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Preparation method of allyl chlorooxyl cephalosporin compound

A technology of allyl chloride and compound, applied in the field of pharmaceutical synthesis, can solve problems such as unfavorable industrial production, high cost of iodide, long reaction route, etc., achieve increased steric hindrance, improve yield and purity, and reduce production cost Effect

Active Publication Date: 2013-08-21
浙江东邦药业有限公司
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Problems solved by technology

On the other hand, after chlorination, the activity and yield of the reaction will be improved through the iodination reaction, the total molar yield of the final product is only about 30%, the purity is low, and the reaction route is too long, and the iodide used ( Sodium iodide) has high cost and is not conducive to industrial production

Method used

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  • Preparation method of allyl chlorooxyl cephalosporin compound
  • Preparation method of allyl chlorooxyl cephalosporin compound
  • Preparation method of allyl chlorooxyl cephalosporin compound

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preparation example Construction

[0046] The preparation method of allyl halooxycephalosporin compound of the present invention specifically comprises the following steps:

[0047] A. Addition reaction: in a halogenated hydrocarbon solvent, the allyl compound compound of formula I is subjected to an addition reaction with chlorine gas, and after the addition reaction is completed, a reaction solution of the dichloro product compound of formula II is obtained. As a preference, after the addition reaction ends, post-treatment is also included, the post-treatment is specifically: adding a mixed aqueous solution containing sodium sulfite and sodium bicarbonate to the reaction liquid for washing; as a preference, the halogenated hydrocarbon solvent is selected from two One or more of methyl chloride, chloroform, and carbon tetrachloride; the temperature of the addition reaction is -10°C to 0°C, more preferably -5°C to 0°C;

[0048] B. Elimination reaction: Add an organic base to the reaction solution of the compoun...

Embodiment 1

[0053] In a 3000mL three-necked flask, add 93g (0.2mol) of the allyl compound of the formula I compound (R in the compound of the formula I is methyl) 93g (0.2mol), then add 1500mL of dichloromethane to make the solution clear, cool down to -5°C, and control the temperature at -5 ℃ ~ 0 ℃, continuously feed chlorine gas under stirring (control the feeding speed to make it fully absorbed) for addition reaction for 5 hours, take samples, and use TLC (the volume ratio of petroleum ether: ethyl acetate is 2:1 ( mL / mL) is the mobile phase) to carry out follow-up detection to confirm that the reaction is complete. After the addition reaction is completed, the reaction solution of the compound of formula II is obtained; after the addition reaction is completed, post-treatment is also included, and the post-treatment is specifically: to the reaction Add 1000g of aqueous solution containing 50g of sodium sulfite and 60g of sodium bicarbonate to the solution, then, control the temperature...

Embodiment 2

[0059]Add 93g (0.2mol) of the allyl compound of the formula I compound (R in the compound of the formula I is methyl) into a 3000mL three-necked flask, then add 1400mL of chloroform to make the solution clear, cool down to -5°C, and control the temperature at - 5 ℃ ~ 0 ℃, continuously feed chlorine gas under stirring (control the feed rate to make it fully absorbed) for addition reaction for 5 hours, take samples, and use TLC (the volume ratio of petroleum ether: ethyl acetate is 2:1 (mL / mL) of the mobile phase) was tracked and detected to determine that the reaction was complete. After the addition reaction was over, the reaction solution of the compound of formula II was obtained; 1000 g of aqueous solution containing 45 g of sodium sulfite and 50 g of sodium bicarbonate was added to the reaction solution, and then the temperature was controlled. Stir at 8°C for 1.5 hours to wash, let stand, separate layers, collect the organic layer, then add 150mL saturated saline to the o...

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Abstract

The invention relates to a preparation method of an allyl chlorooxyl cephalosporin compound, and belongs to the technical field of pharmaceutical synthesis. In order to solve the technical problem that an existing process is long in line and low in product yield and purity, the invention provides the preparation method of the allyl chlorooxyl cephalosporin compound. The method comprises the following steps of: performing an additive reaction on an allyl compound and chlorine to obtain a reaction liquid of a dichloro product; then, adding organic alkali for elimination reaction to obtain a compound shown as a formula III; then, performing a hydrolysis reaction of the compound shown as the formula III in a mixed solvent including dimethyl sulfoxide and water under the catalytic effect of an acidic catalyst and Cu2O to obtain an allyl alcohol intermediate; then, performing annulation under the effect of boron trifluoride diethyl etherate or methanesulfonic acid to obtain a compound shown as a formula V; and then, under the effect of an initiator, performing chlorination of the compound shown as the formula V and a chlorinating agent to obtain the allyl chlorooxyl cephalosporin compound. The method has the advantages of simple process and high product purity and yield.

Description

technical field [0001] The invention relates to an antibiotic drug, more specifically, to a preparation method of an allyl oxycephalosporin compound, belonging to the technical field of drug synthesis. Background technique [0002] Since penicillin came into use in the 1940s, this type of antibiotic has been developed for 70 years. With the widespread clinical application of antibiotics and synthetic antibacterial drugs, the emergence of bacterial resistance to antibiotics, there is an urgent need for new antibiotics to replace the original varieties and change the structure of antibiotics, thereby overcoming the resistance of bacteria to antibiotics. This is one of the directions of research and development of new varieties of antibiotics in recent years. [0003] At present, antibacterial drugs such as Latamoxef and Fluoxefef are widely used antibacterial drugs, and 7β-amino-3-chloromethyl-1-oxo-3-cephem-4-carboxylic acid diphenylmethyl ester is Synthesize the mother nuc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D505/18C07D505/06
Inventor 黄伟平夏俊池正明卢峻李日生池瀛虞正烨
Owner 浙江东邦药业有限公司
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