A kind of preparation method of cefotiam hydrochloride

A technology of cefotiam hydrochloride, which is applied in the field of preparation of cefotiam hydrochloride, can solve the problems of low yield and product purity, difficult reaction control, and difficult operation, and achieve stable yield, easy expansion of production, and simple operation Effect

Active Publication Date: 2016-06-29
VALIANT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this method, hydrogen chloride gas is used, and the reaction is difficult to control, difficult to operate, and the yield is low
[0007] At present, domestic manufacturers of cefotiam hydrochloride preparations mainly rely on imported raw materials for sub-packaging. There are also domestic manufacturers producing this product, but the yield and product purity are relatively low

Method used

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  • A kind of preparation method of cefotiam hydrochloride
  • A kind of preparation method of cefotiam hydrochloride
  • A kind of preparation method of cefotiam hydrochloride

Examples

Experimental program
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Embodiment 1

[0041] The synthesis of embodiment 1FATA

[0042] 326.4g (0.8mol) Ac 2 O, 220.8g (4.8mol) HCOOH was added dropwise under stirring, the temperature was raised, and stirred at room temperature for 0.5h, the system was in a colorless and clear state. Add 126.4g (0.8mol) ATA, raise the temperature to 25°C, stir and react at 30-50°C for 4h, and the reaction solution changes from turbid to clear and then turbid again in about 1h. TLC monitored the reaction to be complete. Cool down in an ice-water bath, add 500g of water dropwise, and control the internal temperature to ≤35°C; add ammonia water dropwise to adjust the pH=2.8 to 3.0, control the internal temperature to ≤15°C, share 150.0g of deammonized water, and stir at 0 to 10°C for 0.5h. Suction filtration, washing with tap water (150g×3). -0.08~-0.09MPa, dried at 75°C for 10h, FATA was obtained as off-white solid 115.2g, yield 77.4%, HPLC purity 96.5%.

Embodiment 2

[0043] The synthesis of embodiment 2FATAA

[0044] Suspend 9.3g (0.05mol) of FATA in 93g of acetonitrile, cool down to -10~10°C, white suspension, add 6.5g (0.06mol) of ethyl chloroformate dropwise, stir and react at -10~10°C for 1h, the reaction solution It became slightly clear, and the reaction was monitored by TLC to complete. The acetonitrile solution of FATAA was directly put into the next step reaction, and the HPLC purity was 95.4%.

Embodiment 3F

[0045] The synthesis of embodiment 3FCEFO

[0046]15.7g (0.033mol) of 7-ACMT, 75g of acetonitrile, cooled to -10-10°C under N2 protection, 31.5g (0.17mol) of tri-n-butylamine was added dropwise, the light yellow suspension turned into a brown clear liquid. Add this liquid dropwise to the mixed anhydride prepared in "Example 2", control the internal temperature to ≤ -15°C, and complete the dropwise addition within 0.5h. Stir and react at -40~-20°C for 2h. Reaction system state: near white suspension → powdery white suspension → brownish yellow clear liquid → near white suspension. Suction filtration, washing with cold acetonitrile (20g×2; -20~-15℃), washing with acetone (20g×1). -0.08~-0.09MPa, dried at 35°C for 5h, FCEFO was obtained as off-white solid 16.8g, yield 68.6%, HPLC purity 99.4%.

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Abstract

The invention relates to a preparation method of cefotiam hydrochloride. ATA is adopted as a raw material. The method includes: performing formylation, and activation by mixed anhydride formation to obtain FATAA, docking the FATAA with 7-ACMT to obtain FCEFO, and performing deformylation to obtain the target compound cefotiam hydrochloride (CEFO). The preparation method has characteristics of cheap and easily available raw materials, mild and safe reaction conditions and simple post-processing operation, and is prone to industrial scale-up and production. The purity of the product of the preparation method can be higher than 97%.

Description

technical field [0001] The invention relates to a preparation method of cefotiam hydrochloride, which belongs to the field of drug antibiotics. Background technique [0002] Cefotiam hydrochloride (cefotiam), chemical name: (6R-trans)-7-[[(2-amino-4-thiazolyl)acetyl]amino]-3-[[1-[2-(di Methylamino)ethyl]-1H-tetrazol-5-yl]thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- Carboxylic acid dihydrochloride, molecular formula: C 18 h 23 N 9 o 4 S 3 , molecular weight: 598.6, structural formula: [0003] [0004] Cefotiam is a second-generation semi-synthetic cephalosporin antibiotic developed by Takeda Pharmaceutical Co., Ltd., and first launched in Japan in 1981. The effect of this product on gram-positive bacteria is close to that of cefazolin, and it has better effects on gram-negative bacteria, such as Haemophilus, Escherichia coli, Klebsiella, Proteus mirabilis, etc. Acid bacilli, indole-positive proteus, etc. also have antibacterial effects. Clinical use o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/06C07D501/36
CPCC07D501/04C07D501/36
Inventor 杨光李忠孙蕊李炬陈新林华强
Owner VALIANT CO LTD
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