FR2470127A1 - Crystalline racemic sodium 2:thienyl glycolate - prepd. from 2-di:chloroacetyl thiophene, is a stable intermediate for 2:thienyl-acetic acid - Google Patents

Abstract

Crystallised racemic sodium 2-thienyl glycolate (I) is new. In its prepn., 2-dichloro acetyl thiophene (III) is heated at 50-100 deg.C in aq. sodium hydroxide, concentrated, and adjusted to pH6 with conc. HCl. The mixture is evaporated and resultant residue is suspended in acetic acid, filtered, and the filtrate evaporated in vacuo to give (I). (I) is starting material for the prepn. of 2-thienyl acetic acid (II) which is used in the prepn. of antibiotics administered orally. (I) is stable on storage and non-hygroscopic unlike the free acid.

Description

The present invention relates to pure crystallized racemic sodium 2-thienyl glycolate of formula:

 Racemic 2-thienyl glycolic acid is described in the prior art. It can be obtained either by reduction of 2-thienyl glyoxylic acid with sodium amalgam according to F. ERNST, Ber., 1886, 19, 3278-82, or by disproportionation in alkaline medium of 2-thienyl glyoxal according to S GRONOWITZ, Arkiv Kemi, 1957, 11, 519-26, or by hydrolysis of methyl 2-thienyl glycolate obtained by reaction of FRANZEN with 2-thienyl glyoxal according to K. KENJI et al., CA, 1969, 70, 11290 r, either by hydrolysis of the cyanhydrin of thiophenecarbalåéhyde- 2 according to Japanese patent application 73 08775, or finally by condensation in an acid medium of glyoxylic acid on thiophene according to Japanese patent application 74 49954. In the free state , 2-thienyl glycolic acid has poor stability and very often after a few hours of storage in the solid state it becomes colored and degraded.

 To obviate these crippling drawbacks to industrial manufacture, the Applicant has now found that the crystallized racemic sodium 2-thienyl-2-glycolate is perfectly stable and not hygroscopic.

 Certain salts of 2-thienyl glycolic acid are described in the literature - F. ERNST, Ber., 1886, 19, 3278-82 prepared calcium 2-thienyl glycolate, barium 2-thienyl glycolate and thienyl -2 silver glycolate, but to the knowledge of the applicant the crystallized racemic sodium thienyl-2 glycolate is not described in the literature.

 According to the invention, the crystallized racemic sodium 2-thienyl-2-glycolate can be prepared, for example, by sodium hydrolysis of 2-dichloroacetyl-thio phene - More precisely, it can be obtained by treatment at alkaline pH and hot, advantageously at 60-65 C, dichloroacetyl-2 'thiophene with an aqueous solution of sodium hydroxide, advantageously with a sodium hydroxide solution of 1 to 4 N and more especially with 2 1 of sodium hydroxide 2 N per mole of dichloroacetyl-2' thiophene implemented, followed by dry concentration under vacuum of the reaction solution cooled to room temperature and acidified to pH = 6 with concentrated hydrochloric acid - At this stage, a crude mixture of 2-thienyl glycolate is obtained of racemic sodium and of sodium chloride. Pure crystallized racemic sodium 2-thienyl-2-glycolate is obtained by taking up the preceding crude mixture with acetic acid, filtration of the insoluble mineral salts, dry concentration under vacuum of the filtrate, residue crystallized with an isopropanol-water solution 100-5 v / v and drying under vacuum at 1100C at constant weight. Is thus isolated with good yields 2-thienyl glycolate racemic crystallized sodium having an instantaneous melting point of 21 t 30C pure in the form of colorless crystals, not hygroscopic; very soluble in water, soluble in acetic acid, methanol, sparingly soluble in isopropanol, insoluble in ether, benzene and carbon tetrachloride.

 The subject of the invention is also the application of crystallized racemic sodium 2-thienyl-glycolate to the preparation of 2-thienyl acetic acid.

2-Thienyl acetic acid is used in the synthesis of various therapeutic substances and in particular for obtaining antibiotics which can be administered orally, such as penicillin or cephalosporin derivatives (see EH FLYNN, "Cephalosporins and Penicillin, Chemistry and Biology ", Academic Press,
New York, NY, 1972, pages 532-582, as well as the United States patent of 3,516,997 and the publication of RR CHAUVETTE, J. Amer. Chem. Soc., 1962, 84, 3401).

 It is known in the prior art to access 2-thienyl acetic acid by hydrogenolysis of the hydroxyl group of 2-thienyl glycolic acid with hydroiodic acid in the presence of red phosphorus according to F.

ERNST, Ber., 1886, 19, 3281.

According to the invention, the application of a similar method on crystallized racemic sodium 2-thienyl glycolate makes it possible to obtain, with excellent yields, 2-thienyl acetic acid.

According to the process of the invention, the crystallized racemic sodium thienyl2 glycolate is dissolved in a C 2 -C 4 alkanol acid such as acetic acid, propionic acid, advantageously in 2 to 7 volumes of alkanoic acid and more especially in 5 volumes of acetic acid or propionic acid. This solution is then acidified with a strong protonic acid with pKa less than 2, in slight excess, so as to completely displace the sodium salt of the racemic 2-thienyl glycolic acid used; advantageously this excess is between 2 and hod of the theory, more especially of 30%. As suitable strong protonic acids there may be mentioned concentrated sulfuric acid, oxalic acid, hydrochloric acid, hydroiodic acid. After, optionally filtration of the insoluble mineral salts, the filtrate or the suspension is heated for a few minutes to boiling in the presence of hydrogen iodide in 57% aqueous solution (d = 1.7) and red phosphorus. More precisely, the reduction is carried out at reflux, advantageously for 15 to 45 minutes, in the presence of 0.01 to 0.1 mole of hydrogen iodide in 57% aqueous solution and from 1 to 5 gram atoms, more especially 2 , 5 to 3 gram atoms of red phosphorus, per mole of crystallized racemic sodium thienyl-2 glycolate put into reaction. At the end of the reaction and after cooling of the reaction suspension, it is filtered to remove the unprocessed phosphorus and possibly the mineral salts. present, then the filtrate is concentrated to dryness under vacuum. The residue thus obtained is taken up in water and with a chlorinated organic solvent such as methylene chloride, it is decanted, then the aqueous phase is re-extracted with methylene chloride and then the combined chloromethylenic organic phases are washed with water, dried over anhydrous sodium sulfate, filtered and finally concentrated to dryness under vacuum. This isolates the 2-thienyl acetic acid, crystallized, characterized by its proton NMR spectrum. After recrystallization from petroleum ether, 2-thienyl acetic acid has a melting point of 62 + 20C.

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

Example 1
A solution of 4 moles (165 g) of sodium hydroxide in 97% pellets in 1800 g of water is heated to 60-650C, then introduced into this solution at a speed such that the temperature is maintained at 60- 650C without the aid of an outdoor heater, 1 mole (195 g) of dichloroacetylthiophene (F. PACCHIANO et al.,
Arzneim. - Forsch., 1964, 14, 363 - 67).

 The introduction finished, heating is continued for one hour at 60-650C, then after cooling to room temperature, this solution is acidified to pH = 6 with concentrated hydrochloric acid, and then it is concentrated to dryness under vacuum. The crystallized residue thus obtained is dried at 500 ° C. for 6 hours in the aeromatic. 370 g of product containing 47.8% of sodium chloride and titrating 2.9 meq / g in carboxylic function are thus isolated.

 This product is suspended with stirring in acetic acid. The insoluble sodium chloride is filtered and the filtrate is then concentrated to dryness under vacuum. The crystallized residue thus obtained is pasted with an isopropanol-water solution (100-5 V / V), then dried under vacuum at constant weight at 1100C. Is thus isolated the pure crystallized racemic sodium 2-thienyl glycolate, having an instantaneous P.F of 214 + 30C, very soluble in water, soluble in methanol and sparingly soluble in methanol.

Microanalysis
C6H503 SNa C% S%
PM = 180.17 Calculated 40.00 17.80
Found 40.1 17.0
Physical analyzes:
NMR (acetic acid d4) S = 5.4 (s, 1H, CH); & 7.0 (m, 3H, thienyl protons)
Potentiometric determination: carboxylate function: 98.9 + 0.5% - To the knowledge of the applicant, this product is not described in the literature.

Example 2
0.36 mol (64.8 g) of pure crystalline racemic sodium 2-thienyl glycolate is dissolved in 5 volumes of acetic acid, then 0.24 mol of concentrated sulfuric acid is introduced and the salts are filtered. minerals. 1.05 gram atom (32.5 g) of red phosphorus and 0.0175 mole (2.31 cm3) of 57% hydrochloric acid are then introduced into the filtrate, then the suspension obtained is heated to reflux for 35 minutes. After the reaction mixture has cooled to room temperature, the unprocessed phosphorus is filtered, the filtrate is then concentrated at 40 ° C. under vacuum, then the residue is taken up with 150 g of water and 150 cm3 of methylene chloride. re-extraction of the aqueous phase with methylene chloride, the combined organic phases are left on 10 g of sodium metabisulfite, then filtered, washed with water (50 g), dried over anhydrous sodium sulfate and concentrated to dryness under empty. Is thus isolated 47.3 g of thienyl2 acetic acid having a melting point of 620C after recrystallization from petroleum ether, ie a yield of 92% of the theory calculated relative to the sodium 2-thienyl glycolate put in artwork.

NMR (acetone d6) = 3.8 (s, 2H, -CH2); = 7.1 (m, 3H, thienyl protons).

Example 3
0.0375 mole (6.75 g) of pure crystallized racemic sodium 2-thienyl glycolate is dissolved in 37.5 cm3 of acetic acid, then the concentrated hydrochloric acid is introduced d = 1.18 to ph = 1 is 0.045 mole (3.8 cm3), then the mineral salts are filtered.

0.001 mol (0.13 cm3) of 57% hydroiodic acid, d = 1.7, and 0.1 gram atom (3 g) of red phosphorus are then introduced into the filtrate, and the suspension obtained is heated for 15 minutes at reflux. After cooling, 35 cm3 of water are added and then the unprocessed phosphorus is filtered. The filtrate is then extracted 3 times with 50 cm3 of dichloroethane, then the combined organic phases are washed with water, dried over anhydrous sodium sulfate, filtered and finally concentrated to dryness under vacuum.

4.5 g (0.031 mol) of 2-thienyl acetic acid are thus isolated, ie a yield of 84% of theory.

Example 11 The procedure is as in Example ^ m ^ -s cn replacing acetic acid with propionlque acid 37.5 cm3.

At the end of the reaction, 2-thienyl acetic acid is isolated with a yield of 85% of theory.

Example 5
0.0375 mol (6.75 g) of pure crystallized racemic sodium 2-thienyl glycolate is dissolved in 37.5 cm 3 of acetic acid, and 0.045 mol (5.85 cm 3) of 57% hydroiodic acid are then introduced , d = 1.7 and 0.1 gram atom (3.1 g) of red phosphorus. This suspension is heated for 15 minutes at reflux, then after cooling to room temperature, the suspension obtained is filtered. The filtrate is then concentrated to dryness under vacuum, then the filtrate is treated as in example 2
Is thus isolated 2-thienyl acetic acid with a yield of 85% of theory.

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 (15)

1. As a new industrial product, crystallized racemic sodium 2-thienyl glycolate.  2. Process for the manufacture of 2-thienyl sodium crystallized racemic glycolate characterized by the fact that hot treatment, in an alkaline medium, in the presence of sodium hydroxide in aqueous solution, of 2-dichloroacetyl thiophene, which dry concentrated under vacuum the resulting aqueous alkaline solution acidified to pH = 6 + 0.2 with concentrated hydrochloric acid, which is then filtered the suspension obtained by taking up the crystallized residue in acetic acid and finally vacuum drying at constant weight the product obtained by dry concentration under vacuum of the previous filtrate. 3. Method according to claim 2 characterized in that the reaction is carried out at a temperature between 50 and 1000C. 4. Method according to claim 3 characterized by the fact cru'on performs the reaction j5 + 5 C. 5. Method according to any one of claims 2,3, 4 charac erls by the fact qL-'or. performs the reaction in soda of normality between 1 and 4 N.  6. Method according to any one of claims 2, 3, 4 and 5 characterized in that the reaction is carried out in 2 1 of 2N sodium hydroxide per mole of dichloroacetyl-2 'thiophene used.  7. Method according to any one of claims 2, 3, 4, 5 and 6 characterized in that one purifies-2-thienyl-sodium glycemic racemic crystallized by washing with aqueous isopropanol. 8. Method according to claim 7 characterized in that the washing solution is a solution obtained by mixing 100 volumes of isopropanol with 5 volumes of water. 9. Application of crystallized racemic sodium 2-thienyl glycolate to the preparation of 2-thienyl acetic acid. 10. Application according to claim 8 characterized in that hot treatment, in a strong acid medium, within a C2 to C4 alkanoic acid, 2-thienyl-2-glycolate racemic with 11 hydroiodic acid in solution 57% aqueous in the presence of red phosphorus. 11. Application according to any one of claims 9 and 10 characterized in that the reaction is carried out at a temperature below 1100C. 12. Application according to any one of claims 9, 10 and 11 characterized in that the alkanolic acid is either acetic acid or propionic acid.  13. Use according to any one of claims 9, 10, 11 and 12 characterized in that the reaction is carried out in the presence of 1 to 5 gram atoms of red phosphorus per mole of racemic sodium 2-thienyl glycolate used . 14. Application according to any one of claims 9, 10, 11, 12 and 13 characterized in that the reaction is carried out in the presence of 0.01 mole to 0.1 mole of 57 hydroiodic acid; in water per mole of racemic sodium 2-thienyl glycolate used.  15. Application according to any one of claims 9, 10, 11, 12, 13 and 14 characterized in that the in situ sodium salt of racemic 2-thienyl glycolic acid is displaced by the addition of an acid strong proton of pka lower than 2, in slight excess.