CS219752B1 - Method of making the derivative of the 2-phenylpropione acid - Google Patents

Description

SOCIALIST REPUBLIC OF CZECHOSLOVAKIA (W) DESCRIPTION OF COPYRIGHT CERTIFICATE 219752 (11) (Bi) (51) Int. Cl.3 C 07 C 57/30 // A 81 K 31/19 (22) Enlisted 17 02 81 (21) (PV 1135-81) DISCUSSION & DISCOVER (40) Published 27 08 82 (45) Released 15 09 85 (75)

Author of the invention PALEČEK JAROSLAV ing. CSc., DEDEK VACLAV prof. CSc., SVOBODAJIŘÍ Ing., LUTIŠANOVÁ MARTA ing., KUBELKA VLADISLAV RNDr.CSc., MOSTECKÝ JIŘÍ prof. DrSc., member of the correspondent of CSAV, PRAGUE (54) Method of production of 2-phenylpropionic acid derivatives 1

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of 2-phenyl-propionic acid derivatives of the formula: EMI2.0 [0017] wherein R is hydrogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 4 atoms carbon or a group of general formula Ia

Painful inflammation of the joints and the surrounding tissue occurring in rheumatoid arthritis, Strel's disease, osteoarthritis and various kinds of non-specific inflammatory conditions), analgesic and antipyretic (e.g., rheumatic fever and their consequences) effects. The substances produced by the process of the invention have superior properties to those of salicylic acid. In general, they exhibit a higher therapeutic index, with an average less toxic, more soluble and more stable in aqueous solutions.

The prior art processes for the preparation and preparation of this class of substances which have used a single liquid hydrogen cyanide (British Patent No. 971,700) are disadvantageous in terms of both safety and hygiene. Another process whereby the corresponding phenylacetic acids obtained from the substituted acetophenols by Willge- tht reaction (e.g., Patent No. 130,611) are methylated and then decarboxylated to the desired 2-phenylpropionic acid derivatives at the same time by hydrolysis. very demanding in terms of technology and technology, whereby the yields in the individual stages of the synthesis are often relatively low.

Other methods that utilize Darzens condensation (e.g., U.S. Patent No. 219,752 wherein R 1 is hydrogen, alkyl of 1 to 3 carbon atoms, or halogen, such as fluoro, chloro, bromo, and iodo.

Said group of compounds of formula I exhibits significant therapeutic effects in both human and veterinary medicine [Nature 181, 773 (1958)]. They are well known for their anti-inflammatory (e.g., at 219,346,226), ie, the reaction of a substituted acetophenone with ethyl chloroacetate in an inert atmosphere in the presence of strongly basic agents such as sodium, sodium amide, sodium hydride, sodium ethylate. to form glycidoesters which can be converted to substituted 2-phenylpropionic acid aldehydes in a known manner. The oxidation of these aldehydes then gives the desired substituted 2-phenylpropionic acids. This method of production also has a number of disadvantages: the difficulty in obtaining pure glycide ester from the reaction mixture after Darzens condensation; for oxidacialdehyde, expensive oxidizing agents (silver oxide) are used, or the desired product is difficult to isolate from the by-products by using available and inexpensive oxidizing agents.

These known processes are followed by a method according to the invention which completely removes or avoids the disadvantages.

The present invention provides a process for the preparation of the 2-phenylpropionic acid derivative of Formula I wherein the substituted benzene derivative of Formula II is 52 4.

ammonium salts, or with inorganic acid halides at 60 to 140 ° C, the corresponding halide of formula V is obtained

(IN)

wherein R is as defined above and X is chlorine, bromine or iodine. In the following step, the substitution of the halogen in the compound of formula V for the nitrile group is carried out either by treatment with alkali metal cyanide in an aprotic polar solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrothiophene-1,1-dioxide, or tetra- alkylammonium cyanide having a carbon number of 1 to 4, and a substituted 2-phenylpropionitrile of formula VI

r-ZA-chcn (lf)

wherein R is as defined above, by acting with an acetyl halide or acetic anhydride in the presence of a Lewis acid (for example, aluminum chloride, ferric zinc chloride) in an environment of a chlorinated organic solvent such as dichloroethane, trichlorethylene to form the substituted acetophenone of formula IIIR (phi) ) wherein R is as defined above. In the next step, the compound

of formula (III) is converted, either by reduction with complex hydride, or by hydrogenation on a nickel catalyst to a hydroxy derivative of formula (IV) wherein R is as defined above.

By reacting the hydroxy derivative of the formula IV with hydrohalic acid, optionally in the presence of its calcium zinc, wherein R is as defined above, it is hydrolysed either in the presence of an acid or alkali. a strong inorganic acid, such as sulfuric acid and phosphoric acid, in a ratio of 1: 1 to 3: 1 to 3 in elevated temperature, 60 to 150 ° C, reaction mixture.

The alkaline hydrolysis is carried out by heating the nitrile of formula VI in an aqueous alcoholic solution in a volume ratio of 0.6 to 1: 1 with sodium hydroxide or potassium hydroxide. After the hydrolysis is complete, the alcohol is distilled from the reaction mixture under reduced pressure, the reaction mixture is cooled and the free acid from the alkali salt is a strong inorganic acid. The crude acid is treated identically in both cases. If it is eliminated in solid form, it is isolated by suction only, while the oily acid is isolated by extraction with a water-immiscible solvent which is then evaporated and the desired product is purified by crystallization or distillation.

The required substituted benzene-general derivatives of formula II, if not commercially available, are preferably prepared by the following sequence of reactions: benzene is acylated with the corresponding acyl halide or anhydride in the presence of Lewis acids, and the obtained phenone is converted by zinc reduction into a concentrated one. hydrochloric acid (Clem-219732 mens reduction) or hydrazine hydrate in an alkaline medium or hydrogenation of molybdenum disulfide to the desired compound of formula II. Further, the compound of formula (II) can be obtained by converting the obtained phenone into ethylthioacetal by reaction with 1,2-ethanedithiol and ethylenetioacetal phenolate to reduce the compound of formula (II) by heating with Raney nickel in methanol or ethanol.

The process according to the invention has a number of advantages: The yields in the individual reaction stages are 60 to 95% high; intermediates readily purify by distillation and the necessary chemicals are readily available and inexpensive.

The method of the invention is illustrated by several examples. EXAMPLE 1 1-Acetyl-4-isobutylbenzene (Compound of Formula III wherein R = CH3 / 2CHCH2) A mixture of 391.3 g of aluminum chloride in 1560 ml of 1,2-dichloroethane was added with vigorous stirring at 0-5 ° C. 260 g of isobutylbenzene and 166.1 g of acetyl chloride over 1 to 1.5 hours. After stirring for 3 hours at 15-20 ° C, the reaction mixture was poured onto 2400 ml of ice, the organic phase was separated and the aqueous extracted with 3 X 300 ml of 1,2-dichloroethane. The combined extracts were washed with water (300 mL), 2% sodium bicarbonate solution (200 mL), water and dried over magnesium sulfate. After distilling off the solvent, distillation of the residue yielded 262 g of product with a boiling point of 139 to 142 ° C at 2 kPa. The spectral characteristics are consistent with the retained structure. Example 2 1-Acetyl-4-phenylbenzene (compound of formula III wherein R = C 6 H 5) To a suspension of 1248 g of aluminum chloride in 1360 mL of 1,2-dichloroethane was added 374.2 g with vigorous stirring at the reaction mixture temperature of 0 to 5 ° C. (406 mL) of acetic hydride over 1-2 hours. After stirring for 20 to 30 minutes at this temperature, 600 g of biphenyl dissolved in 780 ml of the same solvent was added to the reaction mixture over 2 hours. Thereafter, the reaction mixture was worked up as in Example 1 for 10 hours at 16-20 ° C and with ice / water. Distillation gave 409 g of product having a boiling point of 206 to 210 ° C at a pressure of 1.6. kPa, whose structure is consistent with the interpretation of spectra. Example 3 1-Acetyl-4-propylbenzene (compound of formula III wherein R = 11-C3H7)

It was prepared according to the procedure described in Example 1 from 382 g of aluminum chloride, 246 g of propylbenzene and 166 g of acetyl chloride in a yield of 82%. Boiling point 142-144 ° C, 3.5 kPa. Example 4 4-Isobutylphenyl-1-ethanol (compound of formula IV wherein R = CH 3 / CHCH 2)

Procedure A: To a suspension of lithium aluminum hydride (3 g) (150 mL of absolute ether) was added 1-acetyl-4-isobutylbenzene (35.2 g) dissolved in ether (50 mL) over 0.5 hour. After heating the reaction mixture for 1 hour, after cooling, the reaction mixture was quenched with 10 ml of water and finally with 30 ml of dilute hydrochloric acid (1: 1). After separation of the organic phase, the aqueous layer was extracted with 2 x 50 ml of benzene and combined with water extracts. and dried over anhydrous magnesium sulfate. After distilling off the solvents, 32.5 g of product were obtained by distillation of the residue with a boiling point of 92 to 94 ° C and a pressure of 133 Pa. Spectral data confirms the designed structure.

Procedure B: To a solution of 35.2 g of 11-acetyl-4-isobutylbenzene in 80 ml of benzene, 30.3 ml of a 70% benzene solution of sodium bis- (2-methoxyethoxy) aluminum hydride were added with vigorous stirring over 10 minutes and then the reaction was quenched. the mixture was heated for 1 hour and, after cooling, quenched with 90 ml of 10% strength hydrochloric acid. After separation of the benzene layer, the aqueous phase was extracted with 30 ml of benzene, the combined extracts washed with water and worked up as in Method A. 30.6 g of product were obtained with a boiling point of 91-93 ° C at 1 mm Hg. Example 5 4-Isobutylphenyl-1-chloroethane (Compound V, where R = / CH 3 / 2CHCH, X = Cl) Procedure A:

A mixture of 27.2 g of 4-isobutylphenyl-1-ethanol, 36.6 ml of concentrated hydrochloric acid and 16.7 g of calcium chloride was heated to reflux for 2 hours. An additional 18.3 ml of concentrated hydrochloric acid and 8.3 g of calcium chloride were then added and the boiling point was again heated for 4 hours. The cold reaction mixture was extracted with 2 X 20 mL of benzene, the combined organics washed with water, dried with anhydrous calcium chloride, and after distilling off the solvents, 25.3 g of product with a boiling point of 76-78 ° C were obtained at 219752 7 to 133 Pa. whose structure is consistent with the interpretation of the mass spectrum.

Procedure B:

A mixture of 14.6 g of 4-isobutylphenyl-1-ethanol, 25 ml of a hydrobromic acid azeotrope and 10 ml of hydrochloric acid and 0.3 g of triethylbenzylammonium chloride was heated to reflux for 4 hours. After cooling, the organic layer was separated and the aqueous phase extracted with benzene. After analogous treatment as in Procedure A, 15.17 g of product were obtained with a boiling point of 105 to 108 degrees Celsius at a pressure of 400 Pa, whose mass spectrum is identical to the spectrum of the process. A. EXAMPLE 6 4-Isobutylphenyl-1-bromoethane (Formula V compounds wherein R = CH3 / 2CHCH2, X = Br)

A mixture of 32.5 g of 4-isobutylphenyl-1-ethanol, 63 ml of azeotropic hydrobromic acid, 0.4 g of tetrabutylammonium bromide was cooled after 4 hours to boiling, the oil layer was separated and the aqueous phase extracted with 2 x 20 ml of benzene. After analogous treatment of the reaction mixture as in Example 5, 34.8 g of a product having a temperature of 96-98 ° C were obtained at a pressure of 133 Pa, the nuclear magnetic resonance spectrum of which is consistent with the proposed structure. Example 7 2- (4-isobutylphenyl) propionitrile (Compound of Formula VI wherein R = CH3 / 2CHCH2) Intensive stirring of 28.3 g of 4-isobutylphenyl- was added to a suspension of 12.8 g of sodium cyanide in 42 ml of dimethylformamide. Of 1-chloroethane in 30 ml of the same solvent. The reaction mixture was then heated at 100-135 ° C for 6 hours. After cooling, the solids were filtered off with suction, washed with 30 ml of benzene, the filtrate was evaporated in vacuo to give dimethylformamide and the residue was taken up in 50 ml of ice-water, the organic phase separated and the aqueous extracted with 2 x 40 ml of toluene. The combined organics were washed with an unsaturated solution of the kitchen salt, dried over magnesium sulfate, and fractionated on a column (ca. 23.3 g of product was obtained with a melting point of 98 DEG-102 DEG C. at a pressure of 240 mbar). Example 8 2- (4-Isobutylphenyl) propionic acid (a compound of formula I wherein R 1 / CH 3/2 CHCH 2) 1, 3.1 mL of concentrated sulfuric acid, 5 mL of concentrated acetic acid and 3, 1 milliliter was heated with vigorous stirring at a bath temperature of 130-150 ° C for 6 hours, after cooling, the reaction mixture was diluted with 10 ml ice water and the precipitated oil layer after seeding with crystalline solids. 2.65 g of the above acid having a melting point of 72 DEG-74 DEG C. The spectral characteristics are in agreement with the proposed structure.

Procedure A: To 1500 g of amalgam zinc and 800 ml of concentrated hydrochloric acid, 148 g of isobutyrylphenone dissolved in 450 ml of ethanol and 1000 ml of concentrated hydrochloric acid were added under vigorous stirring over 1 to 1.5 hours. (exothermic reaction). The reaction mixture was then heated to boiling for 0.5 to 1 hour and its composition was checked by gas chromatography. The complete reduction was cooled, the zinc separated (1140 g) and washed with 2 x 100 ml of benzene. The organic layer was separated from the liquid phase, the aqueous phase extracted with 2 x 100 ml of benzene after washing, the combined extracts washed with saturated brine, dried with magnesium sulfate and fractionated on a column to obtain 116.5 g of isobutylbenzene at a temperature of 1101 kPa. Process B: 150 g of isobutyrylphenone were hydrogenated in a 1 liter autoclave in the presence of 15 g of fine-powdered molybdenum disulfide at 300 ° C and 10 MPa. After filtering off the catalyst, 120 g of isobutylbenzene boiling 167 to 169 ° C at 101 Pa. Example 10 1-Phenyl-1-ethanol (Compound of Formula IV wherein R-H) To 43 ml of a benzene solution of 70% Synthesis of (bis-2-methoxyethoxy / sodium-sodium) was added dropwise at 25 ° C with vigorous stirring. + 5 ° C 36 g (0.3 mol) of acetophenone dissolved in 100 ml of benzene. Then the reaction mixture was heated to boiling for 1 hour, cooled, quenched with 20% hydrochloric acid, the organic layer was separated and the aqueous phase extracted with 2 x 50 ml of benzene. The combined organic portions were washed with water (50 mL), magnesium sulfate, and solvents.

A mixture of 3.05 g of 2-4-isobutylphenyl) propionitrile 215752 was vacuum-dried on a rotary evaporator. 34.5 g of product was obtained by distillation of the residue. mp 92-94 ° C / 1.6 kPa. The mass spectrum is consistent with the proposed structure. EXAMPLE 11 1- (4-Biphenyl) -1-ethanol (a compound of Formula IV wherein R = GeHs) To a suspension of 15 g of lithium aluminum hydride with 75 ml of ether was added 19.4 g of 4-acetylbiphenyl dissolved in 50 ml of the same. solvents. After analogous treatment with the reaction mixture as in Example 4, 17.0 g of product m.p. 85-86 ° C / hexanebenzene was obtained. EXAMPLE 12 1- (2-Fluoro-4-biphenyl) -1-ethanol (Compound of Formula IV wherein R = 2'-FC6H4) To a suspension of 1 g of lithium aluminum hydride in 60 mL of absolute ether was added 0-5 ° C. 12.7 g of 1- (2'-fluoro-4-biphenylyl-1-ethanone dissolved in 35 ml of e-ther. After analogous treatment of the reaction mixture as in Example 4, 11.9 g of the above product was obtained. Example 13 1-Phenyl-1-chloroethane (compound of formula V where R = Η, X = Cl)

A mixture of 26 g of 1-phenyl-1-ethanol, 40 ml of concentrated hydrochloric acid and 17 g of anhydrous calcium chloride was refluxed for 6 hours. It was then treated as in Example 5 to obtain 24.4 g of the above product, mp 90-91 ° C, at a pressure of 4.4 kPa. Example 14 1- (4-Methoxyphenyl) -1-chloroethane (Compound of Formula V wherein R = CH 3 O, X = Cl 1)

Proceed as in Example 5, 42 g of 1- (4-methoxyphenyl) -1-ethanol, 80 ml of concentrated hydrochloric acid and 38.5 g of anhydrous calcium chloride, to obtain 38.5 g of the above product. 60 to 65 ° C at a pressure of 1.6 kPa, the structure of which is in accordance with the interpretation of the spectrum. EXAMPLE 15 2- (4-Methoxyphenyl) propionitrile (Compound * to Formula VI wherein R = CH3O) To a suspension of 12.8 g of anhydrous sodium cyanide in 42 mL of dimethylformamide was added 25.4 g of 1- ( 4-methoxyphenyl) -1-chloroethane in 15 ml of the same solvent. After treating the reaction mixture as in Example 7, 18.8 g of the above product were isolated. 112-116 ° C at 0.6 kPa. The mass spectrum is in accordance with the proposed structure. Example 16 2- (4-Biphenylyl) propionic acid (Compound of Formula I wherein R = C6H5)

A mixture of 4.8 g of 2- (4-biphenyl) propionitrile, 4.8 ml of concentrated sulfuric acid, 4.8 ml of concentrated acetic acid and 4.8 ml of water was heated with vigorous stirring at 140-145 ° C for 6 hours. After treatment of the reaction mixture as in Example 8, 3.42 g of the above product tt 145-147 ° C (ethanol-hexane), whose mass spectrum is in accordance with the structure, was obtained. Example 17 2- (2'-Fluoro- 4-biphenylyl) propionic acid (compound of formula I wherein R = 2'-FC6H4)

A mixture of 12 ml of concentrated sulfuric acid, concentrated acetic acid and water in a ratio of 1: 0.8: 1.2 and 3.2 g of 2- (2'-fluoro-4-biphenylyl) propionitrile was heated to room temperature for 7 hours. 135 DEG-145 DEG C. was treated as in Example 8. 2.31 g of the above product m.p. 149-151 DEG C. was isolated from benzene-hexane. The mass spectrum is in agreement with the proposed structure. Example 18 2-Phenylpropionic acid (compounds of Formula I wherein R - H)

It was treated as in Example 8. 24.7 g of the above acid were obtained from 28 g of 2-phenylpropionitrile at 160 ° C at a pressure of 3.2 kPa. The methyl ester was prepared from 1.1 g of the acid by treatment with diazomeethane ether 117-111. 119 ° C / 2.7 kPa- Mass spectra are in accordance with the proposed structure.

Claims (10)

219752 11 12 OBJECT A process for the preparation of 2-phenylpropionic acid derivatives of the formula I R 1 - (CH 2) CHOOH CH. J (D wherein R is hydrogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 4 carbon atoms or 1a and 11a where R 1 is hydrogen, alkyl of 1 to 3 carbon atoms, or fluorine, chlorine or iodine) characterized in that the substituted benzene derivative (II) is present wherein R is as defined above, reacting with the acetyl halide or acetic anhydride, the presence of a Lewis acid in an intermediate chlorinated organic solvent to form a substituted acetophenone of formula III R 1 -Y-COCH 5 (III) wherein R is as defined above, which is converted by reduction with a complex hydride or catalytic by hydrogenation to a compound of formula IV (IV) wherein R is as defined above, which reacts with a hydrohalic acid, optionally in the presence of a salt thereof, or with an inorganic acid halide; CHXI CH. (V) wherein R is as defined above and X is chloro, bromo or iodo, which gives a nitrile of formula VI Κ-θ by the action of potassium or sodium cyanide in the middle of polar aprotic solvents or tetraalkylammonium cyanide having a carbon number of 1 to 4 -CHCW CH. 5 (VI) wherein R is as defined above, which is hydrolyzed in an acidic or basic medium. 2. The process of claim 1 wherein the Lewis acids are chloroaluminum, ferric or zinc. 3. A process as claimed in claim 1, wherein the chlorinated solvent is a chlorinated alkanes and alkenes having carbon numbers of 1 to 3, for example 1,2-dichloroethane or trichlorethylene. 4. The process of claim 1 wherein the complex hydride is lithium aluminum hydride, sodium borohydride or sodium bis- (2-methoxyethoxy) aluminum hydride. 5. A process as claimed in claim 1, wherein calcium or zinc salts are used as the hydrohalic acid salt, and thionyl chloride or phosphorus oxytrichloride is used as the inorganic acid halide. 6. A process according to claim 1, wherein the hydrohalic acid salt is a quaternary ammonium salt, preferably tetrabutylammonium halide or triethylbenzylammonium halide. 7. The process of claim 1 wherein the polar aprotic solvents are dimethylformamide, dimethyl acetamide, tetramethylurea, N-methylpyrrolidone, tetrahydrothiophene-1,1-dioxide. 8. The process of claim 1 wherein the quaternary ammonium cyanide is tetraethylammonium cyanide or tetrabulamylammonium cyanide. 9. Process according to claim 1, characterized in that the acid hydrolysis is carried out using a mixture of acetic acid and a strong inorganic acid, for example sulfuric acid or phosphoric acid in a volume ratio of 1: 1 to 3: 1. to 3. 10. Process according to claim 1, characterized in that the alkaline hydrolysis is carried out in a water-alcohol medium in a ratio of 0.6 to 1: 1 by means of sodium hydroxide or potassium hydroxide and after the hydrolysis is finished, the product - acid is released by a strong inorganic acid. -nou.