SE433847B - PROCEDURE FOR PREPARING BROMHEXIN - Google Patents

Description

aeoaa14-9 Oh HCl / Bromhexine, hydrochloride The starting material I is a known substance which can be prepared of 9-aminobenzyl alcohol by condensation e.g. with phosgene.

Intermediate II is a hitherto unknown dibromo compound, which is sparingly soluble in water and forms white crystals, which melts at 21s-220 ° C.

According to a preferred embodiment of the method, the the reaction with N-methylhexylamine according to the invention takes place in solution N-monomethylformamide, thereby achieving a yield of up to 90% in sales. _ The process according to the invention is illustrated by the following working examples.

Example 1 To a solution of 9.0 g (0.0604 mol) of 1,4-dihydro-2H-3,1- benzoxazin-2-one in 40 ml of glacial acetic acid was added 60.9 g (0.38 mol) of bromine, whereby the temperature rose from 240 to 74 ° C. Reaction mixture the mixture was allowed to stand until it cooled to room temperature and was then poured into 500 ml of water, whereby the brominated benzene the oxazin-one compound precipitated. The latter was filtered off and was washed on the filter first with water, then with a diluent solution of sodium hydrogen sulphite and finally with hexane.

From the mother liquor and the washing water could the excess bromine recovered by distillation.

The yield of brominated benzoxazinone was 16.5 g (0.0537 mol) corresponding to 89% gave the theoretical. The melting point was 218-220 ° C and thin layer chromatography showed no impurities.

A mixture of 3.07 g (0.010 mol) of the obtained 6,8-dibromo- 1,4-dihydro-ZH-3,1-benzoxazin-2-one and 4.52 g (0.040 mol) of N-methyl- cyclohexylamine in 10 ml of N-monomethylformamide was heated under 8003874- 8 stirring and refluxing for 2 hours in a 210 ° C hot oil bath.

After cooling, the reaction mixture was poured into 70 ml of water and concentrated hydrochloric acid was added to acidic reaction.

Upon cooling in ice water with stirring crystallized out N- (2-amino-3,5-dibromobenzyl) -N-methyl-cyclohexylammonium chloride (bromohexine, hydrochloride), which after 1 hour is filtered off. was washed, washed with water and dried. The yield was 3.7 g (8.97 mmol), corresponding to 89.7% of theory. Melting point was 232-233.5 ° C, and the substance was analytically pure.

Example 2 A mixture of 1.65 g (5.4 mmol) of according to Example 1 is ~ 6,8-dibromo-1,4-dihydro-2H-3,1-benzoxazin-2-one and 2.4 g (21 mmol) N-methylcyclohexylamine in 10 ml of diethylene glycol heated while stirring and refluxing for 20 hours at a time 210OC hot oil bath. After cooling, 150 ml of water were added and concentrated hydrochloric acid to acid reaction, after which the mixture heated to reflux temperature. To the boiling mixture 10 ml of ethanol and activated carbon were added, after which filtration took place at the reflux temperature.

The filtrate was cooled in ice water so that N- (2-amino-3,5-dibromo- benzyl) -N-methylcyclohexylammonium chloride crystallized out. The subject was filtered off and washed with water. The yield of analytical pure substance was 1.1 g (2.67 mmol), corresponding to 49.4% of it theoretical. ... v ._._..._._..-._. --- .- f -_._. ~ ....-_-- --_-.--- -

Claims (2)

8Û03874 ~ 8 »r PATENTKRAV 1. A process for the preparation of bromohexine of the formula ~ 'Br I mi:' C33 characterized in that 1,4-dihydro-2H-3,1-benzoxazin-2-one of the formula HN = 0 ° C / H2 is reacted in solution with free bromine to 6,8Fdibromo-1,4-dihyro-ZH-3,1-benzoxazin-2-one, which is then reacted with methyl-cyclohexylamine to bromohexine, which is recovered from the reaction mixture in the form of an acid addition salt. Process according to Claim 1, characterized in that the reaction with N-methylcyclohexylamine is carried out in N-monomethylformamide. 8003874-8 SUMMARY The preparation of N- (2-amino-3,5-dibromobenzyl) -N-methyl-cyclohexylamine, the hydrochloride of which has the formula Br NH2-HCl Br / k CH-1®® 2 '~ CH3 takes place by 1 -4-dihydro-ZH-3,1-benzoxazin-2-one brominated with free bromine to the hitherto unknown 6,8-dibromo-1,4-dihydro-2H-3,1-benzoxazin-2-one, which is then reacted with N-methylcyclohexylamine to bromohexine. The reaction is preferably carried out by heating in N-monomethylformamide to its boiling point.