Synthesis method of fosaprepitant dimeglumine

A synthesis method and technology for fosaprepitant, applied in the field of medicine, can solve the problems of inconvenient preparation method, the yield needs to be improved, etc., and achieve the effects of saving steps and solvents, avoiding secondary pollution, and saving steps

Active Publication Date: 2020-09-15
LIANYUNGANG GUIKE PHARMA
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  • Claims
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  • Synthesis method of fosaprepitant dimeglumine
  • Synthesis method of fosaprepitant dimeglumine

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[0013] In an embodiment, a synthetic method of fosaprepitant dimeglumine comprises the following steps: (1) prepare 1.6 parts by weight of aprepitant, 2.2 parts by weight of tetrabenzyl pyrophosphate, in kg / L Add 30 times the volume of anhydrous tetrahydrofuran, cool to -5°C, drop in 4.8 times the volume of sodium hexamethyldisilazide, the dropping temperature is -5-0°C, and the dropping time is 1.5-2h. Keep stirring at -5-0°C for 2 hours, and keep warm for 1 hour; (2) Add 0.1-0.2 parts by weight of sodium carbonate solid and 1-2 parts by weight of mesoporous carbon, heat up to 25°C under nitrogen atmosphere and stir for 2-4 hours (3) Add 0.87 parts by weight of meglumine and 0.02 parts by weight of 3% palladium mesoporous carbon, put it into a hydrogenation kettle, keep it at 2.0MPa, 25°C, hydrogenate for 10-12h, and filter out the solid; (4) filtrate After adding excess deionized water, filter, vacuum-dry the filter cake, dissolve in 10 times the volume of dry methanol in kg...

Embodiment 1

[0016] A synthetic method of fosaprepitant dipglumine, comprising the following steps: (1) prepare 1.6 parts by weight of aprepitant, 2.2 parts by weight of tetrabenzyl pyrophosphate, in kg / L, add 30 times Volume of anhydrous tetrahydrofuran, cooled to -5°C, drop into 4.8 times the volume of sodium hexamethyldisilazide, the dropping temperature is -5-0°C, the dropping time is 1.5h, keep at -5-0°C Stir for 2 hours, heat preservation reaction for 1 hour; (2) add 0.15 parts by weight of sodium carbonate solid and 1.5 parts by weight of mesoporous carbon, heat up to 25 ° C under nitrogen atmosphere and stir for 3 hours; (3) add 0.87 parts by weight of meglumine and 0.02 parts by weight of 3% palladium mesoporous carbon, put it into a hydrogenation kettle, keep it at 2.0MPa, 25°C, hydrogenate for 11h, and filter off the solid; (4) add excess deionized water to the filtrate, filter, and vacuum dry the filter cake Finally, in kg / L, dissolved in 10 times the volume of dry methanol, fi...

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Abstract

The invention discloses a synthesis method of fosaprepitant dimeglumine, and belongs to the technical field of medicines. The synthesis method of fosaprepitant dimeglumine mainly comprises the following steps: reacting tetrabenzyl pyrophosphate, adsorbing impurity tar, hydrogenating palladium mesoporous carbon, refining and the like. According to the invention, a one-pot reaction is adopted; a dibenzyl ester product is generated; sodium carbonate is added for quenching reaction, mesoporous carbon is added for adsorbing impurities and tar, palladium-carbon catalyst deactivation is avoided, thena tetrahydrofuran system is directly utilized for a reaction, palladium mesoporous carbon has high activity and can generate monobenzyl ester first and then remove groups through hydrogenation compared with a common route, steps are saved, and high yield is achieved.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a method for synthesizing fosaprepitant dipglumine. Background technique [0002] Fosaprepitant Diglumine is a water-soluble phosphoryl prodrug of Aprepitant. After intravenous injection, it can be quickly converted into Aprepitant through phosphorylation in the body. It is suitable for patients who cannot be taken orally, Patients with difficulty swallowing or poor digestion. Fosaprepitant dimglumine and aprepitant belong to a group of selective high-affinity receptor blockers called human substance P / neurokinin 1 (NK-1), which mainly block nausea and vomiting signals in the brain mechanism of action. [0003] At present, most of the synthesis methods of fosaprepitant dimeglumine reported in the literature are palladium-catalyzed hydrogenation in the last step, which requires high-pressure reactors, has poor safety, and the production scale is severely limited, so it is not s...

Claims

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Application Information

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IPC IPC(8): C07F9/6558
CPCC07F9/65583
Inventor 刘志卓长城李响薛旺迁刘子畅
Owner LIANYUNGANG GUIKE PHARMA
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