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Preparation method of piperacillin acid

A technology of piperacillin acid and ethyldioxypiperazine, applied in the field of medicine, can solve the problems of low conversion rate of N-ethyldioxypiperazine, large loss of solvent, etc., and achieve high product yield and degraded impurity content. Low, conversion-increasing effect

Active Publication Date: 2019-05-10
山东安舜制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the conversion rate of N-ethyldioxypiperazine is low in the acylation step, and the condensation step produces the non-condensable gas carbon dioxide, so that the solvent loss in the reaction process is relatively large.

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Embodiment 1: (after improvement)

[0029] 1) Take 14.2g (0.10mol) of N-ethyl dioxypiperazine, transfer it into a 500mL three-necked flask, stir, add 200mL of dichloromethane, cool down to -25~-20°C, add dropwise 16.3g (0.15mol) of TMCS , temperature control -25~-20℃, dropwise add 11.9g (0.15mol) pyridine, add 0.018g DMAP, temperature control -25~-20℃, add 11.9g (0.04mol) triphosgene in batches, keep warm for 30-60 minutes Carry out the reaction; after the reaction is completed, filter with suction, wash with 30 mL of dichloromethane, distill to dryness under reduced pressure, add 100 mL of n-hexane to crystallize, filter with suction, and dry to obtain 19.3 g of N-ethyldioxypiperazine chloride, with a yield of 94.3% .

[0030] 2) Transfer 20.2g (0.05mol) of ampicillin into a 500mL three-necked flask, add 100mL of water, 150mL of ethyl acetate, stir, add 5.0g of calcium carbonate, control the temperature at 30-35°C, and drop (12.3g of N-ethylbis Oxypiperazinyl chlorid...

Embodiment 2

[0031] Embodiment 2 (after improvement)

[0032] 1) Take 14.2g (0.10mol) of N-ethyl dioxypiperazine, transfer it into a 500mL three-necked flask, stir, add 200mL of dichloromethane, cool down to -25~-20°C, and dropwise add 16.50g (0.152mol) of TMCS , temperature control -25~-20°C, add 12.0g (0.152mol) pyridine dropwise, add 0.02g DMAP, temperature control -25~-20°C, add 11.9g (0.04mol) triphosgene in batches, keep warm for 30-60 minutes, Suction filtration, washing with 30 mL of dichloromethane, distillation under reduced pressure to dryness, crystallization by adding 100 mL of n-hexane, suction filtration, drying to obtain 19.2 g of N-ethyldioxypiperazine chloride, yield 93.8%.

[0033] 2) Transfer 20.2g (0.05mol) of ampicillin into a 500mL three-necked flask, add 100mL of water and 150mL of ethyl acetate, stir, add 5.2g of calcium carbonate, control the temperature at 30-35°C, and drop (12.3g of N-ethylbis Oxypiperazinyl chloride + 100mL dichloromethane) solution, dripping ...

Embodiment 3

[0034] Embodiment 3 (after improvement)

[0035] 1) Take 14.2g (0.10mol) of N-ethyl dioxypiperazine, transfer it into a 500mL three-necked flask, stir, add 200mL of dichloromethane, cool down to -25~-20°C, add dropwise 16.0g (0.147mol) of TMCS , temperature control -25~-20℃, dropwise add 11.6g (0.147mol) pyridine, add 0.02g DMAP, temperature control -25~-20℃, add 11.9g (0.04mol) triphosgene in batches, keep warm for 30-60 minutes , filtered with suction, washed with 30 mL of dichloromethane, distilled to dryness under reduced pressure, added 100 mL of n-hexane for crystallization, filtered with suction, and dried to obtain 19.1 g of N-ethyldioxypiperazine chloride, with a yield of 93.5%.

[0036] 2) Transfer 20.2g (0.05mol) of ampicillin into a 500mL three-necked flask, add 100mL of water, 150mL of ethyl acetate, stir, add 5.3g of calcium carbonate, control the temperature at 35-40°C, add dropwise (12.3g of N-ethylbis Oxypiperazinyl chloride + 100mL dichloromethane) solution,...

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Abstract

The invention discloses a preparation method of piperacillin acid and aims to overcome the defect that existing preparation methods are low in N-ethyl dioxperazine conversion rate and the defect of high solvent consumption caused by the fact that the condensation step generates non-condensable gas-carbon dioxide. Pyridine is adopted to replace triethylamine as an acid binding agent, and 4-dimethylaminopyridine in a catalysis amount is added as an initiator before triphosgene is added during acylation reaction, so that reaction activity of triphosgene can be improved effectively, and conversionrate of N-ethyl dioxypiperazinyl chloride is increased by about 10%. During condensation reaction, binary weak alkali like calcium carbonate is used to replace unitary weak alkali-sodium hydrogen carbonate, so that reducing of degradation is facilitated, condensation reaction yield is increased about 5%, and yield of the non-condensable gas-carbon dioxide can be reduced by 50%.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of piperacillin acid. Background technique [0002] Piperacillin acid is a semi-synthetic semisynthetic benzyl antipseudomonal penicillin. Its chemical name: (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido )-2-phenylacetamido]-7-oxo-4-thia-1-nitrogen, molecular formula C 23 h 27 N 5 o 7 S, the structural formula is as follows: [0003] [0004] The sodium salt of piperacillin acid, piperacillin sodium (Piperacillin sodium), is a semi-synthetic penicillin antibiotic with broad-spectrum antibacterial effect, and exerts a 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...

Claims

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Application Information

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IPC IPC(8): C07D499/68C07D499/04
Inventor 孙政军樊长莹孙越李勇
Owner 山东安舜制药有限公司
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