JPH0331716B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved process for producing 6-substituted penicillanic acids. More specifically, the present invention is based on the formula () 6-[D(-)-α-(4-alkyl-2,3-dioxo-1-piperazinocarboxylamino)phenylacetamide]penisilane [wherein R is _C1 - _C4 alkyl] This invention relates to an improved method for producing acids. These compounds are useful as antibiotics for the treatment of pneumonia, peritonitis, and blood system infections.

Saikawa et al., in U.S. Patent No. 4,112,090, describe the formula () 4- _C1 - _C4 alkyl-2,3-dioxo-1 [wherein R is _C1 - _C4 alkyl]
−Piperazinocarbonyl chloride formula () 6-[D(-)-α-amino-
phenylacetamide] A method for preparing 6-substituted penicillanic acids of formula () by reaction with penicillanic acid trihydrate is disclosed.

The anhydrous form of formula () is hereinafter referred to as ampicillin. In Example 23 of the above patent, a suspension of compound () in a mixture of 10 parts by weight of water and 4.5 parts by weight of ethyl acetate per 1 part by weight of compound () was cooled to 2°C, and 2 mol of potassium carbonate was added. 1 molar proportion of the compound of formula () where R is methyl at 2-3°C.
Mix for 10 minutes and react at temperature for an additional 15 minutes. The reaction mixture is clarified to remove some insoluble materials and is further mixed with 18 parts by weight of ethyl acetate per part by weight of compound () originally charged in the mother liquor. Then the resulting mixture
Acidify with 1 molar equivalent of 2NHCl at 20-22°C for 5 minutes and stir at 20-22°C for 5 hours. The precipitated crystals were collected, washed successively with water and isopropanol, and dried to give 6-[D(-)-α-(4-methyl-
The dihydrate of 2,3-dioxo-1-piperazinocarbonylimino)phenylacetamido]penicillanic acid is obtained in a yield of 75.4%. In a similar example, when the compound of formula () is R=ethyl, 6-[D(-)-α-(4-ethyl-2,3-
dioxo-1-piperazinocarbonylamino)phenylacetamide] penicillanic acid monohydrate
Obtained with a yield of 84.8%.

There is a need for improved methods that significantly increase the yields obtained. The present invention provides such a method, with a final yield of about 95%.

The present invention comprises adding 4- _C1 - _C4 alkyl-2,3-dioxo-1-piperazinocarbonyl halide to a solution or suspension of ampicillin in a mixture of ethyl acetate and water in the presence of a base. a reaction mixture, stirring the resulting mixture until the reaction is complete, acidifying the reaction mixture, and then recovering the crystalline product.
6-[D(-)-α-(4-C ₁ to C ₄ alkyl-2,
In the method for producing penicillanic acid (3-dioxo-1-piperazinocarbonylamino)-phenylacetamide, (1) about 9 to 12 parts by weight of water and about 0.5 to 8 parts by weight of ethyl acetate per 1 part by weight of ampicillin; A stirred suspension of about 1 molar proportion of ampicillin and an appropriate amount of a suitable base in a solvent mixture consisting of about 10 to 25
4-C1 to _{C4 alkyl} -2,3 while maintaining a pH of about 6 to 8.3 for at least 30 minutes at °C.
-Adding about 1 to 1.5 molar proportion of dioxo-1-piperazinocarbonyl halide; (2) 4- _C1 to _C4 alkyl-2,3-dioxo-1-piperazinocarbonyl halide of step (1); Once the addition is complete, heat the reaction mixture to approximately 10-25 °C.
(3) To this reaction mixture, add about 0.05 to 0.2 parts by weight of activated carbon and super-aid agent per 1 part by weight of ampicillin charged in step (1), and the resulting mixture (4) Clarify the resulting mixture and perform step (1).
Approximately 0.6 to 1 part by weight of ampicillin prepared with
Wash the insoluble material with 2.5 parts by weight of water; (5) Combine the mother liquor and washing liquid obtained in step (4) with about 2 to 12.5 parts by weight of ethyl acetate per 1 part by weight of ampicillin charged in step (1). However, step (1) and
The total amount of ethyl acetate used in step (5) is about 10 to 13 parts by weight per part of ampicillin, and the resulting mixture is heated to about 15 to 25°C; The mixture was heated to about 15-25°C.
acidify to a pH of 2.0-2.5; and (7) acetic acid mixture at about 15-25°C.
6-[D(-)-α-( An improved method for producing 4- _C1 - _C4 alkyl-2,3-dioxo-1-piperazinocarbonylamino)-phenylacetamide penicillanic acid is provided.

The process of the invention provides the product of formula () in about 95% yield.

When carrying out the process of the invention, amounts are such as to provide about 9 to 12, preferably about 10 to 11 parts by weight of water and about 0.5 to 8, preferably about 4 to 6 parts by weight of ethyl acetate per part by weight of ampicillin. A stirred suspension of ampicillin in a mixture of water and ethyl acetate is prepared. This ampicillin is defined as the anhydrous form of the compound ().

Add the appropriate amount of a suitable base to this mixture.
To ensure high yields of the present invention, the amount of base should be sufficient to bring the pH of the initial mixture to about 6-8.3, preferably about _6.5-8 , and 4-C1- _C4 alkyl- It must be sufficient to maintain the PH range during the subsequent addition of 2,3-dioxo-1-piperazinocarbonyl halide. A preferred method of adding base is to introduce into the initial mixture about 2.4 to 3.0, preferably about 2.5 to 2.7, molar equivalents of base, such as sodium or potassium bicarbonate, per mole of ampicillin charged. With this method, subsequent addition of carbonyl halide does not result in a change in PH. Alternatively, a base such as potassium or sodium hydroxide or potassium or sodium carbonate can also be used to bring the initial mixture to a pH of about 6-8.3, preferably about 6.5-8, but then the carbonyl halide During the subsequent addition of PH
must be monitored and care must be taken to maintain this PH range. The PH can be monitored by direct measurement and addition of a suitable acid or base, or the PH can be maintained within a suitable range by adding a suitable non-interfering buffer system to the initial reaction system.
In this case, the buffer system is easily determined by a person skilled in the art.

The initial mixture is heated to about 10-25℃, preferably about 12-18℃
Adjust the temperature to ℃ and apply the formula to this 4- _C1 - _C4 alkyl-2,3-dioxo-1 in which R is _C1 - _C4 alkyl and X is fluorine, chlorine, bromine or iodine.
- Adding about 1 to 1.5, preferably about 1.05 to 1.15 molar proportions of piperazinocarbonyl halide. A compound of formula is then added to the mixture over a period of at least 30 minutes, preferably about 40 to 60 minutes, while the reaction mixture is maintained at the above temperature and pH of about 6 to 8.3, preferably about 6.5 to 8. . In a preferred method,
The compound of the formula is 4-C ₁ -C ₄ alkyl-2,3-
Dioxo-1-piperazinocarbonyl chloride; 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride is particularly preferred.

The resulting mixture is heated at the temperature and pH for at least 15 minutes after the addition of the compound of formula is complete.
Stir preferably for about 20-30 minutes. The reaction mixture is then treated with about 0.05 to 0.2, preferably about 0.08 to 0.1 parts by weight of activated carbon, such as activated carbon or RB type activated carbon (Puttsburgh type activated carbon), per part by weight of ampicillin originally charged.
Coke and Chemical Co.) and about 0.05 to 0.2, preferably about 0.1 to 0.15 parts by weight of a super-aid, e.g.
Hyflo Super−Cel (Johns−Manville Sales
Corp.). The resulting mixture is then stirred at that temperature for at least 10 minutes, preferably about 15-20 minutes.

The reaction mixture is then separated from insoluble materials by conventional methods known to those skilled in the art. A preferred separation method is filtration. The excess residue is about 0.6 to 2.5, preferably about 1.0 to 1.0, per 1 part by weight of ampicillin originally charged.
Wash with 1.2 parts by weight of water. Then add the cleaning solution,
About 2 to 12.5, preferably about 6 to 7 parts by weight of ethyl acetate per weight of ampicillin originally charged is added thereto. However, the total amount of ethyl acetate used, including ethyl acetate present in the original reaction mixture, is about 10 to 13, preferably about 11 to 12, per part by weight of ampicillin originally charged.
Parts by weight.

The resulting mixture is heated to about 15-25°C, preferably 18-25°C.
Warm to 22°C and add at that temperature a dilute mineral acid, e.g.
~5N hydrochloric acid or sulfuric acid about 2.0 to 2.5, preferably about
Acidify to a PH of 2.2-2.3.

The acidified mixture is then stirred at said temperature for at least 1 hour, preferably about 2-3 hours, and the resulting crystals are collected by methods well known to those skilled in the art, such as by filtration or centrifugation. The crystals are then washed with water and dried to yield the desired free acid product in about 94-96% yield. The free acid may be hydrated to varying degrees.

The choice of ethyl acetate as a solvent is critical, as is the relative concentration of ethyl acetate during the crystallization step.
Control of PH during the reaction and crystallization process is also critical. Variation of these factors in the ranges mentioned above may reduce the final yield or result in products having a poor crystal structure, sometimes no crystal structure at all, making the separation and purification of the final product time-consuming and expensive. No amorphous objects are produced.

The free acid obtained above can be converted into a pharmaceutically acceptable salt by methods well known to those skilled in the art. The pharmaceutically acceptable salts include, for example, alkali metal, alkaline earth metal, ammonium, N-
Contains methylglucamine. The sodium salt is preferred and can be obtained by treating the compound of formula (), preferably obtained by the method described above, with an equivalent of sodium bicarbonate in water.

In this specification, unless otherwise specified, all temperatures and temperature ranges are those of Setsu. Percentages or (%) are weight % and moles are g moles. In addition, the term "equivalent" refers to a molar amount of a reactant that is equal to the number of moles of the above-mentioned or below-mentioned reactant shown in the Preparation Examples or Examples, with respect to moles of a limited weight or volume.

The present invention also provides: (1) a suspension containing 2.5 to 2.7 molar equivalents of base in a solvent mixture consisting of about 10 to 11 parts by weight of water and about 4 to 6 parts by weight of ethyl acetate per part by weight of ampicillin; For about 40 to 60 minutes at about 12 to 18℃, about
Adding about 1.05 to 1.15 molar proportion of 4- _C1 to _C4 alkyl-2,3-dioxo-1-piperazinocarbonyl halide while maintaining a pH of 6.5 to 8; (2) Bringing the reaction mixture to about 12 Further stirring for about 20 to 30 minutes at ~18°C; (3) The reaction mixture was mixed with about 0.08 to 0.1 parts by weight of activated carbon and about 0.1 to 0.15 parts by weight of supercharging per 1 part by weight of ampicillin charged in step (1). and stirring the resulting mixture at about 12-18° C. for about 15-20 minutes; (4) After clarification, the insoluble material is reduced to about 1.0% per part by weight of ampicillin charged in step (1). (5) Combine the mother liquor and wash liquor with about 6 to 7 parts by weight of ethyl acetate per part by weight of ampicillin charged in step (1), and mix the resulting mixture with about 18 parts by weight of water; ~
Warm to 22°C, provided that the total amount of ethyl acetate used in steps (1) and (5) is about 11 to 12 parts by weight per 1 part by weight of ampicillin originally charged; Acidify to a pH of about 2.2-2.3 at 22°C; (7) Acidify the acidified reaction mixture to a pH of about 2-2.3 at about 18-22°C;
After stirring for 3 hours, the crystalline free acid is collected; and (8) the free acid is then dissolved in water at a concentration of about 13.125% (weight of anhydrous free acid/volume of water) and alkali metal added thereto. About 1 molar equivalent of carbonate is slowly added; the reaction mixture is stirred at about 6±4° C. for about 3 to 4 hours until the pH drops to at least 6.5, and then
A preferred improved method is provided comprising: collecting the alkali metal salt of the product of formula ().

In order to further understand the invention, the following examples are presented. However, this does not limit the invention;
All parts in the examples are by weight unless otherwise specified.

Example 1 Production of 6-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetamide]penicillanic acid monohydrate Ampicillin trihydrate 27.00 g [equivalent to 22.86 g (0.0654 mol) of pure anhydrous ampicillin], 14.50 g (0.1726 mol) of sodium bicarbonate, 238 g of water
and 119 g of ethyl acetate at a rate that maintains a pH of 6 or higher and a temperature of 15 ± 2°C.
14.73 g (0.0720 mol) of ethyl-2,3-dioxo-1-piperazinocarbonyl chloride was added. After this addition is complete, heat the reaction mixture to 15±2°C.
Stir for 20 minutes and add activated carbon (RB type activated carbon;
(Pittsburgh Coke and Chemical Co.) 2.1 g and super-aid (Hyflo Super-Cel; Johns-
Manville Sales Corp.) 3.0g was added. The mixture was stirred for an additional 10 minutes and the solids were removed by filtration and washed with 26 g of water. The liquid and washing liquid were combined and then mixed with 142.5 g of ethyl acetate.
Adjust the temperature of the resulting mixture to 20-22℃ and add 2N
The pH was adjusted to 2.3 by adding hydrochloric acid. The acidified mixture was stirred for 2.5 hours at 20-22 DEG C., the crystalline precipitate was separated off, washed with 120 g of water and dried to yield 33.49 g (95.58% of theory) of the desired product.

Example 2 Preparation of the sodium salt of 6-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetamide]penicillanic acid Product of Example 1 13.5 (0.025 mol, equivalent to 13.125 g of anhydrous free acid) was dissolved in 100 ml of water, and 2.06 g (0.025 mol,
(equivalent to 15.685% W/W of anhydrous free acid) was added. Then 3~ until the PH drops to at least 6.5
The reaction continued for 4 hours. The reaction mixture was sterilized by refrigeration and poured into asceptic vials.
6-[D(-)-
White or pale yellow crystals of the sodium salt of α-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetamide]penicillanic acid were obtained.

Claims (1)

[Claims] 1 4-C ₁ -C ₄ alkyl-2,3-oxo-1
- adding piperazinocarbonyl halide to a solution or suspension of ampicillin in a mixture of ethyl acetate and water in the presence of a base to form a reaction mixture; stirring the resulting mixture until the reaction is complete; 6-[D(-)-α consisting of acidifying the mixture and recovering the crystalline product therefrom.
-(4-C ₁ -C ₄ alkyl-2,3-dioxo-1
-piperazinocarbonylamino)-phenylacetamide] penicillanic acid, comprising: (a) in a solvent mixture consisting of about 9 to 12 parts by weight of water and about 0.5 to 8 parts by weight of ethyl acetate per 1 part by weight of ampicillin; In a stirred suspension of about 1 molar proportion of ampicillin and an appropriate amount of a suitable base, about 10 to 25
4-C1 to _{C4 alkyl} -2,3 while maintaining a pH of about 6 to 8.3 for at least 30 minutes at °C.
-adding about 1 to 1.5 molar proportion of dioxo-1-piperazinocarbonyl halide; (b) the 4- _C1 to _C4 alkyl-2,3-dioxo-1-piperazinocarbonyl halide of step (a); (c) Add to the reaction mixture about 0.05 to 0.2 parts by weight of each for each part by weight of ampicillin charged in step (a). Activated carbon and superaid are added and the resulting mixture is stirred for at least 10 minutes at about 10-25°C; (d) the resulting mixture is clarified and step (a)
Approximately 0.6 to 1 part by weight of ampicillin prepared with
washing the insoluble material with 25 parts by weight of water; (e) combining the mother liquor and wash liquor obtained in step (d) with about 2 to 12.5 parts by weight of ethyl acetate per part by weight of ampicillin charged in step (a); However, steps (a) and
The total amount of ethyl acetate used in step (e) is about 10 to 13 parts by weight per part of said ampicillin, and the resulting mixture is heated to about 15 to 25°C; (f) obtained in step (e). The mixture was heated to about 2.0 to 2.0℃ at about 15 to 25℃.
acidified to a pH of 2.5; and (g) the acidified mixture at about 15-25°C to a pH of at least 1
6-[D(-)-, characterized in that after stirring for a period of time, the resulting crystalline free acid is recovered; and (h) the free acid is optionally salified to a pharmaceutically acceptable salt. α−(4−C ₁ ~
C ₄ alkyl-2,3-dioxo-1-piperazinocarbonylamino)-phenylacetamide]
Method for producing penicillanic acid. 2 (a) in a suspension containing 2.5 to 2.7 molar equivalents of base in a solvent mixture consisting of about 10 to 11 parts by weight of water and about 4 to 6 parts by weight of ethyl acetate per part by weight of ampicillin. ℃ for about 40 to 60 minutes while maintaining a pH of about 6.5 to ₈ .
Adding about 1.05-1.15 molar proportion of _C4 alkyl-2,3-dioxo-1-piperazinocarbonyl halide; (b) further stirring the reaction mixture at about 12-18°C for about 20-30 minutes; (c ) The reaction mixture is treated with about 0.08 to 0.1 parts by weight of activated carbon and about 0.1 to 0.15 parts by weight of super-aid per part by weight of ampicillin charged in step (a), and the resulting mixture is heated to about 12 to 18°C. (d) Wash the insoluble material with about 1.0 to 1.2 parts by weight of water per part by weight of ampicillin charged in step (a); (e) Add the mother liquor and washing solution to step ( 1 part by weight of ampicillin charged in a) is condensed with about 6 to 7 parts by weight of ethyl acetate, and the resulting mixture is mixed with about 18 to 7 parts by weight of ethyl acetate.
Warm to 22°C, provided that the total amount of ethyl acetate used in steps (a) and (e) is approximately 1 part by weight of the ampicillin.
(f) acidifying the reaction mixture to a pH of about 2.2 to 2.3 at about 18 to 22°C; (g) acidifying the acidified reaction mixture to a pH of about 2 to 2.3 at about 18 to 22°C;
After stirring for 3 hours, the crystalline free acid is collected, washed with water and dried; and (h) the free acid is optionally mixed in a proportion of about 10% of the anhydrous free acid per 1 part of water.
About 1 molar equivalent of alkali metal carbonate is gradually added to the water at a concentration of 131.25 g;
2. A process according to claim 1, characterized in that: stirring for about 3 to 4 hours at ±4° C. and then collecting the alkali metal salt of the product of formula (). 3 4-C ₁ -C ₄ alkyl-2,3-dioxo-
1-piperazinocarbonyl halide is 4-C ₁ ~
The method according to claim 1 or 2, which is C ₄ alkyl-2,3-dioxo-1-piperazinocarbonyl chloride. 4 4-C ₁ -C ₄ alkyl-2,3-dioxo-
3. The method according to claim 1 or 2, wherein the 1-piperazinocarbonyl halide is 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride. 5. A method according to claim 1 or 2, wherein the product is converted into a sodium salt.