Cefotetan disodium and preparation method of intermediate of cefotetan disodium

A technology of cefotetan disodium and dichloromethane, applied in directions such as organic chemistry, can solve problems such as unfavorable industrialized production, and achieve the effects of low cost, high yield and simple process route

Active Publication Date: 2016-06-08
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The synthetic route reactant b has no commercially available raw materials at home and abroad. It is first necessary to prepare the acid chloride compound b

Method used

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  • Cefotetan disodium and preparation method of intermediate of cefotetan disodium
  • Cefotetan disodium and preparation method of intermediate of cefotetan disodium
  • Cefotetan disodium and preparation method of intermediate of cefotetan disodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Preparation of 4-(1-amino-3-tert-butoxy-1,3-dioxo-2-enyl)-1,3-dithietane-2-carboxylic acid (2)

[0033] At room temperature, add 4-carboxy-5-mercapto-3-hydroxy-isothiazole trisodium (5) (24.31g, 0.10mol) into 300ml of dichloromethane, stir to dissolve, add 6mol / L (about 65ml) hydrochloric acid Stir to make the pH to 2-3, add 297mg DMAP and continue to stir for 20 minutes, then add 50ml tert-butanol, 6ml pyridine, Boc 2 O (21.83g, 0.10mol), stirred and reacted at room temperature in a dry environment for 18h, HPLC monitored that the reaction was complete, and the solvent was removed by rotary evaporation to obtain an oily substance that was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate and concentrated. , recrystallized from ethanol to obtain intermediate 6 (24.11 g), with a molar yield of 87% and a HPLC purity of 99.2%.

[0034] Take compound 6 (23.89g, 0.086mol), add 250ml of acetone, stir until dissolved, cool to 5-10°...

Embodiment 2

[0036] Preparation of Compound 4

[0037] Add compound 2 (14.56g, 0.05mol), compound 3 (31.48g, 0.06mol) and dichloromethane 1000ml in turn in the reaction flask, stir to make it dissolve; add 1-hydroxybenzotriazole (HOBT) (8.11g , 0.06mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (9.31g, 0.06mol), the mixture was stirred at room temperature for a reaction time of 18h, and the HPLC monitoring reaction was complete, and then The dichloromethane was removed by rotary evaporation, and 1500ml of ethyl acetate and 1200ml of saturated sodium bicarbonate solution were added to the resulting oil, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and filtered. After the filtrate was concentrated, it was recrystallized with ether to obtain a white solid compound 4 (39.10 g), molar yield 98%, HPLC purity 99.6%.

Embodiment 3

[0039] Preparation of Compound 4

[0040] Add compound 2 (14.56g, 0.05mol), compound 3 (26.23g, 0.05mol) and dichloromethane 1000ml in turn in reaction bottle, stir to make it dissolve; Add N,N-diisopropylethylamine (7.75g , 0.06mol) and dichlorinated phenyl phosphate (PDCP) (12.66g, 0.06mol), the mixture was stirred at room temperature for a reaction time of 32h, and the HPLC monitoring reaction was complete, then rotary evaporation removed dichloromethane, and the resulting oil was added to 1500ml ethyl acetate Esters and 1200ml saturated sodium bicarbonate solution were separated. The organic layer was dried over anhydrous sodium sulfate and filtered. After the filtrate was concentrated, it was recrystallized with ether to obtain white solid compound 4 (37.11g). The molar yield was 93%, and the HPLC purity was 99.5g. %.

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Abstract

The invention discloses cefotetan disodium and a preparation method of an intermediate of cefotetan disodium. Commercially-available raw materials, namely, 4-(1-amino-3-tert-butoxy-1,3-dioxo-2-alkenyl)-1,3-dithietane-2-carboxylic acid (2) and 7-MAC (3) are subjected to a condensation reaction to obtain a compound (4), and then the compound (4) is subjected to deprotection and salification to obtain cefotetan disodium (1). The invention further provides a preparation method of the compound (2). In the route, no chloride agent contaminating the environment in a conventional route is used, and the preparation method has the advantages of being simple in process route and environmentally friendly, lowering the process cost and increasing the total product yield and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, in particular to a preparation method of cefotetan disodium and an intermediate thereof. Background technique [0002] Cefotetan disodium is an antibiotic with the structure shown in formula 1. It was first developed by Fujisawa Company in Japan in 1979, and it was first listed in Japan in the late 1980s. It was launched in the United States on December 27, 1985. [0003] [0004] Cefotetan is by far the drug with the longest half-life among the second-generation cephalosporins (cephalosporins). Cefotetan has a strong affinity and binding to penicillin-binding protein, which blocks the synthesis of bacterial cell wall mucopeptides, thereby exerting its antibacterial activity. Because the 7th carbon atom on its β-lactam ring has a methoxyl group, it is extremely stable to β-lactamase (including penicillinase and cephalosporinase) produced by various bacteria It has a strong antiba...

Claims

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Application Information

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IPC IPC(8): C07D501/57C07D501/04C07D339/00
CPCC07D339/00C07D501/04C07D501/57
Inventor 孙松徐勤艳常志成
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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