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Florfenicol intermediate preparation method

A technology of florfenicol and intermediates, which is applied in the field of preparation of florfenicol intermediates, can solve problems such as poor control of process parameters, unsuitability for industrialized production, and low industrialization value, etc., so as to improve the total conversion rate , Novel synthetic route and reduced production cost

Inactive Publication Date: 2021-09-17
SHANDONG GUOBANG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the existing production process, a D-threo-2-(dichloromethyl)-4,5-dihydro-5-[4-(methylsulfonyl)-phenyl is reported in the patent CN110218199A The preparation method of ]-4-oxazole methanol, this method is raw material with D-p-thymphenyl phenylserine ethyl ester, first adds dichloroacetonitrile and carries out cyclization reaction, then adds boron sodium and carries out reduction and obtains intermediate, this method needs Continuous high temperature, high process risk, difficult control of process parameters, high energy consumption, and low yield, not suitable for industrial production
[0004] Another synthesis method is adopted in the patent CN110256371A. In this process, p-thiamphenicyl benzaldehyde is used as raw material and 2-aminoethanol is added to catalyze Cu(OTf)2 / L complex for asymmetric addition. The reaction temperature is 20-80°C. The reaction time is 4-24 hours to obtain (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl)propane-1,3-diol, then add dichloroacetonitrile and solvent, and keep warm for 50 React at -100°C for 6-24 hours. After the reaction, add water to cool down and precipitate the product. After filtration, D-threo-2-(dichloromethyl)-4,5-dihydro-5-[4-(methyl Sulfonyl)-phenyl]-4-oxazole methanol, this synthesis process needs to use the complex of copper as catalyst and can produce a large amount of copper-containing waste water in the production, and post-treatment is more difficult, if handle badly to follow-up cyclization The process has a great influence, and the color yield will be reduced, and the cost of the process is relatively high, and the implementation of industrialization is of little value

Method used

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Experimental program
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Effect test

Embodiment 1

[0029] In a 500ml four-neck flask, add 300g of methanol and raise the temperature to 30°C, add 45.01g of D-p-thymphenylphenylserine ethyl ester, control the temperature at 30°C, add 8.89g of sodium borohydride, and feed the process of sodium borohydride , use ice water to cool down and control the reaction temperature at 37°C, then keep it warm in a water bath at 37°C, stir and react for 4 hours, after the heat preservation is over, use ice water to cool down to 5°C, add hydrochloric acid to adjust the pH value to 7.0, and weigh the total mass of the raw material solution , the sample was sent to the liquid phase to detect the external standard, and the reduction conversion rate was 96.30%. The reduction reaction obtained a mixed solution of the product D-threo-2-amino-1-p-thiamphenylphenyl-1,3-propanediol and boron ester. Set the temperature of the water bath to 75°C to carry out the distillation operation to recover the boron ester therein, recover until the solution bubbles ...

Embodiment 2

[0031]In a 500ml four-neck flask, add 300g of methanol and raise the temperature to 30°C, add 45.01g of D-p-thymphenylphenylserine ethyl ester, control the temperature at 30°C, add 8.29g of sodium borohydride, and feed the process of sodium borohydride , use ice water to cool down and control the reaction temperature at 37°C, then keep it warm in a water bath at 37°C, stir and react for 4 hours, after the heat preservation is over, use ice water to cool down to 5°C, add hydrochloric acid to adjust the pH value to 7.0, and weigh the total mass of the raw material solution , the sample was sent to the liquid phase to detect the external standard, and the reduction conversion rate was 95.47%. The reduction reaction obtained the product D-threo-2-amino-1-p-thiamphenylphenyl-1,3-propanediol and a mixed solution of boroester. Set the temperature of the water bath to 75°C to carry out the distillation operation to recover the boron ester therein, recover until the solution bubbles and...

Embodiment 3

[0033] In a 500ml four-necked flask, add 300g of methanol and raise the temperature to 30°C, add 45.02g of D-p-thymphenylphenylserine ethyl ester, control the temperature at 30°C, add 9.48g of sodium borohydride, and feed the process of sodium borohydride , use ice water to cool down and control the reaction temperature at 37°C, then keep it warm in a water bath at 37°C, stir and react for 4 hours, after the heat preservation is over, use ice water to cool down to 5°C, add hydrochloric acid to adjust the pH value to 7.0, and weigh the total mass of the raw material solution , the sample was sent to the liquid phase to detect the external standard, and the reduction conversion rate was 96.38%. The reduction reaction obtained a mixed solution of the product D-threo-2-amino-1-p-thiamphenylphenyl-1,3-propanediol and boron ester. Set the temperature of the water bath to 75°C to carry out the distillation operation to recover the boron ester therein, recover until the solution bubble...

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Abstract

The invention discloses a florfenicol intermediate preparation method, which comprises: carrying out a reaction by using D-p-methylsulfonyl phenyl serine ethyl ester as a raw material, and reducing by using sodium borohydride as a reducing agent to obtain D-threon-2-amino-1-p-methylsulfonyl phenyl-1, 3-propylene glycol; preparing a cyclization protection reagent 1, 1-trimethyl dichloroorthoacetate from dichloroacetonitrile, methanol and hydrochloric acid; reacting D-threon-2-amino-1-p-methylsulfonyl phenyl-1, 3-propylene glycol with 1, 1-trimethyl dichloroorthoacetate to obtain the florfenicol intermediate D-threon-2-(dichloromethyl)-4, 5-dihydro-5-[4-(methylsulfonyl)-phenyl]-4-oxazole methanol. The method overcomes the defects of the prior art, shortens the reaction time, improves the yield, reduces the production cost, is simple to operate, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic chemical industry, and also belongs to the technical field of synthesis of veterinary drugs and pharmaceutical raw materials, in particular to a preparation method of a florfenicol intermediate. Background technique [0002] Florfenicol is a broad-spectrum antibiotic of the chloramphenicol class. It can tightly combine with the 50S subunit of bacterial 70S ribosome, inhibit the combination of RNA and ribosome and reduce the activity of peptidyltransferase, thereby inhibiting the extension of peptide chain and interfering with the synthesis of bacterial protein. It is widely distributed in the body and well absorbed. The utilization rate is as high as 96%. It is a new generation of chloramphenicol-type animal-specific broad-spectrum antibiotics. It has a broad antibacterial spectrum and good antibacterial effect. It can pass through the blood-brain barrier and has no cross-resistance with other com...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/18
CPCC07D263/18C07B2200/07
Inventor 廖仕学王兴国刘君王同龙王庆伟
Owner SHANDONG GUOBANG PHARMA
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