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Preparation method for ceftizoxime alapivoxil, intermediates thereof and preparation method for intermediates

A technology of cefizoxime propiproxil and esterification, which is applied in the field of preparation of intermediates and intermediates, and can solve the problems of high cost, harsh reaction conditions and the like

Active Publication Date: 2015-11-04
ZHEJIANG YONGNING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Using 7-ANCA as the raw material, the amino group and carboxyl group need to be protected first, and it is applied to highly toxic reagents such as phosphorus oxychloride, which requires low temperature operation, high cost, and harsh reaction conditions.

Method used

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  • Preparation method for ceftizoxime alapivoxil, intermediates thereof and preparation method for intermediates
  • Preparation method for ceftizoxime alapivoxil, intermediates thereof and preparation method for intermediates
  • Preparation method for ceftizoxime alapivoxil, intermediates thereof and preparation method for intermediates

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Experimental program
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Effect test

Embodiment 1

[0075] Synthesis of BOC-alanylaminothioxime acetate (1c): Weigh 60 g (0.32 mol) of BOC-alanine and add it to 840 ml of ether, stir and dissolve, then cool down to -15°C, and add four drops within 30 minutes. 35.376 g (0.35 mol) of methylguanidine, and 36.16 g (0.33 mol) of ethyl chloroformate were added dropwise. After the dropwise addition, stir for 2 hours, add 65.52 g (0.29 mol) of ethyl aminothioxime acetate, continue the reaction for 1 hour, then raise the temperature to -5°C and stir for 20 hours. After the reaction, wash with 300ml of 1N HCl and 200ml of saturated saline. The organic layer was dried and concentrated to dryness under reduced pressure. After vacuum drying, 84 g of light yellow BOC-alanylaminothioxime acetate (1C) solid was obtained, with a yield of 128.21% and a purity of 99.27%.

[0076] Embodiment 2-10 according to the method for embodiment 1, raw and auxiliary material molar ratio is also the same as embodiment 1:

[0077]

Embodiment 11

[0079] The hydrolysis of BOC-alanylaminothioxime acetate (1c): Weigh the BOC-alanylaminothioxime acetate (1c) 84g (0.21mol) that step 1 makes and join in 62.5ml methanol, Then add 2N NaOH400ml, stir to dissolve, and continue to stir for 8 hours. After the reaction, concentrated hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 8.5, methanol was evaporated to dryness, then 250ml of water and 300ml of dichloromethane were added to the reaction solution for extraction, the layers were left to stand, and the collected water layer was adjusted to pH 8.5 with 3N HCl. The pH was reached to 0.8, stirred rapidly for 1 hour, filtered, and the filter cake was dried to obtain 78.47 g of white BOC-alanylaminothioxime acetic acid (2a) as a solid (93.41% yield) with a purity of 98.83%.

Embodiment 12

[0081] Preparation of active ester Ⅰ (3a): Weigh 40 g (0.11 mol) of BOC-alanylaminothioxime acetic acid (2a) and 22.83 g (0.15 mol) of 1-hydroxybenzotriazole (HOBT), and add In 175ml of dimethylformamide (DMF), stir until dissolved at 20°C, then add 41.09g of dicyclohexylcarbodiimide (DCC) dropwise within 40 minutes, stir for 1 hour after adding, filter, 20ml of dimethylformamide Amide (DMF) washes the filter cake, combines the filtrate, adds water 120ml, separates out a large amount of solids, filters, and a small amount of dimethylformamide (DMF) solution (DMF:H 2 O=1:3) washed the filter cake and dried in vacuum to obtain 49.87 g (yield 124.68%) of light yellow active ester I (3a) solid with a purity of 98.22%.

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Abstract

The present invention discloses a preparation method for ceftizoxime alapivoxil by using a mixture anhydrides method, intermediates 3a / 3b / 3c thereof and a preparation method for the intermediates . The method comprises: putting an ammonia cefotaxime acid ester compound in an organic solvent to react with BOC-alanine by using a mixture anhydrides method; hydrolyzing under condition of organic alcohol; generating intermediates 3a / 3b / 3c; the intermediates 3a / 3b / 3c condensation reacting with 7-ANCA in an organic solvent; generating BOC-alanyl ceftizoxime acid by esterification; the BOC-alanyl ceftizoxime acid reacting with halogenated pentanoic acid methyl ester in the presence of an acid-binding agent, to prepare BOC-alanyl ester ceftizoxime valproate; removing a BOC protection group; and after concentrating, obtaining the target compound ceftizoxime alapivoxil by crystal precipitation in the organic solvent. The preparation method for ceftizoxime alapivoxil has the advantages that raw materials are readily available, the reaction condition is mild, byproducts are fewer, purity is reliable, the yield is high, and the preparation method for ceftizoxime alapivoxil is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a method for preparing ceftizoxime propivoxil by a mixed acid anhydride method, an intermediate and a preparation method of the intermediate. Background technique [0002] Ceftizoxime propivoxil is a bifunctional oral prodrug of ceftizoxime for injection developed by Kyoto Pharmaceutical Company in Japan. It has a broad-spectrum antibacterial effect on Gram-negative bacteria and Gram-positive bacteria. Enzymes are stable. Its structure is characterized by the addition of fat-soluble groups and water-soluble groups, with balanced fat-soluble and water-soluble (fat-water partition coefficient is 1.5), which is conducive to its absorption in the intestinal tract, not only improves the oral absorption rate, but also reduces the The dosage is high, and it has high sweetness and low toxicity, so it is suitable for children. [0003] At present, the synthesis of ceftizoxime propivoxil mainly contains the following three approaches: ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/20C07D501/04C07D417/06
CPCC07D417/06C07D501/04C07D501/20
Inventor 叶天健陈鑫杨宏全洪亮袁尤挺许长红
Owner ZHEJIANG YONGNING PHARMA
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