CS202000B1 - Method of preparing ester of piperazinoalkanol of dibenzo/b,f/thiepine serie - Google Patents

Description

The present invention relates to a novel process for preparing a piperazinoalkanol ester of the dibenzo (b, f) thiepime series of formula I, in two ways, both of which are an amino alcohol of formula II,

^w \ _y ^{N (CH} ^ ^{ooq (CH} « ^, e ^CH *)

i.e. 10- [4- (3-decianoyloxypropyl) piperazino] -8-methylthio-10,11-dihydrodibenzo (b, f) thiepine, known under the trade name " oxyprothepindecanoate ". This ester is a highly potent depot neuroleptic whose single intramuscular dose of 25 mg prevents relapse of the psychotic process in schizophrenics for 2-4 weeks (Dlabač A., Kazdová E., Activ. Nerv. Super. 16, 166, 1974; Ceskoslov. Fysiol 23, 336 (1974), Molcan J. et al.

11th CINP Congress, Vienna, July 1978, abstracts p. 50; Plum J. et al., Ibid. 455). It is therefore a substance of considerable therapeutic and technical importance.

The preparation of the ester of formula I has so far been described as "oxyprothepin". In a first procedure, oxyprothepin of formula II is esterified by treatment with decanoyl chloride in chloroform (Jílek J.O. et al., Collect. Czech. Chem. Commun. 38, 1190, 1973). More recently, it has been found that this reaction is accompanied by an undesirable side reaction, the products of which are 10-chloro-8-methylthio-10,11-dihydrodibenzo (b, f) thiepine III

2Q2QQQ followed by 1-decanoyl-4- (3-decanoyloxypropyl) piperazine (Red I. et al., Collect. Czech. Chem. Commun. 41, 3437, 1976). The second procedure consists in esterifying oxyprothepin of formula II with free decanoic acid in boiling xylene while removing the water formed by distilling the xylene azeotrope with water (Red I. et al., Cited). This latter method is more advantageous, but the necessity of using a relatively high reaction temperature and a longer time results in a colored and contaminated product which requires a fairly difficult cleaning.

It has now been found that the ester of formula I can be conveniently prepared by substituting the chloride of formula III (Pelz K. et al., Collect. Czech. Chem. Commun. 33, 1895, 1968) with 1- (3-decanoyloxypropyl) piperazine of formula IV,

^(IV) whose preparation has been described in the literature (Red I. et al., Cited). This process for preparing the ester of formula I is an object of the present invention. Said substitution reaction may be carried out under various conditions (equivalent or at least 100% excess of amine of formula IV, different solvents, reaction temperatures, use of alkali carbonates as condensing agents, etc.), but the most preferred variant is reaction of chloride of formula III with at least 100% excess of amine of formula IV in boiling chloroform. This variant is described in an exemplary embodiment.

The oxyprothepindecanoate of formula I is a viscous oil. a liquid whose homogeneity is defined by thin-layer chromatography on alumina or silica gel and by spectral methods. Acid neutralization gives crystalline salts which are characterized by melting points. Thus, for example, neutralization with oxalic acid yields, on the one hand, monooxalate melting at 136 ° C and crystallizing from aqueous ethanol, and also bis (hydrogen oxalate) having a melting point of 173 to 175 ° C, also crystallizing from aqueous ethanol. Purification of the ester of formula (I) is based, firstly, on alumina column chromatography, and secondly on conversion to the above-mentioned salts, purification by crystallization, and then liberating purely by base alkalization. The dosage form is a solution of the pure base of formula I in vegetable oil or another - preferably the most stable oily triglyceride.

Exemplary embodiment

A mixture of 23 g of 10-chloro-8-methylthio-10,11-dihydrodiibenzo (b, f) thiepine of formula III, 48 g of 1- (3-decanoyloxypropyl) piperazine of formula IV and 30 ml of chloroform is refluxed for 7 hours. The mixture was then diluted with 500 ml of benzene and the solution was washed quickly with ice-cold 10% sodium hydroxide solution and water. It is dried over potassium carbonate and evaporated under reduced pressure. The residue was dissolved in benzene and the solution was chromatographed on a column of 1.4 kg of alumina (activity II). The first portions of benzene are eluted with 1.5 g of the least polar component, 2-methylthiodibenzo (b, f) thiepine. 14 g (32%) of homogeneous 10- [4- (3-decanoyloxypropyl) piperazino] -8-methylthio-10,11-dihydrodibenzo [(b, f)] thiepine of formula I, which can be characterized by conversion of either to monooxalate with mp 136 ° C (aqueous ethanol) or bis (hydrogenoxalate) with 1.1.173-175 ° C (aqueous ethanol).

Claims (2)

• SUBJECT OF THE INVENTION A process for the preparation of a piperazinoalkanol ester of dibenzo (b, f) thiepine orders of formula I, (III) sch _{3 is} subjected to a substitution reaction with 1- (3-decanoyloxypropyl) piperazine of formula IV (CH 3). 10- [4- (3-decanoyloxypropyl) piperazino] -8-methylthio-10,11-dihydrodibenzo (b, f) thiepine, characterized in that 10-chloro-8-methylthio-10,11-dihydrodibenzo ( b, f) thiepine of formula III ' 2. The process of claim 1 wherein at least 100% excess of the compound of Formula IV is used in the substitution reaction and the reaction is carried out in boiling chloroform.