DK150847B - PROCEDURE FOR PREPARING 2-AMINO-BENZYLAMINES - Google Patents

Description

150847

The present invention relates to a particular process for the preparation of 2-amino-benzylamines of the general formula I (see claim) wherein Hal represents 1 2 a chlorine or bromine atom, R represents a hydrogen, chlorine or bromine atom, R 3 represents a cyclohexyl or hydroxycyclohexyl group and R represents a hydrogen atom or a methyl group.

In organic chemistry, it is a widely accepted doctrine that amino-benzaldehydes are highly unstable and prone to self-condensation. Accordingly, they constitute highly unfavorable starting compounds for further turnover (see, e.g., Fieser & Fieser, Organic Chemistry, 3rd Edition 1956, page 688, Reinhold Publishing Corporation, New York, and Houben-Weyl, The Method of Organic Chemistry, 4 Edition, Volume VII / 1, page 408). Thus, the reductive amination of amino-benzaldehydes with formic acid and amines has not been described so far in the literature, especially since it is known from the literature that the lower the yield of formic acid or the corresponding formamide, the greater the yield. the degree of substitution is for the aromatic aldehyde used (see, e.g., Org. Reactions Vol. 5, 309 (1949)).

It is therefore extremely surprising that compounds of general formula I can be prepared in good yields by the process of the invention, characterized by reacting an aldehyde of general formula II (see claim) wherein Hal and R the meaning given above, with an amine of the general formula III (see claim) wherein R and R have the meaning given above, in the presence of formic acid or the corresponding formamide at temperatures between 150 and 250 ° C and, if R a compound of general formula III represents a hydrogen atom, then the reaction mixture obtained is heated with reflux acid, such as 2N hydrochloric acid.

Of course, from the specification of Danish Patent Application No. 2124/73, there is known a process for the preparation of a compound of formula I, namely the secondary amine N- (trans-4-hydroxycyclohexyl) - (2-amino-3,5-dibromobenzyl) -amine which is produced by reduction of the Schiff base N- (2-amino-3,5-dibromobenzylidene) -trans-4-aminocyclohexanol, especially with a complex metal hydride at low temperature. Said Schiff base is prepared by reacting 2-amino-3,5-dibromobenzaldehyde with trans-4-aminocyclohexanol, i.e. compounds which fall under the above formulas II and III respectively. In relation to this known process, however, for the first time, a process of generating benzylamines, namely both secondary and tertiary benzylamines, from a amino-benzaldehyde is disclosed for the first time, whereby at least for the tertiary in the case of amines, there may be no intermediate formation of a Schiff's base.

The reductive amination is optionally carried out in a solvent and conveniently while simultaneously distilling off the formed water. However, it is particularly advantageous when the amine of general formula III and / or formic acid used simultaneously acts as a solvent in the reaction.

The compounds of general formula I obtained, as already described in the literature, can be transferred into their salts with physiologically acceptable inorganic or organic acids. As acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric or maleic acid proved to be suitable.

The aldehydes of general formula II used as starting materials can be prepared by methods known in the literature, e.g. by oxidation of the corresponding benzyl alcohols with brownstone.

Thus, the invention relates to a novel process for the preparation of compounds of general formula I which have valuable pharmacological properties, in particular secretolytic and / or cough-releasing properties.

3 150847

The process according to the invention is further elucidated by the following examples.

Example 1 N- (2-Amino-3,5-dibromo-benzyl) -N-methyl-trans-4-amino-cyclohexanol-hydrochloride.

5 g of 2-Amino-3,5-dibromo-benzaldehyde, 5.75 g of trans-4-methylamino-cyclohexanol and 2 ml of formic acid are heated to 200 ° C for 30 minutes, distilling off the resulting water. Then add the same amount of amine and formic acid and heat for an additional 1.5 hours. The reaction product is dissolved by shaking with 0.5 liters of dilute ammonia and 50 ml of chloroform. The chloroform phase is separated and the aqueous phase is equipped with 50 ml of chloroform. The combined chloroform phases are evaporated to dryness. The residue is dissolved in 30 ml of ethanol and acidified with ethanolic hydrochloric acid. After adding a certain amount of ether, the hydrochloride crystallizes.

Yield: 6.3 g (82% of theory).

Mp: 216.5-217.5 ° C (dec.).

Example 2 N- (2-Amino-3,5-dibromo-benzyl) -trans-4-amino-cyclohexano1-hydrochloride.

5 g of 2-Amino-3,5-dibromo-benzaldehyde, 5.75 g of trans-4-amino-cyclohexanol and 2 ml of formic acid are heated for 30 minutes at 200 ° C, distilling off the resulting water. Then add the same amounts of amine and formic acid and heat for an additional 1.5 hours. The reaction product is dissolved by shaking with 0.5 liters of dilute ammonia and 50 ml of chloroform. The chloroform phase is separated and the aqueous phase is equipped with 50 ml of chloroform. The combined chloroforms are evaporated to dryness. The residue is dissolved in 200 ml of 2N hydrochloric acid, boiled under reflux for some time, decolorized with activated charcoal, made alkaline with concentrated ammonia and shaken twice with 50 ml of chloroform per ml. walk. The combined chloroform phases are evaporated to dryness. The residue is dissolved in 30 ml of ethanol and acidified with ethanolic hydrochloric acid. After adding a certain amount of ether, the hydrochloride crystallizes.

Yield: 4.5 g (60.6% of theory).

Mp: 233-234 ° C (dec.).

Example 3 N- (2-Amino-3,5-dibromo-benzyl) -N-methyl-cyclohexylamine.

This compound is prepared from 2-amino-3,5-dibromo-benzaldehyde and N-methyl-cyclohexylamine in an analogous manner as in Example 1.

Mp. of the hydrochloride: 232-235 ° C (dec.).

Claims (1)

Example 4 N- (2-Amino-3,5-dibromo-benzyl) -N-methyl-cis-3-amino-cyclohexanol. This compound is prepared from 2-amino-3,5-dibromo-benzaldehyde and cis-3-methylamino-cyclohexanol in an analogous manner as in Example 1. of the hydrochloride: 207-208 ° C (dec.). Process for the preparation of 2-amino-benzylamines of the general formula I Hal CHO-N 2 X. R 2 represents Hal, a chlorine or bromine atom, R * represents a hydrogen, chloro-2 or bromine atom, R represents a cyclohexyl or hydroxycyclohexyl group, and R 3 represents a hydrogen atom or one. methyl group, characterized by reacting an aldehyde of the general formula II Hal V ^ GHO / ^^ NH2 II R wherein Hal and R ^ have the meaning given above, with an amine of the general formula III R2 Η - III \ wherein R and R are as defined above, in the presence of formic acid or the corresponding formamide at temperatures between 150 and 250 C and, if in a compound of the general formula III, R 1 is a hydrogen atom, then the obtained reaction mixture with a dilute acid under reflux.