IE59091B1

IE59091B1 - Manufacturing process for alkanoic acids

Info

Publication number: IE59091B1
Application number: IE258486A
Authority: IE
Original assignee: Hoechst France
Priority date: 1985-10-21
Filing date: 1986-09-30
Publication date: 1994-01-12
Also published as: DE3664763D1; EP0221815B1; ATE45140T1; FR2588869B1; ES2010505B3; EP0221815A1; FR2588869A1; IE862584L; JPH0822833B2; JPS6299341A

Abstract

1. Process für preparing substituted acetic acids of general formula I : Ar-CHR-COOH I in which R represents an atom of hydrogen or a C1 -C4 alkyl radical and Ar represents a radical of aromatic character chosen from the folowing radicals : 2-thienyl, 1-(2-methoxy-naphthyl), 3,4-methylenedioxy phenyl and substituted phenyls of the general formula II : see diagramm : EP0221815,P4,F1 where R1 represents an atom of hydrogen or a C1 -C4 alkyl group and R2 represents a hydrogen atom, a halogen atom, or an alkyl, alkoxyl or hydroxyl group, said process being characterized in that it consists in the hot reduction, in an acid medium, by phosphorous acid in the presence of iodine or hydriodic acid, of an alpha hydroxylated carboxylic acid of the general formula III : see diagramm : EP0221815,P4,F2 in which Ar and R have the same meaning as above.

Description

This invention concerns an industrial process to manufacture alkanoic acids, and more specifically, a process for preparing substituted acetic acids of general formula I: ArCHR-COOH in which R represents an atom of hydrogen or a CpC^ alkyl radical and Ar represents a radical of aromatic character chosen from the following radicals^ 2-thienyl, l"(2-methoxy=naphthyl), 3,4~methylenedioxy phenyl and substituted phenyls of the general formula Ils where Rj represents an atom of hydrogen or a C1 alkyl group and Rg represents a hydrogen atom, a halogen atom, or an alkyl, alkoxyl or hydroxyl group, wherein the process consists of the hot reduction, in an acid medium, by phosphorous acid in the presence of iodine or hydriodic acid, of an alpha hvdroxylated carboxylic acid of the general formula Ills Ar-CR-COOH I OH in which Ar and R have the same meaning as above. The arylacetic acids of general formula I are described at length in other publications. In 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 alkylarvlcetone is converted into arvlalkylcarboxylic 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 arylglvcolic acids, o-acylated arylglycolic acids or 2-halogen 2-aryl alkanoic acids resulting in some cases from the condensation of glyoxylic acid with the corresponding aromatic derivative (European patent, application N° 0 032 374 and N° 0 028 375, European patent M® 0 003 825) or the hydrolysis of an arylalkylacetonxtrile obtained by the reaction of a cyanide ion with a suitably substituted quaternized benzylamine (European patent application N® 0 062 440). These methods, some of which are very recent, required initial feedstocks which are rarely available on the market, which means that they must be prepared beforehand, with all the resulting disadvantages.

However, the Applicant was surprised to discover that it is possible to obtain arylacetic acids of the general formula I, both economically and with excellent yields, in a single stage and homogenous phase, by heat reduction, in an acid medium, by phosphorus acid in the presence of catalytic amounts or xodzne or iodhydric acid, of alpha hydroxylated carboxylic acid of the general formula III : Ar-Cjl-COOH (III) in which Ar and R have the same meaning as above.

More specifically, the invention process consists in reducing one mole of alpha hydroxylated carboxylic acid, of general formula III in which Ar and R are as defined above, in an aetd’medium, at a temperature above 70°Cs with at least the molar equivalent of phosphorous acid in the presence of 0.01 to 0,1 moles of iodine or iodhydric acid, possibly'in a compatible organic solvent such as acetic acid. More specifically, the invention process consists in reducing one mole of alpha hydroxylated carboxylic acid, of general formula III, in an acid medium, at a temperature above 70°C3 with at least the molar equivalent of phosphorous acid in the presence of 0.01 to 0.1 moles of iodine or iodhydric acid, possibly in a compatible organic solvent such as acetic acid, then isolating the acid of general formula I required by already established methods.

Preferably, the invention process consists in reducing one mole of alpha hydroxylated carboxylie acid of general formula III with one mole of phosphorous acid and 0.05 moles of iodine or iodhydric acid under the reflux of the reaction, then isolating the acid required by already established methods.

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

The alpha hydroxylated carboxylic acid can be parahydroxyImandelic acid, 3,4-methylenedioxy mandelic acid, 4-hydroxy 3-methoxy mandelic acid, 3-chloro-A-hydroxy mandelic acid or 2-thiophene-glycolic acid,, At the end of the reaction, the arylacetic acid of general formula I required is isolated from the reaction by already established methods. Generally, after elimination of th® reaction solvents and neutralization of the mineral acids present by a weak acid salt such as sodium acetate, th® reactive medium is used again with water and th® untransformed initial acid 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 advantageous to isolate the arylacetic acid required in the form of one of its salts, such as its sodium salt. Mien remove the salt using a strong mineral acid.

The invention process produces the following substances, among others : - parahydroxyphenylacetic acid, - 4-hvdroxy 3-raethoxy phenylacetic acid, » 3,4-methylenedioxy phenylacetic 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.

Example^! Xn a solution heated under reflux containing : - 0.5 moles of phosphorous acid, - 25 mmoles of 57 85 iodhydric acid, - 78 g of acetic acid, a hot solution (40®C) is added in four hours, consisting of ; - 005 moles of parahydroxymandelic acid, - 180 g of acetic acid.

The reaction is then kept under reflux for 30 minutes and concentrated under vacuum after adding 8 g of anhydrous sodium acetate. The crystallized residue obtained is then heated under reflux for 90 minutes in 350 g of water. After cooling to 40°C9 it is treated with 4 g of sodium bisulphite. The reactive medium is then cooled to 0°C and the precipitate filtered, washed in Iced water and dried at 50"C under vacuum at constant weight. 72.4 % of pure parahvdroxyphenylacetic aeid is thus produced, i.e. a yield of 95.3 Si of the theoretical value calculated with respect to the parahydroxymandelic acid used.

Example 2, A solution of 50 mmoles of 4-hydroxy 3-methoxy mandelic acid in 18 g of acetic acid is added in 75 minutes to a solution of 50 mmoles of phosphorous acid», 2.5 noles of 57 55 iodhydric acid and 8 g of acetic acid kept at 95°C. It is then heated at 95®C for 45 minutes. 0.4 g of sodium acetate is added before cencomtrating th® reactive medium under vacuum. The crystallized residue obtained is dissolved in 20 g of hot water then», if necessary, the solution obtained is bleached by adding sodium bisulphite. It is then crystallized at 0®C. Th® crystallized substance is then filtereds washed with water and dried at 50®C under vacuum at constant weight. This produces 33.8 mmoles of pure 4-hydroxy 3-methoxy phenylaeetic acid.

Example 3, If the same process as that described in example 2 is followed using 3», 4-methylenedioxy mandelic acid initially», pure 3, 4-methylenedioxy phenylaeetic acid is obtained with a yield of 73.4 % of the theoretical value.

Example 4 To a solution of 0.5 moles of phosphorous acid and 6.25 mmoles of iodine in 78 g of acetic acid kept under reflux, in two hours, a solution of 0.5 moles of parahydroxymandelic acid in 180 g of acetic acid preheated to 40^0^ is added.The reactive medium is then kept under reflux for one hour and concentrated under vacuum after adding 2 g of anhydrous sodium acetate. The crystallized residue is then dissolved under reflux in 250 g of weter... The solution is then treated with 4 g of sodium bisulphite before being crystallized at 0°C. The crystallized precipitate is then filtered, washed with water and dried at 50°C under vacuum at constant weight. This produces 0.37 moles of pure parahydroxyphenylscetic acid.

Naturally, this invention has been described in a purely non-restrichive manner and is not in any way exhaustive. Any relevant changes may be made while remaining within the scope of the invention.

Claims

1., Process for preparing substituted acetic acids of general formula I: Ar-CHR-COOH in which R represents an atom of hydrogen or a C^-C^ alkyl radical and Ar represents a radical of aromatic character chosen from the following radicals: 2-thienyl, l-(2-methoxy-naphthyl), 3,4-methylenedioxy phenyl and substituted phenyls of the general formula II: where Rj represents an atom of hydrogen or a alkyl group and Rg represents a hydrogen atom, a halogen atom, or an alkyl, alkoxy1 or hydroxyl group, wherein the process consists of the hot reduction, in an acid medium, by phosphorous acid in the presence of iodine or hydriodie acid, of an alpha hydroxylated carboxylic acid of the general formula Ills Ar»CR-C00H I OH in which Ar and R have the same meaning as above.

2. Process according to Claim 1, wherein one mole of alpha hydroxylated carboxylic acid of general formula III such as that defined in Claim 1 is reduced at a temperature above 70°C, In an acid medium, in a homogeneous phase, by at least one mole of hydrogen iodide, optionally in acetic acid.

3. Application of the process according to any one of Claims 1 or 2 to the manufacture of parahydroxyphenylacetic acid.

4. Application of the process according to any one of Claims 1 or 2 to the manufacture of 4“hydroxy-3-methoxy-phenylacetic acid. I

5. Application of the process according to anyone of Claims 1 or 2 to the manufacture of 3,4-methylenedioxy phenylacetic acid.

6. A process for the preparation of compounds of formula (I claimed in Claim 1, substantially as hereinbefore described by way of Example.

7. Compounds of formula (ΐ) as defined in Claim 1, whenever prepared by a process as claimed in any of Claims '1 to 6.