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New preparation method for fosaprepitant and pharmaceutically acceptable salt thereof

A technology of medicinal salts and supercritical fluids, which is applied in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, and bulk chemical production, and can solve high production costs, expensive precious metals, and waste of precious metals and other problems to achieve the effect of overcoming high production cost, good product quality and short production cycle

Active Publication Date: 2016-01-20
海南金泰药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, due to catalytic hydrogenation under conventional conditions into gas, liquid, and solid heterogeneous reactions, in known methods, the precious catalyst palladium carbon that accounts for 5%-20% of the weight of raw materials is required to carry out the catalytic reaction, and the precious metal is expensive, resulting in Unfavorable factors such as high production cost and serious waste of precious metals; at the same time, there are many heavy metal palladium residues in the finished product; and because the reaction is carried out in the presence of counter ions, debenzylation inevitably occurs during catalytic hydrogenation debenzylation protection and other side reactions, the impurities such as defluorination (formula V) produced are large, and it is very difficult to refine and remove, resulting in low product purity and excessive heavy metals. The clinical use of this fosaprepitant is intravenous drip (requires heavy metal residues to be less than 10ppm), Impurities such as defluorination must be controlled below 0.1%, so it is easy to bring unsafe factors to clinical use

Method used

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  • New preparation method for fosaprepitant and pharmaceutically acceptable salt thereof
  • New preparation method for fosaprepitant and pharmaceutically acceptable salt thereof
  • New preparation method for fosaprepitant and pharmaceutically acceptable salt thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0029] In a 500ml supercritical fluid reaction device, add 50.0g (0.063mol) of aprepitant dibenzyl phosphate and 0.5g of 5% palladium carbon, after replacing the air with carbon dioxide, first feed hydrogen to make the pressure reach 0.3-0.5MPa , and then feed carbon dioxide to make the total pressure reach 13-14MPa, control the temperature at 31-35° C. and stir the reaction for 1 hour. After removing the pressure, add 500ml of methanol, filter, add 24.6g (0.126mol) of N-methyl-D-glucosamine to the filtrate, stir at room temperature for 2 hours under nitrogen protection, drop the obtained solution into acetonitrile, and crystallize under stirring , press-filtered under the protection of nitrogen, and vacuum-dried at room temperature to obtain 55.4 g of fosaprepitant dimeglumine as a white solid, with a yield of 87.5%. Heavy metals are less than 10ppm, purity is 99.75%, defluorinated impurities are 0.03%, and other single impurities are less than 0.1%.

Embodiment 2

[0031] In a 2-liter supercritical fluid reaction device, add 200.0 g (0.252 mol) of aprepitant dibenzyl phosphate and 1.0 g of 10% palladium carbon. After replacing the air with carbon dioxide, first feed hydrogen to make the pressure reach 0.5-0.8 MPa, and then feed carbon dioxide to make the total pressure reach 16-20 MPa, control the temperature at 31-35° C. and stir for 1 hour. After removing the pressure, add 500ml of methanol, filter, add 98.4g (0.504mol) of N-methyl-D-glucosamine to the filtrate, stir at room temperature for 2 hours under the protection of nitrogen, drop the obtained solution into acetonitrile, and crystallize under stirring , press-filtered under the protection of nitrogen, and vacuum-dried at room temperature to obtain 227.8 g of fosaprepitant dimeglumine as a white solid, with a yield of 90.0%. The heavy metal is less than 10ppm, the purity is 99.73%, the defluorinated impurities are not detected, and the other single impurities are all less than 0.1...

Embodiment 3

[0033] In a 500ml supercritical fluid reaction device, add 50.0g (0.063mol) of aprepitant dibenzyl phosphate and 0.25g of 10% palladium carbon, after replacing the air with carbon dioxide, first feed hydrogen to make the pressure reach 0.3-0.5MPa , and then feed carbon dioxide to make the pressure reach 13-14MPa, control the temperature at 35-40°C and stir the reaction for 0.5 hours. After removing the pressure, add 500ml of methanol, filter, add 24.6g (0.126mol) of N-methyl-D-glucosamine to the filtrate, stir at room temperature under nitrogen protection for 1 hour, drop the obtained solution into acetonitrile, and crystallize under stirring , pressure filtration under nitrogen protection, and vacuum drying at room temperature to obtain 52.6 g of fosaprepitant dimeglumine as a white solid, with a yield of 83.1%. The heavy metal is less than 10ppm, the purity is 99.77%, the defluorinated impurities are not detected, and other single impurities are all less than 0.1%.

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Abstract

The present invention provides a new preparation method for fosaprepitant and a pharmaceutically acceptable salt thereof. The method comprises: adopting aprepitant dibenzyl phosphate as a raw material, carrying out catalytic hydrogenation in the absence of counter ions and supercritical fluids to prepare fosaprepitant, and forming the pharmaceutically acceptable salt with an alkali after separation or without separation. According to the present invention, the method has characteristics of good product quality, low production cost, simple operation and short reaction period, and is suitable for industrial production.

Description

Technical field: [0001] The invention relates to the technical field of medicine production, and relates to a preparation method of fosaprepitant and a medicinal salt thereof. Background technique: [0002] Fosaprepitant (fosaprepitant) is a new type of substance P (neurokinin-1) receptor antagonist, which was approved by the US FDA in 2008. It is used for intravenous injection to prevent and treat moderate emetic and high-dose emetic anticancer drug chemotherapy. (including high-dose cisplatin) acute and delayed nausea and vomiting caused by initial and repeated administration. Its chemical name is [3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)basic]ethoxy]-3-(4-fluoro Phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonic acid has the structure of formula I below. [0003] [0004] In the patents CN1147254A, CN101056672A, and CN102558232A, it is disclosed that formula II (dibenzyl aprepitant phosphate) or formula IV (aprepitant monobenzyl phosphate) is prepared ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558
CPCY02P20/54
Inventor 不公告发明人
Owner 海南金泰药业有限公司
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