U.S. patent application number 09/929604 was filed with the patent office on 2002-03-07 for process for preparing eprosartan.
This patent application is currently assigned to SmithKline Beecham Corporation. Invention is credited to Liu, Peng, Matsuoka, Richard T..
Application Number | 20020028951 09/929604 |
Document ID | / |
Family ID | 21898590 |
Filed Date | 2002-03-07 |
United States Patent
Application |
20020028951 |
Kind Code |
A1 |
Matsuoka, Richard T. ; et
al. |
March 7, 2002 |
Process for preparing eprosartan
Abstract
This invention relates to a process for preparing
eprosartan.
Inventors: |
Matsuoka, Richard T.;
(Norristown, PA) ; Liu, Peng; (Norristown,
PA) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham
Corporation
|
Family ID: |
21898590 |
Appl. No.: |
09/929604 |
Filed: |
August 14, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09929604 |
Aug 14, 2001 |
|
|
|
09355186 |
Jul 27, 1999 |
|
|
|
6294675 |
|
|
|
|
09355186 |
Jul 27, 1999 |
|
|
|
PCT/US98/02411 |
Feb 13, 1998 |
|
|
|
60038196 |
Feb 14, 1997 |
|
|
|
Current U.S.
Class: |
548/311.1 |
Current CPC
Class: |
Y02P 20/55 20151101;
A61P 9/12 20180101; C07D 233/64 20130101; C07D 409/06 20130101;
A61P 13/12 20180101; A61P 9/10 20180101; A61P 9/04 20180101; A61P
9/00 20180101; A61P 43/00 20180101 |
Class at
Publication: |
548/311.1 |
International
Class: |
C07D 49/02 |
Claims
What is claimed is:
1. A process for the preparation of eprosartan, a compound of
formula (I): 12or a pharmaceutically acceptable salt thereof, which
process comprises the steps of: (i) treating a compound of formula
(II): 13with base, followed by reaction with a regioselective
nitrogen-protecting reagent; (ii) reacting the compound of formula
(III): 14wherein R1 is a nitrogen protecting group either
consisting of (1) an ethylene bridge connecting the nitrogen to an
electron-withdrawing group, such as an ester (COOR", where
R"=C.sub.1-4alkyl), acid, carbonyl, nitrile, sulfone, or sulfoxide,
or (2) a methylene bridge connecting the nitrogen to a pivalate,
2-(trimethylsilyl)ethoxy, methoxy, tert-butoxy, or benzyloxy, with
a compound of formula (IV): 15wherein R' is C.sub.1-4alkyl, in the
presence of a catalyst; and (iii) reacting the compound of formula
(V): 16wherein R' and R1 are as defined above, with a compound of
formula (VI): 17wherein R'" is C.sub.1-4alkyl and X is halo or OR*,
in which R* is CH.sub.3SO.sub.2-- or
p-CH.sub.3C.sub.6H.sub.4SO.sub.2--, at elevated temperatures; and
thereafter hydrolyzing the R' and R'" ester groups and removing the
N-3 protecting group, and optionally forming a pharmaceutically
acceptable salt.
2. The process according to claim 1 for the preparation of
eprosartan, a compound of formula (I): 18or a pharmaceutically
acceptable salt thereof, which process comprises the steps of: (i)
treating a compound of formula (II): 19with base, followed by
reaction with a C.sub.1-4alkyl ester derivative of acrylic acid;
(ii) reacting the compound of formula (IIIb): 20wherein R" is
C.sub.1-4alkyl, with a compound of formula (IV): 21wherein R' is
C.sub.1-4alkyl, in the presence of a catalyst; and (iii) reacting
the compound of formula (Vb): 22wherein R' and R" are as defined
above, with a compound of formula (VI): 23wherein R'" is
C.sub.1-4alkyl and X is halo, at elevated temperatures; and
thereafter hydrolyzing the R' and R'" ester groups and removing the
N-3 protecting group, and optionally forming a pharmaceutically
acceptable salt.
3. The process according to claim 1 for the preparation of
eprosartan, a compound of formula (I): 24or a pharmaceutically
acceptable salt thereof, which process comprises the steps of: (i)
treating a compound of formula (II): 25with
1,8-diazabicyclo[5.4.0]undec-7-ene, followed by reaction with
methyl acrylate; (ii) reacting the compound of formula (IIIa):
26with a compound of formula (IVa): 27in the presence of
piperidine; and (iii) reacting the compound of formula (Va): 28with
a compound of formula (VIa): 29at elevated temperatures; and
thereafter hydrolyzing the ester groups and removing the N-3
protecting group, and optionally forming a pharmaceutically
acceptable salt.
4. A process for the preparation of eprosartan, a compound of
formula (I): 30or a pharmaceutically acceptable salt thereof, which
process comprises the steps of: (i) reacting a compound of formula
(II): 31with a compound of formula (IV): 32wherein R' is
C.sub.1-4alkyl, in the presence of a catalyst; (ii) treating the
compound of formula (VII): 33with base, followed by reaction with a
regioselective nitrogen-protecting reagent; and (iii) reacting the
compound of formula (V): 34wherein R' is as defined above and R1 is
a nitrogen protecting group either consisting of (1) an ethylene
bridge connecting the nitrogen to an electron-withdrawing group,
such as an ester (COOR", where R"=C.sub.1-4alkyl), acid, carbonyl,
nitrile, sulfone, or sulfoxide, or (2) a methylene bridge
connecting the nitrogen to a pivalate, 2-(trimethylsilyl)ethoxy,
methoxy, tert-butoxy, or benzyloxy, with a compound of formula
(VI): 35wherein R'" is C.sub.1-4alkyl and X is halo or OR*, in
which R* is CH.sub.3SO.sub.2-- or
p-CH.sub.3C.sub.6H.sub.4SO.sub.2--, at elevated temperatures; and
thereafter hydrolyzing the R' and R'" ester groups and removing the
N-3 protecting group, and optionally forming a pharmaceutically
acceptable salt.
5. A compound which is 36wherein R" is C.sub.1-4alkyl.
6. The compound according to claim 5 which is 37
7. A compound which is 38wherein R' and R" independently are
C.sub.1-4alkyl.
8. The compound according to claim 7 which is 39
9. A compound which is 40
10. The compound according to claim 9 which is 41
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a process for preparing
eprosartan. This compound is described in U.S. Pat. No. 5,185,351
as being an angiotensin II receptor antagonist useful in the
treatment of hypertension, congestive heart failure and renal
failure.
BACKGROUND OF THE INVENTION
[0002] U.S. Pat. No. 5,185,351 describes processes for the
preparation of imidazole compounds, in particular the preparation
of eprosartan. Although the processes described in this patent
produce the imidazoles claimed therein, there was a need to improve
these processes when preparing compounds, such as eprosartan, on a
commercial scale.
[0003] It has now been found that eprosartan can be prepared in
three stages. These stages are: (Stage.dagger.1) the regioselective
protection of 2-n-butylformylimidazole; (Stage.dagger.2) the
reaction between the product from Stage 1 and
(2-thienylmethyl)-propanedioic acid, mono-C.sub.1-4alkyl ester; and
(Stage.dagger.3) quaternary salt formation, followed by a basic
work-up and an acidification. The efficiency of this synthetic
sequence and the quality and yield of eprosartan are particularly
important when preparing said product on a large scale for
therapeutic use.
DESCRIPTION OF THE INVENTION
[0004] The present invention provides a process for the preparation
of eprosartan, which is
(E)-.alpha.-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-
-imidazol-5-yl]methylene]-2-thiophene propanoic acid, a compound of
formula (I): 1
[0005] or a pharmaceutically acceptable salt thereof,
[0006] which process comprises the steps of:
[0007] (i) treating a compound of formula (II): 2
[0008] with base, followed by reaction with a regioselective
nitrogen-protecting reagent, such as a C.sub.1-4alkyl ester
derivative of acrylic acid;
[0009] (ii) reacting the compound of formula (III): 3
[0010] wherein R1 is a nitrogen protecting group either consisting
of (1) an ethylene bridge connecting the nitrogen to an
electron-withdrawing group, such as an ester (COOR", where
R"=C.sub.1-4alkyl), acid, carbonyl, nitrile, sulfone, or sulfoxide,
or (2) a methylene bridge connecting the nitrogen to a pivalate,
2-(trimethylsilyl)ethoxy, methoxy, tert-butoxy, or benzyloxy, with
a compound of formula (IV): 4
[0011] wherein R' is C.sub.1-4alkyl, in the presence of a catalyst;
and
[0012] (iii) reacting the compound of formula (V): 5
[0013] wherein R' and R1 are as defined above, with a compound of
formula (VI): 6
[0014] wherein R'" is C.sub.1-4alkyl and X is halo or OR*, in which
R* is CH.sub.3SO.sub.2-- or p-CH.sub.3C.sub.6H.sub.4SO.sub.2--, at
elevated temperatures;
[0015] and thereafter removing the N-3 protecting group and
hydrolyzing the R' and R'" ester group, and optionally forming a
pharmaceutically acceptable salt.
[0016] Acid addition salts of formula (I) are formed with the
appropriate inorganic or organic acids by methods known in the art.
Representative examples of suitable acids are maleic, fumaric,
acetic, succinic, hydrochloric, hydrobromic, sulfuric, phosphoric
or methanesulfonic. Preferably, the pharmaceutically acceptable
acid addition salt for the formula (I) compound is the
methanesulfonic acid addition salt.
[0017] Base addition salts of formula (I) are formed with the
appropriate inorganic or organic bases by methods known in the art.
Cationic salts are prepared by treating the parent compound with an
excess of an alkaline reagent, such as hydroxide, carbonate or
alkoxide, containing the appropriate cation; or with an appropriate
organic amine. Representative examples of cations are Li.sup.+,
Na.sup.+, K.sup.+, Ca.sup.++, Mg.sup.++ and NH.sub.4.sup.+.
[0018] As used herein, C.sub.1-4alkyl means an alkyl group of 1-4
carbons, branched or unbranched. C.sub.1-4alkyl includes methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. The
preferred R' C.sub.1-4alkyl group is ethyl, the preferred R"
C.sub.1-4alkyl group is ethyl or methyl and the preferred R'"
C.sub.1-4alkyl group is ethyl or methyl.
[0019] Scheme I, below, summarizes the three stages of the novel
synthetic pathway used to prepare eprosartan. 7
[0020] According to Scheme I, 2-n-butyl-4-formylimidazole is
treated with a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) or 1,1,3,3-tetramethylguanidine, followed by reaction with a
regioselective nitrogen-protecting reagent, such as methyl
acrylate, ethyl acrylate, acetyl bromide, chloromethyl pivalate
(POM-Cl) or di-tert-butyl dicarbonate, to give derivatization on
the least hindered nitrogen atom of the imidazole ring. This
reaction can be carried out in ethyl acetate, acetonitrile,
toluene, DMF, THF or 1-methyl-2-pyrrolidinone (NMP). Preferably,
this reaction is carried out using DBU and methyl acrylate or ethyl
acetate in ethyl acetate at 50-60.degree. C. Typically, the Scheme
I-1 compound is then reacted with (2-thienylmethyl)propanedioic
acid, monothyl ester in a suitable solvent, such as toluene,
acetonitrile, DMF, THF, NMP, or DMSO, in the presence of a
catalyst, for example, in the presence of piperidine or
piperidinium propionate in excess propionic acid, at a suitable
temperature, such as a temperature of about 70.degree. C. to about
100.degree. C. Preferably, this reaction is carried out using
piperidine in toluene at a reflux temperature of 65.degree.
C.-70.degree. C.; this reflux temperature is obtained by placing
the reaction mixture under reduced pressure. The quaternary salt of
the Scheme I-2 compound is then prepared by reacting this compound
with a benzyl halide, such as methyl or ethyl
4-(bromomethyl)benzoate, or a benzyl mesylate or tosylate at
elevated temperatures, for example, at temperatures of
100-120.degree. C., preferably at 105-110.degree. C. The ester
groups are hydrolyzed and the N-protecting group is removed using,
for example, base, such as aqueous sodium or potassium hydroxide,
to give eprosartan (Scheme I-3). Thereafter, pharmaceutically
acceptable salts may be prepared as described above.
[0021] Alternately, eprosartan can be prepared as summarized in
Scheme II, below. 8
[0022] According to Scheme II, the order of the first and second
steps detailed in Scheme I have been reversed. In this synthetic
sequence, 2-n-butyl-4-formylimidazole is reacted with
(2-thienylmethyl)propanedioic acid, mono-ethyl ester in the
presence of a catalyst, and then the product from this reaction is
regioselectively N-protected. Quaternization and basic work-up is
carried out as detailed in Scheme I to give eprosartan.
[0023] Also included in the scope of the present invention are the
novel intermediates used in the preparation of eprosartan. These
intermediates are described hereinbefore.
[0024] The invention is illustrated by the following example. The
example is not intended to limit the scope of this invention as
defined hereinabove and as claimed hereinbelow.
EXAMPLES
Example 1
Preparation of
(E)-.alpha.-[[2-Butyl-1-[(4-carboxyphenyl)-methyl]-1H-imida-
zol-5-yl]methylene]-2-thiophene propanoic acid (Eprosartan)
[0025] Stage.dagger.1: Preparation of 9
[0026] A heterogeneous solution of 2-n-butyl-4-formylimidazole
(155.0 kg, 1018 mol) in ethyl acetate (775.0 L) was treated at room
temperature with methyl acrylate (131.5 kg, 1527 mol) followed with
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 7.75 kg, 50.9 mol). The
reaction mixture was then heated to 50-60.degree. C. (the mixture
became completely homogeneous when heated) and stirred at that
temperature until the reaction was complete (approximately 2
hours). The excess methyl acrylate and the ethyl acetate were
distilled off under vacuum, maintaining the base temperature below
60.degree. C. The residual bronze-colored oil, containing the
above-noted Stage 1 product, was diluted with toluene (1033 L) and
was used in the next step without further purification.
[0027] Stage.dagger.2: Preparation of 10
[0028] The crude Stage 1 product from above was treated with
(2-thienylmethyl)-propanedioic acid, mono-ethyl ester (267.3 kg @
100%, 1171 mol) and piperidine (21.7 kg, 255 mol). The resulting
solution was heated to reflux (65-70.degree. C.) under reduced
pressure; the water produced during the reaction was removed by the
Dean-Stark method. Reflux was continued until the reaction was
complete (approximately 2-3 hours). The reaction mixture was cooled
to 55-60.degree. C. and was washed with a 20% w/w brine solution
(485.3 L) and demineralised water (485.3 L) to remove much of the
piperidine catalyst. The toluene was then removed by vacuum
distillation, maintaining the base temperature below 60.degree. C.
The residual bronze-colored oil, containing the Stage 2 product,
was used in the next step without further purification.
[0029] Stage.dagger.3: Preparation of 11
[0030] The residual oil containing the crude Stage 2 product was
diluted with toluene (583.0 L). The resulting solution was treated
with solid methyl 4-(bromomethyl)-benzoate (291.6 kg @ 100%, 1273
mol) and was subsequently stirred at 70-75.degree. C. for 30
minutes to ensure that a homogeneous solution was obtained. The
toluene was distilled off under vacuum, maintaining the process
temperature between 60 and 75.degree. C. The resulting thick oil
was heated at 95-100.degree. C. until the reaction was shown to be
complete (approximately 6-10 hours). The reaction mixture was
cooled to 75-80.degree. C. and diluted with IMS (ethanol containing
1% v/v MeOH, 1534.0 L). An aqueous solution of sodium hydroxide
[203.7 kg (5093 mol) dissolved in demineralised water (936.0 L)]
was prepared and added to the ethanolic solution of the
intermediate quaternary salt. The mixture was heated to reflux
(approximately 80.degree. C.) and reflux was continued until the
hydrolysis to the title compound was complete (approximately 2
hours). The reaction mixture was cooled to 50-60.degree. C. and
treated with aqueous 6 N hydrochloric acid solution (approximately
479.0 L, 2874 mol) until a pH of 5.1 to 5.3 was achieved. The
resulting slurry was cooled to 10-15.degree. C. and was held at
that temperature for approximately 2 hours to complete the
precipitation. The slurry was filtered and the wet cake was washed
with 50% v/v aqueous IMS (approximately 520 L) and water
(approximately 1790 L) to afford 344.9 kg (estimated 66.9% yield
over the three stages) of the title compound as a beige-colored wet
solid.
[0031] It is to be understood that the invention is not limited to
the embodiment illustrated hereinabove and the right to the
illustrated embodiment and all modifications coming within the
scope of the following claims is reserved.
* * * * *