Method for preparing sofosbuvir intermediate and recovering byproduct

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 ...

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

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