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Application of borane-pyridine complexe in preparation of pharmaceutical compound

A technology for the preparation of drugs and complexes, which is applied in the field of preparation of important pharmaceutical compounds fosaprepitant, can solve the problems of unsuitability for industrial production, failure to obtain fosaprepitant, cumbersome process, etc., and avoid high pressure environment and heavy metals The effect of increased use, increased safety, and high catalytic efficiency

Inactive Publication Date: 2021-03-12
商河探荣新技术开发中心
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] (1) take aprepitant dibenzyl phosphate as raw material, take palladium carbon as catalyst, prepare fosaprepitant by catalytic hydrogenation, this method uses heavy metal palladium as catalyst, expensive, harsh reaction conditions, and hydrogenation reaction needs Pressure vessels are used, the safety performance is poor, and it is not suitable for industrial production
[0006] (2) take aprepitant dibenzyl phosphate as raw material, first react with methanol to prepare aprepitant monobenzyl phosphate, and then obtain fosaprepitant through hydrogenation reaction, but this method still uses palladium carbon as Catalyst and hydrogen are used as raw materials. In addition to the need for a high-pressure environment and poor safety performance, the process is more cumbersome and still not suitable for industrial production.
[0007] (3) With aprepitant dibenzyl phosphate as raw material, with BCl 3 or BF 3 When Lewis is used as a catalyst, fosaprepitant is generated by debenzylation. This reaction replaces hydrogenation by deprotection of Lewis acid, avoids the use of hydrogen, does not need to react under high pressure environment, solves the safety problem, and does not use heavy metals at the same time Palladium, to avoid excessive heavy metals, but only the crude product of fosaprepitant was obtained, and pure fosaprepitant was not obtained

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  • Application of borane-pyridine complexe in preparation of pharmaceutical compound

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preparation example Construction

[0024] The invention provides a preparation method of fosaprepitant, which is characterized in that it comprises the following steps: aprepitant dibenzyl phosphate is catalyzed to prepare fosaprepitant under the action of a borane-pyridine complex, and the aprepitant The structural formula of repitant dibenzyl phosphate is: Wherein R is independently selected from a hydrogen atom, a C1-6 alkyl group, a halogen atom, preferably a hydrogen atom.

[0025] According to the preparation method of the pharmaceutical compound fosaprepitant of the present invention, aprepitant dibenzyl phosphate and borane-pyridine complex are added to an organic solvent, stirred and reacted, concentrated under reduced pressure, and recrystallized. The fosaprepitant compound is obtained.

[0026] According to the preparation method of the pharmaceutical compound fosaprepitant of the present invention, the molar ratio of the aprepitant dibenzyl phosphate to the borane-pyridine complex is 1:0.1-0.5.

...

Embodiment 1

[0034] step 1)

[0035] Under a nitrogen atmosphere, add 500ml tetrahydrofuran, 0.1mol aprepitant, and 0.12mol tetrabenzyl pyrophosphate to the reaction flask in sequence, lower the temperature of the system to about 0°C, and dissolve 0.2mol hexamethyldisilazol in tetrahydrofuran Sodium azane was added dropwise into the system, and after the dropwise addition was completed, the reaction was incubated for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with methyl tert-butyl ether. The organic layer was washed with 200ml of saturated sodium bisulfate solution, 200ml of saturated sodium bicarbonate solution, and 200ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give aprepitant dibenzyl phosphate as a white solid with a yield of 93.6%. .

[0036] step (2)

[0037] Under a nitrogen atmosphere, mix 50 mmol of the product obtained in the previous step with 100 ml of methanol, stir evenl...

Embodiment 2

[0041] step 1)

[0042] Under a nitrogen atmosphere, add 500ml tetrahydrofuran, 0.1mol aprepitant, and 0.12mol tetrabenzyl pyrophosphate to the reaction flask in sequence, lower the temperature of the system to about 5°C, and dissolve 0.2mol hexamethyldisilazol in tetrahydrofuran Sodium azane was added dropwise into the system, and after the dropwise addition was completed, the reaction was incubated for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with methyl tert-butyl ether. The organic layer was washed with 200ml of saturated sodium bisulfate solution, 200ml of saturated sodium bicarbonate solution, and 200ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give aprepitant dibenzyl phosphate as a white solid with a yield of 93.1%. .

[0043] step (2)

[0044] Under a nitrogen atmosphere, mix 100mmol of the product obtained in the previous step with 180ml of methanol, stir at roo...

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Abstract

The invention provides an application of a borane-pyridine complex in preparation of a pharmaceutical compound fosaprepitant. The application is characterized by comprising the following step: catalyzing aprepitant dibenzyl phosphate under the action of the borane-pyridine complex to prepare fosaprepitant. The borane-pyridine complex is used as the catalyst, aprepitant dibenzyl phosphate can directly generate fosaprepitant, the reaction is mild, the conversion of the raw materials can be quickly completed at the temperature of about room temperature only by using a small amount of catalyst, the catalytic efficiency is high, the reaction condition is mild, and the yield is high. The high-purity and high-yield fosaprepitant can be obtained by recrystallizing the reaction crude product by using deionized water, the post-treatment is extremely simple, and the deionized water is used as a solvent, so that the method is more economical and environment-friendly.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a preparation method of a pharmaceutical compound, more particularly to a preparation method of an important pharmaceutical compound fosaprepitant. Background technique [0002] Fosaprepitant (fosaprepitant), also known as fosaprepitant, is a new type of substance P (NK-1) receptor antagonist, developed by Merck and approved by the US FD-A in 2008. Fosaprepitant is used for intravenous injection to prevent and treat acute and delayed nausea and vomiting caused by initial and repeated chemotherapy of moderately emetic and high-dose anticancer drugs (such as high-dose cisplatin) chemotherapy. Its chemical name is [3-[ [(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)base]ethoxy]-3-(4-fluorophenyl)-4,5- Dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonic acid, its structural formula is as follows: [0003] [0004] The preparation method of fosaprepitant mainly compris...

Claims

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Application Information

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IPC IPC(8): C07F9/6558B01J31/20
CPCC07F9/65583B01J31/1815
Inventor 李治泉
Owner 商河探荣新技术开发中心
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