CS262249B1 - Preparation of 4-cyanomethyl-1-phenyl-3- (4-chlorophenyl) pyrazole - Google Patents

Abstract

The compound of formula I represents an important intermediate in the production of substances with anti-inflammatory effects and is prepared by condensing 3-(4-chlorobenzoyl)propionitrile of formula II with phenylhydrazine of formula III in the presence of a catalytic amount of acid, for example acetic acid, without solvent at a temperature of 80 to 120 °C, or in methanol or ethanol at a temperature of 20 to 55 °C. The obtained phenylhydrazone of formula IV is then cyclized by the action of at least 2 equivalents of phosphoryl chloride in dimethylformamide at a temperature of 60 to 95 °C.

Description

The present invention relates to a process for the preparation of 4-cyanomethyl-1-phenyl-3- (4-chlorophenyl) pyrazole of formula I.

The compound of formula (I) is known and represents an important intermediate for the production of anti-inflammatory agents.

Following the literature procedure [Rainer G. et al., Arzneim. Forsch./Drug Res. 31 (1): 649 (1981); U.S. Patent No. 755,924; Briton. No. 1,373,212], the compound of formula I is produced by cyclizing phenylhydrazone of 4-chloroacetophenone with a mixture of phosphoryl chloride and dimethylformamide, the resulting 4-formyl-1-phenyl-3- (4-chlorophenyl) pyrazole is reduced with either borohydride sodium, or sodium bis (2-methoxyethoxy) dihydroaluminate to the alcohol, which is converted to thionyl chloride by treatment with thionyl chloride and eventually undergoes a substitution reaction with sodium cyanide, the disadvantage of this process, despite generally high yields, and irritating and highly poisonous substances such as thionyl chloride and sodium cyanide The second process (Belgian Patent No. 755 924) produces a compound of formula I by dehydrating the corresponding amide, with the obvious disadvantage of having to laboriously produce the starting amide .

The process according to the invention is characterized in that 3- (4-chlorobenzoyl) propionitrile of the formula II

condensates with a phenylhydrazine of formula III CeH5-NH. NH 2 (III) in the presence of H ⁺ as a catalyst at 80 to 120 ° C, and the obtained phenylhydrazone of 3- (4-chlorobenzoyl) propionitrile of formula IV is cyclized by treatment with phosphoryl chloride, at least 2 equivalents, in dimethylformamide at 60 to 95 Deň: 32 ° C.

In the condensation of a compound of formula II with a compound of formula III, acetic, formic or hydrochloric acid is used as the H ⁺ source. This reaction is carried out without solvent or equally successfully in an environment of a polar organic solvent such as ethanol, methanol or acetonitrile at a temperature of 20 to 55 ° C.

In the cyclization of a compound of formula IV which is novel by the action of phosphoryl chloride, dimethylformamide is not only used as a solvent. It reacts with phosphoryl chloride to form its own cyclizing agent, a strongly electrophilic iminium salt.

It has been found that the compound of formula (I) can be produced by a less laborious process that is easy to implement even on a technological scale. In addition, work with highly toxic sodium cyanide and expensive hydride reagents has been eliminated.

The following examples illustrate but do not limit the generality of the inventive process.

Example 1

(a) Phenylhydrazone of 3- (4-chlorobenzoyl) propionitrile (IV)

To a mixture of 50 g (0.258 mol) of 3- (4-chlorobenzoyl) propionitrile (II) and 27.9 g (0.258 mol) of phenylhydrazine (III) at 80 ° C is added 0.75 ml of acetic acid and the reaction mixture is heated 20 minutes at 110 ° C. After cooling to 60 DEG C., 100 ml of ethanol or methanol are added to the crystalline mixture, cooled to 20 ^DEG C. and held at that temperature for 1 hour. The crystals are then aspirated and washed with 10 ml of the same solvent. 68.3 g (93.3%) of a crystalline product containing one impurity in an amount of about 5%, of satisfactory quality for the subsequent cyclization, is obtained. Recrystallization from acetone / hexane removes the impurity. Melting point: 197-200 ° C.

b) 4-cyanomethyl-1-phenyl-3- (4-chlorophenyl) pyrazole (I)

3.24 g (21.1 mmol) of phosphoryl chloride are added dropwise to the 1C ml of dry DMF at 15-20 ^° C with stirring over 5 minutes, the solution is stirred for 15 minutes at 20 ° C and 2.0 g are added in one portion. (7 mmol) of 3- (4-chlorobenzoyl) -propionitrile (IV) phonylhydrazone The mixture is heated to 80 DEG C. and kept under stirring at this temperature for 2.5 hours. The mixture is cooled, 40 ml of water and 50 ml of ether are added. The aqueous phase is extracted with 15 ml of ether, the combined shakes are washed with water (20 ml) and brine (15 ml), and, after drying over sodium sulfate, are evaporated on a rotary evaporator and the residue is crystallized from ethanol or methanol. . There were obtained 0.79 g of crystals, m.p. 122-124 ^C C. Yield: 38.6% of theory.

Example 2

To a solution of 5.0 g (25.8 mmol) of 3- (4-chlorobenzoyl) prenepouitrile (II) in 25 ml of ethanol at 35 ° C was added 2.79 g (25.8 mmol) of phenylhydrazine (III) and 5 ml of ethanol. drops of acetic acid. The reaction mixture was heated at 55 ° C for 1 hour and then cooled. After standing for 1 hour at 20 ° C, the precipitated crystals are aspirated and the mother liquors are concentrated to 1/3 of the original volume. The separated crystals were combined and dried at room temperature. 89.1% (6.5 g) of phenylhydrazone 3- (4-chlorobenzoyl) -propionilrile (IV), which contains the same impurity as the product of Example 1a, is obtained in an amount of 6.5%.

Example 3

Following the procedure of Example 1b except that 2 equivalents of phosphoryl chloride were used, the nitrile of formula I was obtained in a yield of 20.4%.

Example 4

Following the procedure of Example 1b, except that the condensation was carried out at a temperature of 60 ^° C, the nitrile of formula I was prepared in a yield of 28.7%.

Example 5

Following the procedure of Example 1b, with the condensation being carried out at a temperature of 95 ^° C, the nitrile of formula I was obtained in a yield of 37%. Example 6

Following the procedure of Example 1a, except that formic acid or concentrated hydrochloric acid was used instead of acetic acid, the phenylhydrazone of formula IV was obtained in a yield of 89%.

Example 7

Using the procedure of Example 1a, except that the reaction was carried out at 80 ° C for 1 hour or at 120 ° C for 15 minutes, the phenylhydrazone of formula IV was prepared in 92% yield.

ExampleS

Following the procedure of Example 2, except that the reaction was carried out at 20 ° C for 24 hours and using methanol or acetonitrile instead of ethanol, 79 percent of phenylhydrazone IV was obtained.

Example 9

Using the procedure of Example 2 except that formic acid or concentrated hydrochloric acid was used instead of acetic acid, the phenylhydrazone of formula IV was obtained in a yield of 86.7%.

Claims (3)

A process for preparing 4-cyanomethyl-1-phenyl-3- (4-chlorophenyl) pyrazole of formula I The invention is characterized in that the 3- (4-chlorobenzoyl) propionitrile of the formula II is condensed with a phenylhydrazine of the formula III CeH 5 -NH (NH 3) in the presence of H ⁺ as a catalyst at a temperature of 262249 to 80-120 ° C. The chlorobenzoyl-propionitrile of formula IV is cyclized by treatment with phosphoryl chloride, in an amount of at least 2 equivalents, in dimethylformamide at a temperature of 60 to 95 ° C. 2. The process according to claim 1, wherein the source of H ⁺ is acetic, formic or hydrochloric acid. 3. The process according to claim 1, wherein the reaction of the compound of formula II with the compound of formula III is carried out in a medium of a polar organic solvent such as ethanol, methanol or acetonitrile at a temperature of 20 to 55 ° C.