Synthesis of D(-)-alpha-(4-ethyl-2,3-dioxygen ethylene imine-1-formamido) p-hydroxybenzene acetic acid

A technology of p-hydroxyphenylacetic acid and p-hydroxyphenylglycine, which is applied in the synthesis field of D-α-p-hydroxyphenylacetic acid, can solve the problem of increasing reaction equipment and processing steps, increasing reaction raw materials and reaction steps, and increasing the ease of trimethylchlorosilane. Moisture absorption and decomposition and other problems, to achieve the effect of simplifying the production process, reducing consumption, and being environmentally friendly

Active Publication Date: 2009-08-19
山西新天源药业有限公司
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above synthesis process, 1, in order to make the reaction easy to carry out, it is necessary to use trimethylchlorosilane as an amino activator and carboxyl, hydroxyl protecting agent, which increases the reaction raw materials and reaction steps, and increases the production cost; 2, the reaction ends Finally, the by-product hexamethyldisiloxane generated by the hydrolysis of trimethylchlorosilane and the by-product triethylamine hydrochloride of the acid-binding agent all need to be recovered, which increases the reaction equipment and processing steps; 3, trimethylchlorosilane It is very easy to absorb moisture and decompose, and the synthesis reaction needs to be carried out under anhydrous conditions, which requires high reaction equipment and complicated operation

Method used

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  • Synthesis of D(-)-alpha-(4-ethyl-2,3-dioxygen ethylene imine-1-formamido) p-hydroxybenzene acetic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Add 150g of p-hydroxyphenylglycine and 700mL of water into a 1000mL reaction flask, and adjust the pH value to 7.5 with 10% sodium hydroxide solution to clarify the solution. Cool the solution to 5°C, add 187.5g of 4-ethyl-(2,3-dioxopiperazinyl)formyl chloride-1 in batches, and maintain the pH of the system at 7.5 with solid sodium carbonate during the addition Between ~8, it takes about 2h to finish adding. After adding the materials, the reaction was continued at 5° C. for 2 h. After the reaction, add activated carbon for decolorization, and then adjust the pH of the reaction solution to 2 with 6mol / L hydrochloric acid solution, and white crystals are precipitated, filtered and dried to obtain D(-)-α-(4-ethyl-2,3- Dioxypiperazine-1-carboxamido)p-hydroxyphenylacetic acid (HO-EPCP) pure product 274.2g, yield 91%.

[0019] The content of HO-EPCP determined by HPLC method was 99.89%.

[0020] The characterization of the HO-EPCP product obtained by the reaction:

[002...

Embodiment 2

[0028] Add 150g of p-hydroxyphenylglycine and 650mL of water into a 1000mL reaction flask, and adjust the pH value to 7.5-8 with 10% potassium hydroxide solution to clarify the solution. Cool the solution to 2°C, add 190.21g of 4-ethyl-(2,3-dioxopiperazinyl)formyl chloride-1 in batches, and maintain the pH of the system at 7.5 with solid sodium carbonate during the addition Between ~8, it takes about 2h to finish adding. After adding the materials, the reaction was continued at 2 °C for 5 h. After the reaction, add activated carbon for decolorization, and then use 6mol / L hydrochloric acid solution to adjust the pH of the reaction solution to 1.5. White crystals are precipitated, filtered and dried to obtain 275.7g of pure HO-EPCP with a yield of 91.5%.

[0029] The detection content is 99.88%, the specific rotation .

Embodiment 3

[0031] Add 150g of p-hydroxyphenylglycine and 800mL of water into a 1000mL reaction flask, and adjust the pH value to 8-9 with 10% sodium hydroxide solution to clarify the solution. Cool the solution to 0-2°C, add 190.21g of 4-ethyl-(2,3-dioxopiperazinyl)formyl chloride-1 in batches, and maintain the pH of the system with solid sodium carbonate during the addition Between 7.5 and 8, it takes about 2 hours to finish adding. After adding the material, keep it at 0-2°C and continue the reaction for 3h. After the reaction, add activated carbon for decolorization, and then use 6mol / L hydrochloric acid solution to adjust the pH of the reaction solution to 1.9. White crystals are precipitated, filtered and dried to obtain 271.2 g of pure HO-EPCP with a yield of 90%.

[0032] The detection content is 99.95%, the specific rotation .

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Abstract

The invention provides a synthetic method of D(-)-alpha-(4-ethyl-2,3-dioxypiperazine-1-formamido) p-hydroxyphenylacetic acid. In the synthetic method, p-hydroxyphenylglycine is taken as a starting material, water is taken as a solvent, the p-hydroxyphenylglycine react with 4-ethyl-(2,3-dioxopiperazinyl)formyl chloride-1 in the presence of alkali to directly obtain a target product D(-)-alpha-(4-ethyl-2,3-dioxypiperazine-1-formamido)p-hydroxyphenylacetic acid after acidification. Hydroxyl protection and carboxyl protection of the p-hydroxyphenylglycine are not needed in the synthetic method, and condensation reaction can be directly carried out in aqueous phase, which simplifies the production process and reduces the consumption, and the prepared target product has stable quality.

Description

technical field [0001] The invention relates to a synthesis method of D(-)-α-(4-ethyl-2,3-dioxypiperazine-1-carboxamide) p-hydroxyphenylacetic acid (HO-EPCP), which is used as a medicine The intermediate is mainly used for synthesizing the β-lactam antibiotic cefoperazone, and belongs to the technical field of chemical and pharmaceutical intermediates. Background technique [0002] Cefoperazone is the third generation of cephalosporin antibiotics. It has the characteristics of high efficiency and broad spectrum, low toxicity and enzyme resistance. It is effective against Gram-positive bacteria and negative bacteria. It is suitable for various infections caused by cefoperazone-sensitive bacteria. Wide range of applications. [0003] D(-)-α-(4-ethyl-2,3-dioxypiperazine-1-carboxamide) p-hydroxyphenylacetic acid (HO-EPCP) is an important intermediate in the synthesis of cefoperazone. To synthesize cefoperazone, the production process is mature, the yield is high and the qualit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/18
Inventor 苏斌林陈万成高志伟褚丕明苏蔚康福堂
Owner 山西新天源药业有限公司
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