FI63215C - PROCEDURE FOR THE PRODUCTION OF HYDROXYHALOGENBENYLAMIN DERIVATIVES WITH HOSTSTILLAND SECURITY AND PRODUCTION AVAILABLE IN THE FACTORY - Google Patents

Description

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Federal Republic of Germany Förbundsrepubliken Tyskland (DE) P 21 + 03511-8 (71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, D-7950 Biberach an der Riss, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Johannes Keck, Bi Riss, Gerd Kruger, Biberach / Riss,

Klaus-Reinhold Noll, Warthausen-Oberhofen, Helmut Pieper, Biberach / Riss, Federal Republic of Germany-Germany (7I +) Leitzinger Oy (5I +) Method for the preparation of hydroxyhalobenzylamine derivatives - Addition to the patent 62051 - Addition to the patent 62051 - Addition to the patent 62051

The invention relates to a process for the preparation of hydroxy-halobenzylaridine derivatives according to patent application 3254/73 having a cough-relieving, secretolytic and surfactant-promoting effect, which compounds of general formula I

'£ T <-

where (Hai) 1 OH

Hai is a chlorine or bromine atom, is a hydrogen, chlorine or bromine atom, 1 * 2 is a branched alkyl group having 3 to 5 hydroxyl groups optionally substituted by 3 to 5 carbon atoms, or a group of the formula 2,6321 5 (0ΗΛ k wherein R 1 is a hydrogen atom, a hydroxy group or an alkyl group having 1 to 1 carbon atoms, n is a number 0, 1 or 2, R 1 is a straight-chain or branched alkyl group having 1 to U carbon atoms, a 2-k carbon alkenyl group , a cycloalkyl group having 3 or U carbon atoms, or also a hydrogen atom if there is no hydrogen atom or a branched alkyl group having 3 to 5 carbon atoms optionally substituted by 1 to 3 hydroxyl groups, and 1 is a number 1 or 2, and their physiologically acceptable acid addition salts with inorganic or organic acids and their production methods.

The compounds of the above general formula 1 and their physiologically acceptable acid addition salts have valuable pharmacological properties, in particular, in addition to an increasing effect on the formation of alveolar surfactant or antiatelectase factor, a secretolytic or antitussive effect.

Surprisingly, it has now been found that the compounds of the above general formula I can also be prepared in excellent yields by the following method:

A compound of general formula II 3 6321 5 '' Vy · "* is obtained.

M

(Hal) i OH

wherein R 1, Hal and 1 are as defined above and R 6 is an amino group, which may be optionally mono- or disubstituted, a trialkylammonium or pyridinium group, to react with an amine of general formula III H 2 N - (III)

Xr4 wherein R2 and R1 are as defined above.

In the above general formula, the group Rg represents in particular an amino, methylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, trimethylammonium, triethylammonium, methyldiethylammonium or pyridinium group. The process according to the appended application can thus be carried out with all the groups Rg which allow the formation of the intermediate benzyl cation from the compound of the above general formula II.

The reaction is best carried out in excess of the amine of general formula III used, optionally in the presence of a catalytic amount of an acid such as hydrochloric acid or sulfuric acid, or a metal salt or iodine, at temperatures between 0 and 180 ° C, but most preferably between 100 and 160 ° 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. Suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid or maleic acid.

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

The following examples further illustrate the invention:

Example 1 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine 10 g of 3,5-dibromo-N, N-dimethyl-2-hydroxy-benzylamine hydrochloride and 30 g of trans -4-Amino-cyclohexanol is heated at 160 ° C for 1 hour. The reaction mixture is then allowed to cool, diluted with water and the precipitate is filtered off with suction. The obtained crude base is dissolved in isopropanol and acidified with ethanolic hydrochloric acid to crystallize 3,5-dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride.

Melting point: 212-218 ° C (decomposes).

Example 2 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine-4.5 g of N- (3,5-dibromo-2-hydroxy-benzyl) -trimethylammonium iodide and 8 g of trans -4-Amino-cyclohexanol is heated at 160 ° C for 15 minutes. The cooled reaction product is treated with water and the precipitate is filtered off with suction. When the crude base is dissolved in isopropanol and acidified with ethanolic hydrochloric acid, 3,5-dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride is obtained.

Melting point: 212-218 ° C (decomposes).

Example 3 N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine Hydrochloride melting point: 193-194 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-N, N-dimethyl-2-hydroxy-benzylamine hydrochloride and N-ethyl-cyclohexylamine.

5 6321 5

Example 4 3,5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine Melting point of the hydrochloride: 216-218 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-N, N-dimethyl-4-hydroxy-benzylamine hydrochloride and cis-3-aminocyclohexanol.

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

Hydrochloride melting point: 212-218 ° C (decomposes).

Prepared according to Example 2 from N- (3,5-dibromo-2-hydroxy-benzyl) -pyridinium bromide and trans-4-amino-cyclohexanol.

Example 6 N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine Hydrochloride melting point: 193-194 ° C (decomposes).

Prepared according to Example 2 from N- (3,5-dibromo-2-hydroxy-benzyl) -pyridinium bromide and N-ethylcyclohexylamine.

Example 7 3,5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine

Hydrochloride melting point: 216-218 ° C (decomposes).

Prepared according to Example 2 from N- (3,5-dibromo-4-hydroxy-benzyl) -pyridinium bromide and cis-3-amino-cyclohexanol.

The following compounds were prepared according to Examples 1-7: N-ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine Hydrochloride melting point: 180-181 ° C (decomposes).

3-bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine

Hydrochloride melting point: 194-196 ° C (decomposes).

6321 5 6 3-Bromo-5-chloro-N-cyclohexyl-4-hydroxy-N-methyl-benzyl brine Melting point: 136-138 ° C.

3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine Hydrochloride melting point: 187-189 ° C.

3,5-dichloro-N- (dihydroxy-tert-butyl) -4-hydroxy-benzylamine Melting point of the hydrochloride: 166-169 ° C (decomposes).

3,5-Dibromo-2-hydroxy-N-tert-pentyl-benzylamine Melting point of the hydrochloride: 202-206 ° C (decomposes).

3,5-Dibromo-4-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine

Melting point of hydrochloride: 215-215.5 ° C (decomposes).

Naturally, all the compounds of patent application 3254/73 can be prepared by the process of the appended application.

Claims (1)

A process for the preparation of hydroxyhalobenzylamine derivatives according to patent 62051 (patent application 3254/73) having a cough-relieving, secretolytic and surfactant-promoting effect, which compounds have the general formula I and (?) OH Hal is a chlorine or bromine tower, R 1 is a hydrogen, chlorine or bromine atom, R 2 is a branched alkyl group having 3 to 3 carbon atoms optionally substituted by 1 to 3 hydroxyl groups, or a group of the formula R 3 wherein a hydrogen atom , a hydroxy group or an alkyl group having 1 to 4 carbon atoms, n is a number 0, 1 or 2, R 1 is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a cycloalkyl group having 3 or 4 carbon atom, or also a hydrogen atom, if R 1 is not a hydrogen atom or R 7 is a branched alkyl group optionally substituted by 1 to 3 hydroxyl groups having 3 to 5 carbon atoms, and 1 is a number 1 or 2, and their physiologically suitable acid addition salts with inorganic or organic acids, characterized in that the compound of general formula II) Cf% - in which (Hal) OH R 1, Hal and 1 are as defined above and 6321 58 is an amino group which may be optionally mono- or di-substituted , a trialkylammonium or pyridinium group, is reacted with an amine of the general formula III H - N (III) ^ RU in which and R 1 have the same meaning as above, and the resulting compound of the general formula I is subsequently converted, if desired, into a physiologically acceptable acid addition salt with inorganic or organic acids . l62051 I am refining for the production of hydroxyhalobenzylamine according to the following patents · (patent number 325V73) with a host state, a secretolytic and a production of a strong network, which is preferably used in the form of I (V) "8" ^ (I) The halo is chloro- or bromate, R is en Väte-, chloro- or bromate, Rn is unequivocally with 1-3 hydroxyl groups substituted on the alkyl group with L 3-5 cholatomers, or the group with formula (CVn B3 is a vateatom, a hydroxyl group or an alkyl group with a 1-U cholesterol, is not 0, 1 or 2,