JPH072750B2 - Process for producing 6-D-α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamide-penicillanic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention is commonly referred to as 6-D-α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamide-penicillanic acid (or piperacillin). )
Manufacturing method.

(Prior Art) Piperacillin has broad antibacterial activity, especially gram-negative microorganisms,
Pseudomonas aeru
ginosa), Proteus vulgaris, Serratia spp., enterobacteria and other clinically important anaerobic bacteria. For example, its sodium salt is effectively used for the treatment of pneumonia, meningitis, urethral sepsis and the like.

As a method for producing this piperacillin, Belgian Patent No. 892,37
Silylation of the amino group of D-α-phenylglycine
Acylation with ethyl-2,3-dioxopiperazine and the resulting product in the presence of tuclohexylcarbodiimide 6-
72% of piperacillic acid reacted with aminopenicillanic acid
It is disclosed that it is obtained in a yield of. This patent, as an alternative, from ampicillin trihydrate, a pre-phosgenation treatment of its amino groups and the product 4-ethyl-2,3-
Disclosed is the production of piperacillic acid via a reaction with dioxopiperazine.

British Patent No. 1,517,098 discloses a process for producing piperacillic acid from an ester of 6-phenylacetamido-penicillanic acid or its potassium salt. These starting compounds were decomposed with nomino chloride, and the resulting 6-APA was isolated without isolation from the reaction mixture by anhydrous D-α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino). Acylation is performed with a mixture of phenylacetic acid and ethyl chloroformate. As a result, piperacillic acid
The yield is said to be%.

However, a drawback of these methods is that the production conditions are complicated, such as harmful medium and low temperature, and the yield is poor.

U.S. Pat.No. 4,087,424 describes the silylation of ampicillin with trimethylsilyl chloride in the anhydrous medium of ethyl acetate in the presence of triethanolamine, and then the resulting silylated derivative is 4-ethyl-2,3-dioxopiperazide. After acylation with nocarbonyl chloride at 15-20 ° C. for 2 hours to separate the precipitated triethylamine hydrochloride,
Butanol is added to the solution to precipitate the crystals of piperacillic acid, and as a result, the yield can be 90%. The disadvantage of this method is that the operation is carried out in a completely dry medium and consumes large amounts of organic solvent and silylating agent.

British Patent No. 2,095,661B also discloses a method for obtaining piperacillin in a high yield of 94 to 96% by carefully selecting reaction conditions. Attention is paid to ethyl acetate as a particularly important factor in this delicate combination of conditions. It has been described that changes in the ratio of organic solvent to water and ampicillin, changes in temperature, and pH decrease yields and produce amorphous products and impurities, which are difficult to separate from the reaction medium. . The drawbacks of this method are that crystallization of piperacillin is possible under extremely limited conditions, sticky substances that are difficult to produce are likely to occur, there is a problem in terms of reproducibility, etc., and industrial realization is difficult. Furthermore, the crystallization requires the presence of a large amount of organic solvent, namely ethyl acetate, i.e. a ratio of 10: 1 or more for ampicillin and the final product, about 2: 1 for water.
Is required, and continuous stirring is required for a relatively long time of 2 to 5 hours.

Due to the high miscibility (8.6%) of ethyl acetate with water, it is necessary to recover a large amount of organic solvent from the organic and inorganic phases of the reaction mixture. Therefore, an extra operation is required, which makes the method complicated and costly. Therefore, it is not suitable for application under industrial conditions suitable for mass production of piperacillin.

Given the importance of this piperacillin as an anti-product,
It is desirable to develop a method for mass production in a technically and economically acceptable manner.

(Object of the Invention) The present invention provides a method for industrially producing piperacillin with high yield and high purity, and is good without requiring a dense condition and without requiring a large amount of an organic solvent. An object of the present invention is to provide a method capable of depositing and recovering piperacillin in various crystalline states.

(Means for Solving Problems) As a means for solving the conventional problems and achieving the above object, the present invention provides the following method, that is, ampicillin in water-organic medium in the presence of a base. After acylation with -ethyl-2,3-dioxopiperazinocarbonyl chloride and subsequent acidification, the resulting 6-D-α-
In the method for separating (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido-penicillanic acid, the acylation step is carried out by adding 4 to 6 parts by weight of lower chlorination per 1 part by weight of ampicillin. Conducting in a medium containing an organic solvent selected from hydrocarbons, separating the organic solvent, cooling the water layer to 0 to 10 ° C, adjusting the pH to 1.5 to 2.3, and leaving this acidic solution for a suitable time. The present invention provides a method, which comprises depositing and then depositing.

As a preferred embodiment of the present invention, the acylation of ampicillin is carried out in a medium of 1,2-dichloroethane or methylene chloride, and the water / organic solvent ratio is 10: 5 to
It is desirable to do it at a ratio of 10: 3 (volume). Further, it is desirable that the water layer is cooled to 0 to 5 ° C. and, while maintaining this temperature, acidification, standing and sedimentation are performed.

The sodium salt of piperacillin obtained by the method of the present invention can be obtained by known means.

The ampicillin used as a starting material in the present invention may be directly introduced into the reaction mixture or may be obtained from 6-APA by a known method and used directly without isolation to be acylated to obtain piperacillin. May be.

Surprisingly, according to the method of the present invention, piperacillin is produced with good crystals, is easy to separate, has a high yield, and has a purity that meets the specifications of the U.S.P. is there. Furthermore, the process of the present invention does not require harsh reaction conditions, and particularly does not require harsh conditions regarding the type of organic solvent, the starting material and the ratio to water. Furthermore, there is no risk of the product becoming tacky and hard to pass through. Crystallization can also be performed under conditions suitable for maintaining the characteristics of the product. For example, using only water medium,
It can be manufactured at a lower temperature than before and in a relatively short time.

In the present invention, the organic solvent is almost immiscible with water (it is miscible only with about 1/10 of the case of ethylene acetate), so that the amount used is at least 2
It can be less than a fraction and can be easily separated from the reaction mixture. At the same time, compared to ethylene acetate, it can be recovered more easily, consumes less energy, and does not pollute the environment.

Since the method of the present invention uses a small amount of the organic solvent, the productivity per unit reaction amount is also high, and the presence or addition thereof is not necessary in the crystallization step of the reaction.

Examples Example 1 Preparation of 6-D-α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamide-penicillanic acid hydrate: 1,2-dichloroethane 13.5 g (0.0335 mol) of ampicillin trihydrate suspended in a mixture of 50 ml and 120 ml of water was stirred at a temperature of 15 to 20 ° C and 6.5 g of sodium bicarbonate (0.
0714 mol) and 8.0 g (0.0391 mol) of 4-ethyl-2,3-dioxopiperazinocarbonyl chloride were added over 15 minutes and the pH was adjusted to 7.5-8.5. After stirring at this temperature for 20 minutes, an aqueous phase and an organic phase were separated.

This aqueous phase was treated with 1 g of activated carbon at a temperature of 5 to 10 ° C for 30 minutes. After further passing, the residue on the filter was washed with 20 ml of water. While maintaining the temperature of the liquid and the washing water as they were, 2N hydrochloric acid was added with stirring to adjust the pH to 1.5 to 2.3. After leaving this acidified solution at this temperature for 1 hour, the precipitated 6-D-α- (4-ethyl-2,3-dioxopiperazinocarbonylamino) -phenylacetamide-penicillanic acid 1
Pass the hydrate, wash with 60 ml of water at 5 ℃, and then 40-50 ℃
And dried under vacuum. The yield was 17.38 g (96.25%) (based on ampicillin).

Example 2 Preparation of 6-D-α- (4-Ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamide-piperazlanic acid: 10.2 g (0.0253) of ampicillin trihydrate in 90 ml of water. Mol)
5 g (0.595 mol) of sodium bicarbonate and 7 g (0.0343 mol) of 4-ethyl-2,3-dioxopiperazino-1-carbonyl chloride (dissolved in 40 ml of methylene chloride) were added to a suspension of Add at ~ 20 ° C over 10 minutes and finally
The pH was 7.5-8.5. As a result of stirring this for 20 minutes, an aqueous layer and an organic layer were separated. This aqueous layer was treated with 0.8 g of activated carbon at a temperature of 5 to 10 ° C. for 30 minutes and then passed through. The residue was washed with 15 ml cold water. Combine the liquid and wash water,
To this was added 2N HCl at 5 to 10 ° C to adjust the pH to 1.5 to 2.3. After standing at this temperature for 1 hour, the piperacillic acid that had precipitated was separated, washed with 40 ml of cold water, and then dried under vacuum at a temperature of 40 to 50 ° C. The yield was 13.9 g (96.0%).

Example 3 Preparation of 6-D-α- (4-ethyl-2,3-dioxo-1-piperazinocarbonyl-amino) -phenylacetamide-penicillanic acid sodium salt: 6-D-α- (4-ethyl 12 g (0.0224 mol) of -2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido-penicillanic acid monohydrate was suspended in 90 ml of distilled water, and sodium bicarbonate ( Purity for analysis) 1.
882 g (0.0224 mol) was added in small portions so that the pH reached the boundary of 6-7. After dissolution, the solution was treated with 1.0 g of activated carbon, filtered through a sterile filter and freeze-dried.

Example 4 Preparation of 6-D-α- (4-Ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido-penicillanic acid sodium salt: Ampicillin trihydrate 13.5 g (120 ml of water) 0.335 mol) suspended in sodium bicarbonate 6.5 g (0.0714 mol)
And 4-ethyl-2,3-dioxopiperazino-1-carbonyl chloride 8 g (0.0391 mol) (dissolved in 60 ml dichloroethane) were added over 20 minutes at a temperature of 10-20 ° C.
As a result, the pH of the liquid finally became 7.5 to 8.5. As a result of stirring at this temperature for 20 minutes, a layer of water and an organic substance was separated. The aqueous layer was cooled to 0-5 ° C, treated with activated carbon for 30 minutes and then passed through. The residue on the filter was washed with 20 ml cold water. 2N at the same temperature for a mixture of liquid and wash water
HCl was added to bring the pH to 1.5-2.3. Then, after standing for 1 hour, the deposit was separated and washed with 60 ml of cold distilled water. The water-containing deposit of piperacillic acid obtained was treated with apyrogen distilled water 12
Suspend in 0 ml, add 2.70 g of sodium bicarbonate (purity for analysis) little by little, and finally adjust the pH of the solution to 6.0-6.5.
Adjusted to. This solution was sterilized, the concentration was measured, and then bottled and freeze-dried. Yield is 17.3g (95.
8%).

Example 5 13.15 g (0.13 mol) of triethylamine, 4.5 g (0.075 mol) of urea and 10.8 g of 6-APA in 10 ml of methylene chloride.
(0.05 mol) was added to the suspension with stirring at a temperature of 20 ° C, and 14.87 g (0.13 mol) of trimethylsilyl chloride was added.
Mol) was added. After dissolving at a temperature of 20 ° C for 30 minutes, the temperature was raised to 40 ° C and the mixture was stirred at this temperature for 60 minutes. After that, the suspension was cooled to −25 ° C. and 10.8 g (0.08 mol) of D-α-phenylglycyl chloride chloride hydrogen chloride was added. Next, the temperature was raised to -5 ° C and the stirring was continued for 75 minutes. Next, 110 ml of distilled water was added and the mixture was stirred for 5 minutes. As a result, layers of water and organic matter were separated. Dilute ammonia was added to this aqueous layer to adjust the pH to 6 and sodium bicarbonate at 8.6 g and 4-ethyl-2,3-dioxopiperazino-
Carbonyl chloride 12.07 g (70 ml of methylene chloride 70
(dissolved in ml) was added over 15 minutes. Followed by 20
As a result of stirring for 1 minute, layers of water and organic matter were separated. This aqueous layer was treated with 1.2 g of activated carbon at a temperature of 0 to 5 ° C for 30 minutes and then separated. After washing the residue on the filter with 20 ml of water,
2N HCl was added to the combination of this solution and wash water to adjust the pH.
It was set to 1.5 to 2.3, left for 1 hour at a temperature of 0 to 5 ° C., and then separated. The obtained 6-D-α- (4-ethyl-2,3-dioxopiperazine-1-carbonylamino) -phenylacetamide-penicillanic acid monohydrate was washed with 60 ml of cold water and the temperature was adjusted to 40
Dried under vacuum at ~ 50 ° C. Yield 23.98g (90.4%,
6-APA).

Example 6 Preparation of 6-D-α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido-penicillanic acid sodium salt: 6-D-α- (4-ethyl- 2,3-Dioxo-1-piperazinocarbonylamino) -phenylacetamide-penicillanic acid
2.5 g was dissolved in dry ethyl acetate. After adding 1 g of magnesium sulfate to this solution and stirring for 30 minutes,
Then, 0.3 g of sodium hexanoate (dissolved in 20 ml of dry ethyl acetate) was added dropwise to the solution. As a result, white crystals were deposited. This was separated, washed with dry ethyl acetate and ether and dried under vacuum of 5 mmHg at 40 ° C. As a result, 6-D-α- (4-ethyl-2,
2.7 g of the sodium salt of 3-dioxopiperazinocarbonylamino) -phenylacetamido-penicillanic acid were obtained.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Lubomir Stefanov Changov, Bulgaria, Sofia, Spirka Vilite, First Street 3 (56) Reference JP-A-57-165391 (JP, A)

Claims (4)

[Claims] 1. The 6-D obtained after acylation of ampicillin with 4-ethyl-2,3-dioxopiperazinocarbonyl chloride in the presence of a base in a water-organic medium and then acidifying it. -α- (4-Ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamide-
In the method for separating penicillanic acid, the acylation step is carried out in a medium containing an organic solvent selected from 4 to 6 parts by weight of lower chlorinated hydrocarbon per 1 part by weight of ampicillic acid, and the organic solvent is separated, A method comprising cooling the water layer to 0 to 10 ° C., adjusting the pH to 1.5 to 2.3, allowing this acidic solution to stand for a suitable time, and then passing the deposit. 2. The process according to claim 1, wherein the acylation of ampicillin is carried out in a medium of 1,2-dichloroethane or methylene chloride. 3. A water / organic solvent ratio of 10: 5 to 10: 3 (volume).
Any one of claim 1 and claim 2
The method described in the section. 4. The method according to claim 1, wherein the water layer is cooled to 0 to 5 ° C. and, while maintaining this temperature, acidification, standing and sedimentation are carried out.