The preparation method of cefditoren pivoxil dimer

Abstract

The invention discloses a preparation method of a cefditoren pivoxil dimer. The preparation method is characterized in that an organic solvent and cefditoren sodium are added to a reaction container,and are stirred and dissolved, the temperature is reduced to subzero 20-subzero 50 DEG C, iodomethyl pivalate is added in batches, and iodomethyl pivalate is added again after reacting for a certain time after each addition of iodomethyl pivalate; inorganic or organic base is required to be added to control pH at 7.5-8.5 during the reaction, and subsequent separation and purification are performedafter the reaction to obtain the product. The preparation method has simple steps, simple raw materials and low cost, and is suitable for large-scale preparation. The content of the cefditoren pivoxil dimer prepared with the preparation method provided can reach 92.0% or higher, a theoretical basis is provided for safe use of drugs, effective data support is provided for the quality standard of cefditoren pivoxil, and effective guarantee is provided for safe clinical use of drugs.

Description

technical field

[0001] The invention relates to a preparation method of cefditoren pivoxil dimer, belonging to the field of impurity analysis in drug synthesis. Background technique

[0002] Cefditoren Pivoxil (Cefditoren Pivoxil), the chemical name is (6R,7R)-2,2-dimethylpropionyloxymethyl-7-[(Z)-2-(2-amino-4-thiazolyl) )-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5- Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.

[0003] Cefditoren pivoxil is an ester-type oral third-generation cephem antibiotic developed by Japan Meiji Seika Co., Ltd. It was first listed in Japan in 1994 and listed in China in April 2001. The trade name is Meiact. Clinically, it is mainly used to treat infections caused by Gram-positive and Gram-negative bacteria. This product has a wide range of antibacterial effects, especially against Gram-positive bacteria such as Staphylococcus, Streptococcus (including Streptococcus pneumoniae), Escherichia coli, Klebsiella cata...

Examples

Embodiment 1

[0029] Preparation of cefditoren pivoxil dimer

[0030] Add 125ml of N,N-dimethylformamide (DMF) and 22.2g (0.04mol) of cefditoren sodium into the reaction vessel, stir to dissolve, and lower the temperature to below -80°C.

[0031] Add 0.06 mol of iodomethyl pivalate, and control the temperature below -50°C to react for 20 minutes.

[0032] Then add 0.06 mol of iodomethyl pivalate, and control the temperature below -50°C to react for 20 minutes.

[0033] Finally, 0.04 mol of iodomethyl pivalate was added, and the temperature was controlled below -50°C until the reaction was complete.

[0034] During the reaction, triethylamine needs to be added to control the pH between 7.5-8.5. After the reaction, add 350ml of ethyl acetate and 270ml of pure water to the reaction solution, stir, leave to stand for stratification, and discard the lower aqueous layer. The organic layer was stirred and washed with 0.1% sodium bicarbonate solution and water successively, separated into layers,...

Embodiment 2

[0036] Preparation of cefditoren pivoxil dimer

[0037] Add 150 ml of acetonitrile and 22.2 g (0.04 mol) of cefditoren sodium into the reaction vessel, stir to dissolve, and lower the temperature to below -80°C.

[0038] Add 0.06 mol of iodomethyl pivalate, and control the temperature below -40°C to react for 30 minutes.

[0039] Then add 0.06 mol of iodomethyl pivalate, and control the temperature below -40°C to react for 30 minutes.

[0040] Finally, 0.06 mol of iodomethyl pivalate was added, and the temperature was controlled below -40°C until the reaction was complete.

[0041] During the reaction process, pyridine needs to be added to control the pH between 7.5-8.5. After the reaction, add 350ml ethyl acetate and 270ml pure water to the reaction solution, stir, let stand to separate layers, discard the lower aqueous layer, and discard the organic layer. Stir and wash with 0.5% sodium hydroxide solution and water successively, let stand to separate layers, discard the wa...

Embodiment 3

[0043] Preparation of cefditoren pivoxil dimer

[0044] Add 120 ml of tetrahydrofuran and 22.2 g (0.04 mol) of cefditoren sodium into the reaction vessel, stir to dissolve, and lower the temperature to below -80°C.

[0045] Add 0.10 mol of iodomethyl pivalate, and control the temperature below -35°C to react for 28 minutes.

[0046] Then add 0.10 mol of iodomethyl pivalate, and control the temperature below -35°C to react for 28 minutes.

[0047] Finally, 0.04 mol of iodomethyl pivalate was added, and the temperature was controlled below -35°C until the reaction was complete.

[0048]During the reaction, tributylamine needs to be added to control the pH between 7.5-8.5. After the reaction, add 350ml of ethyl acetate and 270ml of pure water to the reaction solution, stir, leave to stand for stratification, and discard the lower aqueous layer. The organic layer was stirred and washed with 1% sodium bicarbonate solution and water successively, and the layers were allowed to sta...

technical field

[0001] The invention relates to a preparation method of cefditoren pivoxil dimer, belonging to the field of impurity analysis in drug synthesis. Background technique

[0002] Cefditoren Pivoxil (Cefditoren Pivoxil), the chemical name is (6R,7R)-2,2-dimethylpropionyloxymethyl-7-[(Z)-2-(2-amino-4-thiazolyl) )-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5- Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.

[0003] Cefditoren pivoxil is an ester-type oral third-generation cephem antibiotic developed by Japan Meiji Seika Co., Ltd. It was first listed in Japan in 1994 and listed in China in April 2001. The trade name is Meiact. Clinically, it is mainly used to treat infections caused by Gram-positive and Gram-negative bacteria. This product has a wide range of antibacterial effects, especially against Gram-positive bacteria such as Staphylococcus, Streptococcus (including Streptococcus pneumoniae), Escherichia coli, Klebsiella cata...

Examples

Embodiment 1

[0029] Preparation of cefditoren pivoxil dimer

[0030] Add 125ml of N,N-dimethylformamide (DMF) and 22.2g (0.04mol) of cefditoren sodium into the reaction vessel, stir to dissolve, and lower the temperature to below -80°C.

[0031] Add 0.06 mol of iodomethyl pivalate, and control the temperature below -50°C to react for 20 minutes.

[0032] Then add 0.06 mol of iodomethyl pivalate, and control the temperature below -50°C to react for 20 minutes.

[0033] Finally, 0.04 mol of iodomethyl pivalate was added, and the temperature was controlled below -50°C until the reaction was complete.

[0034] During the reaction, triethylamine needs to be added to control the pH between 7.5-8.5. After the reaction, add 350ml of ethyl acetate and 270ml of pure water to the reaction solution, stir, leave to stand for stratification, and discard the lower aqueous layer. The organic layer was stirred and washed with 0.1% sodium bicarbonate solution and water successively, separated into layers,...

Embodiment 2

[0036] Preparation of cefditoren pivoxil dimer

[0037] Add 150 ml of acetonitrile and 22.2 g (0.04 mol) of cefditoren sodium into the reaction vessel, stir to dissolve, and lower the temperature to below -80°C.

[0038] Add 0.06 mol of iodomethyl pivalate, and control the temperature below -40°C to react for 30 minutes.

[0039] Then add 0.06 mol of iodomethyl pivalate, and control the temperature below -40°C to react for 30 minutes.

[0040] Finally, 0.06 mol of iodomethyl pivalate was added, and the temperature was controlled below -40°C until the reaction was complete.

[0041] During the reaction process, pyridine needs to be added to control the pH between 7.5-8.5. After the reaction, add 350ml ethyl acetate and 270ml pure water to the reaction solution, stir, let stand to separate layers, discard the lower aqueous layer, and discard the organic layer. Stir and wash with 0.5% sodium hydroxide solution and water successively, let stand to separate layers, discard the wa...

Embodiment 3

[0043] Preparation of cefditoren pivoxil dimer

[0044] Add 120 ml of tetrahydrofuran and 22.2 g (0.04 mol) of cefditoren sodium into the reaction vessel, stir to dissolve, and lower the temperature to below -80°C.

[0045] Add 0.10 mol of iodomethyl pivalate, and control the temperature below -35°C to react for 28 minutes.

[0046] Then add 0.10 mol of iodomethyl pivalate, and control the temperature below -35°C to react for 28 minutes.

[0047] Finally, 0.04 mol of iodomethyl pivalate was added, and the temperature was controlled below -35°C until the reaction was complete.

[0048]During the reaction, tributylamine needs to be added to control the pH between 7.5-8.5. After the reaction, add 350ml of ethyl acetate and 270ml of pure water to the reaction solution, stir, leave to stand for stratification, and discard the lower aqueous layer. The organic layer was stirred and washed with 1% sodium bicarbonate solution and water successively, and the layers were allowed to sta...

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