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Chiral spiro monophosphine ligand and preparation method thereof

A spiro ring, monophosphine technology, applied in the field of organic synthesis, can solve problems such as less catalyst system, achieve the effects of high yield, optical purity, and significant technical effect

Pending Publication Date: 2020-11-10
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 hydrogenation of aromatic polysubstituted ethylenes.

Method used

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  • Chiral spiro monophosphine ligand and preparation method thereof
  • Chiral spiro monophosphine ligand and preparation method thereof
  • Chiral spiro monophosphine ligand and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0160] Embodiment 1: the preparation of compound 3'-5

[0161]

[0162] Add compound 3'-6 (20.0g, 60mmol), pyridine (14.1mL, 175.0mmol) and 200mL fresh distilled CH in the 500mL 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. Quenched with water, CH 2 Cl 2 After extraction and drying over anhydrous magnesium sulfate, the reaction solution was concentrated and filtered through a silica gel column to obtain 30 g of yellow solid compound 3'-5 (eluent: n-hexane / ethyl acetate=10 / 1), yield: 90% .

[0163] 1 H NMR (400MHz, CDCl 3 )δ1.54-1.61(m,4H),1.67-1.72(m,2H),2.85-2.92(m,2H),2.93-2.99(m,2H),3.08-3.14(m,2H),7.10- 7.12 (m, 2H), 7.26-7.30 (m, 4H) ppm.

Embodiment 2

[0164] Embodiment 2: the preparation of compound 3'-4

[0165]

[0166] Add compound 3'-5 (21.4g, 38.4mmol), Pd(PPh 3 ) 4 (4.4g, 3.8mmol), Zn(CN) 2 (10.5g, 89.7mmol) and 100mL of anhydrous DMF, the reaction system was replaced with nitrogen, the oil bath was heated to 45°C, and the reaction was completed for 16 hours. TLC showed that the reaction was complete. Carefully added sodium hypochlorite solution to the reaction solution until the starch potassium iodide test paper was purple. Add 200 mL of ethyl acetate for extraction, wash with saturated sodium chloride, and dry over anhydrous sodium sulfate. After the reaction solution is concentrated, it is filtered through a silica gel column to obtain 11.5 g of off-white solid compound 3'-4 (eluent: n-hexane / ethyl acetate = 5 / 1), yield: 96%.

[0167] 1 H NMR (400MHz, CDCl 3 )δ1.55-1.69(m,6H),2.90-3.05(m,4H),3.15-3.20(m,2H),7.26-7.35(m,2H),7.45-7.47(d,J=7.6Hz, 2H),7.52-7.54(m,2H)ppm. 13 C NMR (100MHz, CDCl 3 ) δ16.6, 24...

Embodiment 3

[0168] Embodiment 3: the preparation of compound 3'-3

[0169]

[0170] In the 1000mL reaction flask, add compound 3'-4 (14.5g, 46.7mmol), 12M H 2 SO 4 (174mL), 6MHOAc (87mL), water (260mL), the oil bath was heated to reflux, and the reaction was monitored by TLC until the reaction of the raw materials was complete. Added 300mL of water, extracted with ethyl acetate (300mL×3), combined the organic phases, and washed with sodium hydroxide The aqueous solution was back-extracted, and the final concentrated hydrochloric acid was adjusted to a pH of about 3, extracted with ethyl acetate, dried, concentrated, and slurried with n-hexane to obtain a light brown solid. Further purification by column chromatography gave 10.5 g of white solid compound 3'-3, yield: 64%.

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Abstract

The invention provides a chiral spiro monophosphine ligand, and an intermediate and a preparation method thereof. The compounds are structural compounds shown in the following formulas 1, 2 and 3 andcomprise racemates and optical isomers of the compounds, wherein m and n are integers of 0-3; X is CR1R2, NR1, O or S; R1 and R2 are respectively and independently hydrogen, C1-C8 alkyl, phenyl, 1-naphthyl, 2-naphthyl, C1-C8 alkoxy and ester group substituted alkyl; R is hydrogen, C1-C8 alkyl, substituted phenyl, substituted alkyl, C1-C8 alkoxy, phenyl, 1-naphthyl, 2-naphthyl, fluoro, chloro, bromo, iodo, cyano, carboxyl and hydroxyl; Y is O or CH2; Z is NR3R4, OR5 and R6; R3, R4, R5 and R6 are each independently substituted phenyl, a substituted alkyl, C1-C8 alkyl, a phenyl, 1-naphthyl and 2-naphthyl; and M is cyano, carboxyl or substituted alkyl.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a chiral spirocyclic monophosphine 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 WilliamS.Knowles is based on the compound shown in the following formula A with the structure published by Osborn an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6568C07F9/6574C07F9/6596
CPCC07F9/65719C07F9/6568C07F9/6596
Inventor 严普查华允宇程厚安张金柱李原强
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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