FI67689C - (2-AMINOBENZYL) -PHENYL- ELLER METHYL RADIUM BUTTER PROTECTION VI FRAMSTAELLNING AV 2-AMINO-BENZYLAMINER - Google Patents

Description

^ ', ~ 1 r, _ ANNOUNCEMENT / π / q q [β] (11) UTLAGG Nl NGSSKRIFT 67689 • C (45); I, ·: .- -5 i - 5 ^ ^ ^ (51) Kv.ik. * / Int.ci. «C 07 C 93/14 S UO MI —FI NL AN D (21) Patent application - Patentansökning 800859 (22) Application date - Ansökningsdag 20.03.80 (^ "0 (23) Starting date - Giltighetsdag 02.08.7 ** (41) Has become public - Blivit offentllg 20.03.80

National Board of Patents and Registration Date of publication and hearing publication—

Patent- oeh registerstyrelsen '' Ansökan utlagd och utl.skriften publicerad 31 .01 .85 (32) (33) (31) Pyydetty etuoikeus — Begärd priority 08.09.73

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 23ί * 5 **** 3 · 5 (71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, D-7950 Biberach / Riss, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Johannes Keck, Biberach / Riss, Gerd Kruger, Biberach / Riss,

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (7 * 0 Leitzinger Oy (5 * 0 (2-aminobenzyl) -phenyl or methyl ethers which are intermediates in the preparation of 2-amino-benzylamines - (2-aminobenzyl) -phenyl-eller 2-amino-benzylamine (62) Divided by application 2317/7 ** (patent 60551) -Avdelad fran ansökan 2317/7 ** (patent 60551)

The invention relates to (2-aminobenzyl) phenyl or methyl ethers which are intermediates in the preparation of 2-aminobenzylamines.

The compounds according to the invention are characterized in that their general formula II is CH2-O-R1 * R1-nh2

Shark where

Had is a bromine or chlorine atom, R1 is a hydrogen or bromine atom and R1 is a methyl or phenyl group, or acid addition salts thereof.

The compounds of the formula II according to the invention can be used in the preparation of, for example, those described in U.S. Pat. Nos. 3,336,308, 3,661,903 and 3,536,713, e.g. 2-amino-benzylamines of general formula I 2 R 3 67689 CH. - HI \ r2 7 ^ \ »h2 1

Hal where

Hal is a bromine or chlorine atom, R1 is a hydrogen or bromine atom, E1 is a cyclohexyl, hydroxycyclohexyl or morpholinocarbonylmethyl group and R1 is a hydrogen atom or a methyl group, their physiologically acceptable salts with inorganic or organic acids, in particular compounds having valuable pharmacological properties. secretolytic and / or cough suppressant effect.

When a starting material of formula II is used in the preparation of a compound of formula I, a compound of formula II is reacted with an amine of general formula III H - N (III) \ r 2 wherein

Rg and R2 have the same meaning as above.

When a compound of the formula II is used as starting material, the compound of the formula I is obtained in a higher yield than the methods known hitherto. ,,, 1 *

a compound of formula I. This is surprising because of the ether group-OR

generally not considered a very reactive group. The process is generally carried out at a temperature of 1 to 220 ° C and thus it would have been expected that the starting material of formula II containing the free amino group in the 2-position would have reacted with itself and thus reduced the yield of the desired compound of formula I.

The reaction is conveniently carried out in a solvent such as xylene or tetralin, optionally in the presence of an acid catalyst such as ammonium chloride or p-toluenesulfonic acid, but preferably in excess of the amine used at normal or elevated pressure, at temperatures between 1 ° C and 220 ° C. solvent.

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 obtained compounds of the general formula II 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 following Example 1 illustrates the preparation of a compound of the invention. Examples A-C illustrate the use of a compound of formula II in the preparation of benzylamines of formula I.

Example 1 (2-Amino-3,5-dibromo-benzyl) -phenyl ether 19.7 g of phenol and 12.5 g of potassium hydroxide are dissolved in 0.2 liter 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, at which time 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 aa ”1 and 3365 cm’1 NH

-1 .... d 1220 cm etet peak NMR 2 aromatic protons: 7 * 2 and 7 * 5 ppm 5 aromatic protons: 6.8 - 7 * 4 ppm CH2: 4.9 ppm NH2: 4.4 ppm

Example A

2-amino-N-cyclohexyl-3 * 5-dibromo-N-methyl-benzyl «mTinine 1 * 0 g (0.0028 mol) of (2-amino-3,5-dibromo-benzyl) -phenyl ether and 3, 2 g of 67689 1 * (0.028 mol) of N-methyl-cyclohexylamine are heated at 200 [deg.] C. for 15 hours 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 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-dibromo-N-methyl-benzylamine hydrochloride begins to crystallize.

Yield: 0.97 g (8U, 0% of theory)

M.p .: 233 - 23 ^, 5.5 ^ (decomposes).

Example B

2-Amino-3,5-dibromo-N- (trans-U-hydroxy-cyclohexyl) -benzylamine The hydrochloride m.p. 233 - 23 ^, 5.5 ^ (decomposes).

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

Example C

2-Amino-6-chloro-N-methyl-N- (morpholinocarbonylmethyl) -benzylamine M.p .: 116-118 ° C.

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