CS256228B1 - Process for preparing new fluorinated 10-piperazino-10,11-dihydrodibenzo (b, f) thiepine - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is a method for preparing a new fluorinated 10-piperazino-10,11- -dihydrodibenzo(b,f)thiepine of formula I (I), i.e. 3- (4- (7-fluoro-2-isopropyl-10,11-dihydrodibenzo(b,f)thiepin-ll-yl)-1-piperazinyl)-propionamide, which represents a long-term and highly effective neuroleptic for oral administration. The substance is useful in the therapy of schizophrenic psychoses. The subject of the solution is a method for preparing a substance of formula I, which consists in the substitution reaction of 11-chloro- -7-fluoro~2-isopropyl-10,11-dihydrodibenzo-(b,f)thiepine with 3-(1-piperazinyl)propionamide, preferably carried out using a 100% excess of 3-(1-piperazinyl)propionamide.

Description

The present invention relates to a process for the preparation of a novel fluorinated 10-piperazino-10,11-dihydrodibenzo (b, f) thiepine of the formula I

(I) ie 3- (4- (7-fluoro-2-isopropyl-10,11-dihydrodibenzo (b, f) thiepin-11-yl) -1-piperazinyl) propionamide.

The compound of the formula I according to the invention is a highly potent neuroleptic whose action is strongly protracted. This allows low doses to be administered at long intervals, which means less burden on patients and makes it easier to control the use of the product. The substance is used to treat schizophrenic psychoses. It can be administered orally in base or salt form.

The process for the preparation of the compound of formula I according to the invention consists in the substitution reaction of the known 11-chloro-7-fluoro-2-isopropyl-10,11-dihydrodibenzo (b, f) thiepine (Jílek J. et al .: Collect. Czech. Chem. Commun., 49, 2638, 1984) with the known 3- (1-piperazinyl) propionamide (U.S. Pat. No. 3,352,866). This substitution reaction can be carried out under various conditions. The reaction proceeds very well using a 100% excess of 3- (1-piperazinyl) propionamide and in boiling chloroform as the reaction medium. Other solvents can also be used as media, such as acetone, acetonitrile, benzene, dimethylformamide, hexamethylphosphoric triamide, etc. It is also possible to work without the environment and heat both components to temperatures of 100 to 120 ° C. When using the equivalent of 3- (1-piperazinyl) propionamide, it is necessary to work in the presence of hydrogen chloride-binding substances by reactions resulting, for example, anhydrous potassium carbonate or tertiary amines, such as pyridine or triethylamine.

However, under some of these conditions, the undesired elimination reaction product, 2-isopropyl-7-fluorodibenzo (b, f) thiepine, is formed to a greater extent than under the conditions described in the example below.

As already mentioned, the substance of formula I according to the invention is novel. Its identity was ensured not only analytically, but also by means of spectra. The product is a crystalline base of formula I which crystallizes from water as a hemihydrate. The solvate retains its composition even when recrystallized from a mixture of ethanol and petroleum ether; its m.p. mp 108-111 ° C. The following example describes a preferred embodiment of the preparation of a compound of formula I within the meaning of the invention. It is therefore merely an illustration of an embodiment of the invention, but is not intended to fully describe all the possibilities of the invention.

A solution of 9.2 g of 11-chloro-7-fluoro-2-isopropyl-10,11-dihydrodibenzo (b, f) thiepine and 9.5 g of 3- (1-piperazinyl) propionamide in 25 ml of chloroform is stirred and boiled. h under reflux. After cooling, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was diluted with 100 mL of lukewarm (40 ° C) water and extracted with warm benzene. The product from the benzene phase is extracted twice into 50 ml of a 10% methanesulfonic acid solution. The combined acidic extracts were made alkaline with 30 ml of aqueous ammonia, the liberated crystalline base was filtered overnight, washed with water and dried in vacuo. Yield 8.0 g (61%) of the desired compound of formula (I), which, upon crystallization from ethanol / petroleum ether, melts at 108-111 ° C.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of a novel fluorinated 10-piperazino-10,11-dihydrodibenzo (b, f, thiepine of the formula I ch (ch ₃ ) _{2 -} NCH ₂ CH ₂ CONH ₂ (I), characterized in that 1-chloro- 7-Fluoro-2-isopropyl-10,11-dihydrodibenzo (b, f) thiepine is subjected to a substitution reaction with 3- (1-piperazinyl) propionamide. 2. The process of claim 1 wherein the reaction is carried out using a 100% excess of 3- (1-piperazinyl (propionamide) in boiling chloroform).