CN112430207A - Indole derivative and preparation method and application thereof - Google Patents

Indole derivative and preparation method and application thereof Download PDF

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CN112430207A
CN112430207A CN202011134446.5A CN202011134446A CN112430207A CN 112430207 A CN112430207 A CN 112430207A CN 202011134446 A CN202011134446 A CN 202011134446A CN 112430207 A CN112430207 A CN 112430207A
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alkyl
compound
indole
halogen
indole derivative
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钱宇
胡吉迪
尹鑫茹
许爱民
杨晓涵
符立梧
徐新芳
胡文浩
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Sun Yat Sen University
National Sun Yat Sen University
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Abstract

The invention discloses an indole derivative and a preparation method and application thereof. The indole derivative has a structural formula shown as a formula (I):
Figure DDA0002736207470000011
wherein R is1Is straight-chain or branched alkyl, benzyl, substituted benzyl or a saccharide substituent; r2Is hydrogen, mono-or poly-substituted alkyl, halogen or alkoxy; r3Is alkyl, halogen or alkoxy; r4Is hydrogen, alkyl or halogen. The invention provides indole derivativesThe indole medicinal effective group is contained, has good biological activity and can be used as an important chemical or medical intermediate; has strong anticancer drugs and key skeleton structures of the anticancer drugs, and has wide application prospect in the field of preparing the anticancer drugs; containing benzo [ e ]]The indole group enables the indole derivative to be easily prepared, and the preparation method provided by the invention has the advantages of few reaction steps, simple and safe operation, less waste generation, high atom economy, high selectivity and high yield.

Description

Indole derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, and particularly relates to an indole derivative and a preparation method and application thereof.
Background
The benzo [ e ] indole compound is an important organic intermediate, has wide application in the fields of dye, medicine and the like, and can be particularly used as a starting material for synthesizing cyanine dye. In recent years, various benzo [ e ] indole compounds and their sources and efficacies have been disclosed and reported in many patents and literature.
It has been reported in the literature (J.org.chem.2018,83(16), 9190-.
The literature reports (chem.Sci.,2013,4, 29-41), some important synthetic drugs also contain indole skeletons such as 5-hydroxytryptamine receptor agonist sumatriptan, triptans 5-HT1 agonist rizatriptan, and hydroxymethylglutaryl coenzyme reductase inhibitor fluvastatin.
However, the synthesis of the benzo [ e ] indole structural compound at present has the problems of long synthesis steps, complex reaction conditions and separation process and the like (chem. Eur. J.2018,24, 8747-8750).
Therefore, the development of the benzo [ e ] indole structural compound which can be synthesized efficiently and has simple process conditions has important significance and potential application value.
Disclosure of Invention
The invention aims to overcome the defects or shortcomings of long synthesis steps, complex reaction conditions and separation process and the like of the existing benzo [ e ] indole structural compound and provide an indole derivative. The indole derivative provided by the invention contains indole pharmacophores, has good biological activity (such as 5-hydroxytryptamine receptor agonist, 5-HT1 agonist and hydroxymethylglutaryl coenzyme reductase inhibitor), and can be used as an important chemical or medical intermediate; in addition, the indole derivatives have potent anticancer drugs and key skeleton structures of the anticancer drugs, and have wide application prospects in the field of preparing the anticancer drugs; and the indole derivatives are easy to prepare.
The invention also aims to provide a preparation method of the indole derivative.
The invention also aims to provide the application of the indole derivatives as chemical or medical intermediates in preparing 5-hydroxytryptamine receptor agonists, 5-HT1 agonists and HMG-CoA reductase inhibitors or in preparing anticancer drugs.
In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:
an indole derivative has a structural formula shown as a formula (I):
Figure RE-GDA0002882619330000021
wherein R is1Is straight-chain or branched alkyl, benzyl, substituted benzyl or a saccharide substituent;
R2is hydrogen, mono-or poly-substituted alkyl, halogen or alkoxy;
R3is alkyl, halogen or alkoxy;
R4is hydrogen, alkyl or halogen.
The indole derivative provided by the invention contains an indole pharmacophore: benzo [ e ] indoles having good biological activity (e.g. 5-hydroxytryptamine receptor agonists, 5-HT1 agonists, hydroxymethylglutaryl coenzyme reductase inhibitors) can be used as important chemical or pharmaceutical intermediates; in addition, the indole derivatives have key skeleton structures of potent anticancer drugs and anticancer drugs: benzo [ e ] indole has wide application prospect in the field of preparing anticancer drugs.
In addition, the indole derivative is easy to prepare by introducing the azo group, and has the advantages of high atom economy, high selectivity and high yield.
R1Wherein the alkyl group in the linear or branched alkyl group is C1～4An alkyl group; the substituent in the substituted benzyl is C1～4Alkyl radical, C1～4Alkoxy, phenyl, halogen substituted C1～4Alkyl or halogen, halogen being fluorine, chlorine or bromine; the saccharide substituent is diacetone-D-galactose saccharide substituent;
R2in the (b), the alkyl group in the mono-or poly-substituted alkyl group is C1～4Alkyl, the substituent is halogen; halogen is fluorine, chlorine or bromine; alkoxy is C1～4An alkoxy group.
R3The middle alkyl group is C1～4An alkyl group; halogen is fluorine, chlorine or bromine; alkoxy is C1～4An alkoxy group.
R4The middle alkyl group is C1～4An alkyl group; halogen is fluorine, chlorine or bromine.
Preferably, R1Is 4-methylbenzyl, 4-methoxybenzyl, 4-tert-butylbenzyl, 4-phenylbenzyl, 4-trifluoromethylbenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl or piperonyl.
Preferably, R2Is hydrogen, 4-methyl, 4-methoxy, 4-trifluoromethyl, 4-fluoro, 4-chloro, 4-bromo, 3-bromo or 2-bromo.
Preferably, R3Is methyl, chlorine or bromine.
Preferably, R4Is hydrogen, chlorine or methyl.
More preferably, the structural formula of the indole derivative is as follows:
Figure RE-GDA0002882619330000031
the preparation method of the indole derivative comprises the following steps: mixing the compound 2 and the compound 3, adding the compound 1, and reacting in the presence of a catalyst to obtain the indole derivative shown in the formula (I);
Figure RE-GDA0002882619330000032
the preparation method provided by the invention uses azo and diazo as raw materials, uses cheap alcohol as a substrate in the presence of a catalyst, and can prepare a target product through one-step reaction; the preparation method has the advantages of few reaction steps, simple and safe operation, less generated waste, high atom economy, high selectivity and high yield.
Preferably, the molar ratio of the compound 1 to the compound 2 to the compound 3 to the catalyst is 1.05-1.2: 1.2-1.5: 1: 0.01-0.2.
The invention can be catalyzed by metal catalysts which are conventional in the field, and the catalysts have the advantages of stability and high efficiency.
Preferably, the catalyst is one or more of rhodium acetate, rhodium octanoate, rhodium trifluoroacetate, bis [ (Α, Α, Α ', Α' -tetramethyl-1, 3-benzenedipropionic acid) rhodium ], palladium chloride, allyl palladium dichloride, tetratriphenylphosphine palladium, copper trifluoromethanesulfonate, cuprous iodide or copper hexafluorophosphine.
Preferably, the reaction temperature is 0-40 ℃, and the reaction time is 0.5-2 h; the solvent selected for the reaction is one or more of dichloromethane, 1, 2-dichloroethane, toluene, chlorobenzene, tetrahydrofuran, chloroform, methyl tert-butyl ether or ethyl acetate.
Preferably, the compound 1 is pushed into the reaction system by a syringe pump.
The indole derivatives are also used as chemical or medical intermediates in the preparation of 5-hydroxytryptamine receptor agonists, 5-HT1 agonists and HMG-CoA reductase inhibitors, or in the preparation of anti-cancer drugs.
Compared with the prior art, the invention has the following advantages and effects:
the indole derivatives provided by the invention contain indole pharmacophores, have good biological activity (such as 5-hydroxytryptamine receptor agonist, 5-HT1 agonist and hydroxymethylglutaryl coenzyme reductase inhibitor), and can be used as important chemical or medical intermediates.
The indole derivatives provided by the invention have potent anticancer drugs and key skeleton structures of the anticancer drugs, and have a wide application prospect in the field of preparing the anticancer drugs; and the indole derivatives are easy to prepare.
The invention provides a brand new synthesis way for the indole derivatives, so that the indole derivatives are easy to prepare.
Detailed Description
The present invention is further explained with reference to the following examples, which are not intended to limit the present invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the present invention are commercially available.
The compounds of the examples of the invention were prepared as follows:
Figure RE-GDA0002882619330000041
an azo compound (0.20mmol) represented by the compound 3, metal rhodium (0.002mmol, metal catalyst) and an alcohol (0.24mmol) represented by the compound 1 were dissolved in 1.0mL of an organic solvent dichloromethane to prepare a mixed solution, a diazo compound (0.3mmol) represented by the compound 2 was dissolved in 1.0mL of an organic solvent dichloromethane to prepare a solution, and the solution was added to the mixed solution by a syringe pump within 1 hour; stirring vigorously; after the mixed solution is dripped, the reaction is finished; spin-drying the reaction solution, and performing column chromatography on n-hexane: separating and purifying ethyl acetate (20: 1-5: 1) to obtain a target product 4 (namely the indole derivative shown in the formula (I)).
Examples 1 to 32
This example provides a series of indole derivatives, whose structures are shown in table 1, and the compounds of examples 1-32 are 4 a-4 af in sequence, and their preparation methods are as described above.
TABLE 1 Structure of indole derivatives of examples 1 to 32
Figure RE-GDA0002882619330000051
Figure RE-GDA0002882619330000061
Figure RE-GDA0002882619330000071
The spectral data for each compound are as follows:
spectral data for compound 4 a:1H NMR(500MHz,DMSO)δ11.80(s,1H),8.63(d,J＝5.9Hz,1H), 8.01(d,J＝5.6Hz,1H),7.79(d,J＝6.8Hz,1H),7.70(s,2H),7.62(s,2H),7.56–7.43(m,4H), 7.34(s,5H),7.22(s,1H),7.07(s,2H),4.96(d,J＝10.2Hz,1H),4.80(d,J＝10.2Hz,1H),2.02(s, 6H).
spectral data for compound 4 b:1H NMR(400MHz,DMSO)δ12.19(s,1H),8.62(d,J＝8.1Hz,1H), 8.01(d,J＝7.9Hz,1H),7.79(s,2H),7.72–7.68(m,2H),7.62–7.42(m,8H),7.38–7.30(m,5H), 4.93(d,J＝11.1Hz,1H),4.82(d,J＝11.1Hz,1H).
spectral data for compound 4 c:1H NMR(500MHz,DMSO)δ12.16(s,1H),8.61(d,J＝8.0Hz,1H), 8.03–7.95(m,2H),7.77(t,J＝12.4Hz,2H),7.71–7.57(m,4H),7.50(dd,J＝13.0,6.3Hz,3H), 7.42(d,J＝7.0Hz,1H),7.33(s,6H),4.93(d,J＝11.0Hz,1H),4.78(d,J＝10.8Hz,1H).
number of spectra of Compound 4dAccording to the following steps:1H NMR(400MHz,DMSO)δ12.20(s,1H),8.60(d,J＝8.2Hz,1H), 8.01(d,J＝8.0Hz,1H),7.89–7.72(m,4H),7.67(d,J＝8.1Hz,2H),7.63–7.58(m,1H),7.53– 7.40(m,4H),7.34(s,5H),4.92(d,J＝11.1Hz,1H),4.82(d,J＝11.1Hz,1H).
spectral data for compound 4 e:1H NMR(400MHz,DMSO)δ12.19(s,1H),8.57(d,J＝8.1Hz,1H), 8.01(d,J＝7.9Hz,1H),7.83–7.72(m,4H),7.61(t,J＝7.3Hz,3H),7.48(t,J＝7.4Hz,3H),7.44 –7.40(m,1H),7.31(dd,J＝8.4,5.7Hz,2H),7.12(t,J＝8.9Hz,2H),4.92(d,J＝11.2Hz,1H), 4.80(d,J＝11.2Hz,1H).
spectral data for compound 4 f:1H NMR(400MHz,DMSO)δ12.20(s,1H),8.57(d,J＝8.1Hz,1H), 8.01(d,J＝8.0Hz,1H),7.78(d,J＝10.2Hz,4H),7.61(t,J＝7.3Hz,3H),7.48(t,J＝7.2Hz,3H), 7.43–7.39(m,1H),7.35(d,J＝8.2Hz,2H),7.29(d,J＝8.2Hz,2H),4.94(d,J＝11.2Hz,1H), 4.82(d,J＝11.2Hz,1H).
spectral data for compound 4 g:1H NMR(400MHz,DMSO)δ12.18(s,1H),8.55(d,J＝8.1Hz,1H), 8.01(d,J＝8.0Hz,1H),7.85–7.72(m,4H),7.63–7.58(m,3H),7.48(t,J＝8.9Hz,5H),7.43– 7.39(m,1H),7.23(d,J＝8.1Hz,2H),4.93(d,J＝11.6Hz,1H),4.80(d,J＝11.5Hz,1H).
spectral data for compound 4 h:1H NMR(400MHz,DMSO)δ12.20(s,1H),8.55(d,J＝8.2Hz, 1H),8.02(d,J＝8.2Hz,1H),7.77(dd,J＝17.6,8.9Hz,4H),7.69–7.55(m,5H),7.54–7.35(m, 6H),5.09(d,J＝12.0Hz,1H),4.93(d,J＝12.1Hz,1H).
compound 4i spectral data:1H NMR(500MHz,DMSO)δ12.19(s,1H),8.62(d,J＝6.8Hz,1H), 8.00(d,J＝6.6Hz,1H),7.78(d,J＝19.8Hz,4H),7.66(s,2H),7.60(s,1H),7.50(s,3H),7.43(s, 1H),7.19(s,2H),7.14(s,2H),4.87(d,J＝9.6Hz,1H),4.77(d,J＝9.3Hz,1H),2.29(s,3H).
compound 4j spectral data:1H NMR(500MHz,DMSO)δ12.19(s,1H),8.64(d,J＝7.6Hz,1H), 8.00(d,J＝7.5Hz,1H),7.79(d,J＝19.9Hz,4H),7.67(d,J＝6.4Hz,2H),7.62(s,1H),7.51(s, 3H),7.44(d,J＝6.3Hz,1H),7.22(d,J＝7.2Hz,2H),6.88(d,J＝7.3Hz,2H),4.85(d,J＝10.4 Hz,1H),4.75(d,J＝10.5Hz,1H),3.74(s,3H).
compound 4k spectral data:1H NMR(400MHz,DMSO)δ12.19(s,1H),8.64(d,J＝8.2Hz,1H), 8.01(d,J＝8.0Hz,1H),7.79(d,J＝9.5Hz,4H),7.67(d,J＝7.1Hz,2H),7.62(dd,J＝11.6,4.5 Hz,1H),7.49(td,J＝7.1,3.8Hz,3H),7.42(t,J＝7.3Hz,1H),7.35(t,J＝7.4Hz,2H),7.25(d,J＝ 8.2Hz,2H),4.90(d,J＝10.9Hz,1H),4.78(d,J＝10.9Hz,1H),1.28(d,J＝2.7Hz,9H).
compound 4l spectral data:1H NMR(400MHz,DMSO)δ12.23(s,1H),8.66(d,J＝8.2Hz,1H), 8.01(d,J＝7.9Hz,1H),7.79(s,2H),7.70–7.59(m,9H),7.50–7.36(m,10H),4.99(d,J＝11.3 Hz,1H),4.87(d,J＝11.3Hz,1H).
compound 4m spectral data:1H NMR(500MHz,DMSO)δ12.18(s,1H),8.61(d,J＝7.8Hz,1H), 8.01(d,J＝7.7Hz,1H),7.77(s,4H),7.60(dd,J＝20.2,7.0Hz,3H),7.47(s,3H),7.42(d,J＝6.2 Hz,1H),7.33(d,J＝5.8Hz,1H),7.20(t,J＝7.5Hz,2H),7.12(d,J＝6.1Hz,1H),4.94(d,J＝ 11.0Hz,1H),4.83(d,J＝11.0Hz,1H),2.10(s,3H).
compound 4n spectral data:1H NMR(400MHz,DMSO)δ12.22(s,1H),8.58(d,J＝8.0Hz,1H), 8.01(d,J＝7.9Hz,1H),7.78(s,3H),7.62(dd,J＝15.2,7.7Hz,3H),7.49(t,J＝7.3Hz,3H),7.44 –7.40(m,1H),7.36–7.29(m,3H),7.26(d,J＝5.1Hz,1H),4.98(d,J＝11.6Hz,1H),4.85(d,J＝ 11.5Hz,1H).
compound 4o spectral data:1H NMR(400MHz,DMSO)δ12.21(s,1H),8.65(d,J＝8.2Hz,1H), 8.01(d,J＝8.0Hz,1H),7.78(d,J＝9.0Hz,4H),7.68(d,J＝7.5Hz,2H),7.64–7.60(m,1H), 7.51(t,J＝7.5Hz,3H),7.45–7.41(m,1H),6.47(s,2H),6.42(s,1H),4.86(d,J＝11.3Hz,1H), 4.78(d,J＝11.2Hz,1H),3.68(s,6H).
compound 4p spectral data:1H NMR(400MHz,DMSO)δ12.15(s,1H),8.60(d,J＝8.2Hz,1H), 7.99(d,J＝8.1Hz,1H),7.87–7.70(m,4H),7.63(t,J＝7.3Hz,3H),7.49(q,J＝7.0Hz,3H),7.41 (t,J＝7.3Hz,1H),3.78–3.71(m,1H),3.63(t,J＝8.1Hz,1H),1.70–1.59(m,2H),1.46(s,4H), 1.30–1.17(m,3H).
compound 4q spectral data:1H NMR(400MHz,DMSO)δ12.19(s,1H),8.61(d,J＝8.2Hz,1H), 8.00(d,J＝8.0Hz,1H),7.87–7.73(m,4H),7.63(d,J＝7.1Hz,3H),7.49(t,J＝6.6Hz,3H),7.42 (t,J＝7.2Hz,1H),6.84–6.70(m,3H),5.99(d,J＝3.4Hz,2H),4.84(d,J＝10.9Hz,1H),4.71(d, J＝10.9Hz,1H).
compound 4r spectral data:1H NMR(400MHz,DMSO)δ12.19(s,1H),8.69(d,J＝7.8Hz,1H), 7.99(d,J＝7.6Hz,1H),7.78(d,J＝19.9Hz,4H),7.62(d,J＝4.6Hz,4H),7.48(s,3H),7.41(d,J ＝6.9Hz,1H),6.84(d,J＝7.4Hz,1H),6.75(t,J＝7.3Hz,1H),6.67(d,J＝7.5Hz,1H),5.97(d,J ＝6.1Hz,2H),4.89(d,J＝10.4Hz,1H),4.79(d,J＝10.1Hz,1H).
compound 4s spectral data:1H NMR(400MHz,DMSO)δ12.01(s,1H),8.63(d,J＝8.1Hz,1H), 7.99(d,J＝7.6Hz,1H),7.86–7.65(m,4H),7.52(dd,J＝11.1,4.1Hz,1H),7.49–7.44(m,1H), 7.38(t,J＝5.3Hz,5H),7.23(ddd,J＝17.1,11.0,6.8Hz,5H),7.17–7.08(m,5H),6.02(s,1H).
compound 4t profile data:1H NMR(500MHz,DMSO)δ12.16(s,1H),8.59(d,J＝6.7Hz,1H), 7.99(d,J＝7.2Hz,1H),7.77(d,J＝30.9Hz,4H),7.64(d,J＝5.7Hz,3H),7.49(d,J＝6.6Hz, 3H),7.42(d,J＝6.0Hz,1H),3.71(s,1H),3.58(s,1H),1.74–1.56(m,6H),1.15(d,J＝24.5Hz, 3H),0.96(d,J＝9.6Hz,2H).
compound 4u spectral data:1H NMR(400MHz,DMSO)δ12.19(d,J＝23.8Hz,1H),8.78(t,J＝ 8.4Hz,1H),7.99(d,J＝8.0Hz,1H),7.88–7.72(m,4H),7.67(d,J＝7.5Hz,2H),7.58(t,J＝7.5 Hz,1H),7.50(t,J＝7.2Hz,3H),7.45–7.40(m,1H),5.47(dd,J＝15.7,4.8Hz,1H),4.58(s,1H), 4.37(s,1H),4.24(t,J＝7.8Hz,1H),4.13–4.00(m,2H),3.78(dd,J＝8.6,6.2Hz,1H),1.49(s, 1H),1.32(dd,J＝21.6,16.4Hz,11H).
compound 4v spectral data:1H NMR(400MHz,DMSO)δ12.14(s,1H),8.63(d,J＝8.2Hz,1H), 7.98(d,J＝8.1Hz,1H),7.86–7.69(m,4H),7.58–7.54(m,1H),7.46(t,J＝7.4Hz,3H),7.35(dd, J＝15.9,8.1Hz,3H),7.28–7.18(m,3H),5.17(s,2H)
compound 4w spectral data:1H NMR(500MHz,DMSO)δ12.20(s,1H),8.55(d,J＝7.7Hz,1H), 8.01(d,J＝7.8Hz,1H),7.78(s,4H),7.64–7.61(m,1H),7.57(d,J＝6.7Hz,2H),7.51–7.38(m, 5H),7.24(s,2H),5.03(d,J＝11.5Hz,1H),4.86(d,J＝11.6Hz,1H).
compound 4x spectral data:1H NMR(500MHz,DMSO)δ12.18(s,1H),8.66(d,J＝8.1Hz,1H), 8.01(d,J＝7.9Hz,1H),7.85–7.74(m,4H),7.65–7.61(m,1H),7.57(d,J＝7.5Hz,2H),7.51– 7.47(m,1H),7.32(d,J＝7.5Hz,2H),6.83(d,J＝10.4Hz,2H),6.76(d,J＝7.6Hz,1H),6.01(d,J ＝5.7Hz,2H),4.85(d,J＝10.9Hz,1H),4.76(d,J＝10.9Hz,1H),2.40(s,3H).
compound 4y spectral data:1H NMR(400MHz,DMSO)δ12.12(s,1H),8.60(d,J＝7.5Hz,1H), 7.99(d,J＝8.0Hz,1H),7.99(d,J＝8.0Hz,1H),7.82(s,2H),7.74(s,2H),7.60(d,J＝7.5Hz, 1H),7.53(d,J＝7.1Hz,2H),7.47(t,J＝7.5Hz,1H),7.06(d,J＝8.2Hz,2H),6.84–6.78(m,2H), 6.73(d,J＝7.8Hz,1H),5.99(d,J＝5.4Hz,2H),4.83(d,J＝10.8Hz,1H),4.72(d,J＝10.9Hz, 1H),3.82(s,3H).
compound 4z spectrum data:1H NMR(500MHz,DMSO)δ12.21(s,1H),8.65(d,J＝8.2Hz,1H), 8.02(d,J＝8.0Hz,1H),7.87–7.77(m,4H),7.67–7.61(m,3H),7.50(dd,J＝11.4,4.3Hz,1H), 7.34(t,J＝7.9Hz,2H),6.78(dd,J＝18.7,4.6Hz,2H),6.68(dd,J＝7.9,1.3Hz,1H),6.01(d,J＝ 9.9Hz,2H),4.90(d,J＝11.1Hz,1H),4.74(d,J＝11.1Hz,1H).
compound 4aa spectral data:1H NMR(400MHz,DMSO)δ12.21(s,1H),8.60(d,J＝7.6Hz,1H), 8.01(d,J＝7.1Hz,1H),7.79(dd,J＝21.4,12.9Hz,4H),7.54(s,6H),6.82–6.71(m,2H),6.65(d, J＝6.5Hz,1H),5.99(d,J＝10.2Hz,2H),4.90(d,J＝10.4Hz,1H),4.71(d,J＝10.2Hz,1H).
compound 4ab spectrum data:1H NMR(500MHz,DMSO)δ12.23(s,1H),8.63(d,J＝8.1Hz,1H), 8.01(d,J＝7.9Hz,1H),7.85–7.76(m,4H),7.67(d,J＝8.0Hz,3H),7.51(d,J＝8.2Hz,3H), 6.77(d,J＝8.0Hz,2H),6.65(d,J＝7.8Hz,1H),6.00(d,J＝11.5Hz,2H),4.91(d,J＝11.0Hz, 1H),4.73(d,J＝11.0Hz,1H).
compound 4ac spectrum data:1H NMR(400MHz,DMSO)δ12.27(s,1H),8.61(d,J＝8.1Hz,1H), 8.02(d,J＝8.1Hz,1H),7.85–7.75(m,4H),7.66(d,J＝1.6Hz,2H),7.58(t,J＝7.8Hz,2H),7.53 –7.48(m,1H),7.41(t,J＝7.8Hz,1H),6.76(dd,J＝14.6,7.9Hz,2H),6.64(d,J＝7.9Hz,1H), 6.00(d,J＝4.7Hz,2H),4.91(d,J＝11.0Hz,1H),4.71(d,J＝11.0Hz,1H).
compound 4ad profile data:1H NMR(500MHz,DMSO)δ12.20(s,1H),8.64(d,J＝8.2Hz,1H), 8.01(d,J＝8.0Hz,1H),7.78(s,3H),7.65(t,J＝6.9Hz,3H),7.52–7.47(m,3H),7.42(t,J＝7.4 Hz,1H),6.80(dd,J＝15.3,4.6Hz,2H),6.73(dd,J＝7.9,1.4Hz,1H),6.00(dd,J＝5.2,0.8Hz, 2H),4.85(d,J＝11.0Hz,1H),4.73(d,J＝10.9Hz,1H).
compound 4ae spectral data:1H NMR(500MHz,DMSO)δ12.27(s,1H),8.62(d,J＝8.1Hz,1H), 8.03(d,J＝7.9Hz,1H),7.85–7.76(m,4H),7.69–7.65(m,2H),7.60(dd,J＝12.3,7.9Hz,2H), 7.53–7.49(m,1H),7.43(t,J＝7.8Hz,1H),6.80–6.70(m,2H),6.66(d,J＝7.9Hz,1H),6.01(d, J＝5.7Hz,2H),4.92(d,J＝11.0Hz,1H),4.73(d,J＝11.0Hz,1H).
compound 4af spectrum data:1H NMR(500MHz,DMSO)δ11.68(s,1H),8.61(d,J＝8.1Hz,1H), 8.00(d,J＝8.0Hz,1H),7.77(d,J＝8.8Hz,1H),7.68(d,J＝7.4Hz,2H),7.60(d,J＝8.6Hz,2H), 7.54–7.42(m,4H),7.33(s,5H),6.87(s,2H),4.94(d,J＝11.1Hz,1H),4.79(d,J＝11.2Hz,1H), 2.23(s,3H),1.99(s,6H).
it should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims (10)

1. An indole derivative is characterized by having a structural formula shown as a formula (I):
Figure FDA0002736207450000011
wherein the content of the first and second substances,R1is straight-chain or branched alkyl, benzyl, substituted benzyl or a saccharide substituent;
R2is hydrogen, mono-or poly-substituted alkyl, halogen or alkoxy;
R3is alkyl, halogen or alkoxy;
R4is hydrogen, alkyl or halogen.
2. The indole derivative according to claim 1, wherein the alkyl or linear alkyl is C1～4An alkyl group; the branched alkyl is branched C1～4An alkyl group; the substituent in the substituted benzyl is C1～4Alkyl radical, C1～4Alkoxy, phenyl, halogen substituted C1～4Alkyl or halogen; the saccharide substituent is diacetone-D-galactose saccharide substituent;
the substituent in the mono-substituted or multi-substituted alkyl is halogen;
the halogen is fluorine, chlorine or bromine; the alkoxy is C1～4An alkoxy group.
3. The indole derivative according to claim 1, wherein R is1Is 4-methylbenzyl, 4-methoxybenzyl, 4-tert-butylbenzyl, 4-phenylbenzyl, 4-trifluoromethylbenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl or piperonyl;
R2is hydrogen, 4-methyl, 4-methoxy, 4-trifluoromethyl, 4-fluoro, 4-chloro, 4-bromo, 3-bromo or 2-bromo;
R3is methyl, chlorine or bromine;
R4is hydrogen, chlorine or methyl.
4. The indole derivative according to claim 3, wherein the structural formula of the indole derivative is as follows:
Figure FDA0002736207450000021
5. the process for preparing indole derivatives according to any one of claims 1 to 4, which comprises the steps of: mixing the compound 2 and the compound 3, adding the compound 1, and reacting in the presence of a catalyst to obtain the indole derivative shown in the formula (I);
Figure FDA0002736207450000022
6. the preparation method of the indole derivative according to claim 5, wherein the molar ratio of the compound 1, the compound 2, the compound 3 and the catalyst is 1.05-1.2: 1.2-1.5: 1: 0.01-0.2.
7. The process for producing an indole derivative according to claim 5, wherein the catalyst is one or more of rhodium acetate, rhodium octanoate, rhodium trifluoroacetate, bis [ (A, A' -tetramethyl-1, 3-benzenedipropionic acid) rhodium ], palladium chloride, allylpalladium dichloride, tetratriphenylphosphine palladium, copper trifluoromethanesulfonate, cuprous iodide or copper hexafluorophosphine.
8. The preparation method of indole derivatives according to claim 5, wherein the reaction temperature is 0-40 ℃ and the reaction time is 0.5-2 h; the solvent selected for the reaction is one or more of dichloromethane, 1, 2-dichloroethane, toluene, chlorobenzene, tetrahydrofuran, chloroform, methyl tert-butyl ether or ethyl acetate.
9. The process for preparing indole derivatives according to claim 5, wherein compound 1 is pushed into the reaction system by a syringe pump.
10. The indole derivative of any one of claims 1 to 4, as an intermediate in chemical or pharmaceutical industry, for use in the preparation of 5-hydroxytryptamine receptor agonists, 5-HT1 agonists, hydroxymethylglutaryl-coenzyme reductase inhibitors, or for use in the preparation of anti-cancer drugs.
CN202011134446.5A 2020-10-21 2020-10-21 Indole derivative and preparation method and application thereof Pending CN112430207A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109354579A (en) * 2018-11-23 2019-02-19 西北大学 A kind of biaryl axial chirality benzindole-naphthalene compounds and its synthetic method

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109354579A (en) * 2018-11-23 2019-02-19 西北大学 A kind of biaryl axial chirality benzindole-naphthalene compounds and its synthetic method

Non-Patent Citations (2)

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Title
YIN XINRU ET AL.,: "A Rh(II)/phosphoric acid co-catalyzed threecomponent reaction of diazo-ketones with alcohols and azonaphthalenes: access to indole derivatives via a formal [3+2]-cycloaddition", 《ORG. BIOMOL. CHEM.》 *
YU-LONG HU ET AL.,: "Conversion of two stereocenters to one or two chiral axes: atroposelective synthesis of 2,3- diarylbenzoindoles", 《CHEM. SCI.》 *

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