A kind of asymmetric preparation method of florfenicol intermediate cyclic compound

A technology of florfenicol and cyclic compound, which is applied in the field of asymmetric preparation of florfenicol intermediate cyclic compound, can solve the problems of short reaction time, cannot be promoted, cannot have higher yield reaction time and the like, and achieves the The effect of easy operation, saving of raw materials and good preparation effect

Active Publication Date: 2020-12-29
HUBEI ZHONGMU ANDA PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Due to the properties of this molecule, the method cannot be extended to the synthesis of other similar structures
This is determined by the ingenuity of the preparation method, the higher yield and the non-reproducibility of the shorter reaction time obtained from numerous experiments. Other routes basically cannot have higher yield or acceptable reaction time.

Method used

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  • A kind of asymmetric preparation method of florfenicol intermediate cyclic compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] The specific preparation steps are as follows: 1) Cyclization step: D-serine ethyl ester I is selected as raw material A, 2,2-dichloromethyl imidate is selected as raw material B, dichloromethane is selected as solvent C; the molar ratio of raw material A and raw material B is The ratio is 1:1.5, and the quality of solvent C is 16 times of the total mass of raw material A and raw material B; raw material A and raw material B are added in solvent C, and sodium ethylate is selected from the base D group to add, and guarantee the content of the base material If the amount is excessive, stir the reaction at a speed of 2-5r / s at a temperature between -55 and -35°C for at least 12 hours. TLC confirms that the conversion is complete, and distills off methanol under reduced pressure. Use an appropriate amount of deionized water and The dichloromethane was repeatedly extracted several times, the organic phases were combined, dried over anhydrous sodium sulfate, and the dichlorome...

Embodiment 2

[0029] The specific preparation steps are as follows: 1) Cyclization step: D-serine ethyl ester I is selected as raw material A, 2,2-dichloromethylimidate is selected as raw material B, tetrahydrofuran is selected as solvent C; the molar ratio of raw material A and raw material B is The ratio is 1:1.2, and the quality of solvent C is at least 18 times the total mass of raw material A and raw material B; raw material A and raw material B are added to solvent C, and diisopropylethylamine is selected from base D group to add, And ensure that the amount of the alkali substance is excessive, at a temperature between -50 and -30°C, stir the reaction at a speed of 4-7r / s for at least 12h, TLC confirms that the conversion is complete, distills off the methanol under reduced pressure, and uses An appropriate amount of deionized water and dichloromethane were repeatedly extracted several times, the organic phases were combined, dried over anhydrous sodium sulfate, and the dichloromethane...

Embodiment 3

[0035] The preparation steps are as follows: 1) Cyclization step: D-serine ethyl ester hydrochloride is selected as raw material A, 2,2-dichloromethyl imidate is selected as raw material B, and chloroform and isopropanol are selected as solvent C The ratio is 1:1; the molar ratio of raw material A to raw material B is 1:1, and the mass of solvent C is at least 20 times the total mass of raw material A and raw material B; adding raw material A and raw material B to solvent C, Select triethylamine from the base D group to add, and ensure that the amount of the base is excessive, at a temperature between -45 and -25°C, stir the reaction at a speed of 6-9 / s for at least 12h, TLC Confirm that the conversion is complete, remove methanol by distillation under reduced pressure, repeatedly extract several times with appropriate amount of deionized water and methylene chloride, combine the organic phases, dry over anhydrous sodium sulfate, remove methylene chloride by distillation under ...

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Abstract

The invention discloses an asymmetric preparation method of a florfenicol intermediate cyclocompound. An optically pure cyclocompound is prepared by adopting D-ethyl serinate, dichloroacetonitrile, methylsulfonyl bromobenzene and the like as main raw materials, and implementing the five steps of cyclization, reduction, oxidation, asymmetric addition and isomerization reaction. The asymmetric addition reaction in the method has mild conditions; in an organic solvent and under the catalysis of a BINOL chiral ligand-Ti complex catalyst, an addition reaction between 4-methylsulfonyl phenylmagnesium bromide and (4R)-2-(dichloromethyl)-4,5-dihydro-4-oxazole formaldehyde is carried out to complete key steps, and the reaction yield and the selectivity are high.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to an asymmetric preparation method of a florfenicol intermediate ring compound. Background technique [0002] The chemical name of the intermediate cyclic compound of Florfenicol: (4R,5R)-2-(dichloromethyl)-4,5-dihydro-5-[4-thiamphenyl)phenyl]-4- Oxazole methanol, white powder, molecular formula: C 12 h 13 Cl 2 NO 4 S. [0003] Florfenicol is a new generation of chloramphenicol broad-spectrum antibiotics, which has a wide range of uses in clinical medicine and agriculture. The cyclic compound is the key intermediate for the synthesis of florfenicol. The main method for synthesizing the cyclic compound is to use optically pure D-(+)-threo-p-thiamphenicol phenylserine ethyl ester as a raw material in In an alcohol solvent, under the action of a reducing agent, it is reduced to thiamphenicol; thiamphenicol and dichloroacetonitrile undergo a cyclization reaction in gly...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/14
CPCC07D263/14
Inventor 麻红利徐金雷王峥张胜强刘润峰李祖义
Owner HUBEI ZHONGMU ANDA PHARMACEUTICAL CO LTD
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