CS243576B1 - Method of arylalkane acids production - Google Patents

Description

(54) A method for producing arylalkanoic acids

The invention relates to a process for the preparation of arylpropionic acids of the general formula I,

Ar — CH — COOH (I)

CH3 where

Ar is phenyl or naphthyl, optionally substituted with 1 to 2 substituents from the group consisting of alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 2 carbon atoms, or a phenoxy group, or a chlorine or bromine atom.

The compounds of formula (I) belong to the group of non-steroidal anti-inflammatory drugs having a significant analgesic and antipyretic effect. High therapeutic efficacy and minimal side effects on the gastrointestinal tract rank them among the most widely used antirheumatics in medical practice.

Typical representatives of this class of drugs are Ibuprofen (2- (4-isobutylphenyl) propionic acid; British Pat. No. 1,167,198, U.S. Pat. No. 3,285,386). Naprosyn (2- (6-methoxy-2-naphthyl) propionic acid; U.S. Pat. Nos. 3,904,682 and 3,955,012 and Phenoprofen (2- (3-phenoxyphenyl) propionic acid); U.S. Pat. No. 3,600 437).

Most processes for preparing arylalkanoic acids are based on readily available arylcarbonyl compounds (The Organic Chemistry of Drug Synthesis, Wiley, New York 1977; Antiinflammatory Drugs, Springer, Berlin 1979, p. 321; Script World. Pharm. News 10, 497 (1980)). Chronicles of Drugs Discovery, Wiley, New York 1981, p. 149).

From an industrial point of view, the synthesis of arylalkanoic acids advantageously utilizes the solvolytic rearrangement of the--substituted alkylaryl ketones and its derivatives of the general formula A

Aryl — CO — CH — X I

Alkyl (A) using various reagents and solvents. In the rearrangement of halogen derivatives (formula A, X denotes halogen), a stoichiometric amount of silver salt must be used, so that this process cannot be used on an industrial scale. Methods using thallium nitrate rearrangement (see, eg, J. Amer. Chem. Soc. 98, 3037 (1976)) in trimethyl orthoformate and methanol are unusable in view of the high toxicity of thallium salts for the manufacture of medicaments. starting from acetals of «-substituted alkylaryl ketones (see formula A), where the solvolytic rearrangement is accelerated by the presence of a catalytic amount of a Lewis acid (eg zinc, copper, mercury, tin, antimony, palladium, cobalt, bismuth, iron) (EP No. 35,305, 34,871, 71,299; J. Org. Chem. 48, 4,658 (1983)) An analogous method of production which allows the synthesis of one specific enantiomer of 2-arylalkanoic acid of general formula B Aryl — CH — COOH

AND

Alkyl is a rearrangement of acetals of 1-aryl-2-sulfonyloxy-1-alkanones (Formula A, X-OjSR ² ) in a polar solvent in a neutral environment, optionally in the presence of basic agents such as hydroxides, carbonates, alkali metal and alkaline earth metal phosphates; alkali salts of carboxylic acids or in the presence of tertiary organic bases at 0 to 250 ° C (see, e.g., Tetrahedron Lett 22, 5,427 (1982); EP No. 67,989);

A disadvantage of the processes described above is the use of salts of toxic metals such as thallium, mercury, copper, bismuth, which cannot be practically removed from the final product and therefore cannot be used in the manufacture of substances used in human medicine. Another disadvantage is the use of relatively expensive reagents such as trimethyl orthoformate.

These processes are followed in a positive way by the process according to the invention, which successfully solves some of the aforementioned drawbacks.

The process according to the invention consists in the presinylation of the α-sulfonyloxyacetals of the general formula II,

OSO2R ¹

Ar — C — CH — CH3 (II)

A \ o o

RR wherein Ar is as defined above, R is methyl or ethyl, R ¹ is methyl, phenyl or p-tolyl, wherein the solvolytic rearrangement is carried out by treatment with a 0.1 to 5 equimolar excess of alkali metal tetraborate, optionally in the presence of boric acid, aqueous 2-methoxyethanol or 2-ethoxyethanol at 40 to 150 ° C. After completion of the reaction, the reaction mixture is concentrated, the distillation residue is gradually extracted with an organic solvent, acidified with an inorganic acid, and again extracted with an organic solvent from which, after evaporation of the solvent, the product of formula I is obtained in high yield. 1 to 2 carbon atoms and 2 to 4 chlorine atoms such as dichloromethane, 1,2-dichloroethane, tetrachlorethylene, trichlorethylene, carbon tetrachloride or aromatic hydrocarbons such as benzene and toluene. For example, hydrochloric acid or sulfuric acid is used to acidify the mixture.

The use of an alkali metal tetraborate, such as disodium tetraborate, is advantageous both in terms of rearrangement rate and product isolation. Likewise, the solvent used makes it possible to substantially increase the reaction temperature and hence the reaction rate. The recovery of the solvent system, which is reusable, brings considerable solvent savings and significantly reduces wastewater treatment costs. From the above, the technological and economic advantages of the process according to the invention are obvious.

The process according to the invention is illustrated by several examples which are illustrative only and do not limit the scope of the invention in any way.

Example 1

A mixture of 35.4 g of the ester of formula II wherein Ar = 6-methoxy-2-naphthyl, R = R ¹ = CH 3, 100 ml of 2-methoxyethanol, 100 ml of water and 3.8 g of disodium tetraborate decahydrate was under vigorous agitation heated at 125-130 ° C for 7 hours. After evaporation of the solvents on a vacuum rotary evaporator, the distillation residue was extracted with 2 X 100 ml of dichloromethane, then acidified with conc. hydrochloric acid to pH 1 and extracted again with 3 X 100 mL of the same solvent, the combined extracts washed with water, dried over sodium sulfate and evaporated to give 19.3 g (84%) of the acid of formula I where Ar = 6-methoxy -2-naphthyl, mp 153-155 ° C.

Example 2

A solution of 6.2 g of the ester of formula II wherein Ar = 5-bromo-6-methoxy-2-naphthyl, R = R ¹ = CH 3 in 20 mL of 2-ethoxyethanol was added with stirring 2.7 g of disodium tetraborate decahydrate and 0.3 g boric acid in 20 ml water. Analogous to Example 1, 3.3 g (75%) of the acid of formula I were obtained, wherein Ar = 5-bromo-6-methoxy-2-naphthyl, mp 162-164 ° C.

Example 3

A mixture of 4.3 g tosyl formula II wherein Ar - 4-isobutylphenyl, R = CH 3, R ¹ - = p-tolyl, 30 ml of 2-methoxyethanol, 0.8 g of disodium tetraborate decahydrate and 25 ml of water was heated with stirring 24 hours at 130 ° C. After cooling, the mixture was

The reaction was worked up as in Example 1 to give 1.8 g (83%) of an acid of formula I wherein Ar-4-isobutylphenyl, mp 74-76 ° C.

Example 4

8.6 g of an ester of formula II wherein Ar is 3-phenoxyphenyl, R = CH 3, R ¹ = phenyl were dissolved in 30 ml of 2-ethoxyethanol and 1.4 g of disodium tetraborate decahydrate dissolved in 20 ml were gradually added under stirring water and then heated at 140 ° C for 16 hours and after analogous isolation to Example 1, 2.7 g (77%) of the acid of formula I where Ar is 3-phenoxyphenyl, b.p. 166-169 ° C, were obtained. 13 Pa.

Analysis C15H14O3:

calculated: C, 74.36; H, 5.83. Found: C, 74.52; H, 5.93.

Claims (4)

SUBJECT A process for the preparation of arylalkanoic acids of the general formula I, Ar — CH — COOH (I) CH3 wherein Ar is phenyl or naphthyl, optionally substituted with 1 to 2 substituents selected from C1-C4 alkyl, C1-C2 alkoxy or phenoxy or chloro or bromo, from the acetal esters of the α-hydroxyphenones of formula II, OSO2R ¹ Ar — C — CH — CH3 (II) / \ O O R R where Ar is as defined above, R is methyl or ethyl, R ¹ is methyl, phenyl or p-tolyl which are hydrolyzed under concomitant rearrangement in the presence of a base in polar aprotic and protic solvents at 0 to 250 ° C for 1 to 250 hours; that the hydrolysis associated with the rearrangement is carried out with a 0.1-5 equimolar excess of alkali metal tetraborate, optionally in the presence of boric acid, in an aqueous solution of 2-methoxyethanol or 2-ethoxyethanol at a temperature of 40 to 150 ° C, whereupon the reaction mixture is concentrated, extracted with an organic solvent and, after acidifying the aqueous residue with an inorganic acid, extracts the product of formula I with an organic solvent. 2. A process according to claim 1, wherein the alkali metal tetraborate is disodium or potassium tetraborate. 3. A process according to any one of claims 1 to 2, wherein the organic solvent is a halogenated hydrocarbon having 1 to 2 carbon atoms and 2 to 4 chlorine atoms. 4. A process according to any one of claims 1 to 3, wherein the inorganic acid is hydrochloric or sulfuric acid.