CS239416B1 - Preparation method of 7-/1h-tetrazol-1-yl/-acetamidocephalosporane acid - Google Patents

Abstract

The present invention relates to a process for preparing 7- - [1H-Tetrazol-1-yl] -acetamidocfaloaperane acids of formula I and their salts β organic bases and alkali metals. N = N N = CH n-ch 2 -CO-NH E J-CH2OCOCH3 ČOOH The compound of formula I, in its form salts are used as an intermediate in production polesynthotic antibiotics Cefazoline. which has a broad spectrum of action against Oram-nogative and Oram-pazitive bacteria. A compound of formula I of the invention prepares 7-aminocephalospherate by acylation of salts of new acid with mixed acid anhydride 1H-tetrazal-1-yl-acetic acid and suitable tertiary acid: [ce ^ -ΖΟΗ ^ / ^ Ι ^ Ο-ΟΟΟΗ, ve wherein n is 0-16, in an organic solvent and an organic salt of the compound of formula I is isolated by addition of an organic one a solvent in which this is minimal soluble.

Description

(54) A process for the preparation of 7- (1H-tatrazol-1-yl) -acetamidocephalosporanoic acid

The invention relates to a process for the preparation of 7- (1H-tetrazol-1-yl) -acetamidocephaloaperanoic acid of the formula I and their salts with β organic bases and alkali metals.

N = N,

N = CH ₂ n -CH ₂ —CO-NH

E

J - CH ₂ OCOCH ₃

The compound of formula I, in the form of its salts, is used as an intermediate in the preparation of the polesynthotic antibiotic Cefazoline. which has a broad spectrum of activity against both Oramogative and Oram-Positive bacteria.

The compound of formula (I) according to the invention is prepared by acylating the salts of 7-aminocephalosporic acid with a mixed anhydride of 1 H-tetrazal-1-yl-acetic acid and a suitable tertiary acid, in which: 0 to 16, in an organic solvent and an organic salt of a compound of formula I is isolated by adding an organic solvent in which it is minimally soluble.

The present invention relates to a process for the preparation of 7- (1H-tetrazel-1-yl) -acetamidocephalesperanoic acid of formula 1

N = N.

I,

CH = N: _N-CH2 -CO-NH

CH ₂ OCOCH ₃

COOH (I) and their piglets with organic bases, respectively. alkali metals. The compound of formula 1 is used as an intermediate in the farm to produce a semi-synthetic antibiotic with a broad spectrum of activity against both Oram-negative and Oram-positive bacteria.

Until now this compound is produced by reacting 7-sit sowed aminocefalesperánevé acid / T hereinafter kClí / chloride lH-tetrazole-1-yJ. oetavé ^{Iqrseliny-1-vodnž} ecetonovám environment / Fujisawa J. Antiblotic 2, 131, 1970; US Pat. 3,516,997, 1969]. Another method of preparation described is the reaction of 7-ACK with 1 H -tetrazol-1-yl-acetic acid chloride in methanol and in the presence of triethylamine / Teyama: Oer. Offen 2,263,861, 1972].

Another method of preparation is based on the reaction of 7-ACK with 1 H-tetradol-1-yl-acetic acid chloride in a water-immiscible medium with the presence of an organic and inorganic base / Pierrel S.P.A .: Oer. Offen 2,730,579,176; Smith, Kline, Oer.

Offen 2,649,545, 1976]. Another group of preparation methods uses mixed acid anhydrides as acylase reagent instead of 1H-tetrazel-1-yl-acetic acid chloride. One of these is the Fujisawa acylation of 7-ACK in tetrahydrefuran, chloroform in the presence of trimethylamine or triethylamine with mixed ennydride 1H-tetrazel-1-yl-ectic and pivalevic acid / Fujisawa: US Pat. 3,516,997, 1968; Oer. Offen 1,953,861 (1969); S. African Pat. 6,907,500, 1969; Fr. U.S. Pat. 2,068,419, 1969]. It is also known to use mixed 1H-tetrazol-1-yl-acetic anhydride and benzoic acid in an acsten-water / A mixture. Ignite: Anal. Prefilss Drug Subst. £ 1, 1975]. Another preparation method uses mixed anhydrides of 1H-tetrazol-1-yl-acetic acid and pivalic acid or formic acid in tetrahydrofuran and acetone or dimethylformamide in the presence of an organic base, or acylation of 7-ACK with large 1H-tetrazol-t-yl-ecteveic acid in the presence Ν, die-dicyclohexylcarbodiimide / Carlo Srbe: Oer Offen 2,616,442, 1976; Heffmann L. R., Oer. Offen 2,527,291,174; Hoffmenn L. R., Swiss 609,059, 1974]. Another group of methods for preparing the compound of formula I is based on the use of reactive acylating agents synthesized from 1H-tetrazel-1-yl-acetic acid and phosphorus compounds / Gema S. A. Oer. Offen 2,701,751,176; Qema S.A., Antibieticos S.A .: Span. 462,495, 1977 (or pyridinium halides) (Ono Pharm: Japan Kokai 77,144,688, 1976). Another method of acylation with 1 H-tetrazel-1-yl-acetic acid mixed anhydride with formic acid, 1 H-tetrazol-1-yl-acetic acid chloride or with 1 H-tetrazol-1-yl-acetic acid free acid in the presence of secondary or tertiary The amines utilize reactive intermediates formed by the 7-ACK reaction. phosphorus compounds / Sangye Κ. K .: Japan Kakai 7,789,696,176; Seve Terap: Ger. Offen 2,364,759,1973;

Teyama: Ger. Offen 2,218,209,1972; Fujisawa: Japan Kakai 7,493,386 (1973); Sangyo Κ. K .: Japan Kakai 7,793,791, 1976 /, silicon / Teyama: Oer. Offen 2,163,514, 1971; Cibe Geigy:

Oer. Offen 2,537,974 (1975) and Bera (Debfer S. p. A .: Oer. Offen 2,755,902, 1976].

Said processes for the preparation of the compound of the formula I have a number of disadvantages from an industrial point of view, such as the acylation in a mixture of lead-ecetone with 1H-tetrazol-1-yl-acetic acid or mixed anhydride of this acid with a suitable tertiary carboxylic acid. of the reaction mixture in a weakly alkaline region by adding a strong base and a weak acid or a buffering agent. Another disadvantage of acylation in the water-acetone mixture is the need for strict adherence to temperature regimes and increased lanes for cooling the reaction mixture due to the possible competitive reaction of the tertiary acid forming mixed enhydride with 7-ACK as 1 to cleave the unstable beta-lactam ring with water at higher temperatures. thereby reducing the acylation yields.

In acylations in a mixture of a science-organic reaction or in organic solvents alone, a disadvantageous procedure for isolating the compound of formula I is used, where after evaporation of the organic solvent and acidification, the compound of formula I is extracted by multiple extraction with water-immiscible organic solvent, dried. to dryness, the solid residue is dissolved in a suitable organic solvent such as acetone, ethanol, etc., the solution is refined from the present second mixed anhydride component and impurities with activated carbon and the compound of formula I is converted to a suitable salt by addition of a suitable base.

The organic base is used twice in the preparation of the soluble 7-ACK salt and in the precipitation of the organic salt of the compound of formula 1 after extraction. This method of isolation also produces a large amount of wastewater with an increased salt content, which has a negative impact on the environment. Methods which employ a compound of formula I in situ, without isolation, impart reaction by-products and impurities from the starting materials to nucleophilic substitution with heterocyclic thiols, which adversely affects the quality and stability of the final product. All these negative effects reduce production capacity and adversely affect production costs and the economy as a whole.

A process for preparing a compound of formula I according to the invention is based on the reaction of 7-ACK salt of the formula II ^H 2 ^N_ I- (Ί) - CH ₂ OCOCH ₃

COOM (II) wherein M is a cation of the type substituted R'R ² R HN ⁺ wherein R ^1, R ^2, R ^ is hydrogen, C ^ alkyl, C ₃ _gcykloalkyl or benzyl; with mixed anhydride of formula III

N-CH ₂ -CO-O-CO-C ((CH ₂ ) _n CH ₃ J ₃₎

N = CH (III) wherein n = 0 to 16, preferably for n = 0, in an organic solvent such as dioxane, dimethylformamide, dimethylsulfoxide, chloroform, preferably in dichloromethane. The process according to the invention is carried out in such a way that to 1 mol of dimethylbenzylammonium, diisoprooylammonium, dicyclohexylammonium, trimethylammonium, triethylammonium and the like. salts of 7-ACK prepared from 7-ACK and the corresponding amine in dioxane, dimethylformamide, dimethylsulfoxide and the like, preferably in dichloromethane, depending on the impurity content add active carbon in an amount of 1 to 10% of the 7-ACK charge and after filtration add a solution 0.8 to 1.4 moles of mixed anhydride of formula III, wherein n = 0 to 16, preferably for n = 0, in one of the above solvents, preferably in which the preparation of the 7-ACK solution has taken place. The mixing of the two reaction components takes place in portions at a temperature of -20 to 60 ° C, preferably at a temperature of -10 to 25 ° C.

The reaction time is 1 to 5 hours, with a possible gradual change of temperature to room temperature. After completion of the reaction, the compound of formula I is isolated from the reaction mixture by distilling off the organic solvent used, preferably under vacuum. After evaporation to 10 to 30% of the original volume or complete distillation of the solvent, the residue, i.e. dimethylbenzylammonium, diisopropylammonium, dicyclohexylammonium, dimethylammonium, trimethylammonium, triethylammonium and the like, is added to the residue. salts of the compound of formula I add an organic solvent in which the salt is insoluble, such as diethyl ether, ethylmethylketone, isopropyl alcohol, methanol, ethyl alcohol, preferably acetone. The precipitate formed after 1 to 5 hours of standing is isolated by filtration or centrifugation, washed with a suitable solvent such as diethyl ether or acetone and dried, preferably under vacuum.

The solvent can be isolated from the filtrate by distillation under vacuum. higher vacuum tertiary acid that was used to prepare the mixed anhydride. The compound of formula (I) in the form of its organic salt can be used directly into nucleophilic substitution with heterocyclic tholes, or can be converted to the free acid of formula (I) or sodium salt, or purified by precipitation or crystallization.

The conversion to the free acid is accomplished by suspending the organic salt of the compound of formula I in an anhydrous alcohol such as ethanol at 30 to 80 ° C, acidifying with a cation exchanger such as Dowex 50 W until clarifying the solution and resulting pH less than 2. distilling off the alcohol, adding acetone to the solid residue, filtering and vacuum distilling off acetone.

The sodium salt of the compound of formula 1 may be prepared from its organic salt by dissolving it in an anhydrous alcohol such as methanol or ethyl alcohol at a temperature of 0 to 60 ° C, preferably at a temperature of 30 to 60 ° C, followed by addition of an aliphatic carboxylic acid salt. sodium acetate, sodium ethyl hexanoate and the like, in an anhydrous alcohol, preferably one used to dissolve the organic salt of the compound of formula 1. The precipitated sodium salt of the compound of formula 1 is left to crystallize for 1-5 hours, then isolated by filtration, washed with alcohol and dried, preferably under vacuum.

The organic salt of the compound of formula I can be purified by reprecipitation by dissolving the salt in water, adding a water-immiscible organic solvent such as dichloromethane, chloroform, carbon tetrachloride, preferably ethyl acetate, acidifying the solution with stirring with a mineral acid or water. 5 to 3.0, preferably to pH = 2.1, followed by multiple extraction with the organic solvent used, drying of the extracts, vacuum distillation portion or all of the organic solvent used, dissolving the solid acid free residue of formula 1 in anhydrous acetone, purification the resulting activated carbon solution, filtering and adding a suitable organic base such as dimethylbenzylamine, diisopropylamine, dicyclohexylamine, trimethylamine, triethylamine and the like.

The precipitated organic salt of the compound of formula I is separated after 1 to 3 hours of standing by filtration or centrifugation and dried, preferably under vacuum. A further process for purifying the organic salt of the compound of formula (I) without thermally stressing the purified compound comprises dissolving said organic salt in a water-miscible water-miscible solvent such as dioxane, tetrahydrofuran, preferably acetone, wherein the ratio between water and the organic solvent is 1: 1 to 1: 3, preferably 1: 1.5 when a water-acetone mixture is used. The resulting solution is acidified with a mineral acid, preferably concentrated HCl, to a pH of 1.5 to 3.0, preferably to a pH of 2.1, and the solution is then salted by adding a sufficient amount of a suitable inorganic salt, preferably sodium chloride. Salting-out separates the solution into an aqueous layer containing impurities and inorganic substances and an organic solvent layer containing the compound of formula 1. The layers are separated, the water is subjected to multiple extraction with the organic solvent used, the extracts are dried, purified with activated carbon, filtered and added. organic bases such as dimethylbenzylamine, diisopropylamine, dicyclohexylamine, trimathylamine, triethylamine and the like.

The solution is allowed to stand for 2 to 6 hours at reduced temperature, the precipitated organic salt of the compound of formula 1 is separated by filtration or centrifugation and dried, preferably under vacuum.

The organic salt of the compound of formula (I) may be purified by crystallization from a water-miscible water-miscible solvent such as tetrahydrofuran, dioxane, methanol, ethanol, preferably acetone, wherein the ratio between water and organic solvent is 1: 2 to 1:10, preferably 1: 5 using a water-acetone mixture.

The compound of formula 111 may be prepared according to known literature procedures such as by reacting pivaloyl chloride with 1H-tetrazol-1-yl-acetic acid in an aprotic organic solvent, preferably acetone, in the presence of tertiary amines, and preferably triethylamine / Coll. Czech. Chem. Commun. 27, 1273 (1962); S. Patai: The Chealstry of Omidoo 86, Wiley and Son, New York, 970 /. According to the invention, the precipitated triethylammonium chloride is sucked off from the acetone solution of the compound of formula 111, washed with acetone, and after vacuum distillation of acetone at 10-30 ° C, an organic solvent is added to the residue which is used to prepare a 7-ACK organic salt solution. Triethylamine can be recovered from triethylammonium chloride by the known! processes such as dissolving triethylawenium chloride in water, adding a strong inorganic base such as MaOH or KOH, and distilling off the released triothylalanine.

An advantage of the process according to the invention is that, compared to the β acylation processes used hitherto, an increased yield and at the same time improved product quality can be achieved by eutilizing the carborafm purified organic salts of 7-ACK with mixed anhydride of formula III, preferably for n = 0. , preferably in dichloromethane and directly recovering the resulting organic salt of the compound of formula Z by addition of an organic resolvent in which it is minimally soluble. As a result of this process, the technology of minimizing waste generation, the reaction components, i.e. the tertiary acid used in the preparation of the mixed anhydride, triethylamine and the organic solvents used, are to be regenerated and recycled after regeneration.

Further, the invention is described by way of example. These examples further describe some aspects of the preparation and purification of the compound of formula I without, however, limiting the scope of the invention in any way.

He did

To a solution of 0.42 g of 1-tetrazol-1-yl-actic acid and 0.46 ml of triethylamine in 10 ml of anhydrous acetone at -10 ° C is added a solution of 0.40 .mu.l of pivaloyl chloride in 3.0 ml of anhydrous acetone. at said temperature, the mixture is stirred for 30 minutes. The precipitated triethylammonium chloride was filtered off and filtered through 1 l of anhydrous acetone. Acetone is distilled off from the filtrate under vacuum so that the heat of the leak must not exceed 30 ° C. The solid residue was dissolved in 6.0 mL of anhydrous dichloroethane. Thus, the prepared solution of ee anhydride was added at -10 ° C to a triethylamonium eal17-ACK solution prepared from 0.68 g of 7-ACK, 0.46 µl of triethylamine in 12 µl of anhydrous dichloroethane at -5 ° C and read through with 0. 03 g of activated carbon and filtration. The reaction mixture is stirred at -10 ° C for 30 minutes and then at room temperature for 3 hours.

After completion of the reaction, dichlorethethone is vacuum distilled off, 6.0 l of anhydrous acetone are added to the residue and after intensive shaking and the precipitated crystals are sucked off, passing 2 x 1 l of anhydrous acetone with drying and vacuum yielding 1.08 g (89%) of triothylaanium sel. 7- (1H-tetreael-1-yl) -acetaaidocephalosporanoic acid, m.p. 186 DEG-188 DEG C. (dec.).

For C ₁₉ H ₂₉ N ₇ O ₆ S (483.55) calculated: 47.2 ° C, 6.0% H, 20.3% H, 6.6% S determined: 47.5 ° C H, 5.9; N, 20.5;

Example 2

The procedure of Example 1 was followed except that 5.0 L of anhydrous isopropanol was added to the residue by vacuum distillation of dichloromethane. The precipitate was washed with suction twice with 1.0 ml of anhydrous isopropanol and dried in vacuo. There was obtained 1.00 g (83%) of triethylammonium salt of 7- (1H-tetrazel-1-yl) -acetamide of cephalic acid which had a melting point of 186-188 ° C.

Calcd: C, 47.2; C, 6.0; H, 20.2; N, 6.6; S, 47.1; C, 6.1 g; 20.0% N, 6.5 S;

To a suspension of 3.5 g of triethylemmonium salt of 7- (1H-tetrazol-1-yl) -aoetamidocefelosporanoic acid in 150 ml of anhydrous methanol ee at 60 ° C was added Dowex 50 W to a final pH of 2.0, whereupon the solution became clear. After cooling to room temperature, the solution was filtered and methanol was distilled off in vacuo. 50 ml of anhydrous acetone is added to the residue, the solution is stirred well, filtered and acetone is distilled off in vacuo. The solid residue is vacuum dried to constant weight. 3.15 g (90%) of 7- (1H-tetrazol-1-yl) -acetamidocephaloeporanoic acid are obtained in the form of an amorphous foam, m.p. 170 DEG-173 DEG C. (with decomposition).

For C ₁₃ H ₁₄ M ₆ O ₆ S (392.36) calculated: 40.8% C, 3.7% H, 22.0% N, 8.39% S determined; 40.6% C, 3.5% H, 21.8% N, 8.50% S

Example 4

To a solution of 4.84 g of triethylammonium salt of 7- (1H-tetrazol-1-yl) -acetemidocephalosporanoic acid in 150 ml of anhydrous methanol at 50 ° C is added a solution of 0.845 g of sodium acetate in 10 ml of anhydrous methanol. The solution was cooled to room temperature and then vacuum distilled off methanol to 15% of the original volume. The precipitate formed is filtered off, washed with 2 x 5 ml of anhydrous acetone and vacuum dried to give 3.07 g (76%) of 7- (1H-tetrazol-1-yl) -ecetemidocephelosporanoic acid sodium salt, m.p. 200-120 ° C. (from decomposition).

For C ₁₃ H ₁₄ N ₆ O ₆ SNa (404.36) calculated: 38.6% C, 3.2% H, 20.8% N, 7.9% S determined: 38.4% C, 3, 1 H, 20.9 N, 7.8% S

Example 5

To a solution of 7- (1H-tetrezol-1-yl-) acetamido-phthalperanesevic acid triethylammonium salt (7.0 g) in 70 ml of distilled water was added 105 ml of ethyl acetate at room temperature and the resulting emulsion was acidified with conc. HCl at pH = 2.1. Indicative con.

HCl is about 1.4 ml. After stirring for 5 minutes, the layers were separated and the water was extracted with a further 2 x 10 mL of ethyl acetate. The ethyl acetate layers were combined, dried with Nb ₂ SO ₄ and then the ethyl acetate was distilled off in _{vacuo at} 40 ° C. The solid residue, which is 7- (1H-tetrezol-1-yl) -acetamidocephelosporanoic acid as an amorphous foam, is dissolved in 70 ml of anhydrous acetone at 30 ° C. To the solution was added 0.35 g of activated carbon, stirred for a further 10 minutes, filtered and cooled to 20 ° C. To the cooled solution was added dropwise 1.54 g (2.12 ml) of triethylamine and the solution was stirred at room temperature for 2 hours. The precipitated product is filtered, washed with 2 x 5 ml of anhydrous acetone and dried in vacuo. 5.67 g (81%) of the purified triethylammonium salt of 7- (1H-tetrazol-1-yl) acetamldocephalosporanoic acid are obtained in the form of white crystals, m.p. 186 and 188 DEG C. (with decomposition).

For C _{) 9} H ₂₉ N _? 0 ₆ S / 483.55 / calculated: 47.2% C, 6.0% H, 20.3% N 6.6% S determined: 47.3% C, 6.0 H, 20.2 % N, 6.8% S

Example 6

To the solution, 2.42 g of 7- (1H-tetrazol-1-yl) -acetamidocephalosporanoic acid tryethylammonium salt in 20 ml of distilled water was added at 20 ° C and stirred with 30 ml of acetone and the solution was acidified with conc. HCl to pH = 2.1. ORIENTAL CONSUMPTION CONC. HCl Saline about 0.6 ml.

4.5 g NaCl was added to the acidified solution, and the solution was stirred at room temperature for 30 minutes to separate the aqueous layer from the acetone layer. The acetone was removed and the water was extracted with acetone (2 x 10 ml). The acetone extracts were combined, dried over MgSO4, added with 0.12 g of charcoal, stirred for 10 minutes, then filtered and cooled to 0 ° C. To the cooled solution was added dropwise 0.56 g of triethylamine and the solution was allowed to stand at 0 ° C for 3 hours. The precipitated product is then filtered, washed with 2 x 5 ml of anhydrous acetone and dried in vacuo. 1.84 g (76%) of purified 7- (1H-tetrazol-1-yl) acetemidocephelosporanoic acid triethylammonium salt are obtained in the form of small white crystals, m.p. 86 DEG-188 DEG C. (with decomposition).

For C (483.55) calculated: 47.2% C, 6.0% H, 20.3% N, 6.6% S determined: 47.1% C, 6.2% H, 20.0%. N, 6.3% 8

Example 7

A suspension of 3.0 g of the triethylammonium salt of 7- (1H-tetrazol-1-yl) -acetamidoeephthalosporanoic acid in 20 ml of anhydrous acetone is heated to 50 ° C with stirring. At this temperature and with stirring, enough distilled water is added dropwise to the suspension until the solution becomes clear. The approximate consumption of distilled water is approx. 4 ml. After clarification, 0.3 g of activated carbon was added to the solution and stirred for 10 minutes. The solution was then filtered through a preheated filter and the filtrate was slowly cooled to 0 ° C with occasional stirring and maintained at this temperature for 10 hours. The crystallized product is filtered off, washed with 2.times.5 ml of anhydrous acetone and dried under vacuum. 2.25 g (75%) of purified 7- (1H-tetrazol-1-yl) -acetamidocephalosporanoic acid triethylammonium salt are obtained in the form of well-developed white crystals, m.p. 187-188 ° C.

Claims (9)

1. A process for the preparation of 7- (1H-tetrazol-1-yl) -acetamidoeefeloeporanoic acid of formula I PftBOMfiZ VXNÁLSZU CH ₂ -CO-NH-i- N = CH CHjOCOCHj COOH (I) a. their salts with organic bases or alkali metals, characterized in that 1 part mole part of the salt of 7-aminocephalosporanoic acid of the general formula IZ ^Η 2 ^Ν π Γ ⁸ Ί / CHCHOCOCCH 3 ° COOM (II) in which U represents ammonium or a substituted ammonium cation of the type h ' R, R ^j represents hydrogen, C ^ alkyl, _C3 _gcykloalkyl or benzyl is reacted with 0.8 1.4 aí DLR profiles meldmíhe component blend snhydridu formula IIZ N * Ik J H-CH ₂ CO-O-CO-C (/ CH ₃ / CH ₃ (IXI)) N-CH in which n * 0 to 16, in an organic solvent at -20 and 60 ° C and the resulting compound of formula I, in the form of its organic salt, is isolated from the solution by adding an organic solvent in which the salt is minimally soluble and optionally with Biatl or converted to another salt. 2. The process according to claim 1, wherein the organic rospoultdlo for the acylation is dioxane, diaphthaforaamide, diaethylsulfoxide, dichloroethane, chloroform, preferably dichloromethane. 3. A process according to claim 1, wherein the mixed anhydride of formula (III) wherein n · 0 is used. 4. A process as claimed in claim 1, wherein the organic salt of the compound of claim 1 is at least substantially permeable using diothylether, ethyl methyl ketone, isopropyl alcohol, ethyl alcohol, methyl alcohol, preferably acotone. 5. The process of claim 1 wherein the acylation reaction is carried out at a temperature of -10 ° C to 25 ° C. 6. The process of claim 1, wherein the organic salt of the compound of formula I obtained is converted into the sodium salt by addition of sodium carboxylic acid or the free acid of formula I by treatment with a cation exchanger in an anhydrous alcoholic solvent. 7. The process of claim 1 wherein the organic salt of the compound of formula I is. purification by reprecipitation so that said salt is converted to the large acid by acidification with a mineral acid in a water-organic solvent immiscible with water, preferably in a water-ethyl acetate mixture, the free acid of formula 1 is isolated, dissolved in an organic solvent, preferably anhydrous acetone and converted back to the organic salt of the compound of formula 1 by addition of an organic base, preferably triethylamine. 8. A process according to claim 1, wherein the organic salt of the compound of formula I is purified by a process without thermal stress by converting said salt to a large acid by acidification with a mineral acid in a water-miscible water-miscible solvent, preferably of the water-acetone mixture, the solvents are then separated by salting-out and the free acid of formula I dissolved in the organic solvent is converted back to its organic salt by addition of an organic base, preferably triethylamine. 9. A process according to claim 1, wherein the organic salt of the compound of formula (I). crystallizing from a water-miscible water-miscible solvent such as methanol, ethanol, isopropanol, dioxane, tetrahydrofuran and the like, preferably from a water-acetone mixture, wherein the volume ratio between water and organic solvent is 1: 2 to 1 10: preferably 1: 5 using a water-acetone mixture and the maximum crystallization temperature is 60 ° C.