IES65748B2 - Process for the separation of the optical antipodes of racemic phenyl-(2-Pyridyl)-dimethylpropylamines - Google Patents

Abstract

A process for preparing in substantially pure form the d-isor of a compound of the formula I wherein X is chlorine or bromine and n is 0 or 1, or a pharmaceutically acceptable acid addition salt thereof, comprises reacting the d1-form of a compound of the formula I with a D-substituted benzenesulphonyl aspartic acid or a salt thereof as resolving agent and, if desired, converting the compound thus obtained into a pharmaceutically acceptable acid addition salt thereof. These compounds have strong anti-histaminic activity.

Description

PROCESS FOR THE SEPARATION OF THE OPTICAL ANTIPODES OP RACEMIC PHENYL-(2-PYRIDYL)-DIMETHYLPROPYLAMINES This invention relates to a process for the separation ί of the optical antipodes of racemic phenyl-(2-pyridyl)dimethylpropylamines. In particular, it relates to a process for the preparation of the d-isomers of compounds of the formula I wherein X is chlorine or bromine, and n is 0 or 1, and salts thereof.

These compounds are well known and have strong anti-histaminic activity.

U.S. Patent Specification No. 3,061,517 describes a process for the separation of the d-isomers of phenyl-(2-pyridyl)-alkyl substituted tertiary amines and certain halogen-substituted derivatives thereof from a racemic mixture of- same. However, the resolving agent, d-phenylsuccinic acid, used in this process is difficult to prepare and therefore expensive. The reaction must also be carried out in an organic solvent. Furthermore, successive purification steps by recrystallisation are required with consequent low yields of the end products. - 2 S65748 It is an object of the invention to provide an improved process for preparing the d-isomer of a compound of the formula I as defined above.

According to the invention there is provided a process for preparing, in substantially pure form, the d-isomer of a compound of the formula I wherein X and n are as already defined, or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting the dl-form of a compound of the formula I with a D-substituted benzenesulphonyl aspartic acid or a salt thereof as resolving agent and, if desired, converting the compound thus obtained into a pharmaceutically acceptable acid addition salt thereof.

The d-isomers obtained according to the process of the invention are substantially free of their optical antipodes and can be reacted with suitable mineral and organic acids to form the corresponding pharmaceutically acceptable acid addition salts thereof. Examples of suitable acids are hydrochloric acid, hydrobromic acid, tartaric acid, citric acid, succinic acid and maleic acid.

The substituent on the benzenesulphonyl radical of the resolving agent may be, for example, C^_4 alkyl, nitro, bromo or chloro. Preferably, the resolving agent is D-tosylaspartic acid or a salt thereof, preferably the ** sodium salt thereof. 1 Prior to the reaction with the resolving agent, the dl-form of the compound of the formula I is preferably treated with an L-substituted benzenesulphonyl aspartic acid or a salt thereof, in order to remove a large proportion of the undesired 1-isomer of the compound of the formula I. This step eliminates the requirement for subsequent successive purification steps by recrystalisation, thus improving the efficiency of the process and the yield of the end product.

D- and L-substituted benzenesulphonyl aspartic acids can be readily obtained in conventional manner in high yield from the commercially available aspartic acids and without the use of any organic solvents.

The reaction of the dl-form of a compound of the formula I with the resolving agent is preferably carried out in water. The volume of water required is far less than the volume of solvent required in the process described in U.S. Patent Specification No. 3,061,517. The resolving agent in aqueous solution can be readily cycled back into the process without the need for isolation or purification.

The mole ratio of racemate to resolving agent is not critical but is preferably in the range of from about 1:1 to 2:1. f Following the reaction between the racemate and resolving agent, the product can be removed by filtration and washed with solvent, preferably water.

Following extraction of the resulting product into a solvent, the pure d-isomer of the compound of formula I can be obtained by distillation of the solvent. M.

The reaction is typically performed at a temperature of f to 50°C, the preferred temperature being 20 to 30°C.

The invention is illustrated by the following Example.

EXAMPLE io (a) d-3-(2-Pyridyl)-3-p-bromophenyl-N,N-dimethylpropylamine Sixty-five grams of racemic 3-(2-pyridyl)-3-p15 bromophenyl-N,N-dimethylpropylamine are combined with an aqueous solution of sodium L-tosylaspartate (equivalent to about 50 g of L-tosylarpartic acid). The pH is adjusted to about 4 with concentrated hydrochloric acid, and the undesired 2-3-(2-pyridyl)-3-p-bromophenylΝ,Ν-dimethyl-propylamine L-tosy.laspartate salt which precipitates is removed by filtration.

The mother liquor, now greatly enriched in the desired d-isomer, is made strongly alkaline with 40% aqueous sodium hydroxide, and the liberated base is extracted into toluene. The toluene solution is extracted with 170 ml of dilute (10%) hydrochloric acid. The resultant solution (containing about 39 g of crude d-3-(2-pyridyl)3-p-bromophenyl-N,N-dimethylpropylamine) is treated with 120 ml of an aqueous solution of sodium D-tosylaspartate (equivalent to about 33 g of D-tosylaspartic acid). The pH is adjusted to about 4.5 with hydrochloric acid, and the mixture is stirred for about 10 hours. Hydrocholoric acid is used to partially neutralise the racemic 3-(2-pyridyl)-3-p-bromopheny1-N,N-dimethylpropy1amine, thus reducing the requirement for a full equivalent of the tosylaspartic acids. The precipitated product is filtered and washed with water. The wet product is dispersed in about one volume of water, the solution is made alkaline with 40% aqueous sodium hydroxide, and the liberated base is extracted into toluene. The solution is washed with water and the toluene is removed by distillation.

The d-3-(2-pyridyl)-3-p-bromophenyl-N,N-dimethylpropylamine so obtained is a mobile oil; [a]D25° + 73 to + 76° (cone., 10% in toluene). The yield is 80%. d-3-(2-Pyridyl)-3-p-bromophenyl-N,N-dimethylpropylamine maleate Fifteen grams of the above base, d-3-(2-pyridyl)3-p-bromophenyl-N,N-dimethylpropylamine, and 5.3 g of maleic acid are dissolved in 100 ml of ethyl acetate and heated to about 65° to 70°C. The solution is cooled and stirred for ca. 3 hours.

The d-3-(2-pyridyl)-3-p-bromophenyl-N,N-dimethylpropylamine maleate so obtained is filtered, washed with ethyl acetate and dried.

M.P. 105-113°C, [a]D25° + 35.0 to + 38.5° (cone., % in dimethylformamide).

Claims (5)

1. CLAIMS χ

1. A process for preparing in substantially pure form the d-isomer of a compound of the formula I f wherein X is chlorine or bromine and n is 0 or 1, or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting the dl-form of a compound of the formula I with a D-substituted benzenesulphonyl aspartic acid or a salt thereof as resolving agent and, if desired, converting the compound thus obtained into a pharmaceutically acceptable acid addition salt thereof.

2. A process according to claim 1, wherein the resolving agent is D-tosylaspartic acid or a salt thereof, preferably the sodium salt thereof, and the reaction is carried out in water.

3. A process according to claim 1 or 2 wherein the dl-form of the compound of the formula I is treated with an L-substituted benzenesulphonyl aspartic acid or a salt thereof, preferably L-tosylaspartic acid or the sodium salt thereof, prior to the reaction with the resolving agent.

4. A process according to any preceding claim, wherein the compound prepared is d-3-(2-pyridyl)-3-pchlorophenyl-N,N-dimethylpropylamine, d-3(2-pyridyl)-3-p-bromophenyl-N,N-dimethylpropylamine maleate or d-3-(2-pyridyl)-3-phenyl-N,N-dimethylpropylamine .

5. A pharmaceutical composition containing a compound prepared by a process claimed in any preceding claim.