MXPA99007533A - Process for preparing eprosartan - Google Patents

Abstract

This invention relates to a process for preparing eprosartan.

Description

PROCEDURE TO PREPARE EPROSARTAN FIELD OF THE INVENTION The present invention relates to a process for preparing eprosartan. This compound is described in the U.S. patent. No. 5,185,351 as an angiotensin II receptor antagonist useful for the treatment of hypertension, congestive heart failure and renal failure.

BACKGROUND OF THE INVENTION The patent of E.U. No. 5,185,351 describes processes for the preparation of midazole compounds. One of the methods described in this application is the reaction of an aldehyde with a substituted half-acid, a half-ester derivative of a malonate. Although this process produces imidazoles which are mentioned herein, there was a need to improve this procedure when preparing compounds, such as eprosartan, on a commercial scale. It has now been found that eprosartan can be prepared by reacting 4 - [(2-n-butyl-5-formyl-1 H-imidazol-1-yl) methyl] benzoic acid or the addition compound of 4-bisulfite acid. (2-n-butyl-5-formyl-1 H-imidazol-1-yl) methyl] benzoic acid (PCT application WO 95/32189) with (2-thienylmethyl) propanedioic acid monoethyl ester to produce eprosartan efficiently in high performance and high purity. The efficiency of this process and the quality and yield of the imidazole product are particularly important when such a product is prepared on a large scale for therapeutic use.

DESCRIPTION OF THE INVENTION The present invention provides a process for the preparation of eprosartan, which is (E) -a - [[2-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene] - 2-thiophenepropanoic, a compound having the formula (I): or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound having the formula (II): (II) or an acid or a basic addition salt thereof, with a compound having the formula (III): where R 'is C- alkyl, under reduced pressure in the presence of a catalyst, such as piperidine propionate or piperidino in an excess of propionic acid, and subsequently hydrolyzing the R' ester and optionally forming a pharmaceutically acceptable salt. Alternatively, a compound having the formula (I) can be prepared by reacting a compound of the formula (IV): with a compound of the formula (III) under reduced pressure in the presence of a catalyst, such as piperidine propionate or piperidino in an excess of propionic acid, and subsequently hydrolyzing the R 'ester and optionally forming a pharmaceutically acceptable salt. The acid addition salts of the compounds having the formulas (I) and (II) are formed with the appropriate inorganic or organic acids by methods known in the art. Representative examples of suitable acids are maleic, fumaric, acetic, succinic, hydrochloric, hydrobromic, sulfuric, phosphoric or methanesulfonic. Preferably, the pharmaceutically acceptable acid addition salt for the compound of the formula (I) is the methanesulfonic acid addition salt.

The basic addition salts of the compounds having the formulas (I) and (II) are formed with the appropriate inorganic or organic bases by methods known in the art. The cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent such as hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Representative examples of cations are L +, Na +, K +, Ca ++, Mg ++ and NH4 +. The preferred salt form for the compound having the formula (II) is as used herein, "C" -4 alkyl means an alkyl group of 1-4 carbons, branched or unbranched. C 1-4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. The alkyl group of C 'M of R' which is preferred is ethyl.

Typically the process is carried out by combining 4- [(2-butyl-5-formyl-1 H-imidazol-1-yl) methyl] benzoic acid or the addition compound of 4 - [(2-n- butyl-5-formyl-1H-imidazol-1-yl) methyl] benzoic acid with (2-thienylmethyl) -propanedioic acid monoethyl ester in a suitable solvent, such as toluene, in the presence of a catalyst, for example, in the presence of piperidine propionate and an excess of propionic acid, at a suitable temperature, such as at a temperature of from about 75 ° C to about 100 ° C, preferably at a temperature of 80 ° C-85 ° C, under reduced pressure, such as at a reduced internal pressure to about 228-330 mm Hg, preferably 279 mm Hg. The ester precursors for the compound of the formula (I) are hydrolyzed to the corresponding carboxylic acid of formula (I) using a base, such as an aqueous solution of sodium or potassium hydroxide. Subsequently, the pharmaceutically acceptable salts can be prepared as described above.

Alternatively, 4 - [(2-n-butyl-5-formyl-1H-imidazol-1-yl) methyl] benzoic acid or the addition compound of 4 - [(2-n- butyl-5-formyl-1 H-imidazol-1-yl) methyl] benzoic acid and (2-thienylmethyl) propanedioic acid monoethyl ester, to give (E) -a [[2-butyl-1 - [( 4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene] -2-thiophenepropane, heating the two substrates in toluene under reflux under reduced pressure and in the presence of piperidine as a catalyst followed by the hydrolysis of the intermediate ester ((E) -a ethyl [[2-butyl-1 - [(4-carboxyphenyl) methyl-1-H-imidazol-5-yl] methylene] -2-thiophenpropanoate). In this preparation, 4 - [(2-n-butyl-5-formyl-1 H-imidazol-1-yl) methyl] benzoic acid or the addition compound of 4 - [(2- n-Butyl-5-formyl-1 H-imidazol-1-yl) methyl] benzoic acid, (2-thienylmethyl) -propanedioic acid monoethyl ester and toluene to a glass-lined steel vessel and are initially heated to 55-60 ° C to give a homogeneous solution. The catalyst (66% piperidine molar) is added and the reaction is heated to reflux (70-75 ° C) under deduced pressure. The reflux conditions are maintained for 20-35 hours and additional (2-thienylmethyl) -propanedioic acid monoethyl ester is added. Once the reaction is complete, water and aqueous sodium hydroxide solution are added to the vessel, and the reaction mixture is refluxed under atmospheric conditions for 1-3 hours. The reaction is considered complete when the level of ethyl (E) -a - [[2-butyl-1 - [(4-carboxyphenyl) -methyl] -1H-imidazol-5-yl] methylene] -2-thiophenepropanoate It is less than 2.0%. The reaction is cooled to 45-50 ° C and the aqueous and organic phases are separated. The toluene phase is discarded. Ethanol is added to the aqueous phase and the solution is acidified with aqueous hydrochloric acid until a pH of 5.0 to 5.4 is reached, maintaining the temperature at 50-55 ° C. The suspension of the product is cooled and allowed to stir at 10-15 ° C for 2 hours. The product is isolated by centrifugation, washed and stored. Subsequently, the pharmaceutically acceptable salts can be prepared as described above.

The reaction between 4 - [(2-n-butyl-5-formyl-1 H-imidazol-1-yl) methyl] benzoic acid or the addition compound of 4 - [(2-n-butyl-5-bisulphite -formyl-1 H-imidazol-1-yl) methyl] benzoic acid and (2-thienylmethyl) propanedioic acid monoethyl ester catalysed with piperidine, can be successfully performed in solvents (and / or solvent systems) other than toluene; These solvents include cyclohexane, cyclohexane: dichloroethane (12: 5 or 1: 1), cyclohexane: pyridine (12: 5) and cyclohexane: ethyl acetate: pyridine (8: 3: 1).

Other catalysts that successfully promote the reaction between 4 - [(2-n-butyl-5-formyl-1H-imidazol-1-yl) methyl] benzoic acid or the addition compound of 4 - [(2 -n-butyl-5-formyl-1 H-imidazol-1-yl) methyl] benzoic acid and (2-thienylmethyl) propanedioic acid monoethyl ester in toluene under reduced pressure apart from piperidine include morpholine, 1-methylpiperazine and pyrrolidine.

The invention is illustrated with the following examples. The examples are not intended to limit the scope of this invention as defined above and as claimed below.

EXAMPLES EXAMPLE 1 Preparation of (E) -QC-G acid r2-butyl-1-r (4-carboxyphenyl) -metn-1H-imidazol-5-illethylene-2-thiophenepropanoic acid (Eprosartan) Reagents and solvents 1.- 4 - [(2-n-Butyl-5-formyl-1H-imidazol-1-yl) methyl] benzoic acid bisulfite addition compound 12.03 kg 28.82 moles (4 - [(2) acid -n-butyl-5-formyl-1 H -methazol-1-yl) methyl] benzoic acid at 68.57%) 2.- (2-Thienylmethyl) propane dioic acid monoethyl ester, 15.29 kg (80.9 % p / p test) 54.18 moles. 3.- Piperidine 2.85 L 28.82 moles 4.- Propionic acid 8.60 L 115.28 moles 5.- Toluene 56.5 L + 19.0 L = 75.5 L total 6.- Sodium hydroxide 16.7 kg (50% aqueous solution) 208.75 moles 7.- Water 65.0 L 8.- Ethanol 41.2 kg 9.- HCl at 6N Adjust to a pH of 5.0 to 5.2 10. Water 75.0 L Procedure 1.- Charge toluene (56.5 L) to the reactor. 2.- Charge monoethyl ester of (2-thienylmethyl) propanediic acid (15.29 kg), 80.9% w / w test) and addition compound of 4 - [(2-n-butyl-5-formyl-1H-imidazol-1-yl) methyl] benzoic acid bisulfite (12.03 kg, 68.57% of 4 - [(2-n-butyl-5-formyl-1 H-imidazol-1-yl) methyl] benzoic acid) to the reactor and initiate stirring. Reduce the internal pressure to 279 mm Hg and heat to reflux (the internal reaction temperature remained between 80-85 ° C) for 1-2 hours. Set the cover temperature to 110 ° C. Collect water in a Dean-Stark trap. 3.- Charge toluene (19.0 L) followed by propionic acid (6.45 L, 86.46 moles) to a second reactor. Treat the resulting solution slowly with piperidine (2.85 L, 28.82 moles) at room temperature. Stir the resulting mixture for approximately 30 minutes. 4.- Ventilate the first reactor with nitrogen and reduce the cover temperature to 80 ° C. Transfer the solution of propionate of piperidino-propionic acid in toluene from the second reactor to the first reactor. Reduce the internal pressure to 279 mm Hg and heat to reflux (the internal temperature of the reaction was maintained between 80-85 ° C). Set the cover temperature to 140 ° C. Collect water in the Dean-Stark trap. 5.- After 7.5 hours the amount of aldehyde (4 - [(2-n-butyl-5-formyl-1H-imidazol-1-yl) methyl] benzoic acid) remaining in solution was around 20% and the The amount of remaining (2-thienylmethyl) propanedioic acid monoethyl ester was about 20%. An additional charge of (2-thienylmethyl) propanedioic acid monoethyl ester (1.53 kg, 5.42 moles) was added at the 8.5 hour mark. 6.- After 13.5 hours, the reaction was completed and cooled to 70 ° C. (The amount of aldehyde remaining was around 5%). Water (65.0 L) and sodium hydroxide (16.7 kg) were added; aqueous solution at 50% w / w) and the reaction was brought to reflux. 7. The reaction was refluxed for 1 hour. The reaction was tested to verify the presence of ethyl (E) -oc - [[2-butyl-1 - [(4-carboxyphenyl) -methyl] -1 H-imidazol-5-yl] methylene] -2-thiophenepropanoate . If someone is present, reflux for an additional half hour. Repeat test. 8.- Cool the solution to 60 ° C, separate the layers and add ethanol (41.2 kg) to the water layer. Slowly adjust the pH of the solution to 5.2 with HCl at 6N (temperature, 60 ° C). The product will start to crystallize (temperature, 60 ° C). Cool to room temperature and stir for 2 hours.

Filter and wash the product with water (2 X 37.5 L). 9. The solid was dried under vacuum (9.44 kg, 72.2%).

Analytical information CLAR Column Zorbax SB-C18, 3.5 mm, 7.5 cm x4.6 mm Temperature 40 < , of column Speed of 2.0 mL / min. 8 mL flow of the reaction is blown with a Current preparation of nitrogen and subsequently of the sample dissolved in 2 mL of acetonitrile: water 50:50 Volume of 2.0 mL injection Wavelength of 235 nm detection Phase A mobile ammonium acetate 0.1 M (pH = 6.7) Phase B mobile ammonium acetate 0.1 M: acetonitil 50:50 From 0 to 10 minutes, 100% of the phase A mobile ai 100% of the mobile phase B in a Linear gradient program, 5 minutes at 100% of the mobile phase B gradient then rebalance for 5 minutes to 100% of the mobile phase A Time of 15 minutes process Time of 5 minutes equilibrium Acid 4 - [(2-n-butyl- 5-formyl-1 H-imidazol-1-yl) methyl] benzoic 4.81 min. Acid (E) -oc- [[2-butyl-1 - [(4-carboxyphenyl) -methyl] -1 H -imidazol-5-yl] methylene] -2-Thiophenepropanoic time 4.58 min. Retention Monoethyl ester of (2-thienylmethyl) -propanedioic acid 4.13 min. (E) -oc - [[2-butyl-1 - [(4-carboxyphenyl) -methyl] -1H-imidazol-5-yl] methylene] -2-thiophenepropanoate ethyl 8.43 min.

EXAMPLE 2 Preparation of (E) -oc-rr 2 -butyl-1-r (4-carboxyphenyl) -methyl-1H-imidazol-5-n-methylen-2-thiophenepropanoic acid (Eprosartan) A glass-lined steel reaction vessel is charged with 4 - [(2-n-butyl-5-formyl-1 H-imidazol-1-yl) methyl] benzoic acid, (2-thienylmethyl) monoethyl ester ) propanedioic acid (approximately 1.9 molar equivalents relative to 4 - [(2-n-butyl-5-formyl-1 H-imidazol-1-yl) met!] benzoic acid * tested, and toluene (approximately 6.3 g per gram of 4 - [(2-n-butyl-5-formyl-1H-imidazol-1-yl) methyl] benzoic acid tested) and heated to 55-60 ° C. Piperidine (approximately 66% moles) is added. in relation to 4 - [(2-n-butyl-5-formyl-1H-imidazol-1-yl) methyl] benzoic acid.) Subsequently the reaction is heated under reflux with azeotropic removal of water under reduced pressure so that maintain an internal temperature of about 70-75 ° C. The reaction is monitored by IPC 1 to verify the disappearance of 4 - [(2-n-butyl-5-formyl-1 H-imidazol-1-yl) methyl benzoic starting material: Si> 10% of the acid 4 - [(2-n-butyl-5-formyl-1H-imidazol-1- L) starting methyl] benzoic acid remains after 12-30 hours, additional charges of (2-thienylmethyl) propanedioic acid monoethyl ester (0.10 equivalents per charge relative to 4 - [(2- n-butyl-5-formyl-1H-imidazol-1-yl) methyl] benzoic acid) and the reaction must be continued. When the IPC 1 analysis indicates that the reaction of the starting 4 - [(2-n-butyl-5-formyl-1H-imidazol-1-yl) methyl] benzoic acid is essentially complete (< 10% remaining), The solution is cooled to approximately 60-65 ° C. The cooled solution is treated with demineralized water (6.8 g per gram of 4 - [(2-n-butyl-5-formyl-1 H-imidazol-1-yl) methyl] benzoic acid) tested and an aqueous solution, 6.7 N, of sodium hydroxide (approximately 2.0 ml of solution per gram of 4 - [(2-n-butyl-5-formyl-1H-imidazol-1-yl) methyl] benzoic acid tested) and the mixture is heated under reflux for approximately 1.0-3.5 hours. The reaction is tested, by means of I PC 2, to confirm the complete conversion (< 2.0%) for the product. Subsequently the solution is cooled to approximately 50 ° C and the layers are separated. Ethyl alcohol (approximately 5.0 g per gram of 4 - [(2-n-butyl-5-formyl-1 H-imidazol-1-yl) methyl] benzoic acid) is added to the aqueous phase and the pH is adjusted to approximately 5.0-5.4 with aqueous solution, 6N, hydrochloric acid. The resulting suspension is stirred at about 10-15 ° C for about 2 hours to complete the precipitation. The product is separated by centrifugation, washed twice with water and the wet cake is used directly in the next step. The corrected separate yield of the product in this step is typically around 70-85%. Testing a dry sample of product on a w / w basis by HPLC against a standard sample typically indicates a relative purity of about 97-99%.

Analytical information IPC 1 CLAR (Gradient) Apparatus: The following equipment or its equivalent can be used: Instrument Hewlett Packard, Model1050 Ternary pumping system, Low pressure mixing gradient pump, HP 1050 series Injector Autosampler, HP 1050 series UV detector, variable wavelength, HP 1050 series Conditions: Zorbax SB-C18 Column, 7.5 cm x 4.6 mm, 3.5 micron particle size, Manufactured by Rockland Technologies, Inc. American Distributor: MAC-MOD Analytical, Inc. Acetonitrile Dilution Solvent: Water grade of CLAR, 1: 5 Organic eluent: CLAR grade acetonitrile Aqueous solution: 0.1 M ammonium acetate (pH = 6.7) Preparation of the mobile phase Mobile phase A = ammonium acetate at 0.1 M Mobile phase B = 50:50; 0.1 M ammonium acetate: acetonitrile Detection wavelength 235 nm, 0.1 AUFS Flow rate 2.0 ml / min. Temperature 40 ° C Injection volume 20 microliters Analysis time 20 minutes Rebalance time 6 minutes Sample preparation: Approximately 30 mg (2 drops) of the reaction mixture is weighed in a 25 ml volumetric flask and dried under a stream of nitrogen. Subsequently the volumetric flask is filled to expand with the dilution solvent. The sample is sonified for 10 minutes and allowed to cool to room temperature.

Gradient program 1.) Composition of the initial solvent-0% mobile phase B. 2.) Linear gradient from 0% to 100% of the mobile phase B in ten minutes 3.) Keep the mobile phase B 100% for 5 minutes 4.) Linear gradient from 100% to 0% of mobile phase B in 5 minutes 5.) Rebalance the mobile phase B to 0% for six minutes.

IPC 2 CLAR (gradient) Apparatus: The following equipment or its equivalent can be used: Hewlett Packard instrument, model 1050 Ternary pumping system, low pressure mixing gradient pump, HP 1050 Injector autosampler, HP 1050 series UV detector, length variable wave, HP series 1050 Spherisorb SCX Column, 5 um, 250 mm x 4.6 mm Dilution solvent Acetonitrile: water CLAR grade, 1: 5 Organic eluent: CLAR grade acetonitrile Aqueous pH A regulator: 11.5 g of ammonium acid diphosphate dissolved in 1000 mL of water adjusted to a pH of 2.5 with phosphoric acid Preparation of the mobile phase: Mobile phase A = 200 mL of pH A regulator, 700 mL of water, 100 mL of acetonitrile Mobile phase B = 200 mL of pH A regulator, 450 mL of water, 350 mL of acetonitrile Detection wave 235 nm Flow velocity 2.0 ml / min.

Temperature 60 ° C Injection volume 10 microliters Analysis time 20 minutes Rebalance time 5 minutes Sample preparation: Transfer 20 mL of the sample I PC into a 50 mL beaker. Shake and, if necessary, add methanol (one or two mL) until the solution is homogeneous. Using a Pasteur pipette, transfer four drops of the sample I PC (50 uL) into a 25 mL volumetric flask. Dilute with 20 mL of mobile phase B and sonicate for one minute.

Gradient program 1.) Solvent composition from 0 to 3 minutes: 0% mobile phase B 2.) Linear gradient from 0% to 100% of mobile phase B in one minute 3.) Maintain 100% the phase B mobile for 16 minutes 4.) Linear gradient from 100% to 0% of mobile phase B in 5 minutes 5.) Rebalance the mobile phase B to 0% for 5 minutes. It is to be understood that the invention is not limited to the modes illustrated above and that it reserves the right to the illustrated modes and all modifications within the scope of the following claims.

Claims (13)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for the preparation of eprosartan, a compound of the formula (I): or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of the formula (II): or an acid or a basic addition salt thereof, with a compound of the formula (III): (|||) where R 'is a C- ^ alkyl, under reduced pressure in the presence of a catalyst, and subsequently hydrolyzing the R' ester and optionally forming a pharmaceutically acceptable salt.

2. The process according to claim 1, further characterized in that the compound of the formula (II) is.

3. The process according to claim 1, further characterized in that the pharmaceutically acceptable salt of the compound of the formula (I) is the methanesulfonic acid salt.

4. The process according to claim 1, further characterized in that the catalyst is piperidinium propionate and excess propionic acid.

5. The process according to claim 1, further characterized in that the pressure is reduced to about 228-330 mm Hg.

6. The method according to claim 1, further characterized in that the pressure is reduced to 279 mm Hg.

7. The process according to claim 1, further characterized in that the catalyst is piperidine.

8. - A process for the preparation of eprosartan, a compound of the formula (I): or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of the formula (IV): or an acid or a basic addition salt thereof, with a compound of the formula (III): (|||) wherein R 'is C 1-4 alkyl, under reduced pressure in the presence of a catalyst, and subsequently hydrolyzing the R' ester and optionally forming a pharmaceutically acceptable salt.

9. The process according to claim 8, further characterized in that the pharmaceutically acceptable salt of the compound of the formula (I) is the methanesulfonic acid salt.

10. The process according to claim 8, further characterized in that the catalyst is propionate de piperidinium and propionic acid in excess.

11. The method according to claim 8, further characterized in that the pressure is reduced by about 228-330 inches of Hg.

12. The method according to claim 8, further characterized in that the pressure is reduced to 279 mm Hg.

13. The process according to claim 8, further characterized in that the catalyst is piperidine.