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Synthesis method for (2'R)-2'-deoxy-2'-fluorine-2'-methyl uridine

A synthetic method, the technology of methyluridine, which is applied in chemical instruments and methods, preparation of sugar derivatives, sugar derivatives, etc., can solve the problems of high process cost, complicated reaction steps, and low overall yield, and achieve saving The effect of solvent consumption, short steps, and easy operation

Inactive Publication Date: 2015-07-01
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] In view of the fact that the existing synthetic method for preparing the (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine has complex reaction steps, high process cost and low overall yield, it is necessary to develop A more economical and convenient preparation method

Method used

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  • Synthesis method for (2'R)-2'-deoxy-2'-fluorine-2'-methyl uridine
  • Synthesis method for (2'R)-2'-deoxy-2'-fluorine-2'-methyl uridine
  • Synthesis method for (2'R)-2'-deoxy-2'-fluorine-2'-methyl uridine

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Experimental program
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Embodiment 1

[0030]

[0031] Synthesis of 2,4-bis(trimethylsiloxy)pyrimidine: Under argon protection and stirring, add uracil (11.2 g, 0.1mol), ammonium sulfate (1.32 g 0.01mol), HMDS (33.8 g, 0.21mol). The temperature of the oil bath was raised to reflux of chlorobenzene (at this time, the temperature of the oil bath was about 150°C), and the reaction was stirred for 2 hours until the reaction system was dissolved, and then the reaction was continued for half an hour. Post-processing: Cool to room temperature, concentrate with a rotary evaporator (70°C), and then obtain a syrupy substance, which is sealed under argon protection and used directly for the next reaction.

Embodiment 2

[0033]

[0034] Synthesis of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine:

[0035] Operation: Stir at room temperature and under the protection of argon, add 3R, 4R, 5R-2-chloro-3-fluoro-3-methyl-4-benzoyl-5-benzoic acid methyl tetrahydrofuran ( 3.92 g, 0.01 mol), SnCl 4 (10.4 g, 0.04 mol), 2,4-bis(trimethylsiloxy)pyrimidine (5.12 g, 0.02 mol), chloroform 40mL, the oil bath was heated to chloroform reflux. At this time, the internal temperature is about 63°C. Stirring was maintained at this temperature for 16 hours. Post-treatment: Cool to room temperature, pour the reaction solution into dilute hydrochloric acid, continue to stir for about 30 minutes, filter with suction, and wash the filter cake repeatedly with DCM (repeat this operation 3 to 4 times until TLC judges that there is no product in the filtrate). All filtrates were combined and concentrated under reduced pressure with a rotary evaporator to obtain a dark brown solid oil mixture (LCMS detection). Dissolve th...

Embodiment 3

[0038]

[0039] Synthesis of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine:

[0040] Operation: Stir at room temperature and under the protection of argon, add 3R, 4R, 5R-2-chloro-3-fluoro-3-methyl-4-benzoyl-5-benzoic acid methyl tetrahydrofuran ( 3.92 g, 0.01 mol), ZnCl 2 (5.44 g, 0.04 mol), 2,4-bis(trimethylsiloxy)pyrimidine (5.12 g, 0.02 mol), chloroform 40mL, the oil bath was heated to chloroform reflux. At this time, the internal temperature is about 63°C. Stirring was maintained at this temperature for 16 hours. Post-treatment: Cool to room temperature, pour the reaction solution into dilute hydrochloric acid, continue to stir for about 30 minutes, filter with suction, and wash the filter cake repeatedly with DCM (repeat this operation 3 to 4 times until TLC judges that there is no product in the filtrate). All filtrates were combined and concentrated under reduced pressure with a rotary evaporator to obtain a dark brown solid oil mixture (LCMS detection). Dissolve th...

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Abstract

The invention discloses a synthesis method for (2'R)-2'-deoxy-2'-fluorine-2'-methyl uridine, which comprises the following steps: in the presence of an organic solvent and Lewis acid, enabling (R)-3-F-3-methyl furan to react with 2,4-(di-hydroxyl protection) pyrimidine at 25-100DEG C; after the reaction is finished, processing a reaction product to obtain a compound (IV); and performing dehydroxylation protection to obtain the (2'R)-2'-deoxy-2'-fluorine-2'-methyl uridine (V). When adopted to synthesize the (2'R)-2'-deoxy-2'-fluorine-2'-methyl uridine, the method has short synthesis steps, is simple and convenient to operate and has important application values.

Description

technical field [0001] The invention relates to a preparation method of 2'R)-2'-deoxy-2'-fluoro-2'-methyluridine. Background technique [0002] 2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (Ⅴ) is a key pharmaceutical intermediate. The product (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine is a key pharmaceutical intermediate of sofosbuvir (CAS: 1190307-88-0), which has important application significance and economic value. On January 17, 2014, the new hepatitis C drug Sovaldi (sofosbuvir, 400mg tablet) was approved by the European Union as part of the antiviral treatment program for the treatment of adults with chronic hepatitis C (HCV) infection. Sovaldi is a once-daily oral nucleoside analog polymerase inhibitor. The approval paves the way for the drug to be launched throughout the European Union. Previously, Sovaldi had received a positive opinion for approval from the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) in November 2013. In the...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H1/00
CPCY02P20/55
Inventor 李硕梁郑保富高强陈达周治国
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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