Preparation method of fosaprepitant dimeglumine

A technology of fosaprepitant dimeglumine and aprepitant dibenzyl phosphate, applied in the preparation of organic compounds, chemical instruments and methods, preparation of aminohydroxyl compounds, etc., can solve the problem of poor safety and is not suitable for industrialized large-scale production , cumbersome post-processing, many production processes, etc., to achieve the effect of avoiding excessive heavy metals, mild reaction conditions, simple and safe operation

Active Publication Date: 2015-05-27
LUNAN BETTER PHARMA
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  • Abstract
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Problems solved by technology

The disadvantage of this method is that the reaction cycle is long, the production process is many, the yield is low, it is catalyzed by heavy metal palladium, and it uses a high-pressure vessel, which has poor safety and is not suitable for large-scale industrial production.
[0006] Another preparation method of fosaprepitant dimeglumine is reported in WO2011045817A2. Aprepitant is phosphonated to obtain bisbenzyl ester, which is reacted with ammonium formate under the catalysis of Palladium hydroxide-e / carbon and then reacted with ammonium formate N-methyl-D-glucosamine is used to obtain fosaprepitant dimeglumine. Although this route avoids the use of hydrogen, it still needs to consider the problem of heavy metal palladium exceeding the standard, which makes post-processing cumbersome

Method used

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  • Preparation method of fosaprepitant dimeglumine
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  • Preparation method of fosaprepitant dimeglumine

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Add 60ml of tetrahydrofuran, 5.3g of aprepitant and 7.0g of tetrabenzyl pyrophosphate into the reaction flask, stir to make it clear. Control the reaction temperature to 0°C, and slowly add 24ml of 1M sodium bis(trimethylsilyl)amide in tetrahydrofuran dropwise. The end of the reaction was monitored by TLC, the reaction was complete, 60ml of saturated sodium bicarbonate solution and 60ml of methyl tert-butyl ether were added, stirred, and allowed to stand for liquid separation. The organic layer was washed with 60ml 0.5M sodium bisulfate solution, 60ml saturated sodium bicarbonate solution and 60ml saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 7.0g of product (II) with a yield of 88.8% .

[0032] Dissolve 7.0g product (II) in 70ml methyl tert-butyl ether, control the reaction temperature at -5°C, and slowly add 2.6ml 1M BCl dropwise under the protection of nitrogen 3 Dichloromethane solution, after dr...

Embodiment 2

[0035] Add 60L of tetrahydrofuran, 5.3Kg of aprepitant and 7Kg of tetrabenzyl pyrophosphate into the reaction flask, stir to make it clear. Control the reaction temperature to 0°C, and slowly add 24L1M tetrahydrofuran solution of sodium bis(trimethylsilyl)amide. The end of the reaction was monitored by TLC, the reaction was complete, 60L of saturated sodium bicarbonate solution and 60L of methyl tert-butyl ether were added, stirred, and left to stand for liquid separation. The organic layer was washed with 60L 0.5M sodium bisulfate solution, 60L saturated sodium bicarbonate solution and 60L saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give product (II) 7.1Kg, the yield was 90 %.

[0036] Dissolve 7.1Kg product (II) in 70L methyl tert-butyl ether, control the reaction temperature at -5°C, and slowly add 2.6L 1M BCl dropwise under the protection of nitrogen 3 Dichloromethane solution, after dripping, TLC monitors t...

Embodiment 3

[0039] Add 60ml of tetrahydrofuran, 5.3g of aprepitant and 7.73g of tetra-p-methylbenzyl pyrophosphate into the reaction flask, stir to make it clear. Control the reaction temperature to 0°C, and slowly add 24ml of 1M bis(trimethylsilyl) sodium amide solution in tetrahydrofuran dropwise. The end of the reaction was monitored by TLC, the reaction was complete, 60ml of saturated sodium bicarbonate solution and 60ml of methyl tert-butyl ether were added, stirred, and allowed to stand for liquid separation. The organic layer was washed with 60ml 0.5M sodium bisulfate solution, 60ml saturated sodium bicarbonate solution and 60ml saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain product (II) 6.53g, the yield was 80% .

[0040] Dissolve 6.53g of product (II) in 70ml of isopropyl ether, control the reaction temperature at -5°C, and slowly drop 0.8ml of 1M BCl under the protection of nitrogen 3 Dichloromethane solution,...

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Abstract

The invention provides a preparation method of fosaprepitant dimeglumine. The preparation method comprises the following steps: by taking aprepitant as a raw material, carrying out phosphorylation on the raw material under an alkaline condition to obtain a dibenzyl ester intermediate; further hydrolyzing the intermediate to obtain fosaprepitant; and further reacting with N-methyl-D-glucosamine to obtain the fosaprepitant dimeglumine. The method provided by the invention is simple to operate and mild in reaction condition, and avoids pressurization and v, so that the method is safe and effective and suitable for industrial production on a large scale.

Description

Technical field [0001] The present invention relates to the technical field of medical production, in particular to a preparation method of fosapitant dimethyl meglumine. Background technique [0002] Fosaprepitant dimeglumine (Fosaprepitant dimeglumine, trade name Emend), CAS number: 265121-04-8, structural formula is shown in formula IV: [0003] [0004] Fosapitan dimethyl meglumine is developed by Merck and is used to treat acute and delayed nausea and vomiting caused by chemotherapy. It is the prodrug of aprepitant (Ⅰ) oral preparation, and it is rapidly transformed into Aprepitant (Ⅰ). Fosapitan and aprepitant are human substance P / neurokinin 1 (NK-1) selective high-affinity receptor blockers, which mainly act by blocking the brain's nausea and vomiting signals. Aprepitant (Ⅰ) was approved to be marketed in mid-2003, but the poor water solubility of aprepitant made it limited in the application of intravenous drip. Therefore, Merck launched Fosapitant for injection Dimethy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558C07C215/10C07C213/08
Inventor 赵志全白文钦孙秀玲王友国
Owner LUNAN BETTER PHARMA
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