Novel synthetic method of high-purity florfenicol

A florfenicol and high-purity technology, applied in the new field of high-purity florfenicol synthesis, can solve the problem that the finished product cannot meet the high-standard florfenicol finished product, the high-purity florfenicol has high cost, and the single impurity exceeds the standard. Solvent and other problems, to achieve the effect of low cost, less impurities and shortened process steps

Inactive Publication Date: 2014-08-13
京山瑞生制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the high impurity content of the crude product and the dark color of such finished products, the refined finished products still contain a large amount of impurities, often appear too dark in color, poor solubility, excessive single impurity and solvent exceed the standard, so that the finished product cannot meet the high requirements. Specifications Requirements for finished products of Florfenicol, such as requirements for injections, etc.
In actual production, in order to meet the requirements of high-standard Florfenicol finished products, such as injections, etc., it is often necessary to further recrystallize the obtained Florfenicol finished product several times before preparing high-standard Florfenicol finished products , which makes high-purity florfenicol expensive

Method used

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  • Novel synthetic method of high-purity florfenicol
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  • Novel synthetic method of high-purity florfenicol

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Dissolve 33 grams of diethylamine in 330 milliliters of dichloromethane, lower the temperature to -20 ° C, keep stirring, slowly pass in 75 grams of hexafluoropropylene, keep stirring for half an hour after passing through, transfer to a 1-liter high-pressure reactor, and add 100 Gram D-threo-2-(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl)phenyl]-4-oxazolemethanol, the temperature was raised to 100°C, and the pressure in the kettle 0.55MPa, heat preservation reaction for 2 hours, take out to obtain a batch of fluorine substitution reaction liquid. Wash the fluorine substitution reaction solution with 500 ml of 10% aqueous sodium carbonate solution, stir for 0.5 hours, let stand to separate layers, wash the organic phase with 500 ml of water until the pH of the reaction solution is 7, distill part of the solvent at atmospheric pressure, and then cool down Crystallization, the crystals were filtered at 0°C to obtain white high-purity fluorinated product (4S,5R)-2-(di...

Embodiment 2

[0034] Dissolve 33 grams of diethylamine in 330 milliliters of dichloromethane, lower the temperature to -20 ° C, keep stirring, slowly pass in 75 grams of hexafluoropropylene, keep stirring for half an hour after passing through, transfer to a 1-liter high-pressure reactor, and add 100 Gram D-threo-2-(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl)phenyl]-4-oxazolemethanol, the temperature was raised to 100°C, and the pressure in the kettle 0.55MPa, heat preservation reaction for 2 hours, take out to obtain a batch of fluorine substitution reaction liquid. The fluorine substitution reaction solution was first washed with 500 ml of 10% sodium acetate aqueous solution, stirred for 0.5 hours, allowed to stand for stratification, and the organic phase was washed with 500 ml of water until the pH of the reaction solution was 7. After distilling part of the solvent at atmospheric pressure, the temperature was lowered. Crystallization, the crystals were filtered at 0°C to obtain w...

Embodiment 3

[0036] Dissolve 33 grams of diethylamine in 330 milliliters of dichloromethane, lower the temperature to -20 ° C, keep stirring, slowly pass in 75 grams of hexafluoropropylene, keep stirring for half an hour after passing through, transfer to a 1-liter high-pressure reactor, and add 100 Gram D-threo-2-(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl)phenyl]-4-oxazolemethanol, the temperature was raised to 100°C, and the pressure in the kettle 0.55MPa, heat preservation reaction for 2 hours, take out to obtain a batch of fluorine substitution reaction liquid. The fluorine substitution reaction solution was first washed with 500 milliliters of 10% aqueous sodium bicarbonate solution, stirred for 0.5 hours, allowed to stand for stratification, and the organic phase was washed with 500 milliliters of water until the pH of the reaction solution was 7. After distilling part of the solvent under normal pressure, Cool down to crystallize, and filter the crystals at 0°C to obtain a wh...

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Abstract

The invention provides a novel synthetic process of high-purity florfenicol. The process comprises the following steps: by taking a compound D-threo form-2-(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl)phenyl]-4-oxazole methanol as an initial raw material, carrying out fluoro-substitution by using an Ishikawa reagent; crystallizing and purifying to obtain a high-purity fluoro product (4S,5S)-2-(dichloracetyl)-4-(methyl fluoride)-5-[4-(methylsulfonyl)phenyl]-4, 5-dihydrooxazole; and further carrying out a hydrolysis reaction directly on the high-purity fluoro product without being added into an organic solvent to directly obtain a high purity florfenicol product. According to the production process, the fluoro intermediate product is crystallized and purified to obtain a high purity product by adopting a direct hydrolysis process without using the organic solvent, so that the novel synthetic method is simple in process operation, environmental friendly, high in product purity, few in impurity, free from solvent residue and low in cost.

Description

technical field [0001] The invention relates to a chemical synthesis method, in particular to a new synthesis method of high-purity florfenicol. Background technique [0002] Florfenicol, molecular formula: C 12 h 14 CL 2 FNO 4 S, molecular weight: 358.2, CAS No.: 73231-34-2, its structural formula is as follows: [0003] [0004] Florfenicol (Florfenicol) Chinese name: fluprofen; An antibacterial drug that can be used to treat infections caused by Gram-positive bacteria, Gram-negative bacteria, and Rickettsiae. It was first launched in Japan in 1990. In 1993, Norway approved the drug to treat salmon furunculosis. In 1995, France, the United Kingdom, Austria, Mexico and Spain approved it to treat bovine respiratory system bacterial diseases. It is also approved as a feed additive for pigs in Japan and Mexico to prevent and treat bacterial diseases in pigs. [0005] There have been many reports on the synthesis and production methods of Florfenicol. Nagabhushan of ...

Claims

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Application Information

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IPC IPC(8): C07C317/32C07C315/04
Inventor 张治国钟旭辉张伟略谢娜
Owner 京山瑞生制药有限公司
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