Preparation method for florfenicol intermediate, namely thiamphenicol amine

Abstract

The invention provides a preparation method for a florfenicol intermediate, namely thiamphenicol amine, and belongs to the filed of pharmaceutical intermediate synthesis processes. The preparation method comprises the steps that in a pressure kettle, D-4-Methylsulfonylphenyl serine ethyl ester, potassium borohydride and methyl alcohol are subjected to one-time feeding or a continuous feeding reaction through a pipeline reactor, the temperature is controlled to be 35-65 DEG C, the control pressure of a back pressure valve is lower than 0.1 MPA, after the reaction is completed, the pressure in areaction kettle is utilized to conduct flashing on reaction liquid, the obtained thiamphenicol amine continues being reacted, and a florfenicol intermediate cyclic compound is obtained. According tothe preparation method, the catalytic amount of potassium borohydride is adopted for reaction, thus the obtained impurity content can be less than 0.5%, the reaction time is short, product purify is relatively simplified, the hydrogen spillover risk is effectively lowered, and the preparation method is an effective environment-friendly reduction process.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of a florfenicol intermediate thiamphenicol, belonging to the technical field of pharmaceutical intermediate synthesis process amplification, Background technique [0002] (1R,2R)-2-amino-1-(p-methylsulfonyl)-1,3-propanediol, English name (1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1 ,3-propandiol, referred to as thiamphenicolamine. At present, it is obtained by reducing D-thiamphenicol phenylserine ethyl ester, and it is the most important intermediate of veterinary drugs florfenicol and thiamphenicol. [0003] US2007 / 55066 discloses that D-p-thymphenylphenylserine ethyl ester and 1.5 equivalents of potassium borohydride can be quantitatively reduced in methanol solvent at 50-60°C to obtain a solution of thiamphenicolamine; that is, the application uses excess potassium borohydride to carry out Reduction, the reaction will produce a...

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Problems solved by technology

[0006] In the reduction reaction, the feeding speed is very critical. If potassium borohydride is added too quickly, or the temperature reaction is too high, accidents such as the reaction kettle material rushing out of the kettle and explosion will be caused. In addition, hydrogen gas is continuously generated in the process of adding potassium borohydride in batches. Prone to safety accidents; adding potassium borohydride in batches will cause a very long reduction time, and transesterification will occur to generate D-p-thymphenyl phenylserine methyl ester, which cannot be reduced by using less reductive potassium borohydride, reducing the yield rate; although sodium borohydride can be used for complete reduction (reference: US2007 / 55066, react with 1.6 equivalent NaBH4, 50-60°C for 4-8h), but due to increased reactivity, the risk is stronger; the reaction temperature is controlled at -10°C To -15 ℃ cold brine, control the reaction and in the process of distilling methanol, also use refrigerated brine to cool the methanol, and the energy consumption is also high; the whole reduction reaction time is 6 hours, and the utilization rate of the equipment is very low

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