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Preparation method of anti-hepatitis C medicine sofosbuvir

A technology for sofosbuvir and anti-hepatitis C, applied in the field of preparation of anti-hepatitis C drug sofosbuvir, can solve the problems of low total yield of target product, high toxicity of reaction reagents, harsh reaction conditions, etc., and achieves novel routes and equipment. Simple, short synthetic route effects

Active Publication Date: 2020-06-09
IANGSU COLLEGE OF ENG & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this synthesis scheme, the witting reaction needs to be reacted at -70 °, and the reaction conditions are harsh. The same fluorination reaction, the reaction reagent is highly toxic, dangerous, and the total yield of the target product is low.

Method used

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  • Preparation method of anti-hepatitis C medicine sofosbuvir
  • Preparation method of anti-hepatitis C medicine sofosbuvir
  • Preparation method of anti-hepatitis C medicine sofosbuvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: Preparation of 3-((R)-2,2-dimethyl-1,3-dioxolanyl)-3-carbonyl-2-methyl-2-fluoropropionic acid ethyl ester (1 )

[0054] In a 500 ml round bottom flask, add 175 g of β-glycerate ethyl acetone, 200 ml of DMF, 224 g of potassium tert-butoxide, and 130 g of α-fluoroethyl propionate, and the reaction system is heated to 80° for 10 hours. After the reaction, the reaction solution was poured into ice water, extracted twice with 400 milliliters of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, the filtrate was distilled under reduced pressure to recover the solvent, and the residue was distilled under reduced pressure to obtain 206 g of a light yellow liquid (pressure 5 mm Hg, collection temperature 70-75 °) yield 83%.

Embodiment 2

[0055] Example 2: Preparation of 3-((R)-2,2-dimethyl-1,3-dioxolanyl)-3-hydroxyl-2-methyl-2-fluoropropionic acid ethyl ester (2 )

[0056] Take a 500 ml round bottom flask, add 124 g of intermediate 1, 200 ml of ethanol, cool in an ice bath to 0 °, add 10 g of sodium borohydride in batches, during the addition process, control the temperature not to exceed 5 °, and complete the addition in 30 minutes. After the addition, the system continued to react for 2 hours. After the reaction was completed, 20 ml of dilute hydrochloric acid (1mol / L) was added to the reaction system, and the stirring was continued for 10 minutes. Extracted twice with ethyl ester, washed with water, combined organic phases, dried over anhydrous sodium sulfate, filtered, the filtrate recovered the solvent under reduced pressure, and the residue was distilled under reduced pressure to obtain 113 grams of light yellow liquid (5 mm Hg, collection temperature 90-94 °) , yield 91%.

Embodiment 3

[0057] Example 3: Preparation of 3-((R)-2,2-dimethyl-1,3-dioxolanyl)-3-benzoyl-2-methyl-2-fluoropropionic acid ethyl ester (3)

[0058] Take a 500 milliliter three-necked reaction flask, install a constant pressure dropping funnel, nitrogen protection device, under nitrogen protection, add 62 grams of intermediate 3, 100 milliliters of dichloromethane, 30 grams of triethylamine to the system, and cool in an ice bath to 5 ° below, add 40 grams of Benjia acid chloride dropwise. During the dropwise addition, the temperature does not exceed 10°. After the dropwise addition, the system is warmed up to 40°C for 1 hour. After the reaction, add 100 ml of water to the system for liquid separation. The phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was recovered from the filtrate under reduced pressure to obtain a yellow solid. Ethyl acetate:petroleum ether=1:1 was recrystallized to obtain 83.1 g of a light yellow solid, with a yield of 94%. ...

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Abstract

The invention discloses a preparation method of an anti-hepatitis C medicine sofosbuvir. The method comprises the following steps: taking r-ethyl glycerate acetonide as an initial raw material, enabling the r-ethyl glycerate acetonide to react with ethyl alpha-fluoropropionate under the action of potassium tert-butoxide, performing carbonyl reduction, hydroxyl acylation, hydrolytic cyclization under an acidic condition, hydroxyl acylation, red aluminum reduction and chiral column separation so as to obtain a sofosbuvir key intermediate ((2R,3R,4R,5R)-3-(benzoyloxy)-5-hydroxy-4-fluoro-4-methyltetrahydrofuran-2-yl) methyl benzoate, performing 2-hydroxyl acetylation, enabling acetylized material to react with 2-trimethylsiloxy-4-benzamidopyrimidine, removing benzamido under an acidic condition, performing dehydroxylation protection, and finally enabling obtained material to react with N-[(S)-(2,3,4,5,6-Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester to obtain the sofosbuvir. The method has the advantages of short synthesis route, high yield, avoidance of a fluorination reaction step in the synthesis process, and mild synthesis reaction conditions.

Description

technical field [0001] The invention specifically relates to a preparation method of the anti-hepatitis C drug sofosbuvir. Background technique [0002] Sofosbuvir, chemical name (S)-2-{(S)-{{(2R,3R,4R,5R)-5-[2,4-dioxo-3,4-di Hydropyrimidin-1(2H)-yl]-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl}methoxy}(phenoxy)phosphorylamino}propionic acid isopropyl ester, CAS number : 1190307-88-0, trade name Sovaldi, is a new drug developed by Gilead for the treatment of chronic hepatitis C, approved by the U.S. Food and Drug Administration (FDA) for listing in the United States on December 6, 2013, in 2014 On January 16, it was approved by the European Medicines Agency (EMEA) for marketing in EU countries. The drug is the first to safely and effectively treat certain types of hepatitis C without the need for interferon. Clinical trials have confirmed that for hepatitis C types 1 and 4, the overall sustained virological response rate (SVR) of the drug combined with peginterferon an...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/02
CPCC07H19/10C07H1/02
Inventor 严宾冯成亮
Owner IANGSU COLLEGE OF ENG & TECH
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