The method of obtaining enantiomerically pure compounds of imidazolyl, enantiomerically pure acid additive salt of imidazoline and d - or l-pyroglutamic acid, monohydrate hydrochloride enantiomerically pure compounds of imidazolyl

 

(57) Abstract:

The present invention relates to a method for obtaining enantiomerically pure compounds of imidazolyl General formula I, enantiomerically pure additive salts of imidazoline and monohydrate hydrochloride enantiomerically pure compounds of imidazolyl General formula I, where R1is specified in the value formula. The compounds possess biological activity against 5-NG antagonists. 3 S. and 14 C.p. f-crystals, 1 PL.

The present invention relates to a method for obtaining enantiomerically pure compounds of imidazolyl and acid additive salts of this compound.

4,5,6,8,9,10-hexahydro-10-[(2-methyl-1H-imidazol-1-yl) methyl-11N - pyrido[3,2,1-jk] carbazole-11-it is known from European patent N 0297651 and applications N 0601345. In the first publication describes the General class of compounds, including the above-mentioned connection of imidazolyl and homologous he compounds, their preparation and use as 5-HT antagonists. In the second application we are talking about the use of compounds selected from this type, for the treatment of certain diseases.

Various biologically active substances used in pharmaceutical compositions for lectures. Specialists are well aware that often only one of the enantiomers has the requisite biological activity. The presence or composition of another optical antipode may cause or intensify some of the side effects and harm to the recipient, i.e., human or animal. So is increasingly desirable to introduce biologically active substance in the form of essentially pure enantiomers, which most clearly shows the required biological activity. That is why the separation of the racemate into its constituent enantiomers is often an important stage in the technology of pharmacologically active substances.

It is shown that R-(-)-enantiomer of the above compounds of imidazolyl, also known under the trivial name cilansetron, especially useful in the formulations described in European patent application N 0601345. It is therefore desirable to develop a way to separate the R-enantiomer from the racemate.

Essentially there are three ways of separation of racemates on the corresponding enantiomers. The first is the separation based on differences in physical properties such as crystal structure, is used only occasionally.

Breaktimer in the racemate, followed by the separation of the modified enantiomer from unmodified.

Third, the most common method of separation is the reaction of industrially produced optically active reagent to obtain diastereomers with different physical properties. Thus obtained diastereomers can be divided, for example, crystallization, and then select the desired enantiomer chemical treatment.

Specialists are well aware that the separation of enantiomers by preparation of diastereoisomers is a very difficult task. Even experienced researchers are finding that some compounds are not amenable to chemical separation as a separate separating agents and their combinations at different reaction conditions.

Typically, researchers in the area of separation of the enantiomers begin experiments with the use of the reagents and the reaction conditions, which has already shown its effectiveness in the separation of such compounds.

The most common method of separation of racemates of the above compounds of imidazole is in response to any optically active acid, followed by separation of the resulting diastereomers, preferably by crystallization. In European patent application N 0297651 described in the d for the separation of such racemates, since the same acid was used for the separation of chemically similar compounds of imidazolyl - 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] -4H - carbazole-4-it, or ondansetron (see, for example, Netherlands patent 190373, example XX). This is particularly noteworthy given the fact that the separation of the (+)-di-0,0'-n-toluyl-D-tartaric acid is associated with a number of disadvantages, for example, using ineffective solvent mixture of dimethylformamide and water. The solution is diluted such a mixture, the economically disadvantaged, or even unacceptable. Moreover, as the solvent dimethylformamide has such a well-known drawbacks, such as high boiling point and significant toxicity (suspected Carcinogenicity).

Along with the above-mentioned optically active di-0,0'-n-toluyl-D-tartaric acid is industrially produced a number of chiral dicarboxylic, chiral and chiral sulfonic monocarboxylic acids, for example, Dibenzoyl-L-tartaric, L-tartaric, L-malic, D-camphor-10-sulphonic, D-Hinn, 2,3:4,6-di-O-isopropylidene-2-keto-L-Galanova, L-almond, R-2-(4-hydroxyphenoxy) propionic acid and (-)-1,3,2-dioxaphosphinan-5,5-dimethyl-2-hydroxy-4-phenyl-2-oxide. However, as will be shown in Prime enantiomers in the sediment.

The purpose of this invention is to provide an economical method of obtaining enantiomerically pure compounds of imidazole that meets the following requirements:

a) use effective solvent and conducting the reaction without dilution;

b) ease of regeneration of the expensive chiral acid.

This object is achieved in that a method of obtaining enantiomerically pure compounds of imidazolyl General formula

< / BR>
where:

n=0 or 1

m=1 or 2

R1is hydrogen, methyl or ethyl; and

C*- chiral center, as well as its pharmacologically acceptable acid additive salt, which

a) add a carboxylic acid in the optically active form to a solution of the racemic mixture of the above compound I followed by the separation of the crystallized acid additive salts of the above-mentioned mixture of the enantiomers of compound I, is enriched in one enantiomer, from the mother liquor enriched in the other enantiomer;

b) after enrichment crystallized acid additive salt unwanted enantiomer is separated mixture of enantiomers in uterine fluid from the said optically active carboxylic acid and then adding racemizes acid additive salts of the above-mentioned mixture, enriched target enantiomer, from the mother liquor;

C) randomly recrystallized product to achieve the desired degree of enantiomeric purity;

g) then convert this acid additive salt of the target enantiomer in the target enantiomerically pure compound of imidazolyl General formula I or its pharmaceutically acceptable acid additive salt, characterized in that, as specified carboxylic acid is used pyroglutamic acid.

When the resulting acid additive salt is enriched by the target enantiomer, it can be identified and after adjusting to the desired degree of enantiomeric purity by further processing to convert the target enantiomerically pure compound of imidazole or its pharmaceutically acceptable acid additive salt. For convenience, such a direct crystallization of the target enantiomer is preferred.

When the acid additive salt is formed by adding optically active pyroglutamic acid, enriched unwanted enantiomer, using the technique of mutual separation (Eliel, E. L., Wilen, S. H. and Mander, L. N. in proceedings of Stereochemistry or Organic Compaunds, John Wiley & Sons, Inc., New York (1994), 325). It is that after the first studienakademie acid is removed from the dry sludge obtained from the mother liquor, for example, by extraction with a solvent system dichloromethane - water. Then carry out a second stage, adding racemic pyroglutamic acid in a solution mixture of isomers I, which leads to crystallization of acid additive salts of the target enantiomer.

Given that we found (see examples) that is chemically similar connection of imidazolyl - ondansteron - you can not identify in its optical antipodes using active pyroglutamic acid, it is surprising that the above target enantiomer of General formula I can easily be distinguished using pyroglutamic acids in optically active form, and then optionally add racemic pyroglutamic acid, subject to the above requirements. Unexpected was the fact that pyroglutamyl acid so beneficially affects the separation of the racemate of the compound of imidazolyl formula I, given the mediocre results of the application of many other separating agents.

Enantiomerically pure compound of imidazole in accordance with the present invention relates to optically active compounds with excess Anatolia, obtained in accordance with the invention, can be converted to clean itself enantiomer techniques well known in the decomposition of salts. As a rule, can be split under the action of any reason, receiving free enantiomerically pure imidazolidine basis. If desired, specified imidazolidine base can be converted to pharmaceutically acceptable acid additive salt by treatment with acid - hydrochloric, maleic or another, as described in European patent application N 601345.

The present invention relates, in particular, to a method of obtaining cilansetron, i.e., enantiomerically pure compounds of imidazolyl General formula I, where m and n are both equal to 1, R1is methyl, and atom C*has the R - configuration.

The process of crystallization, i.e., the distance crystallizing the acid additive salts of the target enantiomer or, at least, of the racemate, enriched target enantiomer, preferably carried out in an alcohol solvent. As alcoholic solvents for the crystallization process can be used methanol and ethanol. In the method in accordance with the invention used optically active acid D-pyroglutamyl [R-2-pyrrolidone-5-carbon is Amnon division of cilansetron preferably introduced in an amount of from 0.2 to 1.5 equivalent per source racemic mixture.

The amount of solvent to the amount of the enantiomers in the partial mixture may vary within fairly wide limits. When direct crystallization, the ratio of solvent to the amount of enantiomers can be from about 3: 1 to 15:1 (the ratio between the volume of the solvent and the mass of the enantiomers in it). Preferably this ratio is from about 5:1 to about 10:1. In a preferred embodiment of the invention, the volume of solvent and the mass of enantiomers correlated as 7:1. With the mutual separation of the ratio of solvent to the amount of enantiomers is about 3:1 to 15:1 in the first stage and from 5:1 to 15:1 in the second stage. Preferably it is from about 5:1 to about 10:1 in the first stage and from 7: 1 to 12: 1 in the second stage. In a preferred embodiment of the invention, the volume of solvent and the mass of enantiomers correlated as about 7:1 in the first stage and 10:1 in the second stage.

The solution containing the enantiomers can be obtained by dissolving a mixture of enantiomers in a solvent. Typically, the dissolution is carried out at a temperature from about 25oC to 80oC, preferably from about 50oC to about 60oC. the Crystallization can be performed is P>C to about 0oC.

However, the yield of the desired enantiomer remains unsatisfactory theoretically less than 50% of the original racemate. As an additional characteristic of the present invention we have found that the uterine fluid or a mixture of mother liquor from the crystallization processes can be subjected to additional processing, including the stage of racemization that allows you to improve the overall yield of the desired enantiomer to over 50% in the subsequent crystallization, as described above.

Therefore, the present invention relates also to the above-described method, wherein the uterine fluid or a mixture of mother liquor after separation of the crystalline acid salt additive is subjected to subsequent processing by (I) removal of dissolved acid additive salts with the formation of a solution of a mixture of enantiomers of the compounds of imidazolyl General formula I, as described above, a reduced target enantiomer, and (II) the subsequent conversion of the specified solution of racemic mixture under the action of bases. In the case of mutual separation of the acid additive salt, enriched unwanted enantiomer, you can optionally add the ical basis, for example, a hydroxide of an alkali metal.

After the above racemization restored the racemate can again be subjected to the specified crystallization process using optically active pyroglutamic acid, if desired with subsequent input racemic pyroglutamic acid to provide an additional output enantiomerically pure compounds of imidazolyl. If desired, the mother liquor or a mixture of mother liquor from this crystallization can be racemoramide and so on and so on, thereby it is possible to significantly increase the overall yield of the desired enantiomer. Technologically and economically feasible to add the restored racemate to the original racemate during the next process, so that ultimately virtually eliminate the loss of raw materials.

Acid additive salt of the enantiomerically pure compounds of imidazolyl General formula I, in particular cilansetron and D-pyroglutamyl acid, has significant novelty. Thus, the present invention relates also to this acid additive salts that can be obtained as described above crystallization.

Hereinafter the invention will be described in more detail with reference to the following con is 1H-pyrido-[3,2,1-jk] -carbazole - 11-he hydrochloride monohydrate (cilansetron) direct separation

25,00 g of (RS)-4,5,6,8,9,10-hexahydro-10-[(2-methyl-1H-imidazol-1 - yl)methyl] -11N-pyrido-[3,2,1-jk] -carbazole-11-she 10,11 g R-2-pyrrolidone-5-carboxylic acid (D-pyroglutamic acid) in 175 ml of methanol is heated to 50oC. the resulting suspension of the diastereomeric salts is stirred for 1 hour at this temperature. The mixture is cooled to 0oC and stirred for 1 hour at this temperature. The solid is sucked off, washed with cold methanol and dried. Output: 25,91,

The crystallization process is repeated twice more with the consumption of methanol, 5 ml per 1 g of the salt obtained in the first time and 10 ml for the second time. Output: 11,91, the mother liquor from the three stages of crystallization merge together and use on the new stage.

of 10.00 g of the salt obtained is stirred for 15 min with 200 ml of water, 50 ml of dichloromethane and 6.00 g of sodium bicarbonate. After separation of the phases the aqueous phase is twice extracted with 25 ml dichloromethane. Dichloromethane phase is drained and evaporated to dryness.

The obtained dry material was dissolved in 60 ml of isopropanol and added to a solution of 2.5 ml of concentrated hydrochloric acid at room temperature. Stirred for 1 hour and sucked off the formed solid substance was washed with cold isopropanol and petroleum ether in the ratio of 40 who).

Example 2

Obtaining (R)-(-)-4,5,6,8,9,10-hexahydro-10 - [2-methyl-1H-imidazol-1-yl)methyl] -11N-pyrido-[3,2,1-jk] -carbazole-11-she hydrochloride monohydrate (cilansetron) mutual separation

25,00 g of (RS)-4,5,6,8,9,10-hexahydro-10[(2-methyl-1H - imidazol-1-yl)methyl] -11N-pyrido-[3,2,1-jk] -carbazole-11-she 10,11 g S-2-pyrrolidone-5-carboxylic acid (L-pyroglutamic acid) in 175 ml of methanol is heated to 50oC. the resulting suspension diastereomeric salts stirred for 1 hour at this temperature.

The mixture is cooled to 0oC and stirred for 1 hour at this temperature. The solid is sucked off, washed with cold methanol and dried. Output: 18,5 g

The methanol is evaporated from the mother liquor. The residue is stirred for 15 min with 200 ml of water, 50 ml of dichloromethane and 6.00 g of sodium bicarbonate. After separation of the phases the aqueous phase is twice extracted with 25 ml dichloromethane. Dichloromethane phase is drained and evaporated to dryness. The obtained dry matter (11,50 g) and of 4.75 g RS-pyrrolidone-5-carboxylic acid (D,L-pyroglutamic acid) are dissolved in 115 ml of methanol and heated under reflux. The solution is cooled to room temperature and stirred at it for 1 hour. Sucked off the formed solid substance was washed with cold IU the water, 25 ml of dichloromethane and 3.00 g of sodium bicarbonate. After separation of the phases the aqueous phase is twice extracted with 12.5 ml of dichloromethane. Dichloromethane phase is drained and evaporated to dryness.

The obtained dry material was dissolved in 30 ml of isopropanol. To the solution was added 1.25 ml of concentrated hydrochloric acid at room temperature. After 1 h stirring the obtained solid is sucked off, washed with cold isopropanol and petroleum ether 1 in the ratio of 40:65 and dried. The yield of the target compounds: 3,95 g (IE 98%). Melting point: 219oC.

Example 3

Racemization merged uterine fluids to (R,S)-(-)- 4,5,6,8,9,10-hexahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl] -11N - pyrido-[3,2,1-jk]-carbazole-11-she and removing the second collection of R-enantiomer direct division.

The methanol is evaporated from the merged uterine fluids of example 1. The residue is stirred with 250 ml of water, 100 ml of dichloromethane and 10.00 g of sodium bicarbonate.

After separation of the phases the aqueous phase is extracted with 50 ml dichloromethane.

Dichloromethane phase is drained and evaporated to dryness. The obtained solid substance was dissolved in 90 ml of methanol and 20 ml of water. The purpose of racemization add a solution of 20 g of potassium hydroxide in 5 ml of water. After 30 min perey. Water-methanol phase is extracted with 100 ml dichloromethane, then twice with 50 ml. Merged dichloromethane phase is evaporated to dryness.

To the resulting dry matter added to 6.1 g of R-2 pyrrolidone-5-carboxylic acid and 75 g of methanol. The temperature was raised to 50oC. the resulting suspension of the diastereomeric salts is stirred for 1 hour at this temperature. The mixture is cooled to 0oC and stirred for 1 hour at this temperature.

The solid is sucked off, washed with cold methanol and dried. The output of the additive salt - 7,49,

This crystallization process is repeated twice more with the consumption of methanol per 1 g of the obtained salt 5 ml and 10 ml in the second case. The output is equal to 4.97 g

The obtained Sol is stirred for 15 min with 100 ml of water, 25 ml of dichloromethane and 3.00 g of sodium bicarbonate. After separation of the phases the aqueous phase is twice extracted with 15 ml of dichloromethane. Merged dichloromethane phase is evaporated to dryness.

The obtained dry material was dissolved in 30 ml of isopropanol. To this solution was added 1.3 ml of concentrated hydrochloric acid at room temperature. After 1 h stirring the obtained solid is sucked off, washed with cold isopropanol and petroleum ether UP>oC.

In the same way you can racemethionine and kristallizirovany (direct or mutual separation) the mother liquor from example 2 in a mixture with acid additive salt, enriched with unwanted enantiomer.

Example 4

Attempts at separation R,S-1,2,3,9-tetrahydro-9-methyl-3-[(2 - methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-it (ondasetron)

0.50 g (R, S)-1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] -4H-carbazole-4-it and 0.22 g of R-2-pyrrolidone-5-carboxylic acid is heated in 5.0 ml of methanol up to 50oC. the Obtained light-coloured solution is cooled to 0oC for 30 min After 1 h stirring at 0oC the resulting crystals are sucked off, washed with cold methanol and dried. Output - 0,02, high performance liquid chromatography shows the ratio R/S 1:1. This means that enrichment does not occur. The experience is repeated in the same conditions, but instead 5.0 ml of methanol charge of 1.5 ml. Output - 0,12, the Ratio R/S is also 1:1.

Example 5

Comparative experiments

According to the procedure described in example 1, examine the selection of cilansetron of the racemate with the use of a number of industrially produced optically active acids. The results are shown in the attached table. Of these RES-carboxylic acid) allows to achieve the desired enrichment of the R-enantiomer.

1. The method of obtaining enantiomerically pure compounds of imidazolyl General formula I

< / BR>
where n = 0 or 1;

m = 1 or 2;

R1is hydrogen, methyl or ethyl;

C* is a chiral centre,

and its pharmaceutically acceptable acid salt additive, and by adding a carboxylic acid in the optically active form to a solution of the racemic mixture of the above compound I followed by the separation of the crystallized acid additive salts of the above-mentioned mixture of the enantiomers of compound I, enriched in one enantiomer, from the mother liquor enriched in respect to the other enantiomer; (b) in the case of obtaining crystallized acid additive salt enriched in the undesired isomer, with the subsequent removal of the optically active acid from a mixture of enantiomers in the resulting mother liquor, then adding the racemic mixture of the specified carboxylic acid to a solution of the mixture of isomers I and separating the crystallized acid additive salts of the above-mentioned mixture, enriched target enantiomer, from the mother liquor; (C) an optional recrystallization of the product to achieve the desired degree of enantiomeric purity; (d) the conversion of this acid additionalservices acceptable acid additive salt, characterized in that, as specified carboxylic acid is used pyroglutamic acid.

2. The method of obtaining enantiomerically pure compounds of imidazolyl General formula I under item 1, in which n, m, R1and C* have the same values as in paragraph 1 and its pharmaceutically acceptable acid salt additive, a) by adding the optically active carboxylic acid to a solution of the racemic mixture of the above compound I followed by the separation of the crystallized acid additive salts of the above-mentioned mixture, enriched target enantiomer, from the mother liquor; (b) an optional recrystallization of the product to achieve the desired degree of enantiomeric purity; (C) transforming the obtained acid salt additive in the target enantiomerically pure compound of imidazolyl General formula I or its pharmaceutically acceptable acid additive salt, characterized in that as optically active carboxylic acids using D-pyroglutamic acid.

3. The method of obtaining enantiomerically pure compounds of imidazolyl General formula I under item 1, in which n, m, R1and C* have the same values as in paragraph 1 and its pharmaceutically acceptable acid salt additive, and by the subsequent separation of the crystallized acid additive salts of the above-mentioned mixture, enriched target enantiomer, from the mother liquor; (b) separation of the optically active acid from a mixture of enantiomers in the mother liquor, adding the racemic mixture of the specified carboxylic acids, separation of the crystallized acid additive salts of the above-mentioned mixture of enantiomers of compounds of formula I, enriched target enantiomer, from the mother liquor; (C) an optional recrystallization of the product to achieve the desired degree of enantiomeric purity; (d) converting the obtained acid additive salt of the desired enantiomer in the target enantiomerically pure compound of imidazolyl General formula I or its pharmaceutically acceptable acid additive salt, characterized in that carboxylic acid is used pyroglutamic acid, and as its optically active form, L-form specified carboxylic acid.

4. The method according to PP.1 to 3, characterized in that the compound of formula I, where n = 1, m = 1, R1is methyl; atom C* has the R-configuration.

5. The method according to PP.1 to 4, characterized in that pyroglutamic acid in optically active form, enter in the quantity of 0.2 to 1.5 equivalents per the original racemic mixture.

6. The method according to any ሺ/P> 7. The method according to p. 6, characterized in that the crystallization was carried out in methanol or ethanol.

8. The method according to PP.1 to 7, characterized in that the uterine fluid or a mixture of mother liquor after separation of the crystallized acid salt additive is subjected to subsequent processing by (I) splitting the dissolved acid additive salts with obtaining a solution of a mixture of enantiomers of the compounds of imidazolyl formula I on p. 1 with reduced levels of the target enantiomer and (II) the subsequent conversion of the specified solution of racemic mixture under the action of base.

9. The method according to p. 8, characterized in that for racemization apply inorganic base, preferably a hydroxide of an alkali metal.

10. The method according to PP.1 to 9, characterized in that the compound of General formula I is isolated in the form of its hydrochloride monohydrate.

11. Acid additive salt of the enantiomerically pure compounds of imidazolyl General formula I on p. 1, where n, m, R1and C* have the same values as in paragraph 1, and D - or L-pyroglutamic acid.

12. Acid additive salt of the enantiomerically pure compounds of imidazolyl General formula I and D-pyroglutamic acid under item 11.

13. Acid additive salt 4. Acid additive salt p. 12, where n, m, R1and C* have the values listed in paragraph 4.

15. Acid additive salt p. 13, where n, m, R1and C* have the values listed in paragraph 4.

16. The compound of General formula I, where n, m, R1and C* have the values listed in paragraph 1, in the form of its hydrochloride monohydrate.

17. Connection on p. 16, where n, m, R1and C* have the values listed in paragraph 4.

 

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