DE2345443C3 - Process for the preparation of 2-amino-benzylamines - Google Patents

Description

CH, -N

R ₁

SA

Hai NH,

CH, -O-R ₄

χΛ

Hal NH,

in the form of a bromine or chlorine atom, Ri is a hydrogen atom , R _{2 is} a cyclohexyl or hydrocycloh. xyl or morpholinocarbonylmethyl radical ur-d R denotes a hydrogen atom or a methyl group, characterized in that II is a compound of the general formula I!

in which Hal and R are as defined at the outset, and R _{4 is} a methyl or phenyl group, with an amine of the general formula III

H-N

(Uli

Shark

CH ₂ -OR ₄

NH ₂

R,

(H)

in which Hal and R _{1 are} as defined at the outset and R ₄ denotes a meth_1 or phenyl group with an amine of the general formula III

H-N

(III)

in which R ₂ and R _{3 have} the abovementioned meanings, the reaction is carried out at temperatures between 140 and 220.degree.

In USA patents 33 36 308, 35 36 713 and 37 12 924, inter alia, 2-aminobenzylamines of the general formula I.

CH, - N

R,

Hal NH ₂

in which Hai is a bromine or chlorine atom, R _{1 is} a hydrogen or bromine atom, R _{2 is} a cyclohexyl, hydroxycyclohexyl or morpholinocarbonylmethyl radical and R _{3 is} a hydrogen atom or a methyl group, their physiologically acceptable salts with inorganic or organic acids and processes for their Described production, in which R ₂ and R _{3 have} the abovementioned meaning, can be produced at temperatures between 140 and 220 ° C.

It can also be used in a solvent such as xylene or tetrahydronaphthalene, if appropriate in the presence an acidic catalyst such as ammonium chloride or p-toluenesulfonic acid work. Preferably the reaction takes place in an excess of the amine used under normal or increased Pressure.

The starting compounds of the general formula II obtained, for example, from the corresponding acetylated benzyl halides and the alkali

salts of phenol or methanol and subsequent cleavage of the acyl groups.

The ethers used as starting materials are new.
The following examples are intended to illustrate the invention

explain in more detail. Example A describes the preparation of a phenyl ether used as a starting material.

Example A.
(2-Amino-3,5-dibromobenzyl) -pheny! Ether

19.7 g of phenol and 12.5 g of potassium hydroxide are dissolved in 0.2 l of absolute ethanol and used within 20 minutes to a boiling mixture of 85.6 g

2 -diacetylamino-3,5-dibromobenzyl bromide in 0.51 dripped with absolute ethanol. The mixture is 2 hours

(1) the refluxed, with the benzyl bromide

goes into solution and potassium bromide precipitates. After cooling, the inorganic precipitate is sucked off off, the filtrate is mixed with 100 ml of 10n sodium hydroxide solution and reflux for a further 15 hours. The reaction mixture is then filtered and the filtrate was concentrated. The residue is mixed with 0.5 l of water and shaken twice with chloroform out. The organic phase is dried with sodium sulfate and concentrated. The residue it is chromatographed on silica gel with chloroform, 37 g. (52% of theory) (2-amino

Ί>

3,5-dibromo-benzyl) -phenyl ether in pure form as oily substance receives.

Structure proof by UV, IR and NMR spectra.

UV maxima at 247 and 310 nm.

IR spectrum: bands at 3450 and 3365 cm " ¹ (-NH ₂ ) and 1220 cm"'(ether band).

Nuclear Magnetic Resonance Spectrum: 2 aromatic protons at 7.2 and 7.5 ppm, 5 aromatic protons at 6.8 to 7.4 ppm, CH ₂ at 4.9 ppm, NH ₂ at 4.4 ppm.

example 1

2-Amino-N-cyclohexyl-3,5-dibromo-N-methylbenzylamine

1.0 g (0.0028 mol) (2-amino-3,5-dibromobenzyl) phenyl ether and 3.2 g (0.028 mol) N-methyl-cyclohexylamine are heated ^{to 200 ° C. in a closed vessel for 15 hours.} This creates a pressure of around 5 atmospheres. The reaction solution is then taken up in chloroform, extracted three times with water, dried with sodium sulfate and concentrated. The residue is dissolved in a little absolute ethanol, acidified with ethanolic hydrochloric acid and ether is added until the 2-amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine-hydrochloride begins to crystallize.

Yield: 0.97 g (84.0% of theory). Melting point: 233 to 234.5 ° C (decomposition).

Example 2

2-Amino-3,5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine

ίο Analogously to Example 1, (2-amino-3,5-dibromobenzyl) phenyl ether is obtained and trans-4-amino-cyclohexanol 2-amino-3,5-dibromo-N- (trans-4-hydroxycyclohexylj-benzylamine hydrochloride. Melting point: 233 to 234.5 ° C (decomposition).

• 5 Yield: 71% of theory.

Example 3

2-Amino-6-chloro-N-methyl-N- (morpholinocarbonyl-methyl) -benzylamine

Analogously to Example 1, 2-amino-6-chloro-N-methyl-N- (morpholino-carbonylmethyl) -benzylamine is obtained from (2-amino-6-chlorobenzylmethyl) ether and sarcosine morpholide.
Melting point: 116 to 118 ° C.
Yield: 76% of theory.

Claims (1)

Claim: Process for the preparation of 2-amino-benzyI-amines of the general formula I. which have valuable pharmacological properties, in particular secretolytic and / or antitussive effects. It has now surprisingly been found that the compounds of the above general Formula 1 also by reacting a compound of the general formula II