FI60551B - NYTT FOERFARANDE FOER FRAMSTAELLNING AV 2-AMINO-BENZYLAMINER - Google Patents

Description

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Patent- oeh registerstyrelsen '' Ansök * »utltgd och uti.« KrifMn pubikend 30.10.81 (32) (33) (31) Pyydetty atuelkau * —Begird prloritet 08.09 · 7 3

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 23 ^ 5 ^ 3.5 (71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, D-7950 Biberach /

Riss, Federal Republic of Germany-Förbundsrepubliken lyskland (DE) (72) Johannes Keck, Biberach / Riss, Gerd Kruger, Biberach / Riss, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (jb) Leitzinger Oy (5 * 0 New method 2- for the preparation of amino-benzylamines - Nytt förfarande för framställning av 2-amino-benzylaminer

The invention relates to a new process for the preparation of 2-amino-benzylamines of the general formula I

Shark where

Hai is a bromine or chlorine atom, is a hydrogen or bromine atom, R2 is a cyclohexyl, hydroxycyclohexyl or morpholinocarbonylmethyl group and is a hydrogen atom or a methyl group, their physiologically acceptable salts with inorganic or organic acids, and methods for their preparation with 2,605,5 properties, in particular a secretolytic and / or cough suppressant effect.

It has now surprisingly been found that the compounds of the above general formula I can be prepared in excellent yields by reacting a compound of the general formula II - O - R4 (II)

Shark where

Hai and have the same meaning as above and R4 is a methyl or phenyl group, to react in a solvent and at a temperature of 140-220 ° C with an amine of the general formula III ^ R3 H - N (III) * 2 wherein R2 and R3 have the same meaning as above.

The solvent used in the reaction is preferably xylene or tetralin, however, an excess of amine is most preferred.

The starting compounds of the formula II are obtained, for example, from the corresponding acylated benzyl halides and alkali metal salts of phenols or methanol, followed by cleavage of the acyl groups.

The compounds of the general formula I obtained can, if desired, be subsequently converted into their physiologically acceptable salts with inorganic or organic acids. Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid or maleic acid have proved to be suitable acids.

The ethers used as starting material are new.

U.S. Pat. Nos. 3,605,531,336,306, 3,661,903 and 3,536,713 describe methods in which 2-diacylamino-benzyl halides are reacted with the corresponding amines, whereby the acyl group used as a protecting group is finally cleaved. However, such a method gives a total yield of only 18% (Liebigs Ann. Chem. 682, 171-177 (1963)). However, the process according to the invention surprisingly gives a yield of about 84% of theory. This high yield is surprising, especially considering that the ether group contained in the starting material of the invention is generally considered to be considerably less reactive than the halogen atom contained in the starting material of the known process. In addition, it has been hypothesized that aminolysis can in practice only be performed with lower ethers (Houben-Weyl, Band XI, 1, pages 122-126).

The following examples illustrate the invention.

Example 1.

2-Amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine a) (2-Amino-3,5-dibromo-benzyl) -phenyl ether 19.7, phenol and 12.5 g of potassium hydroxide are dissolved in 0, 2 liters of absolute ethanol and added dropwise over 20 minutes to a boiling mixture of 85.6 g of 2-diacetylamino-3,5-dibromo-benzyl bromide in 0.5 liters of absolute ethanol. The mixture is refluxed for 2 hours, whereupon the benzyl bromide dissolves and the potassium bromide precipitates. After cooling, the inorganic precipitate is filtered off with suction, 100 ml of 10N sodium hydroxide are added to the filtrate and the mixture is refluxed for a further 15 hours. The reaction mixture is then filtered and the filtrate is evaporated. To the residue is added 0.5 liters of water and shaken twice with chloroform. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel using chloroform to give (2-amino-3,5-dibromo-benzyl) -phenyl ether in pure form as the upper substance.

The structure is indicated by UV, IR and NMR spectra.

UV maximum: 247 nm and 310 nm IR 3450 cm-1 and 3365 cm-1 1220 cm-1 ether peak NMR 2 aromatic protons: 7.2 and 7.5 ppm 4 60551 5 aromatic protons: 6.8 to 7.4 ppm CH2: 4 .9 ppm NH2: 4.4 ppm b) 2-Amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine 1.0 g (0.0028 mol) of 2-amino-3,5-dibromo benzyl) phenyl ether and 3.2 g (0.028 mol) of N-methylcyclohexylamine are heated for 15 hours at 200 ° C in a sealed vessel. This creates a pressure of about 5 at. The reaction solution is then taken up in chloroform, shaken three times with water, dried over sodium sulfate and evaporated. The residue is dissolved in a small amount of absolute ethanol, acidified with ethanolic hydrochloric acid and ether is added until 2-amino-N-cyclohexyl-3,5-diboron-N-methyl-benzylamine hydrochloride begins to crystallize.

Yield: 0.97 g (84.0% of theory)

Melting point: 233-234.5 ° C (decomposes).

Example 2 2-Amino-3,5-diboro-N- (trans-4-hydroxy-cyclohexyl) -benzylamine

Melting point of the hydrochloride: 233-234.5 ° C (decomposes).

Prepared according to Example 1 from (2-amino-3,5-dibromo-benzyl) -phenyl ether and trans-4-amino-cyclohexanol.

Example 3 2-Amino-6-chloro-N-methyl-N- (morpholinocarbonylmethyl) -benzylamine

Melting point: 116-118 ° C.

Prepared according to Example 1 from (2-amino-6-chloro-benzyl) -methyl ether and sarcosine morpholide.

Claims (1)

A new process for the preparation of 2-aminobenzylamines of the general formula I Hal in which Hal is a bromine or chlorine atom, R 1 is a hydrogen or bromine atom, R 2 is a cyclohexyl, hydroxycyclohexyl or morpholinocarbonylmethyl group and R 3 is a hydrogen atom or a hydrogen atom their physiologically acceptable salts with inorganic or organic acids, characterized in that the (2-amino-benzyl) ether of the general formula II is CH 2 -O-R 4, -cr / V NH 2 Hal in which Hal and R 1 have the same meaning as above and R 4 is a methyl or phenyl group, is reacted in a solvent and at a temperature of 140 to 200 ° C with an amine of the general formula I 1 R 3 H to N wherein R 2 and R 3 are as defined above, and if desired the compound of the formula I obtained is converted into a physiologically acceptable salt of an inorganic or with an organic acid.