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Synthetic method of cefdinir activated thioester

A technology of active thioesters and cefdinir, which is applied in the field of synthesis of cefdinir active thioesters, can solve the problems of difficult removal of crystal water, unstable product quality, and difficult control, etc., so that the use of less types of solvents is beneficial to large Large-scale production, the effect of easy pH control

Active Publication Date: 2016-04-20
SHANDONG JINCHENG KERUI CHEMICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0007] At present, the most commonly used water-phase solvent for large-scale production of cefdinir active thioester is obtained through hydrolysis, then acylation, acid adjustment, dehydration, and condensation process. The pH is difficult to control, the water of crystallization is difficult to remove, and the product quality is not good. Stable, low purity, producing a lot of waste water, not conducive to environmental protection and other disadvantages

Method used

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  • Synthetic method of cefdinir activated thioester

Examples

Experimental program
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Effect test

Embodiment 1

[0039] At room temperature, take a clean three-neck flask, add 50g (0.23mol) of ethyl demethylaminothiaxate, add 350ml of methanol, 50ml of DMF, stir for 30min, then add 19.5g (0.35mol) of potassium hydroxide, add 4.2g (0.23mol) of water , stirred, and reacted at 25°C for 2h;

[0040] Add 28.4g (0.28mol) of acetic anhydride dropwise to the reaction solution, react at 40°C for 1h, cool down to below 5°C, and filter with suction to obtain an adduct with the aprotic polar solvent DMF;

[0041] Add the adduct into the three-necked flask, add 300ml of dichloromethane, then add DM85g (0.26mol), add 50.2g (0.27mol) of triethyl phosphite dropwise at 18±2°C, take 1.5h, cool down to below 7°C, Suction filtration and vacuum drying at 40° C. for 4 hours gave 63 g of cefdinir active thioester with a molar yield of 71.8% and a purity of 99.05%.

Embodiment 2

[0043] At room temperature, take a clean three-neck flask, add 50g (0.23mol) of ethyl demethylaminothiaxate, add 545ml of ethanol, 55ml of DMAC, stir for 30min, then add 19.5g (0.35mol) of potassium hydroxide, add 4.2g (0.23mol) of water , stirred, and reacted at 25°C for 4h;

[0044] Add 28.4g (0.28mol) of acetic anhydride dropwise to the reaction solution, react at 40°C for 1 hour, cool down to below 5°C, and filter with suction to obtain the adduct with aprotic polar solvent DMAC;

[0045] Add the adduct into the three-necked flask, add 700ml of acetonitrile, then add DM100.4g (0.30mol), add 65.6g (0.40mol) of triethyl phosphite dropwise at 18±2°C, take 3h, cool down to below 7°C, pump Filtration, vacuum drying at 40°C for 4 hours, 63.5 g (0.40 mol) of cefdinir active thioester was obtained, the molar yield was 72.3%, and the purity was 99.03%.

Embodiment 3

[0047] At room temperature, take a clean three-necked flask, add 50g (0.23mol) of ethyl demethylthioxamate, add 200ml of isopropanol, 100ml of DMF, stir for 30min, then add 11.2g (0.28mol) of sodium hydroxide, add 8.3g (0.46mol ) water, stirred, and reacted at 25°C for 2h;

[0048] Add 20.4g (0.20mol) of acetic anhydride dropwise to the reaction solution, react at 42°C for 1h, cool down to below 5°C, and filter with suction to obtain the adduct with the aprotic polar solvent DMF;

[0049] Add the adduct into the three-necked flask, add 600ml of toluene, then add DM100.4g (0.30mol), add 65.6g (0.40mol) of triethyl phosphite dropwise at 18±2°C, take 2h, cool down to below 7°C, pump Filtration, vacuum drying at 38° C. for 4 hours, to obtain 63.5 g of cefdinir active thioester, with a molar yield of 72.3% and a purity of 99.10%.

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Abstract

The invention belongs to the field of drug synthesis, and in particular relates to a synthetic method of cefdinir activated thioester. The synthetic method comprises the following steps: in a mixed solvent consisting of alcohol and an aprotic polar solvent, adding ethyl demethylaminothiazolyloximate and inorganic base, reacting, then dropwise adding acetic oxide, carrying out a reaction, carrying out cooling and suction filtration after the reaction is completed to obtain an adduct of 2-(2-aminothiazole-4-yl)-2-acetyloxy imino acetate and the aprotic polar solvent; putting the adduct and DM into an organic solvent, dropwise adding triethyl phosphate, carrying out an esterification reaction, cooling and suction filtration to obtain the cefdinir activated thioester. The mixed solvent is adopted in the acylation process, the pH value is easily controlled, a hydrolysis and the acylation process is realized through a one-step reaction; the acylate is the adduct without containing crystal water, so that the processes of water-phase acid forming and crystal water removal are avoided; the activated process of catalyst adding in the condensation process is omitted, and the technological process is simplified; the synthetic method is high in yield, high in product purity and low in cost, and is beneficial for large-scale production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing cefdinir active thioester. Background technique [0002] Cefdinir active thioester, chemical name: (Z)-2-(2-aminothiazol-4-yl)-2-acetoxyiminothioacetic acid (S-2-benzothiazole) ester, referred to as CAEM , the molecular formula is: C 14 h 10 o 3 N 4 S 2 Molecular weight: 378, molecular structure: [0003] [0004] CAEM is an important raw material for the production of the third-generation cephalosporin cefdinir. Compared with the acyl chloride method, the synthesis of cefdinir by the active ester method reduces the probability of isomerization during the acylation reaction and reduces the generation of impurity E-isomers. At present, (Z)-2-(2-aminothiazol-4-yl)-2-acetoxyiminothioacetic acid (S-2-benzothiazole) ester is gradually used abroad and domestically to replace (Z)-2 -(2-aminothiazol-4-yl)-2-trityloxyiminoacetic acid (2-mercaptobenzothiazo...

Claims

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Application Information

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IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor 张强王辉王君伟周忠玉郑莹
Owner SHANDONG JINCHENG KERUI CHEMICAL CO LTD
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