WO1981003171A1 - Aromatic derivatives of acetic acid alpha-substituted by a sulfo group and production method thereof - Google Patents

Abstract

Aromatic derivatives of acetic acid (Alpha)-substituted by a sulfo group having the formula: (FORMULA) wherein: R represents a hydrogen atom, an alkaline or alkaline-earth cation or an ammonium compound with the restriction that R is identical to M when M represents a hydrogen atom; R1, R2, R3 and R4, identical or different, represent a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group in C1-C5, an alcoxyl group in C1-C5, an acyloxyl group in C1-C5 with the condition that at least one of the two substituants R1 or R2 represents a hydroxyl group; M represents a hydrogen atom or an alkaline or alkaline-earth cation or an ammonium compound, but cannot represent a hydrogen atom when R represents an alkaline or alkaline-earth cation or an ammonium compound. They are obtained by hot reacting a free or salified (Alpha)hydroxy hydroxyarylacetic acid with an excess of a salt of sulfurous or disulfurous acid.

Description

 "Aromatic derivatives of acetic acid substituted at α by a sulfo group and their manufacturing process"

The present invention relates to aromatic derivatives of acetic acid substituted at α by a sulfo group and their manufacturing methods.

The compounds of the invention are aromatic derivatives of acetic acid of general formula, I,:

dans laquelle :

in which :

- R represents a hydrogen atom, an alkaline or alkaline earth cation or an ammonium compound with the restriction that R is identical to M when M represents a hydrogen atom;

-R _1, R _2, R ₃ and R _4, identical or different, represent a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group C ₁ - C ₅ alkoxyl C ₁ - C ₅ , a C ₁ - C ₅ acyloxyl group with the condition that at least one of the two substituents R ₁ or R ₂ represents a hydroxyl group;

- M represents a hydrogen atom or an alkaline or alkaline earth cation or an ammonium compound, but cannot represent a hydrogen atom when R represents an alkaline or alkaline earth cation or an ammonium compound.

Certain compounds of general formula, I, are interesting intermediates in organic synthesis and in particular in the preparation of penicillins or semi-synthetic cephalosporins which can be used in therapy.

The α-sulfo ρ-hydroxyphënylacetic acid as well as its mono and disodium salts which belong to the compounds of general formula, I, are cited in the literature. Thus, α-sulfo p-hydroxyphenylacetic acid can be obtained in aqueous solution by the action of the sulfur trioxide-dioxane complex on p-hydroxyphenylacetic acid according to French Patent No. 2,412,551.

The sodium salt of α -sulfonato p-hydroxyphenylacetic acid and the disodium α -sulfonato p-hydroxyphenylacetate are described in French Patent No. 2,337,136. According to the process described in this patent, a -sulfonato p - crystallized disodium hydroxyphenylacetate is obtained by alkaline hydrolysis of 1 'disodium p-methylsulfonato-disodium loxyphenylacetate resulting from the condensation of the sulfur trioxide-dioxane complex on p-hydroxyphenylacetic acid, the phenolic function of which has been temporarily protected, beforehand, in the form of a methanesulfonic acid ester.

More generally, it is known to access α-sulfo-arylacetic acids either by the action of sodium, potassium or ammonium sulfite on α-halo arylacetic acids (according to J. BRUST, Rec. Trav. Chim. , 1928, 47, 153-168) or by gentle oxidation of α-mercapto arylacetic acids (according to PA LEVENE et al, J. Biol. Chem., 1927, 75, 337-365). However, during the condensation of an alkaline sulfite on α-bromophenylacetic acid, J. BRUST (loc. Cit.) Isolates, alongside the expected sulfonic acid, mandelic acid.

Thus, the known methods either require the use of sulfur trioxide which is inconvenient to handle industrially, or require several operations, either use expensive or rare raw materials or, finally, require laborious purifications.

However, thanks to the process which is the subject of the present invention, the drawbacks of the previous processes have been eliminated and the final products can be obtained easily with good yields.

The process according to this invention for the preparation of aromatic derivatives of acetic acid substituted in 'α with a sulfo group of general formula, I, consists in reacting hot free hydroxy or salified α-hydroxyarylacetic acids with an alkaline base or alkaline earth or an amine, of general formula, II, in which the symbols R ₁ , R ₂ , R ₃ and R ₄ have the meanings indicated for formula I, with a derivative of sulfurous acid.

The hydroxylated α-hydroxy arylacetic acids of general formula II can be obtained, for example, according to French patent application No. 79 - 19171.

The sulfurous acid derivative can be an alkaline, alkaline earth or amine, neutral or acidic salt, sulfurous acid or disulfurous acid such as, for example, sodium sulfite, sodium metabisulfite or sodium disulfite, sodium bisulfite or sodium hydrogen sulfite, ammonium sulfite.

These sulfurous acid derivatives can either be used in a technical aqueous solution or in the anhydrous or hydrated crystallized state, or can be prepared extemporaneously in the reaction medium by the action of sulfurous anhydride on a suitably chosen alkaline agent.

Generally, an excess of sulfurous acid derivative is used. For convenience and to avoid significant consumption of sulfurous acid derivative accompanied by the release of sulfur dioxide, it is preferable to conduct this reaction in a very weakly acidic or alkaline medium (pH> 5). To do this, the α-hydroxy arylacetic hydroxyl acid of general formula, II, is generally neutralized, used extemporaneously with a base having a cation identical to the derivative of sulfurous acid used; advantageously this cation is sodium.

The reaction can be carried out in a solvent chosen from solvents with a dielectric constant greater than 5 and with a boiling point greater than 80 ° C. such as, for example, water or certain alcohols such as monomethyl ether of 1 ethylene glycol (2-methoxy ethanol).

In general, the reaction is carried out at temperatures between 50 and 150 ° C, preferably between 90 and 130 ° C and it gives the expected derivative with good yields. At the end of the reaction, the aromatic derivative of acetic acid is obtained substituted in α by a sulfo group in the form of mono, di or tri salt according to the pE of the reaction medium. If, it is desired to obtain the α-sulfo arylacetic acid whose sulfonic and carboxylic acid functions are salified with an alkaline or alkaline-earth base or an amine, of general formula III, in which the symbols R ₁ , R ₂ , R ₃ and R ₄ have the meanings indicated for formula I and the symbols R and M, identical, represent an alkaline or alkaline-earth cation or an ammonium compound, the reaction medium is neutralized at pH = 7 either with acid concentrated hydrochloric acid, (d = 1.18), either with a base whose cation is identical to the derivative of sulfurous acid used, then the salt sought is isolated by means known per se.

If it is desired to obtain the α-sulfo arylacetic acid of which only the sulfonic function is salified by an alkaline or alkaline-earth cation or an ammonium compound, of general formula IV, in which the symbols R ₁ , R ₂ , R ₃ and R ₄ have the meanings indicated for the formula

I, and the symbol> i represents an alkaline or alkaline earth cation or an ammonium compound, the reaction medium is neutralized at pE = 1 with concentrated hydrochloric acid, (d = 1.18) then the salt sought is isolated according to means known per se.

Finally, if one wishes to obtain free α-sulfo arylacetic acid, of general formula V, in which the symbols R ₁ , R ₂ , R ₃ and R ₄ have the meanings indicated for formula I, the salt of general formula IV in aqueous solution is subjected to leaching with a cation exchange resin with sulphonic groups in acid form such as a polystyrene divinylbenzene resin with sulphonic groups followed by a liophylization or a dry vacuum concentration, at a temperature below 20 ° C, of the filtrate obtained.

Generally the compounds of general formula I very easily provide hydrates by crystallization in water. This property is widely used to isolate the compounds of general formula I in the crystallized state. These hydrates are very often very stable at room temperature and require to lose their water of solvation a few hours of heating under vacuum at a temperature above 50 ° C.

The following examples are given by way of illustration and in no way limit the invention.

Example 1.

A solution of 37.2 g (0.2 mole) of racemic p-hydroxymandelic acid monohydrate, 16 g (0.4 mole) of sodium hydroxide is heated for 7 and a half hours to boiling in a nitrogen atmosphere. in tablets, 37.8 g (0.3 mole) of anhydrous sodium sulfite in 60 g of water. After cooling the reaction medium to room temperature and optional elimination of insoluble mineral salts by filtration, the solution is acidified to pH = 1 with concentrated hydrochloric acid (d = 1.18). The precipitate obtained is dissolved in the reaction medium by heating to boiling, boiling which is maintained until the end of sulfur dioxide release (at this stage, if necessary, a few cm ³ of water are introduced to obtain a complete solution).

The solution is then left to crystallize by slow cooling after having introduced, around 60 ° C, 18 g of isopropanol. After standing for a few hours at room temperature, the crystals formed are drained. Is thus isolated 40.8 g (0.15 mole) of monosodium salt of (p-hydroxyphenyl) -2 sulfonato-2 acetic acid racemic, monohydrate in the form of colorless crystals decomposing without melting at 260 ° C, a yield of 75% of the theory calculated relative to the p-hydroxymandelic acid used.

Microanalysis C% H% S% H ₂ O%

C ₈ H ₇ Na O ₆ S, H ₂ O calculated 35.29 3.33 11.78 6.62 found 35.3 3.4 11.6 6.62 PM = 272.22 determined by the method of K. Fischer.

Example 2.

In a 2-liter autoclave, a solution of 558.5 g (3 moles) of racemic p-hydroxymandelic acid, monohydrate, 120 g (3 moles) is heated for two hours at 130 ° C. in a nitrogen atmosphere. sodium hydroxide pellets and 416 g (3.3 moles) of anhydrous sodium sulfite in 900 g of water. After cooling the reaction medium to room temperature and removing, if necessary, the insoluble mineral salts by filtration, an aqueous solution of the crude (p-oxidophenyl) -2-sulfonato-2-trisodium acetate is obtained which is brought by addition a few grams of water, at a weight of 2066 g.

This aqueous solution is divided into two parts which are treated separately and differently to obtain either (p-hydroxyphenyl) -2 sulfonato-2 disodium acetate or monosodium acid (p-hydroxyphenyl) -2 sulfonato-2 acetic and acid (p-hydroxyphenyl) -2 sulfo-2 acetic.

Neutralized at pH = 7 with concentrated hydrochloric acid (d = 1.18), 100 g of the above solution. The precipitate thus obtained is filtered, washed by pasting with 20 cm 3 of methanol and then dried under vacuum at 40 ° C at constant weight. 20 g (0.06 mole) of (p-hydroxyphenyl) -2 sulfonato-2 disodium acetate are thus isolated in the form of colorless crystals, crystallized with 3 molecules of water, ie a yield of 43.25% of theory calculated with respect to the p-hydroxymandelic acid used.

Acidimetry

- carboxylate function: 3.01 meq / g - (theory: 3.03 meq / g)

- phenol function: 3.01 meq / g (theory: 3.03 meq / g)

Water dosage according to K. FISCHER. H ₂ O% found: 15.9% (theory: 16.4%).

Acidified to pH = 1 with concentrated hydrochloric acid, (d = 1.19), 1000 g of the above aqueous solution of trisodium salt of (p-hydroxyphenyl) -2-sulfo-2 acetic acid. The suspension obtained is then heated to boiling until the end of the release of sulfur dioxide, then the solution obtained is left to crystallize by slow cooling after having introduced, around 80 ° C., 200 cm 3 of isopropanol.

After standing for a few hours at room temperature, the crystals formed are drained and then dried under vacuum at 40 ° C at constant weight. 284 g (1.043 mole) of monosodium salt of (p-hydroxyphenyl) -2-sulfonato-2 acetic acid are thus isolated in the form of colorless crystals crystallized with a molecule of water, ie a yield of 71.8% of the theory compared to the p-hydroxymandelic acid used.

5 g (0.0184 mole) of this monosodium salt of (p-hydroxyphenyl) -2 sulfonato-2 acetic acid, racemic, crystallized with a molecule of water are dissolved in 100 g of water. This solution is then treated with a polystyrene resin divinylbenzene with sulfonic groups in acid form. After removal of the resin by filtration and concentration of the filtrate under vacuum at a temperature below 20 ° C., 4.4 g (0.0164 mole) of racemic (p-hydroxyphenyl) - 2 sulfo-2 acetic acid are isolated. crystallized with two molecules of water, with a melting point of 102-103 ° C, a yield of 89.1% of theory compared to the monosodium salt of acid (p-hydroxyphenyl) -2 sulfonato-2 racemic acetic used. Example 3.

A solution of 186.2 g (1 mole) of racemic p-hydroxy-mandelic acid monohydrate and 40 g (1 mole) of sodium hydroxide pellets in 6 hours is heated to boiling in nitrogen atmosphere for 6 hours. 550 g (2 moles) of 33% aqueous sodium bisulfite solution (d = 1.32). After cooling, the reaction medium is acidified to pH = 1 with concentrated hydrochloric acid (d = 1.18), then the suspension is treated as in Example 1. 149.7 g are thus isolated (0, 55 mol) of monosodium salt of (p-hydroxyphenyl) -2-sulfonato-2 acetic acid racemic crystallized with a molecule of water is a yield of 55% of the theory calculated compared to the p-hydroxymandelic acid put in artwork.

EXAMPLE 4 A solution of 186.2 g (1 mole) of racemic p-hydroxy-mandelic acid monohydrate, of 40 g (1 mole) of sodium hydroxide is heated for 22 hours to boiling in a nitrogen atmosphere. in pellets and 190 g (1 mole) of sodium metabisulfite in 1 liter of 2-methoxy ethanol. After the reaction medium has cooled to room temperature, the precipitate obtained is filtered off, which is immediately dissolved in hot in 2 volumes of water. The solution obtained is then acidified to pH = 1 with concentrated hydrochloric acid (d = 1.18) and then treated as in Example 1. 160.2 g (0.588 mole) of monosodium salt are thus isolated. (p-hydroxyphenyl) -2 sulfona to-2 acetic acid crystallized with a molecule of water, i.e. a yield of 58.8% of the theory calculated relative to the p-hydroxymandelic acid used.

Example 5.

A solution of 18.6 g (0.1 mole) of racemic p-hydroxy-mandelic acid monohydrate and 18.9 g (0.15 mole) of sulfite is heated for 5 hours at the boiling point in a nitrogen atmosphere. anhydrous sodium in 30 g of water acidified with 14.4 g of hydrochloric acid in a 38% aqueous solution, ie 0.15 mol. The pH of the solution is 2.1 - During heating, an evolution of sulfur dioxide occurs.

After two hours of reflux, the pH of the solution stabilizes at pE = 3.8. At the end of the reaction, after cooling the reaction medium to room temperature, it is acidified to pE = 1 with concentrated hydrochloric acid (d = 1.18) and then the suspension obtained is treated as in Example 1. The monodose salt 4e (p-hydroxyphenyl) -2-sulfonato-2 acetic racemic acid crystallized with a water molecule is thus isolated with a yield of 36% of the theory calculated relative to the p-hydroxymandelic acid used .

Example 6.

A suspension of 9.9 g (0.05 mole) of 2-hydroxy-3-methoxy-phenyl) -2 hydroxy-2-acetic acid (2 g) is heated to boiling for 3 hours in a nitrogen atmosphere. 0.05 mol) of sodium hydroxide pellets and 9.45 g (0.075 mol) of anhydrous sodium sulfite in 15 g of water. At the end of the reaction, the suspension obtained is filtered hot to remove the mineral salts then the cooled filtrate is acidified to pE = 1 with concentrated hydrochloric acid (d = 1.18). The precipitate formed is then drained and then dried under vacuum at 40 ° C at constant weight.

Is thus isolated 8.3 g (0.027 mole) of monosodium salt of acid (4-hydroxy-3-methoxyphenyl) -2 sulfonato-2 acetic crystallized monohydrate is a yield of 55% of the theory calculated relative to the acid (4-hydroxy-3-methoxyphenyl) -2 hydroxy-acetic used. This acid can be recrystallized from 1.4 volumes of water.

Microanalysis

C ₉ H ₉ Na O ₇ S, H ₂ OC% H% H ₂ O%

P.M = 302.25 calculated 35.76 3.67 5.96 found 35.5 3.8 6.1 determined according to the method of K. FISCHER. To the knowledge of the Applicant, this product is not described in the literature.

Example 7.

A suspension of 0.05 mol of acid (3,5-dimethoxy-4-hydroxy-phenyl) -2 hydroxy-2-racemic acetic acid of 2 g is heated for 2 hours at boiling in a nitrogen atmosphere.

(0.05 mole) sodium hydroxide pellets and 9.45 g (0.075 mole) anhydrous sodium sulfite in 15 g water. The procedure is then as in Example 6 and the monosodium salt of the acid (3,5-dimethoxy-4 hydroxy-phenyl) -2 sulfonato-2 acetic racemic crystalline monohydrate is isolated with a yield of 75% of the theory calculated by relative to the acid (3,5-dimethoxy-4-hydroxy-phenyl) -2 hydroxy-acetic used.

This acid recrystallizes from 1.6 volumes of water by hot and cold.

Microanalysis C ₁₀ H ₁₁ Na O ₈ S, H ₂ O

PM = 332.3 C% H% and H ₂ O% calculated 36.14 3.94 9.65 574 found 36.15 4.1 9.3 4.8 determined by the method of K. FISCHER.

To the knowledge of the Applicant, this product is not described in the literature. Example 8.

Heated for 5 hours at boiling in nitrogen atmosphere a suspension of 0.05 mole of acid (3-chloro-4-hydroxyphenyl) -2 hydroxy-2 acetic racemic, 2 g (0.05 mole) d sodium hydroxide pellets and 9.45 g (0.075 mol) of anhydrous sodium sulfite in 15 g of water. The procedure is then carried out as in Example 6. The monosodium salt of the (3-chloro-4-hydroxy-phenyl) -2 sulfonato-2 acetic acid racemic crystallized monohydrate is thus isolated with a yield of 49% of the theory calculated relative to with (3-chloro-4-hydroxyphenyl) -2 hydroxy-2 acetic acid used.

This acid recrystallizes from 1 volume of water by hot and cold.

To the knowledge of the Applicant, this product is not described in the literature.

Example 9.

0.62 mole (39.4 g) of sulfur dioxide is added at 0 ° C in 260 g of ammonia containing 1.65 mole of ammonia, and then 0.41 mole is added (76 , 3 g) racemic p-hydroxymandelic acid monohydrate. The solution obtained is then heated for 18 hours to one boil.

At the start of reflux, ammonia is released. At the end of the reaction, a solution is obtained (pE = 6.1) which is acidified to pE = 1 with concentrated hydrochloric acid, (d = 1.18). The ammonium monosalphate of α-sulfonato p-hydroxyphenylacetic acid crystallizes. It is drained, then washed by pasting with isopropanol, then it is dried at constant weight under vacuum at 40 ° C. Is thus isolated 62.5 g (0.25 mole) of ammonium monosel of α-sulfonato p-hydroxyphenylacetic acid racemic crystallized in colorless prisms, a yield of 61.16% of the theory calculated relative to l p-hydroxymandelic acid used. By concentration of the crystallization mother liquors, a second jet of 26.4 g is isolated, ie an overall yield of 86.8%. Microanalysis C ₈ H ₁₁ NO ₆ S

P.M = 249.25 C% H% N% calculated 38.55 4.45 5.62 found 38.6 4.5 5.5

To the knowledge of the Applicant, this product is not described in the literature.

Example 10. The procedure is as in Example 9, but at the end of the reaction, the reaction solution is left to crystallize at around 0 ° C. Racemic, crystallized, diammonium α-sulfonato p-hydroxyphenylacetate crystallizes.

It is drained, then washed by pasting with isopropanol and then dried at 40 ° C. under vacuum at constant weight. The racemic diammonium α-sulfonato p-hydroxyphé nylacetate crystallized in colorless prisms is thus isolated.

Microanalysis

C ₈ H ₁₄ N ₂ O ₆ SC% H% N%

P M = 226.28 calculated 3 6, 08 5, 30 10, 52 found 35, 9 5, 3 10, 4

To the knowledge of the Applicant, this product is not described in the literature.

It goes without saying that the present invention has been described for purely explanatory and in no way limitative and that any useful modification may be made without departing from its scope as defined by the claims below.

Claims

1. - Process for the manufacture of aromatic derivatives of acetic acid substituted in alpha with a sulfo group of formula

in which : - R represents a hydrogen atom, an alkaline or alkaline earth cation or an ammonium compound with the restriction that R is identical to M when M represents a hydrogen atom; R _1, R _2, R ₃ and R _4, identical or different, represent a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group C ₁ - C ₅ alkoxyl, C ₁ - C ₅ , a C ₁ - C ₅ acyloxyl group with the condition that at least one of the two substituents R ₁ or R ₂ represents a hydroxyl group; - M represents a hydrogen atom or an alkaline or alkaline earth cation or an ammonium compound, but cannot represent a hydrogen atom when R represents an alkaline or alkaline earth cation or an ammonium compound, process characterized by the fact which is reacted hot an al pha-hydroxy hydroxyaryl acetic acid that is free or salified, with an alkaline, alkaline-earth base or with an amine, of formula

(in which the symbols R ₁ , R ₂ , R ₃ and R ₄ have the meanings above), with an excess of an alkaline, alkaline-earth or amine salt, neutral or acid, of the sulfurous acid or disulfurous acid. 2. Method according to claim 1, characterized in that it is carried out in water. 3. Method according to claim 1, characterized in that it is carried out at a temperature between 50 and 150 ° C. 4. Method according to claim 1, characterized in that the alkaline salt of the sulfurous acid used is sodium sulfite. 5. Method according to claim 1, characterized in that the alkali salt of disulfurous acid is sodium metabisulfite or sodium disulfite. 6. Method according to claim 1, characterized in that the alkaline acid salt of sulfurous acid is sodium bisulfite or sodium hydrogen sulfide in aqueous solution. 7. Method according to claim 1, characterized in that the amine salt of sulfurous acid is ammonium sulfite. 8. Method according to any one of claims 1 to 7, characterized in that the free or salified alphahydroxy hydroxyaryl acetic acid is racemic p-hydroxymandelic acid not hydrated to give the acid (p-hydroxyphenyl) -2 2-acetic sulfonato and its alkali or alkaline earth or ammonium salts. 9. Method according to any one of claims 1 to 5, characterized in that the free or salified alphahydroxyaryl acetic acid is (4-hydroxy-3-methoxyphenyl) -2 racemic acetic acid, or l (3-chloro-4-hydroxyphenyl) -2 racemic 2-hydroxy acetic acid, or 3,5-dimethyl-4-hydroxyphenyl acid -2 racemic 2-hydroxy acetic acid, or p-hydroxymandelic acid monohydrate racemic 10. Derivatives resulting directly from the process according to claims 1 and 9, characterized in that they are: - (4-hydroxy-3-ethoxy-phenyl) -2-sulfo-2 acetic acid and its salts, neutral or acid, alkaline, alkaline-earth or amines; - (3-chloro-4-hydroxyphenyl) -2-sulfo-2 acetic acid and its salts, neutral or acidic, alkaline, alkaline-earth or amines; - (3,5-4-hydroxy-phenyl) -2-sulfo-2 acetic acid and its salts, neutral or acidic, alkaline, alkaline-earth or amines; - al pha-sulfonato p-hydroxyphenyl diammonium acetate; - the ammonium monosel of alphasuIfonato p-hydroxyphenyl acetic acid