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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 difficult control of purity, long process route, cumbersome operation, etc., to avoid excessive losses, Purity is easy to control, easy to control the effect

Active Publication Date: 2015-05-13
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Abstract
  • Description
  • Claims
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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
[0005] 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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  • Preparation method of ribofuranose phosphate derivative

Examples

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Effect test

Embodiment 1

[0035] Preparation of intermediate formula 1:

[0036] 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 dichloromethane of phenol dichlorophosphate dropwise solution (63g / 120mL); after dropping, stir the reaction for 30min, then raise the temperature to -10°C for 3 hours. Dissolve 55.4g of perfluorophenol and 35.2g of DIPEA in 200mL of dichloromethane, 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, and wash the filter cake with 50mL of dichloromethane , combine the organic phases, concentrate under reduced pressure, then dissolve and beat with 500mL methyl tert-butyl ether, filter with suction, wash the filter cake with 50mL methyl tert-butyl ether, combine the organic phases, and concentrate under reduced pressure to obtain 123.5g off...

Embodiment 2

[0050] Preparation of intermediate formula 1:

[0051] 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, and then dropwise add the dichloride of phenol dichlorophosphate Methane solution (63g / 1200mL); after dropping, stir for 30 minutes, 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 ...

Embodiment 3

[0066] Preparation of intermediate formula 1:

[0067] Add 200mL toluene, 50g L-alanine isopropyl hydrochloride and 26.4g 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 the reaction for 30min, then raise the temperature to -10℃ for 3 hours. Dissolve 46.5 g of 4-bromophenol and 25 g of piperidine in 100 mL of toluene, 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 the filter cake with 50 mL of toluene, and combine the organic phase, concentrated under reduced pressure, and then dissolved in 500 mL of methyl tert-butyl ether for beating, suction filtered, and the filter cake was washed with 50 mL of methyl tert-butyl ether, the organic phases were combined and concentrated under reduced pressure to obtain 119.6 g of off-white...

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Abstract

The invention discloses a preparation method of a ribofuranose phosphate derivative. The preparation method comprises preparation steps as follows: L-alanine isopropyl ester hydrochloride, phenol dichlorophosphate and substituted phenol are taken as starting materials and have a docking reaction under the action of alkali; (2R)-2-deoxy-2-difluoro-2-methyl-D-erythropentonic acid GAMMA-lactone and 3,5-dibenzoate reduce carbonyl in a dichloromethane or ether solvent into an alcoholic hydroxyl group under the action of a strong reducing agent; an intermediate with a formula 2-1 has a reaction with paratoluensulfonyl chloride under the action of alkali to obtain p-toluenesulfonates; an intermediate with a formula 2-2 and a benzoyl cytosine derivative have a docking reaction under the action of a condensing agent; an intermediate with a formula 2-3 converts cytosine into uracil under the action of organic acid; benzoyl protection for an intermediate with a formula 2-4 is released under the action of an alkaline agent; an intermediate with a formula 2-5 and an intermediate with a formula 1 are docked 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 hepatitis C infection rate is about 3%, about 180 million people are infected with HCV, and there are about 35,000 new cases of hepatitis C 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 6 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 Applications(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
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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