Chiral bridge ring skeleton oxindole piperidine compound and synthesis method of compound

A technology of oxindole spiropiperidine and its synthesis method, which is applied in the field of chiral nitroxide-bridged ring skeleton and spiro-ring oxindole compound and its synthesis, which can solve the problems of few reports on the synthesis method and achieve enantioselectivity And the effects of excellent diastereoselectivity, good yield, and good chemoselectivity

Inactive Publication Date: 2018-01-19
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the prior art, the synthesis methods of spiro-oxindole derivatives are relatively common, but the synthesis m

Method used

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  • Chiral bridge ring skeleton oxindole piperidine compound and synthesis method of compound
  • Chiral bridge ring skeleton oxindole piperidine compound and synthesis method of compound
  • Chiral bridge ring skeleton oxindole piperidine compound and synthesis method of compound

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0038] Example one:

[0039]

[0040] 1a (38.1 mg, 0.15 mmol, 1.5 equiv), 2a (21.2 mg, 0.1 mmol) and Cat. (4.1 mg, 0.01 mmol, 10 mol%) are placed in a test tube containing methyl tert-butyl ether (1.0 mL) After reacting for 12 hours at room temperature until the substrate 2a disappeared, the solvent was removed under reduced pressure, the residue obtained was separated by petroleum ether / ethyl acetate (2 / 1) column chromatography, and the obtained product was dissolved in toluene (1.0 ml) , Then add bistrifluoromethanesulfonimide (5.6 mg, 0.02mmol, 20 mol%) to the solution, continue the reaction at room temperature for 12 hours, the system is directly used petroleum ether / ethyl acetate (3 / 1) column chromatography After separation, 29.1 mg of white solid 3aa was obtained, white solid, yield was 65%, 160-161 °C.

[0041] Analysis of the product 3aa, the results are as follows:> 20:1 dr , 97% ee [Daicel Chiralcel AD-H,hexanes / i -PrOH = 80 / 20, flow rate: 1.0 mL·min -1 , λ = 254.4 ...

Example Embodiment

[0043] Embodiment two:

[0044]

[0045] 1b (33.0 mg, 0.15 mmol, 1.5 equiv), 2a (21.2 mg, 0.1 mmol) and Cat. (4.1 mg, 0.01 mmol, 10 mol%) are placed in a test tube containing methyl tert-butyl ether (1.0 mL) After reacting for 12 hours at room temperature until the substrate 2a disappeared, the solvent was removed under reduced pressure, the residue obtained was separated by petroleum ether / ethyl acetate (2 / 1) column chromatography, and the obtained product was dissolved in toluene (1.0 ml) , Then add bistrifluoromethanesulfonimide (5.6 mg, 0.02mmol, 20 mol%) to the solution, continue the reaction at room temperature for 4 hours, the system is directly chromatographed with petroleum ether / ethyl acetate (3 / 1) After separation, 21.5 mg of white solid 3ab was obtained. The yield was 62%, 245-246 °C.

[0046] Analysis of the product 3ab, the results are as follows:> 20:1 dr , 87% ee [Daicel Chiralcel AD-H,hexanes / i-PrOH = 80 / 20, flow rate: 1.0 mL•min–1, λ = 254.4 nm, t (major) =9.4...

Example Embodiment

[0048] Embodiment three:

[0049]

[0050] 1c (35.1 mg, 0.15 mmol, 1.5 equiv), 2a (21.2 mg, 0.1 mmol) and Cat. (4.1 mg, 0.01 mmol, 10 mol%) are placed in a test tube containing methyl tert-butyl ether (1.0 mL) After reacting for 12 hours at room temperature until the substrate 2a disappeared, the solvent was removed under reduced pressure, the residue obtained was separated by petroleum ether / ethyl acetate (2 / 1) column chromatography, and the obtained product was dissolved in toluene (1.0 ml) , And then add bistrifluoromethanesulfonimide (5.6 mg, 0.02mmol, 20 mol%) to the solution, continue the reaction at room temperature for 6 hours, and directly use petroleum ether / ethyl acetate (3 / 1) column chromatography for the system After separation, 22.6 mg of white solid 3ac was obtained. The yield was 63%, 210–211 °C.

[0051] Analysis of the product 3ac, the results are as follows:> 20:1 dr , 73% ee [Daicel Chiralcel AD-H,hexanes / i-PrOH = 80 / 20, flow rate: 1.0 mL•min–1, λ = 254.4 nm,...

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Abstract

The invention discloses a chiral nitrogen oxygen bridge ring skeleton and spiro oxindole compound and a synthesis method of the compound. The method specifically comprises the following steps: takinga 3-pyrrolyl oxindole and beta,gamma-unsaturated alpha-keto ester derived from salicylaldehyde as a reactant, and in the presence of a chiral thiourea compound and bis(trifluoromethanesulfonyl)imide,performing an asymmetric tandem cyclization reaction in a methyl tert-butyl ether and toluene solvent to obtain a product. The method disclosed by the invention has simple and easily available raw materials, mild reaction conditions, simple and convenient post-treatment, wide application range, good yield, and high enantioselectivity and non-enantioselectivity; and therefore, the synthesized product has a potential medicinal value.

Description

technical field [0001] The invention relates to the synthesis of oxindole-spiropiperidine compounds with bridging ring skeleton, in particular to a chiral nitroxide bridging ring skeleton and spiro-ring oxindole compound and a synthesis method thereof. Background technique [0002] Nitroxide heterocyclic skeletons widely exist in natural products and synthetic drug molecules, and have a broad spectrum of physiological and pharmacological activities, so they have attracted extensive attention from many chemical and pharmaceutical researchers. Among them, spiro heterocyclic compounds containing five or six members often also have important physiological and pharmacological activities, such as spiro oxindole pyrrole heterocycle or spiro oxindole piperidine heterocycle. It is of great significance to be able to synthesize chiral oxindole-spiropiperidine compounds with complex structures containing multiple important structural units such as quaternary carbon chiral centers, hete...

Claims

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Application Information

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IPC IPC(8): C07D491/22B01J31/02
Inventor 王兴旺范巍泰
Owner SUZHOU UNIV
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