WO2011102645A2 - An improved process for preparing telmisartan - Google Patents

An improved process for preparing telmisartan Download PDF

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Publication number
WO2011102645A2
WO2011102645A2 PCT/KR2011/001041 KR2011001041W WO2011102645A2 WO 2011102645 A2 WO2011102645 A2 WO 2011102645A2 KR 2011001041 W KR2011001041 W KR 2011001041W WO 2011102645 A2 WO2011102645 A2 WO 2011102645A2
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Prior art keywords
compound
formula
telmisartan
preparing
reaction
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PCT/KR2011/001041
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French (fr)
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WO2011102645A3 (en
Inventor
Yoon-Seok Oh
Jae-Kyung Lim
Jung-Uk Choi
O-Jin Kwon
Jun-Sang Lee
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Dong Wha Pharm. Co., Ltd.
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Publication of WO2011102645A2 publication Critical patent/WO2011102645A2/en
Publication of WO2011102645A3 publication Critical patent/WO2011102645A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to an improved process for preparing a telmisartan used as angiotensin II receptor antagonist.
  • a telmisartan is expressed by the following formula 1.
  • the telmisartan has been prepared by a process described in the following scheme 1 or a process described in the following scheme 2.
  • the preparing process expressed by the following scheme 1 is disclosed in US Patent Application No. 5,591,762 and European Patent Application No. 1,912,975.
  • the following scheme 1 shows the process for preparing a t -butyl ester compound as the compound of the following formula 6 by the condensation reaction of the compound of the following formula 2 and the compound of the following formula 5, and shows the process for preparing the telmisartan as the target compound by the hydrolysis of the compound of the following formula 6 in the process for preparing the telmisartan as the compound of the formula 1
  • the US Patent application No. 5,591,762 is characterized by preparing the compound of the formula 1 by hydrolyzing the t -butyl ester compound as the compound of the formula 6 using trifluoroacetic acid in N,N -dimethylformamide as reaction solvent in the process for preparing the telmisartan as the compound of the formula 1 from the compound of the formula 6 as the intermediate.
  • the prior conventional process needs a work-up process (after adjusting pH using purified water and organic solvent after distillation under reduced pressure, separating layers from each other, washing the organic layer using the purified water, and distilling the extracted organic layer) to remove sodium trifluoroacetate as an inorganic salt corresponding to a byproduct since the hydrolysis reaction is induced by using an excess of trifluoroacetic acid as a poisonously strong acid and an excess of base is used for neutralization.
  • the prior conventional process separates the telmisartan by using a silica gel column chromatography after the work-up process is finished. Accordingly, the prior art has a disadvantage that complexifies a preparing process, thereby causing very low yield.
  • a process for preparing the telmisartan as the compound of the formula 1 using the compound of the formula 6 as the intermediate, namely the t -butyl ester compound is characterized by the steps of: obtaining a t- butyl ester hydrochloride compound by treating the t -butyl ester compound as the intermediate with hydrochloric acid; obtaining a telmisartan dihydrochloride compound by inducing the hydrolysis with hydrochloric acid, and obtaining the telmisartan as the target compound by adjusting pH with aqueous ammonia solution.
  • the prior art is not suitable for mass production, since the process for preparing the telmisartan as the target compound from the compound of the formula 6 as the intermediate is complicated and three processes for preparing the telmisartan as the target compound from the intermediate have a low total yield of 54.5%.
  • the process for preparing the telmisartan described as the following scheme 2 is disclosed in US Patent No. 7,501,448, European Patent No. 1,748,990, European Patent No. 1,805,146, International Patent WO 2009/006860, US Patent Publication No. 2006/276525, Chinese Patent No. 1,344,712, US Patent Publication No. 2006/211866, etc.
  • the compound of the following formula 4 is prepared by the condensation reaction of the compound of the following formula 2 and the compound of the following formula 3 and the telmisartan as the target compound is prepared by hydrolyzing the compound of the following formula 4.
  • US Patent No. 7,501,448 is characterized in that the telmisartan as the target compound is prepared by simultaneously performing the condensation reaction and the hydrolysis reaction using the compound of the formula 2 and the compound of the formula 3 within one process, an excess of base (6.5 ⁇ 8 equivalents) is used for simultaneously performing the condensation reaction and the hydrolysis reaction, and the layers are separated from each other and the organic layer is separately processed after the reactions are finished.
  • the prior conventional process has a weakness that needs a considerable time for obtaining the target compound through the work-up process to remove the inorganic salt as the byproduct since an excess of base is used for performing the condensation reaction and the hydrolysis reaction within one process.
  • the preparing process has a disadvantage that complexifies the preparing process since the organic layers are separately processed to obtain the target compound, thereby causing low yield.
  • the European Patent No. 1,748,990 is characterized in that the telmisartan as the target compound is prepared by simultaneously performing the condensation reaction and the hydrolysis reaction using the compound of the formula 2 and the compound of the formula 3 within one process, an excess of base (5.4 ⁇ 7.6 equivalents) is used for simultaneously performing the condensation reaction and the hydrolysis reaction, and the telmisartan as the target compound is obtained by extracting with dichloromethane, distilling under reduced pressure, adding acetone, and performing a filtering process after the reactions are finished.
  • the preparing process has a disadvantage that needs a considerable time for obtaining the target compound through the work-up process to remove the inorganic salt as the byproduct since an excess of base is used for performing the condensation reaction and the hydrolysis reaction within one process.
  • the preparing process has a fatal disadvantage that does not fit for mass product since the dichloromethane remains as the residual solvent in the telmisartan as the target compound.
  • the European Patent No. 1,805,146 is characterized in that the telmisartan is prepared by performing the condensation reaction and the hydrolysis reaction in two steps, the compound of the formula 4 as the intermediate is prepared by using an excess of methyl 2-[4-(bromomethyl) phenyl] benzoate compound (1.6 equivalents) as the compound of the formula 3 in the condensation reaction step of the reaction steps, and the hydrolysis reaction is performed after preparing telmisartan methylester hydrochloride compound by using hydrochloric acid dissolved in methanol after the condensation reaction is finished.
  • telmisartan potassium salt is obtained by using an excess of potassium hydroxide (5.3 equivalents) in solvent of acetonitrile.
  • the telmisartan is prepared by adjusting pH with acetic acid in the mixed solvent of acetonitrile and water including compound of telmisartan potassium salt.
  • the preparing process has the possibility that the remaining compound of the formula 3 is present as the impurity of the intermediate after the condensation reaction since an excess of the compound of the formula 3 is used in the condensation reaction.
  • the preparing process has a weakness that needs a considerable time for obtaining the target compound through the work-up process since an excess of basic compound is used for performing the hydrolysis.
  • the preparing process has a disadvantage that causes a complicated preparing process and a low yield to prepare the telmisartan as the target compound from the compound of the formula 4.
  • the International Patent Publication WO 2009/006860 is characterized in that the amount of water is maintained at less than 1% in the hydrolysis reaction for preparing the telmisartan as the target compound in the scheme 2, an excess of potassium hydroxide (3.5 equivalents) is added to the compound of the formula 3 as the intermediate, refluxed for 24 hours in solvent of methanol, and the telmisartan is prepared by adjusting pH with acetic acid or formic acid after the reaction is finished.
  • the preparing process has a disadvantage that needs a considerable time for obtaining the target compound since an excess of basic compound is used in the hydrolysis reaction, the reaction time is long, and the filtering time is slow in the filtering process (the hydrolysis reaction includes the reaction in solvent of methanol (including water at less than 1%) and the filtering speed is reduced and the inorganic salt remains in the filtered solid since potassium acetate or potassium formate as inorganic salt is precipitated in adjusting pH after the hydrolysis) .
  • the preparing process of the US Patent Publication No. 2006/276525 is to prepare the telmisartan by reacting with an excess of aqueous sodium hydroxide solution (3.3 equivalents) in methanol of 6 times and the small amount of water, distilling solvent part under reduced pressure after the reaction, filtering an insoluble material after adding water of 10 times at 85°C, and filtering after neutralization with the acetic acid in the scheme 2 for preparing the telmisartan as the target compound using the compound of the formula 4 as the intermediate.
  • the prior conventional process has disadvantages that need the work-up process by using an excess of basic compound in the hydrolysis reaction, reduce largely real filtering speed by precipitating a crystal only in water, obtain a low total yield of 62.3% by performing several times of purification process due to the low purity of the target material, and require a lot of preparing steps unsuitable for the mass production.
  • the telmisartan methylester compound as the intermediate is prepared by using an excess of potassium carbonate (3 equivalents) from the compound of the formula 2 and the compound of the formula 3 in the scheme 2.
  • the telmisartan as the target compound is prepared by using ethanol of 3.8 times and aqueous sodium hydroxide solution of 4M, distilling until the residues become 2.3 times after the reaction is finished, adjusting pH with hydrochloric acid, filtering a crystal, and purifying with N,N-dimethylformamide.
  • the preparing process has disadvantages that need the work-up process by using an excess of basic compound in the condensation reaction, causes the presence of the inorganic salt in the crystal by using the small amount of water, and obtain a low yield of 75.1%.
  • the telmisartan methylester as the intermediate is prepared by using an excess of potassium hydroxide (4 equivalents) and a small amount of t-butylammonium bromide as a phase transfer catalyst and reacting with methylisobutylketone/purified water of 4/5 in the scheme 2.
  • the telmisartan as the target compound is prepared by reacting in aqueous solution of methanol with an excess of potassium hydroxide (4 equivalents) in the hydrolysis reaction.
  • the preparing process needs a process for separating the telmisartan from solvent of methanol by melting, filtering, and condensing the telmisartan including the inorganic salt in the dichloromethane/methanol of 8/2 to remove the inorganic salt as the byproduct included in the telmisartan solid obtained by adjusting pH after the hydrolysis reaction.
  • the preparing process has a disadvantage that obtains the low yield of 73.0%.
  • the inventors of the present invention prepare the intermediate by using mixed solvent of dimethyl sulfoxide of 0.5 ⁇ 1.5 times and isopropanol of 1.5 ⁇ 4.5 times on the basis of the usage of 4-methyl-6-(1-methyl-1 H -benzimidazole-2-yl)-2-propyl-1 H - benzimidazole in the condensation reaction while studying the process for easily removing the inorganic salt as the byproduct generated by the base added in the condensation reaction and the hydrolysis reaction in the process for preparing the telmisartan using the scheme 2.
  • the inventors of the present invention don ⁇ t need an additional process for removing the inorganic salt as the byproduct by preparing the telmisartan through the hydrolysis reaction in the mixed solvent of methanol of 7 ⁇ 9 times and purified water of 5 ⁇ 7 times on the basis of the intermediate. Accordingly, the inventors of the present invention complete the improved process of the telmisartan which can be suitable for the mass production and can be prepared in the high purity and the high yield.
  • the present invention provides a process for preparing methyl 2-(4- ⁇ [4-methyl-6-(1-methyl-1 H -benzimidazole-2-yl)-2-propyl-1 H -benzimidazole-1-yl]methyl ⁇ phenyl)benzoate compound as the intermediate by the condensation reaction from 4-methyl-6-(1-methyl-1 H -benzimidazole-2-yl)-2-propyl-1 H -benzimidazole compound and methyl 2-[4-(bromomethyl)phenyl] benzoate compound, and preparing the telmisartan by performing the hydrolysis reaction thereto.
  • the present invention provides a process which can easily remove the inorganic salt as the byproduct generated in the condensation reaction and the hydrolysis reaction and can prepare the telmisartan as the target compound with the high yield and the high purity.
  • the present invention relates to the process for preparing the telmisartan as the compound of the following formula 1.
  • the telmisartan of the prevent invention is prepared by the process using the following scheme 2 disclosed in the prior art.
  • the Scheme 2 is used for preparing methyl 2-(4- ⁇ [4-methyl-6-(1-methyl-1 H -benzimidazole-2-yl)-2-propyl-1 H -benzimidazole-1-yl]methyl ⁇ phenyl)benzoate compound by performing the condensation reaction for 4-methyl-6-(1-methyl-1 H -benzimidazole-2-yl)-2-propyl-1 H -benzimidazole compound as the compound of the formula 2 and methyl 2-[4-(bromomethyl) phenyl] benzoate compound as the compound of the formula 3.
  • the telmisartan as the compound of the formula 1 is prepared by performing the hydrolysis reaction for the intermediate of the telmisartan as the target compound.
  • the present invention provides the preparing process of the telmisartan which is prepared according to the Scheme 2. Namely, the present invention provides the process for preparing the intermediate by the condensation reaction of the compound of the formula 2 and the compound of the formula 3, and preparing the telmisartan as the compound of the formula 1 by performing the hydrolysis reaction.
  • the process provides that the condensation reaction using dimethyl sulfoxide of 0.5 ⁇ 1.5 times and isopropanol of 1.5 ⁇ 4.5 times on the basis of the usage of the compound of the formula 2 in the preparing step of the compound of the compound of the formula 4 as the intermediate and the hydrolysis reaction in the mixed solvent of methanol of 7 ⁇ 9 times and purified water of 5 ⁇ 7 times on the basis of the usage of the compound of the formula 4 in the preparing step of the telmisartan as the target compound.
  • the prior conventional process for preparing the telmisartan according to the scheme 2 has disadvantages that use an excess of base in the process for preparing the telmisartan methylester compound corresponding to the intermediate as the compound of the formula 4, and need the process for removing the inorganic salt generated as the byproduct.
  • the condensation reaction for preparing the compound of the formula 4 as the intermediate is performed under a stream of nitrogen, reacted using the mixed solvent of dimethyl sulfoxide of 0.5 ⁇ 1.5 times and isopropanol of 1.5 ⁇ 4.5 times and potassium t-butoxide of 1 ⁇ 1.2 equivalents as the base on the basis of the usage of the compound of the formula 2.
  • the compound of the formula 4 as the intermediate can be obtained by stirring after adding purified water of 4 ⁇ 7 times in the mixture, filtering a crystal, washing with purified water and acetone, and drying.
  • the reaction temperature is maintained in the range of 10°C to 80°C desirably in the range of 25°C to 50°C.
  • isopropanol and purified water are fixed in the ratio of 3:5 in order to determine the amount of dimethyl sulfoxide.
  • the amount of dimethyl sulfoxide is changed in orders of 0.1 times, 0.5 times, 1.5 times, and 2.5 times.
  • the compound of the formula 4 is prepared and obtained by the same process as the following example 1 of experiment. The yield and the purity of the compound of the formula 4 are described as follows.
  • the compound of the formula 4 has the low purity of 93.0%. In case using dimethyl sulfoxide of 2.5 times, the compound of the formula 4 has the low yield of 87.5%.
  • the amount of dimethyl sulfoxide must be 0.5 ⁇ 1.5times on the basis of the usage of the compound of the formula 2.
  • dimethyl sulfoxide and purified water are fixed in the ratio of 1:5 in order to determine the amount of isopropanol.
  • the amount of the isopropanol is changed in orders of 0.5 times, 1.5 times, 4.5 times, and 6 times.
  • the compound of the formula 4 is prepared and obtained by the same process as the following example 1 of experiment. The yield and the purity of the compound of the formula 4 are described in the following Table 2.
  • the stirring state and the purity (90.8%) according to the preparation of the compound of the formula 4 are bad.
  • the compound of the formula 4 has the low yield of 80.2%.
  • the amount of the isopropanol must be 1.5 ⁇ 4.5times on the basis of the usage of the compound of the formula 2.
  • dimethyl sulfoxide and isopropanol are fixed in the ratio of 1:3 in order to determine the amount of purified water.
  • the amount of purified water is changed in orders of 2, 4, 7, and 9 times, 1.5 times.
  • the compound of the formula 4 is prepared and obtained by the same process as the following example 1 of experiment. The yield and the purity of the compound of the formula 4 are described in the following Table 3.
  • the compound of the formula 4 as the intermediate has the low yield of 85.4%. In case using purified water of 9 times, the compound of the formula 4 as the intermediate has the low purity of 92.1%.
  • the amount of purified water must be 4 ⁇ 7 times on the basis of the usage of the compound of the formula 2.
  • the condensation reaction according to the present invention is to cause the reaction with the potassium t-butoxide of 1 ⁇ 1.2 equivalents in the reaction solvent of dimethyl sulfoxide of 0.5 ⁇ 1.5 times and isoprpanol of 1.5 ⁇ 4.5 times on the basis of the usage of the compound of the formula 2.
  • the crystal is precipitated and filtered by adding purified water of 4 ⁇ 7 times after the reaction is finished. Accordingly, the condensation reaction according to the present invention can be particularly useful in the mass production since the compound of the formula 4 corresponding to the telmisartan methylester compound as the intermediate can be obtained in the high yield of 95.1% by a simple process.
  • the reaction solvent has the proper ratio of purified water of 5 ⁇ 7 times and methanol of 7 ⁇ 9 times on the basis of the usage of the compound of the formula 4.
  • the sufficient amount of purified water and methanol are added during precipitating a crystal by adding hydrochloric acid.
  • the compound of the formula 1 is prepared by performing washing with the sufficient amount of the purified water in the washing process.
  • the excesses of the base and the acid are used in the process for preparing the telmisartan through the hydrolysis reaction, which needs the process for removing the inorganic salt generated as the byproduct and causes the slow filtering speed in the filtering process of the precipitated solid from the used solvent.
  • the conventional technology using the scheme 1 needs the complicated process for preparing the telmisartan by separating with a silica gel column chromatography after the work-up process after the completion of the reaction in order to remove the inorganic salt generated as byproduct by using trifluoroacetic acid as strong acid.
  • the conventional technologies need the process for removing the inorganic salt as the generated byproduct by using the excess of the base in the condensation reaction and the hydrolysis reaction and are not suitable for the mass production since the filtering process is slow.
  • the hydrolysis reaction for preparing the compound of the formula 1 as the target compound according to the present invention uses the sodium hydroxide of 2 equivalents and purified water of 5 ⁇ 7 times and methanol of 7 ⁇ 9 times as the reaction solvent in the proper ratio on the basis of the usage of the compound of the formula 4.
  • the sufficient amount of the purified water and the methanol are used during precipitating the crystal.
  • Another process for removing the inorganic salt does not need by removing the inorganic salt since the crystal is washed by the sufficient amount of the purified water in filtering and washing. Accordingly, the hydrolysis reaction according to the present invention can be particularly useful in the mass production since the telmisartan can be prepared in the high yield of 94.2% and the high purity (HPLC purity at more than 99.9%) by a simple process.
  • the compound of the formula 1 as the target compound has the low yield of 87.5% and the bad stirring state.
  • the filtering state is bad. Accordingly, the amount of the purified water becomes 5 ⁇ 7 times.
  • the ratio of the reaction solvent is fixed in purified water of 6 times on the basis of the use of the compound of the formula 4.
  • the amount of methanol is changed in orders of 5, 7, 9, and 11 times.
  • the yield and the purity of the compound of the formula 1 prepared by the same process as the following example 2 of experiment are described in the following Table 5.
  • the stirring state and the filtering state for preparing the compound of the formula 1 as the target compound are bad and the unknown impurity in HPLC is at more than 0.1% (reference is at less than 0.1%).
  • the low yield of 84.4% is obtained.
  • the amount of the methanol becomes 7 ⁇ 9 times when the purified water is 6 times on the basis of the use of the compound of the formula 4.
  • the hydrolysis reaction according to the present invention is performed in methanol of 7 ⁇ 9 times and purified water of 5 ⁇ 7 times on the basis of the use of the compound of the formula 4 in order to obtain an effect for removing other impurities and the compound of the formula 1 as the target compound with the high yield of 94.2% and the high purity (HPLC purity at more than 99.9%) by simultaneously removing the inorganic salt and the impurities without an additional process.
  • the present invention performs the hydrolysis reaction of the compound of the formula 4 as the intermediate in the undried and wet state.
  • the basic compound is added to the mixed solvent of purified water and alcohol to cause the reaction.
  • the neutralization process is performed by using the acid after finishing the hydrolysis reaction.
  • the telmisartan as the compound of the formula 1 can be prepared by filtering the precipitated solid.
  • the preparing process of the present invention is performed to prepare the target compound, the telmisartan as the compound of the formula 1 through the hydrolysis reaction after preparing the compound of the formula 4 as the intermediate by the condensation reaction of the compound of the formula 2 and the compound of the formula 3.
  • the preparing process of the telmisartan can obtain the high total reaction yield of 89.6% and the high purity (HPLC purity at more than 99.9%) and provides the simple preparing process for the mass production.
  • the present invention relates to the process for preparing the target compound, the telmisartan as the compound of the formula 1 through the hydrolysis reaction after preparing the compound of the formula 4 as the intermediate by the condensation reaction of the compound of the formula 2 and the compound of the formula 3.
  • the present invention can omit the additional process for removing the inorganic salt by easily removing the inorganic salt as the byproduct generated from the condensation reaction and the hydrolysis reaction. Accordingly, the present invention can prepare the telmisartan as the target compound with the high yield and the high purity and can be useful for the mass production by simplifying a preparing process.
  • Example 1 preparation of methyl 2-(4- ⁇ [4-methyl-6-(1-methyl-1 H - benzimidazole-2-yl)-2-propyl-1 H -benzimidazole-1-yl]methyl ⁇ phenyl)benzoate (formula 4)
  • the 4-methyl-6-(1-methyl-1 H - benzimidazole-2-yl)-2-propyl-1 H -benzimidazole of 50g was added to and stirred in isopropanol of 150ml and dimethyl sulfoxide of 50ml and potassium t-butoxide of 20.28g were added thereto, slowly heated, and stirred at 40 ⁇ 45°C for 1 hour.
  • the reaction mixture was cooled to 30 ⁇ 35°C and the methyl 2-[4-(bromomethyl) phenyl] benzoate of 55.14g was added into the reaction mixture, which was stirred for 6 hours.
  • the purified water of 250ml was added into the mixture and stirred at 20 ⁇ 25°C for 1 hour.
  • the sodium hydroxide of 12.1g was added to and stirred in purified water of 80ml.
  • the methanol of 160ml and the methyl 2-(4- ⁇ [4-methyl-6-(1-methyl-1 H -benzimidazole-2-yl)-2-propyl-1 H -benzimidazole-1-yl]methyl ⁇ phenyl)benzoate of 80g were added to the mixed solution.
  • the reaction mixture was heated at 70 ⁇ 75°C and refluxed for 4 hours.
  • the reaction mixture was filtered at the high temperature and the filtrate was cooled.
  • the methanol of 480ml was added at 20 ⁇ 25°C and hydrochloric acid (20%) was slowly added thereto, and adjusted to pH 7.0. The mixture was stirred for 2 hours.
  • the purified water of 400ml was added to the reaction mixture, which was stirred for 2 hours, and filtered.
  • the crystal was sequentially washed with purified water of 320ml and methanol of 80ml.
  • the telmisartan as the target compound of 73.36g was obtained almost as the white solid by drying the crystal (yield of 94.2%).
  • the potassium hydroxide of 17.0g was added to and stirred in purified water of 80ml.
  • the methanol of 160ml and the methyl 2-(4- ⁇ [4-methyl-6-(1-methyl-1 H -benzimidazole-2-yl)-2-propyl-1 H -benzimidazole-1-yl]methyl ⁇ phenyl)benzoate of 80g were added thereto to the mixed solution.
  • the reaction mixture was heated at 70 ⁇ 75°C and refluxed for 4 hours.
  • the reaction mixture was filtered at the high temperature and the filtrate was cooled.
  • the methanol of 480ml was added at 20 ⁇ 25°C and hydrochloric acid (20%) was slowly added thereto, and adjusted to pH 6.8. The mixture was stirred for 2 hours.
  • the purified water of 400ml was added to the reaction mixture, which was stirred for 2 hours, and filtered.
  • the crystal was sequentially washed with purified water of 320ml and methanol of 80ml.
  • the telmisartan as the target compound of 73.2g was obtained almost as the white solid by drying the crystal (yield of 94.0%).
  • the 4-methyl-6-(1-methyl-1 H - benzimidazole-2-yl)-2-propyl-1 H -benzimidazole of 50g was added to and is stirred in isopropanol of 150ml and dimethyl sulfoxide of 50ml and potassium t-butoxide of 20.28g were added thereto, slowly heated, and stirred at 40 ⁇ 45°C for 1 hour.
  • the reaction mixture was cooled to 30 ⁇ 35°C and the methyl 2-[4-(bromomethyl) phenyl] benzoate of 55.14g was added into the reaction mixture, which was stirred for 6 hours.
  • the purified water of 250ml was added into the mixture and stirred at 20 ⁇ 25°C for 1 hour.
  • the resulting crystals were filtered and sequentially washed with purified water of 50ml and acetone of 50ml to obtain the methyl 2-(4- ⁇ [4-methyl-6-(1-methyl-1 H - benzimidazole-2-yl)-2-propyl-1 H - benzimidazole-1-yl]methyl ⁇ phenyl)benzoate in the wet state.
  • the sodium hydroxide of 12.5g was added to and stirred in purified water of 80ml.
  • the methanol of 160ml and the solid obtained in the wet state were added to the mixed solution.
  • the reaction mixture was heated at 70 ⁇ 75°C and refluxed for 4 hours.
  • the reaction mixture was filtered at the high temperature and the filtrate was cooled.
  • the methanol of 480ml was added at 20 ⁇ 25°C and the hydrochloric acid (20%) was slowly added thereto, and adjusted to pH 7.3. The mixture was stirred for 2 hours.
  • the purified water of 400ml was added to the reaction mixture, which was stirred for 2 hours, and filtered.
  • the crystal was sequentially washed with purified water of 320ml and methanol of 80ml.
  • the telmisartan as the target compound of 75.66g was obtained almost as the white solid by drying the crystal (yield of 89.5%).
  • the 4-methyl-6-(1-methyl-1 H - benzimidazole-2-yl)-2-propyl-1 H -benzimidazole of 50g is added to and is stirred in isopropanol of 150ml and dimethyl sulfoxide of 50ml and potassium t-butoxide of 20.28g were added thereto, slowly heated, and stirred at 40 ⁇ 45°C for 1 hour.
  • the reaction mixture was cooled to 30 ⁇ 35°C and the methyl 2-[4-(bromomethyl) phenyl] benzoate of 55.14g was added into the reaction mixture, which was stirred for 6 hours.
  • the purified water of 250ml was added into the mixture and stirred at 20 ⁇ 25°C for 1 hour.
  • the resulting crystals were filtered and sequentially washed with purified water of 50ml and acetone of 50ml to obtain the methyl 2-(4- ⁇ [4-methyl-6-(1-methyl-1 H - benzimidazole-2-yl)-2-prophy-1 H - benzimidazole-1-yl]methyl ⁇ phenyl)benzoate in the wet state.
  • the potassium hydroxide of 17.5g was added to and stirred in the purified water of 80ml.
  • the methanol 0f 160ml and the solid obtained in the wet state were added to the mixed solution.
  • the reaction mixture was heated at 70 ⁇ 75°C and refluxed for 4 hours.
  • the reaction mixture was filtered at the high temperature and the filtrate was cooled.
  • the methanol of 480ml was added at 20 ⁇ 25°C and the hydrochloric acid (20%) was slowly added thereto, and adjusted to pH 6.8. The mixture was stirred for 2 hours.
  • the purified water of 400ml was added to the reaction mixture, which was stirred for 2 hours, and filtered.
  • the crystal was sequentially washed with purified water of 320ml and the methanol of 80ml.
  • the telmisartan as the target compound of 75.49g was obtained almost as the white solid by drying the crystal (yield of 89.3%).

Abstract

The present invention relates to an improved process for preparing telmisartan from 4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl-1H-benzimidazole and 2-[4-(bromomethyl)phenyl] benzoate by using condensation reaction and hydrolysis reaction wherein the condensation reaction is performed to prepare an intermediate by using mixed solvent of dimethyl sulfoxide and isopropanol as reaction solvent using dimethyl sulfoxide of 0.5~1.5 times and isopropanol of 1.5~4.5 times on the basis of the usage of 4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-prophyl-1H-benzimidazole and the hydrolysis reaction is performed to cause the reaction in mixed solvent of methanol of 7~9 times and purified water of 5~7 times on the basis of the intermediate. The process for preparing telmisartan according to the present invention provides a simple preparing process for mass production and improves a manufacturing yield with high purity by eliminating an additional process for removing an inorganic salt as a byproduct due to a base used in the condensation reaction and the hydrolysis reaction.

Description

AN IMPROVED PROCESS FOR PREPARING TELMISARTAN
The present invention relates to an improved process for preparing a telmisartan used as angiotensin Ⅱ receptor antagonist.
A telmisartan is expressed by the following formula 1.
Formula 1
Figure PCTKR2011001041-appb-I000001
The telmisartan has been prepared by a process described in the following scheme 1 or a process described in the following scheme 2.
The preparing process expressed by the following scheme 1 is disclosed in US Patent Application No. 5,591,762 and European Patent Application No. 1,912,975. The following scheme 1 shows the process for preparing a t-butyl ester compound as the compound of the following formula 6 by the condensation reaction of the compound of the following formula 2 and the compound of the following formula 5, and shows the process for preparing the telmisartan as the target compound by the hydrolysis of the compound of the following formula 6 in the process for preparing the telmisartan as the compound of the formula 1
Scheme 1
Figure PCTKR2011001041-appb-I000002
In the scheme 1, the US Patent application No. 5,591,762 is characterized by preparing the compound of the formula 1 by hydrolyzing the t-butyl ester compound as the compound of the formula 6 using trifluoroacetic acid in N,N-dimethylformamide as reaction solvent in the process for preparing the telmisartan as the compound of the formula 1 from the compound of the formula 6 as the intermediate.
However, the prior conventional process needs a work-up process (after adjusting pH using purified water and organic solvent after distillation under reduced pressure, separating layers from each other, washing the organic layer using the purified water, and distilling the extracted organic layer) to remove sodium trifluoroacetate as an inorganic salt corresponding to a byproduct since the hydrolysis reaction is induced by using an excess of trifluoroacetic acid as a poisonously strong acid and an excess of base is used for neutralization. In addition, the prior conventional process separates the telmisartan by using a silica gel column chromatography after the work-up process is finished. Accordingly, the prior art has a disadvantage that complexifies a preparing process, thereby causing very low yield.
In the scheme 1, the European Patent Application No. 1,912,975, a process for preparing the telmisartan as the compound of the formula 1 using the compound of the formula 6 as the intermediate, namely the t-butyl ester compound is characterized by the steps of: obtaining a t-butyl ester hydrochloride compound by treating the t-butyl ester compound as the intermediate with hydrochloric acid; obtaining a telmisartan dihydrochloride compound by inducing the hydrolysis with hydrochloric acid, and obtaining the telmisartan as the target compound by adjusting pH with aqueous ammonia solution.
However, the prior art is not suitable for mass production, since the process for preparing the telmisartan as the target compound from the compound of the formula 6 as the intermediate is complicated and three processes for preparing the telmisartan as the target compound from the intermediate have a low total yield of 54.5%.
In addition, the process for preparing the telmisartan described as the following scheme 2 is disclosed in US Patent No. 7,501,448, European Patent No. 1,748,990, European Patent No. 1,805,146, International Patent WO 2009/006860, US Patent Publication No. 2006/276525, Chinese Patent No. 1,344,712, US Patent Publication No. 2006/211866, etc. Namely, the compound of the following formula 4 is prepared by the condensation reaction of the compound of the following formula 2 and the compound of the following formula 3 and the telmisartan as the target compound is prepared by hydrolyzing the compound of the following formula 4.
Scheme 2
Figure PCTKR2011001041-appb-I000003
In the scheme 2, US Patent No. 7,501,448 is characterized in that the telmisartan as the target compound is prepared by simultaneously performing the condensation reaction and the hydrolysis reaction using the compound of the formula 2 and the compound of the formula 3 within one process, an excess of base (6.5~8 equivalents) is used for simultaneously performing the condensation reaction and the hydrolysis reaction, and the layers are separated from each other and the organic layer is separately processed after the reactions are finished.
The prior conventional process has a weakness that needs a considerable time for obtaining the target compound through the work-up process to remove the inorganic salt as the byproduct since an excess of base is used for performing the condensation reaction and the hydrolysis reaction within one process. In addition, the preparing process has a disadvantage that complexifies the preparing process since the organic layers are separately processed to obtain the target compound, thereby causing low yield.
The European Patent No. 1,748,990 is characterized in that the telmisartan as the target compound is prepared by simultaneously performing the condensation reaction and the hydrolysis reaction using the compound of the formula 2 and the compound of the formula 3 within one process, an excess of base (5.4~7.6 equivalents) is used for simultaneously performing the condensation reaction and the hydrolysis reaction, and the telmisartan as the target compound is obtained by extracting with dichloromethane, distilling under reduced pressure, adding acetone, and performing a filtering process after the reactions are finished.
However, the preparing process has a disadvantage that needs a considerable time for obtaining the target compound through the work-up process to remove the inorganic salt as the byproduct since an excess of base is used for performing the condensation reaction and the hydrolysis reaction within one process. In addition, the preparing process has a fatal disadvantage that does not fit for mass product since the dichloromethane remains as the residual solvent in the telmisartan as the target compound.
The European Patent No. 1,805,146 is characterized in that the telmisartan is prepared by performing the condensation reaction and the hydrolysis reaction in two steps, the compound of the formula 4 as the intermediate is prepared by using an excess of methyl 2-[4-(bromomethyl) phenyl] benzoate compound (1.6 equivalents) as the compound of the formula 3 in the condensation reaction step of the reaction steps, and the hydrolysis reaction is performed after preparing telmisartan methylester hydrochloride compound by using hydrochloric acid dissolved in methanol after the condensation reaction is finished. In the hydrolysis reaction step, telmisartan potassium salt is obtained by using an excess of potassium hydroxide (5.3 equivalents) in solvent of acetonitrile. The telmisartan is prepared by adjusting pH with acetic acid in the mixed solvent of acetonitrile and water including compound of telmisartan potassium salt.
However, the preparing process has the possibility that the remaining compound of the formula 3 is present as the impurity of the intermediate after the condensation reaction since an excess of the compound of the formula 3 is used in the condensation reaction. In addition, the preparing process has a weakness that needs a considerable time for obtaining the target compound through the work-up process since an excess of basic compound is used for performing the hydrolysis. In addition, the preparing process has a disadvantage that causes a complicated preparing process and a low yield to prepare the telmisartan as the target compound from the compound of the formula 4.
The International Patent Publication WO 2009/006860 is characterized in that the amount of water is maintained at less than 1% in the hydrolysis reaction for preparing the telmisartan as the target compound in the scheme 2, an excess of potassium hydroxide (3.5 equivalents) is added to the compound of the formula 3 as the intermediate, refluxed for 24 hours in solvent of methanol, and the telmisartan is prepared by adjusting pH with acetic acid or formic acid after the reaction is finished.
However, the preparing process has a disadvantage that needs a considerable time for obtaining the target compound since an excess of basic compound is used in the hydrolysis reaction, the reaction time is long, and the filtering time is slow in the filtering process (the hydrolysis reaction includes the reaction in solvent of methanol (including water at less than 1%) and the filtering speed is reduced and the inorganic salt remains in the filtered solid since potassium acetate or potassium formate as inorganic salt is precipitated in adjusting pH after the hydrolysis) .
The preparing process of the US Patent Publication No. 2006/276525 is to prepare the telmisartan by reacting with an excess of aqueous sodium hydroxide solution (3.3 equivalents) in methanol of 6 times and the small amount of water, distilling solvent part under reduced pressure after the reaction, filtering an insoluble material after adding water of 10 times at 85℃, and filtering after neutralization with the acetic acid in the scheme 2 for preparing the telmisartan as the target compound using the compound of the formula 4 as the intermediate.
However, the prior conventional process has disadvantages that need the work-up process by using an excess of basic compound in the hydrolysis reaction, reduce largely real filtering speed by precipitating a crystal only in water, obtain a low total yield of 62.3% by performing several times of purification process due to the low purity of the target material, and require a lot of preparing steps unsuitable for the mass production.
In the preparing process of the Chinese Patent No. 1,344,712, the telmisartan methylester compound as the intermediate is prepared by using an excess of potassium carbonate (3 equivalents) from the compound of the formula 2 and the compound of the formula 3 in the scheme 2. The telmisartan as the target compound is prepared by using ethanol of 3.8 times and aqueous sodium hydroxide solution of 4M, distilling until the residues become 2.3 times after the reaction is finished, adjusting pH with hydrochloric acid, filtering a crystal, and purifying with N,N-dimethylformamide.
However, the preparing process has disadvantages that need the work-up process by using an excess of basic compound in the condensation reaction, causes the presence of the inorganic salt in the crystal by using the small amount of water, and obtain a low yield of 75.1%.
In the preparing process of the US Patent Publication No. 2006/211866, the telmisartan methylester as the intermediate is prepared by using an excess of potassium hydroxide (4 equivalents) and a small amount of t-butylammonium bromide as a phase transfer catalyst and reacting with methylisobutylketone/purified water of 4/5 in the scheme 2. The telmisartan as the target compound is prepared by reacting in aqueous solution of methanol with an excess of potassium hydroxide (4 equivalents) in the hydrolysis reaction.
However, the preparing process needs a process for separating the telmisartan from solvent of methanol by melting, filtering, and condensing the telmisartan including the inorganic salt in the dichloromethane/methanol of 8/2 to remove the inorganic salt as the byproduct included in the telmisartan solid obtained by adjusting pH after the hydrolysis reaction. As a result, the preparing process has a disadvantage that obtains the low yield of 73.0%.
Accordingly, the inventors of the present invention prepare the intermediate by using mixed solvent of dimethyl sulfoxide of 0.5~1.5 times and isopropanol of 1.5~4.5 times on the basis of the usage of 4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl-1H- benzimidazole in the condensation reaction while studying the process for easily removing the inorganic salt as the byproduct generated by the base added in the condensation reaction and the hydrolysis reaction in the process for preparing the telmisartan using the scheme 2. The inventors of the present invention don`t need an additional process for removing the inorganic salt as the byproduct by preparing the telmisartan through the hydrolysis reaction in the mixed solvent of methanol of 7~9 times and purified water of 5~7 times on the basis of the intermediate. Accordingly, the inventors of the present invention complete the improved process of the telmisartan which can be suitable for the mass production and can be prepared in the high purity and the high yield.
The present invention provides a process for preparing methyl 2-(4-{[4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl-1H-benzimidazole-1-yl]methyl}phenyl)benzoate compound as the intermediate by the condensation reaction from 4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl-1H-benzimidazole compound and methyl 2-[4-(bromomethyl)phenyl] benzoate compound, and preparing the telmisartan by performing the hydrolysis reaction thereto.
The present invention provides a process which can easily remove the inorganic salt as the byproduct generated in the condensation reaction and the hydrolysis reaction and can prepare the telmisartan as the target compound with the high yield and the high purity.
The present invention relates to the process for preparing the telmisartan as the compound of the following formula 1.
Formula 1
Figure PCTKR2011001041-appb-I000004
The telmisartan of the prevent invention is prepared by the process using the following scheme 2 disclosed in the prior art.
Scheme 2
Figure PCTKR2011001041-appb-I000005
The Scheme 2 is used for preparing methyl 2-(4-{[4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl-1H-benzimidazole-1-yl]methyl}phenyl)benzoate compound by performing the condensation reaction for 4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl-1H-benzimidazole compound as the compound of the formula 2 and methyl 2-[4-(bromomethyl) phenyl] benzoate compound as the compound of the formula 3. The telmisartan as the compound of the formula 1 is prepared by performing the hydrolysis reaction for the intermediate of the telmisartan as the target compound.
The present invention provides the preparing process of the telmisartan which is prepared according to the Scheme 2. Namely, the present invention provides the process for preparing the intermediate by the condensation reaction of the compound of the formula 2 and the compound of the formula 3, and preparing the telmisartan as the compound of the formula 1 by performing the hydrolysis reaction.
The process provides that the condensation reaction using dimethyl sulfoxide of 0.5~1.5 times and isopropanol of 1.5~4.5 times on the basis of the usage of the compound of the formula 2 in the preparing step of the compound of the compound of the formula 4 as the intermediate and the hydrolysis reaction in the mixed solvent of methanol of 7~9 times and purified water of 5~7 times on the basis of the usage of the compound of the formula 4 in the preparing step of the telmisartan as the target compound.
The prior conventional process for preparing the telmisartan according to the scheme 2 has disadvantages that use an excess of base in the process for preparing the telmisartan methylester compound corresponding to the intermediate as the compound of the formula 4, and need the process for removing the inorganic salt generated as the byproduct.
In order to solve the problems, the condensation reaction for preparing the compound of the formula 4 as the intermediate is performed under a stream of nitrogen, reacted using the mixed solvent of dimethyl sulfoxide of 0.5~1.5 times and isopropanol of 1.5~4.5 times and potassium t-butoxide of 1~1.2 equivalents as the base on the basis of the usage of the compound of the formula 2. After the condensation reaction is finished, the compound of the formula 4 as the intermediate can be obtained by stirring after adding purified water of 4~7 times in the mixture, filtering a crystal, washing with purified water and acetone, and drying. The reaction temperature is maintained in the range of 10℃ to 80℃ desirably in the range of 25℃ to 50℃.
In the condensation reaction for preparing the compound of the formula 4 as the intermediate, the results of the experiment determining the ratio of the reaction solvent and the precipitation solvent are described as follows.
Firstly, isopropanol and purified water are fixed in the ratio of 3:5 in order to determine the amount of dimethyl sulfoxide. The amount of dimethyl sulfoxide is changed in orders of 0.1 times, 0.5 times, 1.5 times, and 2.5 times. The compound of the formula 4 is prepared and obtained by the same process as the following example 1 of experiment. The yield and the purity of the compound of the formula 4 are described as follows.
Table 1
Figure PCTKR2011001041-appb-T000001
As described in Table 1, in case using dimethyl sulfoxide of 0.1 times, the compound of the formula 4 has the low purity of 93.0%. In case using dimethyl sulfoxide of 2.5 times, the compound of the formula 4 has the low yield of 87.5%. In order to prepare the desired compound of the formula 4 having the high yield and the high purity of the present invention, the amount of dimethyl sulfoxide must be 0.5~1.5times on the basis of the usage of the compound of the formula 2.
Secondly, dimethyl sulfoxide and purified water are fixed in the ratio of 1:5 in order to determine the amount of isopropanol. The amount of the isopropanol is changed in orders of 0.5 times, 1.5 times, 4.5 times, and 6 times. The compound of the formula 4 is prepared and obtained by the same process as the following example 1 of experiment. The yield and the purity of the compound of the formula 4 are described in the following Table 2.
Table 2
Figure PCTKR2011001041-appb-T000002
As described in Table 2, in case using isopropanol of 0.5 times, the stirring state and the purity (90.8%) according to the preparation of the compound of the formula 4 are bad. In case using isopropanol of 6 times, the compound of the formula 4 has the low yield of 80.2%. In order to prepare the desired compound of the formula 4 having the high yield and the high purity of the present invention, the amount of the isopropanol must be 1.5~4.5times on the basis of the usage of the compound of the formula 2.
Thirdly, dimethyl sulfoxide and isopropanol are fixed in the ratio of 1:3 in order to determine the amount of purified water. In the extraction process, the amount of purified water is changed in orders of 2, 4, 7, and 9 times, 1.5 times. The compound of the formula 4 is prepared and obtained by the same process as the following example 1 of experiment. The yield and the purity of the compound of the formula 4 are described in the following Table 3.
Table 3
Figure PCTKR2011001041-appb-T000003
As described in Table 3, in case using purified water of 2 times, the compound of the formula 4 as the intermediate has the low yield of 85.4%. In case using purified water of 9 times, the compound of the formula 4 as the intermediate has the low purity of 92.1%. In order to prepare the desired compound of the formula 4 having the high yield and the high purity of the present invention, the amount of purified water must be 4~7 times on the basis of the usage of the compound of the formula 2.
Thus, the condensation reaction according to the present invention is to cause the reaction with the potassium t-butoxide of 1~1.2 equivalents in the reaction solvent of dimethyl sulfoxide of 0.5~1.5 times and isoprpanol of 1.5~4.5 times on the basis of the usage of the compound of the formula 2. The crystal is precipitated and filtered by adding purified water of 4~7 times after the reaction is finished. Accordingly, the condensation reaction according to the present invention can be particularly useful in the mass production since the compound of the formula 4 corresponding to the telmisartan methylester compound as the intermediate can be obtained in the high yield of 95.1% by a simple process.
Meanwhile, sodium hydroxide of 2 equivalents is used in the hydrolysis reaction for preparing the compound of the formula 1 as the target compound according to the present invention. In the hydrolysis reaction, the reaction solvent has the proper ratio of purified water of 5~7 times and methanol of 7~9 times on the basis of the usage of the compound of the formula 4. After finishing the reaction, the sufficient amount of purified water and methanol are added during precipitating a crystal by adding hydrochloric acid. The compound of the formula 1 is prepared by performing washing with the sufficient amount of the purified water in the washing process.
In the conventional technology using the scheme 2, the excesses of the base and the acid are used in the process for preparing the telmisartan through the hydrolysis reaction, which needs the process for removing the inorganic salt generated as the byproduct and causes the slow filtering speed in the filtering process of the precipitated solid from the used solvent. In addition, the conventional technology using the scheme 1 needs the complicated process for preparing the telmisartan by separating with a silica gel column chromatography after the work-up process after the completion of the reaction in order to remove the inorganic salt generated as byproduct by using trifluoroacetic acid as strong acid.
Thus, the conventional technologies need the process for removing the inorganic salt as the generated byproduct by using the excess of the base in the condensation reaction and the hydrolysis reaction and are not suitable for the mass production since the filtering process is slow.
Meanwhile, the hydrolysis reaction for preparing the compound of the formula 1 as the target compound according to the present invention uses the sodium hydroxide of 2 equivalents and purified water of 5~7 times and methanol of 7~9 times as the reaction solvent in the proper ratio on the basis of the usage of the compound of the formula 4. The sufficient amount of the purified water and the methanol are used during precipitating the crystal. Another process for removing the inorganic salt does not need by removing the inorganic salt since the crystal is washed by the sufficient amount of the purified water in filtering and washing. Accordingly, the hydrolysis reaction according to the present invention can be particularly useful in the mass production since the telmisartan can be prepared in the high yield of 94.2% and the high purity (HPLC purity at more than 99.9%) by a simple process.
In the hydrolysis reaction for preparing the compound of the formula 1 as the target compound according to the present invention, the results of the experiment for determining the ratio of the reaction solvent are described as follows.
Firstly, in order to determine the amount of purified water, methanol of 8 times is fixed on the basis of the use of the compound of the formula 4. The amount of purified water is changed in orders of 3, 5, 7, and 9 times. The yield and the purity of the compound of the formula 1 prepared by the same process as the following example 2 of experiment are described in the following Table 4.
Table 4
Figure PCTKR2011001041-appb-T000004
As described in the table 4, in case using purified water of 3 times, the compound of the formula 1 as the target compound has the low yield of 87.5% and the bad stirring state. In case using purified water of 9 times, the filtering state is bad. Accordingly, the amount of the purified water becomes 5~7 times.
Secondly, in order to determined the amount of purified water, in the hydrolysis reaction for preparing the compound of the formula 1 as the target compound according to the present invention, the ratio of the reaction solvent is fixed in purified water of 6 times on the basis of the use of the compound of the formula 4. The amount of methanol is changed in orders of 5, 7, 9, and 11 times. The yield and the purity of the compound of the formula 1 prepared by the same process as the following example 2 of experiment are described in the following Table 5.
Table 5
Figure PCTKR2011001041-appb-T000005
As described in the table 5, in case using methanol of 5 times, the stirring state and the filtering state for preparing the compound of the formula 1 as the target compound are bad and the unknown impurity in HPLC is at more than 0.1% (reference is at less than 0.1%). In case using methanol of 11 times, the low yield of 84.4% is obtained. In order to preparing the compound of the formula 1 as the target compound having the high yield and the high purity, the amount of the methanol becomes 7~9 times when the purified water is 6 times on the basis of the use of the compound of the formula 4.
Accordingly, the hydrolysis reaction according to the present invention is performed in methanol of 7~9 times and purified water of 5~7 times on the basis of the use of the compound of the formula 4 in order to obtain an effect for removing other impurities and the compound of the formula 1 as the target compound with the high yield of 94.2% and the high purity (HPLC purity at more than 99.9%) by simultaneously removing the inorganic salt and the impurities without an additional process.
In addition, the present invention performs the hydrolysis reaction of the compound of the formula 4 as the intermediate in the undried and wet state. In the hydrolysis reaction, the basic compound is added to the mixed solvent of purified water and alcohol to cause the reaction. The neutralization process is performed by using the acid after finishing the hydrolysis reaction. The telmisartan as the compound of the formula 1 can be prepared by filtering the precipitated solid.
As described above, the preparing process of the present invention is performed to prepare the target compound, the telmisartan as the compound of the formula 1 through the hydrolysis reaction after preparing the compound of the formula 4 as the intermediate by the condensation reaction of the compound of the formula 2 and the compound of the formula 3. The preparing process of the telmisartan can obtain the high total reaction yield of 89.6% and the high purity (HPLC purity at more than 99.9%) and provides the simple preparing process for the mass production.
The present invention relates to the process for preparing the target compound, the telmisartan as the compound of the formula 1 through the hydrolysis reaction after preparing the compound of the formula 4 as the intermediate by the condensation reaction of the compound of the formula 2 and the compound of the formula 3. The present invention can omit the additional process for removing the inorganic salt by easily removing the inorganic salt as the byproduct generated from the condensation reaction and the hydrolysis reaction. Accordingly, the present invention can prepare the telmisartan as the target compound with the high yield and the high purity and can be useful for the mass production by simplifying a preparing process.
Example embodiments of inventive concepts will now be described more fully with reference to the accompanying drawings, in which example embodiments of inventive concepts are shown. The invention may, however, be embodied in different forms and should not be construed as limited to example embodiments of inventive concepts set forth herein. Rather, example embodiments of inventive concepts are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
Example 1: preparation of methyl 2-(4-{[4-methyl-6-(1-methyl-1 H - benzimidazole-2-yl)-2-propyl-1 H -benzimidazole-1-yl]methyl}phenyl)benzoate (formula 4)
Under the stream of nitrogen, the 4-methyl-6-(1-methyl-1H- benzimidazole-2-yl)-2-propyl-1H-benzimidazole of 50g was added to and stirred in isopropanol of 150ml and dimethyl sulfoxide of 50ml and potassium t-butoxide of 20.28g were added thereto, slowly heated, and stirred at 40~45℃ for 1 hour. The reaction mixture was cooled to 30~35℃ and the methyl 2-[4-(bromomethyl) phenyl] benzoate of 55.14g was added into the reaction mixture, which was stirred for 6 hours. The purified water of 250ml was added into the mixture and stirred at 20~25℃ for 1 hour. The resulting crystals were filtered and sequentially washed with purified water of 50ml and acetone of 50ml and dried to obtain the methyl 2-(4-{[4-methyl-6-(1-methyl-1H- benzimidazole-2-yl)-2-propyl-1H- benzimidazole-1-yl]methyl}phenyl)benzoate of 82.58g (yield of 95.1%).
m/e 528.6(parent ion); 1H NMR(DMSO-d6) δ0.99(t, 3H, J=7.24Hz), 1.73~1.88(m, 2H), 2.64(s, 3H), 2.92(t, 2H, J=7.42Hz), 3.50(s, 3H), 3.84(s, 3H), 5.64(s, 2H), 7.12~7.32(m, 6H), 7.33~7.82(m, 8H)
Example 2 : preparation of telmisartan (formula 1)
The sodium hydroxide of 12.1g was added to and stirred in purified water of 80ml. The methanol of 160ml and the methyl 2-(4-{[4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl-1H-benzimidazole-1-yl]methyl}phenyl)benzoate of 80g were added to the mixed solution. The reaction mixture was heated at 70~75℃ and refluxed for 4 hours. The reaction mixture was filtered at the high temperature and the filtrate was cooled. The methanol of 480ml was added at 20~25℃ and hydrochloric acid (20%) was slowly added thereto, and adjusted to pH 7.0. The mixture was stirred for 2 hours. The purified water of 400ml was added to the reaction mixture, which was stirred for 2 hours, and filtered. The crystal was sequentially washed with purified water of 320ml and methanol of 80ml. The telmisartan as the target compound of 73.36g was obtained almost as the white solid by drying the crystal (yield of 94.2%).
m.p. 269.2℃(DSC) ; m/e 514.6(parent ion); 1H NMR(DMSO-d6) δ1.00(t, 3H, J=7.32Hz), 1.76~1.88(m, 2H), 2.64(s, 3H), 2.93(t, 2H, J=7.48Hz), 3.82(s, 3H), 5.63(s, 2H), 7.15~7.37(m, 7H), 7.41~7.61(m, 4H), 7.67~7.75(m, 3H)
Example 3 : preparation of telmisartan (formula 1)
The potassium hydroxide of 17.0g was added to and stirred in purified water of 80ml. The methanol of 160ml and the methyl 2-(4-{[4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl-1H-benzimidazole-1-yl]methyl}phenyl)benzoate of 80g were added thereto to the mixed solution. The reaction mixture was heated at 70~75℃ and refluxed for 4 hours. The reaction mixture was filtered at the high temperature and the filtrate was cooled. The methanol of 480ml was added at 20~25℃ and hydrochloric acid (20%) was slowly added thereto, and adjusted to pH 6.8. The mixture was stirred for 2 hours. The purified water of 400ml was added to the reaction mixture, which was stirred for 2 hours, and filtered. The crystal was sequentially washed with purified water of 320ml and methanol of 80ml. The telmisartan as the target compound of 73.2g was obtained almost as the white solid by drying the crystal (yield of 94.0%).
Example 4 : preparation of telmisartan (formula 1)
Under the stream of nitrogen, the 4-methyl-6-(1-methyl-1H- benzimidazole-2-yl)-2-propyl-1H-benzimidazole of 50g was added to and is stirred in isopropanol of 150ml and dimethyl sulfoxide of 50ml and potassium t-butoxide of 20.28g were added thereto, slowly heated, and stirred at 40~45℃ for 1 hour. The reaction mixture was cooled to 30~35℃ and the methyl 2-[4-(bromomethyl) phenyl] benzoate of 55.14g was added into the reaction mixture, which was stirred for 6 hours. The purified water of 250ml was added into the mixture and stirred at 20~25℃ for 1 hour. The resulting crystals were filtered and sequentially washed with purified water of 50ml and acetone of 50ml to obtain the methyl 2-(4-{[4-methyl-6-(1-methyl-1H- benzimidazole-2-yl)-2-propyl-1H- benzimidazole-1-yl]methyl}phenyl)benzoate in the wet state. The sodium hydroxide of 12.5g was added to and stirred in purified water of 80ml. The methanol of 160ml and the solid obtained in the wet state were added to the mixed solution. The reaction mixture was heated at 70~75℃ and refluxed for 4 hours. The reaction mixture was filtered at the high temperature and the filtrate was cooled. The methanol of 480ml was added at 20~25℃ and the hydrochloric acid (20%) was slowly added thereto, and adjusted to pH 7.3. The mixture was stirred for 2 hours. The purified water of 400ml was added to the reaction mixture, which was stirred for 2 hours, and filtered. The crystal was sequentially washed with purified water of 320ml and methanol of 80ml. The telmisartan as the target compound of 75.66g was obtained almost as the white solid by drying the crystal (yield of 89.5%).
Example 5 : p reparation of telmisartan (formula 1)
Under the stream of nitrogen, the 4-methyl-6-(1-methyl-1H- benzimidazole-2-yl)-2-propyl-1H-benzimidazole of 50g is added to and is stirred in isopropanol of 150ml and dimethyl sulfoxide of 50ml and potassium t-butoxide of 20.28g were added thereto, slowly heated, and stirred at 40~45℃ for 1 hour. The reaction mixture was cooled to 30~35℃ and the methyl 2-[4-(bromomethyl) phenyl] benzoate of 55.14g was added into the reaction mixture, which was stirred for 6 hours. The purified water of 250ml was added into the mixture and stirred at 20~25℃ for 1 hour. The resulting crystals were filtered and sequentially washed with purified water of 50ml and acetone of 50ml to obtain the methyl 2-(4-{[4-methyl-6-(1-methyl-1H- benzimidazole-2-yl)-2-prophy-1H- benzimidazole-1-yl]methyl}phenyl)benzoate in the wet state. The potassium hydroxide of 17.5g was added to and stirred in the purified water of 80ml. The methanol 0f 160ml and the solid obtained in the wet state were added to the mixed solution. The reaction mixture was heated at 70~75℃ and refluxed for 4 hours. The reaction mixture was filtered at the high temperature and the filtrate was cooled. The methanol of 480ml was added at 20~25℃ and the hydrochloric acid (20%) was slowly added thereto, and adjusted to pH 6.8. The mixture was stirred for 2 hours. The purified water of 400ml was added to the reaction mixture, which was stirred for 2 hours, and filtered. The crystal was sequentially washed with purified water of 320ml and the methanol of 80ml. The telmisartan as the target compound of 75.49g was obtained almost as the white solid by drying the crystal (yield of 89.3%).

Claims (3)

  1. An improved process for preparing a telmisartan as a compound of the following formula 1 by preparing a compound of the following formula 4 as an intermediate from a condensation reaction of a compound of the following formula 2 and a compound of the following formula 3 and preparing a telmisartan as a compound of the following formula 1 from hydrolysis reaction, wherein the compound of the following formula 4 as the intermediate is prepared by using a mixed solvent including dimethyl sulfoxide of 0.5~1.5 times and isopropanol of 1.5~4.5 times on the basis of the usage of the compound of the formula 2 in the condensation reaction and the hydrolysis reaction proceeds in a mixed solvent including methanol of 7~9 times and purified water of 5~7 times on the basis of the usage of the compound of the formula 4.
    Formula 1
    Figure PCTKR2011001041-appb-I000006
    Formula 2
    Figure PCTKR2011001041-appb-I000007
    Formula 3
    Figure PCTKR2011001041-appb-I000008
    Formula 4
    Figure PCTKR2011001041-appb-I000009
  2. The process for preparing of telmisartan according to claim 1, wherein the precipitated crystal of the compound of the formula 4 by adding purified water of 4~7 times on the basis of the usage of the compound of the formula 2 after the condensation reaction is filtered.
  3. The process for preparing of telmisartan as the compound of the formula 1 according to claim 1, wherein the hydrolysis reaction is performed by using the compound of the formula 4 in the wet state.
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KR101607661B1 (en) * 2013-12-24 2016-03-31 주식회사 파마코스텍 A Novel Method for Preparing of Telmisartan

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WO2005108375A1 (en) * 2004-05-11 2005-11-17 Cipla Limited Process for the preparation of telmisartan
WO2006044754A2 (en) * 2004-10-18 2006-04-27 Dr. Reddy's Laboratories Ltd. Process for preparing telmisartan
US20060276525A1 (en) * 2005-05-18 2006-12-07 Itai Adin Processes of preparing highly pure telmisartan form A, suitable for pharmaceutical compositions
US7501448B2 (en) * 2004-10-15 2009-03-10 Teva Pharmaceutical Industries, Ltd. Process for preparing telmisartan

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WO2005108375A1 (en) * 2004-05-11 2005-11-17 Cipla Limited Process for the preparation of telmisartan
US7501448B2 (en) * 2004-10-15 2009-03-10 Teva Pharmaceutical Industries, Ltd. Process for preparing telmisartan
WO2006044754A2 (en) * 2004-10-18 2006-04-27 Dr. Reddy's Laboratories Ltd. Process for preparing telmisartan
US20060276525A1 (en) * 2005-05-18 2006-12-07 Itai Adin Processes of preparing highly pure telmisartan form A, suitable for pharmaceutical compositions

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