Process to chiral beta amino acid derivatives by asymmetric hydrogenation

A technology of compounds and alkyl groups, applied in the field of preparing chiral beta amino acid derivatives by asymmetric hydrogenation, can solve problems such as difficulties

Inactive Publication Date: 2008-05-07
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Amine protection requires two additional chemical steps (i.e. protection and deprotection) to be introduced into the procedure, thus synthesizing the protected substrates can also be difficult

Method used

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  • Process to chiral beta amino acid derivatives by asymmetric hydrogenation
  • Process to chiral beta amino acid derivatives by asymmetric hydrogenation
  • Process to chiral beta amino acid derivatives by asymmetric hydrogenation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095]

[0096] (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazine-7(8H )- Base]-1-(2,4,5-trifluorophenyl)butan-2-amine (2-5)

[0097] 3-(Trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-α]pyrazine, hydrochloride Preparation of (1-4)

[0098] Process 1

[0099]

[0100] Step A: Preparation of bishydrazide (1-1)

[0101] Hydrazine (20.1 g, 35% by weight in water, 0.22 mol) was mixed with 310 mL of acetonitrile. 31.5 g of ethyl trifluoroacetate (0.22 mol) were added over 60 min. The internal temperature increased from 25°C to 14°C. The resulting solution was aged at 22-25°C for 60 min. Cool the solution to 7°C. At a temperature below 16°C, 17.9 g of 50% by weight aqueous NaOH (0.22 mol) and 25.3 g of chloroacetyl chloride (0.22 mol) were added simultaneously over 130 min. When the reaction was complete, the mixture was vacuum distilled at 27-30°C and 26-27 Hg vacuum to remove water and ethanol. During the distillation, 720...

Embodiment 2

[0127] (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazine-7(8H )- Preparation of -1-(2,4,5-trifluorophenyl)butan-2-amine (2-5)

[0128] Under a nitrogen atmosphere, the chloro(1,5-cyclooctadiene) rhodium(I) dimer {[Rh(cod)Cl] 2} (0.074 mg, 0.15 μmol) and (R,S) tert-butyl Josiphos (0.179 mg, 0.033 μmol), ammonium formate (6.6 mg, 0.15 mmol) and ketoamide 2-3 (6.1 mg, 15 μmol) into a 1-mL reactor. Additional degassed MeOH (200 μL) was added and the mixture was stirred for 5 h at 55° C. in a pressure vessel under nitrogen. The mixture was hydrogenated under 250 psi hydrogen at 55°C for 20 h. The experimental yield was 91% and the optical purity was 95% ee as determined by HPLC.

[0129] The following high performance liquid chromatography (HPLC) conditions were used to determine the percent conversion of the product:

[0130] Column: Agilent Extend C18, 150mm×4.6mm

[0131] Eluent: Solvent A: 80 / 20% by volume Water / Methanol 10mM TRIS pH 9

[01...

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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 an ammonium salt and a transition metal precursor complexed with a chiral ferrocenyl diphosphine ligand.

Description

field of invention [0001] The present invention relates to the efficient preparation of enantiomerically enriched beta amino acid derivatives which can be used in the asymmetric synthesis of biologically active molecules. The method involves the enantioselective hydrogenation of a prochiral β-aminoacrylic acid derivative substrate in the presence of an ammonium salt and a transition metal precursor complexed with a chiral ferrocenediphosphine ligand. Background of the invention [0002] The present invention provides an effective preparation method of enantiomerically enriched β amino acid derivatives of structural formula I: [0003] [0004] In formula I marked with * The stereocenter of has (R)- or (S)-configuration; where [0005] Z is OR 2 、SR 2 or NR 2 R 3 ; [0006] R 1 is C 1-8 Alkyl, aryl, heteroaryl, aryl-C 1-2 Alkyl or heteroaryl-C 1-2 alkyl; [0007] R 2 and R 3 each independently hydrogen, C 1-8 Alkyl, aryl or aryl-C 1-2 Alkyl; or R 2 and R ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/32
CPCC07D487/04
Inventor 肖毅J·D·阿姆斯特隆三世S·W·克尔斯卡E·恩约利托N·R·里韦拉孙勇奎T·罗斯纳A·M·克劳森
Owner MERCK & CO INC
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