Method for preparing sofosbuvir intermediate and recovering byproduct

A by-product, asana technology, applied in the field of medicine, can solve the problems of harsh reaction conditions, emulsification of the system, affecting the yield, etc., and achieve the effects of easy industrial production, mild reaction conditions, and easy to enlarge the output.

Active Publication Date: 2017-10-13
NINGBO TEAM PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The reduction method described above has the following defects and deficiencies, which limit its further expansion in industrial output:
[0008] 1. When preparing modified red aluminum or modified lithium aluminum tetrahydrogen, it needs to be operated in a low temperature environment below -15°C, and the requirements for reaction equipment are high;
[0009] 2. A large amount of hydrogen gas is released during the preparation of modified red aluminum or modified lithium aluminum tetrahydrogen. If it is not handled properly, it is easy to cause hydrogen explosion, and the reaction process is highly dangerous;
[0010] 3. Red aluminum and lithium aluminum tetrahydrogen are extremely sensitive to moisture. A small amount of water vapor in the system may also weaken the metal aluminum salt and affect the yield of the reduction reaction. The reaction conditions are harsh;
[0011] 4. The metal aluminum salt after the reaction is very easy to form aluminum salt jelly in the post-treatment process, causing the emulsification of the system and affecting the yield

Method used

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  • Method for preparing sofosbuvir intermediate and recovering byproduct
  • Method for preparing sofosbuvir intermediate and recovering byproduct
  • Method for preparing sofosbuvir intermediate and recovering byproduct

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Add 300mL ethylene glycol dimethyl ether, 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribonic acid-γ-lactone (50g, 134mmol ), cooled to 10°C, and added sodium borohydride (2.3g, 60mmol, 0.45eq) in three batches, with an interval of one hour between each batch. After the addition, the temperature was naturally raised to room temperature, and the reaction was stirred for 2 hours, followed by spot plate analysis by TLC. The disappearance of raw material spots in the reaction solution was the end of the reaction. After the reaction was completed, the pH was adjusted to 6-7 with acetic acid, and solids were precipitated, and the stirring was continued for 12 hours.

[0043] Filtration; drying the obtained filter cake to obtain the by-product [(2R,3R,4S)-4-fluoro-2,5-dihydroxy-4-methylpentane-1,3-diyl]diphenyl Ester 23.7g, 63mmol. ( 1 H NMR (400MHz, CDCl 3 )δ8.05-7.99(m,4H),7.61-7.37(m,6H),5.55(dd,J=18.0,6.4Hz,1H),4.72-4.37(m,3H),3.89-3.82(m, 2H), 3.64 (s, 2H, -OH), 1.46 (...

Embodiment 2

[0056] Add 300mL ethylene glycol dimethyl ether, 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribonic acid-γ-lactone (50g, 134mmol) into a 500mL reaction bottle , cooled to 10° C., and sodium borohydride (1.3 g, 34 mmol, 0.25 eq) was added in three batches with an interval of one hour between each batch. After the addition was completed, the temperature was naturally raised to room temperature, and the reaction was stirred for 10 hours. The spot plate analysis was carried out by TLC, and the raw materials were slightly left. The pH was adjusted to 6-7 with acetic acid, a solid precipitated out, and the stirring was continued for 12 hours. Filter and dry the filter cake to obtain the by-product [(2R,3R,4S)-4-fluoro-2,5-dihydroxy-4-methylpentane-1,3-diyl]dibenzoate 20.3 g, 54 mmol. The filtrate was concentrated to dryness on a rotary evaporator under reduced pressure, dissolved in 400 mL of ethyl acetate, washed with 150 mL of saturated brine, the organic layer was dried over anh...

Embodiment 3

[0060] Add 300mL ethylene glycol dimethyl ether, 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribonic acid-γ-lactone (50g, 134mmol) into a 500mL reaction bottle , cooled to 10° C., and sodium borohydride (5.1 g, 134 mmol, 1.0 eq) was added in three batches with an interval of one hour between each batch. After the addition, the temperature was naturally raised to room temperature, and the reaction was stirred for 1 hour, followed by spot plate analysis by TLC. The disappearance of raw material spots in the reaction liquid was the end of the reaction. After the reaction was completed, the pH was adjusted to 6-7 with acetic acid, and solids were precipitated, and the stirring was continued for 12 hours. Filter and dry the filter cake to obtain the by-product [(2R,3R,4S)-4-fluoro-2,5-dihydroxy-4-methylpentane-1,3-diyl]dibenzoate 35.3 g, 94 mmol. The filtrate was concentrated to dryness on a rotary evaporator under reduced pressure, dissolved in 400 mL of ethyl acetate, washed with...

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Abstract

The invention relates to a method for preparing a sofosbuvir intermediate [(2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl] methylbenzoate represented by formula (II) and recovering a byproduct (2R,3R,4S)-4-fluoro-2,5-dihydroxy-4-methylpentane-1,3-diyl]dibenzoate represented by formula (III). The method comprises the following steps: (1) reacting a compound (I) 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribosinic acid-gamma-lactone in a first solvent under the action of a reducing agent at a temperature of from 0 DEG C to the reflux temperature of the first solvent for 1-20 hours to produce the sofosbuvir intermediate (II) and the byproduct (III); and (2) filtering the above product to obtain a filter cake which is the byproduct (III), dissolving the filter cake in a second solvent, and reacting the obtained solution in an acidic environment with the pH value of 1-6 under the action of an oxidant and a catalyst at a temperature from 0 DEG C to the reflux temperature of the second solvent for 0.5-5 hours in order to generate the compound (I).

Description

technical field [0001] The present invention relates to the field of medicine, in particular to a sofosbuvir intermediate [(2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxyl-4-methyltetrahydrofuran-2 The preparation method of -yl] methyl benzoate and the by-product formula [(2R,3R,4S)-4-fluoro-2,5-dihydroxy-4-methylpentane-1,3-diyl] Method for the recovery of dibenzoates. Background technique [0002] Sofosbuvir, also known as Sofosbuvir, Sofosbuvir, English name Sofosbuvir, is a breakthrough drug developed by Gilead Sciences for the treatment of chronic hepatitis C, approved by the US Food and Drug Administration in December 2013 It was approved for marketing in the United States, and was approved for marketing in the European Union by the European Medicines Agency in January 2014. Sofosbuvir used alone or in combination (in combination with Ledipasvir or Velpatasvir) can treat all genotypes of hepatitis C, and the cure rate is above 95%. In 2016, Gilead Sciences submitted a ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/20C07C41/01C07C43/178C07D307/33
Inventor 徐骥胡彬彬毛兴波汪伟
Owner NINGBO TEAM PHARMA
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