Preparation method and application of chiral spiro aminophosphine ligand with substituent at 3-position of pyridine ring

A technology of spirocyclic amino group and pyridine ring, which is applied in the field of preparation of chiral spirocyclic aminopyridine tridentate ligands, can solve the problems of high catalyst consumption, harsh reaction conditions, narrow substrate range, etc., and achieve simple synthesis method , mild conditions, the effect of emphasizing the adjustment ability

Active Publication Date: 2020-01-24
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Abstract
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Problems solved by technology

However, there is still no direct synthesis of malonate chiral compounds containing arylalkyl-substituted tertiary carbon chiral centers at the β-position through the asymmetric catalytic hydrogenation of β-arylalkylene malonates. literature report
In addition, although there are reports in the literature that asymmetric catalytic hydrogenation of α,β-unsaturated carboxylic acids and ester derivatives is used to synthesize their deesterified products (Hou, G.; etal.J.Org.Chem.2016,81 , 2070; Kitamura, M.; et al. Tetrahedron 2007, 63, 11399; Diéguez, M.; et al. Adv. Synth. Catal. 2017, 359, 2801; Zhou, J.; et al. Org. Lett. 2006,18,5344), but the scope of the substrate is narrow, the catalyst consumption is high (2 ), and can only give high enantioselectivity to a single-configuration substrate (Z or E)
These factors limit the application of asymmetric catalytic hydrogenation of α,β-unsaturated carboxylic acids and ester derivatives, which is a high atom-economical reaction method.

Method used

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  • Preparation method and application of chiral spiro aminophosphine ligand with substituent at 3-position of pyridine ring
  • Preparation method and application of chiral spiro aminophosphine ligand with substituent at 3-position of pyridine ring
  • Preparation method and application of chiral spiro aminophosphine ligand with substituent at 3-position of pyridine ring

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]

[0038] A mixture of (R)-DTB-SpiroAP (283 mg, 0.44 mmol) and 3-isopropyl-2-pyridinecarbaldehyde (131 mg, 0.88 mmol) in 1,2-dichloroethane (10 mL) was added under nitrogen atmosphere The reaction was stirred at 45 °C for 14 h. When the amount of generation of imine intermediate no longer increased (monitored by TLC), the NaBH(OAc) 3 (148 mg, 0.70 mmol) was added to the system, and the resulting reaction mixture was stirred at the same temperature for 12 h (monitored by TLC). with saturated NaHCO 3 After the solution was quenched, the mixture was extracted with ethyl acetate, the organic phases were combined, and the organic phase was dried over anhydrous magnesium sulfate, the desiccant was removed by suction filtration, and the filtrate was desolvated by a rotary evaporator. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 0.22 g of the corresponding colorless syrup with a yield of 97%; –265 (c=0.5, C...

Embodiment 2

[0040]

[0041] The operation process is the same as in Example 1a. White solid, melting point 74-75°C, 0.35g, 94% yield. 1 H NMR (400MHz, CDCl 3 )δ:7.83(dd, J=4.6,1.4Hz,1H),7.75(dd,J=8.0,1.4Hz,1H),7.2–7.21(m,5H),7.18–7.07(m,5H),7.07 –6.99(m,2H),6.83(dd,J=7.9,1.8Hz,2H),6.68(dd,J=7.4,1.8Hz,2H),6.55(d,J=7.4Hz,1H),5.74( d,J=7.8Hz,1H),5.24(d,J=7.4Hz,1H),3.81–3.58(m,2H),2.97–2.86(m,2H),2.84–2.74(m,1H),2.56 –2.50(m,1H),2.36–2.28(m,1H),1.96–1.88(m,2H),1.72–1.66(m,1H),1.60(s,6H),1.16(s,18H),0.97 (s,18H); 31 P NMR (162MHz, CDCl 3 )δ:-16.26(s); 13 C NMR (101MHz, CDCl 3 )δ: 156.0, 152.1, 151.9, 149.9, 149.8, 149.4, 149.3, 149.2, 146.0, 145.2(2), 144.2(2), 144.0(2), 141.6, 137.5, 137.4, 137.2, 137.1, 135.2, 135.0, 133.2, 133.0, 131.7(2), 129.0, 128.8, 128.6, 128.3, 128.0, 127.8, 126.3, 126.2, 125.7, 125.2, 121.7, 121.1, 120.9, 112.7, 107.4, 71.4, 62.4, 36.3, 4.8 ,35.6,34.8,34.6,31.4,31.3(2),31.1,30.8,30.6(2),27.0.HRMS(ESI)calcd for C 60 h 74 N 2 P[M+H] + :853.5584; Fou...

Embodiment 3

[0043]

[0044] The operation process is the same as in Example 1a. White solid, melting point 86-87°C, 0.33g, 83% yield. 1 H NMR (400MHz, CDCl 3 )δ:7.85(d,J=4.8Hz,1H),7.27–7.22(m,2H),7.19–7.10(m,7H),7.08–7.01(m,3H),6.98–6.92(m,3H) ,6.90–6.84(m,3H),6.78(dd,J=7.8,1.6Hz,2H),6.62(dd,J=7.8,1.6Hz,2H),6.54(d,J=8.0Hz,1H), 6.15(d,J=8.0Hz,1H),5.51(s,1H),5.25(d,J=7.6Hz,1H),4.00(dd,J=15.6,6.0Hz,1H),3.66(d,J =15.2Hz,1H),3.00–2.85(m,2H),2.84–2.74(m,1H),2.58–2.52(m,1H),2.41–2.27(m,1H),1.98–1.93(m,2H ),1.85–1.72(m,1H),1.10(s,18H),0.90(s,18H); 31 P NMR (162MHz, CDCl 3 )δ:-16.33(s); 13 C NMR (101MHz, CDCl 3)δ: 155.1, 152.2, 151.9, 149.9(2), 149.5, 149.4, 146.2, 144.7(2), 144.3, 144.2(2), 142.0, 141.7, 137.6, 137.5, 137.1, 137.0, 136.5, 135.1, 134.9, 5 42.6, 38.0, 36.1, 34.8, 34.6, 31.4, 31.3, 31.2, 30.8. HRMS (ESI) calcd for C 64 h 74 N 2 P[M+H] + :901.5584; Found: 901.5588.

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Abstract

The invention relates to a preparation method and application of a chiral spiro aminophosphine ligand with a substituent at the 3-position of a pyridine ring. The chiral spiro aminophosphine ligand isa compound shown as a formula 1, or a racemate or an optical isomer thereof, or a catalytically acceptable salt thereof, and is mainly structurally characterized by having a chiral spiroindane skeleton and a pyridine group. The chiral spiro aminophosphine ligand can be synthesized by using a 7-diaryl/alkylphosphino-7'-amino-1,1'-spiroindane compound with a spiro skeleton as a chiral starting material. After the chiral spiro aminophosphine ligand and a transition metal (iridium) salt form a complex, the complex can be used for catalyzing asymmetric catalytic hydrogenation reaction of an alpha-arylamine substituted lactone compound, shows very high catalytic activity (with TON reaching 19000) and enantioselectivity (up to 99% ee), and has practical value.

Description

technical field [0001] The present invention relates to a preparation method and application of a chiral spirocyclic aminophosphine ligand substituted at the 3-position on the pyridine ring, especially a preparation method and application of a chiral spirocyclic aminopyridine tridentate ligand with a spirocyclic skeleton. Its application in the asymmetric catalytic hydrogenation reaction of β-aryl alkylene malonate 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 practically used in the industrial production of chiral drugs, pesticides, and spices. The efficiency and selectivity of asymmetric catalytic hydrogenation reactions depend on the activity, stability and efficiency of chiral catalysts. Therefore, the development of novel and efficient chiral ligands and their catalysts is the key to realize efficient, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/58B01J31/24B01J31/22C07C67/303C07C69/612C07C69/65C07C69/78C07C69/734C07D317/60C07D333/24C07D307/54C07C69/608
CPCC07F9/58B01J31/2404B01J31/2295C07C67/303C07D317/60C07D333/24C07D307/54C07B2200/07C07C2601/14B01J2231/645B01J2531/827B01J2531/0261B01J2531/0225C07C69/612C07C69/65C07C69/78C07C69/734C07C69/608
Inventor 谢建华赵乾坤顾雪松周其林王立新
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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