MXPA00010538A - PREPARATION OF&bgr;-LACTAM ANTIBIOTICS IN THE PRESENCE OF UREA OR AMIDE - Google Patents

Abstract

A process to prepare a crystalline&bgr;-lactam compound by the addition of a base to an acidic solution of a&bgr;-lactam compound obtained by the addition of an acid to a solution or suspension of a&bgr;-lactam compound obtained by (a) an acylation reaction of 6-amino-penicillanic acid, 7-amino-cephalosporanic acid, 7-amino-3'-desacetoxycephalosporanic acid or 3-chloro-7-aminodesacetoxydesmethylcephalosporanic acid or derivatives thereof with a mixed-anhydride of the Dane salt of any one of the compound comprising D-phenyl-glycine, D-p-hydroxyphenyl-glycine, D-2(1,4-cyclohexadien-1-yl)glycine or (2-aminothiazol-4-yl)-(2-methoxy-imino-acetic acid) in one or more organic solvents, or (b) dissolving or suspending a crude&bgr;-lactam compound in a solution comprising water and/or one or more organic solvents, wherein, to the solution or suspension of a&bgr;-lactam compound, urea or derivatives thereof and/or amide or derivatives thereof are added.

Description

PREPARATION OF R-LACTAMAS ANTIBIOTICS IN THE PRESENCE OF UREA OR AMIDA The present invention relates to a better process for the preparation of ß-lactam antibiotic compounds in the presence of urea or its derivatives and / or amide or its derivatives. It is commonly accepted that the most economical approach for the isolation of compounds, such as β-lactam antibiotics or their intermediate compounds, from their solutions comprising them, is crystallization. Various methods have been proposed for the preparation of the semi-synthetic β-lactam antibiotic compounds, such as penicillins and cephalosporins. These proposals generally involve the acylation of 6-aminopenicillanic acid (6-APA) or 7-aminocephalosporanic acid (7-ACA) or one of its protective derivatives using, for example, an acyl halide which serves to introduce the desired acyl group. For example, in European Patent Application EP 0011513, a method has been described for the preparation of polar ion antibiotics, for example, ampicillin, amoxycillin or cephalexin by acylation of silylated 6-aminopenicillanic acid or 7-aminocephalosporanic acid with a phenylglycyl halide or p-hydroxyphenylglycyl halide in the presence of N-alkyl pyrrolidone as an acid acceptor. Similarly, the U.S. Patent. No. 4,248,780 for example, describes the preparation of polar ion antibiotic ampicillin by acylation of silylated 6-aminopenicillanic acid with a phenylglycidylchloride hydrochloride using urea as a base. In addition, a number of patent and patent applications describe a method of preparing aminoacylpenicillanic acid derivatives by adding 6-APA with mixed anhydrides derived from modified Dane salts of D-2-amino- (p-hydroxyphenyl) acetic acid, as described in German patent applications Serial No. 1,302,847, No. 2,020,133 and No. 2,065,879 and British Patents No. 1, 327,270 and No. 1, 347,979 and European Patent Application No. 439,096. The patent of E.U.A. 4,358,588 describes a better process for the preparation of D-amino-p-hydroxyphenyl-acetamide-penicillanic acid and cephalosporanic acid derivatives by reacting an appropriate mixed anhydride of a Dame salt with a protected derivative, for example 6-APA or 7 -ACA in the presence of a tertiary amine. This type of acylation is called the Dane salt coupling reaction. Subsequently, the ß-lactam antibiotic compounds are isolated from an aqueous acid solution, obtained by acid hydrolysis of the reaction mixture after the Dane sai coupling reaction, by adding a base and followed by filtration. An important drawback of the procedures for the preparation of ß-lactam antibiotic compounds is the crystallization of unwanted by-products, among which, the hydrochloric acid salts of the antibiotic ß-lactam compounds are the most notorious. This unwanted crystallization of by-products can take place at any stage of the hydrolysis or crystallization process. The formation of acid salts of the ß-lactam antibiotic compounds is strongly dependent on the temperature, pH and time during the acid hydrolysis of the Dame salt coupling reaction. Lower temperatures, lower pH and prolonged time during the hydrolysis of the Dame salt coupling reaction result in the production of a greater amount of acid salt of the corresponding ß-lactam antibiotic compound. At higher temperatures, however, the formation of the corresponding acid salt of the β-lactam during the hydrolysis of the Dame salt coupling reaction is reduced but, on the other hand, the dissociation of the β-lactam increases. Also, the presence of seed crystals, which correspond to the acid salt of the ß-lactam compound, produced during the hydrolysis of the Damage salt coupling reaction., facilitates the formation of acid salts of the ß-lactam antibiotic compounds. Especially, the formation of the seed material during the hydrolysis of the Dane coupling reaction increases in an industrial scale process compared to a laboratory scale process. Thus, the crystalline products resulting from the Dane salt coupling reaction often comprise unacceptable levels of impurities. It was surprisingly discovered that ß-lactam antibiotic compounds free from acid salts of the corresponding ß-lactams can be prepared by the addition of urea or its derivatives and / or amide or its derivatives after the Dane salt coupling reaction at low temperature . Urea or its derivatives and / or amide or its derivatives can also be added during the purification of crude β-lactam antibiotic compounds, during the crystallization phase. In addition to the lower content of the hydrochloric acid salt of the β-lactam produced, these processes also result in a higher yield of the final product. So far, this method has not been described or suggested anywhere for β-lactam compounds.BRIEF DESCRIPTION OF THE INVENTION The present invention provides a better process for the preparation of ß-lactam antibiotic compounds in the presence of urea or its derivatives and / or amide or its derivatives. The β-lactam compounds are crystallized by the addition of a base to an acid solution of a β-lactam compound obtained by the addition of an acid to a solution or suspension of a β-lactam compound obtained by: a) a reaction of acylation of 6-amino-penicillanic acid, 7-amino-cephalosporanic acid, 7-amino-3'-deacetoxydesmethylcephalosporanic acid or its derivatives, with a mixed anhydride of the Dane salt of any one of the compounds comprising D-phenyl -glycine, Dp-hydroxyphenyl-glycine, D-2 (1,4-cyclohexadien-1-yl) glycine O (2-aminothiazol-4-yl) - (2-methoxy -iminoacetic acid) in one or more solvents organic, or b) dissolving or suspending a crude ß-lactam compound in a solution comprising water and / or one or more organic solvents, characterized by the addition, dissolution or suspension of a ß-lactam compound, urea or its derivatives and / or amide or its derivatives. Before starting the crystallization process by the addition of a base, the pH of the solution or suspension of a β-lactam compound is maintained at the desired pH by the addition of an acid. Normally, the pH is maintained between 0.1 and 3.5 and preferably between 0.3 and 2.5, depending on the type of ß-lactam compound to be produced. When the solution of the β-lactam compound is obtained by (a), the acid that is added can aid in the acid hydrolysis of the reaction mixture of the acylation reaction. The temperature at which the acid is added is preferably between -50 ° C and 10 ° C, preferably between -5 ° C and 5 ° C and most preferably between -5 ° C and 0 ° C. The acid can be any acid, preferably an inorganic acid, for example, hydrochloric acid, nitric acid or sulfuric acid.

Preferably, the acid is hydrochloric acid. The temperature during crystallization may vary. Suitably, the crystallization temperature is between -10 ° C and 50 ° C, and preferably between -5 ° C and 35 ° C. It should be clear to those skilled in the art that the preferred conditions should depend on the ß-lactam compound to be prepared.

The β-lactam antibiotic compounds can be isolated in a conventional manner, by adjusting the pH to the isoelectric point of the corresponding β-lactam compounds. The β-lactam compounds are, for example, penicillins and cephalosporins. Examples of penicillins are amoxlcillin, ampicillin and epicillin. Examples of cephalosporins are cefaclor, cefadroxil, cefetamet, cefotaxime, cephalexin, cephaloglycine, cephradine and cefroxadine.

DETAILED DESCRIPTION OF THE INVENTION The process for the preparation of crystalline β-lactam antibiotic compounds according to the present invention comprises the addition of a base to an acid solution of a β-lactam compound obtained by the addition of an acid to a solution or suspension of a compound of β-lactam obtained by: (a) an acylation reaction of 6-amino-penicillanic acid (6-APA), 7-amino-cephalosporanic acid (7-ACA), 7-amino-3'-deacetoxycephalosporanic acid (7) -ADCA) or 3-chloro-7-aminodesacetoxydesmethylcephalosporanic acid (7-ACCA) or its derivatives, with a mixed anhydride of the Dane salt of any one of the compounds comprising D-phenyl-glycine, Dp-hydroxyphenyl-glycine, D-2 (1, 4-cyclohexadien-1-y!) Glycine or (2-aminothiazol-4-yl) - (2-methoxy-iminoacetic acid) in one or more organic solvents, or (b) dissolve or suspending a crude ß-lactam compound in a solution comprising water and / or one or more organic solvents, characterized by the addition, dissolution or suspension of a β-lactam compound, of urea or its derivatives and / or amide or its derivatives with the formula (A) and (B) respectively.

R4R3N-CO-NR1Ra R.j-CO-NR? R.2 (A) in which R ^, R2, R3 and R4 are each independently selected from the group comprising hydrogen, lower alkyl and allyl, or R1 and R3 form -CH2-CH2-, -CH2-CH2-CH2-, -CH -CO- and - CH = CH-CO-, which give rise together with -N-CO-N- to a five or six membered cyclic ring, and esters of Cj-Cg alkanol and Cj-Cg carboxylic acid. Preferably, R-j, R2, R3 and R4 in the formula (A) are each chosen from hydrogen or methyl, and more preferably R-j, R2, Ro and R4 are each hydrogen. The amount of urea or its derivatives and / or amide or its derivatives present during the crystallization process can vary, and is preferably between 0.001 mol / mol of β-lactam and 7.5 mol / mol of β-lactam, and more preferably between 0.1 mol / mol of ß-lactama and 5.25 mol / mol of ß-iactama. By derivatives of 6-APA, 7-ACA, 7-ADCA and 7-ACCA is meant its salts and esters.

Preferably, some of an alkanol of C-j-Cg, specifically methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, or a ketone, specifically acetone, methyl ethyl ketone, methyl isobutyl ketone or an ester, specifically methyl acetate, ethyl acetate , isopropyl acetate, butyl acetate or an ester of carboxylates of C C with an alkanol of C ^ -Cg or one of its mixtures is added as co-disodive to the solution or suspension of a β-lactam compound. The Dame salt coupling reaction is carried out in a dry organic solvent insoluble in water, for example dichloromethane. When the solution or suspension of a β-lactam compound is obtained by (a), the co-solvent is preferably added after the Dane salt coupling reaction. The concentration of the co-solvent is between 0.1% and 60%, and preferably between 25% and 60%, depending on the type of the β-lactam compound to be prepared. The pH of the acid solution is maintained between 0.1 and 3.5, and preferably between 0.3 and 2.5, using an acid. The temperature of the solution during the addition of the acid may vary, and is usually between -50 ° C and 10 ° C, preferably between -5 ° C and 5 ° C, and more preferably between -5 ° C and 0 ° C. At higher temperatures, the dissociation of the sensitive β-lactam ring of the antibiotic compound is increased. The acid is an inorganic acid, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or an organic acid, for example, formic acid and appropriate acetic acid or its derivatives. Preferably, hydrochloric acid is used. The β-lactam antibiotic compound is isolated in a conventional manner, adjusting the pH between 2.0 and 7.0, and preferably to the isoelectric point of said β-lactam antibiotic compound by the addition of a base. In addition, seed material is optionally added to the crystallization solution before the addition of the base. The base is an inorganic base, preferably sodium hydroxide, potassium hydroxide, ammonium hydroxide or an organic base, preferably an amine. Accordingly, after filtration and drying, crystalline products substantially free of impurities, such as the acid salt of the β-lactam compounds themselves, are obtained as known processes without application of urea or its derivatives and / or amide or its compounds. Derivatives give higher levels of impurities, especially when the crystallization is carried out at a lower temperature. The process of the present invention is particularly suitable for the preparation of β-lactam antibiotics in the polar-ion amino acid form. Examples of said antibiotics are amoxicillin, ampicillin, epicillin, cefaclor, cefadroxil, cefetamet, cefotaxime, cephalexin, cephaloglycine, defradine and cefroxadine.

According to a further aspect of the present invention, the β-lactam compound is advantageously crystallized by simultaneous addition of the β-lactam solution and a base to a crystallization vessel, as described in the unpublished European Patent Application. No. 97203484. This crystallization process comprises the simultaneous addition of the acid solution of a β-lactam compound comprising urea or its derivatives and / or amide or its derivatives and a titrant, mainly the base, to a crystallization vessel. The crystallization process of antibiotic compounds, according to the present invention, has a major advantage over existing methods because better matching results are possible. The agreement value referred to the difference between valuation with a strong acid and valuation with a strong base has been defined according to the United States Pharmacopoeia, twenty-first revision, dated January 1, 1985. A small match value means a product of constant quality. Ampicillin trihydrate, for example, isolated from the crystallization of a solution comprising ampicillin hydrochloride has a matching value of less than 1 mol%, while crystallization by a prior art method of a number of experiments has given a matching value between 4 and 8 mol%. The β-lactam antibiotic compounds with small agreement value, that is, comprising lower amounts of acid salt of the corresponding β-lactam antibiotics, are suitable for pharmaceutical formulation purposes. In addition, the bad effect of storage and temperature (above ambient temperature) on the stability of the ß-lactam antibiotic compound is increased due to the presence of very small or negligible amounts of the corresponding acid salt of the ß-lactam antibiotic compound . These acid salts of the β-lactam antibiotic are usually of a hygroscopic nature. Therefore, the product obtained by the process according to the invention is new. The invention will now be described with reference to the following Example, which should not be considered as limiting the invention, and is provided simply for illustrative purposes.

EXAMPLE Stage A Preparation of methoxycarbonyl-D-1-carbomethoxypropen-2-yl) amino-p-hydroxyphenyl-acetate 85 mL of N, N-dimethylacetamide, 116.4 g of Da- [1- (carbomethoxypropen-2-yl) -amino] -p Potassium hydroxyphenylacetate and 0.3 mL of pyridine were added to 267 mL of dichloromethane and the resulting suspension was cooled to -40 ° C. Subsequently, 46.3 g of pivaloyl chloride were added to this solution. While maintaining a temperature of -30 ° C, the mixture was stirred for 90 minutes and then cooled to -50 ° C.

Step B 63.8 g Triethylamine was added to a suspension of 80.0 g of 6-aminopenicillanic acid in 533 mL of dichloromethane at 20 ° C and the mixture was stirred for 90 minutes. The mixture should comprise sufficient water to obtain a clear solution. At 5 ° C, 78 g of 2-ethylhexanoic acid was added and subsequently the solution was cooled to -50 ° C.

Stage C Preparation of Amoxicillin Trihydrate The reaction mixture obtained in STEP A was added, over approximately 3 minutes, to the solution obtained in STEP B, stirring vigorously. Over a period of 3 hours the temperature gradually rose from -40 ° C / -35 ° C to -10 ° C / -5 ° C. Subsequently, a solution of urea (100 g in 800 mL of demineralized water) was added. While maintaining the mixture between -5 ° C and 0 ° C, concentrated hydrochloric acid was added and hydrolysis was continued for 30 minutes at a pH between 1.4 and 1.5. The organic phase was separated and the product was crystallized from the aqueous layer by addition of about 45 mL of 8 N sodium hydroxide solution to a pH between 4.8 and 5.0 at a temperature between 2 ° C and 5 ° C. The suspension was kept overnight under these conditions, filtered, washed with 100 mL of cold and demineralized water and 300 mL of cold acetone. The cake was dried at 35 ° C until constant weight was reached to obtain 143 g of amoxicillin trihydrate with a purity of 86.1% in the form of anhydrous amoxicillin (HPLC).

Claims (2)

NOVELTY OF THE INVENTION CLAIMS

1- A process for preparing a crystalline β-lactam compound by adding a base to an acid solution of a β-lactam compound obtained by adding an acid to a solution or suspension of a β-lactam compound obtained by: (a) an acylation reaction of 6-amino-penicillanic acid, 7-amino-cephalosporanic acid, 7-amino-3'-deacetoxycephalosporanic acid or 3-chloro-7-aminodoacetoxydesmethyl-cephalosporanic acid or salts or esters thereof, with a mixed anhydride of the Dane salt of any of the compounds comprising D-phenyl-glycine, Dp-hydroxyphenyl-glycine, D-2 (1,4-cyclohexadien-1-yl) glycine or (

2-aminothiazol-4-yl) ) - (2-methoxy-imino-acetic acid) in one or more organic solvents, or (b) dissolving or suspending a crude β-lactam compound in a solution comprising water and / or one or more organic solvents, characterized by addition, to the dissolution or suspension of a β-lactam compound, of urea or its derivatives and / or amide or its derivatives with the formulas (A) and (B) respectively, K ^ RjN-CO-NRaRa to -CO-NRjRa (A) (B) wherein R- R2, R and R4 are each independently selected from the group comprising hydrogen, lower alkyl or allyl, and alkanoic esters (Ci-Ce) of carboxylic acid (C? -C6), or R ^ y R form -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CO- and -CH = CH-CO- which give rise, together with -N-CO- N-, to a five or six membered cyclic ring. 2. The process according to claim 1, further characterized in that in the formula (A), R, R, R3 and R4 each is chosen from hydrogen or methyl. 3. The process according to any of claims 1-2, further characterized in that when the solution of a β-lactam compound obtained by (a) is used, the temperature at which the acid is added is maintained between - 50 ° C and 10 ° C. 4. The process according to any one of claims 1-3, further characterized in that the amount of urea or its derivatives and / or amide or its derivatives is between 0.001 mol / mol of ß-lactam and 7. 5 mol / mol of β-lactam, and preferably between 0.1 mol / mol of β-lactam and 5.25 mol / mol of β-lactam. 5. The process according to any one of claims 1-4, further characterized in that the dissolution of the ß-lactam antibiotic compound comprises one or more co-solvents chosen from the alkanol group of Cj-Cg or ketone or ester of a carboxylate of CjC with an alkanol of Cj-Cg 6. The process according to claim 5, further characterized in that when the solution of a β-lactam compound obtained by (a) is used, the co-solvent or Solvents are added after the coupling reaction. 7. The process according to claim 1-6, further characterized in that the pH of the acid solution before the addition of a base has been maintained between 0.1 and 3.5, preferably between 0.3 and 2.5 using an acid. 8. The process according to claim 7, further characterized in that the acid is hydrochloric acid. 9. The process according to any of claims 1-8, further characterized in that during crystallization, the pH is maintained between 2.0 and 7.0, preferably close to the isoelectric point of said ß-lactam compound by the addition of a base. 10. The process according to any of claims 1-9, further characterized in that the base is an inorganic base, preferably sodium hydroxide, potassium hydroxide or ammonium hydroxide. 11. The process according to any of claims 1-10, further characterized in that seed crystals are added before the addition of the base. 12. The process according to any of claims 1-11, further characterized in that the temperature during crystallization is maintained between -10 ° C and 50 ° C, preferably between -5 ° C and 35 ° C. 13. The process according to any of claims 1-12, further characterized in that the β-lactam compounds are penicillins and cephalosporins, preferably amoxicillin, ampicillin, epicillin, cefaclor, cefadroxil, cefatamet, cefotaxime, cephalexin, cephaglycine, cephradine and cefroxadine. 14. The process according to any of the preceding claims, further characterized in that the acid solution of a β-lactam compound and a base are simultaneously added to a crystallization vessel.