CS266520B1 - Method of 1,3-diarylpyrazole-4-ylacetic acids production - Google Patents

Abstract

The acids of formula I in which R denotes hydrogen, chlorine, fluorine, bromine, methyl or a methoxy group, I imagine anti-inflammatory agents and inhibit thrombocyte aggregation. Formula I acids are simply produced by that is cyanohydrins of 1,3-diaryl-4-pyrazolecarboxaldehydes of formula II wherein R is as defined above said meaning, it is reductively hydrolyzed with stannous chloride in an acid mixture acetic acid, hydrochloric acid, a optionally hydroiodic acid has a positive effect on the purity of the products temperature of 60 ° C to the boiling point of the reaction zm s i.

Description

The invention relates to a process for the preparation of 1,3-diarylpyrazol-4-ylacetic acids of the general formula I.

in which the substituent R represents a hydrogen, chlorine, fluorine or bromine atom, or a methoxy or methyl group.

The compounds of the formula I are known and are substances which have a high anti-inflammatory and anti-platelet aggregation activity.

Following a procedure known from the literature (Rainer G. et al .: Arzneim. Forsch./Drug Res. 31 (I), 649 (1981), Belg, Patent No. 755,924; Brit, Patent No. 1,373,212), the compounds formula I is prepared by cyclizing the phenylhydrazones of 4-substituted acetophenones by the action of a mixture of phosphoryl chloride and dimethylformamide, the 1,3-diaryl-4-pyrazolecarboxaldehydes obtained are reduced either with sodium borohydride or sodium bis (2-methoxyethoxy) dihydroaluminate to alcohols which are converted to chlorides by the action of thionyl chloride. The chlorine derivatives obtained are subjected to a substitution reaction with sodium cyanide, and the nitriles thus produced are hydrolyzed acidically or alkali at elevated temperatures. The disadvantage of this process, despite the generally high yields, is the high laboriousness, the use of hydride reagents in the reduction, and other irritants and toxicants such as thionyl chloride and sodium cyanide. According to the second process (European Patent No. 94,555), the compounds of formula I are prepared by reacting 3-aroylpropionic acids with formaldehyde, cyclizing the obtained hydroxymethyl derivatives to give aroylbutanolides, which are heated to high temperatures for a long time with phenylhydrazine. The dihydropyrazole acids obtained are finally oxidized. The disadvantage of this process is that it involves a time-consuming step requiring high temperatures; also the yields are not high.

The essence of the process according to the invention lies in the fact that the cyanohydrins of 1,3-diaryl-4-pyrazolecarboxaldehydes of the general formula II (Czech author's certificate no. 262 099).

in which the substituent R is as defined above, are reductively hydrolysed by the action of stannous chloride in an amount of at least 1 equivalent, in a mixture of acetic acid and hydrochloric acid at a temperature of 60 ° C up to the boiling point of the reaction mixture.

The reductive hydrolysis is preferably carried out in the presence of a catalytic amount of hydroiodic acid, which has a favorable effect on the purity of the acid obtained of formula I.

The crude, wet cyanohydrin of formula II can be advantageously used for the reaction, since water does not affect the course of the reaction and the aldehyde contained in the starting cyanohydrin can be easily separated and regenerated after reductive hydrolysis.

CS 266 520 Bl 3

It has been found that the compounds of the formula I can be prepared by a considerably less laborious process which is easy to implement even on a technological scale.

The compounds of the formula I can also be prepared by reductively hydrolyzing the cyanohydrins of the formula II by the action of a mixture of red phosphorus and hydroiodic acid. The disadvantage of the process is that the reaction products are less pure and the yields are lower.

The following examples illustrate, but do not limit, the generality of the production method according to the invention.

Example 1

To a mixture of 31.0 g (0.1 mol) of cyanohydrin of formula II (R = Cl), 60 ml of acetic acid, 60 ml of concentrated hydrochloric acid and 0.5 ml of concentrated hydroiodic acid are added 24.0 g (0.106 mol) of dihydrate stannous chloride, the mixture is heated to a gentle boil and kept at the same temperature for 2 h. The reaction mixture is cooled to 25 DEG C., filtered and the solid is washed on the filter with 10 ml of acetic acid. The combined filtrates were diluted with water (250 mL) and extracted twice with chloroform (250 and 50 mL). The combined organic phases were washed with water (100 ml) and evaporated to dryness on a rotary evaporator. The solid residue is recrystallized from aqueous ethanol or methanol. 30 g, i.e. 95.9% of the acid of formula I (R = Cl) with a melting point of 151-151.5 DEG C. and a purity of 99.94% according to high pressure liquid chromatography (HPLC), are obtained. *

Example 2

To a mixture of 66 g of crude cyanohydrin of formula II (R = Cl, containing 35.2 g of water, and according to HPLC consisting of 91% cyanohydrin, 6.5% of the corresponding aldehyde and 2.5% of impurities), 115 ml of acetic acid and 70 ml of concentrated hydrochloric acid, 24 g (0.106 mol) of stannous chloride dihydrate are added and the mixture is heated at 110 DEG C. for 3 h. The reaction mixture was cooled to 25 ° C, filtered and diluted with 225 ml of chloroform and 250 ml of water. The aqueous phase is separated and extracted with a further 40 ml of chloroform. The combined organic phases are washed twice with water (100 and 80 ml) and then extracted with 250 ml of 1 N potassium hydroxide solution. The organic phase is separated off and extracted with a further 50 ml of 0.25 N potassium hydroxide solution. The aqueous-alkaline extracts were combined and, after adding 200 ml of chloroform, acidified to pH 3 with hydrochloric acid. After shaking, the chloroform layer was separated and concentrated to reflux in a volume of 60 ml. The solution is cooled to 15 ° C and optionally seeded. After standing for 3 hours, the precipitated crystals are filtered off with suction on a frit and washed with pre-cooled chloroform. 25.8 g (82.5%) of the acid of the formula I (R = Cl) are obtained, the properties of which are identical to Example 1.

Example 3

Following the procedure of Example 1, except that a stoichiometric amount of stannous chloride was used in the reaction, the acid of formula I (R = H) was prepared from the cyanohydrin of formula II (R = H) in a yield of 92.1%, the HPLC purity of which was 99 , 9%. The melting point is in the range of 120.5 to 122 ° C.

Example 4

Following the procedure of Example 2, except that the reaction with stannous chloride was carried out at 60 ° C for 7 h, 83.1% of the acid of formula II was obtained from the crude cyanohydrin of formula II (R = Br, content 92% by HPLC). I (R - Br) m.p. 141-5-142.5 ° C.

Example 5

Following the procedure of Example 2, except that the reaction was carried out in the presence of 0.25 ml of concentrated hydroiodic acid, the acid of formula I (R = CH _{) was prepared from cyanohydrin of formula II (R = CH 3} ) having a purity of 90% by HPLC. ^) in a yield of 84.6% _F mp 140-141 ° C

CS 266 520 31 (from aqueous ethanol).

Example 6

Following the procedure of Example 4, the cyanohydrin of formula II (R = OCH ₃ ), which is 91% pure by HPLC, affords the acid of formula I (R = OCH 3), m.p. 160-161.5 ° C, in 85.1% yield. (crystallized from acetic acid).

Claims (3)

OBJECT OF THE INVENTION A process for the preparation of 1,3-diarylpyrazol-4-ylacetic acids of the general formula I (I) in which the substituent R represents a hydrogen, chlorine, fluorine or bromine atom, or a methoxy or methyl group, characterized in that the cyanohydrins of 1,3-diaryl-4-pyrazolecarboxaldehydes of the general formula II in which the substituent R is as defined above, are reductively hydrolysed by the action of stannous chloride in an amount of at least 1 equivalent, in a mixture of acetic acid and hydrochloric acid at a temperature of 60 ° C up to the boiling point of the reaction mixture. 2. The process according to item 1, characterized in that the reductive hydrolysis is carried out in the presence of a catalytic amount of hydroiodic acid. 3. The process according to items 1 and 2, characterized in that crude cyanohydrin of the general formula II is used for the reductive hydrolysis. Severography, n. P., MOST Price 2.40 CZK