DE960634C - Process for the preparation of substituted tropic acid-N- (ª † -picolyl) -amides - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

ISSUED MARCH 28, 1957

GERMAN PATENT OFFICE PATENT LETTERING

CLASS 12 p GROUP 1oi INTERNAT. CLASS C07d

H 17590 IVb 1 12 p

Dr. se. tech. Gerald Rey-Bellet and Dr. phil. Hans Spiegelberg, Basel (Switzerland)

have been named as inventors

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel (Switzerland)

Process for the preparation of substituted tropic acid-N- (γ-picolyl) -amides

Patented in the territory of the Federal Republic of Germany on September 5, 1953 Patent application published September 20, 1956

Grant of patent announced on March 7, 1957 The priority of the application in Switzerland of October 24, 1952 has been addressed

It has been found that substituted tropic acid amides of the general formula

CH ₉

in which R is a methyl, ethyl or allyl group, are valuable medicines. The representatives of this body class are, with low toxicity animals do excellent antispasmodics for humans. The preparations show in particular in the blood pressure test on the cat after cooling, pronounced antiacetylcholine effect.

The new compounds are produced by condensation of tropic acid chloride with methyl, ethyl or Allyl (y-picolyl) amine or by condensation of acetyltropic acid chloride with methyl, Ethyl or allyl (y-picolyl) amine and subsequent treatment with an acid for the purpose of cleavage the acetyl group. With acids they form salts, e.g. B. the hydrochloride that Hydrobromide, the sulfate.

The substituted γ-picolylamines can, for example by reacting ^ halomethylpyridine with methyl, ethyl or allylamine or by

Conversion of N - (ρ - toluenesulfonyl) - 4 - aminomethyl-pyridine be obtained with a methyl, ethyl or allyl halide or the corresponding sulfate and subsequent deacylation.

example 1

To a mixture of 34.3 parts by weight Methyl (7-picoly 1) amine and 28 parts by weight dry pyridine in 225 parts by weight of dry chloroform becomes the crude, 45 parts by weight Acetyltropic acid chloride obtained in tropic acid with stirring and ice water cooling and after admitted. Finally, the mixture is stirred for a further ι hour at 25 °.

Then the chloroform solution is diluted with 200 parts by weight of ether and with 3N hydrochloric acid shaken. The weakly congosaure solution is heated for ι hour on the steam bath, wherein the acetyl group of the reaction product

ao is split. ¹ is filtered through charcoal and treated with excess concentrated ammonia. The condensation product which precipitates is taken up in chloroform, the chloroform solution is dried and evaporated. By dissolving the residue in a mixture of ethyl acetate and low-boiling petroleum ether, the tropic acid-N-methyl-N- (j> -picolyl) -amide is obtained as colorless crystals with a melting point of 101 ° to 10 °. Yield: 70% based on the amide.

Example 2

To a mixture of 48.7 parts by weight of ethyl (i / -picolyl) amine and 36 parts by weight of dry pyridine in 220 parts by weight of dry chloroform, the crude acetyltropic acid chloride obtained from 60 parts by weight of tropic acid is gradually added with stirring and ice-water cooling. Finally, the mixture is stirred at 23 ° for a further 1 hour. The chloroform solution is then diluted with 200 parts by weight of ether and shaken with 3N hydrochloric acid. The weakly congous acid solution is heated for 1 hour on the steam bath, the acetyl group of the reaction product being split off, filtered through charcoal and treated with excess, concentrated ammonia. The condensation product separates out. It is taken up in chloroform, the chloroform dried and distilled off to give the tropic acid-N-ethyl-N - (}> - picolyl) -amide is obtained as a thick oil, which crystallizes after some time and then at 96-97 ⁰ melts. Yield: 78 ¹ vol.

Example 3

To a mixture of 50 parts by weight of allyl (j> -picolyl) amine and 30.5 parts by weight of dry pyridine in 200 parts by weight of dry chloroform, the crude acetyltropic acid chloride obtained from 57.5 parts by weight of tropic acid is slowly added with stirring and ice-water cooling. Finally, the mixture is stirred for 1 1/2 hours at 25 °. The chloroform solution is then diluted with 200 parts by weight of ether and shaken with 3N hydrochloric acid. The weakly congous acid solution is heated on the steam bath for 1 hour in order to split off the acetyl group of the reaction product, filtered through charcoal and treated with excess, concentrated ammonia. The precipitated condensation product is extracted with chloroform, the chloroform solution is dried and evaporated. The tropic acid-N-allyl-N- (γ-picolyl) -amide obtained in this way is a thick oil, the hydrochloride of which melts at 64 to 66 °. Yield: 62%.

Example 4

The crude tropic acid chloride obtained from 33.2 parts by weight of tropic acid is added dropwise with stirring to a mixture of 27.2 parts by weight of ethyl (i <-picolyl) amine and 21 parts by weight of triethylamine ^{1 in 300 parts by weight of dry chloroform.} With an ice water cooled so that the temperature does not exceed 20 ^0th After the reaction has ended, the chlorofm solution is washed with water, diluted with 200 parts by weight of ether and shaken with 3N hydrochloric acid. The hydrochloric acid solution is then filtered through charcoal and excess concentrated ammonia is added in the cold, the tropic acid] Sr-ethyl-N- (γ-picolyl) -amide precipitating out. This is taken up in chloroform, the solution is dried over sodium sulfate and the chloroform is distilled off. After the distillation residue has been dissolved in ethyl acetate-petroleum ether, the tropic acid-N-ethyl-N- (y-picolyl) -amide is obtained as colorless crystals with a melting point of 96 ° to 97 °. Hydrobromide: melting point 147 to 149 ⁰ , hydrochloride: melting point 123 to 125 ⁰ . Yield: 79%.

Claims (1)

Claim: Process for the preparation of substituted tropic acid-N- (y-picolyl) -amides, characterized in that that one, optionally acetylated, tropic acid chloride with methyl, ethyl or Allyl- (y-picolyI) -amine converts and if necessary the condensation product is deacetylated by treatment with an acid. Considered publications:
German patent specification No. 834 102. © 6TO 619 / 584- ».56 (609 845 3.57)