CS262099B1 - Process for preparing cyanyhydrines of 1,3-diaryl-4-pyrazolcarboxaldehydes - Google Patents

Abstract

Compounds of formula I wherein R is hydrogen, chloro, fluoro, bromo or methoxy or methyl are novel and are important intermediates in the manufacture of anti-inflammatory agents. They are prepared by reacting 1,3-diaryl-4-pyrazolecarboxaldehydes of formula II wherein R is as defined above with a mixture of sodium or potassium cyanide and acetic acid, formic acid, hydrochloric acid or sulfuric acid, in methanol or ethanol. at 10 to 50 ° C.

Description

The compounds of formula I wherein R is hydrogen, chloro, fluoro, bromo or methoxy or methyl are novel and are important intermediates in the production of anti-inflammatory agents. They are prepared by reacting 1,3-diaryl-4-pyrazolecarboxaldehydes of the formula II in which R is as defined above with a mixture of sodium or potassium cyanide and acetic, formic, hydrochloric or sulfuric acid in methanol or ethanol at 10 to 50 ° C.

0) (Ii)

The present invention relates to a process for the preparation of the 1,3-diaryl-4-pyrazolecarboxaldehydes of the formula I

wherein R is hydrogen, chloro, fluoro, bromo, or methoxy or methyl.

The compounds of formula (I) are novel and are important intermediates in the production of anti-inflammatory agents.

The process according to the invention is characterized in that 1,3-diaryl-4-pyrazolecarboxaldehydes of the formula II

wherein R is hydrogen, chloro, fluoro or bromo, or methoxy or methyl, is reacted with hydrogen cyanide in an amount of at least 1.2 equivalents, in methanol or ethanol at a temperature of 10 to 50 ° C.

In the reaction, mixtures of sodium or potassium cyanide and inorganic or organic acids such as acetic, formic, hydrochloric or sulfuric acids are used as the hydrogen cyanide source.

The compounds of the formula I can also be prepared by reacting the aldehydes of the formula II with liquid hydrogen cyanide. The disadvantage of this process, despite very good yields, is the danger associated with working with highly toxic liquid hydrogen cyanide. The compounds of formula (I) are further accessible also by first converting the aldehydes of formula (II) into sodium bis-sulfite addition compounds, which are then reacted with hydrogen cyanide. In this case, the disadvantage of the method lies in its lower yield and greater laboriousness.

The following examples illustrate but do not limit the generality of the process according to the invention,

Example 1

To a mixture of 8.3 g (0.167 mol) of sodium cyanide and 4 ml of water is added 28.3 g (0.1 mol) of 1-phenyl-3- (4-chlorophenyl) -4-pyrazolecarboxaldehyde (II, R). = Cl) and 200 ml of methanol with stirring at 25 ° C. The reaction mixture was stirred for 5 minutes and then 0.9 ml of acetic acid was added over 5 minutes. The heterogeneous mixture was stirred at 25-30 ° C for 1.25 hours, temporarily diluting and then thickening the mixture. The reaction mixture was diluted with water (300 mL) and after stirring for 5 minutes, the solid was suction filtered on a frit and washed twice with 30 mL of water. 66 to 80 g of a wet product are obtained which contains 35 to 49 g of water according to the suction efficiency and which can be used without further treatment for reductive hydrolysis with stannous chloride in an acid medium.

Free air drying yielded 31 g, i.e. quantitative yield of product, which according to HPLC analysis consisted of 91% cyanohydrin of formula I (R = Cl), 6% of aldehyde of formula II (R = Cl) and 3% of unidentified impurities. This product is also suitable for reductive hydrolysis with stannous chloride without further treatment. Recrystallization of the product from methanol or ethanol gave 25.4 g (82.1 percent) of 1-phenyl-3- (4-chlorophenyl) -4-pyrazolecarboxaldehyde cyanohydrin (I, R = Cl), m.p. 124-126, 5 ° C and HPLC purity 99%.

Example 2

Using the procedure of Example 1, except that 1.2 equivalents of sodium cyanide are used and the reaction is carried out in ethanol, from the aldehyde of formula II (R = Cl), crude cyanohydrin is obtained which contains 72.5 percent cyanohydrin of formula I by HPLC. (R = Cl) and 25% aldehyde of formula II (R = Cl).

Example 1 a d 3

Following the procedure of Example 1, except that a potassium cyanide instead of sodium cyanide and the reaction is carried out at 50 ^Q C, from the aldehyde of formula II (R - CH3) are prepared crude cyanohydrin which yield poi drying, 99% of theory . The product composition having a melting point of 121-140 ° C is 92.5% cyanohydrin of formula I (R = CH 3), 5.5% of aldehyde of formula II (R = CH 3) and 2% of unidentified substances. Example 4

Using the procedure of Example 1, except that the reaction is carried out at 10 ° C and the reaction time is extended to 4 hours, cyanohydrin of formula I (R = H) is obtained in quantitative yield from the aldehyde II (R = H). ), which has a purity of 93% by HPLC and a melting point of 119-142 ° C.

Example 5

Using the procedure of Example 1, except that an equivalent amount of formic acid was used in place of acetic acid, the crude cyanohydrin of formula I (R-Br) was obtained in quantitative yield from an aldehyde of formula II (R = Br). 92%. Melting point: 123-144.5 ° C. Example 6

Using the procedure of Example 1, except that an equivalent amount of concentrated hydrochloric acid or 30% sulfuric acid is used in place of acetic acid and water is initially added to the reaction, the aldehyde of formula II (R = OCH 3) is prepared in 98% yield. cyanohydrin of formula I (R-OCH 3), which has an HPLC purity of 90.5 θ / o; mp 119-139 ^q C.

Example 1 a d 7

Using the procedure of Example 1, except that an equivalent amount of potassium cyanide *, concentrated hydrochloric acid or * 50 percent sulfuric acid, and ethanol was used instead of a mixture of sodium cyanide, acetic acid and methanol, from an aldehyde of formula II (R = Fj) gives a quantitative yield of cyanohydrins of the formula I (R = F), 93% pure by HPLC, melting at 138-161 ° C.

Example

Using the procedure of Example 1, except that twice the amount of acetic acid is used, cyanohydrin of formula I (R = Cl) is obtained in quantitative yield from an aldehyde of formula II (R = Cl), the purity of which according to HPLC (high pressure liquid chromatography) is 93.5%.

Claims (2)

1 R E D M E T A process for the preparation of 1,3-diaryl-4-pyrazolecarboxaldehyde cyanohydrins of the general formula I in which R represents a hydrogen, chlorine, fluorine or bromine atom or a methoxy or methyl group, characterized in that 1,3-diaryl-4 -pyrazolecarboxaldehydes of formula II In which R is as defined above, it is reacted with hydrogen cyanide in an amount of at least 1.2 equivalents, in methanol or ethanol at a temperature of 10 to 50 degrees Celsius. 2. A process according to claim 1, wherein the source of hydrogen cyanide is a mixture of sodium or potassium cyanide and an organic or inorganic acid, for example acetic, formic, hydrochloric or sulfuric acid.