DE1156413B - Process for the production of azepine derivatives and their salts - Google Patents

Description

GERMAN

PATENT OFFICE

G27345IVd / 12p

REGISTRATION DATE: JUNE 23, 1959

NOTICE THE REGISTRATION AND ISSUE OF THE EDITORIAL: OCTOBER 31, 1963

The invention relates to a process for the preparation of azepine derivatives and their Salts, which are valuable intermediates for the manufacture of pharmaceuticals and partly are themselves pharmacologically effective.

The new azepine derivatives of the general formula are prepared

R-CH-CH ₂ -NH ₂

in which X is an ethylene or vinylene group, Y and Z are hydrogen or halogen atoms or low molecular weight Alkyl radicals and R a hydrogen atom, a low molecular weight alkyl or aralkyl radical, and their salts according to the invention by adding compounds of the general formula

YfY l \ z II

with aldehydes of the general formula

R - CHO III

and converts hydrogen cyanide and the resulting cyanoalkyliminodibenzyls or cyanoalkyliminostilbenes reduced with alkali-alkaline earth metal hydrides or the cyanoalkyliminodibenzyls with hydrogen in the presence of hydrogenation catalysts, optionally in the presence of ammonia, treated, and optionally reacting the bases obtained with inorganic or organic acids. The reaction with the aldehydes of the general formula III and hydrogen cyanide leads as Intermediate stage to the cyano compound of the general formula

R - CH

Iminodibenzyl (10,11-dihydro-5-dibenzo [b, f] azepine) and the iminostilbene, in particular, are used as starting materials of the general formula II
of azepine derivatives and their salts

Applicant:
JR Geigy AG, Basel (Switzerland)

Representative: Dr. F. Zumstein,
Dipl.-Chem. Dr. rer. nat. E. Assmann

and Dipl.-Chem. Dr. R. Koenigsberger,
Patent Attorneys, Munich 2, Bräuhausstr. 4th

Claimed priority:
Switzerland of June 24, 1958 (No. 60 954)

Dr. Daniel Prins, Riehen (Switzerland),
has been named as the inventor

(5-dibenzo [b, f] azepine), also their mono- and disubstitution products, such as the 3-chloro

a5 iminodibenzyl, 3-ethyl-iminodibenzyl, 3-chloriminostilbene, 3-ethyl-iminostilbene and 2,8-dimethyl-iminodibenzyl into consideration. Suitable aldehydes of the general formula III are, for example, formaldehyde, acetaldehyde, propionaldehyde, Bu-

tyraldehyde, isobutyraldehyde, valeraldehyde, enanthaldehyde and phenylacetaldehyde. The condensation of the azepine derivatives of the general formula II with the aldehydes of the general formula III is preferably carried out in acetic acid, the hydrogen cyanide required ζ. Β. is supplied by a gradually added aqueous alkali metal cyanide solution. The reduction of the 5- (a-cyanoalkyl) - or 5- (a-cyano-aralkyl) -iminodibenzyls or -iminostilbenes of the general formula IV is preferably carried out with lithium aluminum hydride in an ether such as diethyl ether or a cyclic ether. This reduction method is indicated above all in the preparation of iminostilbene derivatives, since it is difficult to avoid simultaneous hydrogenation of the vinylene group in the catalytic hydrogenation of cyano compounds of the iminostilbene series. The catalytic hydrogenation of cyano compounds of the iminodibenzyl series is z. B. using Raney nickel or Raney cobalt, preferably under pressure, carried out as a solvent, hydrous, cyclic ethers , such as hydrousJIMoxane, especially

309 730/324

suitable. Low molecular weight, preferably water-containing alkanols are also used as solvents Consideration. The presence of ammonia is also advantageous for the course of the hydrogenation.

With inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, methanesulfonic acid, ethane disulfonic acid, acetic acid, citric acid, malic acid, succinic acid, Tartaric acid, benzoic acid, phthalic acid, fumaric acid and maleic acid form the N-aminoalkylazepines of the general formula I salts, some of which are water-soluble.

The N-aminoalkyl-azepine derivatives according to the invention of the general formula I potentiate the effect of analgesics and narcotics and can used as cholinesterase inhibitors, antiallergics, antipyretics and serotonin antagonists will.

The following examples are intended to illustrate the process according to the invention in more detail explain. Parts therein mean parts by weight.

example 1

a) 97.5 parts of iminodibenzyl are dissolved in 1200 parts of glacial acetic acid with mild heating, and the solution is cooled to 2O ⁰ C. Then, with stirring 34 parts by volume of acetaldehyde is added and then a solution of 50 parts of potassium cyanide in 80 parts of water is added dropwise such that the temperature remains below 3O ⁰ C. After stirring for 5 hours, 17 parts by volume of acetaldehyde are added, followed by 25 parts of potassium cyanide in 40 parts of water, and after a further 4 to 5 hours another 14 parts by volume of acetaldehyde and 25 parts of potassium cyanide in 40 parts of water are added and the mixture is stirred for a further 10 hours at room temperature. The crystallization that has occurred is completed by cooling and the dropwise addition of 800 parts of water. The precipitate is filtered off with suction and washed with water. The 5- (a-cyano-ethyl) -iminodibenzyl obtained melts at 80 to 82 ° C. (yield 80% of theory).

After recrystallization from ether-methanol or from ether-petroleum ether, prisms are obtained from m.p. 80 to 8ΓC.

In an analogous manner, isobutyraldehyde and valeraldehyde are used in yields between 60 and 90% 5- (a-cyano-isobutyl) -iminodibenzyl, Mp. 130 C, and 5- (q-cyanon-amyl) -iminodibenzyl, amorphous.

b) 5 files 5- (a-cyano-ethyl) -iminodibenzyl are in the presence of 3 to 5 parts of Raney nickel or Raney cobalt in a mixture of 50 parts of water, 1.7 parts of ammonia and 170 parts of dioxane at 60 to 100 ⁰ C and 30 to 140 atm. Pressure, e.g. B. at 8O ⁰ C and 140 atm. Pressure, hydrogenated within 30 minutes. After cooling, the catalyst is filtered off, the filtrate is evaporated, the residue is taken up in 100 parts by volume of ether and the ethereal solution is shaken out with 50 parts by volume of 2N hydrochloric acid. Part of the amine precipitates out in crystalline form as the hydrochloride. The precipitate is filtered off, the layers of the filtrate are separated, and the ethereal phase is extracted again with 25 parts by volume of 2η hydrochloric acid and then with water.

The combined hydrochloric acid and aqueous extracts are made alkaline and extracted with ether, the ether extract is washed with a little water, dried over sodium sulfate and treated with 2 parts by volume of 5.6 normal ethanolic hydrochloric acid, the hydrochloride precipitating in crystalline or amorphous form. The liquid is decanted off and the residue is rubbed with acetone. The crude hydrochloride is then filtered off and recrystallized from methanol with the addition of acetone and ether. This gives 4.9 parts of the hydrochlorides of the 5- (a-aminomethyl-ethyl) -iminodibenzyls in prisms, mp. 228 to 23O ⁰ C.

In an analogous manner from the 5- (a-Cyanon-amyl) -iminodibenzyl in a yield of 90%, the hydrochloride of 5- (a-aminomethyl-n-amyl) -iminodibenzyls, mp. 209 ⁰ C, and from 5 - (a-Cyano-isobutyl) -iminodibenzyl in a yield of 80% the hydrochloride of 5- (a-aminomethyl-isobutyl) -iminodibenzyl, melting point 248 to 250 ° C, obtained.

Example 2

a) 5 parts of iminostilbene are dissolved in 50 parts by volume of glacial acetic acid and 40 parts by volume of tetrahydrofuran. Then add 1.7 parts by volume of acetaldehyde and then one at room temperature with stirring A solution of 2.5 parts of potassium cyanide in 4 parts of water is added, the mixture is stirred for 4 hours and then added again the same amounts of acetaldehyde and potassium cyanide solution. After stirring for a further 14 hours 400 parts of water are added to the reaction mixture, the mixture is extracted with ether and the ether extract is washed neutral, dried it over sodium sulfate and evaporated it, the 5- (a-cyano-ethyl) -iminostilbene remains as oil.

b) A solution of 5 parts of the crude cyano compound obtained in 50 parts by volume of absolute ether is added dropwise with stirring to a solution of 1.7 parts of lithium aluminum hydride in 50 parts of absolute ether. After the end of the dropwise addition, the reaction solution is refluxed for 1 hour, then 5 parts by volume of methanol in 15 parts by volume of ether and then 5 parts of water are added. The white precipitate is filtered off, the filtrate is extracted with 2η hydrochloric acid, the acid extract is made alkaline with sodium hydroxide solution and the base which has separated out is taken up in ether. After washing, drying and evaporating the ether solution, 4.2 parts of crude 5- (a-aminomethylethyl) iminostilbene are obtained. It is dissolved in a little methanol and mixed with 3.5 parts by volume of 8N ethanolic hydrochloric acid, whereupon the hydrochloride of the base crystallizes out. After recrystallization from methanol-acetone, the hydrochloride melts at 266 to 268 ^° C.

Example 3

a) 8 parts of 3-chloro-iminodibenzyl are in 100 parts Glacial acetic acid in the manner described in Example 1, a) first with 2.5 parts by volume of acetaldehyde and 3.5 parts of potassium cyanide in 5 parts of water and then twice with 1.25 parts by volume of acetaldehyde and 1.75 parts of potassium cyanide reacted in 2.5 parts of water. After the reaction has ended, one sets Add 200 parts of water, ether out and wash the ethereal solution neutral; 9 parts of raw material are obtained amorphous 3-chloro-5- (a-cyanoethyl) -iminodibenzyl.

b) 6 parts of the crude iminodibenzyl derivative obtained are described as in Example 2, b),

in 100 parts of absolute ether with 2.2 parts of lithium aluminum hydride reduced and then worked up. When extracting the essential phase with 2N hydrochloric acid the hydrochloride of 3-chloro-5- (a-aminomethyl-ethyl) -iminodibenzyl falls in the form of needles and is filtered off. After recrystallization from methanol-ether, the hydrochloride melts 250 to 252 ° C. Yield 6 parts.

Example 4

a) To a solution of 50 parts of iminodibenzyl and 10 parts by volume of 38% formaldehyde in 800 parts by volume of glacial acetic acid, a solution of 25 parts of potassium cyanide in 50 parts by volume of water is added dropwise with stirring at room temperature. After 4 hours, 10 parts by volume of 38 ^E / _O strength formaldehyde was added at once and added dropwise a solution of 25 parts of potassium cyanide in 50 parts by volume of water. After stirring for 4 hours, the onset of crystallization of the reaction product is completed by the dropwise addition of 800 parts by volume of water, the precipitate is filtered off and the precipitate is washed with water. After drying in vacuo over concentrated sulfuric acid, 48 parts of 5-cyanomethyl-iminodibenzyI with a melting point of 80 ° to 84 ° C. are obtained. Recrystallized from ether-methanol, the pure nitrile melts at 89 to 91 ^° C.

b) A solution of 110 parts of 5-cyanomethyliminodibenzyl in 500 parts by volume of ether and 100 parts by volume of tetrahydrofuran are added dropwise to 26 parts of lithium aluminum hydride in 500 parts of ether, and the mixture is heated under reflux for 14 hours. Then successively 30 parts by volume of methanol, 30 parts by volume of water, 30 parts by volume of 15% sodium hydroxide solution and 90 parts by volume of water are added dropwise, and the solution is filtered off from the precipitate formed. The filtrate is diluted with 300 parts by volume of ether, the separated ether solution is washed with 200 parts by volume of water and then exhaustively extracted with 2 to 4 η hydrochloric acid. The acidic, aqueous extract is made alkaline with concentrated ammonia, and the released bases are extracted with ether, 70 parts of 5 - (/ S-amino-ethyl) -iminodibenzyl being obtained. These are converted into the hydrochloride with ethanolic hydrochloric acid. F. 256 to 258 ⁰ C.

Claims (1)

PATENT CLAIM: Process for the preparation of azepine derivatives of the general formula R-CH-CH ₂ NH ₂ in which X is an ethylene or vinylene group, Y and Z are hydrogen or halogen atoms or low molecular weight alkyl radicals and R is a hydrogen atom, a low molecular weight alkyl or aralkyl radical, and their salts, characterized in that compounds of the general formula ^Y V \ _NH / V ^Z with aldehydes of the general formula
R —CHO and converts hydrogen cyanide and the resulting cyanoalkyliminodibenzyls or cyanoalkyliminostilbenes reduced with alkali-alkaline earth metal hydrides or the cyanoalkyliminodibenzyls with Hydrogen in the presence of hydrogenation catalysts, optionally in the presence of Ammonia, treated, and the bases obtained, optionally with inorganic or converts organic acids. Q 309 730/324 10.