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Chiral phosphine ligand and metal catalyst comprising same and application of chiral phosphine ligand and metal catalyst

A technology of bidentate phosphine ligands and transition metals, which is applied in the application field of chiral phosphine ligands and efficient catalytic hydrogenation of chiral β-arylamides, which can solve the problems of difficult substrate synthesis and insufficient efficiency

Active Publication Date: 2013-05-08
宁波赜军医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the method for the synthesis of chiral β-arylamides by asymmetric hydrogenation has been studied (Angew.Chem.Int.Ed.2009,48,800; Tetrahedron 2012,68,7685; ; Synlett1999,1832; Angew.Chem.Int.Ed.2006,45,1223), but there are still many shortcomings in existing methods, including difficult substrate synthesis, low efficiency, etc.

Method used

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  • Chiral phosphine ligand and metal catalyst comprising same and application of chiral phosphine ligand and metal catalyst
  • Chiral phosphine ligand and metal catalyst comprising same and application of chiral phosphine ligand and metal catalyst
  • Chiral phosphine ligand and metal catalyst comprising same and application of chiral phosphine ligand and metal catalyst

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] In this example, (2S,2'S,3S,3'S)-4,4'-di(9-anthracenyl)-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro -2,2'-dibenzo[d][1,3]oxy,phosphorus-pentaconjugate (1) and its metal complex {(norbornadiene)[(2S,2'S,3S,3'S)- 4,4'-bis(9-anthracenyl)-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro-2,2'-dibenzo[d][1, 3] Oxygen,phosphorus-pentyl yoke} rhodium tetrafluoroborate, namely Rh(nbd)(1)BF 4 The preparation (its reaction scheme as shown below) is an example to describe the preparation method of chiral bisphosphine ligand of the present invention and metal rhodium complex thereof in detail:

[0126]

[0127] 1. (S)-4-(9-anthryl)-3-tert-butyl-2,3-dihydrobenzo[d][1,3]oxo,phospho-pentyl-3-oxo(c) preparation of

[0128] Following known literature procedures, a was converted to (S)-4-(9-anthryl)-3-(tert-butyl)-2,3-dihydrobenzo[d][1,3]oxo, Phosphorus-pentyl-3-oxo (c,Org.Lett.2011,13,1366)

[0129] 2. (2S,2'S,3R,3'R)-4,4'-bis(9-anthracenyl)-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro- Preparati...

Embodiment 2

[0139] This example takes the preparation of substrate 13a (its reaction scheme is shown below) as an example to describe the preparation method of (E)-β-aryl enamide of the present invention in detail:

[0140]

[0141] 1. Preparation of (E)-1,3-dimethoxy-5-(2-nitro-1-propenyl)benzene (f)

[0142] To a 50 mL round bottom flask was added 3,5-dimethoxybenzaldehyde (e, 3.32 g, 20 mmol), ammonium acetate (1 g, 26 mmol), nitroethane (30 mL). After stirring under reflux for 2 hours, it was concentrated, and the residue was dissolved in 50 mL of dichloromethane, and washed with water and saturated brine (50 mL) successively. After drying over anhydrous sodium sulfate, concentrate to obtain the crude target product (E)-1,3-dimethoxy-5-(2-nitro-1-propenyl)benzene (f, 4.24g, 95% yield rate), the product was directly used in the next reaction.

[0143] 2. Preparation of (E)-1-(3,5-dimethoxyphenyl)-2-acetamidopropene (13a)

[0144] Under nitrogen protection, add (E)-1,3-dimethoxy-5...

Embodiment 3

[0147] In this example, the preparation of 2-acetamido-3,4-dihydronaphthalene (13q) (the reaction scheme is shown below) is taken as an example to illustrate the cyclic β-aryl-N-acetylene described in the present invention The preparation method of amine:

[0148]

[0149] Preparation of 2-acetamido-3,4-dihydronaphthalene (13q)

[0150] Under nitrogen protection, add tetralone (1.46g, 10mmol, 1 equivalent), acetamide (1.83g, 25mmol, 2.5 equivalents), monohydrate-p-toluenesulfonic acid (0.19g, 1mmol , 0.1 eq), toluene (60 mL). Put on the water separator, reflux and stir for 20 hours, then cool down to room temperature. 150 mL of saturated aqueous sodium bicarbonate was added for washing, and the aqueous phase was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was subjected to silica gel column chromatography (petroleu...

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Abstract

The invention discloses a chiral phosphine ligand or an enantiomer, a racemate or a diastereoisomer thereof and a transition metal catalyst comprising the chiral phosphine ligand, wherein the structure of the chiral phosphine ligand is shown as in formula I in the specification. The invention also discloses an application of the chiral phosphine ligand or the transition metal catalyst and a method for efficiently synthesizing chiral beta-aryl amide by using catalytic hydrogenation. The transition metal catalyst can be used for carrying out asymmetric catalytic hydrogenation reaction, thereby efficiently synthesizing the beta-aryl amide compound with a high optical purity.

Description

technical field [0001] The present invention relates to the field of metal catalysts. More specifically, the present invention relates to novel chiral phosphine ligands and metal catalysts containing the ligands and their application in efficient catalytic hydrogenation of chiral β-arylamides. Background technique [0002] Chiral β-aryl amides are important structural units in many natural products and drug molecules with important physiological activities. For example, in the large family of naphthaleneisoquinoline alkaloids, many natural products have this chiral unit, such as Korupensamine A, Korupensamine B and Michellamine B. Both Korupensamine A and Korupensamine B have high antimalarial activity, and Michellamine B has been used as a clinical drug because of its strong anti-HIV activity (J.Nat.Prod.1997,60,677; J.Med.Chem.1991,34, 3402; Chem. Rev. 2011, 111, 563). Many drug molecules currently active on the market also have this indispensable important chiral struc...

Claims

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Application Information

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IPC IPC(8): C07F9/6571C07F15/00B01J31/24C07C231/12C07C233/05C07C233/18C07C233/13C07C233/06C07C233/23C07D333/20C07D311/58
Inventor 汤文军刘国都
Owner 宁波赜军医药科技有限公司
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