Preparation method of cefotiam hydrochloride

A technology of cefotiam hydrochloride and hydrochloric acid, which is applied in the field of preparation of cefotiam hydrochloride, can solve the problems that halogenated reagents will pollute the air, acid chloride intermediates are easy to hydrolyze, and are not conducive to industrial production, and achieve high product yield and purity, Fewer by-products and the effect of increasing the total yield of the product

Active Publication Date: 2019-03-26
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Process 1: React aminothiazole acetic acid with a halogenating reagent to produce an activated acid chloride intermediate, and then react with 7-ACA for 7-position acylation. This process requires that the 7-position acylation reaction has strict requirements for low temperature reactions, and the acid chloride intermediate It is easy to hydrolyze, and the addition method must be strictly controlled. In addition, because the acid chloride intermediate is in a slightly soluble state, a solid-liquid two-phase reaction occurs with 7-ACA, which affects the yield of the acylation step and the total yield of the final product.
The halogenated reagents used will pollute the air, which is not conducive to industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0021] Preparation of compound Ⅱ

[0022] 51.97g (0.3mol) of 1-(2-dimethylaminoethyl)-1,2,3,4-tetrazole-5-thiol (DMMT), boron trifluoride-acetonitrile (0.6mol, according to Calculated by boron trifluoride), 200ml of acetonitrile, and 150ml of butanol were added to the reaction tank, and the temperature was controlled at 0-5°C, and 81.68g (0.3mol) of 7-ACA was slowly added dropwise, controlled at 0-5°C and stirred for 1.5h. During the process, 2M hydrochloric acid (0.6mol) was used. After the reaction was completed, dry hydrogen chloride gas was introduced, crystallized with acetone, centrifuged, and dried to obtain 114.72g of compound II with a yield of 90% and a purity of 99.3%.

Embodiment 1

[0024] Preparation of cefotiam hydrochloride

[0025] Add 30g (0.07mol) of compound II, 2-methoxy-4,6-dichloro-1,3,5-triazine (0.077mol), 80ml water and 160ml acetonitrile into the reaction flask for dissolution, and control the temperature at 0 -10°C, slowly add 11.07g (0.07mol) of aminothiazoleacetic acid (Ⅲ), add 0.106mol triethylamine to adjust the pH to 4, carry out the stirring reaction for 1-2h, and control the residue of compound II below 3%, add two Extract with 150ml of methyl chloride, add concentrated hydrochloric acid, add activated carbon for decolorization, crystallize with acetone, centrifuge, and dry to obtain 33.86g of cefotiam hydrochloride (I), with a yield of 80%, a purity of 99.0%, and a maximum of 1.81%.

Embodiment 2

[0027] Preparation of cefotiam hydrochloride

[0028] Add 30g (0.07mol) of compound II, 4,6,-dimethoxy-2-chloro-1,3,5-triazine (0.07mol), 80ml water and 160ml acetone into the reaction flask for dissolution, and control the temperature at 0-10°C, slowly add 11.08g (0.07mol) of aminothiazoleacetic acid (Ⅲ), add 0.106mol triethylamine to adjust the pH to 5, carry out stirring reaction for 1-2h, and control the residue of compound II below 3%, add Extract with 150ml of dichloromethane, add concentrated hydrochloric acid, add activated carbon for decolorization, crystallize with acetone, centrifuge, and dry to obtain 39.96g of cefotiam hydrochloride (I), with a yield of 95%, a purity of 99.6%, and a maximum of 0.05% .

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Abstract

The invention discloses a preparation method of cefotiam hydrochloride and belongs to the technical field of medicine synthesis. The preparation method comprises the steps: adding a compound II, a condensating agent, water and an organic solvent into a reaction flask for dissolution, controlling the temperature at 0-10 DEG C, slowly adding (2-aminothiazole-4-yl)acetic acid (III), adding alkali toregulate the pH, charring out a reaction for 1-2 h by stirring, controlling the residues of the compound II at 3% or below, adding dichloromethane for extraction, adding concentrated hydrochloric acid, adding activated carbon for decoloration, separating out a crystal by using acetone, and carrying out centrifuging and drying to prepare cefotiam hydrochloride (I). By using the preparation method disclosed by the invention, the reaction route is shortened, reactions are easy to operate, the yield and the purity are relatively high, and few byproducts exist in the product; and the preparation method has the advantage of environment friendliness and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, in particular to a preparation method of cefotiam hydrochloride. Background technique [0002] Cefotiam hydrochloride, chemical name (6R,7R)-7-[[(2-amino-4-thiazolyl)acetyl]amino]-3-[[1-[2-(dimethylamino)ethyl] -1H-tetrazol-5-yl]thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid dihydrochloride , is the second-generation cephalosporin antibiotics, and its dihydrochloride (CefotiamDihydrochloride) and buffer sodium carbonate mixed powder preparation (trade name Pansporin) are used clinically. The effect of this product on Gram-positive bacteria is similar to that of cefazolin, and it has a strong antibacterial effect on Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Haemophilus. It also has antibacterial effect on Citrobacter, Enterobacter, and indole-positive proteus. [0003] In the existing method for preparing cefotiam axetil hydrochloride, t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/06
CPCC07D501/06C07D501/36
Inventor 王军姚民龙王晓龙
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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