FI62292B - FRUIT PROOF FOR OPTICAL ACTIVE LAEGRE-ALKYL-1- (1-PHENYL) -1H-IMIDAZOLE-5-CARBOXYLATE - Google Patents

Description

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Patent and registration authorities '' Anttksn utitgd «« h uti. * Krift * n pubiieund 31.08.82 (32) (33) (31) Pnrfstty «tuolkuu. — Buglrd prlorltut 10.03 · 75 Pharmaceutica Naamloze Vennootschap, Turnhoutsebaan 30,

Beerse, Belgium-Belgien (BE) (72) Leopold Fr. C. Roevens, Rijkevorsel, Jozef J.P. Heykants, Vosselaar, Walter A.M. Helsen, Wilrijk, Belgium-Belgien (BE) (jb) Oy Kolster Ab (5M Process for the preparation of optically active lower alkyl 1- (1-phenylethyl) -1H-imidazole-5-carboxylates alkylene-L- (l-fenyletyl) -lF-imid azol-5-karboxylater

The invention relates to a process for the preparation of optically active lower alkyl 1- (1-phenylethyl) -1H-iridazole-5-carboxylates and their pharmaceutically acceptable acid addition salts.

The imidazole carboxylates in question have the formula F? alenpi-alkyl li-OOC N>

C 1 -C 3 (I) δ This formula also encompasses stereochemical isomers. The term "lower alkyl" means methyl, ethyl or propyl.

Compounds of formula (I) in racemic form and methods for their preparation are described in U.S. Patent 3,354,173.

2,67292

The capped compounds of formula (I), and in particular the dextrorotatory isomers thereof, having the R 1 configuration are highly useful short-acting hypnotics and some of them are generally used or well known in the art. Important compounds of formula (I) include, for example, (*) '- methyl 1- (1-phenylethyl) imidazole-5-carboxylate, which is commercially available in Europe as an injectable hypnotic agent for veterinary purposes; R - (+) - ethyl 1- (1-phenylethyl) -1H-imidazole-5-carboxylate, described in Arzneim.-Forsch., 21 (8) 1234 (1971), Brit. J. Anesthesia, 45, 1097 (1973) and Anesthesia, 23, 150 (1974); and (+) - propyl 1- (1-phenylethyl) -1H-imidazole-5-carboxylate (propoxate).

The process of the present invention using a racemic precursor as starting material gives substantially pure optical antipodes of formula (I) which contain almost no second antipode. Such a process is very useful because it allows the preparation of optically pure end products as a less dependent on optically pure precursors. availability.

The process according to the invention is characterized in that the racemic 1- (1-phenylethyl) -1H-imidazole-5-carboxylic acid is reacted with the optically active isomer of N-methylbenzenemethanamine to give an insoluble salt which is separated and treated with a strong, non-oxidizing mineral acid. acid.

The formation of diastereomeric salts is carried out in a suitable inert organic solvent, for example a lower alkanol such as ethanol, propanol, 2-propanol or the like, preferably under reflux conditions. The optically active base used in the process is e - or left - rotating e («methylbenzenemethanamine.

When the R- (+) base is added to a solution of racemic 1- (1-phenylethyl) -1H-imidazole -5-carboxylic acid in a suitable solvent, R - (+) - 1- (1-phenylethyl) -1H-imidazole-5- an addition salt of a carboxylic acid with a base in substantially pure form, from which the free acid can be obtained in substantially optically pure form.

3,62292 The R 1 (+) - (N (d (phenylethyl) -1H-imidazole-5-carboxylic acid or its addition salt with a base thus obtained is readily converted to R- (+) - lower N-alkyl-N (N-phenylethyl) to the 1H-imidazole-5-carboxylate (R- (+) (I)) by conventional esterification methods, for example by refluxing the acid or addition salt in a suitable lower alkanol in the presence of a suitable strong non-oxidizing acid such as hydrochloric acid or sulfuric acid.

The same procedure can be used to separate S - (-) - 1- (1-phenylethyl) -1H-imidazole-5-carboxylic acid using, however, the S - (-) - isomeric form of the optically active base. Accordingly, esterification of the (-) 2 acid thus obtained gives the S - (-) form (S - (-) (I)) of the esters of formula (I).

Whether the R - (+) or S - (-) form of the carboxylic acid is removed from the medium in the form of a diastereomeric salt, the corresponding enantiomer remaining in solution can be recovered in a conventional manner, for example by evaporation from the mother liquor or dilution as a suitable solvent, and if desired by conversion to a lower alkyl ester of formula (I) having the corresponding configuration.

The racemic 1- (1-phenylethyl) -1H-imidazole-5-carboxylic acid used herein as a starting material is described in U.S. Patent 3,354,173 and can be prepared as described therein.

The following examples illustrate the invention. Unless otherwise stated, all parts are by weight and the marking (»0 means + D *

Example 1 a) To a mixture which is stirred at reflux and contains 13 parts of (+) - 1- (1-phenylethyl) -5-imidazolecarboxylic acid and 200 parts of 2-propanol, 3.6 parts of (-) - <* methylbenzenemethanamine and the mixture is stirred at reflux for 10 minutes. The reaction mixture is allowed to cool to room temperature. The precipitated product is filtered off (the filtrate is collected), washed with 2-propanol and crystallized from 160 parts of 2-propanol. The precipitate is filtered off and dried for a couple of days under vacuum at 60 ° C to give the salt of (-) - 1- (1-phenylethyl-1H-imidazole-5-carboxylic acid with (-) -? - methylbenzenemethanamine, mp 194 ° C (<*) D = -51 ° C (c = 1% in water).

4,62292

To the filtrate (see above) is added 3.6 parts of (+) - 4-methylbenzenemethanamine, and the mixture is stirred and heated under reflux for 10 minutes. The reaction mixture is allowed to cool to room temperature. The precipitated product is filtered off, washed with 2-propanol and dried in vacuo for 4 hours at 60 [deg.] C. to give the salt of (+) - 1- (1-phenylethyl) -1H-imidazole-N-carboxylic acid with (+) - (N - methylbenzenemethanamine). , mp 190.3 ° C, (° D = + 52.9 ° (c = 1% in water).

b) A mixed mixture of 2.55 parts of (+) - Λ-methylbenzylamine salt with R - (+) - 1- (ethylmethylbenzyl) -4-imidazolecarboxylic acid and 24 parts of dry absolute ethanol is saturated with gaseous hydrogen chloride. Stirring is then continued for 7 hours at reflux temperature, adding more gaseous hydrogen chloride. The reaction mixture is evaporated to dryness and the residue is added to 30 parts of water. The pH of the resulting solution is adjusted to 6 by adding 10N sodium hydroxide solution and the product is extracted three times with trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is added to 2.4 parts of 2-propanol and the solution is filtered. The filtrate is acidified with sulfuric acid and heated for a short time. 2,2'-Oxybispropane is added until the mixture is almost cloudy and the product is precipitated by scraping while cooling in an ice bath. The product is filtered off, washed with a mixture of 2-propanol and 2,2, -oxybispropane and dried to give (80%) R - (+) - ethyl 1- (<* - methylbenzyl) -5-imidazolecarboxylate sulphate, (or ) = + 22.5 ° (c = 0.1% h 2 O).

Example 2

A mixed mixture of 2.55 parts of S - (-) - 1- (1-phenyl-ethyl) -1H-imidazole-S-carboxylic acid salt with (-) - o (-methylbenzenemethanamine) and 24 parts of dry absolute ethanol The mixture is then taken up in refluxing and the residue is taken up in 30 parts of water. The residue is converted by filtration, washed with methylbenzene and dried to give (52%) of S - (-) - ethyl-1- (o (-methylbenzyl) iridazole-5'-carboxylate nitrate) and evaporated to dryness. , (00 = -31.9 ° (c = 0.1% H 2 O)).