RU2142942C1 - Method of preparing monobenzosulfonate of 2-[(2- aminoethoxy) methyl -4- (2-chlorophenyl)-1,4-dihydro-6- methyl]-3,5-pyridine dicarboxylic acid 3-ethyl-5-methyl ester - Google Patents

Abstract

FIELD: chemical industry. SUBSTANCE: method comprises reacting 3-ethyl-5-methyl ester of 2-[2-(N- phthalimido)ehtoxymethyl)-4-(2-chlorophenyl) 1,4-dihydro- 6-methyl-3,5-pyridine dicarboxylic acid with N-methyl ammonium salt of benzenesulfonic acid in secondary alcohol solvent at temperature of 75-80 C and isolating desired compound by well known procedure. It is desirable to use isopropyl alcohol solvent and to purify final compound by crystallization from water. Method makes it possible to prepare desired product in one stage without isolation of amplodipin base, to use commercially available substances and to use water for crystallization. EFFECT: more efficient preparation method. 3 cl, 2 ex

Description

Амлодипин безилат является блокатором кальциевых каналов, используемым при лечении гипертензии и профилактике ангины.This invention relates to a method for producing 2 - [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridine-3-ethyl-5-methyl ester monobenzenesulfonate carboxylic acid (amlodipine besylate) formula

Amlodipine besilate is a calcium channel blocker used in the treatment of hypertension and the prevention of angina.

 European patent application EP 89167 discloses amlodipine and its various pharmaceutically acceptable salts, as well as methods for preparing amlodipine base.

 In British patent application GB 2188630A in Example No. 1, a method for producing amlodipine besylate salt by reacting amlodipine base with a solution of benzenesulfonic acid and / or its ammonium salt using an inert solvent, industrial ethyl alcohol denatured with methyl alcohol (PMS), is described. This patent application states that amlodipine besylate salt exhibits good solubility compared to other salts. The method is disadvantageous, since solvents like PMS contain moisture. Moisture usually acts as an initiator of hydrolysis and technical breakdown and, therefore, causes instability of the drug.

 Indian Patent No. 168414 describes a process for the preparation of amlodipine besylate salt from two starting materials, namely, amlodipine base and benzenesulfonic acid in an inert solvent, preferably ethanol denatured with methyl alcohol. Since the reaction is carried out in the presence of methanol, which is hygroscopic, this leads to the destruction of benzenesulfonic acid.

 European patent application EP 0599220 B1 describes a process for the preparation of amlodipine benzenesulfonate using two starting materials, the trityl derivative of amlodipine (3-ethyl-5-methyl ether (±) 2- [2- (N-tritylamino) ethoxymethyl] -4- (2-chlorophenyl) - 1,4-dihydro-6-methyl-3,5-py-pyridine-dicarboxylic acid) and benzenesulfonic acids. This invention is based on the simultaneous cleavage of the protective trityl group from the resulting amlodipine precursor, which in this method is not isolated from the crude reaction mixture, which immediately interacts with benzenesulfonic acid and on the direct isolation of amlodipine benzenesulfonate without any formation / isolation of amlodipine as its base.

 Due to the particularly good acceptability of amlodipine besylate as a medicine in comparison with the known salts of amlodipine having good formulation properties and especially suitable for the preparation of pharmaceutical formulations of amlodipine, there is a need to develop a process for preparing benzenesulfonate using readily available starting materials that are safe to handle them and commercially available at a lower price.

The method of the present invention eliminates the disadvantages of the known methods and lies in the fact that (3-ethyl-5-methyl ether 2- [2- (N-phthalimido) ethoxymethyl] -4- (2-chlorophenyl) -1,4-dihydro- 6-methyl-3,5-pyridine-dicarboxylic acid
The method of the present invention eliminates the disadvantages of the known methods and consists in the fact that 3- ethyl-5-methyl ether 2- [2- (N-phthalimido) ethoxymethyl] -4- (2-chlorophenyl) -1,4-dihydro-6 - methyl-3,5-pyridine-dicarboxylic acid interacts with the N-methylammonium salt of benzenesulfonic acid in a solvent - secondary alcohol at a temperature of 75-80 ^o C and the target compound is isolated.

 It is preferable to use isopropyl alcohol (IPA) as a solvent, and the final compound should be purified by crystallization from water. The proposed method has several advantages.

 1. The use of starting materials having a phthalimide protective group that are easy to handle and commercially available at a lower price.

 2. The one-stage method, including the removal of the phthalimide group simultaneously without isolation of amlopidine in the form of a base, interaction with the N-methylammonium salt of benzenesulfonic acid.

 3. The method provides that the final compound is crystallized from water to avoid any organic volatile impurities.

Таким образом, данное изобретение относится к способу получения безилата амлодипина взаимодействием N-метилламмониевой соли бензолсульфокислоты с фталимидоамлодипином во вторичном спирте (с высоким молекулярным весом по сравнению с используемыми ранее спиртами), таком как изопропиловый спирт (ИПС).DETAILED DESCRIPTION OF THE INVENTION
This invention relates to a method for producing 2- [2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridine-dicarboxylic 3-ethyl-5-methyl ester monobenzenesulfonate acids of the formula

Thus, this invention relates to a method for producing amlodipine besylate by reacting the N-methyl ammonium salt of benzenesulfonic acid with phthalimido amlodipine in a secondary alcohol (with a high molecular weight compared to previously used alcohols), such as isopropyl alcohol (IPA).

 The final compound is crystallized from water in such a way as to avoid any organic volatile impurities.

 The novelty of this method is the simultaneous cleavage of the protective phthalimide groups from the amlodipine precursor and the direct isolation of amlodipine benzenesulfonate, avoiding the need to obtain any intermediate forms and isolating amlodipine as its free base. Since the pH of the reaction mixture is 6.8 ± 0.2 during the entire reaction, there is no possibility of the formation of amlodipine free base.

 The general reaction progress is shown in Scheme 1. The following examples illustrate the invention without limiting its scope.

Preparatory example 1. Obtaining N-methylammoniumbenzene sulfonate (N-methylammonium salt of benzenesulfonic acid). 52 g of benzene sulfonic acid (technical grade) is mixed with 40 ml of isopropyl alcohol. To this mixture, 22 ml of monomethylamine (40% solution) was slowly added, bringing the pH of the resulting mixture to 7.5 at a temperature below 25 ^° C. The above solution was used in 3 portions in the following example.

Example 1. Obtaining 3-ethyl-5-methyl ester monobenzenesulfonate 2 - [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridine-dicarboxylic acid (amlopidine benzenesulfonate). 20 g of 2 - [(2-N-phthalimidoethoxymethyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridine-dicarboxylic acid 3-ethyl-5-methyl ester is stirred in 200 ml of isopropyl alcohol The mixture is stirred for 15 minutes at a temperature of 25 ^° C. 30 ml of N-methylammonium benzenesulfonate obtained in preparation 1 are added and the mixture is refluxed for 18 hours.The pH of the reaction mixture is controlled at 6.8 ± 0.2. Cool the reaction mixture to 30 ^o C and then slowly add a second portion. (20 ml) obtained in preparatory example 1 RA solution for more than 15 minutes, the mixture is refluxed for 12 hours and the pH of the reaction mixture is controlled at 6.8 ± 0.2, the reaction mixture is cooled to 30 ^° C. and then a third portion (10 ml) of N- solution is added. methylammoniumbenzenesulfonate. The mixture is refluxed for 12 hours, the resulting clear mixture is cooled to 10 ^° C. and a precipitate is obtained. The reaction mixture is filtered to regenerate unreacted starting materials (phthalimidoamlodipine). The filtrate was distilled in vacuo. 400 ml of water was added to the residue, and the mixture was heated to a temperature of 80-901 ^° C. The solution was filtered hot and the filtrate was cooled to a temperature below 10 ^° C to precipitate the product (amlodipine besilate). The product is filtered and washed with water.

The yield is 4 g of amlodipine besylate. Melting point 201 ^o C.

 The product was recrystallized from water to give pure amlodipine besilate.

 Thus, the proposed method allows to simplify the process by eliminating the stage of removal of the protective group at the base, by using crystallization from water, as well as simpler, safer and commercially available reagents.

Claims (3)

1. The method of obtaining monobenzenesulfonate 3-ethyl-5-methyl ether 2 - [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid (amlodipine benzenesulfonate) formulas

characterized in that the 3- ethyl-5-methyl ester of 2- [2- (N-phthalimido) ethoxymethyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid with N-methylammonium salt of benzenesulfonic acid in a solvent - secondary alcohol at a temperature of 75 - 80 ^o C and the target compound is isolated.  2. The method according to claim 1, characterized in that the secondary alcohol is isopropyl alcohol.  3. The method according to claim 1, characterized in that the final compound is purified by crystallization from water.

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