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HO-EPCP synthesizing method

A technology of HO-EPCP and synthesis method, which is applied in the fields of medicine and chemical industry, and can solve the problems of liquid phosgene transportation and storage hazards, etc.

Inactive Publication Date: 2004-06-30
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the dosage of expensive oxygen piperazine has to be doubled, and the transportation and storage of liquid phosgene are still quite dangerous

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0022] Dissolve 12.0 g of 4-ethyl-2,3-dioxopiperazine in 60 ml of CH 2 Cl 2 12.0 g of trimethylsilyl was added, and 10.0 g of triethylamine was added dropwise at -10°C. After the addition, the reaction was continued at this temperature for 2 hours to obtain siliconized oxygen piperazine (I).

[0023] Dissolve 10.0 g of triphosgene in 40 ml of CH 2 Cl 2 Add 1.0 g of triethylamine as an initiator, add (I) dropwise to the triphosgene solution within 2 hours at about -10°C, and gradually rise to room temperature after adding, this is oxypiperazine chloride (II) .

[0024] Add 12.0 g of p-hydroxyphenylglycine to 150 ml of CH 2 Cl 2 23.2 g of triethylamine was added under stirring, then 26.3 g of trimethylsilane was added dropwise at 10-15°C, and the reaction was continued for 2 hours after the addition was complete. This is siliconized p-hydroxyphenylglycine (III).

[0025] (II) was dripped into (III) at 15-20° C., and the reaction was continued for 3 hours. 200 ml of disti...

Embodiment 2

[0028] With 60.0 grams of piperazine under the same conditions of example 1, carry out silicon esterification with trimethylsilyl and triethylamine to obtain (I), add (I) to 50.0 grams of triphosgene in 3 hours at -15~-20 ℃ 200mlCH 2 Cl 2 In the solution, (initiated by adding 3.5 g of triethylamine in advance) after the addition, the stirring was continued for 2 hours, and gradually rose to room temperature to obtain (II).

[0029] In addition, 60.0 g of p-hydroxyphenylglycine was silicon-esterified under the same conditions as in Example 1 to obtain (III). The remaining operations were the same as in Example 1 to obtain 94.8 g of crude product HO-EPCP with a yield of 98.3%.

[0030] After refining, 86.2 g of white crystals were obtained, the HO-EPCP content was 99.97%, the yield was 89.4%, the melting point was 215.3-216.3°C, and the specific rotation α=-90.78°.

Embodiment 3

[0031] Embodiment 3 (contrast)

[0032] Dissolve 12.0 g of 4-ethyl-2,3-dioxypiperazine in 60 ml of CH 2 Cl 2 Add 12.0 grams of trimethylsilane, add 10.0 grams of triethylamine dropwise at -10°C, continue to stir at this temperature for 2 hours after the addition, gradually rise to 0°C, remove the Et produced by the reaction by filtration 3 N·HCl to obtain a siliconized oxygen piperazine solution (I).

[0033] Dissolve 10.0 g of triphosgene in 40 ml of CH 2 Cl 2 , without adding an initiator, directly drop (I) at about -10°C, and gradually rise to room temperature to obtain (II) after the addition. All the other operations are the same as in Example 1. 10.82 g (crude product) of HO-EPCP was obtained with a yield of 44.9%.

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Abstract

The present invention relates to a method for synthesizing HO-EPCP, i.e. D-(-)-alpha-(4-ethyl-2,3-dioxygen substituted piperazine-1-methanamide) P-hydroxyphenylacetic acid. Said invention uses solid phosgene, i.e. triphosgene as acyl chloridization reagent instead of gas phosgene so as to overcome the defects of high-poison phosgene, large dose and difficult operation. Besides, an initiating agent is added in the triphosgene so as to make the stable triphosgene solution be formed into a stable phosgene source in the reaction, and can close-quantitatively obtain 4-ethyl-2,3-dioxygen substituted piperazine acryl chloride, and further can obviously raise yield of HO-EPCP. The yield of the crude product HO-EPCP is greater than 95%, after it is refined, the crystal HO-EPCP can be obtained, its content is greater than 99.0% and its yield is greater than 85.0%.

Description

technical field [0001] The invention relates to a synthesis method of HO-EPCP, which belongs to the fields of chemical industry and medicine. Background technique [0002] HO-EPCP is the abbreviation of D(-)-α-(4-Ethyl-2,3-dioxopiperazine-1-Carbox-amido-P-Hydroxyphenylacetic acid, the Chinese name D(-)-α-(4-ethyl- 2,3-dioxopiperazine-1-carboxamide) p-hydroxyphenylacetic acid, its structure is as follows: [0003] [0004] HO-EPCP is an important intermediate for the synthesis of the third-generation cephalosporin-cefoperazone. It is usually synthesized in two steps: firstly, oxypiperazine chloride is synthesized, and then it is further condensed with silicon-esterified p-hydroxyphenylglycine and hydrolyzed. [0005] Jp 106883 / 77 reports the reaction of phosgene and 4-ethyl-2,3-dioxopiperazine to obtain oxypiperazine chloride. In this way, HO-EPCP was further synthesized with a yield of about 70%. However, phosgene is highly toxic, and the dosage is large (generally sev...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/04
Inventor 陆庆宁高永红赵洪生陶建伟
Owner SHANGHAI INST OF TECH
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