CS210640B1 - Process for preparing 2- (3-benzoylphenyl) propionic acid - Google Patents

Abstract

The invention relates to a process for the production of 2-(3-benzoylphenyl)propionic acid and its pharmaceutically acceptable salts. These substances have valuable anti-inflammatory effects. 2-(3-benzoylphenyl)propionic acid and its pharmacological properties were first described in French patent No. 1540 478. In this document and in the first supplement No. 94 930, two synthesis methods were also described according to the following reaction schemes: a) 2 CH-COOH CH,, In the scheme, Hal represents a halogen atom (chlorine or (bromine) and R represents an alkyl radical with 1 to 4 carbon atoms,

Description

(54 J Process for preparing 2- (3-benzoylphenyl) propionic acid)

The invention relates to a process for the production of an acid

2- (3-Benzoylphenyl) propionic acid and their pharmaceutically acceptable salts, which have valuable anti-inflammatory effects.

2- (3-behzoylphenyl) propionic acid and its pharmacological properties were first described in French Patent No. 1540 478. In this document and in the first amendment No. 94 930, two methods of synthesis according to the following reaction schemes were also described:

CH-COOH

CH ,,

In the scheme, Hal represents a halogen atom (chlorine or (bromine)) and R represents an alkyl radical of 1 to 4 carbon atoms, b)

CH-CQOH CH ^ ->

HS

OB 40

CH-COOH

From ¹

CH _a

and contamination of the product as resin is formed. In addition, the process must be carried out in liquid ammonia at a temperature of -40 ° C and with the addition of sodium metal, while at the same time a sodium amide type, so that it is necessary to work in a separate apparatus under very vigorous cooling.

We have now found a novel process for the preparation of 2- (3-benzoylphenyl) propionic acid starting from the new compound 3-propidnylbenzophenone. This synthesis can be illustrated by the following reaction scheme:

Br

COC 4 H 5

CuCN _y

DMF

AND

NC _K. COCH ₅ 1. OH '

2.H

The starting amine can be obtained according to the method of F. Nerdel and L. Fischer, Ber. 87, 217 (1954).

The synthesis of 2- (3-benzoylphenyl) propionic acid according to the above-mentioned patent is carried out in 7 steps, the overall yield being 1.0%.

Another method described in French Patent No. 2,163,875 is shorter and follows the reaction scheme:

HOOC

ch-cn

CH ">

The starting nitrile can be obtained by condensation of propionitrile with 2-chlorobenzoic acid according to the method of E. R. Biehl, J. Org. Chem. 31, 602 (1966), but this synthesis is practically limited to laboratory scale. Accordingly, the industrial production of the starting material and hence the process for the preparation of 2- (3-benzoylphenyl) propionic acid according to the above-mentioned patent cannot be carried out on a larger scale and is very difficult. Even if the weight stated by the author is slightly exceeded, there is a large loss of yield

The starting material for the preparation of the new 3-propionylbenzophenone is 3-bromopropiophenone, which can be obtained according to the method of J. Org. Chem. 23, 1412 (1958).

The present invention provides a process for the preparation of 2- (3-benzoylphenyl) propionic acid of formula VII

WHAT,

CHCOOH- ^CH- ivm and its pharmaceutically acceptable salts, which is carried out by reacting 3-propionylbenzophenone of formula V nr ^co t

COC _W H _S (A)

S is oxidized at reflux using thallium (III) salts in an inert solvent, namely a C 1 -C 4 trialkyl orthoformate, optionally containing up to 50% by weight. an alkanol having 1 to 4 carbon atoms, or hexane of pyridine and carbon tetrachloride, the thus obtained ester of the general formula VI (VI) wherein:

R is C 1 -C 4 alkyl, hydrolyzed, and the compound of formula (VII) thus obtained is optionally converted into one of its pharmaceutically acceptable salts.

Among these salts, in particular, metal salts or addition salts with nitrogen bases are mentioned.

The trivalent thallium salt is preferably thallium nitrate.

Suitable solvents include, in particular, a trialkyl orthoformate and a C1-C4 alkyl moiety in the presence of up to 50% by weight of a C1-C4 alkanol, if appropriate.

The reaction lasts 0.5-6 hours and can be favorably influenced by using a trivalent thallium salt on a suitable carrier, for example acid montmorillonite (K-10), the salt is fixed on this clay, using hexane solvents at the same time , pyridine and carbon tetrachloride, in which case the reaction takes from 5 minutes to 2 hours.

The reaction with the trivalent thallium salt is carried out at a temperature of from 0 ° C to the reflux temperature of the reaction mixture, with the upper part of the temperature range being preferred.

Hydrolysis of the ester of formula VI is carried out in a conventional manner with a strong base or a strong acid, preferably at a slightly elevated temperature, for example 20 to 80 ° C. Under these conditions, the reaction takes up to 5 hours.

Preferably, the process of the invention is carried out by heating the compound of formula VI at boiling point, i.e. 65-70 ° C, in a mixture of methanol and water in the presence of a base such as sodium hydroxide or potassium hydroxide or in the presence of an acid such as acid. sulfuric. At this temperature, the reaction is complete in 2 hours.

The crude 2- (3-benzoylphenyl) propionic acid is obtained in the form of a colored oil and can be purified by conventional means, for example by recrystallization from acetonitrile or from a mixture of petroleum ether and benzene, acetone and water or ethanol and water.

The reaction of thallium nitrate trihydrate with trimethyl orthoformate leads to the cleavage of the hydration water so that the reagent itself is anhydrous thallium nitrate and methanol, which are adsorbed to the surface layer of acidic montmorillonite.

A method of oxidative conversion using a thallium nitrate reaction on a support clay has been described (EC Taylor, CS Chiang, A. Mc Killop, JF Whlte, JACS. 98, 6750, 1976 and JA Walker, MD Pillai, Tetrahedron Letters, 42). (3707, 1977), but these reactions have been described for acetophenone, propiophenone and some palkylphenylalkyl ketones or halophenylalkyl ketones.

In an experiment with an oxidation reaction using thallium in the case of 3-propionylbenzophenone, which is a compound with two carbonyl groups in the molecule, it was unexpectedly found that the reaction proceeds selectively only on the propionyl group, whereas a carbonyl group which carries no hydrogen atom . The possibility of an oxidation reaction by the action of thallium to a compound with two or more carbonyl groups in the nucleus is completely new and means a significant improvement in the method disclosed in the above-cited publications.

The reaction proceeds virtually quantitatively and the yield of oxidation of 3-propionylbenzophenone by thallium is 98%.

The process according to the invention for the oxidation of 3-propionylbenzophenone with thallium in the form of thallium nitrate on a carrier, which is acidic montmorillonite, is similar to the previously described procedure, which was carried out with thallium nitrate trihydrate in methanol solution. thus, up to 9 ppm of thallium could be detected by atomic absorption, however, using a carrier, the above-mentioned method showed the absence of thallium in the final product.

The overall yield of 2- (3-benzoylphenyl) propionic acid in the process of the invention is 21%, whereas in the process described in French Patent No. 1,546,478 only a yield of 1.8% can be achieved.

The invention will be further elucidated in the following examples.

Example 1

Process for preparing the starting 3-propionylbenzophenone of formula V

A 500 ml flask was charged with 54 g of CuCN, 106.5 g of 3-propiophenone and 75 ml of dimethylformamide and stirred at a temperature of 15-55 ° C. After 6 hours, the reaction mixture was poured into a solution of 200 g of FeCl 3. 6 H 2 O in 300 mL water, acidified with 50 mL concentrated hydrochloric acid and then stirred at 60-70 ° C for 20 min. The mixture was extracted with toluene (4.times.200 ml), the extracts were combined and washed with 20% (v / v) hydrochloric acid (125 ml), water (125 ml) and 10% sodium hydroxide (125 ml). The extracts were dried over sodium sulfate and evaporated to dryness. Yield: 78.3% of theory

62.3 g of 3-cyanopropiophenone of formula II, m.p. 47-51 ° C.

g of the nitrile thus obtained is dissolved in 539 ml of a 1: 1 v / v mixture of ethanol and water and then 36.6 g of potassium hydroxide are added with stirring. Subsequently, the mixture is refluxed at 82 ° C for 24 hours, evaporated to dryness, dissolved in 900 ml of water, stirred for 15 minutes with 5 g of activated carbon and, after removal of the activated carbon, 5% hydrochloric acid is added. The pH was adjusted to 1 by volume to form a precipitate. After separation of the precipitate by filtration and drying under vacuum at 50 DEG C., the precipitate is collected by filtration; Yield 75.2%, 42.1 g of 3-carboxypropiophenone of Formula III, m.p. 119-124 ° C.

A suspension of 40 g of 3-carboxypropiophenone in 150 ml of carbon tetrachloride is mixed with 4.68 g of 3-carboxypropiophenone of formula III and heated to 40 ° C. After 30 minutes, carbon tetrachloride and phosphorus oxychloride were evaporated and the residue was placed in a still. The main fraction distilled at a temperature of 12.5 to 133 ° C at a pressure of 65 Pa. There was thus obtained 3-propionylbenzoyl chloride (28.1 g), m.p. 73-76 ° C. The yield is 63.6 percent.

g of 3-propioinylbenzoyl chloride is dissolved in 50 ml of benzene and 36.7 g of powdered anhydrous aluminum chloride in 120 ml of benzene is added dropwise. The temperature must not exceed 0 to -5 ° C. After the addition was complete, the reaction mixture was heated to 80 ° C, cooled after one hour and hydrolysed with 500 g of ice containing 50 t concentrated hydrochloric acid, stirred for 2 hours, the layers were separated, the organic layer was washed with 50 ml water, dried over sodium sulfate and evaporated. 31.5 g of the above-mentioned 3-propionylbenzophenone of the formula V are obtained in 96.3% yield. After recrystallization, it has a melting point of 28-25 ° C.

Analysis: 1 _H : NMR (CDCl 3 / TMS) δ (—COCH 2 CH 3): 6.90 (q)

S (-COCH 2 CH 3): 8.78 (t) δ (9H) 1.50 to 2.60 (m).

Example 2

The method of the invention

To a 100 ml flask equipped with a stirrer, a thermometer and a reflux condenser was charged 9.0 g of T1 (NO3) 3. 3 H 2 O in 30 ml of trimethyl orthoformate and methanol 1: 1 and then the solution obtained is mixed with a solution of 4.76 g of 3-propionylbenzophenone in the same amount of solvent. The mixture is heated under reflux to 60 DEG C., cooled after 3 hours and the precipitated thallium nitrate is collected by filtration. The filtrate was diluted with 150 ml of water, dried over sodium sulfate, filtered again and evaporated.

In a yield of 93.3%, 5.0 g of a pale yellow product of formula VI is obtained, containing 91% (gas chromatography) and 9 ppm Tl.

A compound of formula VI can also be obtained using Τ1 (Νθ3) 3 / Κ-10 [EC Taylor, CS Chiang, A. Mc Killop, JF Whlte, JACS, 98, 6750 ¹ (1976)] by in a 500 ml flask adsorbs a solution of 10 g of 3-propionylbenzophenone in 170 g of carbon tetrachloride and 72 g of thallium nitrate to montmorillonite (K-10), while stirring the mixture at reflux at 76 ° C. After an hour, the reaction mixture was filtered, the filtrate was washed twice with 50 ml of water, dried over sodium sulfate and evaporated to dryness. 10.3 g of oily, intense yellow methyl 2- (3-benzoylphenyl) propionate (VI) are obtained in a yield of 91.5%. The substance contains 90% (gas chromatography) and 0 ppm Tl (atomic absorption).

5.0 g of the ester of formula (VI) obtained are dissolved in 53 ml of a 10: 1 mixture of methanol and water, 3.26 g of potassium hydroxide are added with stirring, and the mixture is refluxed at 65-70 ° C. . After 2 hours the mixture is evaporated to dryness, the residue is dissolved in 50 ml of water, extracted with 25 ml of ether and the aqueous layer is acidified with 5% (v / v) hydrochloric acid to pH 1. The resin product is extracted twice with 40 ml of ether. dried over sodium sulfate. After evaporation of the solvent, 3.8 g of the resin product are obtained in a yield of 80.2% of theory, which crystallizes after 24 hours and has a m.p. This product is recrystallized from aceto, nitrile, which is used at 1.3 ml / g of product to give 3.04 g (80%) of 2- (3-benzoylphenyl) propionic acid VII, m.p. from 5 to 95 ^o C. The product contains traces of thallium in an atomic absorption, in thin layer chromatography but contains trace impurities,

Content: 99.7% (Tltr

Analysis: _1H : NMR (CDCH / TMS) δ (—CH3): 8.40 ppm (d) (—OH—): 6.05 (q) δ (9 H): 2.70 (m) δ (- OH): 0.5 (s).

Claims (4)

PftEDMtT VYNALEZU A process for the preparation of 2- (3-benzoylphenyl) propionic acid of the formula VII GCO ^^ CHCOOH OCH ₃ (VII) and pharmaceutically acceptable salts thereof, characterized in that the 3-propionylbenzophenone of formula V (V) is oxidized at reflux temperature using trivalent thallium salts in an inert solvent of the C1 -C4 trialkyl orthoformate type % of the alkyl moiety, optionally containing up to 50 wt. a (C 1 -C 4) alkanol, or pyridine and carbon tetrachloride hexane, the ester of formula (VI) thus obtained wherein: R is C 1 -C 4 alkyl, hydrolyzed, and the compound of formula (VII) thus obtained is optionally converted to one of its pharmaceutically acceptable salts. 2. The process according to claim 1, wherein the thallium salt is thallium nitrate. 3. The process of claim 1, wherein the thallium salt is used on a carrier. 4. A process according to claim 3, wherein the carrier is acidic ¹ mOntmorillonite.