IE862584L

IE862584L - Alkanoic acids.

Info

Publication number: IE862584L
Application number: IE862584A
Authority: IE
Original assignee: Hoechst France
Priority date: 1985-10-21
Filing date: 1986-09-30
Publication date: 1987-04-21
Also published as: EP0221815A1; ATE45140T1; FR2588869B1; DE3664763D1; ES2010505B3; IE59091B1; JPS6299341A; JPH0822833B2; FR2588869A1; EP0221815B1

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

'59091 This invention concerns an industrial process to manufacture alkanoic acids, and more specifically, a 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 lis .OR, \ II where R^ represents an atom of hydrogen or a CtC^ alkyl group and Rg represents a hydrogen atom, a halogen atom, or an alkyl, alkoxyl or 15 hydroxy! groupe wherein the process consists of the hot reduction, in an acid medium, by phosphorous acid in the presence of iodine or hvdriodic acid, of an alpha hvdroxylated carboxvlic acid of the general formula Ills Ar~CR-C00H 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 alkylarylcetone 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 arylglycolic acidse 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 3 (European spplxcsLxon 0 032 37^ snd 0 033 375 ^ European patent W® 0 003 825) or the hydrolysis of an arylalkylacetonitrile obtained by the reaction of a cyanide ion with a suitably substituted quaternized benzylamine (European 5 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 10 it is possible to obtain arylacetic acids of the general formula I j, both economically and with excellent yields 9 in a single stage and homogenous phase,, by heat reduction., in an acid medium, by phosphorus acid in the presence of catalytic amounts or iodine or iodhydric acid, of alpha hydroxyIsted carboxylic 15 acid of the general formula III : Ar-CR-COOH (III) 1 ^hich Ar and R have the same meaning as above., More specifically,, the invention process consists in reducing one mole of alpha hydroxylafeed carboxylic acid,, of general formula III in which Ar and R are as defined above, in an aerd!medium, at a temperature above 70°C3 with at least the molar 25 equivalent of phosphorous acid in the presence of 0.01 to 0.1 moles of iodine or iodhydric acid3 possiblyin a compatible organic solvent such as acetic acid. More specifically:, the invention process consists in reducing one mole of alpha hydroxylated carboxylic acid9 of general formula III, in an acid medium, at a temperature above 70°C3 with at 30 least the molar equivalent of phosphorous acid in the presence of 0.01 to 0.1 moles of iodine or iodhydric acid9 possibly in a compatible organic solvent such as acetic acid9 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 carbo^ylie 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 reaction3 then isolating the acid required by already established methods. 4 The iodhydric acid used is commercial iodhydric acid in a 57wt % aqueous solution.

The alpha hydroxylated carboxylic acid can be parahydroxylmandelic acid9 3 s 4-methvlenedioxy mandelic acids 5 4-hydroxy 3-methoxy mandelic acids 3-chloro-4~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 the 10 reaction solvents and neutralization of the mineral acids present by a weak acid salt such ©s sodium acetate, the reactive medium is used again with water and the untransformed initial acid is eliminated by already established methods then the acid required is isolated by crystallisation or by any other 15 established method With certain substrate, it is sometimes advantageous to isolate the arylacetie acid required in the form of one of its salts, such as its sodium salt.,, fch@n remove the salt using a strong mineral acid.

The invention process produces the following substances, among others s - parahydroxyphenylacetic acid. » 4~hydroxy 3-methoxy phenvlacetic acid? - 3*4-snethy lenedioxy phenvlacetic 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,.

Exasnplc. 1 In a solution heated under reflux containing : 30 -0.5 moles of phosphorous acid, - 25 mraoles of 57 15 iodhydric acid? - 78 g of acetic acid? a hot solution (40eC) is added in four hours s consisting of : ~ 0.05 moles of par&hydroxymandelic acid, 35 - 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 5 40°C., 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 50nC under vacuum at constant weight. 72.4 % of pure parahydroxyphenylaeetic acid is thus produced, i.e. a yield of 95®3 % of the theoretical value 10 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 acids, 2-5 mmoles of 57 % 15 iodhydric acid and 8 g of acetic acid kept at 95°C» It is then heated at 95"C for *5 minutes 0.4 g of sodium acetate is added before cctteaatraiing the reactive medium under vacuum. The crystallised residue obtained is dissolved in 20 g of hot water then s if necessary? fch© solution obtained is bleached by adding 20 sodium bisulphite. It is then crystallised at 0®C™ The crystallized substance is then filtered, washed with water and dried at 50eC under vacuum at constant weight™ This produces 33.8 mmoles of pure 4-hydroxy 3-methoxy phenylacetic acid™ Example _3 If the same process as that described in example 2 is followed using 3; ''-Hiethylenedioxy mandelic acid initially s pure 3,4-methylenedioxy phenylacetic acid is obtained with a yield of 73.4 % of the theoretical value.

Example A 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 40MC? is added.The reactive medium is then kept under reflux for one hour ©,nd 35 concentrated under vacuum after adding 2 g of anhydrous sodium acetate The crystallised residue is then dissolved under reflux 6 in 250 g of water. The solution is then treated with 4 g of sodium bisulphite before being crystallized at Q°C. The crystallised precipitate is then filtered,, washed with water and dried at 50°C under vacuum at constant weight* This produces On,37 moles of pure parahydroxyphenylacetic acid.

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

1. CLAIMS _ 7 - 1„ Process for preparing substituted acetic acids of general formula I: 5 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-thi®nyle l~(2-methoxy-naphthyl), 3,4-methylenedioxy phenyl and substituted phenyls of the general 10 formula II: 15 where Rj represents an atom of hydrogen or a Cj-C^ alkyl group and R^ represents a hydrogen atom, a halogen atom, or an alkyl, alkoxyl or hydroxy1 group, wherein the process consists of the hot reduction, in an acid medium, by phosphorous acid in the presence of 20 iodine or hydriodic acids of an alpha hydroxylated carboxylic acid of the general formula Ills

2.Ar-CR-COOH

3.I 25 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 30 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 acids' Application of the process according to any one of Claims 1 or 2 to 35 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-pheny1acetic acid. I

5. Application of the process according to anyone of Claims 1 or 2 to the manufacture of 3 9 4-methyJLenedioxy phenylacetic acid.

6.S„ A process for the preparation of compounds of formula (I s claimed in Claim ?9 substantially as hereinbefore described by way of ^ Example.

7. Compounds of formula (I) as defined in Claim 13 whenever prepared by a process as claimed in any of Claims I to 6. Dated this 30th day of Septembers 1986. BY:- TOMKINS 6 CO.J Applicants' Agent.'