FI60552C - NYTT FOERFARANDE FOER FRAMSTAELLNING AV 2-AMINO-3,5-DIBROM-BENZYLAMINER - Google Patents

Description

rSSr ^ I [B] (11) MOON, LUTU * | ISSUE 605 5?

LJ 1 'UTLÄGGNINGSSKRIFT

C / ^ tj \ Patent aiytrin, tty! .J vt I f t Patent neddelat 'S *' (51) Kv.ik? /Int.ci.3 c 07 C 87/60

FINLAND - FINLAND (21) '' »« '«»' • Kemut - PatantanaBknlng 2U7I / 7U

(22) Hakaml * pllvl - Anaöknlngadag 22.0Ö.7U

(23) Alkupilvl - Glfclghatadag 22.08.7U

(41) Tullut julkltektl - Bllvit offentllg 20.07.75

National Board of Patents and Registration .... ..... ...,. .....

* (44) Date of dispatch and of issue of the flag. -

Patent · och registerstyrelsen Ansökin utiagd och uti.tkriften pubik <rad 30.10.81

(32) (33) (31) Privilege claimed— Begird prlorltet i9.Ol.7U

Federal Republic of Germany-Federal Republic of Germany (DE) P 2U02577-2 (71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, D-7950 Biberach an der Riss, Federal Republic of Germany-Förbundsrepubliken lysklandCDE) (72) Johannes Reck, Biber , Biberach / Riss, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (7U) Leitzinger Oy (5U) A new process for the preparation of 2-amino-3,5-dibromo-benzylamines of general formula I - Nytt förfarande för framställning av 2-amino- 3,5-Dibromo-benzylaminer

The invention relates to a new process for the preparation of 2-amino-3,5-dibromobenzylamines of the general formula I / R

Bry ^ Y ch2 "n \ r 1 x 2 ™ nh2

Br having a hydrogen atom or a methyl group, r2 is a cyclohexyl or hydroxycyclohexyl group and their physiologically acceptable salts with inorganic or organic acids.

The compounds described above are known e.g. from British Patent Publication Nos. 968,254 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. However, according to the literature (Liebigs Ann. Chem. 682, 171-177 (1963)) 2 60552, such a method gives a poor yield of as little as 18%. On page 175 of the above-mentioned work, it is mentioned that in the preparation of N-13R 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 2-amino-3,5-dibromo-benzyl derivative of the general formula II

Brx ^ \ / CH2 - X

T jT (ID

NH

I 2 wherein Br X is a tri (lower) alkylammonium or pyridinium group is reacted with an amine of general formula III 1 R 1 H - N (III) wherein

R 1 and F 2 have the same meaning as above, at a temperature above 100 ° C, preferably at 140-160 ° C, and the compound of general formula I obtained is, if desired, subsequently converted into its physiologically acceptable acid addition salts with inorganic or organic acids.

The reaction is best carried out in excess of the amine of general formula III used. However, the reaction can also be carried out without a solvent.

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 and maleic acid have proved to be suitable acids.

The compounds of general formula II used as starting materials can be quenched, for example, by reacting the corresponding benzylamine with a corresponding alkylating agent such as methyl iodide or by reacting the corresponding benzyl halide with pyridine.

The process according to the present invention is surprising, since it is known from the literature (see Houben-Weyl XI, Part 2, p. G33) that quaternary ammonium compounds are quite strong alkylating agents. Thus, virtually quantitative yields of the attached method were not expected.

The following examples further illustrate the invention:

Example 1 2-Amino-3,5-dibromo-N- (trans-4-hydroxy-cyclohexyl) -benzylamine 4.5 g (0.01 mol) of N- (2-amino-3,5-dibromo-benzyl) -trimethylammonium iodide and 10 g of trans-4-aminocyclohexanol are heated for 1 hour at 150 ° C. The reaction mixture is then cooled slightly, chloroform and 2N sodium hydroxide are added and shaken vigorously. The organic phase is separated and the alkaline phase is shaken once more with chloroform. The chloroform phase is dried over sodium sulfate and evaporated in a water pump vacuum. The residue is dissolved in absolute ethanol and a small amount of ether and acidified with ethanolic hydrochloric acid, followed by crystallization of 2-amino-3,5-dibromo-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride.

Yield: 3.9 g (94.0% of theory);

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

Example 2 2-Amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine Melting point of the hydrochloride: 232-235 ° C (decomposes).

Prepared according to Example 1 from N- (2-amino-3,5-dibromo-benzyl) -trimethylammonium iodide and N-methyl-cyclohexylamine. Yield: 92.7% of theory.

60552 4

Example 3 2-Amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine 75 g of N- (2-amino-3,5-dibromo-benzyl) -pyridinium bromide and 20 ml of N-methyl-cyclohexylamine are heated 3 hours at 140 ° C. After cooling, the reaction mixture is diluted with water and extracted with chloroform. The organic phase is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo, the oily evaporation residue is dissolved in absolute ethanol and precipitated as the hydrochloride with ethanolic hydrochloric acid. 5.94 g (81%) of N-cyclohexyl-3,5-dibromo-N-methyl-benzylamide hydrochloride are thus obtained. melting point: 233-234.5 ° C (decomposes).

Example 4 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 3 from N- (2-amino-3,5-dibromo-benzyl) -pyridinium bromide and trans-4-amino-cyclohexanol. Yield: 87.5% of theory.

Claims (1)

A new process for the preparation of 2-amino-3,5-dibromo-benzylamines of the general formula I / R 1 Br CH- - N YY R 2 (i) nh 2 Br wherein R 1 is a hydrogen atom or a methyl group, R 9 is a cyclohexyl or hydroxycyclohexyl group and their physiologically acceptable salts with inorganic or organic acids, characterized in that the 2-amino-3,5-dibromo-benzyl derivative of the general formula II CHo "x TT NH2 Br in which X is a tri (lower) alkylammonium or pyridinium group is reacted With an amine of formula III -R1H-N (III) ^ R2 wherein R1 and R2 have the same meaning as above, at a temperature above 100 ° C, preferably at 140-160 ° C, and the resulting compound of general formula I is subsequently physiologically modified if desired suitable for their acid addition salts with inorganic or organic acids.