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Chiral tetrahydrocarbazole derivative and preparation method thereof

A technology for tetrahydrocarbazole derivatives and derivatives, which is applied in the field of chiral tetrahydrocarbazole derivatives and their preparation, can solve the problems of few reports, and achieve the effects of simple operation, high yield and high stereoselectivity

Active Publication Date: 2017-11-24
CHENGDU LIKAI CHIRAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, most of the reported chiral tetrahydrocarbazoles are 1,2,3,4-tetrahydrocarbazole skeletons, but there are relatively few reports on chiral 1a,3,4,4a-tetrahydrocarbazole skeleton molecules

Method used

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  • Chiral tetrahydrocarbazole derivative and preparation method thereof
  • Chiral tetrahydrocarbazole derivative and preparation method thereof
  • Chiral tetrahydrocarbazole derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment one: synthetic compound (I-a)

[0028]

[0029] Add 1-p-toluenesulfonyl-3-nitroindole (II) (31.6 mg, 0.1 mmol), (4E)-3-carbonyl-5-phenyl-4-pentenoic acid ethyl Ester (Ⅲ) (48.2mg, 0.2mmol), chiral catalyst A (14mg, 0.02mmol), cooled to -10°C, then added 0.5ml chloroform, the mixture was stirred at -10°C for 72h, then added triethylamine ( 0.2mmol, 20mg), acetyl chloride (0.2mmol, 15.7mg) and the reaction mixture was stirred at room temperature for 20min. After the reaction was complete, the solvent was evaporated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain compound I-a (white solid, yield 95%, >20:1dr, 95% ee). In the above structural formula I-a, Ts is p-toluenesulfonyl.

[0030] The optical rotation, melting point, hydrogen spectrum, carbon spectrum and mass spectrum data of gained compound I-a are as follows:

[0031] [α] D 20 =-7.5(c 3.25, CH 2 Cl 2 )...

Embodiment 2

[0032] Embodiment two: synthetic compound (I-b)

[0033]

[0034] Add 1-methoxycarbonyl-3-nitroindole (II) (22.0 mg, 0.1 mmol), ethyl (4E)-3-carbonyl-5-phenyl-4-pentenoate to a rigid glass tube (Ⅲ) (48.2mg, 0.2mmol), catalyst A (14mg, 0.01mmol), cooled to 0°C, then added 0.5ml of toluene, and the mixture was stirred at 0°C for 72h. Then potassium carbonate (0.2mmol, 27.6mg) was added, acetyl chloride (0.2mmol, 15.7mg) and the reaction mixture was stirred at room temperature for 20min. After the reaction was complete, the solvent was evaporated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain compound I-b (white solid, yield 90%, >20:1dr, 94%ee).

[0035] The optical rotation, melting point, hydrogen spectrum, carbon spectrum and mass spectrum data of obtained compound I-b are as follows:

[0036] [α] D 20 =+29.2(c 2.28,CH 2 Cl 2 ); m.p.115.2-116.3°C; HPLC (AD-H, ethanol / n-hexa...

Embodiment 3

[0037] Embodiment three: synthetic compound (I-c)

[0038]

[0039] Add 1-ethoxycarbonyl-3-nitroindole (II) (23.4 mg, 0.1 mmol), ethyl (4E)-3-carbonyl-5-phenyl-4-pentenoate to a rigid glass tube (Ⅲ) (48.2mg, 0.2mmol), catalyst A (14mg, 0.005mmol), then 0.5ml of chloroform was added, and the mixture was stirred at 25°C for 72h. Then triethylamine (0.2mmol, 20mg) was added, acetyl chloride (0.2mmol, 15.7mg) and the reaction mixture was stirred at room temperature for 20min. After the reaction was complete, the solvent was evaporated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain compound I-c (white solid, yield 95%, >20:1dr, 92%ee).

[0040] The optical rotation, melting point, hydrogen spectrum, carbon spectrum and mass spectrum data of obtained compound I-c are as follows:

[0041] [α] D 20 =+22.3(c 2.27,CH 2 Cl 2 ); m.p.163.5-165.0℃; HPLC (AD-H, ethanol / n-hexane=20 / 80, flow...

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PUM

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Abstract

The invention discloses a chiral tetrahydrocarbazole derivative and a preparation method thereof and belongs to the technical field of organic synthesis. The chiral tetrahydrocarbazole derivative has a structure shown as a structural formula I. The preparation method comprises the following steps: dissolving 3-nitroindole II, a Nazarov reagent III and a chiral catalyst A in a reaction solvent, stirring at the temperature of -10 to 25 DEG C, reacting for 48-96 hours, adding acetyl chloride and alkali after reaction completion, and separating and purifying to obtain a product I after the reaction is ended. The invention first discloses a type of novel tetrahydrocarbazole compounds and provides rich candidate molecules for clinical screening of new drugs. Moreover, the preparation method disclosed by the invention has the advantages of novelty, rapidness, simplicity in operation, mild reaction conditions, high yield, high stereoselectivity and the like.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to chiral tetrahydrocarbazole derivatives and a preparation method thereof. Background technique [0002] Carbazole is the core skeleton of many natural products and drugs. Most of these natural molecules and drug molecules have been found to have good biological activity and are an important source for the development of new drugs. Among them, the chiral hydrogenated carbazole skeleton is widely found in many natural alkaloids and pharmaceutically active compounds. As shown below, the compound (-)-Aspidospermine was isolated from Quina in the late 19th century. It has antibacterial, diuretic, vasoconstriction and respiratory stimulation activities; Vindoline and Minovincine have anticancer activities. Therefore, the development of effective methods to synthesize polycyclic heterocyclic compounds containing this type of structure can not only provide new ideas and methods for the s...

Claims

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Application Information

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IPC IPC(8): C07D209/88
CPCC07B2200/07C07D209/88
Inventor 徐小英岳登峰赵建强袁伟成刘斌
Owner CHENGDU LIKAI CHIRAL TECH