphatic,
C.sub.3-12 alkyl-cycloaliphatic, C.sub.3-12 alkyl-aryl, C.sub.3-12
alkyl-heteroaryl, or C.sub.3-12 alkyl-cycloaliphatic; [0033] with a
compound of formula V-a
[0033] ##STR00011## [0034] wherein R.sup.1 and R.sup.2 are each
independently C.sub.1-6 aliphatic;
[0035] in the presence of zinc, water, and optionally an additional
suitable solvent to form a compound of formula VI
##STR00012##
[0036] Applicants have found that using the compound of formula IV
in an aqueous solution is advantageous. It should be understood
that in aqueous conditions, the sodium hydrolyzes (i.e.,
dissociates to form an aldehyde. The sodium salt is easier to
handle and more stable to store. However, it may be cumbersome to
use in preparative methods. Applicant's method for pre-forming an
aqueous solution of the salt is an improvement to the standard
processes.
[0037] Another embodiment of this invention provides a process for
preparing a compound of formula VI-a:
##STR00013## [0038] comprising, combining an aqueous solution of
compound of formula IV-a:
[0038] ##STR00014## [0039] wherein R.sup.3 is C.sub.1-12 aliphatic,
C.sub.3-12 alkyl-cycloaliphatic, C.sub.3-12 alkyl-aryl, C.sub.3-12
alkyl-heteroaryl, or C.sub.3-12 alkyl-cycloaliphatic; [0040] with a
compound of formula V-a
[0040] ##STR00015## [0041] wherein R.sup.1 and R.sup.2 are each
independently C.sub.1-6 aliphatic in the presence of zinc and a
suitable solvent to form the compound of formula VI.
[0042] Yet another embodiment provides a process for preparing a
compound of formula I-a:
##STR00016##
[0043] comprising,
A) combining an aqueous solution of the compound of formula
IV-a:
##STR00017##
wherein R.sup.3 is C.sub.1-12 aliphatic, C.sub.3-12
alkyl-cycloaliphatic, C.sub.3-12 alkyl-aryl, C.sub.3-12
alkyl-heteroaryl, or C.sub.3-12 alkyl-cycloaliphatic;
[0044] with a compound of formula V-a
##STR00018##
wherein R.sup.1 and R.sup.2 are each independently C.sub.1-6
aliphatic; in the presence of zinc and a solvent comprising of
water and optionally another suitable solvent (preferably a polar
organic solvent, more preferably dioxane, THF, or other polar
solvents) to form the compound of formula VI:
##STR00019##
B) Acylating the compound of formula VI with a suitable acylating
agent to form the compound of formula VII:
##STR00020##
C) Hydrolyzing the compound of formula VII under suitable
hydrolysis conditions (including acid or base hydrolysis, for metal
hydroxides (see below for examples of metals, H.sub.2SO.sub.4(aq),
HCl(aq)) to form the compound of formula I:
##STR00021##
[0045] In certain embodiments of this invention (particularly in
R.sup.3) in alkylaryl and alkylheteroaryl groups, the aryl and
heteroaryl is not alpha or beta relative to the position the alkyl
is bound to the rest of the molecule. Preferably, the aryl and
heteroaryl is at least at the gamma position or even farther from
the bond. Aliphatic groups are preferably alkyl. Preferred forms of
a C.sub.1-12 group, is a C.sub.1-6 group. The term "alkyl" and
"aliphatic" as used herein means a straight chained or branched
alkyl group.
[0046] In certain embodiments, the process further comprises
reacting the compound of formula VI under suitable acylation
conditions to provide a compound of formula IX
##STR00022##
[0047] In certain embodiments, the compound of formula VI is
reacted with R.sup.5--X or R.sup.5C(.dbd.O)--O--C(.dbd.O)R.sup.5 to
form the compound of formula IX wherein:
X is a suitable leaving group; R.sup.5 is C.sub.1-12 aliphatic,
aryl, heteroaryl, C.sub.1-12 aliphatic-cycloaliphatic, C.sub.1-12
aliphatic-aryl, C.sub.1-12 aliphatic-heteroaryl, or C.sub.1-12
aliphatic-cycloaliphatic. It should be understood that the reaction
conditions tolerate a wide variety of R.sup.5 groups.
[0048] In certain embodiments, the acylation conditions comprise:
[0049] heating the compound with AlCl.sub.3 and
R.sup.5C(.dbd.O)--O--C(.dbd.O)R.sup.5 to form the compound of
formula IX.
[0050] In certain embodiments, the acylation conditions
comprise:
heating the compound with AlCl.sub.3 and Ac.sub.2O in refluxing
dichloromethane to form the compound of formula IX wherein R.sup.5
is methyl.
[0051] In certain embodiments, the process further comprises
reacting the compound of formula IX under suitable hydrolysis
conditions to provide a compound of formula I.
[0052] In certain embodiments, the hydrolysis conditions comprise:
[0053] a suitable base, a suitable solvent, and a reaction
temperature between 20-100.degree. C.
[0054] In certain embodiments, the process base is M(OH).sub.n,
wherein M is a metal selected from lithium, sodium, potassium,
cesium, magnesium, and calcium and n is 1-2. and/or the solvent is
an alcoholic solvent. Preferred bases include KOH, the solvent is
EtOH, and the temperature is that of refluxing ethanol.
[0055] In certain embodiments, the compound of formula IV, the
compound of formula V, and a suitable acid are reacted in water and
a suitable volume of an organic solvent to keep the reaction
mixture in solution. The organic solvent is preferably selected to
keep the reaction in solution.
[0056] In certain embodiments, the compound of formula IV, the
compound of formula V, and acetic acid are reacted in a suitable
volume of water and dioxane to maintain the internal temperature of
the reaction between about 50.degree. C. to about 80.degree. C. In
acetic acid alone, the reaction is too exothermic. Reaction
temperature of over 100.degree. C. are not preferred as
decomposition may be observed. Preferrably, the reaction is
maintained at 80.degree. C. or below.
[0057] In certain embodiments, the compound of formula IV, the
compound of formula V, water, dioxane, and acetic acid are stirred
at about 50.degree. C. to about 65.degree. C. Other preferred
temperatures are at about 58.degree. C. to about 60.degree. C.
[0058] In certain embodiments, the process comprises the step of
adding zinc. Preferred temperature for these reactions include
about 75.degree. C. to about 85.degree. C. Other temperatures are
about 80.degree. C. to about 85.degree. C.; about 80.degree. C. to
about 82.degree. C.
[0059] In preferred processes according to this invention, the zinc
is added portionwise. The reaction is exothermic, therefore adding
the zinc portion-wise helps maintain temperature and is also
safer.
[0060] In certain embodiments of this invention (particularly in
R.sup.3) in alkylaryl and alkylheteroaryl groups, the aryl and
heteroaryl is not alpha or beta relative to the position the alkyl
is bound to the rest of the molecule. Preferably, the aryl and
heteroaryl is at least at the gamma position or even farther from
the bond. Aliphatic groups are preferably alkyl. Preferred forms of
a C.sub.1-12 group, is a C.sub.1-6 group.
[0061] In other embodiments, R.sup.3 is independently C.sub.1-6
alkyl, preferably, each R.sup.3 is independently C.sub.1-3 alkyl.
Most preferably, each R.sup.3 is methyl.
[0062] In other embodiments, each R.sup.2 and R.sup.3 is
independently methyl and R.sup.1 is ethyl.
[0063] In other embodiments, R.sup.5 is C.sub.1-6 alkyl.
Preferably, R.sup.5 is methyl.
[0064] In other embodiments, The R.sup.3 and R.sup.5 is
independently methyl.
[0065] In other embodiments, R.sup.2, R.sup.3, and R.sup.5 is
independently methyl and R.sup.1 is ethyl.
[0066] Each of the general embodiments above (i.e., preparation of
IV, IV-A, or IV-B, or and preparation of VII, VII-A, or VII-B) may
be used separately or together in a process for preparing a
compound of formula I, I-A, or I-B. Sample preparations of a
compound of formula I, I-A, or I-B would be individual reactions
such as those known to skilled practitioners, those of WO
03/087092, and/or those described herein in Examples 1-5.
[0067] Advantageously, the processes set forth in Examples 1-5 have
been done and found to be applicable on a large scale to produce a
compound of formula I, I-A, or I-B. Thus, one embodiment of this
invention is as set forth in Example 1 or Example 3 alone or
Example 1 and/or Example 3 in combination with any one or more of
Example 2, Example 4, or Example 5.
[0068] Specific embodiments of this invention are those of the
Examples herein.
[0069] Although the processes of this invention are depicted with a
free amine, a free carboxylic acid, and an unsubstituted carbonyl
group, each of these groups could be derivatized or protected as
desired (see, e.g., T. W. Greene & P. G. M. Wuts, "Protective
Groups in Organic Synthesis", 3.sup.rd Ed., John Wiley & Sons,
Inc., New York (1999).
[0070] Accordingly to a specific embodiment, this invention
provides a process for preparing a compound:
##STR00023##
[0071] Although, the carboxylic acid prepared according to this
invention may be used as a capping group, a skilled practitioner
could envision other uses for the acid. Any such use that involves
the processes provided herein, are part of this invention.
[0072] Depicted below in Scheme 1 is a specific embodiment of this
invention, wherein each R.sup.2, R.sup.3, and R.sup.5 is methyl and
R.sup.1 is ethyl. Each of the conversions I
##STR00024##
General Synthetic Methodology:
[0073] Process used in connection with this invention, unless
otherwise stated, may be according to general methods known to
those skilled in the art. Except for the embodiments set forth
herein, other equivalent procedures to those of Scheme 1, as
illustrated by the general procedures herein, and the preparative
examples that follow may alternatively be used to synthesize
various portions of the pyrrole carboxylic acid. General principles
of organic chemistry are described in "Organic Chemistry", Thomas
Sorrell, University Science Books, Sausalito: 1999, and "March's
Advanced Organic Chemistry", 5.sup.th Ed., Ed.: Smith, M. B. and
March, J., John Wiley & Sons, New York: 2001; Greene &
Wuts, Protective Groups in Organic Synthesis" John Wiley & Sons
(1999) and the other editions of this book; the entire contents of
each are hereby incorporated by reference.
[0074] In order that this invention be more fully understood, the
following preparative and testing examples are set forth. These
examples are for the purpose of illustration only and are not to be
construed as limiting the scope of the invention in any way.
EXAMPLE 1
TABLE-US-00001 ##STR00025## [0075] Materials Material Mwt Amount
Density Moles Eq. Butanone, 99+% (II-A) 72.11 1.0 kg 0.805 13.87
1.0 Ethyl formate, 97% 74.08 1.54 kg 0.917 20.80 1.5 (III-A) Sodium
t-butoxide 96.11 5.3 L 16.64 1.2 30 wt % in THF Tetrahydrofuran
72.11 1.6 L 0.889
[0076] Method
Step 1: To a 12 L 3-neck round bottom flask, under nitrogen,
equipped with a mechanical stirrer, thermometer, and an addition
funnel, charge 1.0 kg of butanone. Step 2: To the butanone charge
1.6 L of tetrahydrofuran. Step 3: Cool the solution to 5.degree.
C.-10.degree. C. Step 4: To the cooled solution add 1.54 kg of
ethyl formate. Step 5: To the mixture add 5.3 L of 30 wt % sodium
t-butoxide in tetrahydrofuran (Note 1). Step 6: Stir the mixture
overnight at 22.degree.-26.degree. C. (Note 2). Step 7: Collect the
precipitate by suction filtration. Step 8: Rinse the filter cake
with 2.0 L of tetrahydrofuran. Step 9: Pull vacuum on the filter
cake for 1-2 hours. Step 10: Dry the filter cake under high vacuum
for 16-20 hours.
[0077] Results
[0078] Weight: 1.5 kg
[0079] Purity % (w/w) or % (AUC): See Note 3.
[0080] Molar yield or area yield: 80%
[0081] Process Efficiency
[0082] Maximum volume step--9.5 L
[0083] Minimum volume step--9.5 L
[0084] Notes
Note 1--The addition of 30 wt % sodium t-butoxide in
tetrahydrofuran was carried out over 2 hours and the temperature
was not allowed to increase above 20.degree. C. Note 2--There has
not yet been developed an analytical method to monitor the reaction
progress, but .sup.1H NMR, or infrared spectroscopy, could follow
the consumption of butanone. Note 3--The purity is usually
confirmed by .sup.1H NMR, and is .about.90-95% the desired compound
(the vinyl proton of the product at .about.9.0 ppm can be
integrated against a singlet at .about.8.4 ppm thought to be from
the undesired regioisomeric ketoaldehyde sodium salt). The material
also contains 4-5% water as determined by Karl Fisher analysis.
EXAMPLE 2
TABLE-US-00002 ##STR00026## [0085] Materials Material Mwt Amount
Density Moles Eq. Ethylacetoacetate, 99% 130.14 1.0 kg 1.021 7.68
1.0 (V-A) Sodium nitrite, 97+% 69.0 557 g 8.07 1.05 Acetic acid,
glacial, 60.05 2.0 L 1.049 100% Water 18.0 4.0 L tert-Butyl methyl
88.15 3.5 L 0.740 ether 99+% 10% Aqueous potassium 3.0 L carbonate
Saturated sodium 2.0 L chloride
[0086] Process Detail
Step 1: Prepare 10% aqueous potassium carbonate solution: 300 g of
potassium carbonate dissolved in 2.7 L of water. Step 2: Prepare
saturated sodium chloride solution: 529 g of sodium chloride
dissolved in 1.4 L of water. Step 3: Prepare aqueous sodium nitrite
solution: 557 g of sodium nitrite dissolved in 1.0 L of water. Step
4: Prepare ethylacetoacetate/glacial acetic acid solution: 1.0 kg
of ethylacetoacetate dissolved in 2.0 L of glacial acetic acid.
Step 5: Charge to a 3.0 L 3-neck round bottom flask, equipped with
a mechanical stirrer, thermometer, and an addition funnel,
ethylacetoacetate/glacial acetic acid solution. Step 6: Cool the
solution to 3.degree.-6.degree. C. Step 7: Charge the aqueous
sodium nitrite solution to the ethylacetoacetate/glacial acetic
acid solution (Note 1). Step 8: Stir the reaction mixture at
ambient temperature and monitor the reaction progress by .sup.1H
NMR (Note 2). Step 9: Dilute the reaction mixture with 3.0 L of
water. Step 10: Extract the diluted reaction mixture with 3.5 L of
tert-butyl methyl ether. Step 11: Separate the layers. Step 12:
Extract the organic layer with 2.0 L of 10% aqueous potassium
carbonate (Note 3). Step 13: Separate the layers. Step 14: Extract
the organic layer with 1.0 L of 10% aqueous potassium carbonate.
Step 15: Separate the layers. Step 16: Wash the organic layer with
2.0 L of saturated sodium chloride. Step 17: Separate the layers.
Step 18: Concentrate the organic layer to a green colored oil.
[0087] Results
[0088] Weight: 1.2 kg
[0089] Purity % (w/w) or % (AUC): 95% AUC
[0090] Molar yield or area yield: 92%
[0091] Analytical
Method: HPLC: Zorbax SB Phenyl; 5 um, 4.6 mm i.d..times.250 mm, 90%
H2O/10% CH.sub.3CN/0.1% TFA to 10% water over 15 minutes, 10 .mu.L
injection, 1.0 mL/minute, run time=20 minutes, column
temperature=50.degree. C., .lamda.=214 nm.
TABLE-US-00003 Retention Times Peak Rel Retention No. Assignment
Retention Time Time 1 Uncharacterized 8.1 minutes 2 VI-a 8.4
minutes
[0092] Process Efficiency
Maximum volume step: 11 L Minimum volume step: 4.5 L
[0093] Notes
Note 1: The sodium nitrite addition was carried out over 90
minutes, and the temperature was not allowed to increase above
25.degree. C. Note 2: A reaction time of 1-2 hours is typical, and
the reaction is complete when the methylene protons of
ethylacetoacetate are absent. Sample preparation--2.0 mL reaction
aliquot diluted with 2.0 mL of water and extracted with 3.0 mL of
EtOAc. Separate layers, concentrate the organic layer, and dilute
with CDCl.sub.3. Note 3: The base should be added cautiously to
avoid excessive off-gassing.
EXAMPLE 3
TABLE-US-00004 ##STR00027## [0094] Materials Material Mwt Amount
Density Moles Eq VI-A, 90% 159.14 697 g 4.38 1.0 IV-a, 95% 122.10
619 g 4.81 1.1 Zinc, 100% 65.37 487 g 7.45 1.7 Acetic acid,
glacial, 60.05 763 g 1.049 12.70 2.9 100% Water 18.0 7.4 L Dioxane
88.11 1.4 L 1.034 tert-Butyl methyl 88.15 5.0 L 0.740 ether
[0095] Process Detail
Step 1: Prepare aqueous IV-A solution: 619 g of IV-A dissolved in
1.5 L of water. Step 2: To a 22 L 3-neck round bottom flask, under
nitrogen, equipped with a mechanical stirrer, thermocouple/heating
mantle apparatus, and an addition funnel, charge 697 g of VI-A.
Step 3: To the VI-A add 1.4 L of dioxane. Step 4: To the solution
add 3.4 L of water. Step 5: To the solution add 763 g of acetic
acid. Step 6: To the mixture add aqueous IV-a solution. Step 7:
Heat the mixture to 58.degree.-60.degree. C. Step 8: To the mixture
add zinc (Note 1). Step 9: Stir the mixture at
80.degree.-82.degree. C. and monitor the reaction completeness by
HPLC (Notes 2 and 3). Step 10: Cool the mixture to
25.degree.-28.degree. C. Step 11: Extract the mixture with 5.0 L of
tert-butyl methyl ether. Step 12: Filter the bi-layered mixture
through ordinary Whatman filter paper (Note 4). Step 13: Separate
the layers. Step 14: Wash the organic layer with 2.5 L of water.
Step 15: Separate the layers. Step 16: Dry the organic layer over
500 g of magnesium sulfate (Note 5). Step 17: Remove the magnesium
sulfate by filtration. Step 18: Concentrate the filtrate to a dark
brown solid. Step 19: Dry the solid under vacuum at 40.degree. C.
for 16 hours.
[0096] Results
[0097] Weight: 512 g
[0098] Purity % (w/w) or % (AUC): 77% AUC(HPLC)
[0099] Molar yield or area yield: 54%
[0100] Analytical
In process control HPLC: Zorbax SB Phenyl 4.6.times.250 mm i.d., 5
.mu.m, 90% water/10% CH.sub.3CN/0.1% TFA to 10% water over 15
minutes, flow rate=1.0 mL/minute, 10 .mu.L injection, column
temperature=50.degree. C., .lamda.=214 nm. Sample preparation: 3
drops of reaction mixture dissolved in 1.0 mL of 1:1
water/CH.sub.3CN.
TABLE-US-00005 Retention Times Rel Peak Retention No. Assignment
Retention Time Time 1 VI-A 8.5 minutes 2 VII-A 11.4 minutes 3
Multiple smaller uncharacterized peaks.
[0101] Process Efficiency
Maximum volume step--14 L (Step 11). Minimum volume step--9.0 L
(Step 6).
[0102] Notes
Note 1: The zinc is added in 10-15% portions over 90 minutes. The
addition of each portion is accompanied by a temperature increase
of 7.degree.-10.degree. C. Before the next addition, the
temperature is adjusted to 70.degree. C. with a cool water bath.
Note 2: The mixture may or may not reflux at this temperature, but
the reflux temperature is probably 82.degree.-85.degree. C. Note 3:
The reaction is generally complete after this 30 minute stir
period. Note 4: The filtration time is dependent on the amount of
inorganic precipitates and in some cases has required 60 minutes.
Note 5: On scale, the drying agent could probably be replaced by a
solvent exchange into dichloroethane (the solvent for the next
reaction).
EXAMPLE 4
TABLE-US-00006 ##STR00028## [0103] Materials Material Mwt Amount
Density Moles Eq. 1. VII-A (80%) 167.22 223 g 1.33 1.0 2. Aluminum
chloride 133.34 1.0 kg 8.0 6.0 3. Acetic anhydride 102.07 408 g
1.082 4.0 3.0 g/mL 4. Dichloromethane 84.93 3.0 L 5. Saturated
sodium 800 mL chloride
[0104] Process Detail
Step 1: Prepare saturated sodium chloride solution: 220 g of sodium
chloride dissolved in 580 mL of water. Step 2: Prepare acetic
anhydride/dichloromethane solution: 408 g of acetic anhydride
dissolved in 220 mL of dichloromethane. Step 3: Prepare
VII-A/dichloromethane solution: 223 g of VII-A dissolved in 1.1 L
of dichloromethane. Step 4: Charge 1.0 kg of aluminum chloride to a
12 L 3-neck round bottom flask that is under a nitrogen atmosphere,
and is equipped with a water cooled condenser, addition funnel, and
thermocouple. Step 5: Add 880 mL of dichloromethane to the aluminum
chloride. Step 6: Cool the aluminum chloride/dichloromethane
suspension to 5.degree. 10.degree. C. with an ice water bath. Step
7: Add acetic anhydride/dichloromethane solution to the aluminum
chloride suspension (Note 1). Step 8: Stir the aluminum
chloride/acetic anhydride complex for 30 minutes (Note 2). Step 9:
Add VII-A/dichloromethane solution to aluminum chloride/acetic
anhydride complex (Notes 3 and 4). Step 10: Fit the 12 L round
bottom flask with a heating mantle. Step 11: Heat the reaction
mixture at reflux (34.degree.-37.degree. C.) and monitor the
consumption of VII-A by HPLC (Notes 5 and 6). Step 12: Cool the
reaction mixture to 24.degree.-26.degree. C. with a cool water
bath. Step 13: Transfer the black mixture to a 10 L carboy. Step
14: Charge 4.4 L of water to the 12 L vessel. Step 15: Cool the
water to 5.degree.-10.degree. C. with an ice water bath. Step 16:
Quench the VIII-A mixture into the water (Note 7). Step 17:
Separate the layers (Note 8). Step 18: Wash the aqueous layer with
800 mL of dichloromethane. Step 19: Separate the layers. Step 20:
Combine the organic layers. Step 21: Wash the combined organic
layers with 800 mL of saturated sodium chloride. Step 22: Separate
the layers. Step 23: Using rotary evaporation at reduced pressure,
concentrate the organic layer to a black solid.
[0105] Results
[0106] Weight: 223 g
[0107] Purity % (w/w) or % (AUC): 80% AUC
[0108] Molar yield or area yield: 64% corrected yield.
[0109] Analytical
[0110] Method (HPLC)-- Zorbax SB Phenyl; 5 um, 4.6 mm
i.d..times.250 mm length; 90% water/10% acetonitrile/0.1%
trifluoroacetic acid to 90% acetonitrile over 15 minutes, run
time=20 minutes, injection volume=10 .mu.L, flow rate=1.0
mL/minute, column temperature=50.degree. C., wavelength=214 nm.
TABLE-US-00007 Retention Times Peak No. Assignment Retention Time 1
VII-A 11.4 minutes 2 VIII-A 10.6 minutes
[0111] Process Efficiency
Maximum volume step--8.2 L Minimum volume step--1.9 L
[0112] Notes
Note 1: The addition was carried out dropwise over 25-30 minutes
and the temperature was not allowed to increase above 27.degree. C.
Note 2: The mixture should be homogeneous and light green colored.
Note 3: The addition was carried out dropwise over 25-30 minutes
and the temperature was not allowed to increase above 30.degree. C.
Note 4: The mixture will be homogeneous and black colored. Note 5:
A reaction time of 1-2 hours is typical. Note 6: Sample
preparation: 3 drops of reaction mixture dissolved in 1.0 mL of 50%
aqueous acetonitrile. Method (HPLC): see under Analytical section.
Note 7: The quench was carried out dropwise over 2 hours and the
temperature was not allowed to increase above 27.degree. C. Note 8:
The bi-layered mixture will be black and the interface might not be
clear. If the interface is not clear, then removal of the organic
layer by weight or volume is necessary.
EXAMPLE 5
TABLE-US-00008 ##STR00029## [0113] Materials Material Mwt Amount
Moles Liters Eq. VIII-A 209.26 75 0.36 1.0 10% Aqueous potassium
1.79 1.0 5.0 hydroxide Ethyl alcohol, 46.07 .400 absolute (Density
= 0.790 g/mL)
[0114] Procedure:
Step 1: Prepare 10% aqueous potassium hydroxide solution: 100 g of
potassium hydroxide pellets dissolved in 900 mL of water (Note 1).
Step 2: Prepare 2 N hydrochloric acid solution: 150 mL of
concentrated hydrochloric acid dissolved in 750 mL of water (Note
2). Step 3: To a 2.0 L 3-neck round bottom flask charge 75 g of
VIII-A. Step 4: To the VIII-A add 1.0 L of 10% aqueous potassium
hydroxide. Step 5: To the heterogeneous solution add 75 mL of ethyl
alcohol. Step 6: Heat the mixture at 65.degree.-70.degree. C., and
monitor the reaction progress by HPLC (Notes 3 and 4). Step 7: Cool
the mixture to 20.degree.-25.degree. C. Step 8: To the mixture add
900 mL of 2 N hydrochloric acid (Note 5). Step 9: Cool the
precipitated mixture to 15.degree.-20.degree. C. and hold at that
temperature for 30 minutes. Step 10: Collect the precipitate by
suction filtration and pull the filter cake dry for 1 hour. Step
11: Take the filter cake up in 325 mL of ethyl alcohol. Step 12:
Heat the heterogeneous mixture at 55.degree.-60.degree. C. for
30-35 minutes. Step 13: Allow the mixture to cool to
20.degree.-25.degree. C. and then hold at 5.degree.-10.degree. C.
overnight (Note 6). Step 14: Collect the brown precipitate by
suction filtration. Step 15: Dry the I-a under high vacuum at
ambient temperature until a constant weight (Note 7).
[0115] Notes:
Note 1: The dissolution of potassium hydroxide is exothermic and
the solution should be prepared with cooling. Note 2: The
dissolution of concentrated hydrochloric acid in water is
exothermic and the solution should be prepared with cooling. Note
3: A reaction time of 30-60 minutes is typical, and the reaction is
complete when the starting material is consumed. Note 4: HPLC
method: Zorbax SB Phenyl, 5 um, 4.6 mm i.d..times.250 mm length;
90% H.sub.2O/10% CH.sub.3CN/0.1% TFA to 10% H.sub.2O/90%
CH.sub.3CN/0.1% TFA over 15 minutes, run time=20 minutes, 10 uL
injection, 1.0 mL/minute flow rate, column temperature=50.degree.
C., .lamda.=214 nm. [0116] Retention time of VIII-a=10.9 minutes
[0117] Retention time of 1-a=9.7 minutes [0118] Less intense
uncharacterized impurities will also be detected. [0119] Sample
Preparation: 2 drops of reaction mixture in .about.1.0 mL of
CH.sub.3CN/2-3 drops of water. Note 5: The addition of 2 N
hydrochloric acid was carried out over 20-25 minutes. The
temperature was not allowed to increase above 30.degree. C. The
solution pH 2.0-4.0 to universal pH paper. Over acidification might
cause gumming and a less quantitative recovery of crude product.
Note 6: Holding at 5.degree.-10.degree. C. might not be necessary,
but that remains to be determined. Note 7: The 1-a is analyzed by
HPLC (see method in Note 4), and has assayed (percent area ratio)
at 98%-100% pure.
[0120] All of the documents cited herein, are incorporated herein
by reference.
[0121] All documents cited herein are incorporated by reference.
Also incorporated by reference is U.S. provisional application
60/515,283.
[0122] Any embodiments (including preferred embodiments disclosed
for embodiment A or B, apply to the other embodiment.
[0123] While we have described a number of embodiments of this
invention, it is apparent that our basic examples may be altered to
provide other embodiments that utilize the processes of this
invention. Therefore, it will be appreciated that the scope of this
invention is to be defined by any claims rather than by the
specific embodiments that have been represented by way of example
above.
* * * * *