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Chiral synthesis method of Aprepitant intermediate and intermediate synthesized through chiral synthesis method of Aprepitant intermediate

A technology of chiral synthesis and aprepitant, applied in asymmetric synthesis, organic chemical methods, chemical instruments and methods, etc., can solve the problems of being unsuitable for industrialized large-scale production, low product yield, and poor quality, and achieve shortening Effects of synthesis steps, high yield, and high cost

Inactive Publication Date: 2019-12-20
HUAIYIN INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the prior art, the synthesis process of aprepitant intermediates is often more complicated, the cost is higher, and there are also defects of low product yield and poor quality, which cannot be suitable for industrialized large-scale production

Method used

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  • Chiral synthesis method of Aprepitant intermediate and intermediate synthesized through chiral synthesis method of Aprepitant intermediate
  • Chiral synthesis method of Aprepitant intermediate and intermediate synthesized through chiral synthesis method of Aprepitant intermediate
  • Chiral synthesis method of Aprepitant intermediate and intermediate synthesized through chiral synthesis method of Aprepitant intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of Chiral Ligands

[0038] At room temperature, under nitrogen protection, add Pd(PPh 3 ) 4 3.5g (3mmol) and phosphoramidite (R-monoPhos) 2.2g (6mmol) in 200mL reaction solvent anhydrous DMF, then add compound (4) 61g (0.3mol) and compound (5) 51g (0.3mol), React at 100°C, monitor the reaction by TLC, and end the reaction after 12 hours. The reaction solution was lowered to room temperature, then poured into 200ml of saturated ammonium chloride aqueous solution, extracted twice with 200ml of ethyl acetate, combined the organic phase, and the organic phase was washed with 200ml of saturated sodium chloride aqueous solution, separated, and the organic phase was reduced Concentrate under reduced pressure to obtain a crude product of compound (6), which is directly used in the next reaction.

[0039] At room temperature, under the protection of nitrogen, add the crude product of the above compound (6) to 200 mL reaction solvent anhydrous tetrahydrofuran into...

Embodiment 2

[0043] Preparation of compound (1)

[0044] At room temperature, under the protection of nitrogen, add compound (2) 1.91kg (10.0mol) to 5L reaction solvent anhydrous toluene in 20L reactor, slowly add 5L LiHMDS toluene solution containing 2mol / L, after 1 hour After adding, after reacting at room temperature for 1 hour, add the catalyst [(t-Bu 3 P)PdBr] 277g (0.1mol), chiral ligand 46g (0.11mol), after stirring for half an hour, add compound (3) 2.44kg (11.0mol) in 2L toluene solution, TLC monitors the reaction, the reaction ends after 17 hours, slowly add 5L Saturated ammonium chloride aqueous solution was stirred for 30 minutes, separated, the aqueous phase was extracted with dichloromethane, and then the organic phases were combined, and the organic phase was concentrated (0.2mmHg) under reduced pressure to obtain the crude product of compound (1). The crude product was washed with toluene / petroleum The ether was recrystallized to obtain 2.57 kg (9.01 mol) of the refined p...

Embodiment 3

[0051] According to the synthesis method of Example 2, the difference is that the molar ratio of compound (2) to compound (3) is 1:1, the reaction temperature is 0°C, the reaction solvent is anhydrous tetrahydrofuran, and the catalyst is Pd 2 (dba) 3 , the base is LDA, the molar ratio of catalyst to compound (2) is 1:20; the molar ratio of catalyst to chiral ligand is 1:1. Compound (1) has a molar yield of 89.2%, and a purity of 98.55% by HPLC.

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Abstract

The invention discloses a chiral synthesis method of an Aprepitant intermediate and the intermediate synthesized through the chiral synthesis method of the Aprepitant intermediate. According to the synthesis method, with a compound (2) and a compound (3) as initial raw materials, an asymmetric coupling reaction is carried out to produce the compound (1) Aprepitant intermediate; and an equation isas shown in the specification. The completely novel chiral synthesis method of the Aprepitant intermediate is provided, and compared with the prior art where synthesis of the Aprepitant intermediate requires many steps, and a synthesis technology is high in cost and complex, the synthesis method is simple, easy to implement, low in cost, high in yield, good in product quality and suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a chiral synthesis method of an aprepitant intermediate and an intermediate thereof. Background technique [0002] Aprepitant (common name: Aprepitant, trade name Emend), chemical name: 5-[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]B Oxy]-3(S)-(4-fluorophenyl)morpholin-4-ylmethyl]-3,4-dihydro-2H-1,2,4-triazol-3-one. The molecular weight of aprepitant: 534.427; CAS registration number: 170729-80-3; the structural formula is shown in formula 1: [0003] [0004] Aprepitant is developed and produced by Merck (known as Merck in the United States and Canada), and was approved for import registration by the State Food and Drug Administration of China on July 16, 2013. [0005] Aprepitant is the world's first "highly selective NK1 receptor antagonist", which can effectively prevent nausea and vomiting caused by chemotherapy through the central nervous system ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/32C07B53/00
CPCC07B53/00C07B2200/07C07D265/32
Inventor 黄燕鸽华鹏顾凯名李进徐纬川袁君张世忠许莹游庆红
Owner HUAIYIN INSTITUTE OF TECHNOLOGY
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