CS243589B1 - Method of new 2(3-fluorphenylthio)-5-chloracetophenone preparation - Google Patents

Abstract

The solution lies in the field of synthetic drugs. His subject is a way of preparing a new one 2- (3-fluorophenylthio) -5-chloroacetophenone, which is an intermediate product of psychotropic production and neurotrophic drugs. Method of preparation consists in the reaction of 2,5-dichloroacetophenone with 3-fluorothiophenol at 130-140 ° C the presence of potassium carbonate and copper either with or without dimethylformamide as the diluent of the reaction mixture. Main part of the product is obtained by crude crystallization substances from ethanol; another portion is obtained from mother liquor by distillation or chromatography.

Description

(54) A process for preparing the new 2- (3-fluorophenylthio) -5-chloroacetophenone

2

The solution falls within the field of synthetic drugs. The present invention relates to a process for the preparation of novel 2- (3-fluorophenylthio) -5-chloroacetophenone, which is an intermediate product for the production of psychotropic and neurotropic medicaments by reacting 2,5-dichloroacetophenone with 3-fluorothiophenol at 130 to 140 ° C. in the presence of potassium carbonate and copper either in the absence of the medium or with dimethylformamide as the diluent of the reaction mixture, the major part of the product is obtained by crystallization of the crude material from ethanol, the other part being obtained from the mother liquor by distillation or chromatography.

The invention relates to a process for the preparation of the novel 2- (3-fluorophenylthio) -5-chloroacetophenone of formula I

The compound of formula I is an intermediate in the manufacture of psychotropically and neurotrophically active drugs and is therefore technically significant. It has not yet been described in the literature.

The process for the preparation of the compound of formula I according to the invention consists in a substitution reaction

2,5-dichloroacetophenone (Rajsner M. et al., Collect, Czech. Commun. 43, 1276, 1978) with 3-fluorothiophenol (Rajsner M., Protiva M., Collect, Czech. Chem. Commun. 32, 2021, 1967). Of the two chlorine atoms in the molecule

2,5-dichloroacetophenone is only reactive with a chlorine atom in the o-position to the keto group; the chlorine atom in the m-position is substantially non-reactive. By this differentiation a selective course of the reaction can be achieved. Even so, the reaction requires very sharp conditions. A nucleophilic substitution reaction requires the formation of a 3-fluorothiophenolate anion, which is achieved by washing in the presence of anhydrous potassium carbonate. The reaction proceeds at a strongly elevated temperature, at 130 to 140 ° C. This is achieved either by working in the melt, i.e. without using a diluent, or using dimethylformamide as a diluent. Further, the presence of a small amount of finely powdered copper catalyst is required for the reaction to proceed. Due to the sensitivity of the starting 3-fluorothiophenol to atmospheric oxygen, especially at the high temperature used, it is advantageous to work in an inert atmosphere and thus to avoid undesired formation of bis (3-fluorophenyl) disulfide.

The desired product of formula (I) is a crystalline substance, but its crystallization from crude products is difficult. Seeding with a small amount of crystalline product greatly facilitates crystallization. The stitch can be obtained either by distillation of the sample resulting in a highly pure and easily crystalline product, or by chromatography of the sample of the crude material on an alumina column. Both processes just mentioned are also suitable for obtaining a further proportion of the pure product from the mother liquors after the I. product. The boiling point of the compound of formula I is 145-150 ° C / 33 Pa, respectively. 160-164 ° C / 107 Pa; the melting point of the pure substance is 53-54 ° C (the substance crystallizes from ethanol).

The following Examples illustrate details of individual modifications of the method of preparation of Compound (I) of the present invention. Melt yields are between 60 and 70%; when working in dimethylformamide the yield is lower (50%). The purpose of the examples is to illustrate some of the possibilities of the process according to the invention, but is not intended to limit the invention to these possibilities, nor to exhaustively describe all possibilities.

Example 1

To a mixture of 32.5 g of 3-fluorothiophenol and 45 g

2,5-dichloroacetophenone was added with 1.1 g of powdered copper and 56 g of potassium carbonate. The mixture is heated with stirring in a bath of 140-160 ° C for 3.5 h. After cooling to 50 ° C, the mixture is extracted with 100 ml of benzene, the insolubles are filtered off with suction and washed with benzene. Evaporation of the benzene extract gave 68.1 g of a residue which was dissolved in 300 ml of hot ethanol. The solution is filtered with charcoal, the filtrate is concentrated under reduced pressure to a total volume of 120 ml and allowed to crystallize at room temperature for 12 h. 38.1 g (54%) of the compound of formula I melting at 48.5 to 48 are obtained. Deň: 32 ° C. Recrystallization from ethanol gave the analytical product, mp 53-54 ° C.

Example 2

To a mixture of 106 g of 3-fluorothiophenol, 4 g of copper and 145.6 g of 2,5-dichloroacetophenone was added 190 g of freshly calcined potassium carbonate under a nitrogen atmosphere. The mixture turns yellow and an exothermic reaction occurs, resulting in a spontaneous temperature rise to 80 ° C. After 20 min, the mixture solidified spontaneously. After being placed in a bath whose temperature is raised to 150-155 ° C, the mixture turns again so that it can be stirred: its internal temperature is 128-135 ° C. It is kept at this temperature with stirring for 6.5 h. After cooling to 50 ° C, 300 ml of benzene are added and the mixture is stirred for 15 min, the insoluble portion is then filtered off with suction and washed twice with 75 ml of benzene. The filtrate is evaporated under reduced pressure, the residue is dissolved in 1 L of ethanol, the solution is filtered with 20 g of activated carbon and the filtrate is again evaporated under reduced pressure; the rest weighs 216 grams. It is dissolved in hot in 240 ml of ethanol, seeded with a crystal of substance I upon cooling and left to crystallize in a refrigerator overnight.

The crystallized product is filtered off with suction, washed with a little ethanol and dried in vacuo; 114.1 g of compound are obtained. The mother liquors were evaporated and the residue was distilled under vacuum. After separation of 8.0 g of ancestors, a major portion of 45.9 g boiling at 160-162 ° C / 93 Pa was collected. The distillate immediately crystallized to a substance melting at 49-52 ° C. The total yield is thus 160 g (69%).

Example 3

A mixture of 41.9 g of 3-fluorothiophenol, 57.5 g of 2,5-dichloroacetophenone, 1.5 g of copper and 72 g of potassium carbonate was treated in an analogous manner to Example 2. By analogous work-up, the first product is obtained

43.3 g, m.p. 51.5-52.5 ° C. After evaporation of the ethanol, the mother liquor is applied to a column of 480 g of neutral alumina (activity II) with benzene.

Chromatography first eluting with petroleum ether. 11.9 g of less polar and non-crystalline fractions were thus removed. Then, 8.3 g of the desired compound melting at 51-52 ° C is eluted with benzene. Total yield: 51.6 g (61%).

Example 4

A mixture of 180 g of potassium carbonate, 380 ml of dimethylformamide, 51 g of 3-fluorothiophenol, 5 g of copper and 75.2 g of 2,5-dichloroacetophenone is stirred under nitrogen for 5 h in a bath heated to 140-150 ° C. After cooling to 100 ° C, 10 g of activated carbon are added, filtered, and dimethylformamide is completely distilled off in vacuo from the filtrate. The residue (125 g) was applied to a column of 420 g of silica gel with benzene and chromatographed eluting with benzene. 90.8 g of a homogeneous oily product are obtained, which is dissolved in 85 ml of ethanol and left to crystallize. 24.3 g of product melting at 51-52 ° C crystallized. The mother liquor was evaporated and the residue was distilled under vacuum. 30.4 g of II are obtained. m.p. 160-164 ° C / 107 Pa, which upon cooling crystallizes and melts at 52 ° C. A total of 54.7 g (50%) of the desired substance I is thus obtained.

Claims (4)

SUBJECT A process for the preparation of a novel 2- (3-fluorophenylthio) -5-chloroacetophenone of the formula I, characterized in that the reaction is 2,5-dichloroacetophenone with 3-fluorothiophenol. YNÁLEZU 2. The process according to claim 1, wherein the reaction is carried out at a reaction temperature of 130 to 140 [deg.] C. in the presence of potassium carbonate and copper without the use of a diluent. 3. The process of claim 1 wherein the reaction is carried out in a similar manner to that described in step 2, but using dimethylformamide as the diluent. 4. A process according to claim 1, wherein the reaction is carried out in an inert atmosphere, preferably nitrogen.