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A kind of amorphous cefotetan acid and its preparation method of cefotetan disodium and pharmaceutical composition containing the cefotetan disodium

A cefotetan acid, amorphous technology, applied in the field of drug invention, to achieve the effect of improving the dissolution effect, improving the bioavailability, and simplifying the filtration and drying process

Inactive Publication Date: 2016-12-21
SHENZHEN SALUBRIS PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Up to the present, there is no published literature reporting amorphous cefotetan acid of the present invention and its preparation method and the method for preparing cefotetan disodium and the pharmaceutical composition containing cefotetan disodium by it, the present invention In the process of preparing cefotetan, the inventors accidentally obtained amorphous cefotetan acid, that is, the amorphous form of cefotetan acid can only be obtained after being prepared by the method described in the present invention

Method used

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  • A kind of amorphous cefotetan acid and its preparation method of cefotetan disodium and pharmaceutical composition containing the cefotetan disodium
  • A kind of amorphous cefotetan acid and its preparation method of cefotetan disodium and pharmaceutical composition containing the cefotetan disodium
  • A kind of amorphous cefotetan acid and its preparation method of cefotetan disodium and pharmaceutical composition containing the cefotetan disodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The preparation of embodiment 1 cefotetan acid

[0050] (1) Amidation reaction

[0051] Dissolve 100g of 7-MAC in 1500ml of dichloromethane, stir to dissolve 7-MAC, cool down to below 5°C, add 40g of N,N-methylaniline, add 10 minutes, stir for 20 minutes, add 55g of bromoacetyl bromide , 30 minutes to complete the addition, heat preservation and stirring until the reaction is complete (7-MAC residue is less than 1.5%), add 2% sulfuric acid solution to the reaction solution, stir, stand still for phase separation, collect the organic phase, and obtain the reaction solution A.

[0052] (2) Dediphenyl ester reaction

[0053] Take 100g of aluminum trichloride and add it into 300ml of dichloromethane, stir, cool down to below 5°C, then add 120ml of anisole, stir to obtain reaction solution B1.

[0054] The temperature of the reaction solution A was lowered to below 0°C, and the reaction solution B1 was added to react for 1 hour to obtain the reaction solution B2.

[0055]...

Embodiment 2

[0058] Example 2 Preparation of Cefotetan Acid Amorphous Crystals

[0059] Suspend the crude cefotetan acid obtained in Example 1 in water, add hydrochloric acid to adjust the pH to 1.5-2.5, then add 2000ml butanone, stir for half an hour, and filter. Concentrate the butanone phase under reduced pressure below 40°C until 1 / 3 to 1 / 4 of the butanone liquid remains, add 1000ml of ethanol, cool down to below 0°C to grow crystals for 3 hours, filter, wash the filter cake with 300ml of ethanol, and keep it below 50°C Vacuum-dried until the water content was less than 2.0%, discharged and weighed to obtain 723 g of amorphous cefotetan acid with a purity of 98.7%. The X-ray diffraction spectrum of gained amorphous crystalline product, differential scanning calorimetry (DSC) collection of illustrative plates and thermogravimetric analysis (TG) collection of illustrative plates are respectively as follows figure 1 , figure 2 , image 3 shown.

[0060] The obtained amorphous cefotet...

Embodiment 3

[0061] Example 3 Preparation of Cefotetan Disodium

[0062] Take 700 g of cefotetan acid in Example 2, add 7000 ml of water for injection, start stirring, lower the temperature to below 10°C, and slowly add solid sodium bicarbonate until the solid dissolves. Add gac 70g, stir 40 minutes, through decarbonization filtration, sterilizing filtration, carry out lyophilization, to moisture is less than 2.0%, discharging, weigh, obtain cefotetan disodium 650g, purity 98.4%, yield 92.8%. m / e 620.3[M+H] + , 1 H-NMR(500MHz,DMSO)δ(ppm):9.605(d=5.0,1H),9.357(s,1H),6.762(m,1H),4.982(s,0.5H)4.980(s,0.5H) ,4.831(s,0.5H),4.370(d=12.5,0.5H),3.915(s,1.5H),3.585(d=17.5,1H),3.401(s,3H),3.250(d=17.5,1H ).

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Abstract

The invention discloses a novel crystal form of cefotetan acid, a method for preparing cefotetan disodium by the novel crystal form of the cefotetan acid and a pharmaceutical composition containing the cefotetan disodium. The X-ray diffraction pattern of the novel crystal form appears no X-ray diffraction peak; the endothermic peak in the differential thermal analysis pattern is positioned at 158.3 DEG C; the exothermic peak is positioned at 144.6 DEG C. The novel crystal form solves the technical problem of instability of the cefotetan disodium prepared by using the cefotetan acid in the prior art. The used preparation method has good operability and few residues of organic solvent, and is specifically suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical inventions, and in particular relates to an amorphous cefotetan acid, a method for preparing cefotetan disodium therefrom, and a pharmaceutical composition containing the cefotetan disodium. Background technique [0002] Cefotetan (Cefotetan) belongs to the second generation cephalosporin antibiotics, the chemical name is (6R,7S)-7-[4-(carbamoylcarboxymethylene)-1,3-dithietane-2 -Formylamino]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thio-1- Azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was developed by Fujisawa Company in Japan in 1979 and was listed in Japan in March 1984. This product is a derivative of cephamycin, which has a strong binding property with penicillin-binding protein, thereby blocking the synthesis of bacterial cell walls and exerting a strong bactericidal effect in a short time. It is extremely stable to the lactamase produced by various bacteria, and has good ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/57C07D501/12C07D501/04A61K31/546A61P31/04
CPCC07D501/04C07D501/12C07D501/57
Inventor 雷建刚梁贵林杨思远赵丽
Owner SHENZHEN SALUBRIS PHARMA CO LTD
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