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GB2034308A - Process for Manufacturing Racemic Parahydroxymandelic Acid - Google Patents

Process for Manufacturing Racemic Parahydroxymandelic Acid Download PDF

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Publication number
GB2034308A
GB2034308A GB7937472A GB7937472A GB2034308A GB 2034308 A GB2034308 A GB 2034308A GB 7937472 A GB7937472 A GB 7937472A GB 7937472 A GB7937472 A GB 7937472A GB 2034308 A GB2034308 A GB 2034308A
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Prior art keywords
acid
glyoxylic acid
phenol
condensation
water
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GB7937472A
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GB2034308B (en
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Sanofi Aventis France
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Francaise Hoechst Ste
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/367Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Racemic parahydroxymandelic acid is prepared by condensing glyoxylic acid with an excess of phenol in water in the presence of an alkaline agent, at 30 to 100 DEG C.

Description

SPECIFICATION Process for the Manufacturing Racemic Parahydroxymandelic Acid The present invention relates to a process for manufacturing racemic parahydroxymandelic acid by the condensation of glyoxylic acid with phenol, in an alkaline medium.
It is known that carbonyl derivatives such as glyoxylic acid or chloral condense in an alkaline aqueous medium on phenol rings substituted or unsubstituted by hydroxyl, alkoxyl and/or alkyl groups possessing at least one proton on the para position, to provide racemic arylglycolic acids either directly, or by the hydrolysis of racemic aryltrichloromethylcarbinols (Houben-Weyl, phenole 6/1 c, pages 1022-1058, G. Thieme Verlag Stuttgart, 1 976).
Racemic arylglycolic acids are valuable starting materials since it is known how to convert them into aromatic aldehydes (P. Hebert, Bull. Soc.
Chim. France, 27,4th serie, 45-55, 1920). In particular racemic parahydroxymandelic acid provides by decarboxylating oxidation, parahydroxybenzaldehyde (Nagai Shigeki et Coll., Japanese Patent Application No. 76-128 934).
Racemic parahydroxymandelic acid is prepared either by hydrolysis of the cyanhydrin of parahydroxybenzaldehyde (Beil. X, page 410), or by reduction with a sodium amalgam of parahydroxyphenylglyoxylic acid (Beil. X, 1st supple, page 199), or by condensation of glyoxylic acid with phenol (Riedel de Haen A.G., German Patent No. 621 567; Haarmann and Riemer, G.m.b.H., French Patent No. 2,132,364), or lastly by hydrolysis of parahydroxyphenyltrichloromethylcarbinol derived from the condensation of chloral with phenol (H. Haakh and A. Smola, Austrian Patent No. 141159).
However, carbonyl derivatives in an alkaline aqueous medium and particularly glyoxylic acid are subject to the Canizzaro reaction; when hot, glyoxylic acid decomposes completely into oxalic and glycolic acids (Boettinger, Ber. 13, 1 931 (1880)).
It is to avoid this Cannizzaro reaction becoming preponderant and destroying the glyoxylic acid utilized that the condensation process of glyoxylic acid with phenolic rings in an alkaline aqueous medium are carried out at a temperature close to room temperature. Thus in the process described in German Patent No. 621 567, an aqueous alkaline solution of phenol and of glyoxylic acid are left for several days at ambient temperature.
In French Patent No. 2,132,364, the condensation of the glyoxylic acid with an excess of phenol is carried out in 10% caustic soda solution, for 36 hours between 1 5 and 250C.
More generally, the processes of preparing racemic arylglycolic acids by condensation of glyoxylic acids on a phenolic ring are carried out at a temperature below 250C. J. Goodman et Coll., (Biochem. Biophys. Acta, 156, 364-7, 1968) condense glyoxylic acid with guaiacol in 68 hours at 25or, whereas J. Kamlet, (U.S.A.
Patent No. 2,640,083), operates for 48 hours between 1 5 and 200C to prepare racemic 4hydroxy-3-methoxy mandelic acid.
A.I. Fatiadi and R. Schaffer, (J. Research Nat.
Bur. Stand., Sect. A, 78A, 411-12, 1972), studied the temperature factor on the condensation of glyoxylic acid on guaiacol; they concluded that any rise in temperature was detrimental to the yield and recommend carrying out this condensation by introducing the glyoxylic acid into an alkaline aqueous solution of guaiacol cooled to OOC over 4 hours and then leaving it for 20 hours from 0 to 200C. For the manufacture of racemic 3,4-dihydroxy mandelic acid, the Nippon Synthetic Chemical Industry Co. Ltd. in Japanese Patent Application No. 75-29522, teaches carrying out the condensation of the glyoxylic acid with pyrocatechol over 2 hours at 5 to 8 0C, then for 24 hours at 10-1 50C and finally over 24 hours at ambient temperature.
It is obvious that these methods: low temperatures-long reaction times, result in a reduction of the productivity of the plant, an increase in investment and lend themselves with difficulty to large tonnage industrial production.
Accordingly, it is an object of the present invention to provide a method for the manufacture of racemic parahydroxymandelic acid which improves these temperature and time reaction restrictions.
It is another object of the invention to provide such a method which improves the productivity of the installation.
It is a further object of the invention to provide such a process which lends itself more readily to large scale production.
Other objects and advantages of the invention will be apparent from the description which follows.
Applicants have now discovered surprisingly and unexpectedly that the condensation of glyoxylic acid with phenol in an alkaline aqueous medium could be carried out very easily at temperatures comprised between 30 and 1000C, whilst preserving good selectivity, providing excellent yields and considerably shortening the reaction time.
According to the invention, there is provided a process, comprising reacting glyoxylic acid with an excess of phenol in water in the presence of an alkaline agent at a temperature comprised between 30 and 1000C for some minutes, then after neutralization of the reaction medium, removal of the unconverted phenol by extraction with a water immiscible organic solvent, and then, after acidification of the aqueous phase at pH 0.5, extraction of the desired acid with a water immiscible solvent. The racemic parahydroxymandelic acid is thus isolated after evaporation of the extraction solvent.
More precisely, the process comprises condensing between 30 and 1000C, preferably between 70 and 1000C and advantageously between 70 and 850C, in a nitrogen atmosphere, 1 mole of 50% glyoxylic acid in water with 2 to 3 moles of phenol in 2 liters of water containing 2 to 3 moles of sodium hydroxide for a time less than or equal to 70 minutes, then neutralizing the solution with 50% sulphuric acid in water, then extracting the unconverted phenol with 1,2dichloro-ethane. Finally, the aqueous phase acidified to pH=0.5 with 50% sulphuric acid in water, is extracted with ethyl acetate. In this way there is isolated, after evaporation of the ethyl acetate, the crystalline, racemic parahydroxymandelic acid, monohydrate with a yield of 70 to 85% with respect to the glyoxylic acid utilized.
The following examples are given purely by way of illustrative and non-limiting description of the invention.
Example 1 A solution of 296 g (2 moles) of 50% glyoxylic acid in water, 564 g (6 moles) of phenol and 1 60 g (4 moles) of caustic soda in pellets in 3.6 liters of water are heated for 30 minutes at 820C with stirring and under a nitrogen atmosphere. After cooling to 400C, the reaction solution is brought to pH:6.5 with 50% sulphuric acid in water, then after cooling to room temperature, the unconverted phenol is extracted by means of 1,2dichloroethane; 376 g of phenol, after evaporation of-the solvent, are thus isolated. The aqueous phase is then acidified to pH 0.5 with 50% sulphuric acid in water and then, after saturation with sodium chloride, it is extracted several times with ethyl acetate.In this way, after evaporation of the ethyl acetate and drying under vacuum at 400C for 60 hours, 285 g of crystalline racemic parahydroxymandelic acid monohydrate are isolated, having a melting point in tube of 83-850C, namely a yield of 76.5% with respect to the glyoxylic acid utilized.
Example 2 A solution of 296 g (2 moles) of 50% glyoxylic acid in water, 564 g (6 moles) of phenol and 160 g (4 moles) of caustic soda in pellets in 3.6 liters of water are heated for 30 minutes at 1000C with stirring and under a nitrogen atmosphere. Then procedure is as in Example 1. In this way the racemic parahydroxymandelic acid monohydrate is isolated with a yield of 72% with respect to the glyoxylic acid utilized.
Example 3 A solution of 296 g (2 moles) of 50% glyoxylic acid in water, 564 g (6 moles) of phenol and 200 g (5 moles) of caustic soda in pellets in 3.6 liters of water is heated for 1 hour at 500C, with stirring and under a nitrogen atmosphere. Then procedure is as in Example 1. In this way the racemic parahydroxymandelic acid monohydrate is isolated with a yield of 78% with respect to the glyoxylic acid utilized.
Example 4 A solution of 296 g (2 moles) of 50% glyoxylic acid in water, 564 g (6 moles) of phenol and 1 80 g (4.5 moles) of caustic soda in pellets in 3.6 liters of water is heated for 30 minutes from 30 to 850C, then cooled in 30 minutes to 400 C, with stirring and under a nitrogen atmosphere. Then procedure as is in Example 1. In this way the racemic parahydroxymandelic acid monohydrate is isolated with a yield of 81% with respect to the glyoxylic acid utilized.
Example 5 A solution of 296 g (2 moles) of 50% glyoxylic acid in water, 564 g (6 moles) of phenol and 1 60 g (4 moles) of caustic soda in pellets in 3.6 liters of water are heated for 30 minutes at 700 C, with stirring and under a nitrogen atmosphere.
Procedure is then as in Example 1. In this way the racemic parahydroxymandelic acid monohydrate is isolated with a yield of 83.5% with respect to the glyoxylic acid utilized.
Example 6 Into a solution of 133.2 g (0.9 mole) of 50% glyoxylic acid in water and 990 g of water heated under reflux in a nitrogen atmosphere, is introduced with stirring and at once, a hot solution prepared at that moment by dissolving under reflux in a nitrogen atmosphere 253.8 g (2.7 moles) of phenol and 81 g (2.025 moles) of sodium hydroxide in pellets in 630 g of water is introduced. The resulting solution is then kept stirred and under a nitrogen atmosphere, at 1000C for 5 minutes, then the solution is neutralized while hot to a pH of 6.5 with 6N hydrochloric acid. After cooling to room temperature, procedure is as in Example 1. In this way 169 g (1.8 mole) of phenol is recovered and then the racemic parahydroxymandelic acid monohydrate is isolated with a yield of 67.5% with respect to the glyoxylic acid utilized.

Claims (10)

Claims
1. Process for manufacturing racemic parahydroxymandelic acid, comprising condensing in water in the presence of an alkaline agent, at a temperature comprised between 30 and 1000C, glyoxylic acid with an excess of phenol.
2. Process according to Claim 1, wherein the condensation is carried out at a temperature comprised between 70 and 1000C.
3. Process according to Claim 2, wherein the condensation is carried out at a temperature comprised between 70 and 850C.
4. Process according to Claim 1, 2, or 3, wherein the alkaline agent is sodium or potassium hydroxide.
5. Process according to any preceding claim, wherein the condensation is carried out in the presence of 2 to 3 moles of sodium or potassium hydroxide per mole of glyoxylic acid.
6. Process according to any preceding claim, wherein the condensation is carried out in 1 to 3 liters of water per mole of glyoxylic acid.
7. Process according to any preceding claim, wherein 1 mole of giyoxylic acid is condensed with an excess of 2 to 3 moles of phenol.
8. Process according to any preceding claim, wherein the condensation is carried out in a time less than or equal to 70 minutes.
9. Process according to Claim 1 substantially as described in any one of the foregoing Examples.
10. Racemic parahydroxymandelic acid when obtained by a process as claimed in any one of the preceding claims.
GB7937472A 1978-11-03 1979-10-29 Process for manufacturing racemic parahydroxymandelic acid Expired GB2034308B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR7831123A FR2440350A1 (en) 1978-11-03 1978-11-03 PROCESS FOR PRODUCING RACEMIC PARAHYDROXYMANDELIC ACID

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GB2034308A true GB2034308A (en) 1980-06-04
GB2034308B GB2034308B (en) 1983-03-30

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JP (1) JPS5564546A (en)
BE (1) BE879359A (en)
CA (1) CA1125784A (en)
CH (1) CH642047A5 (en)
DE (1) DE2944295C2 (en)
FR (1) FR2440350A1 (en)
GB (1) GB2034308B (en)
IE (1) IE49308B1 (en)
IT (1) IT1124842B (en)
NL (1) NL189910C (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5216052A (en) * 1991-07-01 1993-06-01 Ciba-Geigy Corporation Bisbenzofuran-2-ones
US5252643A (en) * 1991-07-01 1993-10-12 Ciba-Geigy Corporation Thiomethylated benzofuran-2-ones
US5260430A (en) * 1991-11-29 1993-11-09 Ciba-Geigy Corporation Diphenyl acetic acid derivatives
US5356966A (en) * 1992-05-22 1994-10-18 Ciba-Geigy Corporation 3-(carboxymethoxyphenyl)benzofuran-2-one stabilizers
US5367008A (en) * 1992-05-22 1994-11-22 Ciba-Geigy Corporation 3-(alkoxyphenyl)benzofuran-2-ones as stabilisers
US5369159A (en) * 1992-05-22 1994-11-29 Ciba-Geigy Corporation 3-(acyloxyphenyl)benzofuran-2-one stabilizers
US5428177A (en) * 1992-09-23 1995-06-27 Ciba-Geigy Corporation 3-(Dihydrobenzofuran-5-yl)benzofuran-2-ones as stabilizers
US5428162A (en) * 1992-09-23 1995-06-27 Ciba-Geigy Corporation 3-(2-acyloxyethoxyphenyl)benzofuran-2-ones for use as stabilizers

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2462415A1 (en) * 1979-07-25 1981-02-13 Hoechst France PROCESS FOR PREPARING RACEMIC HYDROXYARYLGLYCOLIC ACIDS AND PRODUCTS THEREOF
FR2495137A1 (en) * 1980-11-28 1982-06-04 Hoechst France Para-hydroxy-mandelic acid continuous prepn. - from glyoxylic acid, phenol and sodium hydroxide in aq. soln. in reactors arranged in series
FR2705669B1 (en) * 1993-05-28 1995-08-25 Hoechst France Process for the preparation of hydroxyphenylacetic acids.

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE617763C (en) * 1932-03-22 1935-08-24 J D Riedel E De Haeen Akt Ges Process for the production of aromatic oxyaldehydes
DE621567C (en) * 1932-06-25 1935-11-09 J D Riedel E De Haeen A G Process for the production of aromatic oxyaldehydes
DE2115551C3 (en) * 1971-03-31 1980-01-10 Haarmann & Reimer Gmbh, 3450 Holzminden Process for the production of aromatic hydroxyaldehydes

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5216052A (en) * 1991-07-01 1993-06-01 Ciba-Geigy Corporation Bisbenzofuran-2-ones
US5252643A (en) * 1991-07-01 1993-10-12 Ciba-Geigy Corporation Thiomethylated benzofuran-2-ones
US5260430A (en) * 1991-11-29 1993-11-09 Ciba-Geigy Corporation Diphenyl acetic acid derivatives
US5356966A (en) * 1992-05-22 1994-10-18 Ciba-Geigy Corporation 3-(carboxymethoxyphenyl)benzofuran-2-one stabilizers
US5367008A (en) * 1992-05-22 1994-11-22 Ciba-Geigy Corporation 3-(alkoxyphenyl)benzofuran-2-ones as stabilisers
US5369159A (en) * 1992-05-22 1994-11-29 Ciba-Geigy Corporation 3-(acyloxyphenyl)benzofuran-2-one stabilizers
US5488117A (en) * 1992-05-22 1996-01-30 Ciba-Geigy Corporation 3-(acyloxyphenyl)benzofuran-2-one stabilisers
US5428177A (en) * 1992-09-23 1995-06-27 Ciba-Geigy Corporation 3-(Dihydrobenzofuran-5-yl)benzofuran-2-ones as stabilizers
US5428162A (en) * 1992-09-23 1995-06-27 Ciba-Geigy Corporation 3-(2-acyloxyethoxyphenyl)benzofuran-2-ones for use as stabilizers

Also Published As

Publication number Publication date
FR2440350B1 (en) 1981-05-22
JPS5564546A (en) 1980-05-15
DE2944295A1 (en) 1980-05-08
DE2944295C2 (en) 1982-02-04
NL7908100A (en) 1980-05-07
GB2034308B (en) 1983-03-30
NL189910C (en) 1993-09-01
IE792108L (en) 1980-05-03
IT7926924A0 (en) 1979-10-30
CA1125784A (en) 1982-06-15
IE49308B1 (en) 1985-09-18
FR2440350A1 (en) 1980-05-30
NL189910B (en) 1993-04-01
CH642047A5 (en) 1984-03-30
BE879359A (en) 1980-04-11
IT1124842B (en) 1986-05-14

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Effective date: 19941029