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Method for chiral spirocyclic phosphoric acid catalytic synthesis of optically active benzoazepinoindole derivative

A technology of spirophosphoric acid catalysis and spirophosphoric acid catalyst, applied in the direction of organic chemistry, etc., to achieve the effects of mild reaction conditions, high enantioselectivity, and strong reaction versatility

Inactive Publication Date: 2014-09-10
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the facile and convenient asymmetric catalyzed cyclization to generate trifluoromethyl groups from cyclic quaternary stereocenters has not been well studied and is a great challenge.

Method used

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  • Method for chiral spirocyclic phosphoric acid catalytic synthesis of optically active benzoazepinoindole derivative
  • Method for chiral spirocyclic phosphoric acid catalytic synthesis of optically active benzoazepinoindole derivative
  • Method for chiral spirocyclic phosphoric acid catalytic synthesis of optically active benzoazepinoindole derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Under nitrogen protection, add (S)-O,O'-{7,7'-[6,6'-bis-(3,5-bistrifluoromethylbenzene) of formula (1) into a reaction flask base)-1,1'-spirobisdihydroindane]} phosphoric acid catalyst catalyst (0.005mmol) and 2-o-aminobenzylindole 2 (0.1mmol), 2,2,2-trifluoroacetophenone (0.1 mmol) and 0.5 milliliters of 1,2-dichloroethane, the reaction temperature is controlled at 35 degrees. The reaction process was detected under TLC, and the reaction time was 24 hours. Directly use silica gel column chromatography after the end of the reaction to obtain optically active (S)-12-phenyl-12-trifluoromethyl-5,6,11,12-tetrahydro-benzo[6,7]azepine[ 4,3-b]indole, yield 95%. The optical purity of the product was 93% ee by HPLC.

[0021] HPLC analysis: Chiralpak AD-H (hexane / i-PrOH=95 / 5, 0.8mL / min), t R (minor)17.5min,t R (major)20.7min; [α] D 20 =-24.5 (c=0.45, CH 2 Cl 2 ); 1 H NMR (400MHz, CDCl 3 ): δ=8.08(s,1H),7.47-7.26(m,5H),7.24(s,1H),7.18(d,J=7.6Hz,1H),7.10-6.93(m,3H),6.71-...

Embodiment 2

[0025] Under nitrogen protection, add (S)-O,O'-{7,7'-[6,6'-bis-(3,5-bistrifluoromethylbenzene) of formula (1) into a reaction flask base)-1,1'-spirobisdihydroindane]} phosphoric acid catalyst catalyst (0.005mmol) and 2-o-aminobenzylindole 2 (0.1mmol), 2,2,2-trifluoroacetophenone (0.1 mmol) and 0.5 milliliters of dichloromethane, the control reaction temperature is at 35 degrees. The reaction process was detected under TLC, and the reaction time was 24 hours. Directly use silica gel column chromatography after the end of the reaction to obtain optically active (S)-12-phenyl-12-trifluoromethyl-5,6,11,12-tetrahydro-benzo[6,7]azepine[ 4,3-b]indole, yield 90%. The optical purity of the product was 89% ee by HPLC.

Embodiment 3

[0027] Under nitrogen protection, add (S)-O,O'-{7,7'-[6,6'-bis-(3,5-bistrifluoromethylbenzene) of formula (1) into a reaction flask base)-1,1'-spirobisdihydroindane]} phosphoric acid catalyst catalyst (0.005mmol) and 2-o-aminobenzylindole 2 (0.1mmol), 2,2,2-trifluoroacetophenone (0.1 mmol) and 0.5 milliliters of toluene, the control reaction temperature is at 35 degrees. The reaction process was detected under TLC, and the reaction time was 24 hours. Directly use silica gel column chromatography after the end of the reaction to obtain optically active (S)-12-phenyl-12-trifluoromethyl-5,6,11,12-tetrahydro-benzo[6,7]azepine[ 4,3-b]indole, 85% yield. The optical purity of the product was 89% ee by HPLC.

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Abstract

The invention discloses a method for chiral spirocyclic phosphoric acid catalytic synthesis of an optically active benzoazepinoindole derivative. The method comprises the steps: with N[b]-alpha-naphthyl methyl tryptamine and aldehyde as raw materials, chiral spirocyclic phosphoric acid as a catalyst and benzene as a reaction solvent, in the presence of a 4-angstrom molecular sieve powder, and under the protection of nitrogen gas, a reaction is carried out for 3-50 hours at the temperature of 20-40 DEG C, and the optically active tetrahydro-beta-carboline derivative is obtained by a column chromatography purification and separation process. The method has the advantages of mild reaction conditions, simple process and convenient operation; and the obtained optically active benzoazepinoindole derivative has good potential biological activity, and can be used as a drug synthesis intermediate.

Description

technical field [0001] The invention relates to a method for catalytically synthesizing optically active benzazepine indole derivatives with chiral spirocyclic phosphoric acid. Background technique [0002] A large number of chiral trifluoromethyl-containing compounds have attracted more and more attention because of their important biological activities. The trifluoromethyl group can enhance the chemical and metabolic stability, lipophilicity and membrane permeability of the compound molecule, see [(a) M.A.McClinton and D.A.McClinton, Tetrahedron, 1992, 48, 6555-6666; (b) ( d) K. Múüller, C. Faeh and F. Diederich, Science, 2007, 317, 1881-1186; (e) J. Liu and J.-B. Hu, Future Med. Chem., 2009, 1, 1189- 1191.]. In particular, many cyclic compound molecules comprising a trifluoromethyl quaternary center have many representative example drugs, such as the HIV reverse transcriptase inhibitor efavirenz, progesterone receptor inhibitors, NK-1 receptor inhibitors ( CJ-17493), ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 林旭锋顾昊睿李雪健陈迪
Owner ZHEJIANG UNIV
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