DD144910A5 - PROCESS FOR PREPARING 2- (3-BENZOYLPHENYL) PROPIONE ACID - Google Patents

Abstract

The invention relates to a process for the preparation of

Description

The present invention relates to a novel process for the preparation of 2- (3-benzoylphenyl) propionic acid and its pharmaceutically acceptable salts, which are compounds having significant anti-inflammatory properties.

Characteristic of the known technical solutions

The 2- (3-benzoylphenyl) propionic acid and its pharmacological properties were described for the first time in FK-PS 1 546 478. In this document and in its first supplement Hr. 94930 also described two synthetic routes, according to the following scheme: a)

HOOC

ClOC

CH ₂ CIT

CH-COOH CH ₃

Berlin, d.2O.rwi979 55 934 18

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

CH-COOH

CH ₃

CH-COOH CH ₃

CH-COOH CH ₃

The starting amine is prepared by the method of 3 'Nerdel and L. Fischer, Ber. 87,217 (1954).

The synthesis method of the 2 - (3-benzoylphenyl) propionic acid according to the cited patent is seven steps and the total yield is 1.8%.

The second route according to FE-PS 2 163 875 is shorter and proceeds according to the following reaction scheme:

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Berlin, α.20.11.1979 55 934 18

HOOC

Cloo

The starting nitrile is prepared by condensing propionitrile using 2-chlorobenzoic acid according to the method of EE Biehl, J. Org. Chem. 31 _f 602 (1966), but its synthesis is practically limited to the laboratory scale; the industrial production of the starting material, and thus the synthesis of 2- (3-benzoylphenyl) propionic acid according to the cited patent, appear hardly possible. Even a slight exceed the initial weight given by the author leads to resinification and yield losses and Ee inhe itse inbußen · Working in liquid ammonia at "40 ⁰ C and adding metal sodium to form sodium amide requires large capacity of cooling systems and a corresponding apparatus effort.

Object of the invention

The object of the invention is to provide a new simple, economical and industrially applicable process for the preparation of 2- (3-benzoylphenyl) propionic acid, with which significantly higher yields can be achieved.

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Explanation of the essence of the invention

The invention has for its object to find new Ausgangsko components for the preparation of 2- (3-Benzoy! Phenyl) propionic acid.

According to the invention, a new and less expensive route has now been found for preparing 2- (3-benzoylphenyl) propionic acid starting from 3-propionylbenzophenone, which is a new substance. Its synthesis can proceed according to the following reaction scheme:

COC ₂ H ₅

CuCH DKP

II

COC ₂ H ₅

1.0H "

2.H " ¹

HOOC

III

ClOC

IV

COC ₂ H ₅

Benzene ^ AlCl-,

COG ₂ H ₅

$! 4400 -5.

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The starting material for the preparation of the new compound 3-propionyl-benzophenone is 3-bromopropiophenone (J. Org. Ghem., 23, 1412 1958).

The new process for the preparation of 2- (3-Benzoy! Phenyl) propionic acid of the formula

VII

is carried out according to the invention such that one

a) the 3 '' 'C'pionylbenzophenone of formula (V) above is treated with a thallium (III) salt in a suitable solvent and

b) the recovered ester of the general formula

CH-COOR CH ₃

VI

in which E is an alkyl of 1 to 4 carbon atoms, in the final product, d. the 2- (3-benzyloxy) propionic acid (VII), hydrolyzed. If necessary, the obtained acid of the forms! (VII) in their pharmaceutically acceptable salts, either metal salts or in addition * salts of nitrogenous bases transferred.

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The thallium (III) salt used is preferably Tl (III) nitrate;

The solvent used is a tri-C 1 -C 5 -alkyl orthoformate, optionally containing up to 50% by weight of a C 1 -C 10 -alkanol.

The reaction lasts for 0.5 to 6 hours, but it can be accelerated by previously fixing the thallium (III) salt to a suitable support such as an acid montmorillonite and a solvent from the group consisting preferably of hexane, pyridine In this case, the reaction takes 5 minutes to 2 hours ·

The reaction with the Tl (III) salt is to reflux the reaction mixture executable in the temperature range of 0 ⁰ C ^ being given to the reflux temperature of the preferred "

The hydrolysis of the ester (VI) is carried out in the usual way either with a strong base or a strong acid, preferably at a moderately elevated temperature, for example at 20 to 80 ° C. At this temperature, the reaction is completed in 5 hours.

Most advantageously, this reaction proceeds such that the product (YI) at reflux temperature (65 to 70 ⁰ C) in a mixture of methanol / water, in the presence of a base, for. B · Sodium or potassium hydroxide solution, or in the presence of an acid, for. B · Sulfuric acid is heated · At this temperature, the reaction is completed in two stages *

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The crude 2 ~ (3-benzoylphenyl) -propionic acid (VII), obtained in the form of a colored oil, is purified in a conventional manner, e.g. Example by recrystallization from acetonitrile or a mixture of petroleum ether / benzene, acetone / water or ethanol / water.

The reaction of the thallium nitrate trihydrate with trimethyl orthoformate leads to the splitting off of the water of hydration, in which the anhydrous thallium nitrate and the methanol adsorbed on the surface of the acidic montmorillonite earth act as co-reactions.

The method of the oxidative rearrangement on the Oxythallie "* rungsreäktion means of thallium nitrate on a support ground is known (S _e C. Taylor, CS, Chiang, A. Mc Eillop, JoF. White, JAGS. 98, 6750, 1976, YES Walker, MD Plllal, Tetrahedron Letters, 42,> 3707, 1977), but this section is only described for acetophenone, propionphenone, and some p-alkyl or halo-substituted phenylalkyl ketones

In our experiments on the oxy-thallation of 3-benzophenone, a compound having two carbonyl groups in the molecule, it was surprisingly found that the oxy-metallation occurs selectively only on the propionyl group, while the carbonyl group (which does not have a hydrogen atom in the Λ-position) of the benzophenone half of the molecule does not responding. Oxy-thallation of the compounds having two or more carbonyl groups in the nucleus constitutes a novelty and extension of the process described in the literature cited above.

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The yield of oxythallation of 3-propionylbenzophenone is practically quantitative (98%).

The reaction according to the invention of the oxy-thallation of 3-propionylbenzophehone by means of thallium nitrate on a support (acid montmorillonite) is preferable to the analogous process carried out by thallium nitrate trihydrate in methanolic solution, because thallium residues remain in the end product in the latter (atomic absorption) : Thallium 9 ppm), while no Thalliumreste in the end product can be found when using the carrier (atomic absorption: 0 ppm Thallium).

The process according to the invention gives an overall yield of 21% in the synthesis of 2- (3-benzoylphenyl) propionic acid, whereas in the process described in PR-PS 1 546 478 only a yield of 1.8% is obtained.

embodiment

The invention will be illustrated by the following examples:

example 1

Preparation of the starting material 3-Bropionylbenzophenone (V)

In a 500 ml flask, 54 g of CuCN, 106.5 g of 3-propiophenone and 75 ml of dimethylformamide at I55 to I70 ⁰ C are stirred. After 6 hours, the reaction mixture is poured into a solution of 200 g of EeCl. 6H _P 0 in 300 ml of water, acidified with 50 ml of cone, HCl, poured and stirred at 60 to 7.0 ⁰ C for 20 minutes. It is extracted with 4 χ 200 ml of toluene »and

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the combined extracts with 125 ml 20% VoI./VoI. HCl, 125 ml of water and 125 ml of 10% (w / w = 1 g / 100 g) of NaOH. It is dried over Na ₂ SO ₄ and finally evaporated to dryness. Yields: 62.3 g (78.3% of theory) of 3-Cyanopropiophenon (II), m.p .: 47 to 5I ⁰ O.

50 g of the resulting nitrile are dissolved in 539 nil of a mixture of ethanol / water (VoI ₀ 1: 1) and treated with 35.6 g KOH with stirring. After 24 hours of reflux at 82 ⁰ C is evaporated to dryness, dissolved in 900 ml of water, stirred for 15 minutes with 5 g of activated charcoal and after the deposition of the carbon by addition of 5 % VoI »/ vol. HCl to the pH value of 1 like. After filtering and drying in a vacuum oven at 50 ⁰ C 42.1 g (75.2%) of 3 ~ Carboxypropiophenon (III) with mp. II9 to 124 ° 0 obtained.

The suspension of 40 g 3 ~ Carboxypropiophenon in 150 ml of CCl 4 are added to 4.68 g of PCl ₅ and heated to 40 ⁰ C. After 30 minutes, CCl ₂ , and POCIo are evaporated and the residue is added to a distillation apparatus. The main fraction is distilled at 125 to I33 ° C / 0.5 mm Hg. There are obtained 28.1 g of 3-propionylbenzoyl chloride (IV) with a Schmpo of 73 to 76 ⁰ C. The yield is 63 »6 %.

27 g of 3-propionylbenzoyl chloride are dissolved in 50 ml of benzene and the suspension of 36 · »7 S AlCl ^ (powdered, anhydrous) was added dropwise in 120 ml of benzene. It is ensured that the temperature does not exceed the range of 0 to -5 ⁰ C. After completion of the dropwise addition, the reaction mixture is heated to 80 ⁰ C, cooled after one hour and 500 g of ice,

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acidified with 50 ml of cono. HCl, hydrolyzed. After stirring for 2 hours, the layers are separated, the organic layer is washed with 50 ml of water, dried over Na ₂ SO ₄ and evaporated. 31.5 g (96.3%) of 3-Bropionylbenzophenone (Y) above. The mp of the substance is after crystallization 28 to 35 ⁰ O *

Analysis: 1 _H: NME · (CDCWTMS)

J- (~COCH ₂ CH ₃ ): 6.90 Cq) '

cf (-COCH ₂ CH ₃ ): 8.78 (t)

cT (9H): 1.50 to 2.60 (m) _e

Beis piel 2

(inventive method)

In a 100 ml flask equipped with a stirrer, thermometer and reflux condenser, 9.0 g of Tl (UO ₃ ) are added. 3H ₂ O dissolved in 30 ml of trimethyl orthoformate and methanol in a ratio of 1: 1 and with a solution of 4.76 g of 3-propionylbenaophenone in the same amount of the solvent ver «» under stirring until reflux (about 60 ⁰ C), cooled after 3 hours and the deposited TlKO ₃ filtered off. The filtrate is diluted with 150 ml of water, dried over ITa ₂ SO 4, filtered and evaporated.

Yield: 5.0 g (93.3%) of a pale yellow product containing 91 % (GC) and 9 ppm Tl (atomic absorption),

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The substance (VI) may also be by means of Tl (NOO -, / K-10 reagent (EC _β Taylor, CS, Chiang, A. Mc Klllop, J. * ¹ White, JACS, 98, 6750 (1976)) recovered. are stirred in a 500 ml flask, a solution of 10 g of 3-propionylbenzophenone in 170 g CCl ₄ with 72 g of thallium nitrate (III), adsorbed on montmorillonite (K-10), at reflux temperature (76 ⁰ C). After one hour, the reaction medium is filtered off, the filtrate washed twice with 50 ml of water, dried over Ή 2 ^ 0 ^ and evaporated to dryness · There are 10.3 S (91t5%) of the oily, intensely yellow methyl 2- (3 Content: 90% (GC), content of Tl: 0 ppm (atomic absorption).

5jO g of the obtained ester (VI) are dissolved in 53 ml of a mixture of methanol / water (10: 1), added with stirring 3.26 g KOH and heated to reflux (65 to 70 ⁰ C) »After 2 hours is evaporated to dryness and the residue dissolved in 50 ml of water, extracted with 25 ml of ether and the aqueous layer with 5 % vol./Vol. HCl acidified to pH 1. The resinous product is extracted with 2 χ 40 ml of ether, washed with 30 ml of water and dried over ITa ₂ SO ^ dried. After evaporation of the solvent remain 3.8 g (80.2 % of theory) of a resinous product, which crystallized after 2A hours (mp 89 to 93.5 ⁰ C). It is recrystallized from acetonitrile (1.3 ml / g), and there are 3.04 g (80%) of 2- (3-benzoylphenyl) propionic acid (VII) with a mp of 92.5 to 95 ⁰ C. , receive; There are no thallium traces (atomic absorption). however traces of impurities (TLC),

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55 93 ^

Content: 99.7% (titrimetric)

Analysis: 1 _fl: NMR (CDCWTMS) (TC-CH _3): 8.40 ppm (d) (TC-GH) ί 6.05 Cq) cf (9H): 2.70 (m) IFC-OH) : 0.5 Cs).

Claims (2)

2 1 4 400 Berlin, d.20.11.1979 55 934-18 Claim of invention, 1. A process for the preparation of 2- (3-benzoylphenyl) propionic acid of the formula HCOOH VII and their pharmaceutically acceptable salts, characterized by reacting _# a) 3-3-ropionylbenzophenone of the formula COC ₂ H ₅ treated with a thallium (III) salt in a suitable solvent and b) the recovered ester of the general formula CH-COOR VI 4-4Q0 -14- Berlin, d.20.11.1979 35 934 18 in which E is an alkyl having 1 to 4 carbon atoms, hydrolyzed and then the compound of formula VII, if necessary, converted into their pharmaceutically acceptable salts. 2 * method according to item 1a), characterized in that as (Dhalliuia (III) salt thallium (III) nitrate is used. 3. Process according to item 1a), characterized in that it is heated to the reflux temperature of the reaction mixture » 4 «method according to item 1a), characterized in that the solvent is used in excess. 5e method according to item 1a), characterized in that the solvent Tri-C. Alkyl orthoformate, which may contain up to 50% by weight of a C 1-6 alkanol. The method of item Ia) ₅ characterized _s that the thallium (is IIl) -Sala bound on a suitable support, is used, while an inert ox * ganisches solvent is used from the group of hexane, pyridine and carbon tetrachloride as solvent. 7 »Method according to item 6, characterized in that an acid montmorillonite is used as carrier.