NL192453C - Process for preparing 6- D (-) - alpha {4- (C 1 -C 4 alkyl) -2,3-dioxo-1-piperazinocarbonylamino} phenylacetamido-penicillanic acids. - Google Patents

Description

1 192453

Process for the preparation of 6- [D (-) - a- {4- {C1-C4-alkyl) -2,3-dioxo-1-piperazlnocarbonylamlno} phenyl-acetamldojpenicillanic acids

The invention relates to a process for the preparation of a 6- (0 (-) - 01- (4- (0,04-811 ^ 1) -2,3-5 dioxo-1-piperazinocarbonylamino} phenylacetamido] penicillanic acid wherein: (a) 1-1.5 molar equivalent of a 4- (01-C4-alkyl) -2,3-dioxo-1-piperazinocarbonyl halide is added to a stirred suspension of 1 molar equivalent ampicillin in a solvent mixture consisting of 9-12 parts of water and 0.5-8 parts of ethyl acetate per part of ampicillin at a pH of 6.5-8; (b) stirring the reaction mixture for at least 15 minutes; (d) filtering the mixture and wash the insoluble material with 0.6-2.5 parts by weight of water per part by weight of ampicillin used in step (a); (e) combine the Altrate obtained in step (d) and the washing liquid obtained in step (d) with ethyl acetate and bring the mixture to a temperature of 15-25 ° C; (f) adjust the mixture to a pH of 2.0-2.5; and 15 (g) mix the mixture at 15-25 ° C for at least 1 hour stir and collect the crystals formed.

Such a method is known from U.S. Patent 4,112,090. The product of that process satisfies formula 1, wherein R represents an alkyl group of 1-4 carbon atoms, and the starting materials are represented by formulas 3 and 4, wherein R has the same meaning and X represents a halogen atom.

According to Example 23 of the US patent, the compound of the formula I, in which R is methyl, is prepared according to the method mentioned in the preamble, wherein a temperature of 2-3 ° C during steps (a) and (b) is prepared. handles. The yield obtained is 84.8%. According to Examples 11 and 13, the corresponding preparation of the methyl and ethyl compounds is carried out by the same procedure, but with tetrahydrofuran / triethylamine as the solvent system. In example 11 a temperature of 5-10 ° C is used, while in example 13 a temperature of 10-15 ° C is used; otherwise the conditions are the same. It now appears that an increase in temperature from 5-10 ° C to 10-15 ° C leads to a decrease in yield: for the methyl compound from 84% to 75% and for the ethyl compound from 89% to 72%. On the basis of this, it was to be assumed that if one wanted to achieve an improvement in yield based on the method described in Example 23 of U.S. Patent 30, at least the temperature should not be increased.

Surprisingly, it has now been found that the method according to the preamble can be considerably improved in yield (from about 85% to about 95%), by a specific combination of measures, the most important measure being a temperature increase to 12-18 ° C.

The process of the invention is characterized in that in step (a) the addition of the piperazinocarbonyl halide is allowed to take at least 30 minutes; perform steps (a) and (b) at a temperature of 12-18 ° C; after step (b) in step (c), add 0.05-0.2 parts by weight of both an activated carbon and a filter aid to the reaction mixture and stir the resulting mixture at 12-18 ° C for at least 10 minutes; in step (e) add such an amount of ethyl acetate that the total amount of ethyl acetate used in steps (a) and (e) is 10-13 parts by weight per part by weight of ampicillin used.

In carrying out the method of the invention, a stirred suspension of ampicillin in a mixture of water and ethyl acetate is prepared in amounts of about 9-12, most preferably about 10-11 parts by weight of water and about 0.5-8, at preferably about 4-6 parts by weight ethyl acetate per part by weight ampicillin are obtained. Ampicillin is the anhydric form of the compound of formula 3.

An appropriate amount of a suitable base is added to this mixture. To ensure the high yields of the present invention, sufficient base must be added to bring the pH of the initial mixture to about 6-8.3, preferably about 6.5-8, and to maintain this pH during the subsequent addition of the 4-C 1-4 alkyl) -2,3-dioxo-1-piperazinocarbonyl halide. Preferably about 2.4-3.0, preferably about 2.5-2.7 molecular equivalents of a base, for example sodium or potassium bicarbonate, are added per mole of 50 ampicillin supplied. In this method, the subsequent addition of the carbonyi halide will not cause a pH change. On the other hand, a base, e.g. potassium or sodium hydroxide or potassium or sodium carbonate are used to adjust the pH of the initial mixture to about 6-8.3, preferably about 6.5-8, but then carefully monitor the pH and ensure ensure that this pH range is maintained during the subsequent addition of the carbonyi halide. The pH can be continuously measured and maintained at the desired value by the addition of acid or base, or the pH can be maintained in the appropriate range by the addition to the initial reaction system of a suitable buffer system.

192453 2

The initial mixture is adjusted to a temperature of 12-18 ° C, and about 1-1.5, preferably 1.05-1.15 mole equivalent of a 4- (C 1-4 alkyl) is added to this mixture 2,3-dioxo-1-piperazinocarbonyl halide of formula 4, wherein R 1 is C 1 -C 4 alkyl and X is fluoro, chloro, bromo or iodo. The compound of formula 4 is added to the mixture in a period of at least 5 minutes, preferably in a period of 40-60 minutes, while the reaction mixture is at the above temperature and a pH of about 6-8.3, at 6.5-8 is preferred. Preferably the compound of formula 4 is the compound 4- (C 1 -C 4 -alkyl) -2,3-dioxo-1-piperazinocarbonyl chloride, especially 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride.

The resulting mixture is stirred at said temperature and pH for at least 15 minutes, preferably 20-30 minutes, upon completion of the addition of the compound of formula 4. The reaction mixture is then treated with about 0.05-0.2 , preferably 0.08-0.1 parts by weight of an activated carbon such as activated charcoal or type RB activated carbon (Pittsburgh Coke and Chemical Co.), and about 0.05-0.2, preferably 0.1- 0.15 parts by weight of a filter aid such as Hyflo® Super-Cell (Johns-Manville Sales Corp.), per part by weight of ampicillin originally fed. The resulting mixture is then stirred at said temperature for at least 10 minutes, most preferably 15-20 minutes.

The insolubles are then separated from the reaction mixture by known methods, preferably by filtration. The filter cake is washed with about 0.6-2.5, preferably 1.0-1.2 parts by weight of water per part by weight of ampicillin originally fed. The water liquid is then combined with the mother liquid obtained in the filtration process, and about 2-12.5, preferably 6-7 parts by weight of ethyl acetate per part by weight of ampicillin originally fed is added, provided that the total amount of ethyl acetate used, including the ethyl acetate in the original reaction mixture, is 10-13 parts by weight per part by weight of ampicillin originally fed, preferably 11-12 parts by weight.

The resulting mixture is heated to 15-25 ° C, preferably to 18-22 ° C, and acidified at said temperature to a pH of 2.0-2.5, preferably about 2.2-2.3, with dilute inorganic acid, e.g. 2-5 N hydrochloric or sulfuric acid.

The acidified reaction mixture is then stirred at said temperature for at least 1 hour, preferably about 2-3 hours, and the resulting crystals are collected in a known manner, e.g. by filtration or centrifugation. The crystals are then washed with water and dried to obtain the desired product in a yield of about 94-96%. After all, this end product can be hydrated to a greater or lesser extent.

The choice of ethyl acetate as a solvent is critical, as is the relative concentration of ethyl acetate during the crystallization step. Control of the pH during the reaction and the crystallization steps is also critical. Stepping outside the stated ranges for these factors will either decrease the final yield or lead to an inferior crystallization structure, possibly even lead to an amorphous mass.

The free acid obtained can be converted into a pharmaceutically acceptable salt in a known manner. Pharmaceutically acceptable salts include e.g. alkali metal, alkaline earth metal, ammonium or N-methylglucamine salts. The sodium salt is preferred and is preferably obtained by treating the compound of formula 1 obtained by the above method with an equivalent amount of sodium carbonate in water.

In the present description and example, percentages are by weight% and parts by weight unless otherwise stated.

Example A) Preparation of 6- [D (-) - a- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] penillanic acid monohydrate.

To a stirred suspension of 27.00 g ampicillin trihydrate (equivalent to 22.86 g (0.0654 mole) actual anhydrous ampicillin), 14.50 g (0.1726 mole) sodium bicarbonate, 238 g water, and 119 g ethyl-50 acetate, all at 15 ° C ± 2 ° C, 14.73 g (0.0720 mol) of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride was added at a rate such that a pH greater than 6 and a temperature of 15 ° C ± 2 ° C was maintained. After completion of the addition, the reaction mixture was stirred at 15 ° C ± 2 ° C for 20 minutes, and 2.1 g of activated carbon (type RB activated carbon; Pittsburgh Coke and Chemical Company), and 3.0 g of a filter aid (Hyflo® Super-Cel; Johns-Manville Sales Corp.) 55 added thereto. The mixture was stirred for an additional 10 minutes, and the solids were removed by filtration and washed with 26 g of water. The filtrate and washings were combined and then mixed with 142.5 g of ethyl acetate. The temperature of the obtained mixture

Claims (1)

3 192453 was adjusted to 20-22 ° C, and the pH was adjusted to 2.3 by adding 2 N hydrochloric acid thereto. The acidified mixture was stirred at 20-22 ° C for 2.5 hours and the crystalline precipitate was isolated by filtration, washed with 120 g of water, and dried, yielding 33.49 g (95.58% of theory) of the desired product was obtained. B) Preparation of 6- [D (-) - α- (4-ethyl-2,3-dioxo-1-pipeiazinocarbonylamino (phenylacetamido) penicillanic acid, sodium salt. 13.5 g of product obtained according to A) (0.025) were dissolved mol, equivalent to 13.125 g of the anhydric free acid) in 100 ml of water, and 2.06 g of sodium bicarbonate (0.025 mol. equivalent to 15.685% w / w of sodium bicarbonate) was added to the stirred solution at 6 ° C ± 4 ° C. the anhydric free acid) added h 10 portions of 0.206 g each The reaction was allowed to continue until the pH dropped to at least 6.5 over a period of 3-4 hours The reaction mixture was sterilized by cold filtration, placed in aseptic vials and lyophilized to give white or pale yellow crystals of 6- [D (-) - a- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid, sodium salt. e-fD ^ ja-WC ^ C ^ alkyl) ^, 3-dioxo-1-piperazinocarbonylamirao} 20 phenylacetamidojpenicillanic acid in which: (a) 1-1.5 molar equivalent of ee n 4- (C 1 -C 4 alkyl) -2,3-dioxo-1-piperazinocarbonyl halide to a stirred suspension of 1 mole equivalent ampicillin in a solvent mixture consisting of 9-12 parts by weight of water and 0.5-8 parts by weight parts of ethyl acetate per part of ampicillin at a pH of 6.5-8; (b) further stirring the reaction mixture for at least 15 minutes; (D) filtering the mixture and washing the insoluble matter with 06-2.5 parts by weight of water per part by weight of ampicillin used in step (a); (e) combining the filtrate obtained in step (d) and the washing liquid obtained in step (d) with ethyl acetate and bringing the mixture to a temperature of 15-25 ° C; (f) adjusts the mixture to a pH of 2.0-2.5; and 30 (g) stirring the mixture at 15-25 ° C for at least 1 hour and collecting the crystals formed; characterized in that in step (a) the addition of the piperazinocarbonyl halide is allowed to take at least 30 minutes; perform steps (a) and (b) at a temperature of 12-18 ° C; after step (b) in step (c), add 0.05-0.2 parts by weight of both an activated carbon and a filter aid to the reaction mixture and stir the resulting mixture at 12-18 ° C for at least 10 minutes; in step (e), add an amount of ethyl acetate such that the total amount of ethyl acetate used in steps (a) and (e) is 10-13 parts by weight per part by weight of ampicillin used. Hereby 1 sheet drawing