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A kind of biaryl bisphosphine ligand, its preparation method and application

A technology of bisphosphine ligands and biaryls, applied in the field of bisaryl bisphosphine ligands, can solve the problems of low yield and optical purity of β-hydroxycarboxylates

Active Publication Date: 2020-03-10
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is that the yield and optical purity of the existing catalysts for the asymmetric hydrogenation of β-hydroxycarboxylates are low, therefore, the application provides a P-chiral biaryl bisphosphine ligand , preparation method and application

Method used

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  • A kind of biaryl bisphosphine ligand, its preparation method and application
  • A kind of biaryl bisphosphine ligand, its preparation method and application
  • A kind of biaryl bisphosphine ligand, its preparation method and application

Examples

Experimental program
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Effect test

Embodiment 1

[0110] In this example, (3R,3'R)-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro-4,4'-dibenzo[d][1,3 ] Oxygen, phosphorus-pentyl conjugate (L1) as an example to describe the preparation method of the chiral bisphosphine ligand of the present invention (the reaction scheme is as follows):

[0111]

[0112] 1. Preparation of (S)-3-tert-butyl-3-oxo-2H-benzo[d][1,3]oxy,phospho-pentyl-4-trifluoromethanesulfonate (1)

[0113] Prepared according to known literature methods, Org.Lett.2010,12,176.

[0114] 2. Preparation of (S)-(3-(tert-butyl)-3-oxo-2H-benzo[d][1,3]oxy,phospho-4-)carbamate (a)

[0115] Under nitrogen protection, (S)-3-tert-butyl-3-oxo-2H-benzo[d][1,3]oxy,phospho-pentyl-4-trifluoromethanesulfonate (1 , 5.5g, 15.4mol, 1.0 equivalent), cesium fluoride (3.3g, 21.5mmol, 1.4 equivalent) and tert-butyl carbamate (3.6g, 30.7mmol, 2.0 equivalent) were mixed and dissolved in 77mL tetrahydrofuran, and then three (Dibenzylideneacetone)dipalladium (699 mg, 0.76 mmol, 0.05 equiv) and ...

Embodiment 2

[0150] In this example, (2R,2'R,3R,3'R)-3,3'-di-tert-butyl-2,2'-dimethyl-2,2',3,3'-tetrahydro- 4,4'-Dibenzo[d][1,3]oxo,phosphorus-pentyl conjugate (L2) is used as an example to describe the preparation method of the chiral bisphosphine ligand of the present invention in detail (the reaction scheme is as follows):

[0151]

[0152] 1. (2R,2'R,3S,3'S)-3,3'-di-tert-butyl-2,2'-dimethyl-2H,2'H-[4,4'-dibenzo[d Preparation of ][1,3]oxo,phosphorus-pentaconjugate]3,3'-dioxo(3b)

[0153] Under the protection of nitrogen, 3a (0.2g, 0.48mmol, 1 equivalent) was dissolved in 10mL of tetrahydrofuran, the reaction solution was lowered to -78°C with a dry ice / acetone bath, and lithium diisopropylamide (1.2mL, 2.0 M in n-hexane / tetrahydrofuran, 2.39 mmol, 5 equivalents). Keep stirring at -78°C for 2 hours, then add iodomethane (0.15mmol, 2.39mmol, 5 equivalents), keep stirring at -78°C for 20 minutes, slowly return to room temperature, and react overnight. 10 mL of saturated ammonium chlo...

Embodiment 3

[0167] Referring to the preparation method of Example 2, the following chiral bisphosphine ligands L3 were prepared respectively

[0168]

[0169] 1. (2R,2'R,3S,3'S)-3,3'-di-tert-butyl-2,2'-diisopropyl-2H,2'H-[4,4'-dibenzo[ d] Preparation of [1,3]oxo,phosphorus-pentaconjugate]3,3'-dioxo (3c)

[0170] Under the protection of nitrogen, 3a (300mg, 0.72mmol, 1 equivalent) was dissolved in 15mL of tetrahydrofuran, the reaction solution was lowered to -78°C with a dry ice / acetone bath, and lithium diisopropylamide (1.8mL, 2.0M in n-hexane / tetrahydrofuran, 3.6 mmol, 5 equivalents). Keep stirring at -78°C for 2 hours, then add isopropyl iodide (0.36mmol, 3.59mmol, 5 equivalents), keep stirring at -78°C for 20 minutes, slowly return to room temperature, and react overnight. 10 mL of saturated ammonium chloride solution and 10 mL of dichloromethane were added to the reaction solution. The organic phase was separated, and the aqueous phase was further extracted with (10 mL×2) dichl...

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Abstract

The invention discloses a biaryl diphosphine ligand as well as a preparation method and an application thereof. A biaryl diphosphine ligand compound represented as the formula I in the description ora biaryl diphosphine ligand enantiomer is provided, wherein R<1> is alkyl of C1-C10 or naphthenic base of C3-C30 independently; Ra is hydrogen, alkyl of C1-C10, alkoxy of C1-C4, naphthenic base of C3-C30, halogen, R<1-1> substituted or unsubstituted phenyl, R<1-2> substituted or unsubstituted aryl of C10-C30 and R<1-3> substituted or unsubstituted ceteroary of C4-C15 independently; all R<1-1>, R<1-2> and R<1-3> are halogen, alkyl of C1-C4 or alkoxy of C1-C4 independently. With the adoption of the biaryl diphosphine ligand compound I, a series of chiral beta-hydroxy carboxylates with high optical purity can be effectively prepared through catalyzed synthesis, and the compound is high in economic practicability.

Description

technical field [0001] The invention relates to a biaryl bisphosphine ligand, its preparation method and application. Background technique [0002] Chiral β-hydroxycarboxylates are important structural units in many natural products and drug molecules with important physiological activities. For example, chiral (S)-β-hydroxybutyrate is used to synthesize biological pheromones (Tetrahedron: Asymmetry, 2004, 15, 3397.), (S)-sulcatol (meal beetle pheromone, insecticide) , Carbapenem (carbapenem, antibiotic), (S)-citronellol (fragrance) and gray green streptomycin precursor (J.Mol.Catal.A: Chem.2007,269,90.), L- Carnitine (auxiliary therapeutic agent) (Ind.Eng.Chem.Res.2004,43,4871), the macrolide contained in many natural active substances is also mainly derived from chiral β-hydroxycarboxylate (Org .Lett.2006,8,3709.; J.Org.Chem.2006,71,4428.), the biological activity of these natural products is often closely related to the stereo configuration of β-hydroxycarboxylate (Tetr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6571B01J31/24C07C67/31C07C69/732C07C69/675
CPCB01J31/2471B01J2231/643B01J2531/824C07C67/31C07F9/657163C07C69/732C07C69/675
Inventor 汤文军江文豪
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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