CS218511B1 - Method of making the 2-/substituted phenyl/propionaldehyde - Google Patents

Description

(54) A process for the preparation of 2- (substituted phenyl) propionic aldehydes

The present invention relates to a process for the preparation of 2- (substituted phenyl) propionic aldehydes.

wherein R is hydrogen or (C 1 -C 5) alkyl or a group of formula (Ia),

(wherein R @ ¹ denotes hydrogen or alkyl having 1 to 3 carbon atoms or a halogen atom such as fluorine, chlorine or trifluoromethyl, X denotes hydrogen, fluorine, chlorine or trifluoromethyl.

This group of compounds of formula (I) is an important group of intermediates used to prepare 2-phenylpropionic acid derivatives. These acids are important drugs in human medicine (Nature 181, 773 [1958]} with anti-inflammatory effects in and around the joint inflammation. Analogous anti-inflammatory, analgesic and antipyretic effects, higher than salicylic acid derivatives, also show compounds of formula I.

The hitherto known processes for the preparation and preparation of the compounds of formula I utilize Darzens condensation [cf. U.S. Pat. No. 140,226, Chem. Roar. 55, 283 (1955), Organic Reactions Vol. P. 413 (1957), Methoden der Organischen Chemie (Houben-Weyl) vol. 7/1, p. 326 (1954)], i.e. the reaction of substituted acetophenone with ethyl chloroacetate in an inert atmosphere and in the presence of strongly basic reagents. The glycidoester A prepared in this way,

O

ZI

Ar — C — CHCOOC2 H5,

CHs (A) wherein Ar is a substituted phenyl moiety, upon hydrolysis and decarboxylation, affords the desired aldehyde B,

Ar — CH — CHO

AND

CH 3; (B).

wherein Ar is as defined above.

This process for producing aldehydes has a number of disadvantages. The reaction must be carried out in absolute solvents in an inert atmosphere using hazardous reagents such as sodium, sodium hydride or sodium amide. Obtaining pure glycido ester from the re-conicion mixture after Darzens condensation is difficult. It is always necessary to separate the unreacted starting substituted acetophenone and some of the undesirable by-products of the reaction.

These processes are followed by a process according to the invention which eliminates the known disadvantages. SUMMARY OF THE INVENTION The present invention provides a process for the preparation of 2-subatified phenyl) propionaldehydes of formula (I), which process comprises:

(II) wherein R and X are as defined above, in a strongly alkaline environment, chloroacetonitrile acts in a two-phase aqueous phase-organic phase system in the presence of a phase transfer catalyst at 25 to 70 ° C. The glycidonitrile of formula III obtained,

wherein R and X are as defined above, ihydrolyzed with a solution of hydroxide in an aqueous alcoholic medium to form the glycidic acid salt of formula IV,

wherein R and X are as defined above and M is an alkali metal or alkaline earth metal. Upon liberation of the acid and subsequent decarboxylation, the desired aldehyde of formula I is obtained.

The advantage of the invention is that it is simple to carry out the reaction, cheap reagents and easy

Treatment with reaction mixture. The aldehydes prepared in this way are simply isolated by distillation or crystallization in sufficiently pure form to prepare substituted propionic acids.

The method of the invention is demonstrated in several examples.

Example 1

2-Phenyl-3-cyano-2-methyloxirane (III, R = Η, X = H)

To a mixture of 13.2 g of acetophenone, 20 ml of 50% sodium hydroxide solution, 0.1 g of benzyltrlethylammonium chloride in 30 ml of benzene was added dropwise with vigorous stirring 8.4 g of chloroacetonitrile over 15 minutes at 10 to 20 ° C. After stirring for another 30 minutes at this temperature, the organic phase was separated and the aqueous extracted twice with 10 ml of benzene. The combined organics were washed with water (10 mL), dried over magnesium sulfate and the solvents were distilled off. Distillation of the residue gave 11.2 g of the product of formula III, bp 133-137 ° C at 2.13 kPa. The spectral characteristics were consistent with the proposed structure.

Example 2

2-Phenylpropionaldehyde (I, R = X = H)

A mixture of 9.51 g of 2-phenyl-3-cyano-2-methyloxirane, 50 ml of 10% sodium hydroxide solution and 60 ml of ethanol was heated at reflux for 10 hours (until complete ammonia evolution). The solvents were then removed by rotary evaporation and 30 ml of ethanol-ether (1: 1) was added to the solid residue, the acid salt was filtered off with suction, dissolved in 25 ml of water and acidified with 10 ml of conc. hydrochloric acid was heated in a boiling water bath for 1.5 hours. After cooling, the precipitated oil layer was separated and the aqueous phase was extracted 2 times with 10 ml of benzene. The combined organic layers were washed with water (5 mL), dried (MgSO 4) and the solvents evaporated. Fractionation of the residue yielded 6.1 g of product, m.p. 86-87 ° C at 2.13 kPa, the spectral characteristics of which were consistent with the proposed structure. The product was found to be 98.8% by gas chromatography.

Example 3

2- (4-isoibutylphenyl) -3-cyano-2-methyloxirane [III, R = (CH3) ₂ ] CH2CH2; X = H]

To a mixture of 40.9 g of 4-isobutylacetophenone, 1.2 g of benzaltriethylammonium chloride, 40 ml of 50% sodium hydroxide solution and 50 ml of benzene was added, with stirring, 16.7 g of chloroacetonitrile at a reaction temperature of 10-15 ° C.

218311

WITH

After analogous work-up as in Example 1, 29.5 g of b.p. 120-125 ° C were obtained after column fractionation at a pressure of 93 Pa. The structure of the substance was confirmed by mass and infrared spectra.

Example 4

2.- (4-Phenylyl) -3-cyano-2-methyloxirane (III, R = C 6 H 5; X = II)

To a mixture of 14.3 g of acetylbiphenyl, 14 ml of 50% sodium hydroxide solution, 0.3 g of methyltrioctylammonium chloride, 30 ml of benzene and 7 ml of acetonitrile was added 6.1 g of chloroacetonitrile with vigorous stirring at the reaction temperature over 25 minutes. After stirring for another 40 minutes at this temperature, the reaction mixture was worked up as in Example 1. Crystallization of the residue yielded 12.6 g of the product, mp 72-94 ° C (mixture of geometric isomers). This mixture was separated by silica gel column chromatography to give an isomer of m.p. 104-105 ° C and an isomer of mp 86.5-88.0 ° C. The spectral characteristics are in accordance with the proposed structure.

Example 5

2- (4-isobutylphenyl) propionaldehyde [I; R = (CH3) 2 CHCH2, X = HJ

To 12.4 g of oxiram III, R = (CH 3) 2 CHCH 2, X = H, 50 ml of 10% sodium hydroxide solution, 60 ml of ethanol were added and the reaction mixture was heated at reflux for 12 hours. After analogous work-up as in Example 2, fractionation yielded 6.25 g of the product, m.p. 85-87 ° C at 93 Pa. The mass spectrum is in accordance with the proposed structure.

Example 6

2- (3-fluoro-phenyl) -3-cyano-2-methyloxirane (III; R = Η, X = F).

To a mixture of 15.2 g of 3-fluoroacetophenone (to 80-82 ° C / 1.2 kPa), 20 ml of 50% sodium hydroxide solution, 0.5 g of trioctylmethylammonium chloride in 30 ml of toluene, was added dropwise with vigorous stirring, 6 g of Chloroacetonitrile at a reaction mixture temperature of 10-15 ° C. It was then continued as in Example 1. Distillation yielded 12.5 g of product, m.p.

Claims (6)

Subject A process for the preparation of 2- (substituted phenyl) propionaldehydes of formula I wherein R is hydrogen or C 1 -C 5 alkyl or a group of formula Ia, (Ia) VYNALEZU Wherein R and X are as defined above, the chloroacetonitrile in an alkaline medium acts in a two-phase aqueous-organic phase system in the presence of a phase transfer catalyst at a temperature of 25 to 70 ° C and the glycidonitrile of formula III obtained, wherein R ¹ is hydrogen; alkyl of 1 to 3 carbon atoms or halogen such as fluorine, chlorine or trifluoromethyl, X is hydrogen, fluoro, chloro or trifluoromethyl, characterized in that the substituted acetophenone of formula II, wherein R and X are as defined above, is hydrated with an aqueous alcoholic hydroxide solution to the glycido acid salt of formula IV, 2X8511 where Ra X is as defined above and M is an alkali or non-alkaline earth metal which upon acidification with a strong inorganic acid and subsequent decarboxylation gives the desired aldehyde of formula I. 2. The process of claim 1 wherein sodium or potassium hydroxide or carbonate is used to form the alkaline environment. 3. A process according to claim 1, wherein the organic phase is a corresponding acetophenone or organic solvent, such as benzene, toluene, acetonitrile, dichloromethane. 4. A process according to claim 1, wherein quaternary salts such as triethylbenzylammonium chloride, trioctylmethylammonium chloride or tributylcetylphosphonium bromide are used as the phase transfer catalyst. 5. A process according to claim 1, wherein the hydrolysis of glycidone tril is carried out with sodium, potassium or calcium hydroxide. 6. The process of claim 1 wherein the strong inorganic acid is hydrochloric or sulfuric acid.