CS259646B1 - Process for the preparation of diarylmethyl-4-tetrahydrothiopyranyl ethers and their methoxide - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is a method for preparing diarylmethyl-4-tetrahydrothiopyranyl ethers of the general formula I in which X and Y denote hydrogen atoms, or both together form a bridge —CH2S—, and their methiodides. The method of preparation consists in the reaction of benzhydryl chloride or 11-chloro- -6,ll-dihydrodibenzo[b,e]thiepine with tetrahydrothiopyran-4-ol in boiling xylene in the presence of anhydrous potassium carbonate. The substances of the general formula I are crystalline substances that are obtained from crude products by filtration or chromatography through a silica gel column. By reaction with methyl iodide at room temperature, they provide sulfonium salts, i.e. methiodides. The substances of the general formula I are intermediates in the synthesis of drugs and their methiodides partly exhibit antihistamine activity.

Description

The present invention relates to a process for the preparation of diarylmethyl-4-tetrahydrothiopyranyl ethers of general formula (I)

in which X and Y represent hydrogen atoms, or both together represent a bridge of "CH 2 S", and their methoiodides.

The compounds of the invention are intermediates in the synthesis of drugs with antihistamine and anticholinergic activity and as such are technically significant. Their methojodides (sulfonium salts) already show antihistamine activity. For example, 4- (benzhydryloxy) -1-methyltetrahydrothiopyranium iodide (the methiodide of compound I, where X = Y = H), which is very toxic (LD 50 is greater than 500 mg / kg orally in mice), exhibits at an oral dose of 10 mg / kg in guinea pigs a significant antihistamine effect in the protection against bronchospasm induced by liistamine aerosol (this dose protects more than 50% of the animals). At the same dose, it shows a distinct effect in the guinea pig protection lethality test (25% of animals protect at that dose).

The process for the preparation of the compounds of the formula I according to the invention consists in reacting the chloro derivatives of the formula II in which X and Y are the same as in formula I with tetrahydrothiopyran-4-ol in the presence of anhydrous potassium carbonate in boiling xylene. The desired products of formula (I) are formed in good yields and are obtained in a crystalline state after filtration or chromatography of their solutions in benzene on silica gel. All starting materials are known and references for their preparation are given in the examples. Reactions of the compounds of formula I with methyl iodide yield the methoiodides, the preparation of which is also part of the invention. Further details of carrying out the reactions and methods of isolating the products are given in the examples, which are intended to illustrate the possibilities of the invention, but not all of these possibilities are exhaustively described. The substances described in the examples are new; their identity was ensured both by analyzes and spectral methods.

EXAMPLE 1 11- (4-Tetrahydrothiopyranyloxy) -6,11-dihydrodibenzo [b, e] thiepine

A mixture of 5.3 g of 11-chloro-6,11-dihydrodibenzophobe] thiepine (Seidlova V. et al .: Monatsh. Chem. 96, 650, 1965), 2.75 g of tetrahydrothiopyran-4-ol (Adlerova E. et al .: Collect. Czech. Chem. Commun. 24, 1268 (1959)), 25 ml of xylene and 5.9 g of anhydrous potassium carbonate are stirred and refluxed for 7.5 hours. After cooling, 100 ml of water are added and the mixture is extracted with benzene. The extract was washed with water, dried over potassium carbonate and evaporated under reduced pressure. The residue (7.0 g) was dissolved in 50 ml of benzene and the solution was filtered through a column of 30 g of silica gel. The column is washed with 200 ml of benzene and the filtrates are evaporated. 5.8 g (88%) of the desired compound are obtained, which crystallizes from a mixture of ethanol and cyclohexane and melts in the pure state at 104-107 ° C.

Example 2

4- (Benzhydryloxy) -1-methyltetrahydro 8.1 g of benzhydryl chloride (Gilman H., Kirby JE: J. Am. Chem. Soc. 48, 1 735, 1926), 5.2 g tetrahydrothiopyran-4-ol (cited above) 50 ml of xylene and 5.5 g of anhydrous potassium carbonate were stirred and refluxed for 5 hours, after standing overnight the mixture was quenched with 100 ml of water and after dissolution of the inorganic salts was extracted with benzene and washed with water, dried with potassium carbonate. The residue (15.8 g) was chromatographed on a column of 85 g of silica gel, eluting with benzene in the first fractions to yield 7.0 g (62%) of crystallization from hexane and pure. melts at 87.5 to 90 ° C.

Example 3

4- (Benzhydryloxy) -1-methyltetrahydrothiopyranium iodide

A mixture of 9.3 g of 4- (benzhydryloxy) tetrahydrothiopyran (see Example 2), 20 ml of methanol, 30 ml of benzene and 22.8 g of methyl iodide was allowed to stand at room temperature for 4 days.

The desired product crystallizes in a yield of 12.1 g (87%) which is obtained by filtration, washing with ether and drying at room temperature. Recrystallization from a mixture of methanol and benzene is obtained in the pure state and has a melting point of 151-153 ° C.

Claims (1)

A process for the preparation of diarylmethyl-4-tetrahydrothiopyranyl ethers of formula (I) YNÁLEZU I (II) in which X and Y are hydrogen atoms, or both together a —CH2S— bridge, and their methodes, characterized in that the chloro derivatives of formula II in which X and Y are the same as in Formula I are reacted with tetrahydrothiopyran-4-ol in boiling xylene in the presence of anhydrous potassium carbonate, and the resulting sulfides of formula I are optionally treated with methyl iodide.