CS263993B1 - Process for preparing pure enantiomers of 4-/1-methyl-4-piperidyliden/-4,9-dihydrobenzo/4,5/cyclohepta/1,2-b/thiophen-10-one - Google Patents

Abstract

The solution lies in the field of synthetic drugs. The subject of the present invention is a process for the preparation of pure enantiomers of 4- (1-methyl-4-piperidinyl) -4,9-dihydrobenzo (4,5) cyclohepta- (1,2-b) thiophen-10-one (I), which is known in racemic form as the antihistaminic and antianaphylactically highly effective ketotlfen, used as a prophylactic in the treatment of bronchial asthma. Its cleavage to antipodes is carried out by solving the crystallization of diastereoisomeric mixtures of 1: 1 salts with (+) - or (-) - O, O'-dibenzoyl-D (or L) - tartaric acid or (+) - or (-) - O, O'-di- (p-toluyl) -D (or L) -terminal to constant optical rotation, the homogeneous salts are then quenched with aqueous ammonia and the optically pure base of (+) - and (-) - ketotifene is isolated by organic extraction solvents, evaporation of the extracts and crystallization from ethanol, using isotacho-beta-cyclodextrin as an additive to the electrolyte to verify optical purity. In the form of salts, the two enantiomers of ketotifen (I) are highly potent Hi-antihistamines, and the (-f -) - isomer has considerable antianaphylactoid activity and relatively high antimuscarinic activity.

Description

The present invention relates to a process for the preparation of pure enantiomers of 4- (1-methyl-4-piperidyllaene) -4,9-dihydrobenzo [4,5] cyclohepta] 1,2-b] thiophen-10-one of formula (I) ^.

By known synthetic procedures (Waldvogel E. et al.: Helv. Chim. Act. 59, 866, 1976; German (NSR) Publication Nos. 2,302,970, 2,144,490 and 2,1111071; US Patents Nos. 3,682,930, 3,960,894 and 4128,549), an optically inactive compound of formula I is obtained which, in the form of a salt with fumaric acid, exhibits excellent antihistaminic, antiallergic and anti-anaphylactic properties (Martin U. and Romer D .: Arzneim.-Forsch. 28, 770, 1978; Triangel 17, 141, 1978; Pharmacol. Biochem. Prop. Drug Subst. 3, 424, 1981) and has found widespread practical use as a prophylactic for bronchial asthma attacks (Castaner J., Hillier K .: Drugs Future 2, 108, 1977; 3, 163, 1978; Alhadeff, M .: Med Actual (Drugs Today) 14, 367, 1978; Craps, L .: Sandoz Revue 1981 (2), 15). The substance of formula I is known under the international generic name 'ketotifen'.

The ketotifen (I) molecule does not contain a center of asymmetry and at first glance it does not allow the possibility of chirality and cleavage into optical antipodes (enantiomers). Such a possibility has not been suggested by a detailed work describing the physicochemical and analytical characterization of ketotifen (I) (Mikotic-Mihun Z. et al .: Acta Pharm. Jugosl. 33, 129, 1983; Yugosl. Chem. Papers 8 (1), 23, 1984) nor the ketotifen (I) metabolism study (Le Bjgot JF et al., Drug Metab. Dispos, 11, 585, 1983).

In contrast, a study of molecular models of ketotifen (I) has shown that the non-planar middle ring of the tricyclic system provides the possibility of two boundary conformations whose inversion is severely impeded by the presence of the keto group and which could represent largely stable ketotifen (I) enantiomers. A similar phenomenon was observed for 3-substituted cyproheptadine derivatives which have been shown to have stable chiral conformers (Ebnother A. et al .: Helv. Chim. Acta 48, 1237, 1965; Remy DC et al .: J. Med. Chem., 20, 1013 (1977).

The correctness of this assumption was experimentally confirmed analytically by capillary isotachophoresis and micropreparation. The existence of the chirality of the ketotifen (I) molecule has not been reported yet and its discovery must be considered surprising. A method of resolving racemic ketotifen (I) into antipodes is an object of the present invention.

Crystallization of mixtures of diastereoisomers resulting from the neutralization of a compound of formula I with optically active acids of formula II can be used to resolve a racemic compound of formula I

OOCHCOOH

R @ 1 --COOCHCOOH (H) in which R is hydrogen or methyl, wherein in these salts, preferably 1 base molecule of formula I comprises 1 acid molecule of formula II. Thus, they are optically active hydrogenendibenzoyltartarates or hydrogen-di (p-toluyl) tarates.

Thus, either commercially available (? -) - O, O-dibenzoyl-D-tartaric and (-) - O, O'-dibenzoyl-L-tartaric acids are used for cleavage, or according to literature (Table A., Hofman A). (Helv. Chim. Acta 26, 922, 1943) prepared (-j -) - O, O'-di (p-toluyl) -D-tartaric acid or (-) -O, O'-di (p- toluyl) -L-tartrate.

The neutralization of the racemic base of formula I with optically active acids of the formula II is preferably carried out in ethanol and the precipitated dlastereoisomeric mixtures are crystallized, preferably from aqueous ethanol. The melting points of the individual crystallizates are not characteristic, so they cannot be used as criteria for the degree of resolution achieved. The crystallization must be repeated until a constant optical rotation of the salt is achieved. In addition, it is necessary to release the optically active base from each crystallizate and to control the optical rotation. Complete resolution is characterized by the consistent optical rotation of two successive crystallisates and the bases released therefrom.

Isotachophoresis using β-cyclodextrin as electrolyte leader additive has proven to be a method for assessing the degree of cleavage achieved; the percentage of both enantiomers can be directly determined by this method.

Further details of the process for the preparation of the pure enantiomers of ketotifen (Ij are given in the examples, which are merely illustrative of the possibilities of the invention and are not intended to fully describe the possibilities. Enantiomeric bases of formula I are crystalline substances that crystallize from etha263993. -1] has a specific rotation:

[Α] 20 ^D = + 114 ° (ethanol, c = 1);

the left-handed base [(-) - 1] has:

[.alpha.] D @ 20 = -114 DEG (ethanol, c = 1).

The pharmacological evaluation of both enantiomers (evaluated in the form of aqueous hydrogen fumarate solutions) showed some differences suggesting a stereoselectivity of the effects, albeit not very pronounced. The antihistamine effect (against histamine-H1 receptors) was evaluated by inhibition of histamine aerosol-induced bronchospasm in guinea pigs. The mean protective dose PD 50 for (+ j-ketotifen) is 0.026 mg / kg for oral administration, for (-) - ketotifen the PD 50 = 0.013 milligrams / kg p.o.

Thus, the levorotatory enantiomer in this assay appears to be approximately twice as potent as the dextrorotatory enantiomer. The activity of both enantiomers in this assay is enormously high. Further, the comparison was made in an anaphylactoid skin reaction test in rats induced by administration of 48/80, a known histamine liberator. The anti-anaphylactoid effect of (+) -ketotifen is given by a median protective dose PD 50 = 4.2 mg / kg orally.

For (, j-ketotifen) PD50 could not be determined: dose of 1 mg / kg po limits the development of anaphylactoid skin reaction by 25% (compared to control); increasing doses up to 50 mg / kg po does not result in statistically significant increase in antianaphylactoid effect Thus, in this assay, the dextrorotatory enantiomer appears to be an effective component of the racemate Although it is known that the anticholinergic and antimuscarinic effect of ketotifen (1j is relatively low, both enantiomers were compared for affinity to muscarinic receptors in the rat brain in an in vitro assay wherein the inhibition of ligand binding, i.e., 0.5 nM ( ³ H) of quinuclidinylbenzilate, to binding sites was determined.

Results are reported as the mean inhibition of IC50 concentration. IC 50 = 149 nM for (+ J-ketotifen); IC 50 = 260 nM for racemic ketotifen; IC 50 = 1217 nM for (-J-ketotifen), so also in this case the dextrorotatory enantiomer is an effective component of the racemate. The opposite result in the case of the histamine aerosol test can be explained by the fact that the H1 antihistamine effect is not stereoselective and that the efficacy of the two enantiomers is so enormous that 100% difference between the two results is within experimental error.

In terms of racemization, both enantiomers of ketotifen (IJ) are relatively stable. Racemization occurs rapidly at a melting point of bases (158-160 ° C) and further in boiling aqueous salt. Crystallization of bases from boiling ethanol does not lead to racemization. the energy barrier for inversion of conformations of both enantiomers is considerably high.

Example 1

To a solution of 7.8 g of racemic base ketotife ^nu [(+ H] ^In 50 ml of ethanol was added 10.2 g of (-) -O, O'-di- (p-toluoyl) -L-tartaric acid and the mixture is heated to The resulting acid salt solution is left at 0 ^DEG C. for several days and the precipitated salt is filtered off with suction to give a yield of 16.8 g, which is a mixture of the two diastereoisomers.

Its tt is 189-190 ° C and [α] ^D =, -74.65 ° (70% ethanol, c = 0.2).

The aqueous ammonia-liberated base, isolated by benzene extraction and complete solvent evaporation, has a mp of 159-162 ° C and (qt) 20 ^d = + 10.91 °;

it is 54% (- + -) - 1 and 46% (-) -1, as assessed by isotachophoresis. Single crystallization of this mixture (5.0 g) from 350 ml of 75% aqueous ethanol, 2.4 g of the digested salt mp 184-187 ° C _[W] ^D = -39.02 2o.

The liberated base has [+ 20 ^D = + 98.5 ° and, according to isotachophoresis control, contains 92% (+) -1. Further crystallization of 2.15 g of this salt from 200 ml of 75% ethanol gives

1.5 g of homogeneous salt diastereoisomers of m.p. 184 DEG-187 DEG C. [.alpha.] ^D @ 20 = -33.05 DEG.

The liberated base melts at 159-162 ° C (ethanol) and has a [α] 20 ^D = + 114.14 °.

According to isotachophoresis control, it is a completely homogeneous dextrorotatory base of ketotifen [(+) -1).

Example 2

To a solution of 7.6 g of racemic ketotifen base [(+) -1] in 15 ml of ethanol is added a solution of 10.2 g of (-) -0,0'-dibenzoyl-L-tartaric acid and the solution is left to crystallize for 20 days. Thereafter, 16.8 g of a diastereoisomeric mixture melting at 154-155 ° C are obtained by suction. Triple crystallization successively from 140, 120 and 100 ml of 75% aqueous ethanol

3 9 9 3

S results in 8.5 g of a homogeneous salt diastereoisomer, mp 158-160 ° C, [α] 20 ^D = -20.36 °.

As in the previous example, the liberated base (3.8 g) melts at 159-162 ° C (ethanol), [α] 20 ^υ = + 114.31 °.

Thus, again, it is a completely homogeneous dextrorotatory base of ketotifen [(+) -1), which is identical to the product of Example 1. The systematic treatment of the mother liquors obtained in Examples 1 and 2 results in an additional quantity of (+) -I base, which yield.

Example 3

Neutralization of 12.9 g of racemic ketotifen base ((+) - 1) with 18.1 g of (+) - O, O'-dibenzoyl-D-tartaric acid is carried out in 100 ml of ethanol and the diastereoisomeric salt mixture obtained is added under After stirring for 24 hours, the salt mixture is filtered off with suction: 27.0 g, mp 156-158 [deg.] C. Three-fold crystallization from 85% ethanol yields 7.2 g of a homogeneous salt which melts at 158-160 [deg.] C. and is [of] ^N 2 O = + 19.55 ° (70% ethanol, c = 0.2).

The liberated base melts at 159-162 ° C (ethanol) and has + 1'M ^; = —113.9 L °,

According to the isotachlororesin control, it is a completely homogeneous levorotatory base of ketotifen [(-) -!].

Claims (1)

SUBJECT Process for preparing pure enantiomers of 4- (1-methyl-4-piperidylidene) -4,9-dihydrobenzo [4,5] cyclohepta] 1,2-b] thiophen-10-one of formula I V in N A (. E Z U R @ 1 = (R @ 2), characterized in that the racemic base of the formula I is neutralized with optically active acids of the formula II R - COOCHCOOH (ii) wherein R is hydrogen or methyl, the resulting diastereoisomeric mixtures of acid salts are crystallized from aqueous ethanol to constant optical rotation, decomposed with dilute aqueous ammonia, liberated optically active base (+) - I or (-) - I are isolated by extraction with volatile and water-immiscible solvents, obtained by evaporation of the extracts and crystallization from ethanol, and their optical purity is verified by isotacholoresis with .beta.-cyclodextrin as the electrolyte-leading additive.