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3-Dialkylated-2-indolinone derivative and its preparation method

An indolinone and dialkyl technology, which is applied in the field of 3-dialkylated-2-indolinone derivatives and their preparation, can solve the problems of poor spiro structure plasticity and the like, and achieves less side reactions and high purity , the effect of expanding the application field

Active Publication Date: 2020-09-11
GUANGDONG UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The invention provides a 3-dialkylated-2-indolinone derivative and a preparation method thereof, which solves the problem of only obtaining a 3-dialkylated-2-indolinone derivatives whose C3 position is a spiro ring, most of the 3-dialkylated-2-indolinone derivatives whose C3 position is a spiro ring only have a comparatively good effect in the field of pharmaceutical activity. Multiple applications, little research in other fields such as biological probes, and poor plasticity of the helical ring structure, technical problems that cannot generate more chemical structures based on this structure

Method used

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  • 3-Dialkylated-2-indolinone derivative and its preparation method

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preparation example Construction

[0052] The present invention also provides a preparation method of 3-dialkylated-2-indolinone derivatives, the specific steps are:

[0053] Step 1: Use p-cresol and vinyltrimethylsilane as raw materials to generate trimethyl(2-(p-tolylthio)ethyl)silane through condensation reaction, and the condensing agent for this condensation reaction is preferably azobis Isobutyronitrile.

[0054] Step 2: generate trimethyl (2-(p-toluenesulfonyl) ethyl) silane by oxidation reaction of trimethyl (2-(p-tolylsulfanyl) ethyl) silane, the oxidant of this oxidation reaction is preferably sodium periodate.

[0055] Step 3: Addition reaction of trimethyl(2-(p-toluenesulfonyl)ethyl)silane and acrolein to generate 4-(p-toluenesulfonyl)-6-(trimethylsilyl)hexyl-1 -en-3-ol, specifically trimethyl(2-(p-toluenesulfonyl)ethyl)silane and acrolein, is added to a mixed solution of acrolein, and an addition reaction occurs;

[0056] The above-mentioned base is preferably methyllithium, and the solvent of t...

Embodiment 1

[0072] 1. Synthesis of trimethyl (2-(p-tolylthio) ethyl) silane (II)

[0073]

[0074] Add 5mmol p-cresol (1) and 6mmol vinyltrimethylsilane (2) into a round bottom flask, add 0.05mmol condensing agent azobisisobutyronitrile, raise the temperature to 100°C, and stir for 12h. After the reaction was completed and cooled to room temperature, the obtained product was subjected to silica gel column chromatography, using n-hexane: ethyl acetate = 250:1 as the eluent for separation and purification to obtain 1041 mg of a colorless liquid with a yield of 93%.

[0075] The proton nuclear magnetic resonance spectrum of this product trimethyl (2-(p-tolylthio) ethyl) silane (II), as figure 1 Shown as:

[0076] 1 H NMR (400MHz, CDCl 3 ): δ=7.21(d, J=8.0Hz, 2H), 7.08(d, J=8.0Hz, 2H), 2.90(t, J=8.8Hz, 2H), 2.30(s, 3H), 0.88(t , J=8.8Hz, 2H), 0(s, 9H).

[0077] 2. Synthesis of trimethyl (2-(p-toluenesulfonate) ethyl) silane (III)

[0078]

[0079] Add 10mmol trimethyl(2-(p-tolylth...

Embodiment 2

[0102] 1. Synthesis of N-tert-butoxycarbonyl-5-fluoro-2-indolinone (VIII)

[0103]

[0104] Dissolve 4mmol of 5-fluoro-2-indolinone (VII) in 15ml of tetrahydrofuran solution, add 12mmol of sodium bicarbonate, stir at 66°C, then add 8mmol of di-tert-butyl dicarbonate, follow the reaction with TLC until the raw material disappears, The reaction was quenched with ice water, extracted three times with ethyl acetate, the organic phase was collected and the solvent was spin-dried to obtain the product, which was separated and purified by silica gel column chromatography with n-hexane:ethyl acetate=5:1 as the eluent to obtain 675 mg of white solid, N-tert-butoxycarbonyl-5-fluoro-2-indolinone (VII), yield 67%.

[0105] The product N-tert-butoxycarbonyl-5-fluoro-2-indolinone (VII) 13 C NMR spectra, such as Figure 7 Shown as:

[0106] 1 H NMR (400MHz, CDCl3): δ = 7.78 (dd, J = 4.4Hz, J = 8.4Hz, 1H), 7.02-6.97 (m, 3H), 3.65 (s, 2H), 1.64 (s, 9H)

[0107] The proton nuclear magne...

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Abstract

The invention provides a 3-bisalkylated-2-3-bisalkylated-2-indolone derivative. The derivative has a structural formula represented by a formula I shown in the description, wherein R1 and R2 are halogen or H. The invention further provides a preparation method of the series of derivatives. The method comprises the step of subjecting an N-tert-butyloxycarbonyl-2-3-bisalkylated-2-indolone derivativeand (E)-1-(trimethylsilyl)penta-1,4-diene-3-one to a Michael addition reaction, thereby synthesizing the formula I. According to the 3-bisalkylated-2-3-bisalkylated-2-indolone derivative and the preparation method thereof, provided by the invention, the technical problem during the Michael addition reaction of indolone, of which a C3 position is free of a substituent, at present that only 3-bisalkylated-2-indolone derivatives, of which C3 positions are spiro, are obtained, the majority of the 3-bisalkylated-2-indolone derivatives, of which the C3 positions are the spiro, are only applied to the field of drug activity and are rarely researched in other fields such as biological probes, spiro structures are relatively poor in plasticity, and more chemical structures cannot be produced by taking the structures as a basis is solved.

Description

technical field [0001] The invention belongs to the technical field of synthetic chemistry, and in particular relates to a 3-dialkylated-2-indolinone derivative and a preparation method thereof. Background technique [0002] 2-Indolinone and its derivatives are widely present in natural compounds, have unique chemical and physiological and pharmacological activities, and have important applications in medicine, pesticides, etc., such as preparing anti-inflammatory, anti-tumor, anti-cancer, insecticidal, herbicidal activity. A large number of new compounds with 2-indolinone as the skeleton can be obtained through artificial synthesis. On the one hand, it can make up for the shortage of natural resources, and on the other hand, it can help to solve the structure-activity relationship and analyze the active factors of drugs more reasonably. [0003] At present, there are two main types of Michael addition of 2-3-dialkylated-2-indolinone derivatives and dienone. First, when the...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F7/10
CPCC07F7/10
Inventor 庄桂生刘艳卢汉彬何虹运丸岡啓二
Owner GUANGDONG UNIV OF TECH