U.S. patent application number 10/866940 was filed with the patent office on 2004-11-11 for process for preparing and purifying 1,7'-dimethyl-2'-propyl-2,5'-bi-1h-ben- zimidazole.
This patent application is currently assigned to Boehringer Ingelheim Pharma GmbH & Co. KG. Invention is credited to Belzer, Werner, Dach, Rolf, Fachinger, Volker, Heitzmann, Markus, Schmidt, Hartmut.
Application Number | 20040225129 10/866940 |
Document ID | / |
Family ID | 27214701 |
Filed Date | 2004-11-11 |
United States Patent
Application |
20040225129 |
Kind Code |
A1 |
Belzer, Werner ; et
al. |
November 11, 2004 |
Process for preparing and purifying
1,7'-dimethyl-2'-propyl-2,5'-bi-1H-ben- zimidazole
Abstract
Disclosed is a process which can be used on an industrial scale
for preparing and purifying
1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole in which the crude
product is subjected to charcoal treatment.
Inventors: |
Belzer, Werner; (St. Goar,
DE) ; Dach, Rolf; (Gau-Algesheim, DE) ;
Fachinger, Volker; (Nussbaum, DE) ; Heitzmann,
Markus; (Ingelheim, DE) ; Schmidt, Hartmut;
(Bockenau, DE) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877
US
|
Assignee: |
Boehringer Ingelheim Pharma GmbH
& Co. KG
Ingelheim
DE
55216
|
Family ID: |
27214701 |
Appl. No.: |
10/866940 |
Filed: |
June 14, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10866940 |
Jun 14, 2004 |
|
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|
10345773 |
Jan 16, 2003 |
|
|
|
6770762 |
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60386123 |
Jun 5, 2002 |
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Current U.S.
Class: |
548/304.4 |
Current CPC
Class: |
C07D 235/18
20130101 |
Class at
Publication: |
548/304.4 |
International
Class: |
C07D 235/08 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 18, 2002 |
DE |
DE 102 01 725 |
Claims
What is claimed is:
1. A process for purifying
1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazol- e which has been
prepared by reacting 2-propyl-4-methyl-1H-benzimidazole-6-
-carboxylic acid or a salt thereof with
N-methyl-o-phenylene-diamine or a salt thereof, said process
comprising treating the crude product of said reaction with
charcoal, wherein the charcoal treatment is carried out at a pH of
0.7 to 1.2.
2. A process according to claim 1, wherein
2-propyl-4-methyl-1H-benzimidaz- ole-6-carboxylic acid is reacted
with N-methyl-o-phenylene-diamine or a salt thereof in the presence
of methanesulphonic acid and phosphorus pentoxide.
3. A process according to claim 1, wherein the reaction is carried
out at a temperature of 125 to 145.degree. C.
4. A process according to claim 1, wherein after the end of the
reaction, the reaction mixture produced is subjected to hydrolysis
and pH adjustment, and the reaction mixture is then added to the
charcoal or charcoal is added to the reaction mixture.
5. A process according to claim 4, wherein the charcoal treatment
is carried out at a temperature of 70 to 80.degree. C.
6. A process according to claim 4, wherein the quantity of charcoal
used is from 5 to 20 percent by weight of the
2-propyl-4-methyl-1H-benzimidazo- le-6-carboxylic acid.
7. A process according to claim 4, wherein the charcoal treatment
step is repeated one to three times after filtration or
centrifugation of the reaction mixture.
8. A process according to claim 4, wherein after the treatment with
charcoal, the following steps are carried out in succession: a) an
organic solvent is added to the reaction mixture, b) a base is
added to the reaction mixture to obtain a pH of 5 to 6, c) the
aqueous phase is separated off, and d) the
1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazol- e is isolated from
the organic phase by crystallization and subsequent filtration or
centrifugation.
9. A process according to claim 8, wherein isopropanol is used as
the organic solvent in step a).
10. A process according to claim 8, wherein in step b), the base is
added at a temperature of 70 to 80.degree. C.
11. A process according to claim 8, wherein in step d), the
crystallization is carried out by the addition of water.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of U.S. NonProvisional
application Ser. No. 10/345,773, filed Jan. 16, 2003, which claims
benefit of U.S. Provisional Application Ser. No. 60/386,123, filed
on Jun. 5, 2002, wherein both of said applications are herein
incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The invention relates to a process for preparing and
purifying 1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole which
can be used on an industrial scale.
BACKGROUND OF THE INVENTION
[0003] The preparation of
1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole by reacting
2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid with
N-methyl-o-phenylene-diamine dihydrochloride is known from J. Med.
Chem. (1993), 36(25), 4040-51 and International Patent Application
WO 0063158.
[0004] 1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole is of major
importance as an intermediate product in the industrial synthesis
of pharmaceutically active substances, particularly the
pharmaceutically active substance telmisartan (Drugs of the future
1997, 22(10), 1112-1116). This gives rise to the need for a high
level of purity. The purification process using ethyl acetate and
diethyl ether known from the abovementioned literature is
unsuitable as a large-scale process as diethyl ether, for example,
presents a safety problem and requires careful handling on account
of its toxicity, its tendency to form peroxides and the risk of
explosion of its vapours, e.g. by electrostatic discharge.
[0005] The aim of the present invention is therefore to provide a
process which can be used on an industrial scale for purifying the
1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole prepared by the
abovementioned methods of synthesis and the variants thereof
described in this specification.
DETAILED DESCRIPTION OF THE INVENTION
[0006] Surprisingly it has been found that
1,7'-dimethyl-2'-propyl-2,5'-bi- -1H-benzimidazole may be obtained
in a highly pure form by a process suitable for use on an
industrial scale if the essential purification steps are carried
out using charcoal.
[0007] The invention therefore relates to a process which can be
used on an industrial scale for purifying
1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benz- imidazole which has been
prepared by reacting 2-propyl-4-methyl-1H-benzimi-
dazole-6-carboxylic acid or the salts thereof with
N-methyl-o-phenylene-di- amine or the salts thereof, in which the
crude product is treated with charcoal.
[0008] In a preferred process according to the invention
2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid is reacted
with N-methyl-o-phenylene-diamine or the salts thereof, preferably
in the form of a salt, preferably in the form of the phosphate,
chloride or bromide salt, more preferably in the form of the
phosphate or chloride salt, most preferably in the form of the
phosphate salt, in the presence of methanesulphonic acid and
phosphorus pentoxide.
[0009] Also preferred is a process wherein the reaction is carried
out at a temperature of 125 to 145.degree. C.
[0010] In a particularly preferred process, the charcoal treatment
purification step is carried out after the end of the reaction,
hydrolysis and pH adjustment, by adding the reaction mixture to the
charcoal.
[0011] Also particularly preferred is a process wherein the
charcoal treatment purification step is carried out at a
temperature of 70 to 80.degree. C.
[0012] Of particular importance is a process wherein the charcoal
treatment purification step takes place at a pH of 0.7 to 1.2.
[0013] Also of particular importance is a process wherein the
amount of charcoal used in a purification step is from 5 to 20
percent by weight of the
2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid used.
[0014] In a particularly preferred process, the purification step
is repeated one to three times after the filtration or
centrifugation of the reaction mixture.
[0015] In another particularly preferred process, after the
purification by treatment with charcoal, the following steps take
place in succession:
[0016] a) an organic solvent is added,
[0017] b) a base is added to obtain a pH of 5 to 6,
[0018] c) the aqueous phase is separated off,
[0019] d) the 1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole is
separated from the organic phase by crystallization and subsequent
filtration or centrifugation.
[0020] In another preferred process, isopropanol is used as the
organic solvent in step a).
[0021] Also particularly preferred is a process wherein, in step
b), the base is added at a temperature of 70 to 80.degree. C.
[0022] Also particularly preferred is a process wherein, in step
d), the crystallization is carried out by the addition of
water.
[0023] 1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole is used in
particular for preparing telmisartan. Telmisartan may be prepared
using the method described in Drugs of the future 1997, 22(10),
1112-1116 according to the following synthesis diagram I: 1
[0024] The following variants A, B, C, D and E are particularly
preferred embodiments of the process according to the
invention.
[0025] Variant A:
[0026] 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (PMBC)
and N-methyl-o-phenylenediamine (NMPD) or the salts thereof are
added successively to a solution of an organic acid, preferably
methanesulphonic acid, phosphorus pentoxide, thionyl chloride,
sulphonyl chloride, acetic anhydride or polyphosphoric acid,
preferably methanesulphonic acid, phosphorus pentoxide or thionyl
chloride and/or mixtures or dilutions thereof with inert organic
solvents, preferably N-methylpyrrolidinone, o-, m- or p-xylene,
most preferably N-methylpyrrolidinone, with stirring at a
temperature of 100 to 160.degree. C., preferably at 115 to
150.degree. C., particularly at 125 to 145.degree. C., most
preferably at about 135.degree. C. PMBC and NMPD are used in a
molar ratio of 1.0:0.5 to 1.0:2.0, preferably 1.0:0.7 to 1.0:1.5,
more preferably 1.0:1.0.
[0027] The amount of organic acid and organic solvent is determined
according to the amount of PMBC used. Up to 10 mol, preferably 2 to
8 mol, most preferably about 7 mol of organic acid and up to 2 mol,
preferably 0.5 to 1.5 mol, most preferably about 1 mol of
phosphorus pentoxide are used per mol of PMBC.
[0028] After the addition has ended the mixture is stirred for up
to 10 hours, preferably 1 to 4 hours, most preferably 3 hours at a
temperature of 100 to 160.degree. C., preferably 125 to 145.degree.
C., preferably 135.degree. C. Then, in order to hydrolyse the
excess acid component (anhydride, acid chloride), water is added to
the organic acid used, for example phosphorus pentoxide, at a
temperature of not more than 100.degree. C., preferably not more
than 90.degree. C., in a ratio of 1.0:2.0 to 1.0:0.1, preferably
1.0:1.4 to 1.0:0.2.
[0029] After hydrolysis is complete, the pH is adjusted to 0.2 to
1.8, preferably 0.5 to 1.5, most preferably 0.7 to 1.2, more
preferably 0.9 by the addition of a base, preferably sodium
hydroxide, sodium carbonate or an amine, most preferably sodium
hydroxide, sodium carbonate, ammonia, pyridine or triethylamine,
most preferably sodium hydroxide solution or ammonia, more
preferably sodium hydroxide. The temperature of the reaction
mixture should not exceed 100.degree. C. during this addition and
is preferably below 90.degree. C., most preferably from
70-80.degree. C.
[0030] While the temperature range remains constant, charcoal,
preferably activated charcoal, preferably "dry activated charcoal",
"moist activated charcoal" or "granulated activated charcoal", more
preferably "dry activated charcoal" of the SX 2, SX Ultra or L2S
grade is added to the reaction mixture to purify it. The activated
charcoal preferably used in the process according to the invention
may be obtained for example from the companies Norit, Atofma or
Begerow. The amount of charcoal used in each purification step
should be from 5 to 20 percent by weight, preferably from 6 to 15
percent by weight, most preferably from 8 to 12 percent by weight,
more preferably about 10 percent by weight of the amount of PMBC
used. The reaction mixture combined with charcoal is stirred for at
least 5 min, preferably 5 to 60 minutes, preferably 8 to 50
minutes, most preferably 10 to 30 minutes at a temperature of max.
90.degree. C., preferably at 50 to 80.degree. C., most preferably
at 70 to 75.degree. C. and then filtered or centrifuged, preferably
filtered. The purification step may be repeated one to ten times,
preferably one to five times, most preferably one to three times,
preferably twice, with the reaction mixture which has been filtered
or centrifuged in each case.
[0031] Then an organic solvent, preferably n-butanol,
tert.-butanol, 2-methyl-propanol, n-propanol, isopropanol, ethyl
acetate, dichloromethane, tetrahydrofuran or toluene, preferably
n-butanol or isopropanol, most preferably isopropanol, is added to
the reaction mixture with stirring. The amount of solvent is
determined by the amount of PMBC previously used in the process and
should be from 1:1 to 20:1, preferably from 1:1 to 10:1, most
preferably from 1:1 to 5:1, preferably 3:1.
[0032] After the addition of the solvent has ended, a base,
preferably sodium hydroxide, sodium carbonate or an amine, such as
e.g. ammonia, pyridine or triethylamine, most preferably sodium
hydroxide or ammonia, more preferably sodium hydroxide, is added at
a temperature of not more than 100.degree. C., preferably at 50 to
90.degree. C., most preferably at 70 to 80.degree. C., more
preferably at about 75.degree. C., to obtain a pH of 4 to 8,
preferably 5 to 7, more preferably about 5 to 6. The mixture is
stirred for at least 5 minutes, preferably 10 to 30 minutes, while
the temperature is kept constant. After the phase separation has
ended the aqueous phase is separated off and discarded.
[0033] To crystallise the product, acetone, ethyl acetate or water,
preferably acetone or water, most preferably water, is added to the
organic phase at ambient temperature or elevated temperature,
preferably by refluxing. The amount of water used corresponds to 50
to 200 percent by volume, preferably 70 to 150 percent by volume,
preferably percent by volume, most preferably 80 to 130 percent by
volume, more preferably 120 percent by volume of the organic
solvent used.
[0034] After the water has been added the mixture is cooled to a
temperature of not more than 40, preferably 5 to 30.degree. C.,
most preferably 10 to 20.degree. C., more preferably 15.degree.
C.
[0035] To isolate the product the mixture may be filtered or
centrifuged. The product thus obtained may be treated with a
washing solution containing water and one or more organic solvents
selected from among acetone, n-butanol, tert.-butanol, cyclohexane,
dichloromethane, ethyl acetate, isopropanol, methanol,
2-methyl-propanol, n-propanol, tetrahydrofuran, toluene or xylene,
preferably acetone, isopropanol or ethyl acetate, most preferably
isopropanol. As a rule the washing solution contains a ratio by
volume of organic solvent/water of 1:0 to 1:10, preferably from 1:1
to 1:8, most preferably from 1:1.5 to 1:6, more preferably 1:2.
Then the product is washed with water and dried, preferably in
vacuo, at not more than 110.degree. C., preferably not more than
100.degree. C., most preferably at 75 to 90.degree. C.
[0036] Variant B:
[0037] As a modification of Variant A the strongly acidic reaction
solution can be filtered through charcoal-filled containers or
cartridges at a pH of about 0.2 to 1.8, preferably 0.5 to 1.5, most
preferably 0.7 to 1.2, more preferably 0.9, instead of adding
charcoal to the reaction solution or adding the reaction solution
to the charcoal. The purification of the filtrate by extraction
with an organic solvent and the additional working up may be
carried out as described in Variant A.
[0038] Variant C:
[0039] As a modification of Variant A, instead of treating the
acidic to strongly acidic reaction solution with charcoal, it is
possible to treat the organic product solution with charcoal, for
example to add charcoal, to add it to charcoal or filter it through
charcoal, and the additional working up may be carried out as
described in Variant A.
[0040] Variant D:
[0041] As a modification of Variant A, B or C the extraction may be
carried out with a larger amount of the organic solvent, also at
lower temperature, and this may be reduced again before the
precipitation.
[0042] Variant E:
[0043] Another possible way of obtaining
1,7'-dimethyl-2'-propyl-bis-1H-be- nzimidazole as a pure product
comprises directly precipitating the reaction product once the
reaction has ended and hydrolysing it by the addition of a
sufficient quantity of a base, preferably sodium hydroxide, sodium
carbonate or an amine, such as e.g. ammonia, pyridine or
triethylamine, most preferably sodium hydroxide or ammonia, more
preferably sodium hydroxide or ammonia or adding the reaction
solution to a solution of the base. After subsequent filtration the
crude product, which may be dried, is dissolved in an organic acid
or an organic solvent or a mixture of solvents selected from among
methanesulphonic acid, isopropanol, n-butanol, ethyl acetate,
methanol or toluene, preferably methanesulphonic acid or
isopropanol, and the charcoal purification steps with subsequent
further working up are carried out as described in Variant A. If
methanesulphonic acid is used the precipitation may also be carried
out by the addition of an alcoholic, e.g. methanolic, sodium
hydroxide solution or by piping the product solution into an
alcoholic, for example methanolic, sodium hydroxide solution. In
this variant ascorbic acid or BHT
(2,6-di-tert-butyl-4-methoxyphenol) may be added, preferably
ascorbic acid.
[0044] The following Examples serve to illustrate the preparation
and purification of
1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole. They represent
only possible methods, without restricting the broad scope of the
present invention to their contents.
EXAMPLE 1 (Variant A)
[0045] Preparation and Purification of
1,7'-dimethyl-2'-propyl-2,5'-bi-1H-- benzimidazole
[0046] 70 kg of phosphorus pentoxide are dissolved (at
115-145.degree. C.) in 300 kg of methanesulphonic acid. At
125-145.degree. C., 100 kg of
2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (PMBC) and 90
kg of N-methyl-o-phenylene-diamine (NMPD) are added to this
solution. The reaction mixture is stirred for up to 4 hours at this
temperature and then cooled to about 80.degree. C. The mixture is
quenched with about 350 l of water. The pH is adjusted to about 1
by the addition of about 180 kg of 50% sodium hydroxide solution.
The strongly acidic reaction solution is combined with about 10 kg
of activated charcoal and stirred for at least 5 minutes at
70-80.degree. C. Then the charcoal is filtered off and washed with
water. The charcoal treatment of the solution is repeated up to 3
times. About 400 l of isopropanol are added to the filtrate with
stirring and the pH is adjusted to about 5 to 6 by the addition of
about 190 kg of 50% sodium hydroxide solution. During the
subsequent phase separation the lower aqueous phase is separated
off and discarded. To precipitate the product about 420 l of water
are added to the organic phase at reflux temperature. The mixture
is cooled to about 20.degree. C. The precipitated product is
centrifuged off and washed with about 280 l of a 2:1 mixture of
water and isopropanol and finally with about 70 l of water. The
isolated product is dried for at least 5 hours at not more than
90.degree. C. in vacuo. It has an HPLC purity of at least 99.5
percent by area. The yield is about 85% based on the PMBC used.
EXAMPLE 2 (Variant E)
[0047] Preparation and Purification of
17'-dimethyl-2'-propyl-2,5'-bi-1H-b- enzimidazole
[0048] 70 kg of phosphorus pentoxide are dissolved at
115-145.degree. C. in 300 kg of methanesulphonic acid. At
125-145.degree. C., 100 kg of
2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (PMBC) and 90
kg of N-methyl-o-phenylene-diamine (NMPD) are added to this
solution. The reaction mixture is stirred for up to 4 hours at this
temperature and then cooled to about 80.degree. C. The mixture is
quenched with about 540 l of water. To precipitate the product the
pH is adjusted to 5 to 6 at 50-60.degree. C. with about 370 kg of
50% sodium hydroxide solution. The product precipitated is
centrifuged and washed with 780-1040 l of water and dried at not
more than 90.degree. C. in vacuo. The yield is 80-100% based on the
PMBC used. 150 kg of 1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benz-
imidazole and 3 kg of ascorbic acid (optional) are suspended in 285
l of water and combined with 94 kg of methanesulphonic acid. About
10 kg of activated charcoal are added to the strongly acidic
solution and the suspension is stirred for at least 5 min. at 50 to
60.degree. C. Then the charcoal is filtered off and washed with
water. The charcoal treatment of the solution is repeated up to 6
times. In order to precipitate the product the filtrate is added to
a solution of about 88 kg of 45% sodium hydroxide solution and 150
l of methanol at 60-80.degree. C., with stirring. Alternatively,
the methanolic sodium hydroxide solution may also be added to the
filtrate. Then it is cooled to 10-25.degree. C. and the pH is
adjusted to about 9 to 12 with sodium hydroxide solution. Then the
product is centrifuged and washed with about 700 l of water. The
isolated product is dried at not more than 90.degree. C. in vacuo.
It has an HPLC purity of about 99.0 percent by area. The yield is
about 85% based on the
1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole used.
EXAMPLE 3 (Variant C)
[0049] Purification of
1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole
[0050] 150 kg of 1,7'-dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole
are dissolved at 70-80.degree. C. in 750 l of isopropanol and
combined with 7 kg of charcoal. After a minimum of 5 minutes'
stirring the charcoal is separated off and washed with about 70 l
of isopropanol and about 145 l of water. The charcoal treatment is
repeated up to 3 times. To precipitate the product, about 420 l of
water are added to the organic phase at reflux temperature. The
mixture is cooled to about 20.degree. C. The precipitated product
is centrifuged off and washed with about 400 l of a 2:1 mixture of
water and isopropanol and lastly with about 70 l of water. The
isolated product is dried for at least 5 hours at not more than
90.degree. C. in vacuo. It has an HPLC purity of at least 99.5
percent by area. The yield is 85-95% based on the
1,7'-dimethyl-2'-propyl- -2,5'-bi-1H-benzimidazole used.
* * * * *