MXPA00010537A - A METHOD FOR CRYSTALLIZING A&bgr;-LACTAM ANTIBIOTIC - Google Patents

Abstract

The invention relates to a method for crystallizing a&bgr;-lactam, wherein the&bgr;-lactam is crystallized from a nitric acid solution.

Description

- A METHOD FOR CRYSTALLIZING AN ANTIBIOTICS OF ß-LACTAMA The invention relates to a method for crystallizing a β-lactam and a β-lactam obtainable by said method. The expression "β-lactam" as used herein includes ß-lactam nuclei, for example, 6-aminopenicillanic acid (6-APA), 7-aminocephalosporanic acid (7-ACA), 3-chloro-7 acid aminodesacetoxidesmethylcephalosporanic acid (7-ACCA), and 7-amino-3 - [[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -3-cephem-4-carboxylic acid (7-ATCA), 7-aminodesacetylcephalosporanic acid (7-ADAC), and 7-aminodesacetoxycephalosporanic acid (7-ADCA), fermentation products, for example penicillin G, penicillin V, cephalosporin C, isopenicillin N, intermediates, for example adipyl-6-aminopenicillanic acid , adipyl-7-aminodesacetoxycephalosporanic acid (adipil-7-ADCA), adipyl-7-aminocephalosporanic acid (adipiI-7-ACA), adipyl-7-aminodesacetylcephalosporanic acid (adipil-7-ADAC), 3-carboxyethylthiopropionyl-7- acid aminodesacetoxycephalosporanic acid, 2-carboxylethylthioacetyl-7-aminodesacetoxycephalosporanic acid and 3-carboxyethylthiopropionyl-7-aminodesac acid ethoxycephalosporanic acid, and ß-lactam antibiotics, for example ampicillin, amoxicillin, cephalexin, cephradine, cefprozil, cefaclor and cefadroxil. The last few decades, ß-lactams have received great attention, because many compounds of this class have antimicrobial activity. In particular, ß-lactam antibiotics, for example penicillin and cephalosporin antibiotics are useful because of their antimicrobial activity and play an important role in medicine. This class of antibiotics comprises a wide variety of compounds, all of which have their own activity profile. In general, β-lactam antibiotics comprise a nucleus, called the β-lactam nucleus, which is linked, through its primary amino group, to the so-called side chain via a linear amide bond. Recently, many semi-synthetic routes for β-lactam antibiotics have been reported. According to these semi-synthetic routes, the synthesis of a β-lactam antibiotic generally comprises the preparation of a β-lactam nucleus from fermentation products, for example, isopenicillin N, penicillin G, penicillin V and cephalosporin C The β-lactam core obtained subsequently binds to one of several possible side chains to obtain the antibiotic product. These semi-synthetic routes include enzymatic catalysis, which leads to highly selective and clean preparation processes. In contrast to conventional chemical procedures, enzymatically catalyzed reactions can be carried out in aqueous media and hardly generate any by-products, if any. Also, it is usually not necessary to carry out any protection and deprotection step, which are so often imperative in organic synthesis, in these enzymatically catalyzed processes.

- Although the semi-synthetic routes produce significantly fewer by-products compared to conventional procedures, the intermediate product and the final product, ie the ß-lactam nucleus and the ß-lactam antibiotic, it is still necessary to isolate them from a reaction mixture and purify them. Usually, the β-lactam is isolated from a reaction mixture and purified by crystallization in a process which is essentially the same as the procedure that should be carried out if the product were to be obtained in a conventional synthetic process. A typical example of such a crystallization process is described in British Patent Application 1, 400,236. This document describes a process in which 6-a-minopenicillanic acid is acylated with a-aminophenylacetic acid chloride, and HCl, in aqueous acetone. The final β-lactam antibiotic is isolated by crystallization in a solution in hydrochloric acid by adding an appropriate base, for example, NaOH or ammonia. Conventional crystallization processes begin with a solution in hydrochloric acid of the β-lactam, in which the product is crystallized by the addition of an alkaline solution, usually a solution of NaOH. It has been found that the performance of these conventional crystallization processes is rather low. This is probably due to a significant loss of product in the mother liquors. Surprisingly, it has now been discovered that the performance of a crystallization process of a β-lactam can be increased starting from a solution of the β-lactam in nitric acid. Accordingly, the invention provides a method for crystallizing a β-lactam, in which the β-lactam is crystallized in a solution in nitric acid. In addition to the important improvement in the performance of the product of a method according to the invention, a great advantage of the invention is that the volumetric efficiency of a large-scale production process of β-lactam is increased. It has been discovered that, when the β-lactam crystallizes in a solution in nitric acid, it is feasible to carry out the crystallization process using higher concentrations of β-lactam than previously thought possible. As a result, a smaller volume reactor is needed to obtain an equal amount of β-lactam. A β-lactam that can be crystallized in a method according to the invention preferably has the general formula (I): wherein: R_ is hydrogen or C ^ _ ^ alkoxy; - R.j is hydrogen or a side chain derived from an acid organic; And it is CH2, oxygen, sulfur, or an oxidized form of sulfur; and Z is: wherein R 2 is hydrogen, hydroxy, halogen, C 1-7 alkoxy, branched or linear, saturated or unsaturated C 1 8 alkyl, optionally substituted, and optionally containing one or more heteroatoms, C 5 8 cycloalkyl, optionally substituted and which optionally contains one or more heteroatoms, aryl or optionally substituted heteroaryl, or optionally substituted benzyl. Preferably, R2 is -H, Cl, -OH, OCH3, -CH2 OH, -CH2CI or CH2OC (O) CH3. Formula (I) is proposed to include all ß-lactams described in "Cephalosporins and Penicillins, Chemistry and Biology", Ed. E.H. Flynn, Academic Press, 1972, pp. 151-166, and "The Organic Chemistry of ß-Lactams", Ed. G.l. Georg, VCH, 1992, pp. 89-96, which are incorporated herein by reference. In the context of the invention, an oxidized form of sulfur means that it includes groups, for example, sulfoxide and sulfone. By alkyl, - cycloalkyl, aryl, heteroaryl, and benzyl, optionally substituted, groups are proposed which have substituents, for example, alkyl groups of 1 to 3 carbon atoms. β-lactams especially preferred to crystallize in a method according to the invention are β-lactam antibiotics comprising a β-lactam core coupled to a side chain. These preferred β-lactams are those having the formula (I), wherein R ^ is a side chain. Preferred side chains coupled to a β-lactam nucleus in a β-lactam antibiotic, to be crystallized in a method according to the invention, are D - (-) - phenylglycine, D - (-) - 4-hydroxyphenylglycine, D - (-) - 2,5-dihydrophenylglycine, 2-thienylacetic acid, 2- (2-amino-4-thiazolyl) -2-methoxy-iminoacetic acid, α- (4-pyridyl) acetic acid, 3-thio-phenomalonic acid, 2-cyanoacetic acid, D-mandelic acid, 1 H-tetrazoleacetic acid, 2-furaniI- (Z) -methoxy-iminoacetic acid, (2-aminothiazol-4-yl) acetic acid, acid ( 2-aminothiazol-4-yl) - (Z) -hydroxy-iminoacetic acid, (2-aminotol-4-yl) - (Z) -carboxymethoxy-iminoacetic acid, (2-aminothiazole-4-) iI) - (Z) - (1-carboxy-1-methylethoxy) iminoacetic or its derivatives. The most preferred β-lactams to be crystallized according to the invention are amoxicillin, ampicillin, cephalexin, cefaclor, cefadroxil, cefadrine, epicillin, cefamandole, cefotaxime, cefdinir, cefprozil, cefuroxime, cefepime, cetibuten, and loracarbef.

- - In one embodiment, the β-lactam to be crystallized is obtained synthetically. In a synthetic preparation of a β-lactam antibiotic, a β-lactam nucleus, for example 6-APA, 7-ADCA, 7-ACA, 7-ACCA, 7-ATCA or 7-ADAC, or one of its derivatives Acylate, for example, according to the so-called Dane procedure. In this process, the acylation is carried out with a Damage salt of a precursor for the desired side chain, for example, a Damage salt of phenyl glycine. A Dane salt can be prepared by protecting the amine group of the precursor for the side chain as an enamine, and reacting its product with a reactive acid to form a mixed anhydride. The Dane process has been described, inter alia, in US-A-4,358,588 and EP-A-0 439 096. After the acylation of the β-lactam nucleus with the Dane salt has been completed, the amine group has to be checked out. The deprotection reaction is usually an acid hydrolysis in which the protecting group is separated. When the β-lactam to be crystallized according to the invention has been prepared in a Dane process, the deprotection step can be advantageously carried out in situ using nitric acid to facilitate the acid hydrolysis. In another preferred embodiment, the β-lactam to be crystallized is obtained enzymatically. When a β-lactam nucleus is to be crystallized, it can be obtained, for example, in a process described in EP-A-0 532 341.

When a β-lactam antibiotic is to be crystallized, it is preferably obtained by enzymatic acylation. This means that a β-lactam nucleus or one of its salts is reacted with an appropriate precursor for a side chain in the presence of an appropriate enzyme, for example a penicillin acylase. Enzymes can be isolated from various microorganisms of natural origin, for example, bacteria and fungi. Organisms that have been discovered to produce penicillin acylase are, for example, species of Acetobacter, Aeromonas, Alcaligenes, Aphanocladium, Bacillus sp., Cephalosporium, Escherichia, Flavobacterium, Kluyvera, Mycoplana, Protaminobacter, Pseudomonas, or Xanthomonas. Of course, it is possible to use the enzyme in the form of a free enzyme or in any appropriate immobilized form. In addition, it is possible to use functional equivalents of the enzyme, in which, for example, properties of the enzyme, for example pH dependence, thermal stability or specific weight can be affected by chemical modification or cross-linking. Functional equivalents, for example, mutants or other derivatives, obtained by classical means or via recombinant DNA methodology, and biologically active parts or hybrids of the enzymes can also be used. Suitable salts of a β-lactam nucleus, in this regard, include any non-toxic salt, for example, an alkali metal salt (eg, lithium, potassium, sodium), an alkaline earth metal salt (eg, calcium , magnesium), an ammonium salt, or an organic base salt (for example, trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N, N'-dibenzyl-diethylene diamine). The precursor for a side chain of the β-lactam antibiotic to be prepared in a method according to the invention can be any compound that is admitted by the enzyme defined above, for example, penicillin acylase, and which leads to a product of the class of ß-lactam antibiotics. It is possible to use the compound that corresponds to the side chain itself, but its derivatives can also be used. Suitable derivatives of these compounds are esters and amides, wherein the side chain molecule is attached to an alkyl group of C-C through an ester or amide linkage. After the enzymatic acylation of a β-lactam nucleus in the preparation of a β-lactam antibiotic as described above, the enzyme is separated from the reaction mixture. This can be done, for example, by filtration in case an enzyme is used in immobilized form. After separation of the enzyme, the reaction mixture thus obtained can be used as such in a method according to the invention or can be treated subsequently. Of course, it is also possible to combine the synthetic and enzymatic preparations described above of the β-lactam to be crystallized according to the invention. In a method according to the invention, the β-lactam starting material to be crystallized is dissolved using an aqueous nitric acid solution. It has been found that optimum results are obtained when the pH of the resulting nitric acid solution, in which the β-lactam is dissolved, is between about 0.3 and about 2.0, and preferably between about 0.5 and about 1.5. The concentration of the aqueous nitric acid solution to be added to the β-lactam starting material is preferably between 0.5 mol / L and 11 mol / L, and more preferably between 5 and 10 mol / L. It is also possible to use mixtures of different acids, preferably of strong inorganic acids, which give rise to a pH of the solution, in which the β-lactam is dissolved, within the ranges above. However, it is desired that the concentration of nitrate ions in the mixture in which the β-lactam is present, be at least 0.3 mol / L. It falls within the experience of the experts to choose the amount of inorganic acid other than nitric acid, so that salts (addition) of the ß-lactam should not be formed. In a preferred embodiment of the invention, the β-lactam is crystallized in a solution in nitric acid, in which said β-lactam is present in a very high concentration. In conventional crystallization processes, the concentration of the β-lactam in the solution in hydrochloric acid in which it crystallizes is generally about 0.35 mol / L. It has now been discovered that a higher concentration of the β-lactam in the solution in which it crystallizes results in a higher yield of the crystallization process. In the present specification, the yield is defined in moles of isolated crystal per moles of ß-lactam starting material. It has been found that it is possible to achieve an increase in the yield in a process according to the invention, which corresponds to the decrease in the loss of the desired β-lactam in the mother liquors, during the crystallization, of 25-50%. In addition, a much higher volumetric yield can be achieved when a crystallization process is started in a solution in which a β-lactam is present in a high concentration. A high concentration of β-lactam in the solution in nitric acid, in which it is crystallized according to this preferred embodiment, is greater than about 0.4 moi / L. More preferably, the β-lactam is crystallized from a solution in nitric acid in which it is present in a concentration of more than about 0.5 mol / L. Most preferably, said concentration is greater than about 0.6 mol / L. There is no upper limit for the concentration of the β-lactam in the solution in nitric acid in which it crystallizes. However, it should be evident that a concentration which is so high that the crystallization of the β-lactam in the solution in nitric acid starts spontaneously is not appropriate. In the solution in nitric acid, the β-lactam is preferably crystallized by the addition of an alkaline solution. Particularly suitable for this purpose are solutions of ammonia or hydroxide salts. It is preferred that the hydroxide salt is an ammonium or alkali metal salt. The concentration of the alkaline solution should be between approximately 0.5 and approximately 8 mol / L. Preferably, said concentration is between about 1.5 and about 2.5 mol / L. The temperature at which the method of the invention is carried out should generally be between about -5 ° C and 50 ° C. Preferably, the temperature should be between about 0 ° C and 15 ° C. By addition of the alkaline solution, the β-lactam should crystallize. Subsequently, the obtained β-lactam crystals are filtered and dried in any appropriate manner. In a preferred embodiment, the method of the invention is carried out continuously. The advantages of this embodiment should be apparent to an expert and include short residence times, small losses of the desired product due to the decrease in decomposition, and the possibility of using small facilities that result in a decrease in costs. Preferably, in this embodiment the ß-lactam to be crystallized is dissolved in nitric acid using a static mixer, which results in a particularly efficient process. The invention will now be clarified by the following non-restrictive examples.

COMPARATIVE EXAMPLE I Recrystallization of amoxicillin trihydrate using hydrochloric acid At 20 ° C, amoxycillin trihydrate (132 g) was suspended in water (500 ml) and 12 M concentrated hydrochloric acid (40 ml) was added to achieve a pH of 0.7. In order to dissolve all the material, water (1600 ml) was added. The amoxycillin trihydrate was crystallized by adding a 2 M solution of sodium hydroxide in water until a pH of 5.0 was reached. The crystals thus produced were isolated by filtration, washed with water (200 ml) and dried at 35 ° C for 16 h to give 123 g of amoxicillin trihydrate. The stock solution (2.62 I) contained 8.5 g of dissolved amoxicillin trihydrate.

COMPARATIVE EXAMPLE II Recrystallization of cefaclor monohydrate using sulfuric acid At 20 ° C, cefaclor monohydrate (11.0 g) was suspended in water (55 ml) and 9.4 M sulfuric acid (7.3 g) was added to give a pH of 1.0. In order to dissolve all the material, water (106 ml) was added while the pH was maintained at 1.0 using 9.4 M sulfuric acid (14.3 g). The cefaclor monohydrate was crystallized by adding a 25% solution of ammonia in water (8.9 ml) until a pH value of 6.2 was reached. The crystals thus produced were isolated by filtration, washed with water (15 m) and dried for 16 h at 20 ° C under vacuum to give 8.2 g of cefaclor monohydrate. The stock solution (198 g) comprised 2.7 g of dissolved cefaclor monohydrate.

EXAMPLE I Recrystallization of cefaclor monohydrate using nitric acid At 20 ° C, cefaclor monohydrate (11.0 g) was suspended in water (55 ml) and 4 M nitric acid (8.1 g) was added to give a pH of 1.0. In order to dissolve all the material, water (31 ml) was added while the pH was maintained at 1.0 using 4 M nitric acid (2.5 g). The cefaclor monohydrate was crystallized by adding a 25% solution of ammonia in water (3.8 ml) until a pH value of 6.2 was reached. The crystals thus produced were isolated by filtration, washed with water (15 ml) and dried for 16 h at 20 ° C under vacuum to give 8.8 g of cefaclor monohydrate. The stock solution (110 g) comprised 2.2 g of dissolved cefaclor monohydrate.

EXAMPLE II Crystallization of crude amoxicillin using nitric acid A wet cake obtained by enzymatic condensation described in, for example, WO-A-92/01061 (total weight 3 kg), comprising amoxicillin trihydrate (1451 g), D - (-) - hydroxyphenylglycine (HFG, 134 g) and insoluble, it was suspended by adding water to a total volume of 5 liters. The mixture was cooled to 2 ° C. Then, 5 ml of a 5% EDTA solution was added to the suspension. The mixture was pumped continuously into a dissolution vessel with a speed of 80 ml / min. The pH in the solution vessel was maintained at 0.7 by the addition of 8M nitric acid. The temperature in the vessel was maintained at 5 ° C. By continuously separating acid amoxycillin solution from the reaction vessel, the volume in the vessel was maintained at 800 ml. This solution of acid amoxycillin was continuously pumped through a Seitz T500 filter (10 cm diameter) to remove undissolved impurities. The filtrate was added continuously to a crystallizer. In this crystallizer, the temperature was maintained at 20 ° C and the pH was maintained at 3.7 with the aid of a 2 M sodium hydroxide solution. The volume in the crystallizer was maintained at 1800 ml by continuously transferring the contents to a second crystallizer. In the second crystallizer, the temperature was maintained at 20 ° C and the pH was maintained at 5.0 with the aid of a 2 M sodium hydroxide solution. The volume in the second crystallizer was maintained at 1000 ml by continuously separating the contents from an intermediate vessel. . After the addition of suspension to the solution was complete, the contents of the solution vessel were filtered and added to the first crystallizer, in which the conditions above were maintained. Subsequently, the content of the first crystallizer was transferred to the second crystallizer, in which the above conditions were maintained, followed by transfer of the content of the second crystallizer to the intermediate vessel. The total amount of 8 M nitric acid solution consumed was 625 mL. The total amount of 2 M sodium hydroxide solution consumed was 2,500 mL. The contents of the intermediate vessel were cooled to 2 ° C and kept at this temperature for more than 2 hours. The resulting crystal suspension was filtered and washed with 1500 mL of water. The filter cake was dried in an oven with 35 ° C ventilation. The final yield of amoxicillin trihydrate (test result, 99.5%) (the result of the test is defined herein as grams of amoxicillin trihydrate per grams of * 100% crystals) was 1429 g (98%) ). The masterbatches comprised approximately 26 g (1.8%) of amoxicillin trihydrate.

Claims (12)

NOVELTY OF THE INVENTION CLAIMS

1. - A method for crystallizing a β-lactam, in which the β-lactam is crystallized in a nitric acid solution in which the pH is less than about 2.0, by adding an alkaline solution to the nitric acid solution, and in that the ß-lactam has the general formula (I) wherein RQ is hydrogen or C.sub.2 alkoxy; R4 is hydrogen or a side chain derived from an organic acid; And it is CH2, oxygen, sulfur, or an oxidized form of sulfur; and Z is:

* R_Ho where R2 is hydrogen, hydroxy, halogen, C ^ alkoxy, C ^ _ ^ alkyl branched or linear, saturated or unsaturated, optionally substituted, and optionally containing one or more heteroatoms, cycloalkyl of C ^ g, optionally substituted and optionally containing one or more heteroatoms, optionally substituted aryl or heteroaryl, or optionally substituted benzyl. 2. The method according to claim 1, further characterized in that the pH of the nitric acid solution is between about 0.3 and about 2.0.

3. The method according to claim 2, further characterized in that the alkaline solution is a solution of ammonia or hydroxide salt.

4. The method according to claim 3, further characterized in that the hydroxide salt is an ammonium or alkali metal salt.

5. The method according to claim 4, further characterized in that the β-lactam is a β-lactam antibiotic, comprising a β-lactam nucleus, which is attached to a side chain through its primary amino group .

6. The method according to claim 5, further characterized in that the side chain is selected from the group of D - (-) - phenylglycine, D - (-) - 4-hydroxyphenylglycine, D - (-) - 2, 5-dihydrophenylglycine, 2-thienylacetic acid, 2- (2-amino-4-thiazoliI) -2-methoxy-iminoacetic acid, a- acid. { 4-pyridylthio) acetic acid, 3-thiophaenomalonic acid, 2-cyanoacetic acid, D-mandelic acid and its derivatives.

7. The method according to claim 6, further characterized in that the β-lactam antibiotic is selected from the group comprising amoxicillin, ampicillin, cephalexin, cefaclor, cefadroxil, cefradine, epicillin, cefamandole, cefotaxime, cefdinir, cefprozil, cefuroxime, cefepime, cefibuten and loracarbef.

8. The method according to any of the preceding claims, further characterized in that the β-lactam has been obtained enzymatically.

9. The method according to any of the preceding claims, further characterized in that the concentration of ß-lactam in the nitric acid solution, from which it crystallizes, is greater than about 0.4 moles / liter.

10. The method according to claim 9, further characterized in that the concentration of β-lactam in the nitric acid solution, from which it is crystallized, is greater than about 0.5 moles / liter.

11. The method according to any of the preceding claims, further characterized in that the crystallization is carried out continuously. -

12. - The method according to claim 11, further characterized in that the ß-lactam to be crystallized is dissolved in the nitric acid solution using a static mixer.