FI60550B - NYTT FOERFARANDE FOER FRAMSTAELLNING AV BENZYLAMINER - Google Patents

Description

RSPI [B] (11) MONTH PUBLICATION 60550

MjB l J 1 'UTLÄGGNINGSSKRIFT U

C (45) PaienUi oy: 5r * n · 10 '::' 'Patent meddelat ^ (51) K ».lk.3 / lnt.CI.3 C 07 C 87/60 SUON l - FI m LAN D (21 ) Pat * i * «ll» »k« mi * - P * t «nt» n * öknlng 316/7 ^ (22) Hafcamlsptfvf - Anaöknfngsdag 05 • 02.jh ^ ^ (23) Alkupilvi — Giltlghaudag 05-02.7 ^ (41) Tullut | Küllsakai - Latches offantllg 10.09 · 71 *

Patent and Registration Office ............ . . .

B. . '. (44) Date of signature and earpiece. - _n, n q-,

Patent-och registerstyrelsen Ansftkan utlagd och utl.akrlftan publkarad 30.10.01 (32) (33) (31) Privilege claimed —Begird priority 09 · 0 3 · 73 28.07.73, 28.07 * 73 Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 2311637.2 P 2338U08.9, P 2338U09.0 (71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, D-7950 Biberah /

Riss, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Johannes Keck, Biberach / Riss, Gerd Kriiger, Biberach / Riss, Federal Republic of Germany- Förbundsrepubliken 'I'yskland (DE) (7 * 0 Leitzinger Oy (5 * 0 New method benzylamines - Nytt förfarande för fraraställning av benzylaminer

The invention relates to a new process for the preparation of benzylamines R of general formula I.

ΐχ; -

Hai ^ where

Hai is a chlorine or bromine atom,

R1 is a hydrogen, chlorine or bromine atom, R2 is a hydrogen atom or a methyl group, R3 is a cyclohexyl, hydroxycyclohexyl group or a morpholinocarbonylmethyl group, and their physiologically acceptable salts with inorganic or organic acids.

The compounds described above are known e.g. British Patent Publication Nos. 968,254, 1,098,140 and 1,178,034. These compounds are prepared by reacting a 2-diacylamino-benzyl halide with the corresponding amine and hydrolyzing the resulting 2-acylamino compound.

2 I

60550 daan. However, according to the literature (Liebigs Ann. Chem. 682, 171-177 (1963)), such a method gives a low yield of as little as 18%. On page 175 of the above-mentioned work it is mentioned that in the preparation of N-ε-3,5-dibromo-2-acetamino-benzyl] -pyrrolidine, the yield is 53.5% and the subsequent hydrolysis is 35%. Surprisingly, it has now been found that known compounds can be prepared in significantly better yields according to the invention.

The novel process according to the invention is characterized in that the compound of formula II fX 2 ai) nh,

Hal * wherein R 11 and Hal are as defined above and X is a group of the formula -O-SO 2 -R 4, wherein R 4 suitably represents a methyl or 4-methylphenyl group, a chlorine, bromine or iodine atom or when R 3 is a hydroxycyclohexyl or morpholinocarbonylmethyl group, then X is an organic acyloxy group, is reacted at a temperature of -70 to + 200 ° C with an amine of general formula III / R 2 H - N 2 (III) R 3 wherein R 2 and R 3 are as defined above, in a solvent or using an excess of an amine of the formula III and, if desired, the compound of the general formula I obtained is converted into a physiologically acceptable salt with an inorganic or organic acid.

The reaction takes place in an organic solvent such as ethanol, ether, acetone, tetrahydrofuran, benzene, dioxane, chloroform and carbon tetrachloride, optionally in the presence of an inorganic base such as sodium carbonate or sodium hydroxide, a tertiary organic base such as triethylamine or pyridine, preferably in excess of the amine according to When a tertiary organic base or an excess of an amine of general formula III is used, these can act simultaneously as a solvent.

If X represents a halogen atom, then the reaction is best carried out at temperatures between 0 and 100 ° C. For example, if X represents a 4-methylphenylsulfonyloxy group, the reaction is best carried out at temperatures between -70 and + 50 ° C. If X represents an organic acyloxy group, then the reaction is best carried out at temperatures between 80 and 170 ° C.

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

The starting compounds of general formula II can be prepared from the corresponding benzyl alcohols, which are prepared by reacting the corresponding aldehyde with sodium borohydride, reacting with the corresponding hydrohalic acid, the corresponding sulfonic acid halide in the presence of an acid halide with an organic halide, the corresponding thionyl halide. The starting materials of the general formula II obtained can also be used in the next reaction without isolation.

The novel process of the present invention could not be foreseen because it is known that the ester of general formula II polymerizes in the presence of bases, such as amines of general formula m, and thus is not suitable for use in the presence of bases for other reactions (see e.g. Ber. Dtsch. Chem. Ges. 27, 3509-3525 (1894)). In addition, amides and alcohols are usually formed when amines react with a carboxylic acid ester.

The following examples further illustrate the invention:

Example 1 2-Amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine 10.0 g of 2-amino-3,5-dibromobenzyl alcohol are dissolved in 50 ml of 4,60550 thionyl chloride and allowed to stand overnight. . It is then evaporated to dryness in vacuo at 25 ° C. To the residue is added 10.1 g of N-methyl-cyclohexylamine in 50 ml of absolute ethanol and heated under reflux for 1 hour. The solution is evaporated to dryness. The residue is dissolved in 30 ml of ethanol and acidified with ethanolic hydrochloric acid. The hydrochloride then crystallizes. The yield is 12.6 g (95.7% of theory). Melting point: 232-235 ° C (decomposes).

Example 2 2-Amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine 10.0 g of 2-amino-3,5-dibromo-benzyl alcohol and 100 ml of 4R% hydrobromic acid are heated to 100 ° C. After cooling, it is diluted with water, the precipitate is filtered off with suction and washed with water. This material and 8.7 g of N-methyl-cyclohexylamine and 50 ml of ethanol are then heated at reflux for 30 minutes. The solution is evaporated to dryness. The residue is dissolved in 30 ml of ethanol and acidified with ethanolic hydrochloric acid. The hydrochloride crystallizes. The yield is 9.6 g (65.8% of theory).

Melting point: 232-235 ° C (decomposes).

Example 3 2-Amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine 7.0 g of 2-amino-3,5-dibromo-benzyl alcohol and 1.4 g of sodium hydride (50% dispersion in oil) heated at reflux with stirring for 8 hours in a mixture of 200 ml of absolute ether and 100 ml of absolute tetrahydrofuran: then cool to -70 [deg.] C. and drop by drop 4.75 g of p-toluenesulphonic acid chloride in 100 ml of ether. It is then allowed to slowly warm to -30 ° C and cooled again to -70 ° C. 5.7 g of N-methyl-cyclohexylamine are then added, the cooling bath is removed and stirred until the reaction mixture has reached room temperature. Shake twice with water and evaporate the phase to dryness. For purification, chromatograph on a silica gel column with chloroform / ethyl acetate (10: 1). The corresponding fractions 5 60550 are evaporated, the residue is taken up in ethanol and the hydrochloride is mixed with ethanolic hydrochloric acid. Yield: 2.8 g (27.2% of theory). Melting point: 232-235 ° C (decomposes).

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

Hydrochloride melting point: 233-234.5 ° C (decomposes).

Prepared according to Example 1 from 2-amino-3,5-dibromo-benzyl alcohol, thionyl chloride and trans-4-amino-cyclohexanol.

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

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

Prepared according to Example 2 from 2-amino-3,5-dibromo-benzyl alcohol, hydrobromic acid and trans-4-amino-cyclohexanol.

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

Melting point: 116-118 ° C.

Prepared according to Example 1 from 2-amino-6-chlorobenzyl alcohol, thionyl chloride and sarcosine morpholide.

Example 7 2-Amino-6-chloro-N-methyl-N- (morpholinocarbonylmethyl) -benzylamine

Melting point: 116-118 ° C.

6 60550

Prepared according to Example 2 from 2-amino-6-chlorobenzyl alcohol, 48% hydrobromic acid and sarcosine morpholide.

Example 8 2-Amino-3,5-dibromo-N- (trans-4-hydroxy-cyclohexyl) -benzylamine ___________ 3.5 g (0.01 mol) of butyric acid (2-amino-3,5-dibromo-benzyl) The ester is boiled together with 5.7 g (0.5 mol) of trans-4-amino-cyclohexanol for 2.5 hours under reflux, cooled and dissolved in ether and shaken three times with water. The organic phase is dried over sodium sulfate, concentrated, and the residue is dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid, and ether is added to crystallize the desired compound.

Yield: 2.92 g (77.8% of theory)

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

Example 9 2-Amino-3,5-dibromo-N- (trans-4-hydroxy-cyclohexyl) -benzylamine

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

Prepared according to Example 8 from benzoic acid (2-amino-3,5-dibromo-benzyl ester) and trans-4-amino-cyclohexanol.

Example 10 2-Amino-6-chloro-N-methyl-N- (morpholinocarbonylmethyl) -benzylamine_

Melting point: 116-118 ° C.

Prepared according to Example 8 from benzoic acid (2-amino-6-chloro-benzyl ester) and sarcosine morpholide.

Claims (1)

A new process for the preparation of benzylamines of the general formula I Hal in which Hal is a chlorine or bromine atom, R 1 is a hydrogen, chlorine or bromine atom, R 2 is a hydrogen atom or a methyl group; R 3 is a cyclohexyl, hydroxycyclohexyl group or salts with inorganic or organic acids, characterized in that the compound of formula II A 4-methylphenyl group, a chlorine, bromine or iodine atom or, when R 3 is a hydroxycyclohexyl or morpholinocarbonylmethyl group, then X is an airoane acyloxy group, is reacted at -70 to + 200 ° C with an amine of general formula III / R 2 H - N (III) R 3 wherein r 2 3a r 3 is as defined above, in a solvent or using an excess of an amine of formula lii j If desired, the compound of general formula I obtained is converted into its physiologically acceptable salt with an inorganic or organic acid.