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Monohydrater cefotiam hydrochloride compound and pharmaceutical composition thereof

A technology of cefotiam hydrochloride and cephalosporin hydrochloride, which is applied in the field of medicine and chemical industry, and can solve the problems of difficult control of reaction, difficult operation and low yield

Inactive Publication Date: 2019-01-04
宁应
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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
[0008] 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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  • Monohydrater cefotiam hydrochloride compound and pharmaceutical composition thereof
  • Monohydrater cefotiam hydrochloride compound and pharmaceutical composition thereof
  • Monohydrater cefotiam hydrochloride compound and pharmaceutical composition thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0039] The preparation of embodiment 1 monohydrate cefotiam hydrochloride compound

[0040] making process

[0041] (1) Add 200ml of dichloromethane to the three-necked flask of the reactor, after cooling down to -10°C, add aminothiazole acetate hydrochloride, then add 38g of phosphorus trichloride to react for 2h, filter, and wash with dichloromethane to obtain white wet spare parts;

[0042] (2) Add 250ml of dimethyl carbonate into another three-necked flask of the reactor, cool to 10°C, and slowly introduce BF under stirring 3 Gas 110g (about 1.0h), make the boron trifluoride dimethyl ester solution for subsequent use;

[0043] (3) Add 80g of 7-ACA, 40g of 1-(2-dimethylaminoethyl)-5-mercaptotetrazole, and 250ml of dimethyl carbonate to another dry three-necked flask, stir and react for 10min, and cool down to 10 ℃, add the above-prepared boron trifluoride dimethyl carbonate solution, raise the temperature to 50 ℃ and react for 1.0h, after the reaction is complete, cool t...

Embodiment 2

[0048] The preparation of embodiment 2 monohydrate cefotiam hydrochloride compound

[0049] making process

[0050] (1) Add 400ml of dichloromethane to the three-neck flask of the reactor, after cooling down to -5°C, add aminothiazole acetate hydrochloride, then add 75g of phosphorus trichloride to react for 3.0h, filter, wash with dichloromethane to get white Wet product standby;

[0051] (2) Add 500ml of dimethyl carbonate into another three-necked flask of the reactor, cool to 15°C, and slowly introduce BF under stirring 3 Gas 220g (about 1.5h), the prepared boron trifluoride dimethyl ester solution is standby;

[0052] (3) Add 160g of 7-ACA, 80g of 1-(2-dimethylaminoethyl)-5-mercaptotetrazole, and 500ml of dimethyl carbonate to another dry three-necked flask, stir for 20min, and cool down to 20 ℃, add the above-prepared boron trifluoride dimethyl carbonate solution, raise the temperature to 45 ℃ and react for 1.5h, after the reaction is complete, cool the reaction solut...

Embodiment 3

[0057] The preparation of embodiment 3 monohydrate cefotiam hydrochloride compound

[0058] making process

[0059] (1) Add 300ml of dichloromethane to the three-necked flask of the reactor, after cooling down to 0°C, add aminothiazole acetate hydrochloride, then add 58g of phosphorus trichloride to react for 2.5h, filter, wash with dichloromethane to obtain a white wet spare parts;

[0060] (2) Add 520ml of dimethyl carbonate into another three-necked flask of the reactor, cool to 20°C, and slowly introduce BF under stirring 3 Gas 170g (about 1.0h), the prepared boron trifluoride dimethyl ester solution is standby;

[0061] (3) Take another dry three-necked flask and add 7-ACA 120g, 1-(2-dimethylaminoethyl)-5-mercaptotetrazole 60g, dimethyl carbonate 375ml into it, stir for 15min, cool down to 15 ℃, add the boron trifluoride dimethyl carbonate solution prepared above, raise the temperature to 40 ℃ and react for 1.5h, after the reaction is completed, the temperature of the ...

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Abstract

The invention discloses a monohydrate cefotiam hydrochloride compound and a preparing method thereof. One mole of cefotiam hydrochloride contains one mole of water, and an x-ray diffraction spectrogram of the compound has characteristic peaks at the positions with the diffraction angles 2theta of 14.82-15.22 degrees, 29.92-30.32 degrees, 31.48-31.88 degrees, 35.01-35.41 degrees and 37.79-38.19 degrees. 7-amino-cephalosporanic acid (7ACA) serving as a starting material is condensed with 1-(2-dimethylaminoethyl)-5-thiotetrazole under the catalytic effect of organic solvents dimethyl carbonate boron trifluoride and the like to prepare an intermediate at a C-3 site; then 2-(2-aminothiazol-4-yl) acetic acid hydrochloride reacts with methylene chloride and concentrated hydrochloric acid gas to prepare acyl chloride at a 7 site, and the one-water cefotiam hydrochloride compound is synthesized. The operation is simple and environmentally friendly, the reactants are easily obtained, the reaction conditions are mild, and the yield is high. The one-water cefotiam hydrochloride compound has low hygroscopicity and impurity content, good fluidity and thermodynamic stability and wider applicationprospects.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a cefotiam hydrochloride monohydrate compound and a pharmaceutical composition thereof. Background technique [0002] Cefotiam hydrochloride, cefotiam dihydrochloride, chemical name is (6R-trans)-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]octane -2-ene-2-carboxylic acid dihydrochloride, molecular formula: C 18 h 23 N 9 o 4 S 3 2HCl, molecular weight: 598.56, is a widely used cephalosporin clinically. Its structural formula is: [0003] [0004] Cefotiam hydrochloride is a second-generation semi-synthetic cephalosporin developed by Takeda Corporation of Japan and first listed in Japan in 1981. The effect on gram-positive bacteria is close to that of cefazolin, and it has better effect on gram-negative bacteria, such as Haemophilus, Escherichia coli, Klebsiel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/04A61K31/546A61P31/04
CPCC07B2200/13C07D501/04C07D501/36
Inventor 宁应
Owner 宁应
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