HU204497B - Process for producing phenfluramine - Google Patents

Abstract

The present invention relates to a process for the preparation of 1 - [(3-trifluoromethyl) phenyl] -2-ethylamino-propane hydrochloride by reacting 1 - [(3-trifluoromethyl) phenyl] propanone-2 with ethylamine. by catalytic reduction of the resulting Schiff base and by the formation of hydrochloride by using palladium-on-charcoal as its catalyst. CY HU 204 497 Scope of the description: 4 pages

Description

The present invention relates to an improved process for the preparation of 1- [3- (trifluoromethyl) phenyl] -2- (ethylainino) -prop-N-hydrochloride (Fenfluramine) having anorectic activity. Two processes for the preparation of the above-mentioned compound are known in the literature. According to Belgian Patent No. 609,630, 1- [3- (trifluoromethyl) phenyl] -propanone-2 is first reacted with hydrogen fluorine and then the resulting oxime is converted into an amino compound. and the resulting 1- [3- (trifluoromethyl) phenyl] -2-aminopropane is acylated at the amino group with acetic anhydride. The N-acetyl compound is reduced with lithium aluminum hydride to 1- [3- (trifluoromethyl) phenyl] -2 (ethylamino) propane. The multi-step process provides Fenfluramine in only 34% yield, according to the patent.

According to German patent application A108 971, Schiff's base is reacted with 1- [3- (trifluoromethyl) phenyl] propanone-2-t-ethylamine and then reduced to the amino compound in the presence of Raney nickel catalyst. However, the disclosed patent process generates large amounts of undesirable by-products. The unreacted ketone present in the reaction mixture is reduced to 1- [3- (trifluoromethyl) phenyl] propanol-2 by the Raney nickel catalyst. (Raney Nickel Catalyst, Houben-Weyl TeiI, 6 / lb 28-30 is often used to reduce ketones to secondary alcohol.) Removal of the latter from the reaction mixture requires special process steps. The basic product is first salted in an aqueous medium and the non-basic propanol derivative is extracted from the reaction mixture with an organic solvent. The product, which, however, is present in the form of a salt in the aqueous solution, must be reconstituted by basification so that it can be recovered from the water by organic solvent extraction.

The disadvantages of this procedure are:

1. a large amount of by-product (19%) is formed and

2. requires three further processing steps during processing:

a) aqueous-acid solution - extraction

b) evaporation of the by-product extract

c) alkaline aqueous-extraction solution

We have developed a simple, one-step, by-product process for the production of Fenfluramine, which results in significantly better production than known processes.

In the process of the invention, 1- [3- (trifluoromethyl) phenyl] propanone-2 is preferably reacted with ethylamine in an alcoholic or aqueous alcoholic medium, particularly preferably methanol, and the resulting Schiff base is hydrogenated at room temperature in the presence of a palladium on carbon catalyst. The hydrogenation is preferably carried out at a pressure of ¹ x K 2 x ^{10 5} Pa. The process of the present invention is illustrated by the following example:

Example:

To a solution of ethylamine (g) in methanol (100 mL) was added l - [(3-trifluoromethyl) phenyl] propanone-2 (20.2 g) and palladium on charcoal (5 g) and the reaction mixture was hydrogenated at room temperature under atmospheric pressure. After uptake of the calculated amount of hydrogen (3 hours), the catalyst was filtered off, washed with methanol and the methanolic solution evaporated in vacuo. A sample from the evaporation residue contained 91% of the product by gas chromatography. The oily evaporation residue was dissolved in ethyl acetate, dried over sodium sulfate, decolorized with charcoal, and hydrogen chloride gas was added to the clear solution under external cooling, and the precipitated salt was filtered off with 19 g (71%) of 1- [3-trifluoromethylphenyl]. -2- (ethylamino) -propane hydrochloride was obtained. M.p .: 170-172 C. ^e

Analysis:

Found: C, 53.83; H, 6.40; N, 5.23; 0: 13.25; F, 21.29;

Found: C, 53.71; H, 6.27; N, 5.19; C, 13.18

F: 21.27.

Reference Example (Process according to German Patent Application No. 108971) To 16 g of ethylamine in 1 ml of methanol was added 30.3 g of 1- [3- (trifluoromethyl) phenyl] -2-propanone and 100 ml of methanol and the reaction mixture was allowed to stand for the next day. forget it. After addition of 0.5 ml glacial acetic acid and 8 g Raney nickel catalyst, the reaction mixture is hydrogenated at 50 ° C. The hydrogenation is started at 5 x ^{10 5} Pa and reduced to 3 x 10 Pa. After uptake of hydrogen (3 hours), the catalyst was filtered off and the filtrate was evaporated in vacuo to give 30.5 g of an oily substance containing 70% of product by gas chromatography. The residue was dissolved in water (200 mL), adjusted to pH 1 with concentrated hydrochloric acid and extracted with diethyl ether (200 mL). The ethereal solution was dried over sodium sulfate, evaporated and the residue was distilled in vacuo (b.p. 94 ° C) to give 1- [3- (trifluoromethyl) phenyl] -2-propanol (6.0 g, 19%). .

Analysis:

Found: C, 58.82; H, 5.43; F; 27.92; Found: C, 58.59; H, 5.50; F, 27.83.

The aqueous acidic phase was basified with 40% sodium hydroxide solution, the oily product was extracted with ether (2 x 150 mL), the ether extract was dried over sodium sulfate, evaporated and distilled under vacuum at 108 ° C (18.6 g, 54%). 1- [3- (Trifluoromethyl) phenyl] -2- (ethylamino) -propane was obtained, the hydrochloride of which was separated from n-propanol-diethyl ether by 45 g of hydrochloric acid gas, 16.2 g (41%) of Fenfluramine. we get.

Analysis:

H, 6.40; N, 5.23; 0, 13.25; F, 21.29;

Found: C, 53.72; H, 6.35; N, 5.17; 0: 13.17;

F: 21.29.

Claims (1)

Patent Claim Point 55 Process for the preparation of 1- [3- (trifluoromethyl) phenyl] -2- (ethylamino) propane hydrochloride by reacting 1- [3- (trifluoromethyl) phenyl] propanone-2 with ethylamine to form Schiff's base catalytic reduction and hydrochloride formation, characterized in that palladium on carbon is used as the catalyst.