DD295162A5 - PROCESS FOR PREPARING D-ALPHA- (4-ETHYL-2,3-DIOXO-PIPERAZINE-1-CARBONYLAMINO) -BENZYLPENICILLINE - Google Patents

Abstract

The invention relates to a technically feasible process for the preparation of * in high yield, of very good quality and crystallinity, which is characterized in that ampicillin, ampicillin salts or hydrolytically easily cleavable esters with * as a technical solution in a chlorinated organic solvent such as methylene chloride in the presence of Acid is acidified and during or after Ansaeuerung in a two-phase system water / organic solvent, wherein the organic solvent is a mixture of chlorinated hydrocarbon and esters, such as ethyl acetate, with pure seed crystals of * is added. The reaction product precipitates in this way in high yield and constant very good purity from the reaction mixture, is very easy to isolate and handle technically. {Piperacillin; acylation; ampicillin}

Description

which is particularly evident in the pronounced activity against the microorganisms Pseudomonas aeruginosa, Proteus vulgaris, Seratia species, Klebsieila pneumoniae, enterobacteria and various clinically important anaerobes.

The sodium salt is used successfully in the treatment of pneumonia, respiratory and urinary tract infections, meningitis and other infections.

The present invention can be prepared compound of formula I is suitable as Breitbanc'antibiotikum for controlling infectious diseases of human and veterinary medicine.

Piperacillin is well tolerated when given even at high doses because of its relatively low toxicity.

Characteristic of the known state of the art

The compound producible according to the invention is already known. In DD-PS 117882, the synthesis of Da- (4-ethyl-2,3-dioxo-piperazine-i-carbonylaminoj-benzylpenicillin as the sodium salt and in the acid form of ampicillin or its reactive derivatives, such as its salts or esters, by Reaction with 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride of formula III described.

Instead of the reactive acid chloride of the formula III, it is also possible to use other reactive carboxylic acid derivatives, such as acid azides, acid cyanides, mixed anhydrides, active acid esters or active acid amides.

A method for the preparation of D-a- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyipenicillin is described in DD-PS 117882 in Example 23:

In this case, ampicillin trihydrate with 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride of the formula III in the presence of potassium carbonate in a solvent mixture of water-ethyl acetate (10: 4.5 parts by weight to one part by weight of ampicillin) at a temperature of 2 reacted to 3 ° C.

The compound of formula III is added to the solution of ampicillin in portions over 10 minutes, after which it is allowed to continue to react at this temperature for 15 minutes. The reaction mixture is then filtered to remove any undissolved residues and the solution is mixed with 18 parts by weight of ethyl acetate to one part by weight of ampicillin trihydrate.

The monohydrate of the Da- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzylpenicillanic acid of the formula I, wherein M is hydrogen and η is 1, precipitates out of the reaction solution for 5 hours after the same acidified with 2normaler hydrochloric acid and subsequently stirred at a temperature of 20 to 22 ° C.

The yield is 84.8%. The resulting monohydrate of the formula I, wherein M is hydrogen, is converted with an aqueous sodium bicarbonate solution into the pharmaceutically usable sodium salt of the formula I and the solution is subsequently lyophilized.

In BE 892 586 a process for the preparation of the compound of formula is given, wherein ampicillin trihydrate with 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride of the formula III in the presence of sodium bicarbonate in water and ethyl acetate (9 to 12 parts by weight Water and 0.5 to 8 parts by weight of ethyl acetate to 1 part by weight of ampicillin) at 10 to 25 ° C.

The compound of formula III is added portionwise over a period of 30 to 60 minutes, after which the solution is stirred for 15 to 20 minutes at the indicated temperature. Thereafter, the reaction mixture is treated with activated charcoal and decolorized and added to one part by weight of ampicillin 6 to 7 parts by weight of ethyl acetate.

The monohydrate of D-a- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzylpenicillanic acid is precipitated from the reaction solution by acidification and subsequent stirring at a temperature of 15 to 25 ° C. The yield is 95.58%.

The compound is then converted to the sodium salt of the compound of formula I in the same manner as described in DD-PS 117882.

In the two abovementioned patents, the isolation of the monohydrate of the compound I, wherein M is hydrogen and n1, at a temperature of 15 to 25 ° C, carried out at a pH of 2.0 to 2.5 and as a solvent water and ethyl acetate in a weight ratio of 1: 2.2, which corresponds to a volume ratio of 1: 2.5 of DD-PS 117882, and in a weight ratio of 1: 0.54 to 1: 0.66-which corresponds to the volume ratio of 1: 0, 6 to 0.85 of the BE-PS 892 586 corresponds angewandt.

In the last patent, it was also found that a close attention to the specified conditions of isolation of the acid form of the monohydrate of the compound of formula I, in particular the ratio of water to ethyl acetate is essential. If the specified conditions are not met, either a reduction in the final yield, a deterioration in the crystal quality or the formation of an amorphous mass can take place. This would result in costly and time-consuming cleaning of the reaction product.

These two recited methods for the preparation of the penicillin of the formula I, although they give relatively high yields, have a number of disadvantages which are particularly apparent when carrying out the process on an industrial scale.

A disadvantage is the relatively long addition time of the compound of formula III in solid form. This acid chloride is an unstable product, which is decomposed under the influence of humidity as well as high temperature.

It should also be borne in mind that the acid chloride of the formula III is irritating to the mucosa, which makes it difficult to handle it when dosing for the acylation reaction.

The portionwise addition of this compound in solid form caused on an industrial scale, a partial decomposition of the acid chloride of the formula IM and thus the reduction of the yield of the final product. This is particularly evident when the acid chloride of the formula III is used as crude product of technical grade for the reaction.

The acylation at 2O ⁰ C and higher in the presence of water also entails a partial decomposition of the acid chloride of the formula III, which may affect the quality of penicillin penicillin of the formula I as an end product disturbing.

In DE-OS 3518207 is ethyl-ethyl ^ .S-dioxo-piperazine-i-carbonylaminol-benzyl-penicillin of the formula I, wherein M is hydrogen or sodium, by reacting 4-ethyl-2,3-dioxo-piperazine-1 Carbonyl chloride of the formula III with a mixture of water with ethyl acetate in the presence of a base.

The ampicillin used for this synthesis is used as a reaction solution obtainable by reacting 6-aminopenicillanic acid with a reactive D (-) - phenylglycine derivative.

The ethyl ^, S-dioxo-piperazine-i-carbonyl chloride of the formula III is added in the form of a suspension or an aqueous solution, optionally together with a water-immiscible organic solvent, at a temperature between 4 and 10 ° C.

After completion of the reaction, the reaction mixture is decolorized by addition of activated carbon, filtered and acidified in the presence of a water-immiscible organic solvent to a pH of 1.5 to 2.0, the organic layer containing the penicillin, separated and the Penicillin sodium salt precipitated by addition of sodium 2-ethylcapronate or acidified the reaction mixture in the absence of an organic solvent at a temperature of 25 to 40 ° C to a pH of 2.0 to 2.5 and the precipitated penicillin monohydrate of formula I, wherein M is hydrogen, then filtered in an organic solvent and dissolved with a solution of sodium 2-ethylcapronate in an organic solvent, preferably acetone, is converted into the penicillin sodium salt of formula I or an aqueous suspension of the monohydrate the compound of formula I wherein M is hydrogen with sodium bicarbonate n eutralized and the resulting solution is lyophilized or spray dried.

This process has the particular disadvantage that in the extraction with an organic solvent after adjusting the reaction solution to pH 1.5 to 2.0, the penicillin acid of formula I, wherein M is hydrogen, the by-products or impurities formed during the reaction, which result from the use of technical starting materials, are transferred together with into the organic phase and thus influence the quality of the isolated end product.

As described in this patent, a suspension or aqueous solution of the acid chloride 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride of formula III for the acylation reaction with ampicillin can be used: This is practically not feasible because the substance of formula III in the attempt of dissolution or suspension formation in water without the presence of ampicillin spontaneously decomposed in seconds and therefore is not present for the actual acylation reaction. Piperacillin can not be isolated in this way!

Further, in this method, it is to be considered that by using the precipitating agent sodium 2-ethylcapronate additional costs and expenses for both this precipitating agent and the organic solvent in which the precipitating agent is dissolved and reacted with the above-mentioned extract are caused ,

In the isolation of the compound of formula I, wherein M is hydrogen and η is 1, from water, without the use of an additional organic solvent is to be noted that the reaction product is very finely powdery and by the reaction or the use of technical products resulting impurities adhering to the reaction product or be precipitated with this.

This is evidenced by the fact that pure penicillin acid of formula I, wherein M is hydrogen and η is 1, is very slightly soluble in ethyl acetate and methylene chloride. As soon as impurities due to the synthesis or the quality of the starting compounds are contained in this penicillin acid, this compound becomes increasingly soluble in organic solvents.

The method described in DE-OS 3518207 proves to be less suitable from the viewpoint given, since it must lead to products of inferior quality and is technically unacceptable on Grur.d.

In DD-DD DD 237166, the hydrochloride or triethylamine salt of ampicillin is reacted with the acid chloride of formula III to react the hydrochloride of ampicillin in water-miscible solvents and the triethylamine salt of ampicillin in water-immiscible solvents. The resulting in this reaction penicillin acid of the formula I, wherein M is hydrogen and η is the number 0, is isolated from water by acidification and then dissolved with aqueous sodium bicarbonate and freeze-dried.

This process is characterized by a number of significant drawbacks, which have a particular effect on the economics of the synthesis process: the yield obtainable by this process is 66% from the hydrochloride of ampicillin and 82% from the triethylamine salt of ampicillin low. Furthermore, the isolation from water of the penicillin acid of the formula I, where M is hydrogen and η is 0, causes the product to precipitate as a fine precipitate, which is difficult to isolate and dry, especially with larger amounts of sales. Such precipitates have the property of binding impurities, which can occur especially when using technical qualities of the feedstock, which may then necessitate additional cleaning operations.

In the Offenlegungsschrift DE 3627581 it is pointed out that the crystallization of the compound of the formula I in which M is hydrogen and η is 1, can be carried out from water / ethyl acetate only within critically narrow limits of the technological parameters, which is to endanger this compound to convert it into a sticky mass which is not to be filtered, and which should make the process feasible and industrially inapplicable.

In the published patent application DE 3518207 it is further pointed out that a precise observation of the crystallization conditions of the monohydrate of the formula I, wherein M is hydrogen, in particular the ratio of water to ethyl acetate is essential.

If these conditions were not met, either a reduction in the final yield, a deterioration of the crystal quality or even the preservation of an amorphous mass could take place, which can lead to time-consuming and costly cleaning of the final product. In summary, all of the preparation processes of Da (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzylpenicillanic acid from solid 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride in the acylation of ampicillin out.

However, this substance is relatively sensitive to hydrolysis, which greatly affects its handling, especially on an industrial scale.

Object of the invention

The object of the invention is to provide a technically feasible and economically advantageous synthesis of analytically pure Da (4-ethyl-2, 3-dioxo-piperazine-1-carbonylamino) -benzylpenicillin, which is characterized by a repeatable excellent quality and very high yield of the reaction product of formula I, wherein M is hydrogen and η 1, emphasizes, however, does not have the resulting by processing of solid acid chloride of the formula III disadvantages.

Explanation of the essence of the invention

The object of the invention was therefore to develop an improved synthesis process, according to which a highly pure product of the formula I, where η is the number 1 and M is hydrogen, is obtained in high yield in a reproducible manner, without a dosing in the solid state Use acid chloride of formula III.

The product is said to be easily recovered from the reaction solution by filtration, and the organic and inorganic substances adhered to the surface are easily removed by washing with water and organic solvent.

The product should have a coarse-grained texture, be easy to dry, and develop little dust when dried.

Its nature and quality should be such as to produce pharmaceutically acceptable salts of excellent quality by neutralization processes. These products are intended to conform to the American Pharakopo XXI.

It has surprisingly been found that it is possible to carry out the acylation of the compound of the formula II without prior isolation of the compound III from the solvent present, preferably methylene chloride.

Anschießend the solvent is replaced by another or another to add, so that a two-phase system water / organic solvent is formed, wherein the organic phase preferably consists of a mixture of methylene chloride and ethyl acetate. Anschießend sets a pH below 4 and sets purest crystals of the compound of formula I, in which M is hydrogen and η 1, at a temperature in a range of up to 50, but preferably between 15 and 3O ⁰ C under strong Stirring and separates the crystals from.

This is all the more surprising as in the patents DE 3518207 and DE 3627581 there is talk that in order to obtain suitable products exact compliance with technologically tight reaction conditions is necessary, mainly to an exact compliance with the composition of the two-phase water / ethyl acetate and the Temperature can be reduced, otherwise incurred either amorphous products or sticky masses, the costly additional cleaning operations entail.

Under the conditions of the process procedure selected in the present patent specification, acidification of the reaction solutions with dilute mineral acid in the two-phase system water / organic solvent, preferably a mixture of ethyl acetate and methylene chloride, initially results in dissolution of the resulting piperacillin acid in the organic medium with stirring.

At this time, by adding pure seed crystals of the compound of the formula I, where M is hydrogen and η is 1, the crystallization is intiiert and technologically safe lusgeführt be controlled.

Under the reaction conditions used it is possible to prevent the formation of greasy, unclean or even amorphous reaction products. The result is uniform, crystalline, analytically pure and technically excellently manageable products. These products are characterized by crystallinity, fast absorbency and drying as well as a high storage stability.

Furthermore, it has been found that the narrow technological limits set forth in the patents DE 3518207, DE 3627581, DD 237166, BE 892586 and DD 117882 show the implementation of the reaction and in particular the fact that an isolation of the piperacillin acid of the formula I, wherein M Wassoff and η is the number 1, in the purest form of a two-phase system water / organic solvent is to achieve, eir. Represents prejudice. The inhiierbare crystallization according to invention by inoculation with purest crystal material is a handling not usual in the Penicillinchemie and therefore an all the more surprising effect.

This is all the more significant when one considers that impurities occur when using technical products that have a lasting effect on the quality of the end product of the reaction, ie the piperacillin acid (monohydrate).

The mixture of methylene chloride / ethyl acetate is separable by fractional distillation, so that both substances can be used again.

By the method described in the present invention for the preparation of piperacillin acid (monohydrate), it is possible to generally dispense with the isolation of 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride in solid form, on the one hand the disadvantages the handling of solid 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride, such as mucosal irritation and high sensitivity to hydrolysis omitted and on the other hand in high yield and very good crystallinity piperacillin acid (monohydrate) on an industrial scale in excellent quality and pharmakopögerechtem Sodium salt can be processed.

embodiments

The process is illustrated by, but not limited to, the following examples.

example 1

8.06 g of ampicillin trihydrate are suspended in 80 ml of distilled water. This suspension is cooled to 5 to 10 ° C. in an ice-water bath. Then, with stirring, 6 g of sodium bicarbonate and 36 ml of ethyl acetate are added.

After the ampicillin trihydrate has completely dissolved, is added dropwise with stirring at 10 to 15 ^C C 5g 4-ethyl-2.3-dioxopiperazin-1-carbonyl chloride, dissolved in 10ml of dried Methylenchlorid.zügig.

The pH does not fall below 6.

It is stirred for 5 minutes after, gibtweitere44ml ethyl acetate added and heated the reaction solution at 22 ⁰ C. The mixture is acidified at this temperature to pH 2.0 with hydrochloric acid 2normaler. After the pH 4 has been reached, 200 mg of analytically pure Da (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are added, the reaction solution being stirred vigorously.

After 3 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed twice with 20 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours and receives 8.4 g of reaction product.

Yield: 78.42% of theory, based on monohydrate

IR spectrum (mineral oil trituration, 1 / cm): 1775 (β-lactam), 3425, 3285, 1740, 1710, 1665, 1665, 1520, 1375, 1290, 1250, 1220, 1120, 720, 695.

identical to piperacillin USP reference standard substance

TLC:

Run medium: ethyl acetate (water-saturated) -acetic acid = 10: 1 stationary phase: silica gel UV-254 detection: UV, then iodine chamber R _F = 0.66

HPLC analysis:

Sample: approx. 10mg in 50ml eluent, 10 microliter sample loop

Eluent: 200ml p.A. Methanol + 50 ml of 0.2 molar disodium hydrogen phosphate solution in water + 1.2 g of 12.5% tetra-n-butylammonium hydroxide solution + 220 ml of water,

It is adjusted with 3 N phosphoric acid to pH 5.5 and filled with water to 50OmI.

Detection: UV absorption at 254nm

Flow rate: 1 ml per minute

Column: 6cm Spherisorb-C ₆ , 3 micrometers, with precolumn (Knauer)

Content: 98-102%, based on USP reference standard substance

mercurometric titration:

Content: 98-102%, based on the monohydrate

of which degradation products: 0.2%

Example 2

8.06 g of ampicillin trihydrate are suspended in 80 ml of distilled water and this suspension is cooled to 5 to 10 ^° C. in an ice-water bath. Then, with stirring, 6 g of sodium bicarbonate and 36 ml of ethyl acetate are added.

After the ampicillin trihydrate has completely dissolved, is added dropwise at 10 to 15 ° C 6g 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride in 12 ml of methylene chloride rapidly.

The pH does not fall below 6.

The mixture is stirred for 5 minutes, an additional 44 ml of ethyl acetate are added and the reaction solution is warmed to 22 ° C. It is acidified at this temperature to pH 2.0 with 2 normal hydrochloric acid. After the pH 4 has been reached, 200 mg of analytically pure D-α- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are added, the reaction solution being stirred vigorously.

After 3 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed twice with 20 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours and receives 8.72 g of reaction product.

Yield: 81.4% of theory, based on monohydrate

Example 3

108.66 g of ampicillin trihydrate are suspended in 500 ml of distilled water, and this suspension is cooled to 5-10 ° C. in an ice-water bath. Then, with stirring, 10 g of sodium hydroxide in 250 ml of water.

After the ampicillin trihydrate has completely dissolved, it is added to 125 ml of ethyl acetate and 27.3 g of sodium bicarbonate. At 10 to 15 ° C 56.3g4-ethyl-2.3-dioxo-piperazine-1-carbonyl chloride, dissolved in 120 ml aboslutiertem methylene chloride, at a temperature of 25 to 30 ⁰ C registered quickly.

The pH does not fall below 6.

The mixture is stirred for 5 minutes, are added a further 500 ml of ethyl acetate and the reaction solution is heated to 20 ⁰ C. Suction at this temperature up to a pH of 2.0 with 2normaler hydrochloric acid. After the pH 4 has been reached, 200 mg of analytically pure DaH-ethyl ^ S-dioxo-piperazine-i-carbonylaminoJ-benzyl-penicillanic acid monohydrate are added, the reaction solution being stirred vigorously.

After 2 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed twice with 100 ml of water and ethyl acetate and dried at 40 ⁰ C for 3 hours and receives 118.2 g of reaction product.

Yield: 81.9% (based on monohydrate)

Example 4

Suspend 322.77 g of ampicillin trihydrate in 1600 ml of distilled water and cool this suspension in an ice-water bath to 10 to 15 ° C from. Then, with stirring, 32 g of sodium hydroxide in 800 ml of distilled water are added in the course of 5 minutes.

After the ampicillin trihydrate has completely dissolved, 92.41 g of sodium bicarbonate are rapidly introduced at 10 to 15 ° C.

Subsequently, 400 ml of ethyl acetate are added to the reaction solution and also at 10 to 15 ° C 179.5g acid chloride of formula III, dissolved in 400ml of methylene chloride at room temperature, quickly added dropwise with stirring. The pH does not fall below 6.

The mixture is stirred for 5 minutes, is an additional 1600 ml of ethyl acetate added and the reaction solution is heated to 20 to 22 ° C.

It is acidified at this temperature to pH 2.0 with 2 normal hydrochloric acid. After the pH 4 has been reached, 200 mg of analytically pure D-α- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are introduced, the reaction solution being stirred vigorously.

After 2 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed four times with 250 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours under water pump vacuum and receives 380 g reaction product.

Yield: 88.7% based on piperacillin acid (monohydrate)

Example 5

Suspend 161.4 g of ampicillin trihydrate in 800 ml of distilled water and cool this suspension in an ice-water bath at 10 to 15 ° Cab. Then, while stirring, add 16 g of sodium hydroxide in 400 ml of distilled water over 5 minutes.

After the ampicillin trihydrate has completely dissolved, it is rapidly introduced at 10 to 15 ⁰ C 45g sodium bicarbonate.

Then, 200 ml of methylene chloride are added to the reaction solution and also at 10 to 15 ° C90g acid chloride of formula III, suspended in 150ml of dried ethyl acetate, quickly added with stirring. The pH does not fall below 6.

The mixture is stirred for 5 minutes and added to the aqueous phase 800 ml of ethyl acetate and the reaction solution is heated

It is acidified at this temperature to pH 2.0 with 2 normal hydrochloric acid. After pH 4 has been reached, 50 mg of analytically pure D-α- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are introduced, the reaction solution being stirred vigorously.

After 2 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed four times with 250 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours and receives 175 g of reaction product.

Yield: 81.7% of theory, based on the monohydrate

Example 6

20.17 g of ampicillin trihydrate are suspended in 100 ml of distilled water and this suspension is cooled to 10 to 15 ^° C. in an ice-water bath. Then 2 g of sodium hydroxide in 50 ml of distilled water are added with stirring over the course of 5 minutes

After the ampicillin trihydrate has completely dissolved, is introduced at 10 to 15 ° C 5g sodium bicarbonate.

Subsequently, 50 ml of butyl acetate are added to the reaction solution and also at 10 to 15 ° C 12g acid chloride of formula III, dissolved in 25ml of dried methylene chloride at 20 to 25 ° C, added dropwise with stirring rapidly. The pH does not fall below 6.

It is stirred for 5 minutes after, are further added 200 ml Essigsäurebutyl ester and heating the reaction solution to 20 to 22 ⁰ C. The mixture is acidified at pH 2.0 with dieserTemperaturbiszum 2normaler hydrochloric acid. After the pH 4 has been reached, 20 mg of analytically pure Da (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are added, the reaction solution being stirred vigorously.

After 2 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed four times with 250 ml of water and butyl acetate.

It is dried at 40 ⁰ C for 3 hours under water pump vacuum and receives 24.1 g of reaction product.

Yield: 90% d. Th., Based on piperacillic acid (monohydrate)

Example 7

20.17 g of ampicillin trihydrate are suspended in 100 ml of distilled water and this suspension is cooled to 10 to 15 ^° C. in an ice-water bath. Then, with stirring, 2 g of sodium hydroxide in 50 ml of distilled water are added over 5 minutes.

After the ampicillin trihydrate has completely dissolved, 5 g of sodium bicarbonate are introduced at 10 to 15 ° C.

Subsequently, 30 ml of methylene chloride are added to the reaction solution and also added at 10 to 15 ° C 12 g of acid chloride of formula III with stirring quickly. The pH does not fall below 6.

The mixture is stirred for 5 minutes, 200 ml of butyl acetate added to the reaction solution and the reaction solution is warmed to 22 ° C.

At this temperature, it is acidified to pH 2.0 with 2 normal hydrochloric acid. After pH 4 has been reached, 50 mg of analytically pure D-α- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are introduced, the reaction solution being stirred vigorously.

After 2 hours, the crystallization is complete. It is filtered off with suction, washed the crystals each time four times with 100 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours and receives 24.5 g of reaction product.

Yield: 91.5%, based on monohydrate

Example 8

Dissolve 13.55 g of ampicillin triethylammonium salt in 90 ml of distilled water and cool this solution in an ice-water bath at 10 to 15 ° Cab. Thereafter, 4 g of sodium bicarbonate are added.

Subsequently, 15 ml of ethyl acetate are added to the reaction solution and also at 10 to 15 ° C 7.2 g of acid chloride of formula III, dissolved in 15 ml of methylene chloride at 25 ° C, added dropwise with stirring rapidly. The pH does not fall below 6.

The mixture is stirred for 5 minutes, are added a further 60 ml of ethyl acetate and the reaction solution is heated to 20 to 22 ° C. It is acidified at this temperature up to pH 2.3 with 2 normal hydrochloric acid. After the pH 4 has been reached, 20mg

enter analytically pure D-a-H-ethyl ^ .S-dioxo-piperazine-i-carbonylaminol-benzyl-penicillanic acid monohydrate, the reaction solution is stirred vigorously.

After 2 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed four times with 25 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours under water pump vacuum and receives 14.5 g of reaction product.

Yield: 90.2% of theory based on piperacillic acid monohydrate

Example 9

20.17 g of ampicillin trihydrate are suspended in 100 ml of distilled water and this suspension is cooled to 10 to 15 ° C. in an ice-water bath. Then, while stirring, 2 g of sodium hydroxide in 50 ml of water and 25 ml of ethyl acetate are added.

After the ampicillin trihydrate has completely dissolved, 6 g of sodium bicarbonate are added and a solution of 12 g of 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride in 25 ml of dried methylene chloride is added dropwise at 10 to 15 ° C. rapidly. The pH does not fall below 6.

It is stirred for 5 minutes after, are added a further 50 ml of ethyl acetate and heating the reaction solution at 22 ⁰ C. The mixture is acidified with 2.0 dieserTemperaturbiszumpH 2normaler with hydrochloric acid. After the pH 4 has been reached, 20 mg of analytically pure Da (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are added, the reaction solution being stirred vigorously.

After 3 hours, the crystallization is complete. It is suctioned off, the precipitated crystals washed twice with 50 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours and receives 22.1 g of reaction product.

Yield: 82.5%, based on monohydrate

Example 10

Mansuspended 20.17gmpicillin trihydrate in 200 ml of distilled water and this suspension is cooled to 10 to 15 ⁰ C in an ice water bath. Then, while stirring, 2 g of sodium hydroxide in 50 ml of water and 25 ml of ethyl acetate are added.

After the ampicillin trihydrate has completely dissolved, 6 g of sodium bicarbonate are added and added at 10 to 15 ⁰ C 12g4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride, in the form of a solution in the amount just required dry methylene chloride, rapidly.

The pH does not fall below 6.

It is stirred for 5 minutes after, are added a further 50 ml of acetic acid ethyl ester and heating the reaction solution at 22 ⁰ C. The mixture is acidified at this Tmeperatur to pH 2.0 with hydrochloric acid 2normaler. After the pH 4 has been reached, 20 mg of analytically pure Da (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are added, the reaction solution being stirred vigorously.

After 3 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed twice with 50 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours and receives 23.5 g of reaction product.

Yield: 87.8% (based on monohydrate)

Example 11

Dissolve 18.72 g of ampicillin sodium in 150 ml of distilled water and cool this solution in an ice-water bath to 10 to 15 ° Cab.

Thereafter, 6 g of sodium bicarbonate are added. Subsequently, 50 ml of ethyl acetate are added to the reaction solution and also at 10 to 15 ° C 12 g of acid chloride of the formula III, in 25 ml of methylene chloride, added dropwise with stirring rapidly.

The pH does not fall below 6.

The mixture is stirred for 5 minutes, add another 100 ml of ethyl acetate and the reaction solution is heated to 20 to 22 ° C. It is acidified at this temperature to pH 2.3 with 2 normal hydrochloric acid. After the pH 4 has been reached, 20 mg of analytically pure D-α- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are added, the reaction solution being stirred vigorously.

After 2 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed four times with 50 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours under water pump vacuum and receives 23.4 g of reaction product.

Yield: 87.4% d. Th., Based on monohydrate

Example 12

61.7 g of ampicillin trihydrate are suspended in 300 ml of distilled water and this suspension is cooled to 10 to 25 ° C. in an ice-water bath. Then 6 g of sodium hydroxide in 150 ml of distilled water are added with stirring over the course of 5 minutes

After the ampicillin trihydrate has completely dissolved, 19.2 g of sodium bicarbonate are rapidly added at 10 to 15 ° C.

Subsequently, 33 g of acid chloride of formula III in 70 ml of methylene chloride in the reaction solution with stirring at 10 to 15 ⁰ C.

The pH does not fall below 6.

150 ml of ethyl acetate are added to the reaction solution, and the reaction mixture is heated to 20 to 22 ° C. It is acidified at this temperature to pH 2.0 with 2 normal hydrochloric acid. After the pH 4 has been reached, 50 mg of analytically pure D-α- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are added, the reaction solution being stirred vigorously.

After 3 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed four times with 50 ml of water and ethyl acetate.

It is dried at 40 ° C for 3 hours and receives 65.5 g of reaction product.

Yield: 81.5%, based on monohydrate

Example 13

20.17 g of ampicillin trihydrate are suspended in 100 ml of distilled water and this suspension is cooled to 10 to 15 ° C. in an ice-water bath. Then 2 g of sodium hydroxide in 50 ml of distilled water are added with stirring over the course of 5 minutes

After the ampicillin trihydrate has completely dissolved, carry at 10 to 15 ° C7g potassium bicarbonate quickly

Subsequently, 25 ml of ethyl acetate are added to the reaction solution and also at 10 to 15 ° C 12g acid chloride of formula III, dissolved in 30ml of dried methylene chloride bie 25 to 30 ⁰ C, quickly added dropwise with stirring. The pH does not fall below 6.

The mixture is stirred for 5 minutes, and 100 ml of ethyl acetate are added and the reaction solution is heated to 20 to 22 ° C.

It is acidified at this temperature to pH 2.0 with 2 normal hydrochloric acid. After the pH 4 has been reached, 10 mg of analytically pure D-α- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are introduced, the reaction solution being stirred vigorously.

After 2 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed four times with 25 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours and receives 21.8 g of reaction product.

Yield: 81.4%, based on the monohydrate

Example 14

20.17 g of ampicillin trihydrate are suspended in 200 ml of distilled water and this suspension is cooled to 10 to 15 ^° C. in an ice-water bath. Then 5 g of triethylamine in 50 ml of distilled water are added with stirring over a period of 5 minutes.

After the ampicillin trihydrate has completely dissolved, carry at 5 to 15 ° C 5g sodium bicarbonate quickly

Subsequently, 125 ml of ethyl acetate are added to the reaction solution and also at 10 to 15 ° C 12g acid chloride of formula III, dissolved in 25ml of methylene chloride, added dropwise with stirring quickly.

The pH does not fall below 6.

The mixture is stirred for 5 minutes, and 100 ml of ethyl acetate are added and the reaction solution is heated to 28 to 30 ⁰ C.

It is acidified at this temperature to pH 2.0 with 2 normal hydrochloric acid. After the pH 4 has been reached, 10 mg of analytically pure D-α- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are added, the reaction solution being stirred vigorously.

After 2 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed four times with 250 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours and receives 20.8 g of reaction product.

Yield: 77.7%, based on acid monohydrate

Example 15

Suspending 108,66g ampicillin trihydrate in 500 ml of distilled water and this suspension is cooled in ice-water bath to 5 to 10 ⁰ C from. Then, with stirring, 10 g of sodium hydroxide in 250 ml of water.

After the ampicillin trihydrate has completely dissolved, it is added to 125 ml of ethyl acetate and 27.3 g of sodium bicarbonate. At 10 to 15 ° C with vigorous stirring 56.3g 4-ethyl-2.3-dioxo-piperazine-1-carbonyl chloride, dissolved in 120ml of dried methylene chloride, added dropwise.

The pH does not fall below 6.

The mixture is stirred for 5 minutes, an additional 500 ml of ethyl acetate are added and the reaction solution is warmed to 20 ° C. It is acidified at this temperature to a pH of 2.0 with 2 normal hydrochloric acid. Due to the fact that several Acylierungsansätze have been carried out in the reaction vessel, were enough nuclei of penicillin of the formula I, wherein M is hydrogen and η is 1, in the apparatus, so that a seeding could be omitted.

The reaction solution is stirred vigorously at 20 to 23 ° C.

After 2 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed twice with 100 ml of water and ethyl acetate and dried at 40 ⁰ C for 3 hours and receives 122 g of reaction product. Yield: 119.28g; 82.7%, d. Th. (Relative to monohydrate)

Example 16

At 15 to 20 ⁰ C, 3.5 g of anhydrous ampicillin are suspended in 50 ml of dry methylene chloride and added dropwise with stirring 3 g of triethylamine.

After the ampicillin has completely dissolved, 1.1 g of trimethylchlorosilane are added in 5 ml of methylene chloride and stirred for 10 minutes at -5 to -10 ⁰ C.

Thereafter, 2.1 g of acid chloride of the formula III in 25 ml of absolute methylene chloride are added dropwise within about 5 minutes and the reaction solution is stirred without cooling for 1 hour.

5 ml of n-propanol are added, the mixture is stirred at room temperature for 30 min, concentrated to dryness on a vacuum rotary evaporator at 35 ° C bath temperature under water pump vacuum and finally distributed the remaining residue between 40 ml of distilled water and 40 ml of ethyl acetate.

By addition of 2normaler hydrochloric acid at 20 to 25 ° C is adjusted with vigorous stirring, a pH of 1.5 to 2.5 and finally with 10 mg of compound I, wherein M is hydrogen and η is 1, inoculated and at The same temperature within 2 to 3 hours with stirring to crystallize.

It is suctioned off, washed three times each with 30 ml of water and 25 ml of ethyl acetate and dried at 40 ° C to constant weight.

Yield: 4.6 g (85.9% of theory), max. on the monohydrate

Example 17 - '

At 15 to 2O ⁰ C 3.5 g of anhydrous ampicillin were suspended in 50 ml of dry methylene chloride and added dropwise 3 g of triethylamine under stirring.

After the ampicillin has completely dissolved, at this temperature, 2.1 g of acid chloride of the formula III in 25 ml of dry methylene chloride are added dropwise within about 5 minutes and the reaction solution is stirred for 1 hour.

It is then concentrated on a vacuum rotary evaporator at 35 ⁰ C bath temperature on a water jet vacuum to dryness and finally distributed the remaining residue between 40 ml of distilled water and 40 ml of ethyl acetate.

By addition of 2normaler salsic acid at 20 to 25 ° C is adjusted with vigorous stirring, a pH of 1.5 to 2.5 and finally with 10 mg of compound I, wherein M is hydrogen and η is 1, inoculated and at The same temperature within 2 to 3 hours with stirring to crystallize.

It is suctioned off, washed three times with 30 ml of water and 25 ml of ethyl acetate and dried at 4O ⁰ C to Gewichtskonstants.

Yield: 4.6 g (86%), based on the acid monohydrate

Example 18

20.17 g of ampicillin trihydrate are suspended in 200 ml of distilled water and the supernatant is cooled to 10 to 15 ° C. in an ice-water bath. Then, with stirring, 5.1 g of N-methylmorpholine in 50 ml of distilled water are added in the course of 5 minutes.

After the ampicillin trihydrate has completely dissolved, carry at 5 to 15 ° C 5g sodium bicarbonate quickly

Then 125 ml of ethyl acetate are added to the reaction solution and also at 10 to 15 ° C 12g acid chloride of formula III, dissolved in 25ml of dried methylene chloride, added dropwise with stirring.

The pH does not fall below 6.

The mixture is stirred for 5 minutes and 100 ml of ethyl acetate are added and the reaction solution is heated to 28 to 30 ° C.

It is acidified at this temperature to pH 2.0 with 2 normal hydrochloric acid. After the pH 4 has been reached, 10 mg of analytically pure D-α- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are added, the reaction solution being stirred vigorously.

After 2 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed four times with 250 ml of water and ethyl acetate.

It is dried at 40 ° C for 3 hours and receives 22.0 g of reaction product.

Yield: 82.2% of theory, based on the monohydrate

Example 19

Suspending 20,17g ampicillin trihydrate in 200 ml of distilled water and this suspension is cooled in ice-water bath to 10 to 15 ⁰ C from. Subsequently, while stirring, 1.9 g of tributylamine in 50 ml of distilled water and 10 ml of ethyl acetate are added in the course of 5 minutes.

After the ampicillin trihydrate has completely dissolved, carry at 5 to 15 ° C 5g sodium bicarbonate quickly

Subsequently, 125 ml of ethyl acetate are added to the reaction solution and also at 10 to 15 ⁰ C 12g acid chloride of formula III, as a saturated solution at 25 ° C in methylene chloride, added dropwise with rapid stirring. The pH does not fall below 6.

The mixture is stirred for 5 minutes, and 100 ml of ethyl acetate are added and the reaction solution is heated to 28 to 3O ⁰ C.

It is acidified at this temperature up to pH 2.0 with 2 normal hydrochloric acid. After the pH 4 has been reached, 10 mg of analytically pure D-α- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are added, the reaction solution being stirred vigorously.

After 2 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed four times with 250 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours and receives 21.4 g of reaction product.

Yield: 79.9%, based on the monohydrate of the acid

Example 20

20.17 g of ampicillin trihydrate are suspended in 200 ml of distilled water and this suspension is cooled to 10 to 15 ° C. in an ice-water bath. Then 1.3 g of dimethylaniline in 50 ml of distilled water and 10 ml of ethyl acetate are added with stirring over the course of 5 minutes.

After the ampicillin trihydrate has completely dissolved, carry at 5 to 15 ° C 5g sodium bicarbonate quickly

Subsequently, 125 ml of ethyl acetate are added to the reaction solution and likewise added dropwise at 10 to 15 ° C 12g acid chloride of formula III in 40 ml of methylene chloride with stirring. The pH does not fall below 6.

The mixture is stirred for 5 minutes and 100 ml of ethyl acetate are added and the reaction solution is heated to 28 to 3O ⁰ C.

It is acidified at this temperature to pH 2.0 with 2 normal hydrochloric acid. After the pH 4 has been reached, 10 mg of analytically pure D-α-W-ethyl ^ .S-dioxo-piperazine-i-carbonylaminol-benzyl-penicillanic acid monohydrate are added, the reaction solution being stirred vigorously.

After 2 hours, the crystallization is complete. It is suctioned off, the deposited crystals washed four times with 250 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours and receives 20.8 g of reaction product.

Yield: 77.7% (monohydrate)

Example 21

50 g of penicillin acid of the formula I, where M is hydrogen and η is 1, obtainable from one of the aforementioned examples, are suspended in 250 ml of distilled water, mixed with the equimolar amount of sodium bicarbonate with stirring and stirred until almost everything has dissolved. The solution is filtered and then, as is usual in the case of parenterally administered drugs, sterile filtered and lyophilized. Yield: approximately quantitative

Example 22

Dissolve 13.95 g of ampicillin N-ethylmorpholinium salt in 90 ml of distilled water and cool this solution in an ice-water bath at 10 to 15 ° Cab. Thereafter, 4 g of sodium bicarbonate are added.

Subsequently, 15 ml of ethyl acetate are added to the reaction solution and likewise added dropwise at 10 to 15 ° C 7.2 g of acid chloride of the formula III in 20 ml of methylene chloride with stirring. The pH does not fall below 6.

The mixture is stirred for 5 minutes, are added a further 60 ml of ethyl acetate and the reaction solution is heated to 20 to 22 ° C. It is acidified at this temperature to pH 2.3 with 2 normal hydrochloric acid. After the pH 4 has been reached, 20 mg of analytically pure D-α- (4-ethyl-2,3-dioxo-piperazine-1-carbonylamino) -benzyl-penicillanic acid monohydrate are added, the reaction solution being stirred vigorously.

After 2 hours, the crystallization is complete. Mansaugtab, the deposited crystals washed four times with 25 ml of water and ethyl acetate.

It is dried at 40 ⁰ C for 3 hours under water pump vacuum and receives 13 g of reaction product.

Yield: 78.5%, based on monohydrate

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15 B.90-O678349

Claims (5)

A process for the preparation of di - ^ - ethyl ^ S-dioxo-piperazine-i-carbonylaminoJ-benzylpenicillin of the formula I, wherein M is hydrogen or a pharmaceutically acceptable cation and η is a number between 0 and 2, by acylation of a compound of Formula II, wherein Z has the meaning of M and additionally a blocking function for a carboxyl group or +
HNR ₃ where R is three identical or different C ₁ to C ₆ alkyl, aryl, aralkyl radicals; or two radicals R together form a bivalent radical of the formula - (CH ₂ ) pX- (CH ₂ ) _q - where ρ and q are numbers between 0 and 3 and X is oxygen, sulfur, a chemical bond or the rest -N (RV in which R ^{1 is} a C ₁ - to C ₄ alkyl radical, m is the number 0 or 3, with a compound of formula III in the presence of a base or of substances which have a buffering effect favorable for the acylation, in water , an organic solvent or a solvent mixture or a mixture of water with an organic solvent or solvent mixture in a temperature range between -10 and + 50 ⁰ C, preferably between +5 and +20 ⁰ C at a pH between 5.5 and 8.5; characterized in that the acylation is carried out without prior isolation of the compound of formula III in the existing solvent methylene chloride or the existing solvent mixture replaced by another or another organic solvent is added, so that a two-phase system water / organic phase is formed, wherein the organic phase preferably consists of a mixture of methylene chloride and ethyl acetate, one sets a pH of less than 4 and the precipitating reaction product by addition of pure crystals of the compound of formula I, wherein M is hydrogen and η 1, in a temperature range between 0 and + 50 ° C, preferably between +15 and +35 ⁰ C, brings with vigorous stirring in the two-phase system water / organic phase to crystallize, separated and converted into pharmaceutically acceptable salts. 2. The method according to claim 1, characterized in that 3 after a single or multiple implementation of the method in a plant, the inoculation can be carried out by the pure crystals present in the plant. 3. The method according to claim 1, characterized in that the two-phase system of organic solvent or a solvent mixture of esters, such as ethyl acetate, butyl acetate and chlorinated hydrocarbons, such as dichloromethane, and water. 4. The method according to claim 1, characterized in that the compound of formula I, wherein M is hydrogen and η 1, is preferably converted by neutralization process with sodium bicarbonate in the pharmaceutically acceptable sodium salt. 5. The method according to claim 1, characterized in that the compound of formula III is used as a crude, technically available product dissolved in a chlorinated hydrocarbon, such as methylene chloride, or as a suspension in an ester. For this 1 page formulas Field of application of the invention The invention relates to a process for the preparation of D-a-fa-EthyW ^ -dioxo-piperazine-i-carbonylaminoi-benzylpenicillin of the formula I in analytically pure form, which is known under the international name piperacillin. Piperacillin shows a broad antibacterial spectrum against both Gram-positive and Gram-negative bacteria,