A kind of synthetic method of cefditoren pivoxil mother nucleus

A technology of cefditoren pivoxil and a synthesis method, which is applied in directions such as organic chemistry to achieve the effects of easy operation, high product purity and convenient post-processing

Active Publication Date: 2017-06-27
山东昌邑四方医药化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Take ionic liquid as reaction medium, under the effect of metal palladium catalyst, utilize Heck reaction to synthesize cefditoren pivoxil mother nucleus and have not been reported so far

Method used

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  • A kind of synthetic method of cefditoren pivoxil mother nucleus
  • A kind of synthetic method of cefditoren pivoxil mother nucleus
  • A kind of synthetic method of cefditoren pivoxil mother nucleus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1: In a 100 ml three-necked flask, add 2.26 g (10 mmol) of 7-amino-3-vinyl-3-cephem-4-carboxylic acid, 1.34 g (10 mmol) of 4-methyl-5-chlorothiazole , 22.6g of 1-methyl-3-butylimidazolium tetrafluoroborate ionic liquid, 0.224g (1mmol) of palladium acetate, 0.26g (1mmol) of triphenylphosphine, and 1.0g (10mmol) of triethylamine were added to the reactor , react at 50°C for 10 hours, after the reaction is complete, add saturated sodium bicarbonate solution to adjust the pH to 8-10, extract the reaction solution with 5×3 mL of dichloromethane for 3 times, dry the extract with anhydrous sodium sulfate, and concentrate , recrystallized from ethanol to obtain 2.62 g of a light yellow solid product with a yield of 81%. 99% pure. Melting point: Decompose at 220°C. MS: m / e=323 (M + ).

Embodiment 2

[0021] Example 2: In a 100 ml three-necked flask, add 7-amino-3-vinyl-3-cephem-4-carboxylic acid 2.26g (10mmol), 4-methyl-5-bromothiazole 1.78g (10mmol) , 22.6g of 1-methyl-3-butylimidazolium tetrafluoroborate ionic liquid, 0.224g (1mmol) of palladium acetate, 0.26g (1mmol) of triphenylphosphine, and 1.0g (10mmol) of triethylamine were added to the reactor , react at 50°C for 5 hours, after the reaction is completed, add saturated sodium bicarbonate solution to adjust the pH to 8-10, extract the reaction solution with 5×3 mL of dichloromethane for 3 times, dry the extract with anhydrous sodium sulfate, and concentrate , recrystallized from ethanol to obtain 2.72 g of a light yellow solid product, with a yield of 84%. 99% pure. Melting point: Decompose at 220°C. MS: m / e=323 (M + ).

Embodiment 3

[0022] Example 3: In a 100 ml three-necked flask, add 2.26 g (10 mmol) of 7-amino-3-vinyl-3-cephem-4-carboxylic acid, 2.25 g (10 mmol) of 4-methyl-5-iodothiazole , 22.6g of 1-methyl-3-butylimidazolium tetrafluoroborate ionic liquid, 0.224g (1mmol) of palladium acetate, 0.26g (1mmol) of triphenylphosphine, and 1.0g (10mmol) of triethylamine were added to the reactor , react at 10°C for 10 hours, after the reaction is completed, add saturated sodium bicarbonate solution to adjust the pH to 8-10, extract the reaction solution with 5×3 mL of dichloromethane for 3 times, dry the extract with anhydrous sodium sulfate, and concentrate , recrystallized from ethanol to obtain 2.65 g of a light yellow solid product, with a yield of 82%. 99% pure. Melting point: Decompose at 220°C. MS: m / e=323 (M + ).

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Abstract

The invention discloses a synthetic method of a cefditoren pivoxil mother nucleus. The synthetic method comprises the following steps: adding quantitative 7-amino-3-vinyl-3-cephem-4-carboxylic acid as shown in the formula (I), 4-methyl-5- halogenothiazole as shown in the formula (II) and an ionic liquid as shown in the formula (III), an inorganic base or an organic base, palladium acetate and triphenylphosphine into a reactor, taking a reaction for 1-10 hours at 10-150 DEG C till ending, and then performing aftertreatment to obtain the cefditoren pivoxil mother nucleus as shown in the formula (IV), wherein in the formula (III), R is C1-C10 alkyl, and L- is BF4- or BF6-.

Description

technical field [0001] The invention relates to a pharmaceutical intermediate, especially a method for synthesizing a cefditoren pivoxil core. Background technique [0002] Cefditoren axetil is the third generation of oral cephalosporin antibiotics, which was developed by the Japanese Meiji Seika Company in 1994, and is used to treat infections caused by Gram-positive and Gram-negative bacteria, especially for grapevine Gram-positive bacteria of the genus Streptococcus, including Streptococcus pneumoniae, Gram-negative bacteria such as Escherichia coli, Branhamella catarrhalis, Klebsiella, Proteus, and Haemophilus influenzae And Peptostreptococcus, Propionibacterium acnes, Bacteroides and other anaerobic bacteria have shown strong antibacterial activity. Because of its broad antibacterial spectrum, cefditoren axetil is widely used in clinical practice. The chemical name of the parent nucleus of cefditoren pivoxil is (6R,7R)-7-amino-3-[(1Z)-2-(4-methyl-5-thiazole)vinyl]-8-o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/24C07D501/04
Inventor 顾士崇孙会裴文
Owner 山东昌邑四方医药化工有限公司
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