FI68808C - FOERFARANDE FOER FRAMSTAELLNING AV BROMHEXIN OCH EN NY DIBROMFOERENING FOER ANVAENDNING SOM MELLANPRODUKT VID FOERFARANDET - Google Patents

Description

rRl M1. ADVERTISEMENT ΑποΠο B 11 UTLÄGGNINGSSKRIFT OOoUo C (45) Patents granted 11.11.1985 Patent meddelat (51) Kv.lk.4 / lnt.Cl. * C 07 C 87/60, C 07 D 265/18 FINLAND —FINLAND (21) Patent application - Patentansökning 801 705 (22) Filing date - Ansökningsdag 2 7.05.80 (23) Starting date - Giltighetsdag 27.05.80 (41) Made public - Blivit offentlig Q2 12 80

National Board of Patents and Registration Date of publication and publication. - n7 fic

Patent- och registrstyrelsen '' Ansökan utlagd och utl.skriften publicerad y I .u / .05 (32) (33) (31) Privilege requested — Begärd priority 01 .06.79 01.06.79 Denmark-Danmark (DK) 2300/79, 2301/79 (71) A / S GEA, 89, Holger Danskevej, 2000 Kdbenhavn F, Denmark-Danmark (DK) (72) Bdrge Alhede, Greve Strand, Niels Gelting, Hvalsd,

Herbert Preikschat, Birkertfd, Denmark-Danmark (DK) (7 * 0 Oy Kolster Ab (5 ^) Process for the preparation of bromhexine and a new dibromo compound used as an intermediate in the process the method,

The invention relates to a new process for the preparation of bromohexine, i.e. N- (2-amino-3,5-dibromobenzyl) -N-methylcyclohexylamine, and to a novel dibromo compound used as an intermediate in the process. Bromhexine is a known mucolytic and cough irritant.

Several different processes for the preparation of bromhexine are known from the Danish patent publications DK 101066, DK 101301, DK 101795 and DK 119408 and from the published publications DK 135499, DK 135574 and DK 135680 and from the German application DE 2273193.

All of these known methods of preparation have their drawbacks, which are either related to the temporary protection of unreacted substituents, difficult-to-obtain starting materials or expensive reducing agents, and all of these methods have in common that the drawbacks lead to reduced yields.

2 68808

A new process for the preparation of bromohexine has now been invented which avoids the above-mentioned disadvantages and which gives bromohexine in high yield and in high purity.

The invention relates to a process for the preparation of N- (2-amino-3,5-dibromobenzyl) -N-methylcyclohexylamine (bromohexine) of the formula A-, "XX / \

ch \ VcY

characterized in that 1,4-dihydro-2H-3,1-benzoxazin-2-one of the formula ocv H 2 is reacted with free bromine in glacial acetic acid or another suitable solvent, the reaction being initiated at room temperature or at a slightly elevated temperature, followed by 6,8-dibromo-1,4-dihydro-2H-3,1-benzoxazin-2-one of the formula

Br H

^ C = 0

1 1 II

H 2 is reacted with N-methylcyclohexylamine of the formula ch3nh-111 3 68808 at elevated temperature and in the presence of an acid and preferably an inert solvent to give bromohexine which is recovered from the reaction mixture in the form of an acid addition salt.

The reactions take place according to the following reaction scheme: f f Ϊ1 YVN Ί = 0 —Br2_ ^ YVN "'p-0 ch3cooh x

I II

Br, - ·. X NH -HCl CH0-NH- <H \ 2

3 -------- .. I I

HCl ^ - <T H

2 I X - CH3 bromohexine, hydrochloride The starting material I is a known compound which can be prepared from o-aminobenzyl alcohol by condensation with, for example, phosgene.

Intermediate II is a new dibromo compound which is poorly soluble in water and forms white crystals which melt at 218-220 ° C.

In a preferred embodiment, the reaction with N-methylhexylamine is performed in a solution of N-monomethylformamide to give up to 90% yield.

The method according to the invention is illustrated by the following examples.

Example 1

To a solution of 9.0 g (0.0604 moles) of 1,4-dihydro-2H-3,1-benzoxazin-2-one in 40 ml of glacial acetic acid was added 60.9 g (0.38 moles) of bromine. whereby the temperature rose from 24 ° C to 74 ° C. The reaction mixture was allowed to stand until it had cooled to room temperature and then poured into 500 ml of water, whereupon the brominated benzoxazinone precipitated. The precipitate was filtered and washed as a filter first with water, then with dilute sodium hydrogen sulfite solution and finally with hexane.

4 68808

Excess bromine could be recovered from the mother liquor and washings by distillation.

The yield of brominated benzoxazinone was 16.5 g (0.0537 moles), corresponding to 89% of theory. The melting point was 218-220 ° C and thin layer chromatographic analysis showed no impurities.

A mixture of 3.07 g (0.010 moles) of 6,8-dibromo-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4.52 g (0.040 moles) of N-methylcyclohexylamine obtained In 10 ml of N-monomethylformamide, heated under stirring and refluxing for 2 hours in an oil bath at 210 ° C. After the reaction mixture was cooled, it was poured into 70 ml of water and concentrated hydrochloric acid was added until the acidic reaction.

Upon cooling in ice water with stirring, N- (2-amino-3,5-dibromobenzyl) -n-methyl-cyclohexylammonium chloride (bromohexine hydrochloride) crystallized, which was filtered off after one hour, washed with water and dried.

The yield was 3.7 g (8.97 nmoles), corresponding to 89.7% of theory. The melting point was 232-233.5 ° C and the material was analytically pure.

Example 2

A mixture of 1.65 g (5.4 mmol) of 6,8-dibromo-1,4-dihydro-2H-3,1-benzoxazin-2-one obtained in Example 1 and 2.4 g (21 nmoles) of N-methylcyclohexylamine in 10 ml of diethylene glycol, was heated with stirring and refluxed for 20 hours in an oil bath at 210 ° C. After cooling, 150 ml of water and concentrated hydrochloric acid were added until the acid reaction was reacted, after which the mixture was heated to reflux. To the boiling mixture were added 10 ml of ethanol and activated carbon, after which it was filtered clear at reflux temperature.

The filtrate was cooled in ice water, whereupon N- (2-amino-3,5-dibromobenzyl) -N-methylcyclohexylammonium chloride crystallized.

The material was filtered off and washed with water. The yield of analytically pure material was 1.1 g (2.67 nmoles), corresponding to 49.4% of theory.

Claims (5)

68808 A process for the preparation of N- (2-amino-3,5-dibromobenzyl) -N-methyl-cyclohexylamine (bromohexine) of the formula Br j 2 -'AAcvt, Q characterized in that 1,4-dihydro-2H- 3,1-Benzoxazin-2-one of the formula H N-co H 2 is reacted with free bromine in glacial acetic acid or another suitable solvent to initiate the reaction at room temperature or at slightly elevated temperature, followed by 6,8-dibromo-1 , 4-dihydro-2H-3,1-benzoxazin-2-one of formula n Br y | I ΑΛΓ -o ii Br 2 C H 2 is reacted at elevated temperature and in the presence of an acid and preferably an inert solvent with N-methylcyclohexylamine of the formula ch3nh-Q 1 6 68808 to give bromohexine which is recovered from the reaction mixture in the form of an acid addition salt. in terms of. Process according to Claim 1, characterized in that the reaction with N-methylcyclohexylamine takes place in N-monomethylformamide. Dibromo compound for use as an intermediate in a process according to claim 1 or 2, characterized in that it is 6,8-dibromo-1,4-dihydro-2H-3,1-benzoxazin-2-one of the formula Br H Nx = o il II Br I H2 II 7 68808 A process for the preparation of N- {2-amino-3,5-dibromobenzyl) -N-methylcyclohexylamine (bromhexine) with the formula Br '1 ^ CH3 is converted to 1,4-dihydro-2H-3,1 -benzoxazin- 2-one with the formula H Y'v Nvc = o I 1 'r h2 omsätts i isättika eller et etan lampiigt lösningsmedel med fritt Brom, varvid omsättningen inleds vid rumstemperatur ellot face face temperature, varefter den erhällna 6,8-dibrom -1,4-Dihydro-2H-3,1-benzoxazin-2-one in the form of Br HII II Br- ^ YY ^ fO U2 is present at the temperature and in the nerve and at the same time as inert solvents with N-methylcyclohexylamine. formeln ch3nh ____ / \ III