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Trifluoromethyl-containing indole ketone compound, and preparation method and application thereof

A technology of trifluoromethyl compounds, which is applied in the field of trifluoromethyl-containing indolinone compounds and their preparation, can solve the problems of limited druggability, strong cytotoxicity, and poor stability of some compounds, and is easy to achieve Implementation and Scale, Operational Ease of Effects

Active Publication Date: 2012-09-19
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recently, it has been reported in the literature that some indolinone compounds have certain anti-HIV reverse transcriptase activity, but due to factors such as complex structure, difficult synthesis, often strong cytotoxicity and poor stability of some compounds, their further development is limited. Druggability

Method used

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  • Trifluoromethyl-containing indole ketone compound, and preparation method and application thereof
  • Trifluoromethyl-containing indole ketone compound, and preparation method and application thereof
  • Trifluoromethyl-containing indole ketone compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: Preparation of 3-hydroxyl-6-(1'-pyrrolidinyl)-3-trifluoromethylindol-2-one

[0030]

[0031] Take 3-pyrrolidinylaniline (365mg) and add 1mL of 1,2-dichlorobenzene, and slowly add ethyl trifluoropyruvate (0.3mL) dropwise at room temperature. After the addition, the reaction system is placed in a microwave reactor, and the power 500W, react at 150°C for 10 minutes, after the reaction is over, add a large amount of ethyl acetate to the system after cooling, extract, wash with water, wash with salt water, dry over anhydrous sodium sulfate, concentrate under reduced pressure and then purify by flash column chromatography to obtain the product. Yield 91%.

[0032] 1 H NMR (DMSO-d 6 , 400MHz) δ2.00-2.04(m, 4H), 3.28-3.31(m, 4H), 6.07(s, 1H), 6.17(d, J=2.0Hz, 1H), 6.23(dd, J=2.2, 8.2Hz, 1H), 7.25(d, J=8.8Hz, 1H), 9.46(brs, 1H). HRMS. Calculated value C1 3 h 13 f 3 N 2 o 2 : 286.0929. Measured value: 286.0926.

Embodiment 2

[0033] Example 2: Preparation of 3-hydroxyl-6-(1'-piperidinyl)-3-trifluoromethylindol-2-one

[0034]

[0035]Take 3-piperidinylaniline (397mg) and add 1mL of toluene, slowly add methyl trifluoropyruvate (0.3mL) dropwise at room temperature, after the addition, put the reaction system in a microwave reactor with a power of 500W, and react at 100°C After 10 minutes, the reaction was completed. After cooling, a large amount of ethyl acetate was added to the system, extracted, washed with water and brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by flash column chromatography to obtain the product with a yield of 94.5%. Mp 100.0~101.3℃;

[0036] 1 H NMR (Acetone-d 6 , 300MHz) δ1.50-1.56(m, 6H), 3.10-3.13(m, 4H), 6.07(s, 1H), 6.41(d, J=2.4Hz, 1H), 6.48(dd, J=2.4, 8.4Hz, 1H), 7.14(d, J=8.1Hz, 1H), 9.39(brs, 1H). HRMS. Calculated value C 14 h 15 f 3 N 2 o 2 : 300.1086. Measured value: 300.1084.

Embodiment 3

[0037] Example 3: Preparation of 8-hydroxyl-8-trifluoromethyl-6,8-dihydro-1,4-dimethylenedioxyindol-7-one

[0038]

[0039] Take 6-amino-1,4-benzodioxane (679.5 mg) and add 2 mL of chlorobenzene, slowly add methyl trifluoropyruvate (0.75 mL) dropwise at room temperature, and place the reaction system in a microwave reaction after the addition is complete. In the reactor, power 500W, react at 130°C for 15 minutes, after the reaction is over, add a large amount of ethyl acetate to the system after cooling, extract, wash with water, wash with salt water, dry over anhydrous sodium sulfate, concentrate under reduced pressure and then purify by rapid column chromatography to obtain an oil Product, the yield is 72%.

[0040] 1 HNMR (Acetone-d 6 , 300MHz) δ4.10-4.18(m, 4H), 6.25(s, 1H), 6.35(s, 1H), 6.84(s, 1H), 9.39(brs, 1H).

[0041] HRMS. Calculated value C 11 h 8 f 3 NO 4 : 275.0405. Measured value: 275.0402.

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Abstract

The invention discloses a trifluoromethyl-containing indole ketone compound, and a preparation method and application thereof. The compound has the chemical structural general formula I, wherein Y is carbon or oxygen; or the compound has the chemical structural general formula II, wherein Y is carbon or oxygen and X is oxygen or sulfur; or the compound has the chemical structural general formula III, wherein Y is hydrogen or halogen and X is oxygen or sulfur; or the compound has the chemical structural general formula IV, wherein Y is hydrogen or halogen. The compound is prepared by reacting substituted aniline with methyl trifluoropyruvate or ethyl trifluoropyruvate in a microwave reactor. The trifluoromethyl-containing indole ketone compound has anti-HIV reverse transcriptase activity, basically has no toxicity on cells, is expected to serve as an HIV reverse transcriptase inhibitor, and has important value on research of the HIV reverse transcriptase inhibitor.

Description

technical field [0001] The invention relates to indolinone compounds, in particular to a trifluoromethyl-containing indolinone compound and its preparation method and application. Background technique [0002] Reverse transcription is unique to retroviral replication. Viral replication requires the reverse transcription of the viral RNA genome by a virally encoded reverse transcriptase to produce a DNA copy of the viral sequence. Since inhibition of virally encoded reverse transcriptase interrupts viral replication, reverse transcriptase is a clinically relevant target for chemotherapy of retroviral infections. [0003] A number of compounds are effective in the treatment of human immunodeficiency virus (HIV), a retrovirus that causes progressive destruction of the human immune system and is responsible for the pathogenesis of AIDS. For nucleoside-based inhibitors, such as zidovudine, and non-nucleoside-based inhibitors, through inhibitors of HIV reverse transcriptase are ...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D403/04C07D209/38C07D491/056A61P31/18
Inventor 姜标张琛李敬云庄道民陈思远
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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