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Preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine

A technology of methyl uridine and methyl uridine is applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., and can solve the problems of increasing the difficulty of purifying formula I, increasing production costs, and expensive organic bases. , to achieve the effect of simplifying the post-processing method, reducing the production cost and shortening the reaction time.

Inactive Publication Date: 2016-08-17
JINGHUA PHARMA GRP NANTONG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the above route, the organic base is used to catalyze the deprotection formula II, the reaction time is longer, and there is an incomplete reaction phenomenon, which increases the difficulty of purifying the formula I, and the price of the organic base is relatively expensive, and the above factors increase the production cost.

Method used

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  • Preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine
  • Preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Add 140.00g (0.30mol) of uridine compound, 700mL of anhydrous methanol, 1.00g (0.03mol) of sodium hydroxide and 1.00g (0.01mol) of anhydrous sodium sulfate into a dry and clean 1L three-necked flask, stir, and the reaction solution is It was white and turbid, and the temperature was raised to reflux. When the reaction system was brown and clear, it was reacted for 7 hours. The reaction solution was concentrated to dryness and recrystallized with ethyl acetate to obtain 82.16 g of crude compound I.

[0018] Add 500 mL of anhydrous methanol to the above crude product and stir until completely dissolved, then add 10% H 2 SO 4 / methanol solution to neutralize the pH of the system, decolorize with activated carbon, concentrate and dry to obtain a white granular solid, which is recrystallized using a mixed solvent of absolute ethanol and ethyl acetate, filtered with suction, and dried to obtain 70.01 g of refined compound Ⅰ, with a yield of 90.02%.

Embodiment 2

[0020] Add 140.00g (0.30mol) of uridine compound, 700mL of anhydrous methanol, 1.00g (0.03mol) of sodium hydroxide and 1.00g (0.01mol) of anhydrous magnesium sulfate into a dry and clean 1L three-necked flask, stir, and the reaction solution is It was white and turbid, and the temperature was raised to reflux. When the reaction system was brown and clear, it was reacted for 7 hours. The reaction solution was concentrated to dryness and recrystallized with ethyl acetate to obtain 81.19 g of crude compound Ⅰ.

[0021] Add 500 mL of anhydrous methanol to the above crude product and stir until completely dissolved, then add 10% H 2 SO 4 / methanol solution to neutralize the pH of the system, decolorize with activated carbon, concentrate and dry to obtain a white granular solid, which is recrystallized using a mixed solvent of absolute ethanol and ethyl acetate, filtered with suction, and dried to obtain 70.11 g of refined compound Ⅰ, with a yield of 90.15%.

Embodiment 3

[0023] Add 140.00g (0.30mol) of uridine compound, 700mL of anhydrous methanol, 1.00g (0.01mol) of sodium carbonate and 1.00g (0.01mol) of anhydrous sodium sulfate into a dry and clean 1L three-necked flask, stir, and the reaction solution turns white It was turbid and heated to reflux. When the reaction system was brown and clear, it was reacted for 8 hours. The reaction solution was concentrated to dryness and recrystallized with ethyl acetate to obtain 78.17 g of crude compound I.

[0024] Add 500 mL of anhydrous methanol to the above crude product and stir until completely dissolved, then add 10% H 2 SO 4 / methanol solution to make the pH of the system to neutral, decolorize with activated carbon, concentrate and dry to obtain a white granular solid, which is recrystallized using a mixed solvent of absolute ethanol and ethyl acetate, filtered with suction, and dried to obtain 68.12 g of refined compound Ⅰ, with a yield of 87.59%.

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Abstract

The invention relates to a preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (I). The preparation method comprises the steps that (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine 3', 5- dibenzoate (II) is adopted as the raw material, and catalysis for deprotection is conducted through a catalyst in anhydrous polar solvent, so that the (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (I) is obtained, wherein the catalyst is a mixture of inorganic base and inorganic salt or an alcoholic alkali metal compound. The preparation method has the advantages that an inorganic compound or the alcoholic alkali metal compound is adopted, reaction time is shorted and only needs 4-10 hours, a reaction is conducted completely, the post-treatment mode is simplified, the production cycle is shorted, and in addition, the inorganic compound is relatively low in price, so that production cost is lowered; meanwhile, the yield of a product prepared through the preparation method can reach 95% or above, and extremely great industrialized production prospect is achieved.

Description

technical field [0001] The invention belongs to the technical field of medicines, relates to the preparation of a medicine intermediate, in particular to a preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine. Background technique [0002] Sofosbuvir (Sofosbuvir) is a new drug developed by Gilead for the treatment of chronic hepatitis C. It was approved by the US Food and Drug Administration (FDA) for marketing in the United States on December 6, 2013, and approved by the European Union on January 16, 2014. The Medicines Agency (EMEA) approves the marketing in EU countries. Not yet available in China. [0003] [0004] (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (I) is the key intermediate for the synthesis of sofosbuvir, and it is used as The intermediate (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine 3',5'-dibenzoate (Ⅱ) is used as a raw material, and the deprotection is catalyzed by an organic base, and the reaction Formula I was obtained in 12-20 hours. [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073C07H1/00
CPCC07H19/073C07H1/00
Inventor 严宾朱春林吴玉祥
Owner JINGHUA PHARMA GRP NANTONG
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