IE49820B1 - 3,1-benzoxazine-2-one derivative and process for the production of bromhexin - Google Patents

Abstract

N-(2-amino-3,5-dibromobenzyl)- N-methyl-cyclohexylamine, the hydrochloride of which has the formula is prepared by brominating 1,4- dihydro-2H-3,1-benzoxazin-2-one with free bromine to form the hitherto unknown intermediate 6,8-dibromo- 1,4-dihydro-2H-3,1-benzoxazin-2- one, and reacting this with N-methyl- cyclohexylamine to bromhexin. Preferably, the reaction takes place by heating in N-monomethylformamide to the boiling point of the latter.

Description

The invention relates to a novel process for the production of bromhexin, a non-proprietory name for N(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylamine, which is a known compound having a mucolytic and cough5 relieving effect, and to an intermediate for use in the process .

Different methods of producing bromhexin are known and described in the Danish Patents Nos. 101,066, 101,301, 101,795, and 119,408, in the Danish published patent spe10 cifications Nos. 135,499, 135,574, and 135,680, and DE-OS 2,273,193.

These known methods have disadvantages either in the form of needing temporary protective measures for non-reacting substituents or in difficultly accessible starting materials or costly reduction agents, and common to all of them is that the disadvantages result in reduced yields.

The object of the invention is to provide a process for the production of bromhexin, in which the said dis20 advantages are avoided, and the bromhexin is recovered in a high yield and extremely pure.

In the process of the invention, l,4-dihydro-2H3,l-benzoxazin-2-one is reacted with free bromine to give 6,8-dibromo-l,4-dihydro-2H-3,l-benzoxazin-2-one, which is then reacted with N-methyl-cyclohexylamine to form bromhexin, the latter being recovered as an acid addition salt from the reaction mixture. - 3 The reactions take place according to the following scheme of reactions: bromhexin acid addition <-Bromhexin salt The starting material I is a known compound, which can be prepared from o-aminobenzyl alcohol by condensation with for example phosgene.

The hitherto unknown intermediate II is a white, crystalline compound being slightly soluble in water and melting at 218-220°C.

In a preferred embodiment of the process, the reaction with N-methylhexylamine according to the invention takes place in solution in N-monomethylformamide, since hereby a yield of up to 90% is obtained by the reaction.

The process of the invention is illustrated by the following Examples.

Example 1 To a solution of 9.0 g (0.0604 mole) of 1,4-dihydro2H-3,l-benzoxazin-2-one in 40 ml of glacial acetic acid were added 60.9 g (0.38 mole) of bromine, whereby the - 4 temperature increased from 24° to 74°C. The reaction mixture was left to cool to room temperature and was then poured into 500 ml of water, whereby a precipitation of the brominated benzoxazinone took place. The precipitate was filtered off and washed on the filter, first with water, then with a weak solution of sodium hydrogen sulphite and finally with hexane.

The excess bromine could be recovered from the parent lye and washwater by distillation.

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

A mixture of 3.07 g (0.010 mole) of the recovered 6,8-dibromo-l,4-dihydro-2H-3,l-benzoxazin-2-one and 4.52 g (0.040 mole) of N-methy1-cyclohexylamine in 10 ml of N-monomethylformamide was heated with stirring and refluxing for 2 hours on a 210°C hot oil bath. After cooling, the mixture was poured into 70 ml of water, and concentrated hydrochloric acid was added until acid reaction.

By cooling in ice-water with stirring, N-(2-amino3,5-dibromobenzyl)-N-methyl-cyclohexylammonium chloride (bromhexin hydrochloride) crystallized and was filtered off after one hour, washed with water, and dried. The yield was 3.7 g (8.97 millimoles), corresponding to 89.7% of the theoretical yield. The melting point was 232233.5°C, and the compound was analytically pure.

Example 2 A mixture of 1.65 g (5.4 millimoles) of the 6,8dibromo-l,4-dihydro-2H-3,l-benzoxazin-2-one of Example 1 and 2.4 g (21 millimoles) of N-methy1-cyclohexylamine in 10 ml of diethyleneglycol was heated for 20 hours with stirring and refluxing on a 210°C hot oil bath. After cooling, 150 ml of water were added, and then hydrochloric - 5 acid was added until acid reaction, after which the mixture was heated to reflux temperature. To the boiling mixture were added 10 ml of ethanol and active carbon, after which clear filtration at reflux temperature was carried out.

The filtrate was cooled in ice-water, whereby N-(2amino-3,5-dibromobenzyl)-N-methyl-cyclohexylammonium 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), corresponding to 49.4% of the theoretical yield.

Claims (4)

1. Process for the production of bromhexin, characterized in that l,4-dihydro-2H-3,l-benzoxazin-2-one is reacted with free bromine to form 6,8-dibromo-l,4-di5 hydro-2H-3,l-benzoxazin-2-one, which is then reacted with N-methyl-cyclohexylamine to form bromhexin, which is recovered from the reaction mixture as an acid addition salt.

2. The process of claim 1, in which the reaction with 10 N-methyl-cyclohexylamine takes place in solution in Nmonomethylformaraide.

3. 6,8-Dibromo-l,4-dihydro-2H-3,l-benzoxazin-2-one.

4. Process for the production of bromhexin, substantially as herein described in Example 1 or Example 2.