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Preparation method of (2'R)-2'-deoxidation-2'-fluorine-2'-methylurea glucoside

A technology of methyl uridine and methyl, applied in the field of preparation of (2'R)-2'-deoxy-2'-fluorine-2'-methyl uridine, can solve the problem of unsuitable large-scale industrial production, technology Complex routes and other problems, to achieve the effect of reducing the amount of solvent used, the overall yield is high, and reducing the generation of solid waste

Active Publication Date: 2016-11-09
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the process route for synthesizing (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine is complex, requires the use of highly toxic substances such as barium chloride, and produces a large amount of solid waste, which is not suitable for Large-scale industrial production

Method used

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  • Preparation method of (2'R)-2'-deoxidation-2'-fluorine-2'-methylurea glucoside

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Effect test

Embodiment 1

[0026] 1. Preparation of intermediate Ⅰ

[0027] Under anhydrous and oxygen-free conditions, add 80g 2-C-methyl-D ribono-1,4-lactone, 4g 4-dimethylaminopyridine, 187g 1,3-dichloro-1, 1,3,3-Tetraisopropyl dimethylsiloxane and 1500mL acetonitrile, stirred, cooled to 15-20°C to react, TLC to monitor the reaction; after the reaction was completed, evaporate acetonitrile under reduced pressure, add 1000mL ethyl acetate and 300mL saturated Sodium bicarbonate solution, stirred, left to stand for liquid separation, the aqueous layer was extracted with ethyl acetate (800mL×2), the organic phases were combined, washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered with suction, concentrated to dryness under reduced pressure , to obtain crude brown-yellow solid. The crude product was refined with 5 times the amount of isopropanol to obtain 169 g of light yellow solid product. Yield: 85%.

[0028] 2. Preparation of Intermediate II

[0029] Add 169g of int...

Embodiment 2

[0037] 1. Preparation of intermediate Ⅰ

[0038] Under anhydrous and oxygen-free conditions, add 65g 2-C-methyl-D ribono-1,4-lactone, 8g N,N-diisopropylethylamine, 150g 1,3-di Chloro-1,1,3,3-tetraisopropyl dimethyl siloxy ether and 1000mL tetrahydrofuran, stirred, cooled to 15-20°C to react, TLC to monitor the reaction; after the reaction was completed, distill off tetrahydrofuran under reduced pressure, add 600mL toluene and 100mL saturated sodium bicarbonate solution, stirred, allowed to stand for liquid separation, extracted the aqueous layer with toluene (400mL×2), combined the organic phases, washed with sodium chloride solution, dried over anhydrous sodium sulfate, suction filtered, and concentrated to dryness under reduced pressure , to obtain crude brown-yellow solid. The crude product was refined with 5 times the amount of isopropanol to obtain 137 g of light yellow solid product. Yield: 86%.

[0039] 2. Preparation of Intermediate II

[0040] Add 137g of intermed...

Embodiment 3

[0048] 1. Preparation of intermediate Ⅰ

[0049] Under anhydrous and oxygen-free conditions, add 48g 2-C-methyl-D ribono-1,4-lactone, 8g piperidine, 112g 1,3-dichloro-1,1,3,3 -Tetraisopropyl dimethyl siloxy ether and 800mL acetonitrile, stirred, cooled to 15-20°C to react, TLC to monitor the reaction; after the reaction was completed, the acetonitrile was evaporated under reduced pressure, and 800mL ethyl acetate and 200mL saturated sodium bicarbonate solution were added, Stir, stand still for liquid separation, extract the aqueous layer with ethyl acetate (300mL×2), combine the organic phases, wash with sodium chloride solution, dry over anhydrous sodium sulfate, filter with suction, and concentrate to dryness under reduced pressure to obtain a brown-yellow solid Crude. The crude product was refined with 5 times the amount of isopropanol to obtain 101 g of a light yellow solid product. Yield: 85%.

[0050] 2. Preparation of Intermediate II

[0051] Add 101g of intermediat...

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Abstract

The invention discloses a preparation method of (2'R)-2'-deoxidation-2'-fluorine-2'-methylurea glucoside. According to the method, the (2'R)-2'-deoxidation-2'-fluorine-2'-methylurea glucoside is prepared by using 2-C-methyl-D ribotide-1,4-lactone as a starting material through the steps of silanization, fluorination, reduction, etherification, butt joint and hydrolysis reaction. The preparation method has the advantages that the route is simple and short; the use of highly toxic and harmful substances of barium chloride is avoided; the generation of a large number of solid wastes such as triphenylphosphine oxide is avoided; the acid of the catalytic amount is subjected to deprotection reaction; the use of a large amount of ammonia gas methyl alcohol for protecting group degreasing is avoided; the usage amount of dissolvent and the generation quantity of industrial wastes are reduced; the target product of alpha isomers can be recovered and used; the generation of solid wastes is reduced to the greatest degree. The total yield of the route is high; the intermediate is easily refined and purified; the preparation method is suitable for large-scale industrial production.

Description

technical field [0001] The present invention relates to a preparation method of an important intermediate of sofosbuvir, in particular to a preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine . Background technique [0002] (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine is an important intermediate for the synthesis of sofosbuvir, CAS registration number: 863329-66-2, as shown in formula IV. [0003] [0004] At present, the process route for synthesizing (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine is complicated, requires the use of highly toxic substances such as barium chloride, and produces a large amount of solid waste, which is not suitable for Large-scale industrial production. Therefore, a new technical solution is needed to solve the above technical problems. Contents of the invention [0005] The purpose of the present invention is to solve the above technical problems, to provide a short process route, avoid the use of barium chloride and other toxic ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073C07H1/00C07D497/04
CPCY02P20/55C07H19/073C07D497/04C07H1/00
Inventor 李泽标张兆国林燕峰张磊丁海明严军
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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