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Preparation method of 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribo-gamma-lactone

A technology of isopropyl dibenzoyl and phosphorylalanine, which is applied in the field of medicine and chemical industry, can solve the problems of production safety hazards and Chen Bengao, and achieve the goals of avoiding explosiveness, increasing safety and reducing production costs Effect

Inactive Publication Date: 2014-05-21
苏州东南药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The cost of industrial production is relatively high, and there are hidden dangers in production safety
There is no literature report on the preparation of 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribose-γ-lactone (sofosbuvir) from 4-trifluoromethylphenol as raw material. )Methods

Method used

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  • Preparation method of 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribo-gamma-lactone
  • Preparation method of 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribo-gamma-lactone
  • Preparation method of 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribo-gamma-lactone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Preparation of (S)-2-[(4-trifluoromethyl-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester (±) under nitrogen / argon protection, in a circle Add 7.95g (47.4mmol) L-alanine isopropyl hydrochloride, 10.0g (47.4mmol) phenyl dichlorophosphate, and 100mL technical grade dichloromethane into the bottom reaction bottle, drop to -10°C, and Stir well at this temperature, then slowly add 13.2mL of triethylamine (95mmol) in 30mL of dichloromethane solution dropwise, keep the temperature not higher than -5°C, after the dropwise addition, slowly return to 5°C, and Stir at ℃ for 12-24 hours; then cool down to 0℃, add 7.29g of 4-trifluoromethylphenol (45.0mmol), then slowly add 6.28mL of triethylamine in 30mL of dichloromethane solution dropwise, keeping the temperature not higher than 5°C, after the dropwise addition, slowly return to room temperature, and stir at room temperature for 12-24 hours; add cold water, stir and separate layers, wash the organic layer...

Embodiment 2

[0041] Example 2 Preparation of (S)-2-[(S)-(4-trifluoromethyl-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester Under nitrogen / argon protection, the Add 10.2g of crude product (S)-2-[(4-trifluoromethyl-phenoxy)-phenoxy-phosphorylamino]propanoic acid isopropyl ester (±) into 15mL of methyl tert-butyl ether, Then 45 mL of petroleum ether was added, cooled to -20°C, and stirred at this temperature for 12-24 hours. While cold filtered, the solid was washed with petroleum ether at -20°C to obtain (S)-2-[(S)-(4-trifluoromethyl-phenoxy)-phenoxy-phosphorylamino]propionic acid iso Propyl ester, further recrystallized with petroleum ether to obtain high-purity (S)-2-[(S)-(4-trifluoromethyl-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester After drying, 2.58 g of the product was obtained, with a yield of 25.3%. 1H-NMR (CDCl 3 -d 6 ,400MHz)δ(ppm):1.226(d,3H,J=2.4Hz,-C H 3 ),1.242(d,3H,J=2.4Hz,-CH 3 ),1.393(d,3H,J=6.8Hz,-CH 3 ),3.873-3.926(m,1H,),4.063-4...

Embodiment 33

[0042] Example 33, Preparation of 5-dibenzoyl-2-deoxy-2-fluoro-2methyl-D-ribose-γ-lactone (Sofosbuvir) Under nitrogen protection, 100mg (2'R )-2'-deoxy-2'-fluoro-2'-methyluridine (0.384mmol) and 1.0mL of anhydrous tetrahydrofuran were added to the reaction flask, lowered to 0°C, and then slowly added dropwise 1.3M tert-butylmagnesium chloride solution (0.62 mL, 0.806 mmol, 2.1 equiv). After stirring for 30 min, 265 mg (S)-isopropyl 2-[(S)-(4-trifluoromethyl-phenoxy)-phenoxy-phosphorylamino]propionate (0.614 mmol) was added. The mixture was stirred at room temperature for 48 h, then washed with saturated NH 4 Quenched with aqueous Cl (10 mL). The mixture was partitioned between ethyl acetate 20 mL and water. The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel chromatography (200-300 mesh GF254 silica gel) using a 10-15% ethyl acetate / petroleum ether gradient method to obtain 75.6 mg of a white s...

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Abstract

The invention provides a preparation method of 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribo-gamma-lactone (sofosbuvir). The method comprises the following steps: adding alkali into a mixed solution of L-alanine isopropyl ester or an acid salt thereof and phenyl dichlorophosphate for reacting to obtain (S)-2-phenoxy-chloro-phosphoryl amino isopropyl propionate, reacting the (S)-2-phenoxy-chloro-phosphoryl amino isopropyl propionate with 4-trifluoromethylphenol in the presence of alkali at the temperature of 0-10 DEG C to obtain racemic (S)-2-[(4-trifluoromethyl-phenoxyl)-phenoxy-phosphoryl amino)]alanine isopropyl ester, dissolving the racemic (S)-2-[(4-trifluoromethyl-phenoxyl)-phenoxy-phosphoryl amino)]alanine isopropyl ester into an ether or alkane solvent at the normal temperature, cooling to 50-10 DEG C below zero, and separating (S)-2-[(S)-(4-trifluoromethyl-phenoxy)]-phenoxy-phosphoryl amino)]alanine isopropyl ester out; and reacting the (S)-2-[(S)-(4-trifluoromethyl-phenoxy)]-phenoxy-phosphoryl amino)]alanine isopropyl ester with (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine in the presence of organic alkali with high steric hindrance to obtain the 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribo-gamma-lactone. The method has the advantages of simple steps, mild reaction and suitability for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a preparation method of 3,5-dibenzoyl-2-deoxy-2-fluoro-2methyl-D-ribose-γ-lactone (sofosbuvir) . Background technique [0002] Hepatitis C virus (HCV) infection is a major health problem leading to chronic liver diseases such as cirrhosis and hepatocellular carcinoma, with an estimated 2-15% of individuals worldwide infected with this virus. According to data, there are about 40 million HCV-infected people in China, accounting for 3.2% of my country's population, and there is an increasing trend. According to the World Health Organization, more than 200 million people are infected with HCV worldwide, and the number increases by about 4 million each year. HCV infection is mainly transmitted through blood sources, such as blood and blood product contamination, syringe contamination, unclean sex and mother-to-child transmission. Once infected with HCV, onl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/02
Inventor 吉民刘海东蔡进李锐
Owner 苏州东南药业股份有限公司
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