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Preparation method of florfenicol oxazoline intermediate

A technology of florfenicol oxazoline and intermediates, which is applied in the field of drug synthesis, can solve the problems of prone to punching and explosion, unsafety, and the inability of one-time input of reducing agents, etc., and achieves easy operation, slow speed, and difficult The effect of punching and explosion accidents

Active Publication Date: 2014-04-02
JIANGSU HANSYN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method produces hydrogen at a very fast rate during the reduction reaction, and the reducing agent cannot be put in at one time, which not only wastes time, but also is extremely unsafe in the production process, and is prone to material flushing and explosion accidents

Method used

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  • Preparation method of florfenicol oxazoline intermediate
  • Preparation method of florfenicol oxazoline intermediate
  • Preparation method of florfenicol oxazoline intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] In parts by weight, weigh 550 parts of methanol, add it into the reaction bottle, weigh 0.5 part of sodium methoxide, add it into methanol and stir to dissolve. Weigh 95 parts of D-p-thymphenylphenylserine ethyl ester, stir and add it into the reaction flask at room temperature. Weigh 20 parts of sodium borohydride, add it into the reaction bottle at room temperature at one time, and then react at a temperature of 50° C. for 6 hours. After the reaction, methanol was concentrated under reduced pressure, then 150 parts of glycerin was added, and the pH was adjusted to 6-7 with glacial acetic acid; 42 parts of dichloroacetonitrile was weighed and added dropwise to the reaction solution, and the temperature was raised to 50°C for 18 hours. After the reaction, 250 parts of 25% ethanol aqueous solution was added dropwise to the reaction solution with stirring and dropping to room temperature, followed by suction filtration, washing and drying to obtain 103 parts of white powd...

Embodiment 2

[0030] In parts by weight, weigh 600 parts of ethanol, add it into the reaction bottle, weigh 0.7 part of sodium ethylate, add it into the ethanol and stir to dissolve. Weigh 100 parts of D-p-thymphenylphenylserine ethyl ester, stir and add it into the reaction flask at room temperature. Weigh 18 parts of sodium borohydride, add it into the reaction bottle at room temperature at one time, and then react at a temperature of 50° C. for 6 hours. After the reaction, ethanol was concentrated under reduced pressure, 170 parts of glycerin was added, and the pH was adjusted to 6-7 with glacial acetic acid. Weighed 45 parts of dichloroacetonitrile and added dropwise to the reaction solution, and heated to 50°C for 18 hours. , after the reaction, stir and drop 250 parts of 25% ethanol aqueous solution in the reaction solution, suction filter after cooling down to room temperature, wash and dry to obtain 102 parts of white powdery florfenicol oxazoline intermediate, molar yield 86.7 %,...

Embodiment 3

[0032] In parts by weight, weigh 600 parts of methanol, add it into the reaction bottle, weigh 0.7 parts of potassium tert-butoxide, add it into methanol and stir to dissolve. Weigh 100 parts of D-p-thymphenylphenylserine ethyl ester, stir and add it into the reaction flask at room temperature. Weigh 18 parts of sodium borohydride, add it into the reaction bottle at room temperature at one time, and then react at a temperature of 48° C. for 6 hours. After the reaction, the methanol was concentrated under reduced pressure, 180 parts of glycerin was added, and the pH was adjusted to 6-7 with glacial acetic acid. Weighed 40 parts of dichloroacetonitrile and added dropwise to the reaction solution, and heated to 50°C for 18 hours. After the reaction, 250 parts of 25% ethanol aqueous solution was added dropwise to the reaction solution with stirring and dropping to room temperature, followed by suction filtration, washing, and drying to obtain 102 parts of white powdery florfenico...

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Abstract

The invention relates to a preparation method of a florfenicol oxazoline intermediate, and belongs to the technical field of drug preparations. The preparation method of the florfenicol oxazoline intermediate as shown in a formula (I) comprises the following steps: using D-p-methyl sulfone phenyl ethyl serinate as a raw material, adding a reducing agent into an alcohol proton solution of organic alkali in one time, performing a reducing reaction to generate ADS (amino diol sulfone), and controlling a reaction endpoint by HPLC (high performance liquid chromatography); after the reducing reaction, concentrating a solvent; adding glycerin for destroying the excess reducing agent, adjusting the pH value to be 6-7 by acid, dropwise adding dichloroacetonitrile, heating to 50 DEG C, performing a cyclization reaction, and controlling a reaction endpoint by the HPLC; after the cyclization reaction, dropwise adding an ethanol water solution, conducting a centrifugal process, washing, and drying to obtain the florfenicol hydroxyl oxazoline intermediate as shown in the formula (I). According to the method, the reducing agent can be added in one time; meanwhile, the hydrogen release speed in the preparation process is very slow, so that the safety is greatly improved.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of a florfenicol oxazoline intermediate. Background technique [0002] Florfenicol is a broad-spectrum antibiotic for veterinary use. Generally, in order to protect one of the hydroxyl groups in the preparation process of Florfenicol, the Florfenicol oxazoline intermediate should be prepared first. Schering company patent CN1233244A provides a preparation method for preparing florfenicol oxazoline intermediate: take D-p-thymphenylphenylserine ethyl ester as raw material, in alcoholic protic solvents such as methanol, ethanol, ethylene glycol, glycerine Alcohol and its mixture, slowly add reducing agent such as NaBH 4 , Ca(BH 4 ) 2 、KBH 4 、LiBH 4 Wait for the reduction to generate ADS (aminodiol sulfone), HPLC controls the reaction end point, after the reduction reaction is completed, add glycerin to destroy the excess reducing agen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/14
CPCC07D263/14
Inventor 王希林王旭蒋成华
Owner JIANGSU HANSYN PHARMA
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