Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-16
2002-04-02
Huang, Evelyn Mei (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S311400, C548S534000
Reexamination Certificate
active
06365743
ABSTRACT:
The present invention relates to a process for the preparation of an enantiomerically pure imidazolyl compound, as well as to an acid addition salt of this compound.
4,5,6,8,9,10-Hexahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl-11H-pyrido[3,2,1-jk]carbazol-11-one is known from EP-B-0297651 and from EP-A-0601345. In the former patent publication a general class of compounds, including the above imidazolyl compound and homologous compounds, their preparation and their use as 5-HT antagonists is described. The latter patent publication describes the use of a selection of these type of compounds for the treatment of certain diseases.
Various biologically active substances that are used in pharmaceutical compositions for human or veterinary application, contain a chiral centre in their molecular structure and therefore give rise to optical isomerism. It is generally known in the art, that often only one of the enantiomers presents the desired optimum biological activity. The presence of the other optical antipode in a composition or agent may cause or invigorate certain side effects and burden the recipient, i.c. the human or animal body. It is generally deemed more and more desirable to administer the biologically active substance in the form of a substantially pure enantiomer, which specifically exhibits the desired biological activity. Therefore, the resolution of a racemate into its enantiomers is often an important step in the preparation process of pharmacologically active substances.
It has been found, that the R-(−)-enantiomer of the above-defined imidazolyl compound, also known under its generic name cilansetron, is especially useful in the indications mentioned in EP-A-0601345. It is therefore desirable to dispose of a method for the separation of the R-enantiomer from the racemate.
There are essentially three methods available to resolve racemates into their respective enantiomers. The first of these, viz. a resolution based on difference in physical properties, e.g. in crystal structure, is only occasionally applicable.
In a more recent method of resolution, enzymes are applied to chemically modify one enantiomer of a racemate selectively, followed by a separation of the modified from the unmodified enantiomer.
The third and by far most generally used method of resolution involves a reaction with a—commercially available—optically active reagent to produce diastereomers, which differ in physical properties. So, the diastereomers obtained in this manner can be separated, e.g. by crystallization, after which the desired enantiomer can be isolated by a chemical after-treatment.
It is generally known in the art that the resolution of enantiomers by preparing diastereomers is a very difficult task. Even experienced investigators find that certain compounds resist chemical resolution by any one of a number of combinations of resolving agents and reaction conditions. As a general rule, investigators in the art of separating enantiomers commence a study by using reagents and conditions that have been found to be successful in the past in resolving similar compounds. A generally preferred method for resolving racemates of the above imidazolyl compounds is a reaction with an optically active acid, after which the diastereomers obtained can be separated, preferably by crystallization. In EP 0297651 the use of (+)-di-O,O′-p-toluyl-D-tartaric acid is described. Apparently this optically active carboxylic acid is the reagent of choice for resolving such racemates, because the same acid has also been used for the resolution of a chemically closely related imidazolyl compound, viz. 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or ondansetron (e.g. NL-B-190373, Example XX). This is indeed remarkable in view of the fact that the resolution with (+)-di-O,O′-p-toluyl-D-tartaric acid has various disadvantages, such as the use of a high dilution and the application of a less acceptable solvent system, viz. DMF-water. Such a diluted solution is not attractive or even not feasible from an economical point of view. Furthermore, the solvent DMF has well-known disadvantages, such as a high boiling point and a considerable toxicity (suspected carcinogenity).
In addition to the above optically active di-O,O′-p-toluyl-D-tartaric acid, a number of chiral dicarbonic acids, chiral sulfonic acids or chiral monocarbonic acids are commercially available, such as dibenzoyl-L-tartaric acid, L-tartaric acid, L-malic acid, D-camphor-10-sulfonic acid, D-quinic acid, 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid, L-mandelic acid, R-2-(4-hydroxyphenoxy)propionic acid, and (−)-1,3,2-dioxa-phosphorinane-5,5-dimethyl-2-hydroxy-4-phenyl-2-oxide. As will become apparent from the Examples, however, these acids either do not effect a precipitation of the addition salt with one of the enantiomers, or do not accomplish enrichment of one of the enantiomers in the precipitate.
It is the objective of the present invention to provide an economically operative method for the preparation of enantiomerically pure imidazolyl compounds, which method should meet the following requirements: (a) using non-diluted reaction conditions and an acceptable solvent, (b) easy recycling of the relatively expensive chiral acid.
This objective 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;
m is 1 or 2;
R
1
is hydrogen, methyl or ethyl; and
C* denotes a chiral centre;
as well as its pharmaceutically acceptable acid 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 separation of the crystallized acid addition salt of said mixture of enantiomers of compound I enriched in one enantiomer, from the mother liquor enriched in the other enantiomer,
b) when the crystallized acid addition salt is enriched in the undesired enantiomer, by then separating the mixture of enantiomers in the mother liquor from said optically active carboxylic acid, followed by addition of a racemic mixture of said carboxylic acid to a solution of the obtained mixture of isomers of I, and by separation of the crystallized acid addition salt of said mixture, enriched in the desired enantiomer, from the mother liquor, and
(c) optionally recrystallizing the product until the desired enantiomeric purity is obtained, and by then
(d) converting this acid-addition salt of the desired enantiomer to the desired enantiomerically pure imidazolyl compound of the general formula I or to its pharmaceutically acceptable acid addition salt,
characterized in that pyroglutamic 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 further treatment, be converted into the desired enantiomerically pure imidazole compound or its pharmaceutically acceptable acid addition salt. For the sake of convenience such a direct crystallization of the desired enantiomer is preferred. When the acid addition salt formed upon addition of the optically active pyroglutamic acid is enriched in the undesired enantiomer the mutual resolution approach (Eliel, E. L., Wilen, S. H and Mander, L. N. in Stereochemistry or Organic Compounds, John Wiley & Sons, Inc., New York (1994), 325)is used. In this approach, after the first resolution step yielding the acid addition salt enriched in the undesired enantiomer, the optically active pyroglutamic acid is removed from the dry substance obtained from the mother liquor, e.g. by a solvent extraction in a dichloromethane/water system. Subsequently the second step is performed by adding racemic pyroglutamic acid to a solution of the mixture of isomers of I obtained, leading to the crystallization of the acid addition salt of the desired enantiomer.
In view of the finding (see the Examples), that the chemically closely related imidazolyl compound ondansetron
van der Meij Paulus F.C.
Verbeek Jan-Maarten
Duphar International Research B.V.
Stevens Davis Miller & Mosher L.L.P.
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