U.S. patent application number 12/672264 was filed with the patent office on 2011-09-15 for process for the preparation of olmesartan medoxomil.
This patent application is currently assigned to LEK PHARMACEUTICALS D.D.. Invention is credited to Renata Toplak Casar.
Application Number | 20110224271 12/672264 |
Document ID | / |
Family ID | 39789494 |
Filed Date | 2011-09-15 |
United States Patent
Application |
20110224271 |
Kind Code |
A1 |
Toplak Casar; Renata |
September 15, 2011 |
PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL
Abstract
The present invention relates to a process for the preparation
and purification of trityl olmesartan medoxomil and olmesartan
medoxomil.
Inventors: |
Toplak Casar; Renata;
(Logatec, SI) |
Assignee: |
LEK PHARMACEUTICALS D.D.
Ljubljana
SI
|
Family ID: |
39789494 |
Appl. No.: |
12/672264 |
Filed: |
August 7, 2008 |
PCT Filed: |
August 7, 2008 |
PCT NO: |
PCT/EP2008/060400 |
371 Date: |
September 3, 2010 |
Current U.S.
Class: |
514/381 ;
548/253 |
Current CPC
Class: |
A61P 9/12 20180101; C07D
405/14 20130101; A61P 9/00 20180101 |
Class at
Publication: |
514/381 ;
548/253 |
International
Class: |
A61K 31/41 20060101
A61K031/41; C07D 403/10 20060101 C07D403/10; A61P 9/12 20060101
A61P009/12 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 8, 2007 |
EP |
07114000.8 |
Aug 8, 2007 |
EP |
07114004.0 |
Claims
1. A process for making trityl olmesartan medoxomil, the process
comprising the steps of: a) alkylating ethyl
4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (2)
with 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (3) in an
organic solvent, in the presence of a base, to produce trityl
olmesartan ethyl ester (4); b) hydrolysing the trityl olmesartan
ethyl ester (4) in an organic solvent, in the presence of a base,
to form trityl olmesartan salt (5); and c) esterifying the trityl
olmesartan salt (5) with
4-chloromethyl-5-methyl-1,3-dioxolene-2-one (7) in an organic
solvent, in the presence of a base, to form trityl olmesartan
medoxomil (6); wherein steps a) to c) are performed without
isolation of the intermediate products.
2. The process according to claim 1, wherein the same type of
organic solvent is used in each of steps a) to c).
3. The process according to claim 2, wherein the organic solvent is
N,N-dimethylacetamide.
4. The process according to claim 1, wherein the whole amount of
added base ranges between 2.5 and 10 equivalents, preferably
between 3 and 5 equivalents.
5. The process according to claim 1, wherein the same base is used
in each of steps a) to c).
6. The process according to claim 1, wherein the base is lithium
hydroxide or its hydrate.
7. The process according to claim 1, wherein the base is added
stepwise.
8. The process according to claim 1, wherein step a) is performed
at the temperature between 20 and 90.degree. C.
9. The process according to claim 1, wherein step b) is performed
at the temperature between 20 and 70.degree. C.
10. The process according to claim 1, wherein step c) is performed
at the temperature between 20 and 70.degree. C.
11. Trityl olmesartan medoxomil (6) obtained by a process according
to claim 1.
12. A process of preparing olmesartan medoxomil (1), the method
comprising the process according to claim 1 and then converting
trityl olmesartan medoxomil (6) to olmesartan medoxomil (1).
13. The process according to claim 12, wherein converting trityl
olmesartan medoxomil (6) to olmesartan medoxomil (1) comprises the
steps of: d) forming a solution containing the trityl olmesartan
medoxomil (6) and hydrohalic acid; e) forming olmesartan medoxomil
hydrohalide salt in solid form and isolating the olmesartan
medoxomil hydrohalide salt; and f) converting the olmesartan
medoxomil hydrohalide salt to olmesartan medoxomil (1).
14. The process according to claim 13, wherein step f) is performed
in the presence of a base, wherein the amount of base used raises a
pH to a value of about 5 to 8.
15. A process of obtaining a pharmaceutical formulation comprising
olmesartan medoxomil the method comprising the process according to
claim 12 and further comprising mixing the olmesartan medoxomil
with a pharmaceutically acceptable excipient.
16. The process according to claim 8, wherein step a) is performed
at the temperature between 30 and 60.degree. C.
17. The process according to claim 9, wherein step b) is performed
at the temperature between 40 and 60.degree. C.
18. The process according to claim 10, wherein step c) is performed
at the temperature between 40 and 60.degree. C.
19. The process according to claim 14, wherein step f) is performed
in the presence of a base, wherein the amount of base used raises a
pH to a value of about 5.5 to 6.5.
Description
FIELD OF THE INVENTION
[0001] The present invention is in the field of organic synthesis
and relates to a process for the preparation and purification of
trityl olmesartan medoxomil and olmesartan medoxomil.
BACKGROUND OF THE INVENTION
[0002] Olmesartan medoxomil is the name commonly given to
(5-methyl-2-oxo-1,3-dioxo--4-yl)methyl
1-(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2--
propyl-1H-imidazole-5-carboxylate, shown as (1) below. This
chemical is known as an antagonist of angiotensin-II receptors and
acts as an antihypertensive agent.
##STR00001##
[0003] According to an article in J. Med. Chem, 1996, 39, 323-338
titled Nonpeptide Angiotensin II Receptor Antagonists, by
Yanagisawa et el, olmesartan medoxomil is prepared as shown in the
Scheme 2. In this process chemical intermediates are isolated in
each step.
##STR00002## ##STR00003##
[0004] In the patent application WO2007/017135 two improved
processes for the synthesis of olmesartan medoxomil are
disclosed.
[0005] The first process includes the step of alkylating ethyl
4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (2)
with 4-[2-trityltetrazol-5-yl)phenyl]benzylbromide (3) and
isolating the resulting product as shown below in scheme 3.
##STR00004##
[0006] This step is followed in WO2007/17135 by the steps of
hydrolysis of the ethyl ester (4), the esterification with
4-substituted methyl-5-methyl-1,3-dioxolene-2-one derivative (7)
and the subsequent deprotection of the trityl protection group in a
one-pot process, i.e. without any isolation during the process, as
shown below in scheme 4. However, the presented one-pot process
includes partial purification of the intermediate trityl olmesartan
medoxomil (6) by extraction and exchange of the solvent before the
last reaction step.
##STR00005##
[0007] The second method provides the same alkylation reaction step
with isolation of the alkylation product and an alternative
synthetic approach in a one-pot process. Thus, the one-pot process
comprises the hydrolysis of the ethyl ester (4), the esterification
with 4-substituted methyl-5-methyl-1,3-dioxolene-2-one derivative
(7) and the subsequent cycloaddition reaction of the cyano moiety
forming the tetrazole group. But no experimental support is given
for this approach.
[0008] It would be desirable to improve the efficiency of known
processes for the preparation of olmesartan medoxomil, particularly
olmesartan medoxomil of high purity.
SUMMARY OF THE INVENTION
[0009] According to a first aspect, the present invention provides
a process for the preparation of trityl olmesartan medoxomil, the
process comprising the steps: [0010] a) alkylating ethyl
4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate with
4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in an organic
solvent, in the presence of a base, to produce trityl olmesartan
ethyl ester; [0011] b) hydrolysing the trityl olmesartan ethyl
ester in an organic solvent, in the presence of a base, to form
trityl olmesartan salt; and [0012] c) esterifying the trityl
olmesartan salt with 4-chloromethyl-5-methyl-1,3-dioxolene-2-one in
an organic solvent, in the presence of a base, to form trityl
olmesartan medoxomil; [0013] wherein steps a) to c) are performed
without isolation of the intermediate products.
[0014] According to another aspect, the present invention provides
trityl olmesartan medoxomil (6) obtained by a process according to
the first aspect of the invention.
[0015] According to yet another aspect, the present invention
provides a process of preparing olmesartan medoxomil (1),
characterized by comprising the process according to the first
aspect of the invention and converting trityl olmesartan medoxomil
(6) to olmesartan medoxomil (1).
[0016] According to further aspect, the present invention provides
a process of obtaining pharmaceutical formulation comprising
olmesartan medoxomil, characterized by comprising the process
according to previous aspect of the invention and further
comprising tableting.
[0017] Hence, the present aspect involves a "one-pot process" in
which intermediates are not isolated and preferably no material is
removed or exchanged. In preferred embodiments, the same type of
solvent and the same base are used in steps a) to c). Hence, the
process of the invention allows for improvements in efficiency to
be obtained as it is possible to use less solvent and less base as
it does not need to be changed during the process. The use of a
one-pot solution for manufacturing trityl olmesartan medoxomil is
simple and cost effective. The resultant trityl olmesartan
medoxomil is a crucial intermediate in the synthesis of olmesartan
medoxomil.
DETAILED DESCRIPTION OF THE INVENTION
[0018] Further aspects, advantageous features and preferred
embodiments of the first aspect of the invention summarized in the
following items, respectively alone or in combination, further
contribute to solving the object of the invention:
(i) The process according to the aforementioned first aspect,
wherein the same type of organic solvent is used in each of steps
a) to c). (ii) The process according to (i), wherein the organic
solvent is N,N-dimethylacetamide. (iii) The process according to
the first aspect, (i) or (ii), wherein the whole amount of added
base is ranging between 2.5 and 10 equivalents, preferably between
3 and 5 equivalents. (iv) The process according to the first aspect
or (i) to (iii), wherein the same base is used in each of steps a)
to c). (v) The process according to any one of the first aspect or
(i) to (iv), wherein the base is lithium hydroxide or its hydrate.
(vi) The process according to any one of the first aspect or (i) to
(v), wherein the base is added stepwise. (vii) The process
according to the first aspect, wherein step a) is performed at the
temperature between 20 and 90.degree. C., preferably between 30 and
60.degree. C. (viii) The process according to the first aspect,
wherein step b) is performed at the temperature between 20 and
70.degree. C., preferably between 40 and 60.degree. C. (ix) The
process according to the first aspect, wherein step c) is performed
at the temperature between 20 and 70.degree. C., preferably between
40 and 60.degree. C. (x) Trityl olmesartan medoxomil (6) obtained
by a process according to any one of the first aspect or (i) to
(ix). (xi) A process of preparing olmesartan medoxomil (1),
characterized by comprising the process according to the first
aspect or (i) to (ix) and converting trityl olmesartan medoxomil
(6) to olmesartan medoxomil (1). (xii) The process according to
(xi), wherein converting trityl olmesartan medoxomil (6) to
olmesartan medoxomil (1) comprises the steps of: [0019] d) forming
a solution containing the trityl olmesartan medoxomil (6) and
hydrohalic acid; [0020] e) forming olmesartan medoxomil hydrohalide
salt in solid form and isolating the olmesartan medoxomil
hydrohalide salt; and [0021] f) converting the olmesartan medoxomil
hydrohalide salt to olmesartan medoxomil (1). (xiii) The process
according to (xii), wherein step f) is performed in at least one
water miscible solvent and water. (xiv) The process according to
claim (xii), wherein step f) is performed in the presence of a
base, wherein the amount of base used raises a pH to a value of
about 5 to 8, more preferably of about 5.5 to 6.5. (xv) A process
of obtaining pharmaceutical formulation comprising olmesartan
medoxomil, characterized by comprising the process according to any
of the (xi) to (xiv) and further comprising mixing with
pharmaceutically acceptable excipient.
[0022] A one-pot process for the preparation of trityl olmesartan
medoxomil according to the preferred embodiments of the invention
is shown below in scheme 5.
##STR00006## ##STR00007##
[0023] In the embodiment shown in scheme 5, lithium hydroxide
hydrate is used as the base in each step, as is preferred in the
invention. The use of this soft base in all of the reaction steps
minimises the formation of impurities. The whole amount of base
necessary can be added at the beginning of the reaction, or can be
added stepwise during the one-pot process. Optionally, different
base can be used in any step.
[0024] Hence, the first step of the invention, step a), is
alkylating ethyl
4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (2)
with 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (3) in an
organic solvent, in the presence of a base, to produce trityl
olmesartan ethyl ester (4). The reaction is started by dissolving
(2) and (3) in an appropriate organic solvent and adding a base. An
appropriate type of organic solvent is selected from a group of
polar aprotic solvents such as N,N-dimethylformamide,
N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethylsulfoxide,
acetonitrile and mixtures thereof, preferably N,N-dimethylacetamide
is used. A base can be selected from a group of alkali metal
hydroxides such as lithium hydroxide, sodium hydroxide, potassium
hydroxide; a group of metal carbonates such as sodium carbonate,
potassium carbonate, caesium carbonate; a group of metal alkoxides
or a group of organic amines, preferably alkali metal hydroxides
are used, most preferable is lithium hydroxide. At the beginning of
the reaction step either 1 equivalent of the base can be added and
the following amount can be added step-wise during the one-pot
process or the whole amount of the base can be added at the
beginning of the alkylating reaction step. Preferably, 1 equivalent
of the base is added at the beginning of the alkylating reaction
step and the rest is added stepwise during the one-pot process. The
whole amount of the added base is ranging between 2.5 to 10
equivalents, preferably between 3 and 5 equivalents. The alkylating
reaction step is done by stirring the reaction mixture for 0.5 to
24 hours, preferably for 1 to 4 hours, at the temperature between
20 and 90.degree. C., preferably between 30 and 60.degree. C. After
alkylating reaction step is completed the resulting product trityl
olmesartan ethyl ester (4) is not isolated from the reaction
mixture.
[0025] The next step, b), involves hydrolysing the trityl
olmesartan ethyl ester (4) in an organic solvent, in the presence
of a base, to form trityl olmesartan salt (5). This reaction step
is done by optionally adding the next portion of a base to the
reaction mixture obtained by completion of the previous alkylation
step. A base is selected from a group of alkali metal hydroxides
such as lithium hydroxide, sodium hydroxide, potassium hydroxide,
preferably lithium hydroxide is used. The amount of the added base
is ranging between 1 and 5 equivalents, preferably 1 to 3
equivalents of the base are added. The reaction mixture is stirred
for 5 to 120 hours, preferably between 24 and 72 hours at the
temperature ranging from 20 to 70.degree. C., preferably at the
temperature between 40 and 60.degree. C. After hydrolysing reaction
step is completed the resulting product trityl olmesartan salt (5)
is not isolated from the reaction mixture.
[0026] The final step in the one-pot process is step c),
esterifying the trityl olmesartan salt (5) with
4-chloromethyl-5-methyl-1,3-dioxolene-2-one (7) in an organic
solvent, in the presence of a base, to form trityl olmesartan
medoxomil (6). This is done by optionally adding the next portion
of a base to the reaction mixture obtained by completion of the
previous hydrolysing step. A base can be selected from a group of
alkali metal hydroxides such as lithium hydroxide, sodium
hydroxide, potassium hydroxide or a group of metal carbonates such
as sodium carbonate, potassium carbonate, ceasium carbonate,
preferably lithium hydroxide or potassium carbonate in an amount of
0.5 to 1.5 equivalent are added to the reaction mixture. Addition
of the base is followed by addition of
4-chloromethyl-5-methyl-1,3-dioxolene-2-one (7). Preferably,
reagent (7) is dissolved in an organic solvent and the solution is
added dropwise to the reaction mixture, most preferably the same
solvent as in reaction mixture is used for preparation of solution
of (7). (7) is added in an amount of 1 to 2.5 equivalents,
preferably in an amount between 1.2 to 2 equivalents. The reaction
is performed by stirring the reaction mixture for 2 to 24 hours,
preferably 3 to 8 hours at the temperature ranging between 20 and
70.degree. C., preferably at the temperature between 40 and
60.degree. C. After esterification reaction step is completed the
resulting product trityl olmesartan medoxomil (6) is isolated from
the reaction mixture. The mixture is poured into large amount of
water or water acetone mixture (V/V 95:5) and the product is
precipitated from the medium. Intermediate (6) is collected by
filtration and optionally purified by recrystallisation to obtain
final intermediate for preparation of olmesartan medoxomil of high
purity.
[0027] By "one-pot process" we mean that the relevant steps are
performed in sequence without isolating the product of each step,
furthermore the process of the invention is additionally simplified
by omitting removal or exchange of any other component of the
reaction mixture.
[0028] Using a one-pot process is a simple and cost effective
method of organic synthesis but is only commercially valuable where
the level of impurities can be minimised to give a reasonable
yield. In the present case, the inventors have found that use of a
one-pot process gives good results, particularly with the use of
lithium hydroxide hydrate as a base. Such a procedure does not
allow unacceptable levels of unreacted intermediates and side
products to accumulate and because the one pot reaction does not
include the last chemical step of preparation of the active
pharmaceutical ingredient, further purification is conveniently
carried out. The impurities are efficiently removed by simple
recrystallisation of (6) and/or during the further step of reaction
of deprotection of (6), during the isolation and purification of
final product (1) in order to reach an active pharmaceutical
ingredient of high chemical purity substantially free of unreacted
intermediates and side products such as olmesartan ethyl ester (8)
(Scheme 6).
##STR00008##
[0029] Thus, olmesartan medoxomil can be prepared by converting
trityl olmesartan medoxomil into olmesartan medoxomil by any known
or invented process for cleavage of trityl protection group. Scheme
7 below shows a synthetic method for deprotection of trityl
olmesartan medoxomil, which may be applied in the invention.
##STR00009##
[0030] In a preferred embodiment of the invention, the process of
converting trityl olmesartan medoxomil to olmesartan medoxomil
comprises the steps of: d) forming a solution containing the trityl
olmesartan medoxomil (6) and hydrohalic acid; e) forming olmesartan
medoxomil hydrohalide salt in solid form and isolating the
olmesartan medoxomil hydrohalide salt; and d) converting the
olmesartan medoxomil hydrohalide salt to olmesartan medoxomil (1).
This method of forming olmesartan medoxomil is particularly
advantageous as it leads to the product of high purity.
[0031] In this embodiment of the invention, there are essentially
two possible routes. In the first, (6) is deprotected in the
solution containing hydrohalic acid comprising a mixture of one or
more water miscible organic solvents and water. The water miscible
organic solvent is preferably selected from the group consisting of
a C.sub.1 to C.sub.6 alcohol, a C.sub.1 to C.sub.6 ketone, a
C.sub.1 to C.sub.6 nitrile, a C.sub.1 to C.sub.6 amide, a C.sub.1
to C.sub.6 ether, dimethyl sulfoxide, or mixtures thereof, wherein
the water miscible organic solvent preferably comprises acetone,
acetonitrile, ethanol, t-butanol, or 1,4-dioxane and most
preferably comprises acetone.
[0032] Hydrohalic acids are preferably used as water solutions in
concentrations above 10 w/w %, most preferably commercial
concentrated acids like 48% or 62% hydrobromic acid or 35-38%
hydrochloric acid. 48% hydrobromic acid is the most preferable. The
organic solvent to water ratio is preferably between 10:1 and 1:4
by volume, more preferably between 4:1 and 1:1 by volume.
[0033] In this case, the deprotection, preferably detritylation
reaction is carried out at temperatures from 20.degree. C. to
reflux preferably from 25 to 30.degree. C. Prior to separating the
precipitated triphenylmethanol, water is added to the mixture to
change the organic solvent to water ratio to about 1:3 to about
1:5, preferably to about 1:4. Triphenylmethanol is subsequently
separated from the solution by any means known in the art, such as
centrifugation or filtration.
[0034] The filtrate is concentrated to completely or partially
remove organic solvents and the resulting aqueous suspension is
stirred at temperatures ranging from 0.degree. C. to room
temperature to achieve maximum yield, then filtered to collect
olmesartan medoxomil hydrohalide salt.
[0035] In the second possible route of this embodiment of the
invention, (6) is deprotected in tetrahydrofuran in the presence of
hydrohalic acid. The detritylation reaction is carried out at
temperatures from 20.degree. C. to reflux preferably from 25 to
30.degree. C., and isolation is performed by cooling to -10 to
5.degree. C. preferably to around 0.degree. C. In this case
triphenylmethanol remains dissolved, while olmesartan medoxomil
hydrohalide salt is precipitated by said cooling or by adding
antisolvent selected from aromatic or aliphatic hydrocarbons and
acyclic ethers, particularly preferably acyclic ethers, most
preferably diisopropylether.
[0036] Olmesartan medoxomil hydrohalide salt can optionally be
recrystallised, preferably from tetrahydrofuran.
[0037] In order to convert the olmesartan medoxomil hydrohalide
salt to olmesartan medoxomil, the olmesartan medoxomil hydrohalide
salt is dissolved in the mixture of at least one water miscible
solvent and water. Suitable water miscible organic solvents
include, but are not limited to, acetone, acetonitrile, lower
alcohols, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide,
N,N-dimethylformamide, N,N-dimethylacetamide. Alcohols, acetone and
acetonitrile are preferred; acetone is the most preferred. The
organic solvent to water ratio is preferably between 2:1 and 1:3 by
volume, more preferably about 1:2 by volume.
[0038] To this solution is added aqueous solution of inorganic base
selected from alkali and alkaline earth carbonates, hydrogen
carbonates, hydroxides, alkoxides, preferably hydrogen carbonates,
more preferably NaHCO.sub.3. The amount of base used should be such
to raise the pH to about 5 to 8, more preferably 5.5 to 6.5. The
temperature of the mixture should be maintained at about 0 to about
30.degree. C., more preferably at about 20 to about 25.degree. C.,
until olmesartan medoxomil is precipitated, and then at about 0 to
about 5.degree. C. to achieve maximum yield.
[0039] The precipitated olmesartan medoxomil is collected using any
method known in the art, such as centrifugation or filtration.
[0040] Optionally olmesartan medoxomil may be recrystalized from a
suitable solvent such as acetone, acetonitrile, methanol, ethanol,
propanol, 2-propanol, methyl acetate, ethyl acetate, isopropyl
acetate and mixtures thereof or mixtures thereof with water;
preferably acetone and acetonitrile, more preferably
acetonitrile.
[0041] Olmesartan medoxomil obtained by a process comprising any of
the aforementioned embodiments can be further used in a process of
obtaining the pharmaceutical formulation comprising olmesartan
medoxomil. The pharmaceutical formulation comprising olmesartan
medoxomil can be prepared by methods well known to a person skilled
in the pharmaceutical technology. For example, olmesartan medoxomil
is mixed with pharmaceutically acceptable excipient, which can be
selected from a group of binder, filler, disintegrant, surfactant,
glidant, lubricant, wetting agent, colouring agent, acidifying or
alkalizing agents, and the like. Preferably, prepared mixture is
further used in tableting. Tableting may be performed after wet
granulation or preparation of a mixture for direct compression or
other possible preparatory technology on a tableting equipment.
EXAMPLES
[0042] The following examples are merely illustrative of the
present invention and they should not be considered as limiting the
scope of the invention in any way, as these examples and other
equivalents thereof will become apparent to those versed in the art
in the light of the present disclosure, and the accompanying
claims.
Example 1
One-Pot Synthesis of Trityl Olmesartan Medoxomil (6)
[0043] 4 g (16.7 mmol) of ethyl
4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (2),
9.28 g (16.7 mmol) of
4-[2-(trityltetrazol-5-yl)phenyl]benzylbromide (3) and 0.7 g (16.7
mmol) of lithium hydroxide hydrate are suspended in 70 mL of
N,N-dimethylacetamide.
[0044] The reaction mixture is stirred for 3 h at 50.degree. C. and
then an additional 1.05 g (25 mmol) of lithium hydroxide hydrate is
added to the reaction mixture. The reaction mixture is stirred for
the next 40 hours at 50.degree. C., which is followed by addition
of the third portion of lithium hydroxide hydrate (0.35 g, 8.33
mmol) and portion-wise addition of a solution of 3.84 g (24.6 mmol)
of 4-chloromethyl-5-methyl-1,3-dioxolene-2-one (7) (94%) in 10 mL
of N,N-dimethylacetamide.
[0045] A further 7 hours of stirring the reaction mixture at
50.degree. C. is needed to complete the reaction. In order to
precipitate the product the reaction mixture is poured into 400 mL
of water and the formed suspension is stirred overnight. The
precipitate is filtered off and washed with 200 mL of water. The
wet filter cake is recrystallised from acetone yielding 10.16 g
(76%) of trityl olmesartan medoxomil (6) (HPLC purity 93.1 area
%).
Example 2
One-Pot Synthesis of Trityl Olmesartan Medoxomil (6)
[0046] 4 g (16.7 mmol) of ethyl
4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (2),
9.28 g (16.7 mmol) of 4-[2-(trityltetrazol-5-yl)phenyl]
benzylbromide (3) and 1.75 g (41.6 mmol) of lithium hydroxide
hydrate are suspended in 70 mL of N,N-dimethylacetamide.
[0047] The reaction mixture is stirred for 46 hours at 50.degree.
C. and then 2.53 g (18.32 mmol) of K.sub.2CO.sub.3 and portion-wise
4.0 g (23.0 mmol) of 4-chloromethyl-5-methyl-1,3-dioxolene-2-one
(7) (85%) in 10 mL of N,N-dimethylacetamide are added. The reaction
mixture is stirred at 50.degree. C. for the next 5 hours to
complete the reaction.
[0048] The product is precipitated from the reaction mixture by
pouring it into 400 mL of a mixture of water and acetone
(V/V=95/5). The formed suspension is stirred overnight and the
precipitate is filtered off and washed with 200 mL of water. The
wet filter cake is recrystallised from acetone yielding 9.95 g
(75%) of trityl olmesartan medoxomil (6) (HPLC purity 97.7 area
%).
Example 3
One-Pot Synthesis of Trityl Olmesartan Medoxomil (6)
[0049] 4 g (16.7 mmol) of ethyl
4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5 carboxylate (2),
9.28 g (16.7 mmol) of
4-[2-(trityltetrazol-5-yl)phenyl]benzylbromide (3) and 0.7 g (16.7
mmol) of lithium hydroxide hydrate are suspended in 70 mL of
N,N-dimethylacetamide. The reaction mixture is stirred for 45 min
and then next portion of lithium hydroxide hydrate (2.10 g, 50
mmol) is added to the reaction mixture. After stirring for 48 hours
at 50.degree. C. portion-wise 4.9 g (31.0 mmol) of
4-chloromethyl-5-methyl-1,3-dioxolene-2-one (7) (94%) in 10 mL of
N,N-dimethylacetamide is added. The reaction mixture is stirred
further at 50.degree. C. for 6 hours to complete the reaction. The
product is precipitated from the reaction mixture by pouring it
into 400 mL of a mixture of water and acetone (V/V=95/5). The
formed suspension is stirred overnight and the precipitate is
filtered off and washed with 200 mL of water. The wet filter cake
is recrystallised from acetone yielding 9.56 g (72%) of trityl
olmesartan medoxomil (6) (HPLC purity 96.3 area %).
Preparation Procedure 4:--Transformation of Trityl Olmesartan
Medoxomil (6) to Olmesartan Medoxomil (1)
[0050] 10 g (12.5 mmol) of trityl olmesartan medoxomil (6) prepared
by the example 1 is suspended in 50 mL of a mixture acetone and
water (V/V=3:1). 4.75 mL of 48% hydrobromic acid is added to the
suspension. After stirring the reaction mixture for 2 hours 100 mL
of water is added. The precipitated triphenylmethanol is filtered
off. Acetone is evaporated from the filtrate. The resulting
concentrate is stirred at room temperature for 0.5 hour and for
additional 1 hour at 0.degree. C. The precipitated olmesartan
medoxomil hydrobromide is filtered (1) (HPLC purity 99.80 area %).
Olmesartan medoxomil hydrobromide is then dissolved in a mixture of
water (55 ml) and acetone (30 ml). To a clear solution saturated
aqueous NaHCO.sub.3 is added to raise pH to 5.6. The mixture is
stirred for 1 hour at room temperature and 2 hours at 0.degree. C.
The precipitate is filtered, washed with water and then
recrystallised from acetonitrile (45 ml) to give olmesartan
medoxomil.
Preparation Procedure5:--Transformation of Trityl Olmesartan
Medoxomil (6) to Olmesartan Medoxomil (1)
[0051] Trityl olmesartan medoxomil (250 g, 310 mmol) (97.3% area)
is dissolved in THF (1560 ml) and 48% aqueous hydrobromic acid
(70.6 ml, 625 mmol) is added slowly. The mixture is stirred for at
25.degree. C. After 1 hour the precipitate forms. The mixture is
stirred for 1 additional hour at 25.degree. C., then cooled to
-5.degree. C. and stirred for 1.5 hours at -5.degree. C. The
precipitate is filtered. 940 ml of THF is added to the precipitate
and the mixture is stirred for 1 h at 25.degree. C. and then 1 hour
at -5.degree. C. Then precipitate is filtered off and washed with
cold THF (150 ml). It is then dissolved in a mixture of water (875
ml) and acetone (440 ml). To a clear solution 5% aqueous solution
of NaHCO.sub.3 is added to raise pH to 5.15. The mixture is stirred
for 1 hour at room temperature and 1 hour at 0.degree. C. The
precipitate is filtered, washed with water and then recrystallised
from a mixture of acetonitrile (280 ml) and water (70 ml) to give
124.5 g of olmesartan medoxomil (99.68% area).
* * * * *