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Preparation method of piperacillin

A technology of piperacillin and ampicillin is applied in the field of preparation of piperacillin and can solve the problems of air pollution, pollution, hazardous waste environment and the like

Active Publication Date: 2021-02-05
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The reaction conditions of this process are mild, but trimethylchlorosilane is used in the acylation reaction, so hydrochloric acid and hexamethyldisiloxane will be produced in the production process, the treatment cost is high, and hazardous waste is generated, causing environmental pollution
Sodium bicarbonate is used in the condensation reaction, so carbon dioxide will be generated during the production process, which will take away a large amount of reaction solvent and pollute the air; and the condensation reaction needs water as a solvent, and N-ethyl-2,3-dioxypiperazine chloride will be more sensitive to water when it meets water. Many hydrolyzed products affect the reaction yield

Method used

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  • Preparation method of piperacillin
  • Preparation method of piperacillin
  • Preparation method of piperacillin

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Experimental program
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Effect test

Embodiment 1

[0029] Embodiment 1: (after improvement)

[0030] 1) Acylation reaction: Add 85.2g of dichloromethane and 14.2g (0.10mol) of N-ethyl-2,3-dioxypiperazine to the reaction flask, cool down to 15°C, and add 10.1g (0.034mol) of triphosgene; Control the temperature at 10-20°C, add 15.5g (0.102mol) DBU dropwise, take 34 minutes to complete the drop, and keep the temperature for 30 minutes to react; Methane feed solution (external standard contains 19.0g (0.093mol) N-ethyl-2,3-dioxypiperazine chloride, yield 93.0%); add 30% sodium hydroxide solution and water to the filter residue to adjust pH=9.5, DBU was recovered by vacuum distillation, and the distillate was dried with potassium hydroxide to obtain DBU.

[0031] 2) Condensation reaction: Add 297.6g of water, 111.6g of ethyl acetate, 37.2g (0.092mol) of ampicillin, 14.3g (0.094mol) of DBU into the reaction flask, cool down to 5-10°C, and dropwise add the above-mentioned N-ethyl - Dichloromethane feed solution of 2,3-dioxypiperazi...

Embodiment 2

[0032] Embodiment 2: (after improvement)

[0033] 1) Acylation reaction: Add 85.2g of dichloromethane and 14.2g (0.10mol) of N-ethyl-2,3-dioxypiperazine to the reaction flask, cool down to 15°C, and add 10.1g (0.034mol) of triphosgene; Control the temperature at 10-20°C, add 15.5g (0.102mol) DBU dropwise, take 34 minutes to complete the drop, and keep the temperature for 30 minutes to react; Methane feed solution (external standard contains 18.9g (0.092mol) N-ethyl-2,3-dioxypiperazine chloride, yield 92.4%); add 30% sodium hydroxide solution and water to the filter residue to adjust pH=9.6, DBU was recovered by vacuum distillation, and the distillate was dried with potassium hydroxide to obtain DBU.

[0034] 2) Condensation reaction: Add 293.6g of water, 110.1g of ethyl acetate, 36.7g (0.091mol) of ampicillin, 14.1g (0.093mol) of DBU into the reaction flask, cool down to 5-10°C, and dropwise add the above-mentioned N-ethyl - Dichloromethane feed solution of 2,3-dioxypiperazi...

Embodiment 3

[0035] Embodiment 3: (after improvement)

[0036] 1) Acylation reaction: Add 85.2g of dichloromethane and 14.2g (0.10mol) of N-ethyl-2,3-dioxypiperazine to the reaction flask, cool down to 15°C, and add 10.1g (0.034mol) of triphosgene; Control the temperature at 10-20°C, add 15.5g (0.102mol) DBU dropwise, take 34 minutes to complete the drop, and keep the temperature for 30 minutes to react; Methane feed liquid (external standard contains 19.2g (0.094mol) N-ethyl-2,3-dioxypiperazine chloride, yield 93.9%); add 30% sodium hydroxide solution and water to the filter residue to adjust pH=9.6, DBU was recovered by vacuum distillation, and the distillate was dried with potassium hydroxide to obtain DBU.

[0037]2) Condensation reaction: Add 300.0g of water, 112.5g of ethyl acetate, 37.5g (0.093mol) of ampicillin, 14.4g (0.095mol) of DBU into the reaction flask, cool down to 5-10°C, and dropwise add the above-mentioned N-ethyl - Dichloromethane feed solution (0.094mol) of 2,3-dioxy...

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Abstract

The invention discloses a preparation method of piperacillin. According to the method, DBU with stronger alkalinity is used as an initiator to promote the reaction of N-ethyl-2, 3-dioxopiperazine andtriphosgene to obtain N-ethyl-2, 3-dioxopiperazine acyl chloride, so that the use of trimethylchlorosilane is avoided; In the condensation reaction, sodium acetate is used as an acid-binding agent, sothat the pollution of carbon dioxide to the environment is avoided. The alkalinity of sodium acetate is weaker than that of sodium bicarbonate, the hydrolysis degree in the reaction process is low, meanwhile, DBU is used as a catalyst, and the N-ethyl-2, 3-dioxopiperazine acyl chloride hydrolysate can also react with ampicillin to obtain piperacillin, so that the reaction yield is increased, andthe production cost is further reduced.

Description

technical field [0001] The invention relates to a preparation method of piperacillin, which belongs to the technical field of medicine. Background technique [0002] Piperacillin, the chemical name is: (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piper (oxazinylamino)-2-phenylacetamido]-7-oxo-4-thia-1-nitrogen, the structural formula is as follows: [0003] [0004] Piperacillin is a semisynthetic semicarbazine antipseudomonal penicillin antibiotic. The sodium salt of piperacillin piperacillin sodium is a semi-synthetic penicillin antibiotic with broad-spectrum antibacterial effect and exerts bactericidal effect by inhibiting the synthesis of bacterial cell walls. Enterobacteriaceae such as Escherichia coli, Proteus, Serratia, Klebsiella, Enterobacter, Citrobacter, Salmonella and Shigella, and Pseudomonas aeruginosa , Acinetobacter, Haemophilus influenzae, Neisseria and other Gram-negative bacteria have good antibacterial effect. This product also has certa...

Claims

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Application Information

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IPC IPC(8): C07D499/68C07D499/04
CPCC07D499/68C07D499/04
Inventor 吕德帅王欣翟长均孟令华李东建王仕川孙明尧
Owner 山东安信制药有限公司