Process for the preparation of enantiomerically enriched beta amino acid derivatives

An enantiomer, alkyl technology, applied in the field of β-amino acid derivatives, can solve problems such as synthesis difficulties

Inactive Publication Date: 2007-05-30
MERCK & CO INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The need for amine protection introduces two additional chemical steps into the sequence, protection and deprotection, so synthesis of protected substrates can also be difficult

Method used

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  • Process for the preparation of enantiomerically enriched beta amino acid derivatives
  • Process for the preparation of enantiomerically enriched beta amino acid derivatives
  • Process for the preparation of enantiomerically enriched beta amino acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0230]

[0231] (2R)-4-oxo-4-[3-trifluoromethyl-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)- base]-1- (2,4,5-trifluorophenyl)butane-2-amine (2-5)

[0232] Preparation of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (1-4)

[0233] plan 1

[0234]

[0235] Step A: Preparation of bishydrazide (1-1)

[0236] Hydrazine (20.1 g, 35 wt% in water, 0.22 mol) was mixed with 310 mL of acetonitrile. 31.5 g of ethyl trifluoroacetate (0.22 mol) were added within 60 minutes. The internal temperature increased 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. At a temperature below 16°C, 17.9 g of a 50 wt% aqueous NaOH solution (0.22 mol) and 25.3 g of chloroacetyl chloride (0.22 mol) were added simultaneously within 130 minutes. When the reaction was complete, the mixture was vacuum distilled at 27-30°C under a vacuum of 26-27 Hg to remove water and ethanol. During th...

Embodiment 2

[0287]

[0288] (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H )-base]-1- (2,4,5-trifluorophenyl)butane-2-amine (2-5)

[0289]

[0290] Bis(norbornadiene) rhodium(I) tetrafluoroborate {[Rh(nbd) 2 ] BF 4} (41.55mg, 0.1mmol), ligand D (69.73mg, 0.1mmol) and enaminoamide 2-4 (45 g, 111.1 mmol) into the flask. To this mixture was added 37.5 mL of a solvent mixture of methanol (very dry and degassed) and 112.5 mL of 2,2,2-trifluoroethanol (distilled and degassed). The slurry was then transferred to a stainless steel autoclave under nitrogen and sealed. The autoclave was then heated to 50°C and pressurized to 500 psig with hydrogen. Analysis of a sample taken after 17 hours using HPLC confirmed that the reaction was complete giving 94% assay yield and 94% ee.

Embodiment 3-5

[0292]

[0293] Table 1 a

[0294] Example

Ligand

metal precursor

%Yield b

%ee c

structure

3

4

5

A

B

C

[Rh(cod) 2 ] BF 4

[Rh(cod)Cl] 2

[Rh(cod)Cl] 2

77

58

15

88

76

78

R

R

S

[0295] a: Reaction conditions: 5 mol% metal precursor, 5 mol% ligand, 90 psig H in TFE 2 , 50°C, 18 hours;

[0296] b: Tested by HPLC; c: AS-RH chiral column eluted with 20% acetonitrile / water as mobile phase, tested by chiral HPLC

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Abstract

The present invention relates to a process for the efficient preparation of enantiomerically enriched beta amino acid derivatives wherein the amino group is unprotected. The product chiral beta amino acid derivatives are useful in the asymmetric synthesis of biologically active molecules. The process comprises an enantioselective hydrogenation of an amine-unprotected prochiral beta-amino acrylic acid or derivative thereof in the presence of a rhodium metal precursor complexed with a chiral mono- or bisphosphine ligand.

Description

field of invention [0001] The present invention relates to a process for the efficient preparation of enantiomerically enriched β-amino acid derivatives in which the amino group is unprotected. Chiral β-amino acid derivative products are frequent building blocks of drug candidates and can also be used in the asymmetric synthesis of other biologically active molecules. The process involves the enantioselective hydrogenation of amine-unprotected prochiral [beta]-aminoacrylic acid or derivatives thereof in the presence of a rhodium metal precursor complexed with a chiral mono- or diphosphine ligand. Background of the invention [0002] The invention provides a preparation marked with * An efficient method for enantiomerically enriched structural formula Iβ-amino acid derivatives on the carbon atom: [0003] [0004] in [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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/32C07C231/18C07D213/55C07D213/64C07D487/04C07C229/34
Inventor 肖毅孙勇奎T·罗斯纳N·R·里维拉S·W·克尔斯卡A·M·克劳森J·D·阿姆斯特隆三世F·斯平德勒C·马兰
Owner MERCK & CO INC
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