CS224978B1 - The production of new 7-/1-methyl-4-piperidile/thieno/2,3-c/-2-benzothiepine-4/9h/ and its hydrogenmaleates - Google Patents

Description

The present invention relates to a process for the preparation of a novel 7- (1-methyl-4-piperidyl) thieno (2,3-c) -2-benzothiepin-4 (9H) -one of formula I

(I) and its hydrogen maleate.

The compound of formula I is an intermediate in the preparation of thieno (2,3-c) -2-benzothiepine-derived drugs and as such is technically important.

In literature (Rajšner M., Metz J., Protiva M., Collect. Czech.Chem.Commun. 32, 2854, 1967) it has been reported that by reaction of thieno (2,3-c) -2-benzothiepin-4 (9H). ) -one of formula II ^(II)

O with 1-methyl-4-piperidylmagnesium chloride is expected

4- (1-methyl-4-piperidyl) -4,9-dihydrothieno (2,3-c) -2-benzothiepine

4-ol of formula III (III)

as the only product. A detailed study of the reaction product has now revealed the surprising fact that in addition to the tertiary alcohol of formula III, this reaction produces a considerable amount of the aminoketone of formula I as a 1,6-addition product (for similar sterically hindered ketone reactions see Gaertner R., Chem.Revs.

45 (493, 1949). Thus, the reaction of ketone II with 1-methyl-4-piperidylmagnesium chloride in tetrahydrofuran affords a mixture of substances which is separated according to the invention by extraction with ethanol. The insoluble portion is the amino alcohol III, which is obtained in a yield of about 50%. The soluble fraction is the crude aminoketone I formed in a similar yield. Pure I is obtained from the crude product by a combination of crystallization and silica gel chromatography. Its identity was ensured by 1) analysis, 2) by mass spectra (molecular ion of 329, which corresponds to the composition of C ^ QHH NNOSg} the main fragment om / z 70, which corresponds to the N-methyl-Nvinyl-N-methylenammonium ion produced cleavage of the methylpiperidyl moiety bound to the aromatic carbon), 3) by ultraviolet spectrum (high degree of conjugation indicating the presence of the diarylketone fragment), 4) by infrared (diarylketo band at 1611 cm ', absence of hydroxyl group) and 5) by 1 H NMR spectrum (shows the presence of only 5 aromatic protons whose signals are well differentiated and individual protons can be localized to individual skeleton positions, the proton at position 7 is missing, and the hydroxyl group proton is missing).

in

Pure I is a crystalline compound melting at 212-213 ° C; the substance crystallizes from mixtures of cyclohexane and ethanol or chloroform and ethanol. Neutralization with maleic acid in ethanol gives the hydrogen maleate, which crystallizes from aqueous ethanol and melts in the pure state at 206 to 208 ° C. 224 978

Thus, the preparation of the new 7- (1-methyl-4-piperidyl) thieno (2,3-c) 2-benzothiepin-4 (9H) -one (I) is carried out as follows:

By reaction of 20.0 g of 4-chloro-1-methylpiperidine with 3.65 g of magnesium in 60 ml of tetrahydrofuran, a solution of Grignard reagent is prepared, using iodine grains and a few drops of 1,2-dibromoethane to start the reaction (Adler E. et al., _t . The mixture is refluxed for an additional 1 hour until practically all of the magnesium is dissolved, cooled to 15 ° C and a solution of 23.2 g of thieno (2,3-c) -2-benzothiepine is added dropwise with stirring over 30 minutes. ~ 4 (9H) -one (II) (Rajsner M. et al., Collect. Chem.Chem.Commun. 32, 2854, 1967; 39, 1366, 1974; Protiva M. et al., Collect.Czech.Chem (Commun. 29, 2161, 1964) in 50 ml of tetrahydrofuran. The mixture was stirred at room temperature for 30 min and quenched with external cooling to 20-28 ° C by slowly adding a solution of 67.5 g of (+) - tartaric acid in 300 mL of water. The resulting clear solution was washed with toluene, basified with conc. aqueous ammonia and the liberated bases were isolated by extraction with chloroform. The extract was washed with water, dried over potassium carbonate, filtered with charcoal and the filtrate was evaporated under reduced pressure. The residue is briefly boiled with 50 ml of ethanol, the suspension is left overnight at 0-5 ° C, the solid is filtered off, washed with petroleum ether and dried in vacuo. There was thus obtained 17.8 g of homogeneous 4- (1-methyl-4-piperidyl) -4,9-dihydrothieno (2,3-c) 2-benzothiidin-4-ol of formula III which, after a single crystallization, had S @ +. from ethanol at 212-213C. Evaporation of the ethanolic extract yielded 11.5 g of crude I, which was crystallized first from a mixture of 10 ml of ethanol and 10 ral of hexane for purification, then chromatographed on a 60 g silica gel column (Silpearl), eluting with 60 ml. % chloroform, 35% chloroform saturated with ammonia and 5% methanol, and finally crystallized from a mixture of cyclohexane and ethanol or chloroform and ethanol. Pure Compound I melts at 212-213 ° C, i.e. at the same temperature as Compound III, but from which it differs in substantially lower polarity.

224 978

Neutralization of I with maleic acid in ethanol yields hydrogen maleate, which crystallizes from aqueous ethanol and melts in the pure state at 206-208 ° C with decomposition.

Claims (1)

A process for the preparation of the novel 7- (1-methyl-4-piperidyl) thieno (2,3-c) -2-benzothiepin-4 (9H) -one of formula I and its hydrogen maleate by reaction of thieno (2,3-c) -2- Benzothiepin-4 (9H) -one with 1-methyl-4-piperidylmagnesium chloride in tetrahydrofuran, characterized in that the resulting base mixture is separated by extraction with ethanol, while removing the currently formed 4- (1-methyl-4-piperidyl) - 4,9-Dihydrothieno (2,3-c) -2-benzothiepin-4-ol and evaporation of the ethanolic extract yields the crude title compound which is purified by combining crystallization from ethanol / aprotic solvent mixtures, preferably hexane, cyclohexane or chloroform. , and chromatography on silica gel and the pure desired compound is optionally converted by neutralization with maleic acid in ethanol to hydrogen maleate.