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Preparation method of cefotiam hexetil hydrochloride

A technology of cefotiam and cefotiam, applied in the field of drug antibiotics, can solve the problems of unsuitability for large-scale industrial production, complex post-processing operations of products, high by-products, etc., and achieve the effect of low production cost, short time and long time

Inactive Publication Date: 2010-01-06
余小强
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Problems solved by technology

[0007] A kind of method for preparing cefotiam axetil by reaction of cefotiam potassium and -1-iodoethyl cyclohexyl carbonate in DMF is given in the document (THE JOURNAL OF ANTIDIOTICS VOL.XXXIX NO.9,1986), but the The yield of the preparation method is low, and the obtained by-products are especially the isomer Δ 2 Relatively high, more than 2% of the standard stipulated in the Japanese Pharmacopoeia
[0008] Document (THE JOURNAL OF ANTIDIOTICS VOL.XL NO.1, 1986) also provides a kind of method for preparing cefotiam axetil by reacting cefotiam potassium and -1-iodoethyl cyclohexyl carbonate in DMF, and Ability to control by-products especially isomers Δ 2 content, but this method still has the problem of low yield (the yield is only 20%) and the product post-treatment operation is complicated and requires column treatment, which is not suitable for industrialized large-scale production

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  • Preparation method of cefotiam hexetil hydrochloride
  • Preparation method of cefotiam hexetil hydrochloride
  • Preparation method of cefotiam hexetil hydrochloride

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Embodiment 1

[0044] The preparation of embodiment 1 cefotiam hydrochloride

[0045] The preparation method of the present embodiment cefotiam axetil hydrochloride, its concrete steps are as follows:

[0046] (1) Add 500ml of methanol into a 2000ml reaction bottle, cool down to -2°C, add 50g (0.084mol) of cefotiam hydrochloride, and dissolve to obtain a methanol solution of cefotiam hydrochloride; at the same time, dissolve potassium acetate into the methanol solution 5% methanol solution of potassium acetate was prepared in the method; 250ml (0.105mol) of 5% methanol solution of potassium acetate was taken, and slowly added dropwise to the methanol solution of cefotiam hydrochloride, the drop was completed within 1 hour, stirred for 30min, and 500ml of Propanol, stirred for 1 hour, crystallized at -5°C for 1 hour, filtered, and the filter cake was dried in a vacuum oven at 40°C until constant weight to obtain 39.4 g of cefotiam potassium salt;

[0047] (2) Add DMF (200ml) to a 500ml react...

Embodiment 2

[0052] The preparation of embodiment 2 cefotiam hydrochloride

[0053] The preparation method of the present embodiment cefotiam axetil hydrochloride, its concrete steps are as follows:

[0054] (1) Add 500ml of methanol into a 2000ml reaction flask, cool down to -2°C, add 50g (0.084mol) of cefotiam hydrochloride, and dissolve to obtain a methanol solution of cefotiam hydrochloride; at the same time, dissolve sodium acetate into the methanol solution Prepare 5% sodium acetate methanol solution; take 200ml of 5% sodium acetate methanol solution, slowly add it dropwise to cefotiam hydrochloride methanol solution, drop it within 1 hour, stir for 30min, add 500ml isopropanol, stir 1h, placed at -5°C for crystallization for 1 hour, filtered, and dried the filter cake in a vacuum oven at 40°C to constant weight to obtain 41.6g of cefotiam potassium salt;

[0055] (2) Add 200ml of DMF to a 500ml reaction bottle, cool down to 3°C, add 20g (0.035mol) of cefotiam potassium, stir until ...

Embodiment 3

[0060] The optimization of embodiment 3 extraction conditions

[0061] A preparation method of cefotamate hydrochloride, the method may further comprise the steps:

[0062] (1) cefotiam and acetate react to prepare cefotiam salt;

[0063] (2) the cefotiam salt prepared by step (1) is subjected to an esterification reaction with 1-iodoethyl cyclohexyl carbonate in the presence of potassium carbonate;

[0064] (3) After the esterification reaction of step (2) ends, add an organic solvent to the reaction solution, keep the organic solvent layer after extraction; add hydrochloric acid to the organic solvent layer, and collect the hydrochloric acid layer after extraction;

[0065] (4) The pH of the hydrochloric acid layer obtained in step (3) is adjusted to weak acidity, then extracted with an organic solvent, and the organic layer extract is collected;

[0066] (5) Crystallize and filter the organic layer extract obtained in step (4) to obtain cefotiam axetil hydrochloride.

[...

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Abstract

The invention discloses a preparation method of cefotiam hexetil hydrochloride, comprising the following steps: carrying out reaction on cefotiam an acetate to prepare cefotiam salt; carrying out reaction on the cefotiam salt and carbonic acid-1-iodine ethyl ester cyclohexyl to prepare cefotiam hexetil in the presence of potassium carbonate; and crystallizing and purifying the obtained cefotiam hexetil to prepare and obtain the cefotiam hexetil hydrochloride. The preparation method has simple operation in the preparation process; in particular the part of purifying the reaction product mainly adopts the combination of extraction and crystallization to obtain the finished product with high purity and good yield without being purified by chromatographic column. The prepared cefotiam hexetil hydrochloride has high purity, and is detected to have less than 3 percent of total impurity and less than 6 percent of the related impurity in the Japanese pharmacopeia according to the HPLC method, therefore, the prepared product is superior to the standard of the Japanese pharmacopeia. The yield of the prepared cefotiam hexetil is about 60 percent with low production cost, therefore, the invention is favorable for industrialized production.

Description

technical field [0001] The invention relates to the field of drug antibiotics, in particular to the preparation of cefotiam, in particular to a preparation method of cefotiam hydrochloride. Background technique [0002] Cefotiam (CTM) is the second generation cephalosporin, and its structural formula is as shown in formula (I), and cefotiam ethyl esterification can obtain cefotiam hexatil (Cefotiam hexetil), and its structural formula is as shown in formula (II) Show. [0003] [0004] Cefotiam can be made into oral antibiotics. The oral antibiotics themselves have no antibacterial effect. After oral administration, they are quickly hydrolyzed into cefotiam in the intestinal mucosa and absorbed. Cefotiam has the same antibacterial activity against Gram-positive and negative bacteria as The previous oral cephalosporins are the same, and are stable to β-lactamase, and are effective against clinically isolated Staphylococcus aureus, coagulase-negative staphylococcus, Strept...

Claims

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Application Information

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IPC IPC(8): C07D501/36C07D501/04C07D501/12
Inventor 余小强
Owner 余小强
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