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Preparation method of aprepitant intermediate

A technology for aprepitant and intermediates, applied in the field of pharmaceutical preparation, can solve the problems of increased cost, low yield and the like, and achieve the effects of less waste discharge, high yield and lower production cost

Active Publication Date: 2015-03-25
REYOUNG PHARMA
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  • Description
  • Claims
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Problems solved by technology

[0011] The document (2R,3S)-2-[(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride Synthesis of salt; 2-[(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-( 4-methoxybenzyl) morpholin-3-one was induced to convert (R)-2-[(R)-1-[3,5-di( Trifluoromethyl) phenyl] ethoxy]-4-(4-methoxybenzyl) morpholin-3-ketone, use isopropyl ether single solvent in this document, productive rate is lower, increased greatly cost in mass production

Method used

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  • Preparation method of aprepitant intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Weigh 25g of 2-[(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-benzylmorpholin-3-one in a dry three-necked flask and add Dissolve 5ml of diethyl ether, then add 75ml of tetrahydrolinalool, after cooling down to -5°C, slowly add tetrahydrolinalool potassium solution, then react at this temperature for 2h, then add 65ml of petroleum ether, and add 0.5mol / 125ml of L hydrochloric acid was used to stop the reaction, and finally 50ml of saturated sodium bicarbonate solution was added to adjust the pH to 8.5 before liquid separation, and the organic layer was cooled to 0°C for crystallization and suction filtration to obtain the product white crystals, with a yield of 91.5%, a purity of 99.8%, and a melting point of 93 ℃.

[0032] Wherein, potassium tetrahydrolinalool solution is 7.5 g of potassium tetrahydrolinalool dissolved in 10 ml of ether.

Embodiment 2

[0034] Weigh 25g of 2-[(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-benzylmorpholin-3-one in a dry three-necked flask and add Dissolve 20ml of diethyl ether, slowly cool down to -5°C, add potassium tetrahydrolinalool solution, then react at this temperature for 2h, then add 65ml of petroleum ether, and add 125ml of 0.5mol / L hydrochloric acid to terminate the reaction, and finally add saturated carbonic acid The sodium hydrogen solution adjusts the pH to 8.5 and then separates the liquids. The organic layer is cooled to 0°C to crystallize and then suction filtered to obtain the product as white crystals with a yield of 91.8%, a purity of 99.8%, and a melting point of 93°C.

[0035] Wherein, potassium tetrahydrolinalool solution is that 7.5 g of potassium tetrahydrolinalool is dissolved in 55 ml of ether and 15 ml of tetrahydrolinalool.

Embodiment 3

[0037] Weigh 25g of 2-[(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-benzylmorpholin-3-one in a dry three-necked flask and add Dissolve 20ml of ether, slowly cool down to 0°C, slowly add potassium tetrahydrolinalool solution, then react at this temperature for 2h, then add 65ml of petroleum ether, and add 125ml of 0.5mol / L hydrochloric acid to terminate the reaction, and finally add saturated carbonic acid The sodium hydrogen solution adjusts the pH to 8.5 and separates the liquids. The organic layer is cooled to 0°C for crystallization and then suction filtered to obtain the product as white crystals with a yield of 91.1%, a purity of 99.8%, and a melting point of 93°C.

[0038] Wherein, tetrahydrolinalool potassium solution is that 7.5g tetrahydrolinalool potassium is dissolved in 55ml ether and 15ml tetrahydrolinalool.

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Abstract

The invention relates to a preparation method of an aprepitant intermediate. Crystallization-induced chiral configuration inversion is carried out on 2-[(R)-1-[3,5-bis(trifluoromethyl) phenyl] ethyoxyl]-4-benzyl morpholine-3-one so as to synthesize (R)-2-[(R)-1-[3,5-bis(trifluoromethyl) phenyl] ethyoxyl]-4-benzyl morpholine-3-one, wherein an ether-tetrahydrolinalool system is adopted in the method. According to the preparation method disclosed by the invention, reaction is easy to carry out, a reaction rate is speeded up, a production cycle is greatly shortened, production cost is reduced and the discharge of waste liquid is reduced, and the effects of reducing cost and protecting environment are achieved; and the preparation method, as an efficient and green synthesis method, has the advantages of high yield, short reaction time, high atom utilization ratio, low waste discharge and the like.

Description

technical field [0001] The invention relates to a preparation method of an aprepitant intermediate, belonging to the technical field of medicine preparation. Background technique [0002] (R)-2-[(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-benzylmorpholin-3-one is the synthesis of aprepitant Important intermediate, its chemical structure is as shown in (I): [0003] [0004] The compound is mainly crystallized by 2-[(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-benzylmorpholin-3-one to induce chiral configuration It is produced by inversion, and its conversion reaction equation is shown in (II). This synthetic route has the advantages of high yield, short production cycle, high atom utilization rate, and less waste generation. [0005] [0006] Currently, there are known patents for the synthesis of (R)-2-[(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-benzylmorpholin-3-one There are no reports, and there are mainly two methods to query known literature mentio...

Claims

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Application Information

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IPC IPC(8): C07D265/32
CPCC07D265/32
Inventor 苗得足王福生李广杨祥龙李金凤苏艳华
Owner REYOUNG PHARMA
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