DE1140937B - Process for the preparation of N-substituted azepines and their salts. - Google Patents

Description

GERMAN

PATENT OFFICE

G25992IVd / 12p

REGISTRATION DATE: DECEMBER 19, 1958

NOTICE
THE REGISTRATION
AND ISSUE OF
EDITORIAL: DECEMBER 13, 1962

The invention relates to a method of manufacture of N-substituted azepines of the general formula

A /

CH = CH

X>

CH ₂ - CH - CH ₂ OH

Ri

R ₂

in which X and Y are hydrogen or halogen atoms, Ri and R _{2 are} low molecular weight alkyl radicals or Ri and R ₂ are linked together with the nitrogen atom to form a saturated heterocyclic ring which may contain an oxygen atom, and salts thereof.

It has been found that these compounds have pharmacologically valuable properties, in particular have spasmolytic, antiallergic and hypnotic activity. You can also to potentiate the effect of medicines and to treat mental illnesses, in particular Depression, find use. Opposite that from the German Auslegeschrift 1 006 421 known 5 - (3 '- diethylamino - 2' - hydroxypropyl) -iminodibenzyl shows z. B. 5- (3'-Diethylamino-2'-hydroxypropyl-iminostilbene a much stronger spasmolytic activity with approximately the same toxicity. From the new connection is to attainment same antagonistic effect against acetylcholine, hystamine and serotonin as with the known compound a ten times or four times or twice less amount of substance is necessary.

The N-substituted azepines of the given general formula I are obtained according to the invention, by in a manner known per se a 5- (2 ', 3'-epoxypropyl) -5-dibenzo [b, f] azepine of the general formula

CH = CH

CH ₂ - CH - CH ₂

Process for the preparation of N-substituted azepines and their salts

Applicant: J. R. Geigy A. G., 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 December 20, 1957 (No. 54 024)

Dr. Walter Schindler, Riehen (Switzerland), has been named as the inventor

with a secondary amine of the general formula

Ri

HN

III

R ₂

reacted and optionally treated the base obtained with an inorganic or organic acid.

The reactions of the epoxypropyl compounds with the secondary amines can be carried out in an or Absence of solvents or diluents can be carried out. Can be used as a diluent for example, use an excess of the secondary amine to be reacted and the reaction z. B. at the boiling point of the Carry out amine under normal pressure. Furthermore, the reaction can also be achieved by heating the Components in an inert solvent, e.g. B. benzene, toluene or xylene, also ethanol or Methanol. When using volatile amines, ζ. B. dimethylamine, also comes the reaction of the components in an inert organic solvent in the autoclave into consideration.

The starting materials of the general formula II

can from the 5-dibenzo [b, f] azepine (iminostilbene)

209 747> 322

or its C-substitution products in a per se known Way by reacting their alkali metal compounds, especially their sodium compounds, can be obtained with epichlorohydrin. The iminostilbene and its C-substitution products are derived from 10, ll-dihydro-5-dibenzo [b, f] azepine (iminodibenzyl) or its C-substitution products available in accordance with patent 1,056,133. Starting materials of the general formula II are, for. B. that 5- (2 ', 3'-Epoxypropyl) -iminostilbene and the 5- (2', 3'-Ep- ι ο oxypropyl) -3,7-dichloro-iminostilbene. These epoxypropyl compounds can, for example, with dimethylamine, Methyl-ethylamine, diethylamine, din-propylamine. Methyl-n-propylamine. Methyl isopropylamine, Ethyl-n-propylamine, di-n-butylamine. Methyl-n-butylamine, diisobutylamine, pyrrolidine, piperidine and morpholine are implemented.

With inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, methanesulfonic acid, ethane disulfonic acid, acetic acid, succinic acid, fumaric acid, maleic acid, Malic acid, tartaric acid, citric acid, benzoic acid and phthalic acid, make up the tertiary ones Base salts, some of which are water-soluble.

The following examples are intended to describe the process for the preparation of N-substituted azepines and explain their salts in more detail. Parts therein mean parts by weight.

example 1

24.9 parts of 5 - (2 ', 3'-Epoxypropyl) - iminostilbene (Kp.o, o ₂ 150 to 160 ° C) are mixed with 75 parts of pure diethylamine boiled for 16 hours under reflux. The excess diethylamine is then distilled off in vacuo and the residue is taken up in ether. The basic components are removed from the ethereal solution with 30% acetic acid, the acetic acid solution is made alkaline with concentrated sodium hydroxide solution and the separated oil is taken up in petroleum ether. After drying, evaporation this solution to a small volume, the 5- (3'-diethylamino-2'-hydroxypropyl) iminostilbene crystallized melting point of 105 to 106 ⁰ C. Overall yield 64% of theory.

In an analogous manner one obtains the 5- (3'-diethylamino - 2 '- hydroxypr opyl) -3,7- dichloro - iminostilbene, its hydrochloride (obtained by adding absolutely alcoholic hydrochloric acid to the essential Solution of the iminostilbene derivative and recrystallization from alcohol-ether) at 268 to 270 ° C melts.

Example 2

24.9 parts of 5- (2 ', 3'-epoxypropyl) -iminostilbene are refluxed with 50 parts by volume of piperidine for 16 hours. The reaction mixture is then poured into water and extracted exhaustively with ether. The ethereal solution is extracted with 2N hydrochloric acid, and the basic components which have passed over in it are precipitated again by making them alkaline with concentrated sodium hydroxide solution and absorbed in ether. The ether solution is dried over sodium sulfate and evaporated. Upon distillation of the residue under a high vacuum yields 5- (3'-piperidino-2'-hydroxypropyl) iminostilbene from Kp.0,002 186-188 ⁰ C. Yield 70% of theory.

In an analogous manner, using 50 parts of pyrrolidine in place of piperidine, the 5- (3'-pyrrolidino-2'-hydroxypropyl) iminostilbene from Kp.0,002 185 ⁰ C. Yield 64% of theory.

Claims (1)

PATENT CLAIM: Process for the preparation of N-substituted azepines of the general formula x-l CH = CH ι γ Ri CH ₂ -CH-CH ₂ -N OH R ₂ in which X and Y are hydrogen or halogen atoms, Ri and R2 are low molecular weight alkyl radicals or Ri and R2 are linked together with the nitrogen atom to form a saturated heterocyclic ring optionally containing an oxygen atom, and salts thereof, characterized in that one is in a manner known per se a 5- (2 ', 3'-epoxypropyl) -5-dibenzo [b, f] -azepine of the general formula CH ₂ -CH-CH ₂ with a secondary amine of the general formula Ri HN R ₂ converts and optionally the base obtained treated with an inorganic or organic acid. Documents considered: German Auslegeschrift No. 1006 421. When the registration was announced, a test report (4 pages) was displayed. © 209 747/322 12.