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Preparation method of 4-position substituted chiral spirocyclic aminophosphine ligand on pyridine ring and application thereof

A spirocyclic amino and pyridine ring technology is applied in the field of preparation of chiral spirocyclic aminopyridine tridentate ligands, which can solve problems such as low enantioselectivity, and achieve strong adjustment ability, mild conditions and high catalytic activity. and the effect of the chirality-inducing effect

Active Publication Date: 2019-07-05
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the asymmetric hydrogenation of such racemic α-arylamine-substituted lactones directly catalyzed by the developed iridium complexes only gave relatively low enantioselectivities (not more than 84% ee)

Method used

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  • Preparation method of 4-position substituted chiral spirocyclic aminophosphine ligand on pyridine ring and application thereof
  • Preparation method of 4-position substituted chiral spirocyclic aminophosphine ligand on pyridine ring and application thereof
  • Preparation method of 4-position substituted chiral spirocyclic aminophosphine ligand on pyridine ring and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]

[0038] In an argon atmosphere, weigh (R)-7'-bis-(3,5-di-tert-butylphenyl)phosphino-7'-amino-1,1'-spirodihydroindane SpiroAP (160mg, 0.25mmol) into a 100mL dry Schlenk tube, inject 30mL of anhydrous methanol into a syringe, and stir to dissolve. 4-Carboxylic acid ethyl pyridinecarbaldehyde (89.5mg0.50mmol) and glacial acetic acid (45mg, 0.75mmol) were added dropwise. The reaction was stirred at room temperature for 2 hours. Open the anti-port plug and pour NaBH at one time 3 CN (31.5mg, 0.50mmol), the reaction was carried out at 40°C for 12 hours. Cool to room temperature after the reaction, spin the system to dryness, add ethyl acetate to dissolve, and quench with saturated sodium bicarbonate solution. Extract with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous magnesium sulfate, remove the desiccant by suction filtration, and remove the solvent from the filtrate with a rotary evaporator. The residue was subjected to silica gel...

Embodiment 2

[0041]

[0042] The operation process is the same as in Example 1a. White solid 164mg, 80% yield. Melting point: 99-100°C. 1 H NMR (400MHz, CDCl 3 )δ: 8.23(d, J=4.8Hz, 1H), 7.32(d, J=7.2Hz, 1H), 7.24(s, 1H), 7.22–7.17(m, 2H), 7.12–7.05(m, 2H ), 7.02(d, J=4.4Hz, 1H), 6.91(s, 1H), 6.85(d, J=6.8Hz, 2H), 6.76–6.65(m, 3H), 6.11(d, J=8.0Hz ,1H),4.19(br,1H),4.00(dd,J=16.0,6.8Hz,1H),3.57(d,J=16.0Hz,1H),3.11–2.82(m,4H),2.55–2.42( m,1H),2.25–2.17(m,2H),2.16–2.07(m,1H),1.73–1.66(m,4H),1.14(s,18H),1.07(s,18H),0.70–0.60( m,6H). 13 C NMR (101MHz, CDCl 3 )δ158.5, 155.3(2), 152.7, 150.0(2), 149.9(2), 148.7, 144.5, 144.3, 144.2, 144.1, 144.1, 138.5, 138.4, 136.1, 136.0, 135.0, 134.8, 134.1(2), 133. ,133.1,128.4,128.2,128.1,128.0(2),126.9,125.8,122.3,121.5,119.0,117.6,114.0,108.9,77.1,67.2,61.9,61.8,48.4,39.0,38.9,35.92,34.8 ,34.7,31.4,31.3,31.0,29.9,7.8,7.7. 31 P NMR (162MHz, CDCl 3 )δ:–18.41. HRMS (MALDI) Calcd for C 56 h 74 N 2 OP([M+H] + ):821.5533; Found: 821.5538.

Embodiment 3

[0044]

[0045] The operation process is the same as in Example 1a. White solid 166mg, 80% yield. Melting point: 96-97°C. 1 H NMR (400MHz, CDCl 3 )δ: 8.22(d, J=5.2Hz, 1H), 7.32(d, J=7.2Hz, 1H), 7.24(s, 1H), 7.22–7.17(m, 2H), 7.12–7.04(m, 2H ),7.04–7.01(m,1H),6.93(s,1H),6.85(dd,J=8.0,1.6Hz,2H),6.72(dd,J=7.6,1.6Hz,2H),6.68(d, J=7.6Hz, 1H), 6.09(d, J=7.6Hz, 1H), 4.25(d, J=4.4Hz, 1H), 4.04–3.93(m, 1H), 3.56(dd, J=16.0, 2.4 Hz,1H),3.09–3.03(m,1H),3.01(s,3H),2.98–2.85(m,2H),2.54–2.44(m,1H),2.26–2.17(m,2H),2.15– 2.08(m,1H),1.82–1.72(m,2H),1.67–1.60(m,2H),1.14(s,18H),1.07(s,18H),0.65–0.56(m,6H). 13 C NMR (101MHz, CDCl 3 )δ158.3,153.9,152.9,152.7,149.9(2),148.6,144.4,144.3,144.2,144.1,144.1,138.6,138.5,136.2,136.1,134.9,134.7,134.1(2),1301.2,1283. ,128.2,128.1,128.0,127.9,126.9,125.8,122.2,121.4,119.8,118.7,113.9,108.9,81.0,61.9,61.8,49.5,48.4,39.0(2),35.9,35.0(2),34.8(2 ), 34.6, 31.4, 31.0, 28.3, 7.4(2). 31 P NMR (162MHz, CDCl 3 )δ:-19.00. HRMS (MALDI) Calcd for C 57...

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Abstract

The invention relates to a preparation method of a four-position substituted chiral spirocyclic aminophosphine ligand on a pyridine ring and an application thereof. The four-position substituted chiral spirocyclic aminophosphine ligand on the pyridine ring comprises a compound shown in a formula 1, or a racemate or an optical isomer thereof, or a catalytically acceptable salt thereof, and is characterized by comprising a chiral spiroindane skeleton and a pyridyl group. The four-position substituted chiral spirocyclic aminophosphine ligand on the pyridine ring can be synthesized by using a 7-diaryl / alkylphosphine-7'-amino-1 and 1'- spiroindane compound comprising a spirocyclic skeleton as chiral original raw materials. After the four-position substituted chiral spirocyclic aminophosphine ligand on a pyridine ring and the transition metal (iridium) salt form a complex, the complex can be used for catalyzing asymmetric catalytic hydrogenation of alpha-aromatic amine to substitute lactonecompounds. By the adoption of the preparation method of the four-position substituted chiral spirocyclic aminophosphine ligand on the pyridine ring and the application thereof, extremely high catalytic activity (TON up to 5000) and enantioselectivity (up to 98% ee) are achieved, and practical value is achieved.

Description

technical field [0001] The present invention relates to a preparation method and application of a chiral spirocyclic aminophosphine ligand substituted at the 4-position on a pyridine ring, especially a preparation method and application of a chiral spirocyclic aminopyridine tridentate ligand with a spirocyclic skeleton. The application of the method in the dynamic kinetic asymmetric catalytic hydrogenation reaction of α-arylamine substituted lactone compounds belongs to the technical field of organic synthesis. Background technique [0002] Asymmetric catalytic hydrogenation is the most green and atom-economical method for the synthesis of chiral compounds, and has been widely used in the industrial production of chiral drugs and spices. Chiral ligands and their catalysts are the key to realize highly efficient, highly selective and industrially applicable asymmetric catalytic hydrogenation reactions. For this reason, academia and industry have been concerned about designin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/58B01J31/24C07B41/02C07C213/00C07C213/08C07D317/66C07C215/10C07C217/84
CPCB01J31/2447C07C213/00C07C213/08C07D317/66C07B41/02B01J2231/643B01J2531/827C07C215/10C07C217/84
Inventor 谢建华顾雪松周其林于娜王立新朱安特
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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