MXPA96004670A - Procedure for the preparation of compounds of imidazolyl enantiomerically pu - Google Patents

Abstract

The invention relates to a method for the preparation of an enatiomerically pure imidazolyl compound of the general formula (See Formula) wherein: n is 0 or 1; m is 1 or 2; R 1 is hydrogen, methyl or ethyl, and C * denotes a chiral center, as well as its pharmaceutically acceptable addition salt, a) by adding a carboxylic acid in an optically active form to a solution of a racemic mixture of the above compound I, followed by the separation of the crystallized addition salt of said mixture of enantiomers of the compound I enriched in one enantiomer, of the mother liquor enriched in the other enantiomer, b) when the crystallized addition salt is enriched in the undesired enantiomer, then separating the enantiomer mixture in the mother liquor of said carboxycho-optically active acid, followed by the addition of a racemic mixture of said carboxylic acid to a solution of the mixture of isomers obtained from I, and by the sep of the crystallized addition salt of said mixture, enriched in the desired enantiomer, of the mother liquor, and c) recrystallizing the product optionally until the desired enantiomeric purity is obtained, and d) then converting this addition salt of the desired enantiomer to the compound of desired enantiomerically pure imidazolyl of the general formula I or its pharmaceutically acceptable addition salt, further characterized in that the pyroglutamic acid is used as the carboxylic acid, the invention further relates to a racemized method and to a novel addition salt of this compound of the formula I and acid D-pyroglutamine

Description

PROCEDURE PfíRfl Lñ PREPñRflCION LDE COMPOUNDS OF IILIDflZQLILO ENñNTIOriERICfírlENTE PUROS The present invention relates to a process for the preparation of an enantiornerically pure irnidazolyl compound, as well as to an addition acid for this compound. La, 5, 6, S, 9,10-hexahydro-10 ~ E (2-? Netil-iH-imi azol -1-? L) rnet? L-llH-p? RidsC3,2, l-jk3carbazol-li -one eß known from EP-B-029765L1 and EP-R-0601345. In the later patent publication a general class of these / including the aforementioned imidazolyl compound and homologous compounds, its preparation and use as 5-HT antagonists are described. The latest patent publication describes the use of a selection of this type of compounds for the treatment of certain diseases. Several biologically active substances which are used in pharmaceutical compositions for human and veterinary application, contain a chiral center in their molecular structure and therefore increase the optical isornerism. It is generally known in the art that many times only one of the enantiomers exhibits the desired optimal biological activity. The presence of the other optical antiode in a composition or agent can cause or invigorate certain side effects and charge the recipient, for example, a human or animal body. It is generally considered increasingly desirable to administer the biologically active substance in the form of a purely substantial enantiomer, which specifically exhibits the desired biological activity. Therefore, the decomposition of a racernizer into its enantiomers is normally an important step in the process of preparing pharmacologically active substances. It has been found that the enantiomer of R - (-) of the imidazolyl compound defined above, also known under its generic name cilansetron, is especially useful in the indications mentioned in EP-FL-0601345. It is therefore desirable to have a method for the separation of the R-enantiomer from the racernate. There are essentially three methods available to decompose the racemates into their respective enantiomers. The first of these, namely, a decomposition based on the difference of physical properties, for example in the crystalline structure, is occasionally applicable. In a more recent decomposition method, enzymes are applied to chemically modify the enantiomer of a racemate selectively, followed by separation of the modified enantiomer from the unmodified one. The third and by far more generally used decomposition method involves the reaction with an optically active reagent - available commercially - to produce diastereomers, which differ in physical, physiological properties, the diasterers obtained in this way can be separated, for example by crystallization, after which the desired enantiomer can be isolated by a subsequent chemical treatment. It is generally known in the art that the decomposition of enantiomers by preparing diasterorneros is a very difficult task. Even experienced researchers find that certain compounds resist the chemical decomposition of any of a number of combinations of resolving agents and reaction conditions. As a general rule, researchers in the technique of separating enantiomers begin a study using reagents and conditions that have been shown to be successful in the past in breaking down similar compounds. A generally preferred method for decomposing the racernates of the imidazolyl compounds mentioned is a reaction with an optically active acid, after which the obtained diastereomers can be separated, preferably by crystallization. EP 0297651 describes the use of (+) - di-0,0 '-? - toluyl-LD-tartaric acid. Apparently, this optically active carboxylic acid is the reagent chosen to decompose said racernatos, because the same or acid has also been used for the decomposition of a closely related imidazolyl compound, namely, 1,2,3,9-tetrahydro-9-rnethyl-3-C (2-r-ethyl-1H -nitridazol-1-yl) rnetyl-3H-carbazol-4-one or ondansetron (for example NL-B-190373, Example XX). This is really remarkable in view of the fact that decomposition with (+) - di-0,0'-p-toluyl-LD-tartaric acid has several disadvantages, such as the use of a high dilution and the application of a system of less acceptable solvent, namely, water-DMF. Such a diluted solution is not attractive or even not convenient from an economic point of view. In addition, the DMF solvent has well-known disadvantages, such as a high boiling point and considerable toxicity (presumed carcinogenicity). In addition to the aforementioned optically active di-0,0'-p-toluyl-D-tartaric acid, a number of chiral dicarboxylic acids, chiral sulfonic acids or rnonocarbonic acids are commercially available, such as dibenzoyl-L- acid. tartaric acid, L-tartaric acid, L-rnálico acid, D-camphor-10-sulfonic acid, D-quinic acid, 2,3: 4,6-di-0-isopropiliden-2-q? et-L acid -gulonic, L-rnandélico acid, R-2- (4-hidroxifenoxi)? ropiónico acid and 2-oxide of (-) - l, 3,2-dioxa-fosforinan-5,5-dimetil-2-hidroxi ~ 4 ~ phenyl. As will be evident from the examples, however, these acids either do not effect the precipitation of the addition salt with one of the enantiomers, or do not achieve enrichment of one of the enantiomers in the precipitate. The object of the present invention is to provide an economical operating method for the preparation of enantiornilically pure irnidazolyl compounds, which must satisfy the following requirements: (a) the use of undiluted reaction conditions and an acceptable solvent, (b) easy recirculation of relatively expensive chiral acid. This object can be achieved by a method for the preparation of an enantiomerically pure imidazolyl compound of the general formula wherein n is 0 or 1 is 1 or 2 Rl is hydrogen, methyl or ethyl; and C * denotes a chiral center; thus its pharmaceutically acceptable acid addition salt; (a) adding a carboxylic acid in an optically active form to a solution of a racemic mixture of the above compound I, followed by the separation of the crystallized addition acid salt of said mixture of the enantiomers of compound I enriched in an enantiomer, mother liquor enriched in the other enantiomer, (b) when the acid addition salt is enriched in the undesired enantiomer, then separating the enantiomer mixture in the parent liquid of said optically active carboxylic acid, followed by the addition of a racemic mixture of said carboxylic acid to a solution of the mixture of isomers obtained from I, and by separation of the crystallized addition acid salt of said mixture, enriched in the desired enantiomer, from the mother liquor, and (c) recrystallizing optionally from the product. until the desired enantiomeric purity is obtained, and therefore (d) converting this acid addition salt of the enantiomer It is desired in the desired enantiomerically pure imidazolyl compound of the general formula I, or its pharmaceutically acceptable acid addition salt, further characterized in that the pyroglutaric acid is used as said carboxylic acid. When the acid addition salt formed is enriched in the desired enantiomer, it can be isolated and, as soon as it has the desired enantiomeric purity by itself. subsequent treatment, be converted to the desired pure enantiomeric imidazolyl compound or its pharmaceutically acceptable acid addition salt. For purposes of convenience, said direct crystallization in the desired enantiomer is preferred. When the acid addition salt formed by the addition of the optically active pyroglutamic acid is enriched in the unwanted enantiomer, the mutual decomposition approach is used (Eliel, EL, Wilen, SH and Mander, LW in Stereochemistry or Organic Conpo? Nds, John Uiley &Sons, Inc., New York (1994), 325). In this approach, after the first step of decomposition producing the acid addition salt enriched in the unwanted enantiomer, the optically active pyroglutatic acid is removed from the dried substance obtained from the parent liquid, for example, by solvent extraction in a dichloromethane / water system. Subsequently, the second step is carried out by adding racemic pyroglutamic acid to a solution of the mixture of isomers obtained from I, leading to the crystallization of the acid addition salt of the desired enantiomer. In view of the conclusion (see examples), that the chemically closely related irnidazolyl ondansetron compound can not be decomposed in its optical antipodes with the use of optically active pyroglutamic acid, it is indeed a surprise that the enantiomer The aforementioned desired formulation of the general formula I can be so easily obtained by the use of pyroglutamic acid in an optically active form, optionally followed by the addition of racemic pyroglutaric acid, while satisfying the requirements defined above. It goes beyond any expectation that pyroglutamic acid will have such a favorable effect on the decomposition of a racemate of formula I of an irnidazolyl compound, in view of the deficient results obtained with a wide range of other decomposition agents. It should be understood that the enantiornilically pure irnidazolyl compound according to the present invention encompasses optically active compounds having an enantiomeric excess (e.e.) of greater than 90%. The crystalline addition acid salt of the desired enantiornomerically pure irnidazolyl compound obtained can be converted to the pure enantiomer as such, by methods which are well known in the salt division art. Generally a division under the influence of a base can be used, wherein the desired free base of enantiomerically pure irnidazoyl is formed. If desired, said imidazolyl base can be converted into a pharmaceutically acceptable acid addition salt by treating it with an acid such as HCl, rnaleic acid and other suitable acids as defined in EP-A-601345. The present invention relates more particularly to a method for the preparation of cilansetron, that is to say, of an enantiornilically pure irnidazolyl compound of the general formula I, wherein rn and n are both 1, Ri is methyl and the C * atom has the R configuration. The crystallization process, for example, the separation of the crystallized addition acid salt from the desired enantiomer or at least the racernate enriched in the desired enantiomer, is preferably carried out in an alcohol solvent. Suitable examples of alcohol solvents for this crystallization process are methanol and ethanol. In the process of the invention, the optically active acid used, namely, D-pyroglutamic acid [R-2-α-urea-5-carboxylic acid in the direct approach and L-pyroglutaric acid [S-2-pyrrolidone acid] 5-carboxylic3 in the mutual decomposition approach for the decomposition of cilansetron, is preferably added in an amount of between 0.2 and 1.5 equivalent, calculated in the racemic starting mixture. The ratio of the volume of the solvent to the amount of enantiomers in the mixture that is being decomposed can be varied on a relatively broad scale. In the direct approach, the ratio of the amount of solvent to the amount of enantiomers can typically be from 3: 1 to 15: 1, where the ratio is expressed as the volume of solvent relative to the weight of the enantiomers in the solvent . Preferably the ratio is almost 5.1 to 10: 1. In a preferred embodiment, the ratio of the volume of the solvent to the weight of the enantiomers is 7: 1. In the mutual decomposition approach the ratio of the amount of solvent to the amount of enantiomers can be typically from 3: 1 to 15: 1 in the first step and 5: 1 to 15: 1 in the second step. Preferably the ratio is from 5: 1 to up to 10: 1 in the first step and 7: 1 to 12: 1 in the second step. In a preferred embodiment, the ratio of the volume of solvent to that of the weight of the enantiomers is 7: 1 in the first step and 10: 1 in the second step. The solution containing the enantiomers can be prepared by dissolving the enantiomeric mixture in the solvent. The solution can typically be carried out at a temperature of from 25 ° C to up to 80 ° C, but will generally be carried out at a temperature of from 50 ° C to 60 ° C. The crystallization can typically be carried out at a temperature of from -20 ° C to + 20 ° C, but will generally be carried out at a temperature of from -10 ° C to 0 ° C. It remains unsatisfactory, however, that the desired enantiomer yield is theoretically below 50%, based on the starting racemate. As an additional feature of the present invention, it has now been discovered that the mother liquor or the combined mother liquors remaining after the crystallization process can be subjected to a subsequent treatment comprising a racernization step, to allow a full yield of the desired enantiomer of about 50% after the subsequent crystallization procedure, as described above. Accordingly, the present invention also relates to a method defined hereinabove, which method is further characterized in that the mother liquor or the combined mother liquors remaining after the separation of the crystallized acid addition salt, is (are) subject to a subsequent treatment successively (i) by dividing the dissolved acid addition salt to produce a solution of a mixture of enantiomers of the irnidazolyl compound of the general formula I, presented above, whose mixture has a reduced content of the desired enantiomer, and (ii) then converting said solution into a racemic mixture under the influence of a base. In the case of the mutual decomposition approach, the acid addition salt enriched in the unwanted enantiomer can optionally be added to the mother liquid (s) (combined). Preferably an inorganic base such as an alkali metal hydroxide is used for racernization. After the racemization described above, the recovered racernate can be subjected back to the crystallization process described above, using optically active pyroglutamic acid, optionally followed by racemic pyroglutaric acid, to relax another culture of enantiornterically pure imidazolyl compound. If desired, the mother liquor (s) (combined) of this last crystallization process can be redrawn, etc. In this way, the total yield of the combined culture of the desired enantiomer can be increased considerably. In a technically and economically attractive embodiment, the recovered racemate can be added to the starting racemate for the next batch, so that in the entire reaction process substantially no material is lost. The acid addition salt of an enantiomerically pure imidazolyl compound of the general formula I, in particular of cilanseton, and D-pyroglutaric acid is novel. Therefore, the present invention also relates to this acid addition salt which can be obtained by the crystallization process as described hereinabove.

DESCRIPTION OF THE INVENTION OF THE INVENTION The invention will be described in more detail with reference to the following specific examples.

EXAMPLE I Preparation of monohydrate d-hydrochloride (cilansetron) of (R) - (-) - 4,5,5,8, g, 10-hexahydro-10-C (2-methyl-lH-imidazol-1-yl) methylL 3 -llH -pi gone- [3,2, l-jk! I-carbazol-ll-one by direct decomposition . 00 g of (R,?) - 4,5,6,8,9,10-hexahydro-10 - [(2-methyl-lH-irnidazol-1-yl) rnetyl-1H-pi- [3, 2 , l-jk -carbazol-11-one and 10.11 g of R-2-pyrrolido-5-carboxylic acid (D-pyroglytic acid) in 175 ml of methanol are heated to 50 ° C. The then formed suspension of the diastereomeric salts is removed for 1 hour at that temperature. The mixture is cooled to 0 ° C and stirred for 1 hour at that temperature. The solid substance is suctioned, washed with cold methanol and dried. Yield: 25.91 g. The crystallization process is repeated twice using 5 ml of methanol per 1 g of the salt obtained for the first repetition, and 10 rnl of methanol per 1 g of salt for the second repetition. Yield: 11.91 g. The mother liquors of the three catalysts are combined and used for the gain of a second crop. 10.00 g of the salt obtained above are removed for 15 minutes with 200 ml of water, 50 nl of dichloromethane and 6 g of sodium bicarbonate. After separation of the two layers, the water layer is extracted twice with 25 rnl of dichloromethane. The combined dichloromethane layers are evaporated until dried. The dried substance thus obtained is distilled in 60 nmol of isopropanol. 2.5 ml of concentrated hydrochloric acid is added to this solution at room temperature. After stirring for 1 hour, the solid formed is succinated, washed with cold isopropanol and 40-65 petroleum ether and dried. The yield of the title compound is 7.93 g (e.e. 94%). Melting point: 219 ° C COÍ.3D-S - -6.9 (C = 1.8, rnetanol).

EXAMPLE II Preparation of hydrochloride monohydrate (cilansetron) from (R) - (-) -4, 5, 6, 8, 9, 10-hexahyd? ~ o-lC l-lI (2-methyl-lH- -imidazol-1-yl) methyl 3 -L HH-p ?rido-C3, 2, l- -jkH-carbazol-11-one by mutual decomposition . 00 g of (R, S) -4,5,6,8,9,10-hexahydro-10 - [(2-methyl-1H-imidazol-1-yl) methyl-3H-piido-C 3, 2 , 1- k -carbazole-11-one and 10.11 g of S-2-? -rololidone-5-carboxylic acid (L-pyroglutanic acid) in 175 ml of rnetanol, are heated to 50 ° C. The suspension thus formed of diastereomeric salts is removed for 1 hour, at that temperature. The mixture is cooled to 0 ° C and stirred for 1 hour at that temperature. The solid substance is suctioned, washed with cold methanol and dried. Yield: 18.5 g. The methanol is evaporated from the mother liquid. The residue is removed for 15 minutes with 200 ml of water, 50 ml of dichloromethane and 6.00 g of sodium bicarbonate. After separation of the two layers, the water layer is extracted twice with 25 ml of dichloromethane. The combined dichloromethane layers are evaporated until dried. The thus obtained dry substance (11.50 g) and 4.75 g of R, S-? Irrolidone-5-carboxylic acid (D-L-pyroglutamic acid) are dissolved in 115 nl of methanol by heating to reflux. The solution is cooled to room temperature and stirred for 1 hour at that temperature. The solid substance formed is suctioned, washed with cold methanol and dried. Yield: 6.00 g (e.e. 97%). 5.00 g of the salt obtained above is removed for 15 minutes with 100 rnl of water, 25 rnl of dichloromethane and 3.00 g of sodium bicarbonate. After separation of the two layers, the water layer is extracted twice with 12.5 ml of dichloromethane. The combined dichloromethane layers are evaporated until dried. The dried substance thus obtained is dissolved in 30 rnl of isopropanol. 1.25 l of concentrated hydrochloric acid is added to this solution at room temperature. After stirring for 1 hour, the solid substance formed is suctioned, washed with cold isopropanol and 40-65 petroleum ether and dried. The yield of the title compound is 3.95 g (e.e. 98%). Melting point: 219 ° C EXAMPLE III Racized from the combined mother liquors to (R, S) - (-) - 4,5,6,8,9, 10-hexahydro-lQ-C (2-methyl-lH-imidazol-l-yl) methyl] - llH-pyrido-E3,2, l-jk3-carbazol-ll-one and the gain of a second culture of the R-enantiomer by direct decomposition.

The methanol is evaporated from the combined mother liquids of example I. The residue is removed for 15 minutes with 250 nl of water, 100 nl of dichloromethane and 10.00 g of sodium bicarbonate. After separation of the two layers, the water layer is extracted with 50 nmol dichloromethane. The combined dichloromethane layers are evaporated until dried. The dried substance thus obtained is dissolved in 90 ml of methanol and 20 ml of water. For the racemized, 2.0 g of potassium hydroxide, dissolved in 5 rnl of water are added. After stirring for 30 minutes, the reaction mixture is neutralized with hydrochloric acid at 2 N. 500 rnl of water are added to this solution- The rnetanol / water layer is extracted with dichloromethane, once with 100 rnl and twice with 50 ml. The combined dichloromethane layers are evaporated to s? drying To the dry substance thus obtained, 6.1 g of R-2-pyrrolidone-5-carboxylic acid and 75 ml of methanol are added. The temperature is elevated to 50 ° C. The suspension thus formed of diastereomeric salts is removed for 1 hour at that temperature. The mixture is cooled to 0 ° and stirred for 1 hour at that temperature. The solid substance is suctioned, washed with cold and dried rnetanol. Performance of the addition salt. 7.49 9- This crystallization procedure is repeated twice using 5 rnl of methanol per 1 g of the salt obtained for the first repetition, and 10 ml of methane! for 1 g of salt for the second repetition. Yield: 4.97 g. The salt thus obtained is removed for 15 minutes with 100 ml of water, 25 nl of dichloromethane and 3.00 g of sodium bicarbonate. After separation of the two layers, the water layer is extracted twice with 15 rnl of dichloromethane. The combined dichloromethane layers are evaporated until dried. The dried substance thus obtained is dissolved in 30 rnl of isopropanol. 1.3 rnl of concentrated hydrochloric acid are added to this solution at room temperature. After stirring for 1 hour, the solid substance formed is suctioned, washed with cold isopropanol and petroleum ether 40-65 and dried. An additional amount of the title compound is obtained from 3.12 g (e.e. 95%). Melting point: 219 ° C. In the same way, the mother liquids of the example II, combined with the acid addition salt enriched in the unwanted enantiomer, can be racernized and crystallized (by direct approach or mutual decomposition approach).

Example IV; Attempted decomposition of R, S-1, 2, 3, 9-tetrahydro-9-methyl-3-C (2-methyl-lH-imidazol-1-yl) methyl-4H-carbazol-4-one (ondansetron) 0. 50 g of (R, S) ~ 1, 2, 3, 9-tetrahydro-9 ~ methyl-3- [(2-ethyl-lH-irnidazol-1-yl) methyl-4H-carbazol-4-one and 0.22 g of R-2-? -rollolidon-5-carboxylic acid in 5.0 ml of methanol, are heated to 50 ° C. The clear solution thus formed is cooled to 0 ° C in 30 minutes. After stirring for 1 hour at 0 ° C, the crystals formed are sucked, washed with cold rnetanol and dried. Yield: 0.02 g. According to the CLAR, the R / S ratio is 1: 1. This means that no enrichment has occurred. This experiment is repeated on the same scale, but instead of 5.0 rnl of methanol, 1.5 rnl is used. Yield: 0.12 g. The R / S ratio is also 1: 1.

Example V: Comparative experiments In a manner corresponding to that described in Example I, the separation of the cilansetron from the racernate is investigated with the use of a number of commercially available optically active acids. The results obtained are tabulated below. From these results the following conclusion can be drawn: Conclusion: Only with the use of D-pyroglutamic acid (R-2-pyrrolidone-5-carboxylic acid), the desired enrichment in the R-enantiomer is obtained. -: experiment X was not carried out: there was no precipitation: precipitation R = S: there was no enrichment R > B: R enriched in the crystal; low selectivity (e.e. up to 50%) R > > S: R enriched in the crystal; good selectivity (e.e. over 50%) R < S: R enriched in the mother liquid, little selectivity

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - Method for the preparation of a pure enantiormeric imidazolyl compound of the general formula: wherein: n is 0 or 1; rn is 1 or 2; Ri is hgen, methyl or ethyl; and C * denotes a chiral center; as well as its pharmaceutically acceptable acid addition salt; a) adding a carboxylic acid in an optically active form to a solution of a racemic mixture of the above compound I, followed by the separation of the crystallized addition acid salt of said enantiomer mixture of compound I enriched in an enantiomer, of the parent liquid enriched in the other enantiomer, b) when the acidic crystallized addition salt is enriched in the unwanted enantiomer, then separating the enantiomer mixture in the parent liquid of said optically active carboxylic acid, followed by the addition of a racemic mixture of said carboxylic acid to a solution of the mixture of isomers obtained from I, and by the separation of the crystallized addition acid salt of said mixture, enriched in the desired enantiomer, from the mother liquid, and c) recrystallizing the product optionally until the enantiomeric purity desired is obtained, and by d) then converting this acid addition salt of the desired nucleic acid to the desired enantiomerically pure imidazolyl compound of the general formula I or to its pharmaceutically acceptable acid addition salt, further characterized, because the pyroglutamic acid is used as said carboxylic acid.

2. Method for the preparation of a pure enantiormeric irnidazolyl compound of the general formula (I) according to claim 1, further characterized in that n, rn, Ri and C * have the same meanings given in claim 1, its pharmaceutically acceptable acid addition salt; a) adding an optically active carboxylic acid to a solution of a racemic mixture of the aforementioned compound and followed by the separation of the crystallized addition acid salt of said mixture, enriched in the desired enantiomer, from the mother liquor, and b) optionally recrystallizing to the product until the desired enantiomeric purity is obtained, and then c) converting this acid addition salt to the desired pure enantiormeric imidazolyl compound of the general formula I, or to its pharmaceutically acceptable acid addition salt, further characterized, that the D-pyroglutaric acid is used as the optically active carboxylic acid.

3. Method for the preparation of a purely pure enantio-irnidazolyl compound of the general formula (I) according to claim 1, further characterized in that n, rn, Ri and C * have the same meanings given in claim 1 , as well as its pharmaceutically acceptable acid addition salt; a) adding a carboxylic acid in an optically active form to a solution of a racemic mixture of the aforementioned compound I, followed by the separation of the crystallized addition acid salt of said mixture, enriched in the undesired enantiomer, from the mother liquid, b) separating the mixture of enantiomers in the mother liquor of said optically active carboxylic acid, the addition of a racemic mixture of said carboxylic acid, the separation of the crystallized addition acid salt of said mixture of enantiomers of compound I, enriched in the desired enantiomer, of the parent liquid, and c) optionally recrystallizing the product until the desired enantiomeric purity is obtained, and then d) converting the acid addition salt of the desired enantiomer obtained, to the desired pure enantiorneric imidazolyl compound of the general formula I, or its pharmaceutically acceptable acid addition salt, characterized in addition to s because pyroglutanic acid is used as the carboxylic acid and form L of said carboxylic acid is the optically active form.

4. Method according to claims 1 to 3, further characterized in that a compound of formula I is prepared, wherein: n is 1; m is 1; Ri is methyl; and the atom C * has the configuration R.

5. Method according to claims 1 to 4, further characterized in that the pyroglutamic acid in an optically active form is added in an amount of between 0.2 and 1.5 equivalent, calculated in the mixture racemic to ti.

6. Method according to any of the preceding claims, further characterized in that the crystallization is carried out in an alcohol solvent.

7. Method according to claim 6, further characterized in that the crystallization is carried out in methanol or ethanol.

8. Method according to any of claims 1 to 7, further characterized in that the mother liquor or the combined mother liquors, resulting after the separation of the acid crystallized addition salt, is (are) subject to a subsequent treatment by the successive division (i) of the acid addition salt to produce a solution of the irnidazolyl compound of a mixture of enantiomers of the formula I, presented in claim 1, whose mixture is reduced in the desired enantiomer, and (ii) by then converting said solution to a racemic mixture under the influence of a base.

9. Method according to claim 8, further characterized in that an inorganic base, preferably an alkali metal hydroxide, is used for 9 ~ the racemized.

10. An acidic addition salt of an enantio purely enantio-irnidazolyl compound of the general formula I, presented in claim 1, wherein n, rn, Ri, and C * have the meanings given in claim 1, and D-pyro 1utatic acid.

11. An acid addition salt of an enantiomerically pure irnidazolyl compound of the general formula I presented in claim 1, wherein n, rn, Ri and C * have the meanings given in claim 4, and acid D- p roglu amico. SUMMARY OF THE INVENTION The invention relates to a method for the preparation of an enantiomerically pure irnidazolyl compound of the general formula wherein: n is 0 or 1; m is 1 or 2; R1 is hydrogen, methyl or ethyl; and C * denotes a chiral center; thus with its pharmaceutically acceptable acid addition salt; a) adding a carboxylic acid in an optically active form to a solution of a racemic mixture of the above compound I, followed by the separation of the crystallized addition acid salt of said mixture of enantiomers of compound I enriched in an enantiomer, of the mother liquor enriched in the other enantiomer, b) when the crystallized addition salt is enriched in the undesired enantiomer, then separating the enantiomer mixture in the parent liquid of said optically active carboxylic acid, followed by the addition of a racemic mixture of said carboxylic acid to a solution of the mixture of isomers obtained from I, and by the separation of the crystallized addition acid salt of said mixture, enriched in the desired enantiomer, from the mother liquid, and c) optionally recrystallizing the product until the desired enantio purity is obtained, and d) then converting this acid addition salt of the enanti The desired one is the desired enantiomerically pure imidazolyl compound of the general formula I or its pharmaceutically acceptable acid addition salt, further characterized, because the pyroglutamic acid is used as said carboxylic acid; The invention also relates to a racernized method and to a new acid addition salt of this compound of the formula I and D-pyroglycanic acid. JNR / cg / io P96-662