RS50301B - PROCEDURE FOR OBTAINING HIGH PURITY AMLODIPINE BENZENSULPHONATE - Google Patents

Abstract

Process for the preparation of 3-ethyl 5-methyl (+/-) 2 - [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinecarboxylate benzenesulfonate ( amlodipine benzenesulfonate) by translating the substance 3- (ethyl 5-methyl (+/-) 2- [2- (N-tritylamino) ethoxymethyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3, 5-Pyridinecarboxylate and benzenesulfonic acid, where the translation of the substance is carried out in ethanol at a temperature between 20 ° C and reflux temperature, with the isolation and purification of amiodipine benzenesulfonate.

Description

TECHNICAL FIELD TO WHICH THE INVENTION BELONGS (MKP C 07 D 211/90)

This invention belongs to the field of heterocyclic compounds and the pharmaceutical industry and relates to a process for obtaining high-purity amlodipine benzenesulfonate, which contains a total amount of impurities that is significantly less than 0.3%, as well as to a new process for obtaining a pharmaceutical composition containing the aforementioned amlodipine benzenesulfonate. Amlodipine benzenesulfonate is an effective agent for blocking calcium channels and can be useful as an anti-ischemic and anti-hypersensitive agent.

Technical problem

There is a need for high-purity amlodipine benzenesulfonate, according to a new process for its preparation, which would obtain the desired substance in an easily feasible manner with high yield and high purity.

STATE OF THE ART

Amlodipine is the generic name for 3-ethyl 5-methyl (+/-)-2-(2-aminoethoxy)methyl]-4-(l-chlorophenyl^l^-dihydro-c-methyl-S.S-pyridinedicarboxylate, which was described as a new substance in European Patent No. EP-B-00 89 167, as a useful anti-ischemic and anti-hypertensive agent. Pharmaceutically acceptable acid addition salts were also described amlodipine, among which the maleate salt is particularly suitable for use.

Amlodipine in the form of a simple base can be obtained based on the procedures described in European Patent EP-B-0 89 167. According to these procedures, the amlodipine base is obtained from the precursor of amlodipine, which is a derivative of 1,4-dihydropyridine, which has an amino group in position 2 protected by selected protective groups, in such a way that these amino protective groups are removed from the derivative of 1,4-dihydropyridine with a protected amino group. In case the amino group is protected with a benzyl group, the protecting group is removed by catalytic hydrogenation with a palladium catalyst in a solvent such as methanol at room temperature. In a particularly suitable process, where the protecting group for the amino group in the 1,4-dihydropyridine derivative is preferably a phthaloyl protecting group, where the amino protecting group is removed from the derivative by converting the 1,4-dihydropyridine derivative with the protecting amino group in an alkaline environment, with a) a primary amine, such as methylamine, b) hydrazine hydrate or c) alkaline metal hydroxide, with treatment with hydrogen chloride and sulfur acid. If necessary, the resulting amlodipine base is converted into its pharmaceutically acceptable acid addition salt.

European Patent EP-B-00 89 167 also describes a process for the preparation of amlodipine base from amlodopine precursor, with an azide group in position 2, which reduces the yield of amlodipine base, and is then optionally translated into its pharmaceutically acceptable acid addition salt.

The yields for the aforementioned amlodipine precursors, which are prepared according to the well-known Hantzsch procedure for the preparation of asymmetric, 1,4-dihydropyridine diesters, are relatively low. The process in which the phthaloyl group is used to protect the amino group requires the use of toxic agents, which are not permitted in the preferred pharmaceutically acceptable acid addition salt. Toxic and carcinogenic chemical compounds are methylamine, and especially hydrazine hydrate. In addition, the reduction of the azide derivative of 1,4-dihydropyridine leads to lower yields of the desired chemical compound, and in addition, working with azide herme compounds is unpleasant, due to the known explosiveness of azide structures.

European Patent EP-B-00 244 944 describes a new benzenesulfonate (benzylate) salt of amlodipine and its pharmaceutical forms. Due to its good solubility in water, high stability, non-hygroscopicity and good properties for processing, this salt is extremely favorable for the preparation of pharmaceutical forms of amlodipine.

According to the patent description, amlodipine benzenesulfonate is prepared by reacting amlodipine base with benzenesulfonic acid or with ammonium benzenesulfonate in an inert solvent such as industrial methylated methanol.

European Patent EP-B-0 599 220 describes a process for the preparation of amlodipine benzenesulfonate, according to which the conversion of a new precursor of amlodipine, which is chemically 3-ethyl 5-methyl (+/-)-2-[2-(N-tirtylamino)-ethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, prepared according to the Hantzsch process, with benzenesulfonate with acid in a water/methanol solvent mixture, at a temperature between 20°C and the reflux temperature, with isolation of the amlodipine benzenesulfonate salt and purification. The process is characterized by good overall yields of the desired chemical compound, avoiding working with toxic and carcinogenic chemicals, as well as avoiding obtaining and isolating the amlodipine base required in the process, as described in European Patents EP-O-00 89 167 and EP-B-00 244 944. According to the scope of the invention described in the patent EP-B-0 599 220, the amlodipine base is generally not obtained by the process conversion of one compound into another.

DESCRIPTION OF THE SOLUTION OF THE TECHNICAL PROBLEM WITH WORKED EXAMPLES

The subject of the invention relates to a process for obtaining high-purity amlodipine benzenesulfonate, which contains a total amount of impurities that is significantly less than 0.3%, based on which high-purity amlodipine benzenesulfonate is obtained and which can be easily isolated from the reaction mixture. This goal is achieved by combining the features of patent claims 1 and 2.

A further subject of the invention relates to a process for obtaining pharmaceutical preparations, namely tablets, capsules and sterile aqueous solutions, containing amlodipine benzenesulfonate with a total amount of impurities that is less than 0.3% together with pharmaceutically acceptable diluents and/or carriers. In relation to the given invention, a procedure for preparing tablets containing amlodipine benzenesulfonate in combination with excipients is described.

Preferred compositions of the present invention are those containing amlodipine benzenesulfonate in combination with a thickening agent, such as microcrystalline cellulose, additives for achieving tablet gloss such as anhydrous dibasic calcium phosphate, a disintegrant, such as ascorbic sodium glycolate, and a lubricant such as magnesium stearate.

Unexpectedly, it was found that high yields of high-purity amlodipine benzensulophate, which is easily isolated as the desired substance from the reaction mixture after conversion, in accordance with the procedure described in European Patent EP-B-0 599 220, if the procedure according to the given invention is carried out in ethanol, instead of in methanol or in an aqueous medium for methanol.

Firstly, the condensation reaction of 1,4-dihydropyridine, obtained by the Hantzsch method for obtaining asymmetric diesters, with ethyl 4-2-(N-tritylamino)ethoxy acetoacetate, methyl-(E)-3-amino crotonate and 2-chlorobenzaldehyde, in ethanol, at the reflux temperature of the reaction mixture, gives 3-ethyl 5-methyl (+/-) 2-[2-(N-tritylarmno)ethoxymethyl]-4-(2-M^without isolation from the reaction mixture with ethanol, the conversion of the substance is carried out with benzenesulfonic acid in ethanol, at a temperature between 20°C and the reflux temperature. After the completion of the conversion process, the resulting amlodipine benzenesulfonate is isolated and purified, including mixing after the completion of the conversion of the substance, at a temperature below 0°C, preferably around -10°C, in order to tyrphenylmethyl ethyl ester, which is separated after conversion of the substance, was removed.

The resulting amlodipine benzenesulfonate according to the present invention has a high purity and contains a total amount of impurities that is significantly less than 0.3%.

2-Chlorobenzaldehyde and methyl (E)-3-aminocrotonate, which are required for the Hantzsch synthesis of asymmetric 1,4-dihydropyridine esters, are commercially available, while ethyl 4-[2-(N-tritylamino)-ethoxy]acetoacetate is obtained as described in European

EP-B-0 599 220 as described in the example below.

The present invention is illustrated by the following examples:

Example 1

10.7 mol (0.428 kg) of 60% sodium hydride in mineral oil and 2.4 liters of anhydrous tetrahydrofuran are placed in the first reactor. In the second reactor, a solution of 4.4 mol (1,337 kg) of N-trityl-2-aminoethanol (obtained as described in European Patent EP-B-O-599 220) in 3.4 liters of anhydrous tetrahydrofuran is placed. A solution of N-trityl-2-aminoethanol, at a temperature between 20°C and 30°C, is slowly added to the sodium hydride suspension (2 to 2.5 hours) with vigorous stirring and in a stream of nitrogen. After that, the reaction mixture is stirred for the next 2 hours, at a temperature between 25°C and 30°C.

In the third reactor, a mixture of 4.45 mol (0.773 kg) of ethyl-4-chloroacetate and 0.9 liters of anhydrous tetrahydrofuran is prepared and cooled to a temperature of 0°C to 5°C. A solution of ethyl-4-chloroacetatoacetate is slowly added (3-4 hours) with vigorous stirring and in a stream of nitrogen, to the reaction mixture of N-trityl-2-aminoethanol, at a temperature between 20°C and 30°C. Then the reaction mixture is stirred for five hours at a temperature between 5°C and 10°C, at a temperature between 20°C and 30°C, all the time with a gentle blowing of dry nitrogen.

During nitrogen blowing, the reaction is stopped by the addition of ethanol (0.45 liters) and demineralized water (14 liters). After that, nitrogen blowing is stopped. The reaction mixture is neutralized with concentrated hydrochloric acid to a pH value of 7 (acid consumption is 0.25 liters), after which it is stirred for another 20 minutes at a temperature between 25°C and 35°C, and each of the layers is separated.

The upper organic layer is diluted with 5.6 liters of ethyl acetate, 0.25 kg of sodium chloride is added, and washed with 6.56 liters of demineralized water. The aqueous phase is separated, and washed again with 6.5 liters of demineralized water, with the addition of 0.25 kg of sodium chloride. The organic phase is concentrated on a rotary vacuum evaporator, and the remaining oil (1.95 kg) is redissolved in 2.7 liters of absolute ethanol. The resulting solution is further used according to the present invention.

A solution of ethyl-4-(2-N-tritylamino)ethoxy acetoacetate in ethanol, obtained according to the above procedure, 3.9 liters of absolute ethanol, and 3.72 mol (0.429 kg) of methyl (E)-3-aminocrotonate are placed in the reactor. The reaction mixture is heated to a temperature of 45°C to 55°C and stirred at that temperature for 30 minutes. After that, an additional amount of 3.70 mol (0.520 kg) of 2-chlorobenzaldehyde was added to the reaction mixture, heated to the reflux temperature of the reaction mixture, and heated at the reflux temperature for 20 minutes.

In the second reactor, a solution of technical 95% benzenesulfonic acid (3.86 mol, 0.643 kg) in 0.8 liters of absolute ethanol is prepared. Ethanol solution was slowly added (1.5 h) at reflux temperature to the reaction mixture, and it was heated at that temperature for an additional 1h, then cooled to 0°C to -10°C, and stirred at that temperature for the next three hours. The precipitate (1.1 kg) of triphenylmethyl ethyl ether is isolated and filtered, and the filtrate is concentrated in vacuo to a precipitate (2.6 kg).

Demineralized water (7.2 liters) is added to the precipitate, heated to a temperature of 40°C to 50°C, and the aqueous phase is separated. The procedure is repeated twice, after which another 4 liters of a mixture of toluene and n-heptane (1 : 1) are added and 4 liters of demineralized water are added; after that, the mixture is heated to 60°C to 70°C, and placed in a continuous extractor for extraction with specific light solvents. A solvent mixture consisting of toluene and n-heptane (1:1) is added to the extracted sample.

The mixture in the form of a precipitate (three-phase system: resin-water-toluene/n-heptane) is continuously extracted at an interval of 24 hours, with the temperature of the extractor between 50°C and 60°C. At the end of the extraction, the toluene/n-heptane phase and the aqueous phase are separated and the residue is concentrated under vacuum, after which 1.35 kg of solid amorphous residue is obtained.

Ethyl acetate (3.0 liters) and water (0.1 liters) are added to the evaporated residue, with heating to dissolve (at a temperature of 40 to 50°C), and then cooled to -10°C to -15°C. At that temperature, the reaction mixture is stirred for 20 hours, the obtained precipitate is filtered and washed with 0.5 liters of cooled ethyl acetate, whereby 1.05 kg of wet precipitate is obtained.

Fresh ethyl acetate (2.1 liters) and water (0.08 liters) are again added to the wet precipitate; the reaction mixture is heated to dissolution (50°C to 60°C), and the solution is cooled to -10°C to -15°C. At that temperature, the reaction mixture was stirred for 10 hours, the resulting precipitate was filtered and washed with 0.5 liters of cold ethyl acetate, after which 0.85 kg of wet precipitate was obtained.

The wet precipitate is placed in a reactor, 7.2 liters of demineralized water are added and the reaction mixture is heated to dissolve (50° to 60°C). The composition is cooled very slowly to 0°C to 10°C (up to 10 hours), and the resulting crystals are filtered off and dried under vacuum to yield 0.57 kg of dry crystallized amlodipine benzenesulfonate.

The resulting product crystallizes from methanol (1.1 liters) and the resulting crystals are filtered (0.45 kg of wet crystals), and then the crystallization procedure from methanol (0.8 liters) is repeated. After filtration and vacuum drying, 0.38 kg (0.67 mol) of high purity white crystals of amlodipine benzenesulfonate are obtained, containing significantly less than 0.3% impurities (as determined by the HPLC method). The melting point of the obtained amlodipine benzenesulfonate is 201.0°C.

Claims (3)

1. Procedure for obtaining 3-ethyl 5-methyl (+/-) 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate (amlodipine benzenesulfonate) by converting the substance 3-(ethyl 5-methyl (+/-) 2-[2-(N-tritylamino)ethoxymeu]-4-(2-Worophenyl)-1,4-dihydro-6-methyl-pyridinecarboxylate and benzenesulfonic acid, where the conversion of the substance is carried out in ethanol, at a temperature between 20°C and the reflux temperature, with the isolation and purification of amiodipine benzenesulfonate. 2. The method according to patent claim 1, characterized in that the obtained 3-ethyl 5-methyl (+/-) 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate (amlodipine benzenesulfonate) contains a total amount of impurities that is significantly less than 0.3%. 3. A method for obtaining a pharmaceutical composition containing amlodipine benzenesulfonate, characterized in that it includes the steps from patent claim 1 and the subsequent combination of amlodipine benzenesulfonate with a pharmaceutically acceptable diluent or carrier.