CS243594B1 - Method of new wsters of 1-(4-methylsulphonylphenyl)-2-(4-phenylpiperazino-)ethan-1-ol and their maleates preparation - Google Patents

Abstract

The solution lies in the field of synthetic drugs. Its subject is a way of preparing new ones of 1- (4-methylsulfonylphenyl) -2- (4- -phenylpiperazino) ethan-1-ol of the formula Wherein R is methyl, ethyl, phenyl or nitrophenyl, and their maleates. General Substances Formula I intermediates are pharmacodynamically active ingredients and their maleates exhibit mild tranquilizers and sedative. Process for the preparation of general substances of formula (I) consists in the acylation of 1- (4-methylsulfonylphenyl) -2- ( 4-phenylpiperazino) - ethan-1-ol acid chlorides of the formula II wherein R is the same as in Formula I, v pyridine at 70-115 ° C, and the following neutralization of the base of formula I obtained maleic acid.

Description

(54) A process for the preparation of novel 1- (4-methylsulfonylphenyl) -2 (4-phenylpiperazino) ethan-1-ol esters and their maleate

The solution falls within the field of synthetic drugs. Its subject is a process for preparing novel esters of l- (4-methylsulfonylphenyl) -2- (4-phenyl) ethan-l-ol of the formula I / = \ / ~ Λ ^CH 3 ^S rV_Z ° ^C-5

OCOR (R) wherein R is methyl, ethyl, phenyl or nitrophenyl, and the maleate thereof. The compounds of formula (I) are intermediates for the preparation of pharmacodynamically active substances and their maleates exhibit the properties of mild tranquilizers and sedatives. The process for the preparation of the compounds of the formula I consists in the acylation of 1- (4-methylsulfonylphenyl) -2- (4-phenylpiperazino) ethan-1-ol with the acid chlorides of the formula II

RCOC1 (II), wherein R is the same as in Formula I, in pyridine at 70-115 ° C, and in subsequent neutralization of the obtained bases of Formula I with maleic acid.

The present invention relates to a process for the preparation of the novel esters of 1- (4-methylsulphonylphenyl) -2- (4-phenylpiperazino) ethan-1-ol of formula (I).

OCOf? ₍₁₎ wherein R is methyl, ethyl, phenyl or nitrophenyl, and the maleate thereof.

The compounds of formula I are intermediates for the preparation of pharmacodynamically active substances. Moreover, their maleates have certain biological effects per se which suggest practical applicability in therapy. They are very toxic substances. Their mean lethal dose (LD50 for oral mice is 2500 mg / kg or more. In several animal tests they indicate the pharmacological profile of centrally depressing tranquilizers and sedatives. At doses of 100 to 300 mg / kg, they cause rotating rods in mice At the same doses, they significantly inhibit the spontaneous locomotor activity of mice in both known and unknown environments At doses of 10 to 100 mg / kg after prolonged thiopental sleep of the mice to 200% of control values Some at 300 mg / kg after In mice at doses of 100 to 300 mg / kg po significantly decrease (by 1 ° C) the body temperature of rats measured rectally,

The process for the preparation of the compounds of the formula I according to the invention consists in the reaction of 1- (4-methylsulfonylphenyl) -2- (4-phenylpiperazino) ethan-1-ol {Vejdelek ZJ et al., Collect. Czech. Chem. Commun. 40, 1 204 (1975) with acid chlorides of the formula II

RCOC1 (II), wherein R is the same as in Formula I, in boiling pyridine. The method of product isolation is described in detail in the examples. First, crystalline bases of the formula I are obtained, which are then converted into crystalline maleate salts by neutralization with maleic acid. This process for preparing these salts is part of the process of the invention.

The compounds of the invention are novel and have been assured in terms of identity by analysis and spectral methods. The following examples are merely illustrative of the process of the invention and are not intended to limit the invention to the conditions described therein, nor to exhaustively limit the scope of the invention.

Example 1 [1- (4-Methylsulfonylphenyl) -2- (4-phenylpiperazino) ethyl acetate (I, R = CH3)

To a stirred solution of 5.2 g of 1- (4-methylsulfonylphenyl) -2- (4-phenylpiperazino) ethan-1-ol (literature cited) in 50 ml of pyridine was added dropwise at 50 ° C 2.2 g of acetyl chloride and The mixture is refluxed for 2 hours, poured into 700 ml of cold water after cooling, the product precipitates first as an oil which crystallizes rapidly on standing, suctioned off, dissolved in 120 ml of benzene, filtered with charcoal and the filtrate evaporated The residue was dissolved in 30 ml of hot benzene and crystallization was added by addition of cyclohexane, and suction, washing with a little cyclohexane and drying in vacuo gave 4.60 g (79%) of a base melting at 126-127 degrees Celsius. 96% ethanol and chloroform: maleate composition C25H30N2O8S + -j- 0.5 H2O, ie hemihydrate, melting in pure state at 147-148 ° C.

Example 2 [1- (4-Methylsulfonylphenyl) -2- (4-phenylpiperazino) ethyl] propionate (1, R = C2H5)

A similar reaction of a solution of 7.2 g of 1- (4-methylsulfonylphenyl) -2- (4-phenylpiperazino) ethan-1-ol in 70 ml of pyridine with 2.5 g of propionyl chloride and a similar treatment of the mixture as in Example 1 gives 7.1 g (87%) of crystalline base C22H28N2O4S, which crystallizes from a mixture of benzene and hexane and melts in the pure state at 116-117 ° C. Neutralization with maleic acid in 96% ethanol gives the maleate sesquihydrate composition C26H32N2O8S + 1.5 H2O, which crystallizes from a mixture of 96% ethanol and chloroform and melts in the pure state at 150-151 ° C.

Example 3 [1- (4-Methylsulfonylphenyl) -2- (4-phenylpiperazinoethyl) benzoate (I, R = C6H5)

To a solution of 5.2 g of 1- (4-methylsulfonyl) -2- (4-phenylpiperazino) ethanol-1-ol in 50 ml of pyridine was added 2.43 g of benzoyl chloride and the mixture was heated at 70-80 ° C for 1.5 h. C. After cooling, it is poured into 600 ml of water, the oily product is separated by decantation, dissolved in 250 ml of benzene, dried over sodium sulphate and evaporated. The residue crystallized upon addition of 1 ml of benzene and 1 ml of hexane. 4.80 g (73%) of a crystalline base melting at 122-125 ° C are obtained. Recrystallization from benzene / hexane gave an analytically pure product, C28H23N2O4S, melting at 128-129 ° C. Neutralization of the base with maleic acid in aqueous ethanol gives the crystalline maleate C30H32N2O8S, which melts in the pure state at 195-196 ° C (aqueous ethanol J.

Example 4 [1- (4-Methylsulfonylphenyl) -2- (4-phenylpiperazinoethyl) -4-nitrobenzoate (I, R = 4-C6H4NO2)

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The crude base (9.0 g) was prepared similarly to 9.0 g of 1- (4-methylsulfonylphenyl) -2- (4-phenylpiperazino) ethan-1-ol and 5.2 g of 4- nitrobenzoyl chloride in 70 ml of pyridine Since the attempts to purify this base by crystallization fail, it is dissolved in 40 ml of chloroform and the solution is chromatographed on a column of 210 g of neutral alumina (activity IIj). can be crystallized from a mixture of benzene and hexane, 6.4 g (51%), mp 84-85 [deg.] C, composition C26H27N3O6S, neutralization of the base with maleic acid in aqueous ethanol gives the maleate hemihydrate C30H31N3O10S + 0.5

H2O, which melts at 175-176 ° C.

Claims (1)

SUBJECT A process for preparing novel esters of l- (4-methylsulfonyl-methanesulphonyl-phenyl) -2- (4-phenyl-piperazin j ethan-ol of formula I, ^{1 1} CH 2 SO 4 --CH 2 CH 2 N 2 NC ₆ H ₅ OCOR (|) wherein R is methyl, ethyl, phenyl or nitrophenyl, and their maleate, characterized by the fact that 1- (4-methylsulfonylphenyl) -2- (4-phenylpiperazino) ethan-1-ol is acylated with acid chlorides of formula II RCOC1 (II), wherein R is the same as in formula I, in pyridine at a temperature of 70-115 ° C, then the bases of formula I obtained are converted into maleicates by neutralization with maleic acid.