Preparation method of high-purity cefditoren pivoxil

A technology for cefditoren pivoxil and cefditoren sodium, which is applied in the preparation of cefditoren pivoxil and the field of compound preparation, can solve the problems of low refining efficiency, low product purity of cefditoren pivoxil, cumbersome industrial production and the like , to achieve the effect of ensuring follow-up treatment, mild and complete reaction

Pending Publication Date: 2020-01-07
BEIJING JIMEITANG MEDICINE RES CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The purpose of the present invention is to solve the technical difficulties of low product purity of cefditoren pivoxil obtained from cefditoren pivoxil, cumbersome industrial production and low refining efficiency in view of t

Method used

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  • Preparation method of high-purity cefditoren pivoxil
  • Preparation method of high-purity cefditoren pivoxil
  • Preparation method of high-purity cefditoren pivoxil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1, the preparation of cefditoren pivoxil

[0051]Control the temperature below 30°C, add 180g of cefditoren sodium to 1.08L of N,N-dimethylformamide, stir until clear, cool down to -35°C, add 78.4g of iodomethyl pivalate dropwise, and control the temperature- 30~-35 ℃ of reaction 1-2 hour, sampling HPLC detects (residual cefditoren sodium is less than 5% is reaction end point), the result shows remaining cefditoren sodium 3.22%, reaction is complete.

[0052] Add 4.4L of isopropyl acetate / water (V / V, 1:1) mixed solvent pre-cooled to 0-5°C to the reaction solution, control the temperature at 0-10°C, stir, extract and separate. Add 0.1% aqueous sodium bicarbonate solution (2.2 L) pre-cooled to 0-5°C to the organic phase, control the temperature at 0-10°C, stir, extract and separate. Add purified water (2.2 L) pre-cooled to 0-5°C to the organic phase, control the temperature at 0-10°C, stir, extract and separate. The organic phase was slowly added to isopropyl...

Embodiment 2

[0053] The mol ratio of embodiment 2, cefditoren sodium and iodomethyl pivalate is: 1:1.1

[0054] Control the temperature below 30°C, add 180g of cefditoren sodium to 1.19L of N,N-dimethylformamide, stir until clear, cool down to -35°C, add 78.4g of iodomethyl pivalate dropwise, and control the temperature- 30~-35 ℃ of reaction 1-2 hour, sampling HPLC detects (residual cefditoren sodium is less than 5% is reaction end point), the result shows remaining cefditoren sodium 1.65%, reaction is complete.

[0055] Add 4.4L of isopropyl acetate / water (V / V, 1:1) mixed solvent pre-cooled to 0-5°C to the reaction solution, control the temperature at 0-10°C, stir, extract and separate. Add 0.1% aqueous sodium bicarbonate solution (2.2 L) pre-cooled to 0-5°C to the organic phase, control the temperature at 0-10°C, stir, extract and separate. Add purified water (2.2 L) pre-cooled to 0-5°C to the organic phase, control the temperature at 0-10°C, stir, extract and separate. The organic pha...

Embodiment 3

[0057] Embodiment 3, the reaction temperature of cefditoren pivoxil is changed to -20~-25 ℃

[0058] Control the temperature below 30°C, add 180g of cefditoren sodium to 1.08L of N,N-dimethylformamide, stir until clear, cool down to -25°C, add 78.4g of iodomethyl pivalate dropwise, and control the temperature- 20~-25 ℃ of reaction 1-2 hour, sampling HPLC detects (residual cefditoren sodium is less than 5% is reaction end point), the result shows remaining cefditoren sodium 2.74%, reaction is complete.

[0059] Add 4.4L of isopropyl acetate / water (V / V, 1:1) mixed solvent pre-cooled to 0-5°C to the reaction solution, control the temperature at 0-10°C, stir, extract and separate. Add 0.1% aqueous sodium bicarbonate solution (2.2 L) pre-cooled to 0-5°C to the organic phase, control the temperature at 0-10°C, stir, extract and separate. Add purified water (2.2 L) pre-cooled to 0-5°C to the organic phase, control the temperature at 0-10°C, stir, extract and separate. The organic p...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of high-purity cefditoren pivoxil. The preparation method comprises following specific steps: controlling the temperature of cefditoren sodium (1) and iodomethyl pivalate (2) to be -30 DEG C to-35 DEG C for reaction to obtain a cefditoren pivoxil (3) solution; extracting with an organic phase/water mixed solvent, washing with a 0.1% sodium bicarbonate aqueous solution, crystallizing with an organic phase inert solvent, and carrying out ethyl acetate crystal transformation purification onan obtained crude product to obtain the high-purity cefditoren pivoxil of which the purity is greater than 99.5% and the individual impurity content is less than 0.1%, thereby reaching the USP bulk drug standard of the variety. The technical scheme discloses in the invention further provides a refining method of cefditoren pivoxil, a crystalline cefditoren pivoxil product is obtained by directlydissolving and crystallizing with ethyl acetate, and the refining method is simple to operate, easy to control, high in yield, good in quality and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a preparation method of a compound, in particular to a preparation method of cefditoren pivoxil. Background technique [0002] Cefditoren pivoxil, chemical name: 2,2-dimethylpropionyloxymethyl(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methanol Oxyiminoacetamido]-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5-thia-1-nitrogen Heterobicyclo[4.2.0]oct-2-ene-2-carboxylate is the third-generation cephalosporin developed by Japan Meiji Seika Co., Ltd., which was listed in Japan in 1994 under the trade name Meiact. It is used for the treatment of Infections caused by Gram-positive and Gram-negative bacteria. [0003] The preparation method of cefditoren pivoxil is disclosed in US20060173175, WO2005016936 and US4839350. In many routes, cefditoren sodium (formula 1) and iodomethyl pivalate (formula 2) are esterified to obtain cefditoren pivoxil Ester (formula 3), the reaction equation is as...

Claims

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Application Information

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IPC IPC(8): C07D501/04C07D501/12C07D501/24
CPCC07D501/04C07D501/12C07D501/24
Inventor 张翔韩立成白明龙王辉
Owner BEIJING JIMEITANG MEDICINE RES CO LTD
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