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A kind of preparation method of ribofuranose phosphate derivative

A technology of ribofuranose phosphate and derivatives, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems of long process route, difficult to control the purity, cumbersome operation, etc., and the purity is easy to control and avoid The effect of excessive loss and easy operation

Active Publication Date: 2016-04-06
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The standard treatment regimen is pegylated interferon (Peg-IFN) combined with ribavirin (RBV), the overall cure rate is less than 50%, and it is necessary to adhere to a sufficient dose of continuous treatment for more than one year
[0006] At present, most of the preparation methods of sofosbuvir have the following disadvantages: the yield of the docking reaction of the main chain side chain fragments is low, the product is not easy to purify, which affects the quality of the subsequent reaction; the process route is long and the operation is cumbersome; there are many types of solvents used, which are difficult to recycle; The reaction yield of sofosbuvir finished product is low, the content of isomers is relatively large, and the purity is difficult to control

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  • A kind of preparation method of ribofuranose phosphate derivative

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Experimental program
Comparison scheme
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Embodiment 1

[0037] Preparation of intermediate formula 1:

[0038] Add 200mL of dichloromethane, 50g of L-alanine isopropyl hydrochloride and 38.3g of DIPEA into the reaction flask, stir, cool down to -78°C, react for 30min, then add dropwise the dichloromethane solution of phenol dichlorophosphate ( 63g / 120mL); after dropping, stir the reaction for 30min, then raise the temperature to -10℃ for 3 hours. Dissolve 55.4g of perfluorophenol and 35.2g of DIPEA in 200mL of dichloromethane, and add dropwise to the above-mentioned reaction solution; after dropping, stir the reaction, and monitor the reaction by TLC; after the reaction is completed, filter with suction, and wash the filter cake with 50mL of dichloromethane. Combine the organic phases, concentrate under reduced pressure, dissolve and beat with 500 mL of methyl tert-butyl ether, filter with suction, wash the filter cake with 50 mL of methyl tert-butyl ether, combine the organic phases, and concentrate under reduced pressure to obtai...

Embodiment 2

[0052] Preparation of intermediate formula 1:

[0053] Add 200mL of dichloromethane, 50g of L-alanine isopropyl hydrochloride and 30g of triethylamine into the reaction flask, stir, cool down to -78°C, react for 30min, then add dropwise dichloromethane of phenol dichlorophosphate solution (63g / 1200mL); after dropping, stir the reaction for 30min, then raise the temperature to -10°C for 3 hours. Dissolve 42.7g of 4-nitrophenol and 30.6g of triethylamine in 200mL of dichloromethane, and add dropwise to the above-mentioned reaction solution; after dropping, stir the reaction, and monitor the reaction by TLC; Wash with methyl chloride, combine the organic phases, concentrate under reduced pressure, dissolve and beat with 500 mL of isopropyl ether, filter with suction, wash the filter cake with 50 mL of isopropyl ether, combine the organic phases, and concentrate under reduced pressure to obtain 116.2 g of off-white crude product. The crude product was refined and purified with et...

Embodiment 3

[0068] Preparation of intermediate formula 1:

[0069] Add 200mL of toluene, 50g of L-alanine isopropyl hydrochloride and 26.4g of piperidine into the reaction flask, stir, cool down to -78°C, react for 30min, then add dropwise the toluene solution of phenol dichlorophosphate (63g / 120mL); after dropping, stir for 30min, then raise the temperature to -10°C for 3 hours. Dissolve 46.5g of 4-bromophenol and 25g of piperidine in 100mL of toluene, and add dropwise to the above reaction solution; after dropping, stir the reaction and monitor the reaction by TLC; after the reaction is completed, filter with suction, wash the filter cake with 50mL of toluene, and combine the organic phases , concentrated under reduced pressure, then dissolved with 500 mL of methyl tert-butyl ether for beating, suction filtered, washed the filter cake with 50 mL of methyl tert-butyl ether, combined the organic phases, and concentrated under reduced pressure to obtain 119.6 g of off-white crude product....

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Abstract

Disclosed in the present invention is a method for preparing ribofuranose phosphate derivatives, and the preparation steps thereof comprises: coupling starting materials of isopropyl L-alanine hydrochloride, phenol dichlorophosphate and substituted phenol under the action of alkali; reducing carbonyl into alcoholic hydroxyl by means of treating (2R)-2-deoxy-2-fluoro-2-methyl-D-erythro pentonic acid GAMMA-lactone 3,5-dibenzoate with a strong reducing agent in the solvent of dichloromethane or ethers; reacting the intermediate of formula 2-1 with p-toluene sulfonyl chloride under the action of alkali to obtain p-toluene sulfonate; coupling the intermediate of formula 2-2 with a benzoyl cytosine derivative under the action of a condensation agent; converting cytosine of the intermediate of formula 2-3 into uracil under the action of an organic acid; removing benzoyl acting as protecting group from the intermediate of formula 2-4 under the action of an alkaline reagent; and coupling the intermediate of formula 2-5 with formula 1 under the action of a Grignard reagent to obtain Sofosbuvir.

Description

technical field [0001] The invention relates to a preparation method of ribofuranose phosphate derivatives, which belongs to the field of pharmaceutical chemical synthesis. Background technique [0002] Hepatitis C virus (referred to as hepatitis C, hepatitis C) is a viral hepatitis caused by hepatitis C virus (HCV) infection. According to the statistics of the World Health Organization, the global infection rate of hepatitis C is about 3%, about 180 million people are infected with HCV, and about 35,000 new cases of hepatitis C occur every year. Hepatitis C is a global epidemic, which can lead to chronic inflammation, necrosis and fibrosis of the liver. 1% to 5% of 100 patients may develop liver cirrhosis or even die from hepatocellular carcinoma (HCC). [0003] Currently, there are six genotypes of HCV virus. The standard treatment regimen is pegylated interferon (Peg-IFN) combined with ribavirin (RBV). The overall cure rate is less than 50%, and sufficient doses must be...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/10C07H1/02
CPCC07H1/02C07H19/06C07H19/10Y02P20/55
Inventor 李泽标丁海明严军戴宇顾文超张兆国
Owner NANTONG CHANGYOO PHARMATECH CO LTD