CS239481B1 - Process for the preparation of (±) - 27-isobutylphenyl / propionitrile - Google Patents

Abstract

The method for producing (i)-2-(4-isobutylphenyl) propionitrile from a readily available halogen derivative of the general formula II and an alkali metal cyanide according to the invention consists in carrying out the reaction in a two-phase organic solvent-water system in the presence of phase transfer catalysts, with the molar ratio of the reactants being 1.0:1.0 to 5.0:0.01 to 0.1, at a temperature of 40 to 110 C, after which the aqueous layer is separated after the reaction is complete and the product of the formula I is isolated from the organic phase.

Description

The present invention relates to a process for the preparation of (R) -2- (4-isobutylphenyl) propionitrile of formula I. Said compound of formula 1 is one of the important intermediates in the synthesis of 2- (4-isobutylphenyl) propionic acid, the drug Ibuprofen, currently one of the most commonly used anti-inflammatory drugs with analgesic and antipyretic effects. It is used in inflammation of the joints, rheumatoid arthritis, osteoarthritis, Still's disease and various non-specific inflammatory conditions.

Hitherto known methods of fabric manufacture (see e.g. AO No. 219 752, Jap. U.S. Pat. J5 21, 1536) of formula X from 1- (4-isabutylphenyl) -1-halo-ethanes of formula II wherein X is halogen preferably chlorine or bromine by treatment with an alkali cyanide in a dipolar aprotic solvent such as dimethylsulfoxide, dimethylformamide disadvantages, namely difficulties in regenerating the solvent and removing its residues from the waste water. Longer their relatively high cost in some cases, such as hexamethylphosphoric triamide and its toxicity. Another method protects DD pat. No. 113,889, wherein the starting compound is 2- (4-isobutylphenyl) propionaldehyde prepared by the Darzens reaction from the corresponding acetophenone. Said aldehyde is dehydrated to the desired nitrile of formula 1 after conversion to the corresponding oxime. The disadvantage of this process is the difficulty of carrying out the entire reaction sequence, often requiring work in an inert atmosphere, the use of expensive and hazardous reagents and solvents associated with low yields in some reaction steps. Performing this procedure under technical conditions is difficult, requires complex apparatuses and is therefore disadvantageous from an economic point of view.

These known processes are followed by a process according to the invention which partially or completely removes the existing disadvantages of the known processes. The process for the preparation of the compound of the formula I from the halogenated compound of the formula II prepared according to the known process (No. AO No. 2,9752) and the alkali metal cyanide according to the invention is characterized in that the reaction is carried out in a two-phase organic phase-water medium. phase transfer catalysts based on quaternary ammonium salts, such as tetrabutylammonium hydrogen sulfate, or tetrabutylammonium chloride, or tetrabutylammonium bromide, technical trioctylmethylammonium chloride (Adogen 464, Alignat 336), benzyltriethylammonium chloride. The organic solvent used is an aromatic hydrocarbon such as benzene, toluene, xylene, or a halogenated hydrocarbon having 1 to 2 carbon atoms and 2 to 4 chlorine atoms, preferably dichloromethane or 1,2-dichloroethane. The process according to the invention is carried out by adding to the solution of the halide of the formula II and the quaternary ammonium salt in an organic solvent under intensive stirring at a temperature of 40 to 110 ° C a 50% aqueous solution of alkaline cyanide. up to 20 hours. The molar ratio of the reactants is 1.0: 0.01 to 0.1: 1.0 to 5.0. After completion of the reaction (malting by gas chromatography), the organic phase is separated, washed with water and after drying and distillation of the solvent, a crude product is obtained which contains small amounts of a styrene derivative and 1- (4-isobutylphenyl) -1-ethanol. The crude product can be used without purification for the next reaction step, or by fractional distillation to obtain the pure compound of formula I. The phase transfer catalyst is extracted from the organic phase with water after completion of the cyanation. The combined aqueous extracts are supplemented with the necessary amount of phase transfer catalyst and alkali metal cyanide, untreated or after concentration, and used in a repeated cyanation reaction. This process regenerates 70 to 80% of the phase transfer catalyst.

The advantages of the process according to the invention are the simple carrying out of the reaction, the use of inexpensive solvents combined with their ease of regeneration and the technical isolation of the product. From the above, the economic advantage of this process is obvious.

The invention is illustrated by several exemplary embodiments, which are illustrative and in no way limit the scope of the invention.

Example 1

A solution of 58.0 g (0.295 mol) of the halide of formula II (X = C1) in 400 ml of toluene and a solution of 66.0 g (1.350 mol) of sodium cyanide in 90 ml of water were stirred in the presence of

10.0 g (29.5 mmol) of tetrabutylammonium hydrogen sulfate at 110 ° C for 17 hours (100% conversion of the halide of formula II to products). The organic layer was separated and washed with 3 x 50 mL water. The crude product (61.8 g) was also dewatered by distilling off toluene, which was further distilled under vacuum. The distillate (weight 51.9 g, distillation range 88 ° C / 0.5 kPa to 26 ° C / 1.1 kPa) contained 73 56 nitrile I, 7% styrene derivative and 13 56 l- / 4 according to gas chromatographic analysis. -butylphenyl / ethanol.

Example 2

A solution of 13.2 g (67 mmol) of halide II (X = Cl) in 85 ml of toluene and a solution of 20.0 g (408 mmol) of sodium cyanide in 20 ml of water were stirred in the presence of 1.14 g (3.37). mmol / tetrabutylammonium hydrogen sulfate at 1.0 ° C for 25 hours. The organic layer was separated, washed with 3 x 15 mL of water, and after distilling off the toluene, the crude product was distilled in vacuo. The distillate (weight 11.8 g, distillation range 86 to 1.0 ° C / 0.5 kPa) contained 76% nitrile of formula I, 11 56 1- (4-isobutylphenyl) ethanol and 6 56 styrene derivative according to gas chromatography analysis, The washings were concentrated to a volume of 20 ml and used to further cyanate with the same amount of halide II, sodium cyanide and toluene as in the first reaction. The losses of the phase transfer catalyst during its regeneration were covered by the addition of 0.30 g of tetrabutylaonium hydrogen sulfate. The reaction was complete after 20 hours and the reaction mixture was worked up in the usual manner. 12.4 g of distillate / dest were obtained. containing from 7.5 to the nitrile of the formula I, 86 to the styrene derivative and 14 to 56 (1- (4-isobutyiphenyl) ethanol).

Example 3

A solution of 19.7 g (100 mmol) of a halide of formula II (X = C1) in 50 ml of toluene and a solution of 11.0 g (225 mmol) of sodium cyanide in 1.5 ml of water were stirred in the presence of 1.1 g / 5 mmol. of benzyltriethylammonium chloride at 1.0 ° C for 30 hours. Isolation of the products as described in Examples 1 and 2 gave 17.5 g of distillate / dest. ranging from 75 to 85 ° C (0.4 kPa) of 72 56 nitrile of formula I, 17 56 styrene derivative and 7 56 1- (4-isobutylphenyl) ethanol.

Example 4

A solution of 13.3 g (67.7 mmol) of halide II (X = C1) in 85 ml of toluene and a solution of 20.0 g (408 mmol) of sodium cyanide in 20 ml of water were stirred in the presence of 1.36 g of Aliquat 336. at boiling point for 50 hours. Isolation as described in Examples 1 and 2 yielded 18.4 g of distillate / dest. ranging from 86 to 99 ° C (0.9 kPa) containing 76 56 of a nitrile of the formula I, 356 of a styrene derivative and 456 of (4-isobutylphenyl) ethanol.

Claims (3)

SUBJECT OF THE INVENTION A process for the preparation of (-) - 2- (4-isobutylphenyl) propionitrile of the formula I from a halogenated derivative of the general formula 11, wherein X represents halogen, preferably chlorine or bromine, and an alkali metal cyanide in an organic solvent medium. performs in a two-phase organic solvent-water system in the presence of quaternary ammonium salt type phase transfer catalysts, wherein the molar ratio of the reactants is 1.0: 1.0 to 1.0 5.0: 0.01 to 0.1, at a temperature of 40 to 1.0 ° C, after which the aqueous layer is separated and the product of formula 1 is isolated from the organic phase. 2. A process according to claim 1, wherein the organic solvent is an aromatic hydrocarbon, such as benzene, toluene, xylene or a halogenated hydrocarbon having 1 to 2 carbon atoms and 2 to 4 chlorine atoms, preferably dichloromethane or 1,2-dichloroethane. . 3. A process according to claim 1 wherein the quaternary ammonium salt is tetra-butylammonium hydrogen sulfate, or tetrabutylmonium chloride or tetrabutylammonium bromide, benzyltriethylammonium chloride, trioctyimethylammonium chloride.