IE59090B1 - Process to obtain alkonoic acids - Google Patents

Abstract

1. A process for the preparation of substituted acetic acids having the general Formula I : Ar-CHR-COOH where R denotes a hydrogen atom or a C1 -C4 alkyl radical and Ar denotes a radical of aromatic nature selected from the following radicals : 2-thienyl, 2-methoxy-1-naphthyl, 3,4-methylenedioxy phenyl and substituted phenyls having the general Formula II : see diagramm : EP0224401,P5,F2 where R1 denotes a hydrogen atom or a C1 -C4 alkyl group and R2 denotes a hydrogen atom, a halogen atom, an alkyl, alkoxyl or hydroxyl group, the process being characterized in that a carbonylated alpha carboxylic acid having the general Formula III : R-CO-COOH where R has the above meaning, is reacted hot in homogeneous phase in an acid medium in the presence of phosphoric acid and catalytic quantities of iodine and hydriodic acid with an unsaturated derivative of aromatic nature selected from the following : thiophene, 2-methoxy naphthalene, 1,2-methylenedioxy benzene and substituted aromatic hydrocarbons having the general Formula IV : see diagramm : EP0224401,P5,F1 where R1 and R2 have the above meanings, if necessary in a compatible organic solvent.

Description

This invention concerns an industrial process to manufacture alkanoic acids, and more specifically, a process to manufacture substituted acetic acids, hereinafter referred to as arylacetic acids, of the general formula I, Ar-CHCOOH R (I) in which R represents a hydrogen atom or a alkyl radical and Ar represents a radical of the aromatic series from the following group s 2-thienyl, l"(2-methoxyl naphthyl), 3,4-methylenedioxy-phenyl and the substituted phenyls of general, formula II, (II) where R^ represents a hydrogen atom or a alkyl group end represents a hydrogen atom, a halogen atom and an alkyl, alkoxyl or hydroxyl group. The arylacetic acids of general formula ί ar© described at length in other publications. Xn particular, they are useful feedstocks for the synthesis of active pharmaceuticals.

It is therefore very useful to be able to prepare them as rationally as possible.

Numerous methods are known for preparing substituted acetic acids. Of these, the Willgerodt-Kindler reaction, in which an alkylarylcetone is converted into a arylalkylcarboxylic acid, is one of the most widely known. However, yields are usually only moderate to mediocre and sulphur by-products are produced which are responsible for pollution which is considered unacceptable today. To solve these problems, more elaborate methods are used which require the use of multistage reactions such as chemical or catalytic hydrogenolysis of arylglyeolie acids, o-acylated arylglyeolie or 2-halogen 2-aryl alkanoic acids, resulting In some cases from the condensation of glyoxylic acid with the corresponding aromatic derivative (European patent applications W® 00032376 and N° QQ28375 and European patent H® 003825), the hydrolysis of an arylalkylacetonitrile obtained by reaction of the cyanide ion with a suitably substituted quatemired benzylamine (European patent application 0062640). These methods» some of which are very recent, require initial feedstocks which are rarely available on the market, which means they must be prepared beforehand, with all the resulting disadvantages.

It has also been suggested that arylacetic acids be prepared by a heat reaction in an acid medium in the presence of red phosphorous and catalytic amounts of iodine or iodhydric acid, of an alpha cerbonylated carboxylic acid with a suitable aromatic hydrocarbon (French patent application Ns 83 07157)» Both the use of red phosphorous and the fact that the reaction is carried out in a heterogenous medium are considerable constraints resulting in strict, and therefore costly, safety precautions and restrictions» However, the Applicant was surprised to discover that it is possible to obtain srylaeetie acids of the general formula I, both economically and with excellent yields, in a single stage and homogenous phase, by a heat reaction in ths presence of phosphorous» acid, and catalytic amounts of iodine or iodhydric acid of an alpha carbonylated carboxylic acid of the general formula III» R-CO-COOH, in which R has ths meaning given above, with en unsaturated derivative of th® aromatic series from the following group s thiophene, 2-methoxy naphthalene, 1,2-methylenediaxy benzene ax· 1,3-benzodiuxoi eirtd the substituted aromatic hydrocarbons of the general formula IV, in which Rj and R9 have the same meaning as above s 3© O^i b2 IV Subsequently, this set of unsaturated substances of th© aromatic series will be referred to as A.

Wore specifically, the process used in this invention consists in causing a reaction to occur st a temperature above 70°C in an acid medium., between one mole of alpha carbonylated carboxylic acick of the general formula III, and one to ten moles of a derivative from group A in the presence of at least a molar equivalent of phosphorous acid and 0,01 to Chi moles of iodine or iodhydric acid» and if desired in a compatible organic solvent, such as particularly acetic acid, then isolating the acid required by already established methods Advantageously» the invention process consists in reacting under reflux of the reaction medium, one mole of an alpha carbonylated carboxylic acid of general formula (III) with one to fen moles of a derivative from the above defined group A in the presence of one mole of phosphorous acid and of 0.05 moles of iodine or iodhydric acid then isolating the acid required by known means.

The iodhydric acid used is commercial iodhydric acid in a 57 wt % aqueous solution.

The alpha carbonylated carboxylic acid can be glyoxylic acid, pyruvic acid, 3-methyl 2-oxo butanoic acid, 2-oxo butanoic acid or trimethylpyruvic acid.

At the end of the reaction, th® arylacetic aeid of general formula X required is isolated from the reaction by already established methods. Generally, after elimination of the reaction solvents and neutralization of the mineral acids present using a weak acid such as sodium acetate, the reactive medium is used again with water and the untransformed aromatic derivative is eliminated by already established methods, then the acid required is isolated by crystallisation or by any other established method.

With certain substrate, it is sometimes more advantageous to isolate the arylacetic acid required in the form of one of its salts such as its sodium salt, then remove the salt using a strong mineral acid.

The invention process enables th© following substances to be produced, among others - sodium 3-chloro A-hydroxy phenylacetate, - 2«thiophene acetic acid, - 2-isopropyl 2-parahydroxylphenyl acetic acid» Other features of this invention will become apparent on reading the following description and examples These are given by way of illustration and are not in any way exhaustive. 2© Example 1 The following solution is heated at 60®C for one hour then at 80°C for 4 hours s -1..5 moles of orthochlorophenol , - 0.5 moles of 80 wt So glyoxylic acid in water, - 0.5 moles of phosphorous acid. ~ 12.5 mmoles of 57 So iodhydric acid. - 31 g of acetic acid.

The solution is then diluted with 500 g of water and neutralized at 20®C to pH = 6. It then undergoes steam distillation to eliminate the untransformed chlorophenol and at 0°C» The precipitate obtained is filtered., water and dried at constant weight at 50°C under vacuum. Thi® produces 0.29 moles of pure sodium 3-chloro 4-hydroxy phenylacetate.

Example 2 The following solution is heated under reflux for two hours : crystallized washed with - 7 moles of thiophene, - 1 mole of phosphorous acid. - 1 mole of 80 wt % glyoxylic acid in wetter, - 50 mmoles of 57 Si iodhydric acid. - 420 g of acetic acid.

The solution is cooled then treated with 5 g of anhydrous sodium acetate and finally concentrated under vacuum. The residue is then mixed with 100 g of water and 4 g of sodium bisulphite and the aeid required extracted with toluene. All the organic phases are then washed with water, dried erad concentrated under vacuum. The oily residue obtained is then distilled under a vacuum of 0.2 sstin of mercury. This gives 0,6 moles of pure 2-thiophene acetic acid with a melting point of 62 ** 1«C.

Example 3 The following solution is heated under reflux for fifteen hours : - 5 moles of thiophene. - 0.5 moles of pyruvic acid? - 0.5 moles of phosphorous acid. - 25 nmoles of 57 % iodhydric acids - 210 g of acetic acid.

The solution obtained is then concentrated under vacuimi after adding 13.2 g of anhydrous sodium acetate. The residual oil is taken of with 350 g of diethyl oxide ; the ethereal phase is washed with an aqueous solution saturated with sodium bicarbonate then water. After elimination of the ether under vacuum», the acid required is distilled under a vacuum of 8 mm of merqury. This gives 0.435 moles of 2-(2-thienyl) propionic acid, distilling at 135 + 2°C under 8 ran of mercury.

Example 4 The following solution is heated under reflux for 270 minutes s <- 2.5 moles of phenol. - 0.5 moles of phosphorous acid. - 0.5 moles of 3-methy1 2-oxo butanoic acid? - 25 nmoles of 57 % iodhydric acid, - 31 g of acetic acid.

The solution is then concentrated under vacuum after adding 8 g of sodium carbonate. The residual oil is then taken of with 300 g of water,, alkalinated to pH s 7.5 then washed with isopropyl acetate. All the organic phases are then washed with an aqueous solution saturated with sodium bicarbonate. All the aqueous phases are collected and the last traces of solvent are eliminated therefrom under vacuum then 5 grs of sodium bisulphite are added and the resulting aqueous phase is acidified to pH s 1 at 15®C. The precipitate obtained is filtered then washed with water and vacuum dried at constant weight at 50aC. This gives 0.24 moles of pure 2-isopropyl 2-parahydroxyphenyl acetic acid with a melting point of 172 j 1BC„ Naturally» this invention has been described in a purely non-restrictive manner and is not in any way exhaustive. Any relevant changes may be made while remaining within the scope of the invention.

Claims (6)

1.,, Process to obtain substituted acetic acids of general formula I s Ar-CHRCQOH (I) in which R represents an atom of hydrogen or a alkyl radical and Ar represents a radical of the aromatic series taken from the group comprising the following radicals ; 2-thienyl» 2-methoxy 1-naphthvl» 3.4-me thy lenedioxy phenyl and the substituted phenyl radicals of general formula 11 s where R^ represents a hydrogen atom or a Cj-C^ alkyl group and R 9 represents a hydrogen atom» a halogen atom» an alkyl» alkoxyl or hydroxyl group» said process being characterized in that it consists of a heat reaction» in an acid medium» in homogenous phase» in the presence of phosphorous acid and catalytic amounts of iodine or iodhydric acid» between an alpha carbonylated carboxylic acid of general formula III s R-CO-COOH (III) in which R has the same meaning as above» and an unsaturated derivative of the aromatic series taken from the group including thiophen» 2-methoxy naphthalene» 1»2--methylenedioxy benzene and substituted aromatic hydrocarbons of general formula IV : in which R^ and R2 have the same meaning as above and» if desired» in a compatible organic solvent.

2. Process according to Claim 1 characterized in that of alpha carbonylated carboxylic acid of general such as that defined in Claim 1, is made to react ten moles of an unsaturated derivative of fhe that defined in Claim 1, at a in an acid medium, in fhe one mole formula IXI, with one to aromatic series such as temperature of more than 70°C, presence of at least one mole of phosphorous acid and 0.01 to 0,.1 mole of desired. 3. Claims 1 or characterized series used acid used is < 4. Claims 1 or Application of the process according to anyone of 2 to the manufacture of 2-thiophen acetic acid 2 to the manufacture of alpha methyl 2-thiophen acetic acid, characterized in that the unsaturated derivative of fhe aromatic series used is thiophen and the alpha carbonylated carboxylic acid used is pyruvic acid.

3. 5., Application of the process according to anyone Claims 1 or 2 to the manufacture of 2-isopropyl parahydroxy-2-phenyl acetic acid, characterized in that the unsaturated derivative of the aromatic series used is phenol and the alpha carbonylated carboxylic acid used is 3-methyl 2-oxo butanoic acid.

4. 6,, Application of fhe process according to anyone of Claims 1 or 2 to the manufacture of the 3-chloro 4-hydroxy phenyl acetic acid, characterized in that the unsaturated derivative of fhe aromatic series used is orfhochlorophenol and the alpha carbonylated carboxylic acid used is glyoxylic acid.

5. 7. A process for the preparation of compounds of formula (I) as claimed in Claim 1 s substantially as hereinbefore described by way of Example.

6. 8. Compounds of formula (I) as defined in Claim 1 9 whenever prepared by a process as claimed in any of Claims 1 to