Chiral alpha-fluoroallamine derivative as well as preparation method and application thereof

A technology of high allylamine and derivatives, which is applied in the field of chemical medicine to achieve high yield, low catalyst consumption and good corresponding selectivity

Active Publication Date: 2019-10-01
WUHAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, so far, no research group has reported the synthesis of chiral α-fluorine-containing homoallylamine from fluorine-containing isatin imine by asymmetric catalyzed allylation

Method used

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  • Chiral alpha-fluoroallamine derivative as well as preparation method and application thereof
  • Chiral alpha-fluoroallamine derivative as well as preparation method and application thereof
  • Chiral alpha-fluoroallamine derivative as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] preparation of

[0056] Add 0.005mmol[Ir(COD)Cl] to 25mL reaction tube 2 , 0.010mmol (S, S, S)-L1, 0.5mL deoxygenated THF and 0.5mL deoxygenated n-propylamine, reacted at 50°C for 30 minutes, and evaporated the solvent under reduced pressure to obtain an iridium catalyst. Under nitrogen protection at 25°C, 1 mL of dichloromethane was added, followed by 0.20 mmol of trifluoroethyl isatin imine and 0.22 mmol of cinnamyl methyl carbonate. After stirring for 24 h, the product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate 20:1) to obtain a yellow liquid. Yield 99%, enantioselective excess of product 95%, HPLC (Chiralpak AS-H, i-propanol / hexane=5 / 95, flow rate 1.0mL / min, λ=254nm); t r =4.88and 5.29min); [α] 25 D =-90.0(c 0.18, CH 2 Cl 2 ); 1 H NMR (400MHz, CDCl 3 )δ7.70(d, J=7.6Hz, 1H), 7.41(t, J=7.6Hz, 1H), 7.26–7.14(m, 5H), 7.09(t, J=7.6Hz, 1H), 6.70( d,J=7.6Hz,1H),6.23(d,J=16.0Hz,1H),6.17–6.05(m,2H),3.04–2.93(m,4H),2.64–2.53(m,...

Embodiment 2

[0058] preparation of

[0059] Add 0.005mmol[Ir(COD)Cl] to 25mL reaction tube 2 , 0.010mmol (S, S, S)-L1, 0.5mL deoxygenated THF and 0.5mL deoxygenated n-propylamine, reacted at 50°C for 30 minutes, and evaporated the solvent under reduced pressure to obtain an iridium catalyst. Under nitrogen protection at 25°C, 1 mL of dichloromethane was added, followed by 0.20 mmol of trifluoroethyl isatin imine and 0.22 mmol of p-methylphenylallyl methyl carbonate. After stirring for 24h, the product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate 20:1) to obtain a yellow solid with a yield of 90%, a melting point of 80-82°C, and an enantioselective excess of 93% of the product, HPLC (Chiralpak AS-H, i-propanol / hexane=5 / 95, flow rate 1.0mL / min, λ=254nm; t r =4.62 and 4.83min.); [α] 25 D =-124.6(c 0.13, CH 2 Cl 2 ) 1 H NMR (400MHz, CDCl 3 )δ7.69(dd, J=7.6,0.8Hz,1H),7.41(td,J=7.9,1.2Hz,1H),7.13–6.98(m,5H),6.70(d,J=8.0Hz,1H ),6.21(d,J=15.6Hz,1H),6....

Embodiment 3

[0061] preparation of

[0062] Add 0.005mmol[Ir(COD)Cl] to 25mL reaction tube 2 , 0.010mmol (S, S, S)-L1, 0.5mL deoxygenated THF and 0.5mL deoxygenated n-propylamine, reacted at 50°C for 30 minutes, and evaporated the solvent under reduced pressure to obtain an iridium catalyst. Under nitrogen protection at 25°C, 1 mL of dichloromethane was added, followed by 0.20 mmol of trifluoroethyl isatinimine and 0.22 mmol of p-methoxyphenylallyl methyl carbonate. After stirring for 24h, the product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate 20:1) to obtain a yellow liquid with a yield of 92% and an enantioselective excess of 94%. Chiralpak AS-H, i-propanol / Hexane=5 / 95, flow rate 1.0mL / min, λ=254nm, t r =6.48and 6.78min.)[α] 30 D =-81.0(c 0.20, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 )δ7.69(d, J=7.2Hz, 1H), 7.41(td, J=8.0, 1.2Hz, 1H), 7.15–7.05(m, 3H), 6.77(d, J=8.8Hz, 2H), 6.70(d,J=7.6Hz,1H),6.16(d,J=16.0Hz,1H),6.11–6.01(m,1H),6.01–5.88(m,...

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Abstract

The invention discloses a method of synthesizing a chiral alpha-fluoroallamine derivative through a novel Ir-catalyzed fluoroindirubin-participated dipole reversal allylation/2-aza-Cope rearrangementreaction. The synthesis method comprises the following steps of in an organic solvent, under the inert gas protection, allyl carbonic ester and fluoroindirubin are used as raw materials; Ir catalystsare used as catalysts; reaction is performed for 12 to 36 hours at the temperature of 25 DEG C; a target compound is obtained through column chromatography.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and in particular relates to a chiral α-fluorine-containing homoallylamine derivative and a preparation method and application thereof. Background technique [0002] Chiral α-fluorinated homoallylamine structural units widely exist in compounds with important biological activities (such as marketed drugs). Therefore, the efficient, universal and easy-to-use synthesis method of chiral α-fluorinated homoallylamine has always been a hot research field in synthetic chemistry. Fluorine-containing isatin imine is cheap and easy to obtain. This compound is widely used as a synthon in the synthesis of fluorine-containing compounds. However, so far, no research group has reported the synthesis of chiral α-fluorine-containing homoallylamine from fluorine-containing isatin imine by asymmetric catalytic allylation. (a) Ojima, I., Ed.; Wiley-Blackwell: New York, 2009. (b) Bégué, J.-P., Bonnet-Delpon, D...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/40C07D405/12C07D401/12C07D409/12B01J31/02C07C209/52C07C211/29C07D207/10
CPCB01J31/0241C07B2200/07C07C211/29C07D207/10C07D209/40C07D401/12C07D405/12C07D409/12
Inventor 王春江石力敏
Owner WUHAN UNIV
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