Chiral spiro monophosphine-oxazoline ligands and preparation method thereof

An oxazoline and spiro ring technology, applied in the field of organic synthesis, can solve problems such as few catalyst systems, and achieve the effects of high yield, optical purity, and significant technical effects

Pending Publication Date: 2021-01-12
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] In the field of asymmetric catalytic hydrogenation, although many chiral ligands and catalysts have been reported, overall, there are few catalyst systems applied to the asymmetric hydrogenation of unsaturated carboxylic compounds.

Method used

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  • Chiral spiro monophosphine-oxazoline ligands and preparation method thereof
  • Chiral spiro monophosphine-oxazoline ligands and preparation method thereof
  • Chiral spiro monophosphine-oxazoline ligands and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0224] Embodiment 1: the preparation of compound 5

[0225]

[0226] Add (S,S,S)-6 (17.5 g, 60 mmol), pyridine (14.1 mL, 175.0 mmol) and 200 mL of freshly distilled CH to a 500 mL reaction flask 2 Cl 2 , Add trifluoromethanesulfonic anhydride (25.5 mL, 150 mmol) dropwise at 0°C, after the addition is complete, stir at room temperature overnight. Add dilute hydrochloric acid to quench the reaction, adjust the pH of the aqueous phase to 6-7, CH 2 Cl 2 extraction. Organic phase with saturated NaHCO 3 The solution was washed successively with saturated brine, and dried over anhydrous sodium sulfate. After the filtrate was concentrated, 32.0 g of a light yellow solid was obtained by silica gel column chromatography (eluent: n-hexane / ethyl acetate=10 / 1), yield: 96%.

Embodiment 2

[0227] Embodiment 2: compound 3-1 (R 3 =Ph) Preparation

[0228]

[0229] To a 250mL reaction flask was added bistrifluoromethanesulfonate 5 (15.0g, 27.0mmol) of the spiro compound, diphenylphosphine oxide (7.0g, 35.0mmol), palladium acetate (303mg, 1.35mmol), 1, 4-Diphenylphosphinobutane (dppb, 576 mg, 1.35 mmol) and 70 mL of anhydrous DMSO. Diisopropylethylamine (19 mL, 108.0 mmol) was added under stirring, and heated to 100° C. for 6 hours. Cool to room temperature, add EtOAc / water to dilute, filter, the filtrate is desolventized and subjected to silica gel column chromatography (eluent: n-hexane / ethyl acetate=5 / 1) to obtain 15.0 g, yield 91%; light yellow solid.

Embodiment 3

[0230] Embodiment 3: compound 3-1 (R 3 =Xyl) Preparation

[0231]

[0232] Add bistrifluoromethanesulfonate 5 (15.0 g, 27.0 mmol) of the spiro compound, bis(3,5-dimethylphenyl) phosphine oxide (9.0 g, 35.0 mmol), palladium acetate into a 250 mL reaction flask (303 mg, 1.35 mmol), 1,4-diphenylphosphinobutane (dppb, 576 mg, 1.35 mmol), and 70 mL of anhydrous DMSO. Diisopropylethylamine (19 mL, 108.0 mmol) was added under stirring, and heated to 100° C. for 6 hours. Cooled to room temperature, added EtOAc / water to dilute, filtered, and the filtrate was subjected to silica gel column chromatography (eluent: n-hexane / ethyl acetate=5 / 1) to obtain 15.4 g, yield 86%; light yellow solid.

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Abstract

The invention provides chiral spiro monophosphine-oxazoline ligands as well as intermediates and a preparation method thereof. The ligands are structural compounds shown in the following formulas 1, 2and 3 and comprise racemates and optical isomers of the compounds, and m and n are integers of 0-3; X is CR<1'>R<2'>, NR<1'>, O or S; R1 and R2 are respectively and independently hydrogen, alkyl, phenyl, 1naphthyl, 2naphthyl, alkoxy and ester substituted alkyl; R is hydrogen, alkyl, substituted phenyl, substituted alkyl, alkoxy, phenyl, 1-naphthyl, 2-naphthyl, halogen, cyano, carboxyl and hydroxyl; R2 is hydrogen, alkyl, phenyl, 1-naphthyl, 2-naphthyl or alkyl substituted phenyl; M' is P(O)(R3)2 or P(R3)2; R3 is alkyl, phenyl, 1-naphthyl, 2-naphthyl, substituted phenyl, furyl or thienyl; M isOTf, COOH or COOR5; OTf is trifluoromethanesulfonic acid group; and R5 is alkyl.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a chiral spirocyclic monophosphine-oxazoline ligand, an intermediate thereof and a preparation method thereof. Background technique [0002] Asymmetric catalytic reactions are research hotspots in the field of organic synthesis, and asymmetric catalytic hydrogenation reactions are research hotspots in the field of asymmetric catalytic synthesis. Asymmetric catalytic hydrogenation is one of the most favored asymmetric synthesis methods due to its perfect atom economy, cleanliness and high efficiency. [0003] In the early 1960s, people did not know whether the catalytic asymmetric hydrogenation reaction was feasible, and whether an excess of a certain enantiomer could be produced through the catalytic asymmetric reaction was confirmed by William S. Knowles. The experiment of William S.Knowles used the compound shown in the following formula A according to the structure published ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/653C07F9/53C07F9/50B01J31/24C07D209/08
CPCB01J31/249B01J2531/827C07B2200/07C07D209/08C07F9/5022C07F9/5325C07F9/653
Inventor 严普查华允宇程厚安林祖鹏李原强
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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