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Preparation method of D-threo-2-(dichloromethyl)-4, 5-dihydro-5-(p-(methylsulfonyl) phenyl)-4-oxazole methanol

A technology of dichloromethyl and oxazole methanol, applied in the field of preparation of florfenicol intermediates, can solve the problems of high cost, long process steps, cumbersome operation, etc., and achieve low cost, simple operation and high yield high effect

Active Publication Date: 2009-10-07
JIANGSU HANSYN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

All of the above have the disadvantages of long process steps, cumbersome operation and high cost.

Method used

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  • Preparation method of D-threo-2-(dichloromethyl)-4, 5-dihydro-5-(p-(methylsulfonyl) phenyl)-4-oxazole methanol
  • Preparation method of D-threo-2-(dichloromethyl)-4, 5-dihydro-5-(p-(methylsulfonyl) phenyl)-4-oxazole methanol
  • Preparation method of D-threo-2-(dichloromethyl)-4, 5-dihydro-5-(p-(methylsulfonyl) phenyl)-4-oxazole methanol

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Add 100 g of D-p-thymphenylphenylserine ethyl ester (I) into 700 g of methanol solvent, add 27 g of potassium borohydride, and react at 30-50° C. After the reduction reaction is completed in about 6 hours. Distill under reduced pressure below 40°C, remove 600g of methanol, add 300g of glycerin to form a mixed solvent, add hydrochloric acid to neutralize, adjust pH = 7.5, add 44g of dichloroacetonitrile, stir at 50°C for 18 hours, recover methanol by distillation under reduced pressure below 40°C , add isopropanol aqueous solution, stir, filter, and dry to obtain D-threo-2-(dichloromethyl)-4,5-dihydro-5-[p-(thysulfonyl)phenyl]- 103 g of 4-oxazole methanol (III). Melting point: 143-144°C; Optical rotation: [a] 20 D +11.5, IR KBr cm-1:: 3350, 2930, 1670; ESI-MS (M+1): 339.7; hydrogen spectrum data, carbon spectrum data are shown in Table 2, yield 103%.

[0046] Table 2

[0047]

[0048] Literature sources of reference compounds: Guangzhong Wu, Doris P.Schumacher, ...

Embodiment 2

[0050] Add 100 g of D-p-thymphenylphenylserine ethyl ester (I) into 700 g of methanol solvent, add 27 g of potassium borohydride, and react at 30-50° C. After the reduction reaction is completed in about 6 hours. Distill under reduced pressure below 40°C, remove 600g of methanol, add 300g of glycerin to form a mixed solvent, add sulfuric acid to neutralize, adjust pH = 10.0, add 44g of dichloroacetonitrile, stir at 50°C for 18 hours, and recover methanol by distillation under reduced pressure below 40°C , add isopropanol aqueous solution, stir, filter, and dry to obtain D-threo-2-(dichloromethyl)-4,5-dihydro-5-[p-(thysulfonyl)phenyl]- 82 g of 4-oxazole methanol (III), the yield was 82%.

Embodiment 3

[0052] Add 100 g of D-p-thymphenylphenylserine ethyl ester (I) into 700 g of methanol solvent, add 27 g of potassium borohydride, and react at 30-50° C., after 6 hours of reduction reaction. Distill under reduced pressure below 40°C, remove 600g of methanol, add 300g of glycerin to form a mixed solvent, add acetic acid to neutralize, adjust pH=7.1, add 44g of dichloroacetonitrile, stir at 50°C for 18 hours, and recover methanol by distillation under reduced pressure below 40°C , add isopropanol aqueous solution, stir, filter, and dry to obtain D-threo-2-(dichloromethyl)-4,5-dihydro-5-[p-(thysulfonyl)phenyl]- 99g of 4-oxazolemethanol (III), the yield is 99%.

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Abstract

The invention relates to a preparation method of florfenicol intermediate, in particular to a preparation method of D-threo-2-(dichloromethyl)-4, 5-dihydro-5-(p-(methylsulfonyl) phenyl)-4-oxazole methanol, which comprises the detailed steps as follows: 100 portions of D-p-methylsulfino phenyl ethyl serinate (I) are dissolved in 500 to 700 portions of methanol; then 24 to 27 portions of potassium borohydride are added; the reaction temperature is between 30 and 50 DEG C and the reaction time is between 4 and 8 hours; 80 to 150 portions of methanol are recycled and 230 to 300 portions of glycerol are added; then acid is used for neutralizing the reaction solution to adjust the pH of the solution to be between 7 and 10; and 42 to 45 portions of dochloroacetonitril are added to generate the D-threo-2-(dichloromethyl)-4, 5-dihydro-5-(p-(methylsulfonyl) phenyl)-4-oxazole methanol (II). The preparation method has the characteristics of few technique steps, simple operation and low cost.

Description

1. Technical field [0001] The present invention relates to the preparation method of florfenicol intermediate, particularly relate to D-threo-2-(dichloromethyl)-4,5-dihydro-5-[p-(thymphenyl)phenyl]- The preparation method of 4-oxazole methanol. 2. Background of the invention [0002] Florfenicol is a veterinary broad-spectrum antibiotic used to treat Gram-positive, Gram-negative and Rickettsial infections in animals. Its synthetic method is as CN1233244A adopts D-p-thymphenyl phenylserine ethyl ester (I) reduction, acidification becomes D-threo-2-amino-1-[(p-thymphenyl) phenyl]-1,3- Propylene glycol (ADS, II), or thiamphenicol is hydrolyzed to obtain ADS, and the cyclic compound is synthesized from dichloroacetonitrile in glycerol solvent under acidic conditions: A D-threo-2-(dichloromethyl)-4,5 -Dihydro-a-[p-(thymphenyl)phenyl]-4-oxazolemethanol (IV) and D-threo-2-(dichloromethyl)-4,5-dihydro-5- [P-(methylsulfonyl)phenyl]-4-oxazolemethanol (III) (A:B=30:70), isolate A, r...

Claims

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Application Information

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IPC IPC(8): C07D263/14
Inventor 周留扣唐忠松张汉兴
Owner JIANGSU HANSYN PHARMA
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