CH642617A5 - METHOD FOR PRODUCING BROMHEXINE. - Google Patents

Description

The present invention relates to a new process for the preparation of bromhexine, i. H. of N- (2-amino-3,5-dibromobenzyl) -N-methylcyclohexylamine, which is a known compound and has a mucolytic and cough-relieving effect.

Various processes for the production of bromhexine are known and are described in Danish Patent Nos. 101 066,

H

The starting material I is a known compound which can be prepared from o-aminobenzyl alcohol by condensation with, for example, phosgene.

The previously unknown intermediate II is a white crystalline compound which is slightly soluble in water and has a melting point of 218-220 "C.

In the preferred embodiment of the process of the present invention, the reaction with N-methyl-cyclohexylamine in solution in N-monomethylformamide is carried out because a yield of up to 90% is obtained.

The process of the present invention is illustrated by the following examples.

example 1

60.9 g (0.38 mol) of bromine were added to a solution of 9.0 g (0.0604 mol) of 1,4-dihydro-2H-3, l-benzoxazin-2-one in 40 ml of glacial acetic acid, where the temperature rose from 24 ° C to 74 ° C. The reaction mixture was allowed to cool to room temperature and then poured into 500 ml

101 301, 101 795 and 119 408. as well as in Danish published patent specifications No. 135 499, 135 574 and 135 680, and DE-OS 2 273 193.

These known processes have the disadvantage that they either require intermediate protection for the substituents which are not involved in the reactions or start from starting materials which are difficult to access or require expensive reactants. All of these processes have in common that the disadvantages manifest themselves in a low yield. The aim of the present invention is to provide a process for the production of bromhexine in which the disadvantages mentioned are avoided and in which bromhexine in a high yield and is obtained extremely pure.

15 In the process according to the invention, 1,4-dihydro-2H-3, l-benzoxazin-2-one is reacted with bromine to give 6,8-dibromo-l, 4-dihydro-2H-3, l-benzoxazin-2-one, which subsequently reacts further with N-methyl-cyclohexylamine to give bromhexine, the latter being obtained from the reaction mixture as an acid addition salt.

The reaction sequence is illustrated by the following reaction scheme:

Br H

Water, whereby a precipitate formed from brominated benz-oxazinone. The precipitate was filtered off and washed on the filter first with water, then with a weak solution of sodium bisulfite and finally with hexane.

The excess bromine could be recovered from the mother liquor and the wash water 55 by distillation.

The yield of brominated benzoxazinone was 16.5 g (0.0537 mol), which corresponds to a yield of 89% in theory. The melting point was 218-220 ° C and no contamination could be found by thin layer chromatography.

A mixture of 3.07 g (0.010 mol) of 6,8-dibromo-l, 4-dihydro-2H-3, l-benzoxazin-2-one and 4.52 g (0.040 mol) of N-methyl-cyclohexylamine in 10 ml of N-monomethylformamide was heated with stirring and refluxed on a 210 ° C. oil bath for 2 65 hours.

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

Br2

CH3COOH

3rd

642 617

By cooling in ice water and stirring, N- (2-amino-3,5-dibromobenzyl) -N-methylcyclohexylammonium chloride (bromhexine hydrochloride) crystallized, which was filtered off after one hour, washed with water and dried. The yield was 3.7 g (8.97 millimoles), which corresponds to a yield of 89.7% in theory. The melting point was 232-233.5 ° C and the compound was analytically pure.

Example 2

A mixture of 1.65 g (5.4 millimoles) of 6,8-dibromo-l, 4-dihydro-2H-3, l-benzoxazin-2-one from Example 1 and 2.4 g (21 millimoles) of N- Methyl cyclohexylamine in 10 ml diethylene

glycol was refluxed on a 210 ° C oil bath with stirring for 20 hours. After cooling, 150 ml of water was added and then hydrochloric acid was added until an acid reaction.

5 The reaction mixture was then heated to reflux temperature. 10 ml of ethanol and activated carbon were added to the boiling mixture and after filtering off the hot reaction product, a clear filtrate was obtained.

The filtrate was cooled in ice water, whereby N- (2-io amino-3,5-dibromobenzyl) -N-methyl-cyclohexyl-

ammonium chloride crystallized. The compound was filtered off and washed with water. The yield of the analytically pure compound was 1.1 g (2.67 millimoles), which corresponds to a yield of 49.4% in theory.

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Claims (2)

642 617 PATENT CLAIMS 1. A process for the preparation of bromhexine, characterized in that l, 4-dihydro-2H-3, l-benzoxazin-2-one with bromine to 6,8-dibromo-l, 4-dihydro-2H-3, l- benzoxazin-2-one is reacted, which subsequently reacts further with N-methyl-cyclohexylamine to give bromhexine, the latter being obtained from the reaction mixture as an acid addition salt. 2. The method according to claim 1, characterized in that the reaction with N-methyl-cyclohexylamine is carried out in solution in N-monomethylformamide.