IE42652B1

IE42652B1 - Method for the preparation of optically pure loweralkyl imidazole carboxylates

Info

Publication number: IE42652B1
Application number: IE482/76A
Authority: IE
Original assignee: Janssen Pharmaceutica Nv
Priority date: 1975-03-10
Filing date: 1976-03-09
Publication date: 1980-09-24
Also published as: PT64879A; BG24806A3; DE2609573A1; ES445450A1; IT1057941B; YU60876A; NO144884C; SU677656A3; CH629192A5; AU1180676A; AU503733B2; FI62292C; NL7602444A; CS203116B2; SE7601959L; GB1535566A; HU172026B; PL99926B1; IE42652L; ATA171776A

Abstract

Optically active C1-C3-alkyl esters of 1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid are prepared by reacting racemic 1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid with an optically active isomer of 1-phenylethylamine, 1-(1-naphthyl)ethylamine or 1-(2-naphthyl)ethylamine. The resulting insoluble diastereomeric salt is separated off and treated with a strong non-oxidising mineral acid. The resulting optically active 1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid is then esterified with a C1-C3-alcohol. In another process, the resulting optically active acid is firstly converted into the acid halide and then correspondingly esterified. The prepared compounds can be used as hypnotics.

Description

The present invention relates to a method of preparing 1 -(1 - phenylethyl) - IH - imidazole - 5 carboxylic acid, or a base or acid addition salt thereof and lower alkyl 1-(1- phenylethyl) - IH - imidazole 5 5 - carboxylates in optically pure isomeric form.

The imidazole carboxylates with which the present invention is concerned are generally represented by the formula: and the stereochemical optical isomers thereof, wherein the term loweralkyl is a group having from 1 to 3 carbon atoms. The pharmaceutically acceptable acid addit· ion salts of these compounds are included within the scope of formula (I). 42852 - 3 Compounds of formula (I) in racemic form and methods for their preparation are described in United States Patent Specification No. 3,354,173.

The compounds of formula (I), and. in particular the dextrorotatory isomers thereof, having the R configuration, are very useful as short-acting hypnotic agents, and some of them are now currently used in practice or well-known in the art. Important members of the group of compounds within the scope of the formula (I) are, for example, (+) - methyl 1-(1- phenylethyl) imidazole - 5 - carboxylate, generically designated as metomidate, which is commercially available in Europe as an Injectable hypnotic for veterinary use; R - ¢+) ethyl 1-(1- phenylethyl) * 1H - Imidazole - 5 carboxylate, generically designated as eomidate, reports of which have appeared in Arzneum. - Firsche., 21 (8), 1234 (1971), Brit. J. Anaesthesia, 45, 1097 (1973), and Anaestheslst, 23, 150 (1974); and {+) - propyl 1-(1phenylethyl) - IH - imidazole - 5 - carboxylate, generically designated as propoxate.

The present invention provides a method of preparing substantially pure optical isomers of formula (I), essentially free of the other, starting from racemic precursors. It is highly desirable to have such a method available since it makes the production of optically pure end products dependent to a lesser degree on the availability of optically pure precursors.

A convenient method of preparing substantially pure R- and S-forms of the compounds of formula (I) comprises resolving racemic 1-(1- phenylethyl) - lH - imidazole 5 - carboxylic acid into its optically active enantiomorphs and thereafter converting each optical isomer of the acid into the desired loweralkyl ester according to known esterification procedures.

The resolution of racemic 1 - (.1 - phenylethyl) 42653. - 4 lH - imidazole - 5 - carboxylic acid into its optical isomers may be carried out by salt formation with the appropriate isomeric form of a suitable optically active base, mechanically separating the insoluble diastereo5 meric salt thus formed, and liberating the corresponding free acid in the usual manner, for example, by treatment of the acid-base salt with a suitable acid, e.g., a strong non-oxidizing mineral acid, in an amount sufficient to neutralize the basic moiety. If the imidazole10 carboxylic acid is to be isolated then the free optically active base is first liberated from the diastereomeric salt by the addition of aqueous alkali to about pH 11, thereafter the base extracted with an appropriate water-immiscible organic solvent such as, 2,2' - oxybis15 propane, and the pH of the remaining alkaline aqueous phase adjusted to neutral or slightly acidic with an appropriate acid, preferably a loweralkyl carboxylic acid such as, acetic acid or propionic acid, whereupon the desired imidazolecarboxylic acid precipitates. The opti20 cally.active base used in the resolution is thereby recovered and, consequently, the need for additional optically pure reagents is minirnalized.

The formation of the above described diastereomeric salts is conducted in an appropriate inert organic solvent such as, a lower alkanol, e.g. ethanol, propanol or - propanol, preferably under reflux conditions. Suitable optically active bases for the purpose of this invention, include the dextro- and levo-forms of 1 - plienylethylamine, 1-(1- naphthyl)ethy1 amine, and 1-(230 naphthyl)ethylamino, the first mentioned being preferred. i 1 For example, when R - (+) - 1 - phenylethylamine is added to a solution of racemic 1-(1- phenylethyl) IH - imidazole - 5 - carboxylic acid in an appropriate solvent, an addition salt of R - (+) - 1 - (1 - phenyl35 ethyl) - ill - imidazole - 5 - carboxylic acid with R (+) -1-r phenylethylamine in substantially pure form is 42SK2 precipitated, from which the free acid may be obtained in essentially optically pure form.

The thus - obtained R - (+) -1- (1- phenylethyl) IH - imidazole - 5 - carboxylic acid or the addition salt thereof with R - (+) - 1 - phenylethylamine is easily converted into a R - (+) - loweralkyl 1-(1- phenylethyl) IH - imidazole - 5 - carboxylate, designated as R - (+) (I), according to conventional esterification methods, for example, by refluxing the acid or the addition salt in an appropriate lower alkanol in the presence of a strong non oxidising mineral acid such as, hydrochloric or sulfur acid. Alternatively, the R - (+) acid may be transformed into an acyl halide according to standard procedures and the acyl halide reacted with an appropriate lower C-^g alkanol, e.g. methanol, ethanol or propanol, to provide the desired ester. For example, the hydroxy function of the acid may be readily transformed into a chloro function by reaction of the acid with such chloro-transfer agents as oxalyl chloride, sulfinyl chloride (thionyl chloride) which is preferred, sulfuryl chloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride. The thus-obtained R - (+) (I) product may be further purified by known purification procedures and, if desired, transformed into a pharmaceutically acceptable acid addition salt thereof by reaction with an appropriate acid.

The same procedure may be utilized equally well, mutatls mutandis, to separate S - (-) 1 - (1 - phenylethyl) - IH - imidazole - 5 - carboxylic acid, using, however, the alternate S - (-) isomeric form of the optically active base. Similarly, esterification of the thus-obtained S - (-) acid yields the S - (-) form of the formula (I) esters, designated as S - (-) (I).

Whether the R - (+) or S - (-) form of the carboxylic acid is removed from the medium in diastereomeric 2 652 - fi salt form, the respective enantiomer which remains in the solution may be recovered by conventional means, for example, by evaporation of the mother liquor from which the precipitated diastereomer was obtained or by dilut5 ion with an appropriate non-solubilizing solvent, and, if desired, transformed into a lower alkyl ester of formula (I), having the corresponding configuration.

The racemic 1-(1- phenylethyl) - lit - imidazole · 5 - carboxylic acid used as a starting material herein is described in United States Patent No. 3,354,173 and may be prepared according to the procedures outlined therein.

The substantially pure optically isomeric forms of 1-(1- phenylethyl) - 111 - imidazole - 5 - carboxylic acid and addition salts thereof with optically active bases, essentially free of their other respective enantiomers, are novel and are accordingly included within the scope of this invention. In addition to salt formation with bases, the dextro- and levo-forms of the imidazolecarboxylic acids may also form acid addition salts with acids..

Since one of the optically isomeric forms, more particularly the one having the S - (-) configuration, of the- compounds of formula (I) is less preferred as a hypnotic agent, it is economically advantageous to use S 25 (-) form of the precursor carboxylic acid in the production of the desired dextrorotatory isomers R:- (+) (I), for example, by first racemizing such S - (-) form and then resolving the thus-obtained racemate as previously described. This conversion is also included within the scope of the present invention.

It has tnus been found that Π - (-) 1 - (1 - phenyl otliyl) - 111 - imidazole - 5 - carboxylic acid way la· transformed into its racemic form Upon treatment wilh a catalytic amount of an appropriate strong base, preferably in an appropriate solvent. Suitable bases for this purpose - 7 include strong alkali metal bases, such as, alkali metal hydrides, e.g., sodium hydride? alkali metal loweralkoxides, e.g. potassium t - butoxide, sodium methanolate or sodium ethanolate; alkali metal amides, e.g., sodium amide? and certain organometallic compounds such as butyl lithium and phenyl lithium. The S - (-) 1-(1- phenylethyl) - IH - imidazole 5 carboxylic acid is preferably used in the form of a metal salt, in which case less of the basic catalyst is employed.

Suitable solvents for the racemization include polar organic solvents such as, for example, hexamethylphosphoric triamide, dimethyl formamide and dimethylsulfoxide. Elevated temperatures enhance the rate of racemization and preferably the reaction is carried out in an inert atmosphere at temperatures of from 20° C to 120°C. The reaction mixture is allowed to cool, then diluted with water, and the resultant aqueous phase is separated and acidified to about a neutral pH to yield the racemic acid in crystalline form.

The resultant racemate may be obtained from the reaction mixture by extraction with water. Acidification of the aqueous extract to about a neutral pH yields the racemate in crystalline form. The racemic form which is obtained may in turn be resolved into its dextro- and levoisomeric forms according to the procedures described above.

Although emphasis is laid on the racemization of the less desired levo-isomers, the same procedure is applicable to the dextro-isomer when it is desired to transform a dextro-isomer into a racemic mixture. Such a procedure is also included within the scope of this invention.

The following Examples are given in order to illustrate and not to limit the invention thereto. Unless otherwise stated all parts are by weight and the symbol £aj stands for «D 2 6 5 2 EXAMPLE I To a stirred and refluxing mixture of 13 parts of (+) - 1 - (i - phenylethyl) - 5 - imidazolecarboxylic acid and 200 parts of 2 - propanol are added 3,6 parts of (-) 5 a - methylbenzenemethanamine and the whole is stirred and refluxed for 10 minutes. The reaction mixture is allowed to cool to room temperature. The precipitated product is filtered off ,(the filtrate is set aside), washed with 2 propanol and crystallized from 160 parts of 2 * propanol.

It is filtered off and dried over week-end in vacuo at 60°C., yielding (-)-1-(1- phenylethyl) - IH - imidazole - 5 - carboxylic acid salt with (-) - a - niethylbenzenemethanamine; m.p. 194°C.; /^7^=-51.0° (c=l% in water).

To the filtrate (see above) are added 3.6 parts of (+) - a - methylbenzenemethanamine and the whole is stirred and refluxed for 10 minutes. The reaction mixture is allowed to cool to room temperature. The precipitated product is filtered off, washed with 2 - propanol arid dried in vacuo for 4 hours at 60°C., yielding (+) -1-(.120 phenethyl) - IH - imidazole - 5 - carboxylic acid salt with (+) - a - methylbenzenemethanamine; m.p. 190.3°C.; [nJ^=+52.9° (c=l% in water).

EXAMPLE II A stirring mixture of 2.55 parts of (+) - a-methyl25 benzylamine salt with R - (+) - 1 - (a - methylbenzyl) 5 - imidazolecarboxylic acid and 24 parts of dry absolute ethanol is saturated with gaseous hydrogen chloride. Upon completion, stirring is continued for 7 hours at reflux temperature, while gaseous hydrogen chloride is still introduced. The reaction mixture is evaporated and the residue is taken up in 30 parts of water. The resulting solution is adjusted to pH=6 with sodium hydroxide solution ION and the product is extracted three times with trichloromethane. The combined extracts are dried filtered and eva12 6 52 - 9 porated. The residue is taken up in 2.4 parts of 2 - propanol and the solution is filtered. The filtrate is acidified with sulfuric acid and warmed for a while. 2,2' Oxybispropane is added till almost turbid and upon scratching, the product is precipitated while cooling in an icebath. It is filtered off, washed with a mixture of 2 - propanol and 2,2' - oxybispropane, and dried, yielding 80% of R - (+) - ethyl 1- (a - methylbenzyl) - imxdazolecarboxylate sulfate; /re7=+22.5° (c=o.l% H?o).

EXAMPLE III A stirring mixture of 2.55 parts of S x (-) -(1phenylethyl) - IH - imidazole - 5 - carboxylic acid salt with (-) - a - methylbenzenemethanamine and 24 parts of dry absolute ethanol is saturated with gaseous hydrogen chloride. Upon completion, stirring is continued for 7 hours at reflux temperature, while gaseous hydrogen chloride is still introduced. The reaction mixture is evaporated and the residue is taken up in 30 parts of water. The solution is adjusted to pH=6 with a sodium hydroxide solution ION and the product is extracted three times with trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is converted into the nitrate salt in methylbenzene while cooling in an ice-bath. The salt is filtered off, washed with methylbenzene and dried, yielding 52% of S - (-) - ethyl 1 - (a - methylbenzyl) - imidazole 5 - carboxylate nitrate; /0/=-31.9° (c=0.1% H^O)· EXAMPLE IV A. A mixture of 1 part of {+) - a - methylbenzylamine salt with R - (+) - 1 - (a - methylbenzyl) - 5 imidazolecarboxylic acid and 6 parts of sodium hydroxide solution IN is shaken in a closed tube till all solid enters solution (pH=+ll). The resulting solution is shaken five times for 1 minute, each time after the addition of 1.4 parts of 2,2' — oxybispropane. The organic phases are combined (the alkaline aqueous phase is set aside) and evapora4 3652 - ίο ted, yielding R -, (+) - a - methylbenzylamine.

The alkaline aqueous phase (see above) is adjusted to pH-6.2 with acetic acid. While cooling in ice-water and upon scratching, the product is precipitated. It is filtered off and crystallised twice from 2 - propanol, yielding, after drying for 3 hours in vacuo at 60°C., R - (+) - 1 (a - methylbenzyl) - 5 - imidazolecarboxylic acid; m.p. 155°C.; /0/=+65.9° (c=l% Η-,Ο) .

B. By repeating the foregoing procedure, except that an equivalent amount of (-) - 1 - (1 - phenylethyl) IH - imidazole - 5 - carboxylic acid salt with (-) - a methylbenzenemethanamine is used, there is obtained (-) 1-(1- phenylethyl) - IH - imidazole - 5 - carboxylic acid; m.p. 155.2°C; /VD=-67.8O (c=0.1S H20).

EXAMPLE V Λ. A mixture of 10 parts of R - (+) - 1 - (a methylbenzyl) - 5 - imidazolecarboxylic acid and 105 parts of sulfinyl chloride is stirred and refluxed for 2 hours.

The reaction mixture is cooled and diluted with 2,2’ — oxybispropane. The precipitated product is filtered off, washed with 2,2' - oxybispropane and dried, yielding 90% of (+) - 1 - (1 — phenylethyl) - III - imidazole - 5 carbonyl chloride hydrochloride.

B. A mixture of 25.5 parts of (-) - 1 - (1 25 phenylethyl) - lH - imidazole - 5 - carboxylic acid and 280 parts of sulfinyl chloride is stirred and refluxed for 2 hours. The reaction mixture is cooled in an ice-bath. The product crystallizes upon the addition of 2,2' oxybispropane. It is filtered off, washed with 2,2' - oxybispropane and dried, yielding 94% of (-) - 1 - (1 - phenylethyl) IH - imidazole - 5 - carbonyl chloride hydrochloride. 2 6 52 - 11 EXAMPLE VI Λ mixture of 5.5 parts of (+) -1-(1- phenylethyl) - IH - imidazole — 5 - carbonyl chloride hydrochloride and 80 parts of methanol is stirred and refluxed overnight. The reaction mixture j.s cooled and evaporated. The residue is dissolved in 1O0 parts of wator, alkalized with sodium hydroxide and the product is extracted with 2,2' - oxybispropane. The extract is dried, filtered and evaporated. The residue is converted into the sulfate salt in 2 - propanol and 2,2' - oxybispropane. The salt is filtered off, washed with 2,2' - oxybispropane and dried, yielding 73% of (+) - methyl 1-(1- phenylethyl) IH - imidazole - 5 - carboxylate sulfate; m.p. 103.8°C.; /07-+20.51° (c=l% CllgOII) .

EXAMPLE VII A mixture of 5.5 parts of (+)-1-(1- phenylethyl) - IH - imidazole - 5 - carbonyl chloride hydrochloride and 80 parts of 1 - propanol is stirred and refluxed overnight. The reaction mixture is cooled and evaporated. The residue is dissolved in 100 parts of water and the solution is alkalized with a sodium hydroxide solution. The product is extracted with 2,2' - oxybispropane. The extract is dried, filtered and evaporated. The residue is converted into sulfate salt in 2 - propanol and 2,2' - oxybispropane. The salt is filtered off, washed with 2,2' - oxybispropane and dried, yielding 65% of (+) - propyl 1-(1- phenylethyl) - IH - imidazole 5 - carboxylate sulfate hydrate; m.p. 106°0.; /q7=+22.68° (c=l% CHgOII) .

EXAMPLE VIII A mixture of 5.5 parts of (-)-1-(1- phenylethyl) - IH - imidazole - 5 - carbonyl chloride hydrochloride and 80 parts of methanol is stirred and refluxed overnight. The reaction mixture is cooled and evaporated. - 12 The residue is dissolved in water and the solution is alkalized with a sodium hydroxide solution 60%. The product is extracted with 2,2' - oxybispropane. The extract is dried, filtered and evaporated. The residue is con5 verted into the sulfate salt in 2 - propanol and 2,2' oxybispropane. The salt is filtered off and dried, yielding 60% of (-) - methyl 1-(1- phenylethyl) IH - imidazole - !j - carboxylate sulfate; m.p. 97.8°C.; /07=-22.39° (c=l% CIIjOH) .

J.0 EXAMPLE IX A mixture of 5.5 parts of (-) - 1 - (1 - phenylethyl) - IH - imidazole - 5 - carbonyl chloride hydrochloride and 80 parts of 1 - propanol is stirred and refluxed overnight. The reaction mixture is cooled and evaporated. The residue is dissolved in water. The solution is alkalized with a sodium hydroxide solution 60%. The product is extracted with 2,2' - oxybispropane. The extract is dried, filtered and evaporated. The residue is converted into the sulfate salt in 2 - propanol and 2,2' - oxybispropane. The salt is filtered off and dried, yielding 60% of (-) - propyl 1-(1- phenylethyl) IH - imidazole - 5 - carboxylate sulfate hydrate; m.p. 73.3°C.; /0/=-22.24° (c=l% CHgOH).

EXAMPLE X 40 Parts of R - (+) - ethyl 1 - (a - methylbenzyl)imidazole - 5 - carboxylate nitrate are dissolved in water and the solution is alkalized with sodium carbonate. After extraction with chloroform, the latter is dried and evaporated. The residue is dissolved in diisopropyl30 ether and the solution is acidified with gaseous hydrogen chloride: an oil is precipitated. It is dissolved in water, alkalized with ammonium hydroxide and the free base is extracted with chloroform. The extract is dried and evaporated. To the residue are added a few parts of 2 0 5 2 -13dlisopropylether and the whole is seeded with a crystal of dl - ethyl 1 - (n - methylbenzyl)imidazole - 5 carboxylate. After cooling for 4 hours at -20°C., the precipitated product is filtered off and dried, yielding parts of R - (+) - ethyl 1 - (a - methylbenzyl)imidazole - 5 - carboxylate? m.p. 67°C.; +66° (c=l% ethanol).

Claims

1. CLAIMS:1. (+)-1-(1- Phenylethyl) - IH - imidazole 5 - carboxylic acid.

2. (-)-1-(1- Phenylethyl) - IH - imidazole 5 5 - carboxylic acid.

3. A base salt or acid addition salt of a compound as claimed in claim 1 or claim 2.

4. A (+) - acid (+) - base salt wherein the (+) acid is (+)-1-(1- phenylethyl) - IH - imidazole 10 5 - carboxylic acid and the (+) - base is (+) -1phenylethylamine, (+) -1-(1- naphthyl) - ethylamine or (+) -1-(2- naphthyl)ethylamine.

5. A (-) - acid (-) - base salt wherein the (-) acid is (-) -1-(1- phenylethyl) - IH - imidazole 15 5 - carboxylic acid and the (-) - base moiety is (-) 1 - phenylethylamine, (-)-1-(1- naphthyl)ethylamine or (-) - 1 - (2 - naphthyl)ethylamine.

6. (+) - 1 - (1 - Phenylethyl) - III - imidazole 5 - carboxylic acid salt with (+) - 1 - phenylethylamine 20 having a melting point of about 190.3°C and a rotation of about (Χρ^θ+52.9 0 (concentration 1%, I^O) .

7. (-, - 1— (1 - Phenylethyl) - lit - imidazole 5 - carboxylic acid salt with (-) - 1 - phenylethylamine having a melting point of about 1Μ°0 and a rotation of 25 about αθ^θ-δΙ.Ο 0 (concentration 1%, ^0).

8. A method of preparing (-) - 1 - (1 - phenylethyl) - IH - imidazole - 5 - carboxylic acid which comprises resolving (+) - 1 - (1 - phenylethyl) - IH - imidazole - 5 - carboxylic acid by mixing the acid with the 30 (-) - isomer, substantially free of the (+) - isomer, of 1 - phenylethylamine, 1-(1- naphthyl)ethylamine or 1 (2 - naphthyl)ethylamine in an inert - organic solvent, mechanically separating the insoluble (-) - 1 - (1 15 phenylethyl) - ΙΗ - imidazole - 5 - carboxyl·ir arid (-) - base salt and treating the (-) - aoid and (-) base acid salt with an acid.

9. Λ method of preparing (-) -1-(1- phenylethyl) - IH - imidazole - 5 - carboxylic acid substantially as hereinbefore described with reference to Example IV.

10. (-) - 1 - (Phenylethyl) - IH - imidazole 5 - carboxylic acid whenever prepared by a method as claimed in claim 8 or claim 9.

11. A method of preparing (+)-1- (I - phenylethyl) - IH - imidazole - 5 - carboxylic acid which comprises resolving (+) - 1 - (1 - phenylethyl) - IH imidazole - 5 - carboxylic acid by mixing said acid with the (+) - isomer, substantially free of the (-) - isomer, of 1 - phenylethylamine, 1-(1- naphthyl)ethylamine or 1-(2- naphthyl)ethylamine in an inert organic solvent, mechanically separating the insoluble (+) - 1 - (1.phenylethyl) - 111 - imidazole - 5 - carboxylic acid (+) base salt and treating the (+) - acid and (+) - base salt with an acid.

12. A method of preparing (+) - 1 - (1 - phenylethyl) - IH - imidazole - 5 - carboxylic acid substantially as hereinbefore described with reference to Example IV.

13. (+)-1- (Phenylethyl) - IH - imidazole 5 - carhoxyllc acid whenever prepared by a method as claimed in claim 11 or claim 12.

14. A method of preparing a (-) - loweralkyl 1-(1- phenylethyl) - IH - imidazole - 5 carboxylate which comprises esterifying (-) - (1 - phenylethyl) ·ν 111 - imidazole - 5 - carboxylic acid with a lower alkyl esterifying agent.

15. A method of preparing a (+) - lower-alkyl 1 -

16. (1 - phenylethyl) - IH - imidazole - 5 - carboxylate which comprises esterifying (+) - 1 - (1 - phenylethyl) IH - imidazole - 5 - carboxylic acid with a lower alkyl esterifying agent. 5 16. A method as claimed in claim 14 or claim 15 wherein the esterification is effected by treatment with a lower alkanol in the presence of a strong nonoxidizing mineral acid.

17. A method as claimed in claim 16 wherein the 10 alkanol is methanol, ethanol or propanol.

18. A method as claimed in claim 14 substantially as hereinbefore described with reference to Example III.

19. A method as claimed ih claim 15 substantially as hereinbefore described with reference to Example II. 15

20. A (-) - loweralkyl 1-(1- phenylethyl) IH - imidazole - 5 - carboxylate when prepared by a process as claimed in any one of claims 14 or 16 to 18. • .

21. A (+) - loweralkyl 1-(1- phenylethyl) IH - imidazole - 5 - carboxylate. when prepared by a pro20 cess as claimed in any one of claims 15 to 17 or claim 19.

22. (-) -1-(1- Phenylethyl) - IH - imidazole 5 - carbonyl chloride.

23. (+) - 1 - (1 - Phenylethyl) - IH - imidazole 25 5 - carbonyl chloride.

24. An acid addition salt of a compound as claimed in claim 22 or claim 23.

25. A method for the preparation of (-)-1-(1phenylethyl) - IH - imidazole - 5 - carbonyl chloride 30 which comprises transforming the hydroxy group of (-) 1-(1- phenylethyl) - IH - imidazole - 5 - carboxylic acid to a chloro group.

26. A method as claimed in claim 25 substantially 4 2 6 5 2 - 17 is hereinbefore described with reference to Example V.

27. (-) - 1 - (1 - Phenylethyl) - III - imidazole 5 - carbonyl chloride when prepared by a process as claimed in claim 25 or claim 26.

28. A method for the preparation of (+) - 1 (1 - phenylethyl) - 115 - imidazole - 5 - carbonyl chloride which comprises transforming the hydroxy group of (+) - 1 - (1 - phenylethyl) - IH - imidazole - 5 carboxylic acid to a chloro group.

29. A method as claimed in claim 28 substantially as hereinbefore described with reference to Example V.

30. (+) - 1 - (1 - Phenylethyl) - IH - imidazole 5 - carbonyl chloride when prepared by a process as claimed in claim 28 or claim 29.

31. A method of preparing a (-) - loweralkyl 1 (1 - phenylethyl) - 111 - imidazole - 5 - carboxylate which comprises treating {-) - 1 - (1 - phenylethyl) - IH imidazole - 5 - carbonyl chloride with a lower C·^ alkanol or an acid addition salt thereof.

32. A method as claimed in claim 31 wherein the alkanol is methanol, ethanol or propanol.

33. A method as claimed in claim 31 substantially as hereinbefore described with reference to Example VIII or Example IX.

34. A method of preparing a (+) - loweralkyl 1 (1 - phenylethyl) - IH - imidazole - 5 - carboxylate which comprises treating (+) - 1 - (1 - phenylethyl) - IH imidazole - 5 - carbonyl chloride with a loweralkanol or an acid addition salt thereof.

35. A method as claimed in claim 34 wherein the lower alkanol is methanol, ethanol or propanol.

36. A method as claimed in claim 34 substantially as hereinbefore described with reference to Example VI or Example VII.

37. {-) - Loweralkyl 1-(1- phenylethyl) - IH imidazole - 5 - carboxylates when prepared by a process as claimed in any one of claims 31 to 33.

38. (+) - Loweralkyl 1-(1- phenylethyl) - IH imidazole - 5 - carboxylates when prepared by a process as claimed in any one of claims 34 to 36.

39. A method of preparing racemic 1 - (1 phenylethyl) - 1Π - imidazole - 5 - carboxylic acid which comprises treating the (+) - isomer or the (-) - isomer of the acid, or a metal salt thereof, with a strong base in a polar organic solvent at a temperature in the range of from 20° to 120°C.

40. A method as claimed in claim 39 wherein the alkali metal salt of the (+) - isomer or the (-) - isomer of the acid is treated with sodium hydride in hexamethylphosphoric triamide in an inert gas atmosphere, the cooled reaction mixture diluted with water and the resultant aqueous phase acidified to about a neutral pH to yield crystallized racemic 1 - (1-phenylethyl) IH - imidazole - 5 - carboxylic acid.