Regioselective deoxidation thionation reaction for 7-azaindole-nitrogen oxide

A regioselective, azaindole technology, applied in organic chemistry and other fields, can solve problems such as low efficiency, poor adaptability, high toxicity, etc., achieve great application prospects, increase universality, and simple operation

Inactive Publication Date: 2020-02-07
SHAANXI UNIV OF SCI & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In order to overcome the problems of the prior art, the object of the present invention is to provide a thiolation method for the regioselective deoxygenation of 7-azaindole-nitrogen oxides, to overcome the high toxicity, inefficiency and adaptability of the prior art. sex problem

Method used

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  • Regioselective deoxidation thionation reaction for 7-azaindole-nitrogen oxide
  • Regioselective deoxidation thionation reaction for 7-azaindole-nitrogen oxide
  • Regioselective deoxidation thionation reaction for 7-azaindole-nitrogen oxide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]

[0030] Under room temperature conditions, 53.6 mg (0.4 mmol) of 7-azaindole-nitrogen oxide, 52.3 mg (0.24 mmol) of diphenyl disulfide, molecular iodine (10 mol%) and PEG-200 ( 2.0mL); The mass ratio of 7-azaindole-nitrogen oxide and diphenyl disulfide is 1:0.6; the mass ratio of 7-azaindole-nitrogen oxide and iodine catalyst is 1:1; Add the measured reactants to a 25mL pressure tube equipped with magnets in turn, close the pressure tube, stir on a magnetic stirrer at room temperature, then slowly heat to 110°C, at 0.1MPa, The reaction was stopped after 20 hours, cooled to room temperature, the mixture was extracted with diethyl ether (10mL×3), the organic phases were combined, and the excess solvent was removed by a rotary evaporator, and the residue was separated by column chromatography, and 300-400 mesh silica gel As a stationary phase, the product is purified and separated with a mixed solvent of ethyl acetate and petroleum ether as an eluent.

[0031] The phy...

Embodiment 2

[0036]

[0037] At room temperature, accurately weigh 53.6 mg (0.4 mmol) of 7-azaindole-nitrogen oxide, 99.2 mg (0.24 mmol) of bis(2-aminophenyl) disulfide, molecular iodine (10 mol%) and PEG-800 3mL; the molar ratio of 7-azaindole-nitrogen oxide to bis(2-aminophenyl) disulfide is 1:1; the ratio of 7-azaindole-nitrogen oxide to iodine catalyst The molar ratio of the substances is 1:0.5; the measured reactants are sequentially added to a 25mL pressure-resistant tube equipped with a magnet, and dodecyltrimethylammonium chloride (DTAC) is added, the pressure-resistant tube is closed, and the pressure-resistant tube is kept at room temperature Stir on a magnetic stirrer, then slowly heat to 80 ° C, under 0.1 MPa, stop the reaction after 22 h, cool to room temperature, extract the mixture with diethyl ether (10 mL × 3), combine the organic phases, and purify (same as in Example 1).

[0038] The physical properties and characterization data of the obtained compound are as follow...

Embodiment 3

[0043]

[0044] At room temperature, accurately weigh 53.6mg (0.4mmol) of 7-azaindole-nitrogen oxide, 137.76mg (0.48mmol) of 4,4'-dichlorodiphenyl disulfide, and molecular iodine (10mol% ) and toluene 5mL; 7-azaindole-nitrogen oxide and 4,4'-dichlorodiphenyl disulfide substance ratio is 1:1.2; 7-azaindole-nitrogen oxide and iodine The mass ratio of the catalyst is 1:0.8; the measured reactants are sequentially added to a 25mL pressure tube equipped with a magnet, and tetrabutylammonium bromide (TBAB) is added, the pressure tube is closed, and the Stir on a magnetic stirrer, then slowly heat to 100°C, under 0.1MPa, stop the reaction after 15h, cool to room temperature, extract the mixture with diethyl ether (10mL×3), combine the organic phases, and purify (same as

[0045] Example 1).

[0046] The physical properties and characterization data of the obtained compound are as follows:

[0047] white solid: 1 H NMR (400MHz, DMSO-d 6 ):δ=12.33(s,1H),8.32(dd,J=4.7Hz,J=1.6Hz,1...

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Abstract

The invention relates to the fields of organic synthesis and medicine and chemical industry, in particular relates to an iodine-catalyzed regioselective deoxidation thionation reaction method for 7-azaindole-nitrogen oxide, and aims to overcome the problems of high toxicity, low efficiency and poor adaptability existing in the prior art. The technical solution adopted in the invention is characterized in that the method comprises the following steps: by using the 7-azaindole-nitrogen oxide as a substrate and an internal oxidant, and a disulfide as a thioetherification reagent, under the condition of the molar ratio of the 7-azaindole-nitrogen oxide to the disulfide of 1:(0.5-2), adding molecular iodine as a catalyst, and performing a deoxidation thioetherification reaction in a solvent, wherein the use amount of the solvent is 2-10 mL, and the molar concentration of the 7-azaindole-nitrogen oxide is 0.1-0.5 mol / L; and sequentially adding the measured reactants into a pressure-resistanttube with a magneton, sealing the pressure-resistant tube, performing stirring on a magnetic stirrer at room temperature, performing a reaction at pressure of 0.1 MPa and temperature of 80-120 DEG Cfor 12-36 h, performing cooling to room temperature, performing extraction for several times, combining organic phases, removing the solvent, and performing purification to obtain 7-azaindole sulfide.

Description

technical field [0001] The invention relates to the fields of organic synthesis and pharmaceutical chemical industry, in particular to an iodine-catalyzed thiolation method for regioselective deoxygenation of 7-azaindole-nitrogen oxides. Background technique [0002] 7-azaindole compounds, as biological isomers of indole compounds, are widely used in medical and chemical fields. Some drugs containing 7-azaindole, such as vemurafenib (ZelborafTM), Venetoclax and GSK1070916 (C.K.E.F.Gosselin, et.al.Organic Process Research & Development, 2017,21,664; P.G.K.A.P.Das, et.al.Chemical Communications,2017,53, 9446) is in various stages of clinical development, and its corresponding sulfide and selenide have been identified as 5-HT6 receptor agonists, respectively (X.Z.-L.Y.N.X.-Y.Y.-H.Y.-Z.L.-M.Y.-F.Li, et.al. Neuropharmacology, 2018, 138, 1), MKK4 kinase inhibitor (W.S.R.P.B.Praefke, et.al.PCT Int.Appl.2018, WO2018134254A1, 20180726), 5BRD4 inhibitor (J.J.K.P.N.J.P.S.W.G.J.Wu, et....

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 刘珊珊周鲜颖赵晨杨恒张建华
Owner SHAANXI UNIV OF SCI & TECH
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