Preparation methods of high-purity cefotiam hexetil and dihydrochloride of high-purity cefotiam hexetil

A technology of cefotiam and cefotiam, which is applied in the field of preparation of high-purity cefotiam and its dihydrochloride, can solve problems such as being unsuitable for industrialized large-scale production, unsuitable for industrialized large-scale production, and high in product impurities. problem, to achieve the effect of small impurities, simple and easy preparation method, and high purity

Active Publication Date: 2011-03-30
LIVZON PHARM GRP INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Using the preparation method reported in this document, although the preparation method can control the by-products, especially the isomer Δ 2 content, but the yield is low, only 20%; and the post-treatment is more cumbersome, and requires column processing, so it is not su

Method used

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  • Preparation methods of high-purity cefotiam hexetil and dihydrochloride of high-purity cefotiam hexetil
  • Preparation methods of high-purity cefotiam hexetil and dihydrochloride of high-purity cefotiam hexetil
  • Preparation methods of high-purity cefotiam hexetil and dihydrochloride of high-purity cefotiam hexetil

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Embodiment 1

[0038] The preparation of embodiment 1 high-purity cefotiam

[0039] Add DMA (160ml) to a 500ml reaction flask, add cefotiam potassium (20g, 0.035mol), stir until completely dissolved, cool to -5°C, add anhydrous potassium carbonate (4.84g, 0.035mol), add carbonic acid- 1-iodoethyl cyclohexyl ester (21.14g, 0.07mol), stir until the reaction is complete, add 700ml of ethyl acetate to the reaction solution, add 350ml of purified water, let stand to separate layers, add 0.5mol / L hydrochloric acid solution 140ml of aqueous solution, stirring, standing for stratification, adding 700ml of ethyl acetate (a benign solvent), adjusting the pH value to 6.0 with 2% sodium bicarbonate solution, then standing for stratification, and drying the organic layer with anhydrous magnesium sulfate and activated carbon Remove impurities, filter, concentrate the filtrate, add 74ml of methanol (good solvent) to the residue, add 400ml of isopropyl ether (crystallization solvent), stir and crystallize ...

Embodiment 2

[0042] The preparation of embodiment 2 high-purity cefotiam

[0043] Add DMA (160ml) to a 500ml reaction flask, add cefotiam sodium (20g, 0.035mol), stir until completely dissolved, cool to 0°C, add anhydrous potassium carbonate (7.26g, 0.053mol), add carbonic acid-1 - Iodoethyl cyclohexyl ester (21.14g, 0.07mol), after stirring until the reaction is complete, add 700ml of ethyl acetate to the reaction solution, add 350ml of purified water, let stand to separate layers, add 140ml of 0.5mol / L hydrochloric acid solution Aqueous solution, stirring, static layering, adding 700ml of ethyl acetate, adjusting the pH value to 5.8-6.5 with 2% sodium bicarbonate solution, then static layering, the organic layer was dried with anhydrous magnesium sulfate and activated carbon to remove impurities, Filtrate, concentrate the filtrate, add 74ml of methanol to the residue, add 400ml of isopropyl ether, stir and crystallize at 15-20°C for 2h, filter, wash the filter cake with isopropyl ether, ...

Embodiment 3

[0046] The preparation of embodiment 3 high-purity cefotiam axetil

[0047] Add 14 g of the above-prepared cefotiam to the reaction bottle, add 42 ml each of methanol and acetone, dissolve, add 300 ml of isopropyl ether, stir and crystallize at 15-20 ° C for 2 hours, filter to obtain 12 g of white cefotiam, Yield 85.7%.

[0048] Detected by HPLC: purity 99.3%; Δ 2 Isomers: 0.5%.

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Abstract

The invention provides a method for preparing high-purity cefotiam hexetil as shown in formula (I). The method is as follows: cefotiam hydrochloride taken as a raw material reacts with carbonic acid-1-iodine ethyl ester cyclohexyl in an organic solvent in the presence of carbonates to obtain the high-purity cefotiam hexetil. The invention also provides a method for preparing dihydrochloride of the cefotiam hexetil, comprising the following steps: the cefotiam hexetil is dissolved in a reaction solvent containing hydrogen chloride and a devitrification solvent to carry out crystallization for 1-2h at the temperature of 5-30 DEG C. The methods of the invention are simple and practicable, are suitable for industrial production, special equipment is not required, and the cost is low; and the cefotiam hexetil and the dihydrochloride of the cefotiam hexetil have high purity, low impurity content and high yield.

Description

technical field [0001] The invention belongs to the field of antibiotic drugs, and in particular relates to a preparation method of high-purity cefotiam and dihydrochloride thereof. Background technique [0002] Cefotiam hexetil (Cefotiam hexetil, formula I), chemical name is: (6R, 7R)-7-[2-(2-aminothiazol-4-yl) acetamido]-3-[[[1-[2 -(N,N-Dimethylamino)ethyl]-1H-tetrazol-5-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0 ] Oct-2-ene-2-carboxylic acid 1-(cyclohexaneoxycarbonyloxy) ethyl ester, developed by Takeda Corporation of Japan, was listed in Japan by Takeda Corporation under the trade name Taketiam in 1990, and was launched in France in 1994 The company Sanofi-Aventis markets it under the trade name Texodil. It is currently available in the Philippines and South Korea. [0003] Cefotiam is an oral antibiotic obtained by converting cefotiam for injection (formula III) or its salt (formula II) with 1-iodoethyl cyclohexyl carbonate (formula IV). This product itself has...

Claims

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Application Information

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IPC IPC(8): C07D501/36C07D501/04
Inventor 周月广毛文金闫松吴起娟陈剑
Owner LIVZON PHARM GRP INC
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