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Preparation method of aprepitant intermediate

A technology for aprepitant and intermediates, applied in the field of medicinal chemistry, can solve the problems of increased difficulty in the purification of final products, inability to meet industrialized production, and harsh reaction conditions, and achieve great practical application value, easy large-scale preparation, and overall The effect of high yield

Inactive Publication Date: 2015-04-29
武汉励合生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method has the disadvantages of harsh reaction conditions, complex process and expensive reagents. Its yield is low and impurities that are difficult to remove in the final product are introduced, which makes the purification of the final product more difficult and cannot meet the needs of industrial production.

Method used

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  • Preparation method of aprepitant intermediate
  • Preparation method of aprepitant intermediate
  • Preparation method of aprepitant intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Add 25g of 4-benzyl-2-hydroxy-morpholin-3-one II, 50g of trifluoroacetic anhydride and 80g of anhydrous acetonitrile into the reaction kettle, stir at 5°C for 1 hour, add (R)-1-[3 , 5-bis(trifluoromethyl)phenyl]ethanol III 60g and boron trifluoride diethyl ether 17g were stirred and condensed at 25°C for 4 hours, and the reaction solution was post-treated and crystallized to obtain compound IV. Add 2g of magnesium, 40g of tetrahydrofuran and 16g of p-fluorobromobenzene in the reaction kettle, heat to initiate the reaction until the magnesium disappears, and then obtain the Grignard reagent and cool it for use; compound IV is dissolved in 100g of tetrahydrofuran to form a solution, and the above-mentioned Grignard reagent is added dropwise until the reaction is complete 16 g of methanol was added to quench the reaction, 0.5 g of palladium carbon was added to the above reaction solution, and hydrogen gas was introduced to carry out the hydrogenation reaction until the reac...

Embodiment 2

[0034] Add 20.7g of 4-benzyl-2-hydroxy-morpholin-3-one II, 40g of trifluoroacetic anhydride and 70g of anhydrous acetonitrile into the reaction kettle, stir at -10°C for 2 hours, add (R)-1 -[3,5-bis(trifluoromethyl)phenyl]ethanol III 25.8g and (R)-2-methyl-CBS-oxazoboridine 2.7g, stirred and condensed at 35°C for 6 hours, and the reaction After liquid treatment and crystallization, compound IV was obtained. Add 1.6g of magnesium, 30g of tetrahydrofuran and 26g of p-fluorobromobenzene into the reaction kettle, heat to initiate the reaction until the magnesium disappears, and then the Grignard reagent is obtained and cooled for use; compound IV is dissolved in 90g of tetrahydrofuran to form a solution, and the above-mentioned Grignard reagent is added dropwise until the reaction Completely, 15 g of methanol was added to quench the reaction, 0.9 g of Raney nickel was added to the above reaction solution, and hydrogen gas was introduced to carry out the hydrogenation reaction unti...

Embodiment 3

[0036] Add 20.7g of 4-benzyl-2-hydroxy-morpholin-3-one II, 50g of trifluoroacetic anhydride and 100g of anhydrous acetonitrile into the reaction kettle, stir at 10°C for 2 hours, add (R)-1- [3,5-bis(trifluoromethyl)phenyl]ethanol III 51.6g and (R)-2-methyl-CBS-oxazoboridine 5.4g were stirred and condensed at 15°C for 3 hours, and the reaction solution After workup and crystallization, compound Ⅳ was obtained. Add 2.6g of magnesium, 50g of tetrahydrofuran and 32g of p-fluorobromobenzene into the reaction kettle, heat to initiate the reaction until the magnesium disappears, and then the Grignard reagent is obtained and cooled for use; Compound IV is dissolved in 110g of tetrahydrofuran to form a solution, and the above-mentioned Grignard reagent is added dropwise until the reaction Complete, add 20g of methanol to quench the reaction, add 3g of sodium triacetate borohydride to the above reaction solution to carry out hydrogenation reaction until the reaction is complete, filter ...

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Abstract

The invention discloses a method for synthesizing an aprepitant intermediate (2R, 3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyoxyl]-3-(4-fluorophenyl)-morpholine hydrochloride I. The method comprises the following steps: performing a condensation reaction on the raw materials 4-benzyl-2-hydroxy-morpholine-3-one II and (R)-1-[3,5-bi(trifluoromethyl)phenyl]ethanol III in the presence of a catalyst to obtain a compound IV, adding a Grignard reagent to the obtained compound IV for having a Grignard reaction and converting the compound IV into a compound V under a reduction condition, and performing a hydrochlorination reaction on the obtained compound V to obtain the target compound I. The method is simple in preparation flow and suitable for industrial production, and has the advantages of high total recovery, convenient intermediate purification, high target product purity and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to aprepitant intermediate (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]- The preparation method of 3-(4-fluorophenyl)-morpholine hydrochloride. Background technique [0002] Aprepitant (Aprepitant), the chemical name is 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]- 3-(4-Fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one is a neural Kinin-1 (NK-1) receptor antagonist, whose tablets were approved by the US FDA in 2003, is used to prevent acute and delayed nausea and vomiting caused by highly emetogenic anti-tumor chemotherapy drugs. [0003] (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-morpholine hydrochloride It is the key intermediate for preparing aprepitant, its structure is shown in formula I. [0004] [0005] Currently preparing (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-...

Claims

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Application Information

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IPC IPC(8): C07D265/32
CPCC07D265/32
Inventor 彭凡李娜胡霞李玲彭良莹
Owner 武汉励合生物医药科技有限公司
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