Preparation method of sofosbuvir intermediate

An intermediate and volume ratio technology, applied in the field of intermediate preparation, can solve the problems of cumbersome post-processing operations, low product purity, and low reaction conversion rate, and achieve high reaction conversion rate and product purity, environmental friendliness, and low cost Effect

Active Publication Date: 2014-11-19
CHEMVON BIOTECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is to overcome the defects of low reaction conversion rate, cumbersome post-treatment operation and low product purity in the existing method for preparing the intermediate chiral phospholipid fragment of sofosbuvir, and provides A kind of preparation method of the intermediate of sofosbuvir

Method used

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  • Preparation method of sofosbuvir intermediate
  • Preparation method of sofosbuvir intermediate

Examples

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Embodiment 1

[0048] Dissolve 6.23g (29.8mmol) of phenyl dichlorophosphate and 5g (29.8mmol) of L-alanine isopropyl hydrochloride in 50mL DCM under the protection of nitrogen. The dichloromethane solution of the amine (6.01 g of triethylamine dissolved in 5 mL of DCM) was added dropwise into the reaction system, and the temperature was naturally raised to react overnight.

[0049] Add 5.70g (31.0mmol) of pentafluorophenol to the above reaction system, under the same nitrogen protection, control the temperature at about 20°C, add a dichloromethane solution of triethylamine (6.01g of triethylamine is dissolved in 5mL DCM) dropwise, after the addition is complete The reaction takes about 3 hours.

[0050] After the reaction was completed, the reaction solution was poured into ice water, the organic phase was washed twice with saturated sodium bicarbonate (50mL×2), and finally washed once with saturated brine 50mL until neutral, and all the aqueous layers were combined and extracted once with 3...

Embodiment 2

[0061] According to the preparation method of the compound of formula (II) in Example 1, after the compound of formula (II) is obtained, crystallize and purify with n-heptane and ethyl acetate (4:1), and filter to obtain the mother liquor (the isomer in the mother liquor (i.e. the formula III compound) with a mass content of 79%, and the product (compound of formula (I)) with a mass content of 21%), the mother liquor was concentrated to dryness to obtain a mother liquor concentrate, which was refrigerated for use. Take 10 g of mother liquor concentrate, dissolve in 50 mL of dry ethyl acetate, add 0.5 g of triethylamine, stir at room temperature for 10 hours, NH 4 Cl washed and dried. Through HPLC detection (chiral purity), the mass content of isomer is 43%, and the mass content of product is 56% (see image 3 ). Concentrate properly, add n-heptane, precipitate a white solid, and filter. HPLC detection (chiral purity), the mass content of isomer is 1.3%, and the mass content...

Embodiment 3

[0071] According to the preparation method of the compound of formula (II) in Example 1, after the compound of formula (II) is obtained, crystallize and purify with n-heptane and ethyl acetate (4:1), and filter to obtain the mother liquor (the isomer in the mother liquor (i.e. the formula III compound) mass content is 79%, product (formula (I) compound) mass content is 21%), mother liquor is concentrated to dryness, stand-by. Take 3 g of mother liquor concentrate, dissolve in 20 mL of dry methyl tert-butyl ether, add 0.1 g of potassium tert-butoxide, stir at room temperature for 12 hours, NH 4 Cl washing, drying, crude product is detected (chiral purity) through HPLC, and the mass content of isomer is 46%, and the mass content of product is 54% (see Figure 5 ). Concentrate properly, add n-heptane, precipitate a white solid, and filter. HPLC detection showed that the mass content of the isomer was 1.0%, the mass content of the product was 99.0%, and the mass of the precipita...

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Abstract

The invention discloses a preparation method of a sofosbuvir intermediate, which comprises the following step: in an anhydrous non-protonic solvent, carrying out dynamic kinetic resolution on a compound disclosed as Formula (II) under the action of an organic alkali and/or inorganic alkali to prepare a compound disclosed as Formula (I), wherein the non-protonic solvent is one or more of ester solvent, ketone solvent and ether solvent, the organic alkali and/or inorganic alkali account/accounts for 0.1-10 wt% of the compound disclosed as Formula (II), the temperature of the dynamic kinetic resolution is 10-30 DEG C, and the time of the dynamic kinetic resolution is 5-10 hours. The preparation method has the advantages of high conversion rate, high product purity and low cost, and is environment-friendly.

Description

technical field [0001] The invention relates to a preparation method of an intermediate of sofosbuvir. Background technique [0002] The global infection rate of hepatitis C virus (HCV) is high, and there is a lack of effective therapeutic drugs. On December 6, 2013, the U.S. Food and Drug Administration (FDA) approved the listing of new molecular entity drug sofosbuvir (sofosbuvir) tablets, namely (S)-2-{[(2R, 3R, 4R, 5R) -5-(2,4-dioxo-3,4-dihydropyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy](phenoxy base) phosphorylamino}-propionic acid isopropyl ester, which has the general formula shown below, trade name Sovaldi, for the treatment of chronic hepatitis C. Sofosbuvir is an HCV polymerase inhibitor, which acts on the nucleotide analog NS5B polymerase site of viral RNA replication, can stop virus replication, and is the only marketed variety targeting NS5B polymerase. [0003] [0004] There are many publications and patents disclosing the meth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/24
Inventor 王猛王方道姚建忠蔡茂军周杰王东叶庆华
Owner CHEMVON BIOTECH CO LTD
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