A kind of preparation method of cefditoren pivoxil intermediate

Abstract

The invention discloses a cefditoren pivoxil intermediate preparation method. The method includes steps: 1) in existence of sodium iodide, allowing contact reaction of GCLE and triphenylphosphine in a first mixed solvent, cooling to 8-10 DEG C, adding sodium hydroxide to regulate pH to 8-9, stirring for 10-20min, and standing for layering to obtain an organic layer which is phosphorus ylide containing mixer, wherein the contact reaction temperature is 25-35 DEG C, the contact reaction time is 1-2 hours, and the first mixed solvent is a mixed solvent of water and dichloromethane; 2) controlling the temperature to be 0-5 DEG C, adding gluconate and 4-methyl-5-thiazole formaldehyde into the phosphorus ylide containing mixer obtained at the step 1), stirring for reaction for 1-2 hours, cooling to a temperature ranging from -20 DEG C to -10 DEG C, stirring for reaction for 3-5 hours, reheating to -5-0 DEG C, stirring for reaction for 2 hours, adding water for quenching, and performing dichloromethane extraction, concentration and methanol recrystallization to obtain a cefditoren pivoxil intermediate. By the cefditoren pivoxil intermediate preparation method, yield is effectively increased, high selectivity is achieved, and the content of e-isomers is greatly reduced.

Description

technical field

[0001] The invention belongs to the field of medicine and chemical industry, in particular, relates to a preparation method of cefditoren pivoxil intermediate, more specifically, relates to a 7-amino-3-[(Z)-2-(4-methyl- The preparation method of 5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid. Background technique

[0002] Cefditoren Pivoxil (Cefditoren Pivoxil) is a third-generation oral cephalosporin developed by Japan's Meiji Seika Co., Ltd. It was launched in Japan in 1994 and in China in April 2001. The trade name is Meiact , the chemical name is 2,2-dimethylpropionyloxymethyl(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl Amino]-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2. 0] Oct-2-ene-2-carboxylate. Cefditoren axetil is mainly used to treat infections caused by Gram-positive bacteria and Gram-negative bacteria, including infections caused by Streptococcus pneumoniae, Klebsiella pneumoniae, Staphylococcus aureus...

Examples

Embodiment 1

[0025] A kind of preparation method of cefditoren pivoxil intermediate, the method comprises the following steps:

[0026] 1) In the presence of sodium iodide (19.5g, 0.13mol), 7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (48.7g, 0.1mol) and triphenyl Phosphine (30.2g, 0.115mol) was reacted in 500mL of the first mixed solvent, then the temperature was lowered to 10°C, sodium hydroxide was added to adjust the pH to 9, stirring was continued for 15 minutes, and the layers were left to stand, and the organic layer contained The mixture of phosphorus ylides, the conditions of the contact reaction include: the contact reaction temperature is 35° C., and the reaction time is 1.5 hours, and the first mixed solvent is a mixed solvent of water and dichloromethane (the volume ratio of water and dichloromethane is 1:3);

[0027] 2) Control the temperature at 3°C, add sodium gluconate (17.9g, 0.04mol) and 4-methyl-5-thiazole formaldehyde (31.8g, 0.25mol) in...

Embodiment 2

[0029] A kind of preparation method of cefditoren pivoxil intermediate, the method comprises the following steps:

[0030] 1) In the presence of sodium iodide (16.5g, 0.11mol), 7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (48.7g, 0.1mol) and triphenyl Phosphine (31.5, 0.12mol) was reacted in 500mL of the first mixed solvent, then the temperature was lowered to 8°C, sodium hydroxide was added to adjust the pH to 9, stirring was continued for 20 minutes, and the organic layer contained phosphorus. The mixture of ylides, the conditions of the contact reaction include: the contact reaction temperature is 25 ° C, the reaction time is 2 hours, and the first mixed solvent is a mixed solvent of water and methylene chloride (the volume ratio of water and methylene chloride is 1 :2);

[0031]2) Control the temperature at 0°C, add sodium gluconate (35.9g, 0.08mol) and 4-methyl-5-thiazole formaldehyde (25.4g, 0.2mol) into the mixture containing phosphorus y...

Embodiment 3

[0033] A kind of preparation method of cefditoren pivoxil intermediate, the method comprises the following steps:

[0034] 1) In the presence of sodium iodide (22.5g, 0.15mol), 7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (48.7g, 0.1mol) and triphenyl Phosphine (28.9g, 0.11mol) was contacted and reacted in 500mL of the first mixed solvent, then the temperature was lowered to 10°C, sodium hydroxide was added to adjust the pH to 8, stirring was continued for 15 minutes, and the layers were left to stand, and the organic layer contained The mixture of phosphorus ylides, the conditions of the contact reaction include: the contact reaction temperature is 25 ° C, the reaction time is 1 hour, and the first mixed solvent is a mixed solvent of water and dichloromethane (the volume ratio of water and dichloromethane is 2:1);

[0035] 2) Control the temperature at 5°C, add sodium gluconate (26.9g, 0.06mol) and 4-methyl-5-thiazole formaldehyde (28g, 0.22mol...

technical field

[0001] The invention belongs to the field of medicine and chemical industry, in particular, relates to a preparation method of cefditoren pivoxil intermediate, more specifically, relates to a 7-amino-3-[(Z)-2-(4-methyl- The preparation method of 5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid. Background technique

[0002] Cefditoren Pivoxil (Cefditoren Pivoxil) is a third-generation oral cephalosporin developed by Japan's Meiji Seika Co., Ltd. It was launched in Japan in 1994 and in China in April 2001. The trade name is Meiact , the chemical name is 2,2-dimethylpropionyloxymethyl(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl Amino]-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2. 0] Oct-2-ene-2-carboxylate. Cefditoren axetil is mainly used to treat infections caused by Gram-positive bacteria and Gram-negative bacteria, including infections caused by Streptococcus pneumoniae, Klebsiella pneumoniae, Staphylococcus aureus...

Examples

Embodiment 1

[0025] A kind of preparation method of cefditoren pivoxil intermediate, the method comprises the following steps:

[0026] 1) In the presence of sodium iodide (19.5g, 0.13mol), 7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (48.7g, 0.1mol) and triphenyl Phosphine (30.2g, 0.115mol) was reacted in 500mL of the first mixed solvent, then the temperature was lowered to 10°C, sodium hydroxide was added to adjust the pH to 9, stirring was continued for 15 minutes, and the layers were left to stand, and the organic layer contained The mixture of phosphorus ylides, the conditions of the contact reaction include: the contact reaction temperature is 35° C., and the reaction time is 1.5 hours, and the first mixed solvent is a mixed solvent of water and dichloromethane (the volume ratio of water and dichloromethane is 1:3);

[0027] 2) Control the temperature at 3°C, add sodium gluconate (17.9g, 0.04mol) and 4-methyl-5-thiazole formaldehyde (31.8g, 0.25mol) in...

Embodiment 2

[0029] A kind of preparation method of cefditoren pivoxil intermediate, the method comprises the following steps:

[0030] 1) In the presence of sodium iodide (16.5g, 0.11mol), 7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (48.7g, 0.1mol) and triphenyl Phosphine (31.5, 0.12mol) was reacted in 500mL of the first mixed solvent, then the temperature was lowered to 8°C, sodium hydroxide was added to adjust the pH to 9, stirring was continued for 20 minutes, and the organic layer contained phosphorus. The mixture of ylides, the conditions of the contact reaction include: the contact reaction temperature is 25 ° C, the reaction time is 2 hours, and the first mixed solvent is a mixed solvent of water and methylene chloride (the volume ratio of water and methylene chloride is 1 :2);

[0031]2) Control the temperature at 0°C, add sodium gluconate (35.9g, 0.08mol) and 4-methyl-5-thiazole formaldehyde (25.4g, 0.2mol) into the mixture containing phosphorus y...

Embodiment 3

[0033] A kind of preparation method of cefditoren pivoxil intermediate, the method comprises the following steps:

[0034] 1) In the presence of sodium iodide (22.5g, 0.15mol), 7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (48.7g, 0.1mol) and triphenyl Phosphine (28.9g, 0.11mol) was contacted and reacted in 500mL of the first mixed solvent, then the temperature was lowered to 10°C, sodium hydroxide was added to adjust the pH to 8, stirring was continued for 15 minutes, and the layers were left to stand, and the organic layer contained The mixture of phosphorus ylides, the conditions of the contact reaction include: the contact reaction temperature is 25 ° C, the reaction time is 1 hour, and the first mixed solvent is a mixed solvent of water and dichloromethane (the volume ratio of water and dichloromethane is 2:1);

[0035] 2) Control the temperature at 5°C, add sodium gluconate (26.9g, 0.06mol) and 4-methyl-5-thiazole formaldehyde (28g, 0.22mol...

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