CH653324A5 - AROMATIC DERIVATIVES OF ACETIC ACID SUBSTITUTED IN ALPHA BY A SULFO GROUP AND THEIR MANUFACTURING METHOD. - Google Patents

Description

The present invention relates to a process for the preparation of aromatic derivatives of acetic acid substituted in alpha with a sulfo group and derivatives thus obtained.

The compounds which can be obtained by means of the process according to the present invention are derivatives of general formula I:

CR-COO-R I

SO.-M

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,

- Ri, R2, R3 and R4, identical or different, represent a hydrogen atom, a halogen atom, a hydroxyl group, a Q-C5 alkyl group, a C1-C5 alkoxyl group, an acyloxyl group in Cj-Cs with the condition that at least one of the two substituents Ri 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.

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

Α-sulfo-p-hydroxyphenylacetic 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. 2412551.

The monosodium salt of a-sulfonato-p-hydroxyphenylaceous acid and the disodium a-sulfonato-p-hydroxyphenylacetate are described in French Patent No. A-2337136. According to the process described in this patent, the crystallized disodium α-sulfonato-p-hydroxyphenylacetate is obtained by alkaline hydrolysis of the disodium α-sulfonato-p-methylsulfonyloxyphenylacetate derived from the condensation of the sulfur trioxide-dioxane complex on l p-hydroxyphenylacetic acid whose phenolic function has been temporarily protected, beforehand, in the form of an ester of methanesulfonic acid.

More generally, it is known to access a-sulfoaryl-acetic acids either by the action of sodium, potassium or ammonium sulfite on a-haloarylacetic acids (according to J. Brust, Ree. Trav. Chim., 1928, 47, pp. 153-168) or by gentle oxidation of α-mercantoarylacetic acids (according to PA Levene et al., J. Biol. Chem., 1927, 75, pp. 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

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several operations, either using 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 a by a sulfo group of general formula I consists in reacting hot, free or salified hydroxylated α-hydroxyarylacetic acids with an alkaline or alkaline earth base. or an amine, of general formula II, in which the symbols Rls R2, R3 and R4 have the meanings indicated for formula I, with an excess of a derivative of sulfurous or disulfurous acid

• ÇH-COOH

OH

The hydroxylated α-hydroxyarylacetic acids of general formula II can be obtained, for example, according to French patent application No. 79.19171.

The sulfurous acid derivative is an alkaline, alkaline earth or amine, neutral or acid salt, sulfurous acid or disulfurous acid such as, for example, sodium sulfite, sodium metabrsulfite 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 ex-temporally 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 hydroxylated α-hydroxyarylacetic acid of general formula II used is generally neutralized, extemporaneously with a base having a cation identical to the sulfurous acid derivative 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 the ethylene glycol monomethyl ether (methoxy -2 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 substituted in a is obtained by a sulfo group in the form of mono-, di- or trisel depending on the pH of the reaction medium. If it is desired to obtain α-sulfoarylacetic acid, the sulfonic and carboxylic acid functions of which are salified with an alkaline or alkaline-earth base or an amine, of general formula III, in which the symbols R1; R2, R3 and R4 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 l '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.

CH-COO-R

If it is desired to obtain α-sulfoarylacetic acid, the sulfonic function of which is only salified by an alkali or alkaline cation

earthy or an ammonium compound, of general formula IV, in which the symbols Rj, R2, R3 and R4 have the meanings indicated for formula I, and the symbol M represents an alkali or alkaline-earth cation or an ammonium compound, neutralize at pH = 1 the reaction medium with concentrated hydrochloric acid (d = 1.16) then the salt sought is isolated by means known per se.

Finally, if it is desired to obtain free α-sulfoarylacetic acid, of general formula V, in which the symbols Rt, R2, R3 and R4 have the meanings indicated for formula I, the salt of general formula IV is subjected in aqueous solution to a leaching with a cation exchange resin with sulfonic groups in acid form such as a polystyrene divinylbenzene with sulfonic groups followed by lyophilization or a concentration under dry vacuum, at a temperature below 20 ° C., filtrate obtained.

CH-COOH

SO, H

CH-COOH IV SO, M

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 a few hours of heating under vacuum to a temperature above 50 ° C. to lose their sol-vation water.

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 mol) of racemic p-hydroxymandelic acid monohydrate, 16 g (0.4 mol) of sodium hydroxide is heated to 7 h at boiling point in a nitrogen atmosphere. lozenges, 37.8 g (0.3 mol) of anhydrous sodium sulfite in 60 g of water. After the reaction medium has cooled to room temperature and possible 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 square centimeters of water are introduced to obtain a complete solution).

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

Microanalysis for C8H7Na06S, H20:

Calculated: C 35.29 H 3.33 S 11.78 H20 6.62% '

Found: C 35.30 H 3.40 S 11.60 H20 6.62% 'P.M. = 272.22

* determined by the method of K. Fischer.

Example 2:

In a 2 L autoclave, a solution of 558.5 g (3 mol) of racemic p-hydroxymandelic acid, monohydrate, 120 g (3 mol) is heated for 2 hours at 130 ° C. in a nitrogen atmosphere. ) sodium hydroxide pellets and 416 g (3.3 mol) of anhydrous sodium sulfite in 900 g of water.

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After the reaction medium has cooled to room temperature and elimination, if necessary, of the insoluble mineral salts by filtration, an aqueous solution of the crude trisodium (p-oxidophenyl) -2-sulfonato-2-acetate is obtained, by adding a few grams of water, to a weight of 2066 g.

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

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 mol) of disodium (p-hydroxyphenyl) -2-sulfonato-2-acetate are thus isolated in the form of colorless crystals, crystallized with 3 molecules of water, giving a yield of 43.25% of the 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 H20% found: 15.9% (theory: 16.4%).

Acidified to pH = 1, with concentrated hydrochloric acid (d = 1.19), 1000 g of the preceding 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 cm3 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 mol) 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 theory compared to the p-hydroxymandelic acid used.

5 g (0.0184 mol) of this monosodium salt of racemic (p-hydroxyphenyl) -2-sulfonato-2-acetic acid crystallized with a molecule of water are dissolved in 100 g of water. This solution is then treated with a polystyrene divinylbenzene resin 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 mol) of (p-hydroxyphenyl) -2-sulfo-2 acid are isolated racemic acetic crystallized with two molecules of water, having a melting point of 102-103 ° C, a yield of 89.1% of theory compared to the monosodium salt of acid (p-hydroxyphenyl) -2 racemic -sulfonato-2-acetic used.

Example 3:

A solution of 186.2 g (1 mol) of racemic p-hydroxymandelic acid monohydrate and 40 g (1 mol) of sodium hydroxide pellets in 550 g is heated to the boiling point for 6 hours in a nitrogen atmosphere. (2 mol) of 38% 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 (0.55) are thus isolated mol) of monosodium salt of racemic (p-hydroxyphenyl) -2-sulfonato-2-acetic acid crystallized with a molecule of water, ie a yield of 55% of the theory calculated relative to p-hydroxymandelic acid put implemented.

Example 4:

A solution of 186.2 g (1 mol) of racemic p-hydroxymandelic acid monohydrate, 40 g (1 mol) of sodium hydroxide pellets and

190 g (1 mol) of sodium metabisulfite in 11 of methoxy-2-ethanol.

After the reaction medium has cooled to room temperature, the precipitate obtained is filtered off and dissolved immediately 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 mol) of monosodium salt are thus isolated. '(p-hydroxyphenyl) -2-sulfonato-2-acetic acid crystallized with a molecule of water, ie a yield of 58.8% of the theory calculated compared to the p-hydroxymandé-lique acid used.

Example 5:

A solution of 18.6 g (0.1 mol) of racemic p-hydroxymandelic acid monohydrate and 18.9 g (0.15 mol) of sodium sulfite is heated for 5 hours at the boiling point in a nitrogen atmosphere. anhydrous 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, a release of sulfur dioxide occurs.

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

Example 6:

A suspension of 9.9 g (0.05 mol) of (hydroxy-4-methoxy-3-phenyl) -2-hydroxy-2-acetic acid (racemic) is heated for 3 h at boiling in a nitrogen atmosphere. 2 g (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 and then the cooled filtrate is acidified to pH = 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 mol) of monosodium salt of (hydroxy-4-methoxy-3-phenyl) -2-sulfonato-2-acetic acid crystallized monohydrate is a yield of 55% of the theory calculated by compared to the acid (hydroxy-4-methoxy-3-phenyl) -2-hydroxy-2-acéti-that used. This acid can be recrystallized from 1.4 volumes of water.

Microanalysis for C, H9Na07S, H20:

Calculated: C 35.76 H 3.67 H20 5.96% *

Found: C 35.50 H 3.80 H20 6.10% '

M.P. = 302.25 determined according to the method of K. Fischer.

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

Example 7:

Heated for 2 h at the boiling point in a nitrogen atmosphere a suspension of 0.05 mol of acid (dimethoxy-3,5-hydroxy-4-phenyl) -2-hydroxy-2-acetic racemic, of 2 g ( 0.05 mol) of sodium hydroxide pellets and 9.45 g (0.075 mol) of anhydrous sodium sulfite in 15 g of water. Then proceed as in Example 6 and isolate the monosodium salt of the acid (dimethoxy-3,5-hydroxy-4-phenyl) -2-sulfonato-2-acetic racemic crystallized monohydrate with a yield of 75% of the theory calculated relative to the acid (dimethoxy-3,5-hydroxy-4-phenyl) -2-hydroxy-2-acetic used.

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

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Microanalysis for Cj0HnNaO8S, H2O:

Calculated: C 36.14 H 3.94 S 9.65 H20 5.40% "

Found: C 36.15 H 4.10 S 9.30 H2CM, 80% '

M.P. = 332.3

* determined by the method of K. Fischer.

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

Example 8:

Heated for 5 h at the boiling point in a nitrogen atmosphere a suspension of 0.05 mol of acid (chloro-3-hydroxy-4-phenyl) -2-hydroxy-2-acetic racemic, 2 g (0, 05 mol) sodium hydroxide pellets and 9.45 g (0.075 mol) anhydrous sodium sulfite in 15 g of water. The procedure is then carried out as in Example 6. The monosodium salt of the (chloro-3-hydroxy-4-phenyl) -2-sulfonato-2-acetic acid racemic crystallized monohydrate is thus isolated with a yield of 49% of the theory calculated relative to the acid (chloro-3-hydroxy-4-phenyl) -2-hydroxy-2-acetic used.

This acid recrystallizes from 1 volume of water by hot and cold. To the knowledge of the holder, this product is not described in the literature.

Example 9:

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

At the start of reflux, ammonia is released. At the end of the reaction, a solution is obtained (pH = 6.1) which is acidified to pH = 1 with concentrated hydrochloric acid (d = 1.18). The ammonium monosal p-hydroxyphenylacetic acid a-sulfonato crystallizes. It is drained, then washed by pasting with isopropanol, then it is dried at constant weight under vacuum at 40 ° C. It is thus isolated

62.5 g (0.25 mol) of ammonium monosalt of racemic a-sulfonato-p-hydroxyphenylacetic acid crystallized in colorless prisms, i.e. a yield of 61.16% of the theory calculated relative to the acid p-hydroxymandelic used. By concentration of the 5 mother liquors of crystallization, a second jet of 26.4 g is isolated, ie an overall yield of 86.8%.

Microanalysis for Cg-Hj! N06S:

Calculated: C 38.55 H 4.45 N 5.62%

I0 Found: C 38.60 H 4.50 N 5.50%

M.P. = 249.25

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

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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. The racemic cris-20 tallise diammonium α-sulfonato-p-hydroxyphenylacetate.

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

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Microanalysis for C8HI4, N206S:

Calculated: C 36.08 H 5.30 N 10.52%

Found: C 35.90 H 5.30 N 10.40%

M.P. = 226.28

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To the knowledge of the holder, 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.

R

Claims (10)

653,324 1. Process for the manufacture of aromatic derivatives of acetic acid substituted in alpha with a sulfo group of formula CH - CDO-R SO, -M 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, - Rj, R2, R3 and R4, identical or different, represent a hydrogen atom, a halogen atom, a hy-droxyl group, a Q-C5 alkyl group, a C1-Cs alkoxyl group, a group Cj-Cs acyloxyl with the condition that at least one of the two substituents Rt 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, process characterized by the fact that a free or salified α-hydroxy hydroxyarylacetic acid is reacted hot with an alkaline, alkaline-earth base or with an amine, of formula II: - C00 H 2. Method according to claim 1, characterized in that it is carried out in water. '2 in which the symbols Ru R2, R3 and R4 have the above meanings, with an excess of an alkaline, alkaline earth or amine, neutral or acid salt, sulfurous acid or disulfurous acid. 2 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 alkaline salt of disulfurous acid is sodium metabisulfite or sodium di-sulfite. 6. Method according to claim 1, characterized in that the alkaline acid salt of sulfurous acid is sodium bisulfite or sodium hydrosulphite 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 one of claims 1 to 7, characterized in that the free or salified a-hydroxy hydroxyarylacetic acid of formula II is the racemic p-hydroxymandelic acid not hydrated to give the acid (p-hydroxyphenyl ) -2-sulfonato-2-acetic and its alkali or alkaline earth or ammonium salts. 9. Method according to one of claims 1 to 5, characterized in that the free or salified a-hydroxyarylacetic acid of formula II is (hydroxy-4-methoxy-3-phenyl) -2-hydroxy- acid Racemic 2-acetic acid, or racemic (chloro-3-hydroxy-4-phenyl) -2-hydroxy-2-acetic acid, or acid (dimethoxy-3,5-hydroxy-4-phenyl) - Racemic 2-hydroxy-2-acetic, or racemic p-hydroxymandelic acid monohydrate. 10. Derivatives resulting from the process according to claim 1, characterized in that they are: - (hydroxy-4-methoxy-3-phenyl) -2-sulfo-2-acetic acid and its salts, neutral or acidic, alkaline, alkaline-earth or amines, - (chloro-3-hydroxy-4-phenyl) -2-sulfo-2-acetic acid and its salts, neutral or acid, alkaline, alkaline-earth or amines, - (3,5-dimethoxy-4-hydroxy-4-phenyl) -2-sulfo-2-acetic acid and its salts, neutral or acid, alkaline, alkaline-earth or amines, - diammonium α-sulfonato-p-hydroxyphenylacetate, - the ammonium monosalt of a-sulfonato-p-hydroxy-phenylacetic acid.