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Process for the preparation of chiral beta amino acid derivatives by asymmetric hydrogenation

A compound and alkyl technology, applied in the field of preparation of chiral β-amino acid derivatives by asymmetric hydrogenation, can solve problems such as difficult synthesis of reactants

Inactive Publication Date: 2006-04-19
MERCK SHARP & DOHME BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the need for amine protection, two additional chemical steps, protection and deprotection, are introduced in the reaction scheme, and the synthesis of protected reactants can also be difficult

Method used

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  • Process for the preparation of chiral beta amino acid derivatives by asymmetric hydrogenation
  • Process for the preparation of chiral beta amino acid derivatives by asymmetric hydrogenation
  • Process for the preparation of chiral beta amino acid derivatives by asymmetric hydrogenation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098]

[0099] (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine- 7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (2-5)

[0100] Preparation of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, hydrochloride (1-4)

[0101] Reaction scheme 1

[0102]

[0103]

[0104] Step A : Preparation of bishydrazide (1-1)

[0105] Hydrazine (20.1 g, 35 wt % solution in water, 0.22 mol) was fainted with 310 mL of acetonitrile. 31.5 g of ethyl trifluoroacetate (0.22 mol) were added over 60 minutes. Increase the internal temperature from 14°C to 25°C. The resulting solution was aged at 22-25°C for 60 minutes. The solution was cooled to 7°C. 17.9 g of 50 wt% aqueous NaOH (0.22 mol) and 25.3 g of chloroacetyl chloride (0.22 mol) were added simultaneously at a temperature below 16°C over 130 minutes. When the reaction was complete, the mixture was vacuum distilled at 26-27 Hg and 27-30° C. to remove water and ethanol. D...

Embodiment 2

[0159]

[0160] (3S)-3-Amino-3-(6-methylhydropyridin-3-yl)propionic acid methyl ester (3-2)

[0161] Add (1,5-cyclooctadiene)rhodium(I) chloride dimer {[Rh(cod)Cl] to a 7 mL bottle under nitrogen atmosphere 2} (14.2 mg, 0.029 mmol) and (R,S)-t-Bu Josiphos (31.3 mg, 0.058 mmol). Degassed methanol (1 mL) was then added and the catalytic complex was stirred at room temperature for 45 minutes. In a separate 2-mL bottle, the enaminoester 3-1 (0.1 g, 0.5 mmol) was dissolved in 0.9 mL of distilled 2,2,2-trifluoroethanol. Add 0.1 mL of the prepared catalyst solution to the same bottle to obtain a 1 mol% catalyst loading and a 90 / 10 mixture of 2,2,2-trifluoroethanol / methanol. The hydrogenation bottle was then sealed and transferred to a hydrogenation vessel under nitrogen. After degassing with hydrogen 3 times, the enaminoester was hydrogenated under 90-psig hydrogen at 50°C for 13.5 hours. The yield by HPLC was 88%, and the optical purity was 89% ee.

[0162] 1 H-NMR (400M...

Embodiment 3-6

[0164]

[0165] Ex.

[0166] A: Reaction condition: 0.15mol% [Rh(cod)Cl] 2 ; 0.33mol% (R, S)-t-BuJosiphos, 50°C, 100psig H 2 . B Determined yield; c Determined by chiral HPLC using AS-RH or AD-RH chiral columns, eluting with 25-40% acetonitrile / water as mobile phase.

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Abstract

The present invention relates to a process for the efficient preparation of enantiomerically enriched beta amino acid derivatives which are useful in the asymmetric synthesis of biologically active molecules. The process comprises an enantioselective hydrogenation of a prochiral beta amino acrylic acid derivative substrate in the presence of a transition metal precursor complexed with a chiral ferrocenyl diphosphine ligand.

Description

field of invention [0001] The present invention relates to a method for the efficient preparation of enantiomerically enriched β-amino acid derivatives useful in the asymmetric synthesis of biologically active molecules. The process of the invention comprises the enantioselective hydrogenation of a prochiral [beta]-amino acid derivative in the presence of a transition metal precursor complexed with a chiral ferrocenyldiphosphine ligand. Background of the invention [0002] The present invention provides an efficient method for preparing enantiomer-enriched β-amino acid derivatives shown in formula I: [0003] [0004] Said derivatives have (R)- or (S)-configuration at the stereogenic centers marked with *; [0005] where Z is OR 2 、SR 2 or NR 2 R 3 ; 1 is C 1-8 Alkyl, aryl, heteroaryl, aryl-C 1-2 Alkyl or heteroaryl-C 1-2 Alkyl; R 2 and R 3 are independently hydrogen, C 1-8 Alkyl, aryl or aryl-C 1-2 Alkyl; or R 2 and R 3 Together with the nitrogen atom to w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/52C07F17/02B01J31/24C07D487/04C07D249/00C07D241/00B01J31/22C07C227/16C07C231/12C07C237/20
CPCB01J2231/645B01J31/2409C07C231/12B01J2531/0286C07C231/18B01J2531/0263B01J31/2295B01J2531/822C07D487/04B01J31/24B01J2531/842C07C227/16C07C237/20
Inventor 肖毅J·D·阿姆斯特隆三世S·W·克尔斯卡E·诺利托N·R·里维拉孙勇奎T·罗斯纳
Owner MERCK SHARP & DOHME BV
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