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Preparation method for sofosbuvir

A technology of sofosbuvir and uridine, which is applied in the field of preparation of drug sofosbuvir, can solve the problems of low conversion rate and many reaction steps, and achieve the effects of promoting development, easy availability of raw materials, and simple process

Inactive Publication Date: 2015-04-01
SUZHOU MIRACPHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Obviously, this preparation method has many reaction steps, low conversion rate and needs multiple protection and deprotection

Method used

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  • Preparation method for sofosbuvir
  • Preparation method for sofosbuvir
  • Preparation method for sofosbuvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add uridine (II) (12.2g, 50mmol) and 250mL of anhydrous pyridine into the reaction flask, add 1,3-dichloro-1,1,3,3- Tetraisopropyl-1,3-disiloxane (16.0 mL, 50 mmol) was added after dropping, warmed up to room temperature, and reacted for 12 hours, and the reaction was detected by TLC. Cool in an ice bath and quench the reaction with 5 mL of water. The solvent was recovered under reduced pressure, the residue was dissolved in dichloromethane, washed with water, saturated brine and water successively, dried over anhydrous sodium sulfate, concentrated, and the obtained crude product was weighed with dichloromethane and n-hexane (4:1, V / V). Crystallized and dried in vacuo to obtain 16.8 g of white solid 3',5'-O-(tetraisopropyldisiloxane-1,3-diether)uridine (III), yield 77.1%, mass spectrum (EI): m / z 437 (M+H).

Embodiment 2

[0031] Add 3',5'-O-(tetraisopropyldisiloxane-1,3-diether)uridine (III) (8.74g, 20mmol) into the reaction flask, Molecular sieves (5 g) and dichloromethane 100 mL were added to PCC (10.8 g, 50 mmol) in batches at room temperature, and reacted at room temperature for 14 hours, and the reaction was detected by TLC. Add 200 mL of diethyl ether, stir and filter, and wash the filter cake twice with diethyl ether. The organic phases were combined, and the resulting residue was purified by silica gel column (diethyl ether / n-hexane: 1 / 1), concentrated, and dried in vacuo to obtain a white solid 2'-carbonyl-3',5'-O-(tetraisopropyldi Siloxane-1,3-diether)uridine (IV) 7.47g, yield 85.9%, mass spectrum (EI): m / z 435 (M+H).

Embodiment 3

[0033] Add 3',5'-O-(tetraisopropyldisiloxane-1,3-diether)uridine (III) (8.74g, 20mmol) and 100mL tetrahydrofuran into the reaction flask, add DMSO ( 4.7g, 60mmol), the temperature was lowered to -78°C, and a solution of oxalyl chloride (3.8g, 30mmol) in anhydrous tetrahydrofuran (50mL) was added dropwise. After about 3 hours of dripping, the temperature was slowly raised to 0° C., and the reaction was continued for 2 hours, and the reaction was detected by TLC. Triethylamine was added to neutralize excess acid. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column (diethyl ether / n-hexane 1 / 1), concentrated, and dried in vacuo to obtain a white solid 2'-carbonyl-3',5'-O-(tetraisopropyldisilazol Oxyalkane-1,3-diether)uridine (IV) 7.85g, yield 90.2%.

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Abstract

The invention discloses a preparation method for preparing sofosbuvir (Sofosbuvir,I) with uridine as a raw material and through etherification, oxidation, addition, condensation and other steps; the preparation method has the advantages of easily obtained raw materials, concise process, economy, and environmental protection, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of sofosbuvir, a medicine for treating hepatitis C. Background technique [0002] Sofosbuvir is an NS5B polymerase inhibitor developed by Pharmasset and later acquired by Gilead in 2011, and developed and marketed by Gilead as a drug for the treatment of hepatitis C. The drug was approved by the US FDA in December 2013 as part of an antiviral treatment program for the treatment of chronic hepatitis C (HCV), and its trade name is Sovaldi. Sofosbuvir is the first drug approved for an all-oral regimen for hepatitis C, which eliminates the need for the traditional injectable drug interferon when used in the treatment of specific genotypes of chronic hepatitis C. [0003] The chemical name of Sofosbuvir is: (S)-2-[(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidine- 1-base)-4-fl...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/00
CPCC07H1/00C07H19/06C07H19/10
Inventor 许学农
Owner SUZHOU MIRACPHARMA TECH
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