Application of borane-pyridine complex in preparation of NK-1 receptor antagonist

Abstract

The invention provides an application of a borane-pyridine complex in preparation of an NK-1 receptor antagonist fosaprepitant dimeglumine. The application is characterized by comprising the followingsteps: step 1) catalyzing aprepitant dibenzyl phosphate under the action of the borane pyridine complex to prepare fosaprepitant; and 2) reacting fosaprepitant with N-methyl-D-glucosamine to generatefosaprepitant dimeglumine. The borane-pyridine complex is used as the catalyst, aprepitant dibenzyl phosphate can directly generate fosaprepitant, then the fosaprepitant dibenzyl phosphate reacts with N-methyl-D-glucosamine to generate fosaprepitant dimeglumine, the reaction is mild, and conversion of raw materials can be completed quickly at the temperature of about room temperature only by using a small amount of catalyst. The catalytic efficiency is high, the reaction conditions are mild and the yield is high. The high-purity and high-yield fosaprepitant can be obtained by recrystallizingthe reaction crude product with deionized water, the post-treatment is extremely simple, and the fosaprepitant dimeglumine is generated by reacting the reaction crude product with N-methyl-D-glucosamine so that the purity and the yield are high.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, in particular to a preparation method of a pharmaceutical compound, and more particularly to a preparation method of an important NK-1 receptor antagonist fosaprepitant dimeglumine. Background technique [0002] Fosaprepitant dimeglumine (Fosaprepitant dimeglumine, trade name: Emend), the Chinese chemical name is deoxy-1-(methylamino)-D-sorbitol [3-[[(2R,3S)-2-[(1R )-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl-2,5-dihydro- 5-Oxo-1H-1,2,4-triazol-1-yl]phosphate (2:1), molecular formula C 23 h 22 f 7 N 4 o 6 P·2C 7 h 17 NO 5 , the molecular weight is 1004.83, it is white to off-white powder, odorless, hygroscopic, easily soluble in methanol and water, very slightly soluble in absolute ethanol, and the specific rotation is +28°~+33°. The drug is a new type of chemotherapy-related antiemetic drug developed by Merck, which was first launched in the...

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Problems solved by technology

[0005] (1) Using aprepitant dibenzyl phosphate as raw material, using palladium carbon as a catalyst, in the presence of N-methyl-D-glucosamine, catalytic hydrogenation followed by catalytic hydrogenation to prepare fosaprepitant dimeglucose Amine, this method uses heavy metal palladium as a catalyst, the price is expensive, the reaction conditions are harsh, and the hydrogenation reaction needs to use a pressure vessel, the safety performance is poor, and it is not suitable for industrial production

[0006] (2) Using aprepitant dibenzyl phosphate as a raw material, first react with methanol to prepare aprepitant monobenzyl phosphate, which is then obtained by hydrogenation in the presence of N-methyl-D-glucosamine Fosaprepitant dimeglumine, but this method still uses palladium carbon as a catalyst and hydrogen as a raw material. In addition to requiring a high-pressure environment and poor safety performance, the process flow is more cumbersome, and it is still not suitable for industrial production

[0007] (3) With aprepitant dibenzyl phosphate as raw material, with BCl 3 or BF 3 Waiting for Lewis as a catalyst, the crude product of fosaprepitant is generated by debenzylation, and then reacted with N-methyl-D-glucosamine to generate fosaprepitant dimeglumine. This reaction replaces hydrogenation by deprotection of Lewis acid , avoids the use of hydrogen, does not need to react in a high-pressure environment, solves the safety problem, and does not use heavy metal palladium to avoid excessive heavy metals, but it needs to react at low temperature, which is not easy to operate

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