CN108003086B - Preparation method of 3-amino-2-indolone compound - Google Patents
Preparation method of 3-amino-2-indolone compound Download PDFInfo
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Abstract
The invention provides a simple, cheap and efficient green synthesis method for preparing 3-amino-2-indolone compounds, which takes 2-indolone compounds 1a and amine 2a as raw materials, and uses I2Amination reaction is carried out under the condition of 60 ℃ under a-TBHP system, and the 3-amino-2-indolone compound 1 is simply and conveniently prepared with excellent yield. The reaction formula is as follows:
Description
Technical Field
The invention relates to a22-indolone compound C (sp) under metal-free green catalytic system of-TBHP3) -H amination process, in particular with 2-indolone derivatives and amines as starting materials, in I2The amination reaction is carried out under the condition of 60 ℃ under a-TBHP system, and the 3-amido-2-indolone compound is prepared.
Background
The indolone skeleton has attracted extensive and lasting attention of chemists and biologists due to its unique structural characteristics and physiological activities. 3-amino-2-indolone as an important subclass of indolone skeleton widely exists in natural products and bioactive molecules, wherein the following are representative (see formula one below):
as the 3-amino-2-indolone compounds and the derivatives thereof are very important organic intermediates, and a plurality of natural compounds contain the skeletons, the 3-amino-2-indolone compounds have good pharmaceutical activity and are widely applied in the aspects of medicine, biology and the like. Therefore, it is important to develop a convenient, environment-friendly and efficient method for synthesizing 3-amino-2-indolone and its derivatives.
The inventor finds that the synthetic route for synthesizing and preparing the 3-amino-2-indolone compounds in the prior art mainly comprises the following steps: amide intramolecular alpha-arylation reaction, 3-aminoindole alkylation reaction, imine nucleophilic addition reaction and Mannich addition reaction. In recent years, researchers have developed methods for preparing 3-amino-2-indolone compounds from 2-indolone compounds. For example, see the following documents:
(1)“A Catalytic Metal-Free Ritter Reaction to 3-Substituted 3-Aminooxindoles”，Feng Zhou et.al.，Org.Biomol.Chem.，2012，10，3178；
(2)“Synthesis of 3-Amino-3-hydroxymethyloxindoles and 3-Hydroxy-3-hydroxymethyloxindoles by Rh2(OAc)4-Catalyzed Three-Component Reactions of 3-Diazooxindoles with Formaldehyde and Anilines or Water”，Chengjin Wang et.al.，J.Org.Chem.2014，79，3908-3916；
(3)“Facile and Efficient Enantioselective Hydroxyamination Reaction：Synthesis of 3-Hydroxyamino-2-Oxindoles Using Nitrosoarenes”，Ke Shen et.al.，Angew.Chem.Int.Ed.2011，50，4684-4688。
however, in the methods for preparing 3-amino-2-indolone compounds using 2-indolone compounds reported in the prior art as raw materials, the reaction conditions are severe and the reaction cost is high, for example, strong acids such as perchloric acid and the like are used, and/or expensive catalytic systems such as noble metal rhodium, nitrogen ligand and the like are used. Therefore, finding a more efficient, cheaper, greener synthesis remains a challenging topic.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a green synthesis method for preparing 3-amino-2-indolone compounds with simple process, high efficiency and low cost, wherein the method takes 2-indolone compounds and amine as raw materials, and uses I23-amino 2-indolone compounds are conveniently prepared with excellent yield under the condition of 60 ℃ in a TBHP system.
The invention provides a preparation method of a 3-amido-2-indolone compound, which takes the 2-indolone compound as a raw material and is prepared by the following steps:
adding the 2-indolone derivative (1a), the amine compound shown in the formula 2a, a catalyst, an oxidant and an organic solvent into a Schlenk reaction bottle, placing the reaction bottle at 60 ℃ under the air atmosphere condition, stirring in an oil bath for reaction, monitoring the reaction process by TLC or GC until the raw materials are completely reacted, and carrying out aftertreatment to obtain the target product 3-amino 2-indolone compound (I).
The chemical reaction formula of the preparation method of the 3-amino-2-indolone compound provided by the invention can be expressed as (see formula II):
in the above reaction, the organic solvent may be one or more selected from dichloroethane, dichloromethane, acetonitrile, and tetrahydrofuran, and preferably dichloroethane is used as the solvent.
The post-processing operation is as follows: and (3) concentrating the reaction liquid after the reaction is finished under reduced pressure, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product 3-amino-2-indolone compound (I).
In the raw material 2-indolone compound represented by the formula 1a and the product 3-amino-2-indolone compound represented by the formula I, R is1 Represents 1 or more substituents on the phenyl ring to which it is attached, each R1Independently of one another, from hydrogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Acyl radical, C1-C6Ester group, halogen, cyano, nitro, C3-C6Cycloalkyl radical, C5-C14Aryl radical, C5-C14Heteroaryl, -NRaRb. Wherein R isa，RbIndependently of one another, from C1-C6Alkyl or hydrogen; the heteroatom of the heteroaryl group is selected from O, S or N.
R2Represents hydrogen, C1-C6Alkyl, halogen, cyano, C3-C6Cycloalkyl radical, C5-C14Aryl radical, C5-C14A heteroaryl group; the heteroatom of the heteroaryl group is selected from O, S or N.
R3Represents hydrogen, tert-butyloxycarbonyl (Boc), C1-C6Alkyl radical, C1-C6Acyl radical, C3-C6Cycloalkyl radical, C5-C14Aryl radical, C5-C14aryl-C1-C6Alkyl radical, C5-C14A heteroaryl group, the heteroatom of which is selected from O, S or N.
Wherein each of the above alkyl, alkoxy, cycloalkyl, aryl and heteroaryl groups may be further substituted with a substituent selected from halogen or C1-C6Alkyl group of (1).
Preferably, R1Represents 1 or more substituents on the phenyl ring to which it is attached, each R1Independently of one another, from hydrogen, C1-C6Alkyl, halogen, C1-C6Alkoxy, nitro, C5-C14An aryl group; wherein said C1-C6Alkyl and/or C5-C14The aryl group may be further substituted, said substituents being selected from halogen or C1-C6Alkyl group of (1).
Preferably, R2Represents hydrogen, C1-C6Alkyl, halogen, cyano, C5-C14Aryl, wherein said C1-C6Alkyl and/or C5-C14The aryl group may be further substituted, said substituents being selected from halogen or C1-C6Alkyl group of (1).
Preferably, R3Represents hydrogen, tert-butyloxycarbonyl (Boc), C1-C6Alkyl radical, C1-C6Acyl, phenyl, benzyl, wherein said C1-C6Alkyl and/or C1-C6The acyl, phenyl and/or benzyl groups may be further substituted, the substituents being selected from halogen or C1-C6Alkyl group of (1).
The compound represented by the above formula 2a represents various amine compounds. The compound of formula 2a is preferably added in an amount of 150 to 300 mol% of the 2-indolone derivative (1a), and most preferably 200 mol% of the 2-indolone derivative (1 a).
Among these, TBHP, as described above and elsewhere in this specification, is in the form of the chemical abbreviation known in the art as t-Butyl peroxide, the british name tert-Butyl hydroperoxide.
The invention has the beneficial effects that: provides a new method for preparing 3-amido-2-indolone compounds, which takes 2-indolone compounds and amine as reaction raw materials, in the step I2C (sp) at 60 ℃ in a TBHP system3) -H amination to give a series of target products in high yields. The method does not use acid, metal catalyst or ligand, and the reaction atmosphere is air, has the advantages of wide reaction substrate application range, simplicity, high efficiency, economy and environmental protection, and is particularly suitable for industrial production.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of the product 3-morpholino-3-phenyl-2-indolone.
FIG. 2 is the nuclear magnetic carbon spectrum of the product 3-morpholino-3-phenyl-2-indolone.
FIG. 3 is a schematic diagram of the mechanism of the reaction of the present invention.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1 Compounds
Synthesis of (2)
To a Schlenk reaction flask having a volume of 20mL were added 0.3mmol of 3-phenyl-2-indolone, 0.6mmol of morpholine, 0.06mmol of I2Placing a reaction bottle at 60 ℃ and under the condition of air atmosphere, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials completely react (4 hours), concentrating the reaction liquid after the reaction is finished under reduced pressure, and carrying out column chromatography separation on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain the target product 3-morpholino-3-phenyl-2-indolone.
White solid (83% yield);1H NMR(400MHz，CDCl3)：7.92(s，1H)，7.58(d，J＝8.0Hz，2H)，7.36-7.29(m，4H)，7.24(d，J＝8.0Hz，1H)，7.06(t，J＝7.6Hz，1H)，6.89(d，J＝7.6Hz，1H)，3.71(t，J＝4.4Hz，4H)，2.64(t，J＝4.4Hz，4H)；13C NMR(100MHz，CDCl3)：177.3，140.4，138.1，129.3，129.0，128.7，128.1，127.6，126.3，122.8，110.1，74.4，67.5，47.6；HRMS m/z(ESI)calcd for C18H19N2O2([M+H]+)295.1441，found 295.1443。
example 2 replacement of I with the catalyst tetrabutylammonium iodide2Otherwise, the process was carried out in the same manner as in example 1, except that the yield of the objective product was 60%.
Example 3 replacement of I with the catalyst tetrabutylammonium bromide2The other conditions were the same as in example 1, and the yield of the desired product was < 5%.
Example 4 replacement of TBHP by the oxidant di-tert-butyl peroxide, the same procedure as in example 1, gave a 51% yield of the desired product.
Example 5 the TBHP was replaced with benzoyl peroxide as the oxidizing agent under the same conditions as in example 1, giving a yield of 56% of the desired product.
Example 6 the solvent dichloromethane was used instead of dichloroethane and the conditions were the same as in example 1, the yield of the desired product was 68%.
Example 7 the dichloroethane was replaced by acetonitrile solvent, the conditions were the same as in example 1, and the yield of the desired product was 70%.
Example 8 the solvent tetrahydrofuran was used instead of dichloroethane and the conditions were the same as in example 1, the yield of the desired product was 45%.
Example 9 the reaction atmosphere was adjusted to a nitrogen atmosphere (1atm), and the other conditions were the same as in example 1, whereby the yield of the objective product was 81%.
Example 10 Compounds
Synthesis of (2)
To a Schlenk reaction flask having a volume of 20mL was added 0.3mmol of 3-phenyl-2-indolone, 0.6mmol of indoline, 0.06mmol of I20.6mmol of TBHP and dichloroethane (2mL), placing a reaction bottle at 60 ℃ under the condition of air atmosphere, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials completely react (4 hours), concentrating the reaction solution after the reaction is finished under reduced pressure, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product.
Black liquid (70% yield);1H NMR(400MHz，CDCl3)：8.76(s，1H)，7.59(d，J＝7.2Hz，2H)，7.34(t，J＝5.6Hz，4H)，7.25-7.19(m，1H)，7.04(d，J＝7.2Hz，1H)，6.96(t，J＝7.6Hz，1H)，6.89(d，J＝7.6Hz，1H)，6.75(t，J＝7.6Hz，1H)，6.65(t，J＝7.6Hz，1H)，5.99(d，J＝8.0Hz，1H)，3.52(t，J＝10.4Hz，1H)，3.05(t，J＝8.8Hz，1H)，2.95(t，J＝10.0Hz，1H)，2.85(t，J＝8.8Hz，1H)；13C NMR(100MHz，CDCl3)：177.3，149.4，140.9，138.1，131.7，129.6，129.3，128.8，128.5，126.4，126.2，124.7，123.1，119.0，115.3，111.7，110.3，71.8，50.8，28.1；HRMS m/z(ESI)calcd for C22H19N2O([M+H]+)327.1492，found 327.1496。
example 11 Compounds
Synthesis of (2)
To a Schlenk reaction flask having a volume of 20mL were added 0.3mmol of 3-phenyl-2-indolone, 0.6mmol of N-methylbenzylamine, and 0.06mmol of I20.6mmol of TBHP and dichloroethane (2mL), placing a reaction bottle at 60 ℃ under the condition of air atmosphere, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials completely react (4 hours), concentrating the reaction solution after the reaction is finished under reduced pressure, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product.
Light yellow liquid (73% yield);1H NMR(400MHz，CDCl3)：9.00(s，1H)，7.71(d，J＝8.0Hz，2H)，7.42(d，J＝7.6Hz，3H)，7.33-7.21(m，7H)，7.07(t，J＝7.6Hz，1H)，6.93(d，J＝7.6Hz，1H)，3.75-3.64(m，2H)，2.16(s，3H)；13C NMR(100MHz，CDCl3)：178.8，140.7，139.6，139.5，130.1，128.8，128.6，128.4，128.2，128.1，127.5，126.8，125.9，122.7，110.4，75.1，55.7，35.9；HRMS m/z(ESI)calcd for C22H21N2O([M+H]+)329.1648，found 329.1644。
example 12 Compounds
Synthesis of (2)
To a Schlenk reaction flask having a volume of 20mL were added 0.3mmol of 3-phenyl-2-indolone, 0.6mmol of N-methylaniline, and 0.06mmol of I20.6mmol of TBHP and dichloroethane (2mL), placing a reaction bottle at 60 ℃ under the condition of air atmosphere, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials completely react (4 hours), concentrating the reaction solution after the reaction is finished under reduced pressure, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product.
White solid (55% yield);1H NMR(400MHz，CDCl3)：8.12(s，1H)，7.59(d，J＝7.6Hz，2H)，7.37-7.27(m，5H)，7.06-7.02(m，3H)，6.95(d，J＝8.0Hz，2H)，6.87(t，J＝7.6Hz，1H)，6.78(d，J＝8.0Hz，1H)，2.92(s，3H)；13C NMR(100MHz，CDCl3)：178.3，149.4，140.0，139.2，130.6，128.9，128.5，128.2，128.1，127.8，126.3，124.0，122.8，122.6，110.2，74.2，39.3；HRMS m/z(ESI)calcd for C21H19N2O([M+H]+)315.1492，found 315.1488。
example 13 Compounds
Synthesis of (2)
To a Schlenk reaction flask having a volume of 20mL were added 0.3mmol of 3-phenyl-2-indolone, 0.6mmol of aniline, 0.06mmol of I20.6mmol of TBHP and dichloroethane (2mL), the reaction flask was placed at 60 ℃ under an air atmosphereStirring to react under the condition, monitoring the reaction process by TLC or GC until the raw materials completely react (4 hours), concentrating the reaction liquid after the reaction is finished under reduced pressure, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product.
White solid (83% yield);1H NMR(400MHz，CDCl3)：8.44(s，1H)，7.57(d，J＝8.0Hz，2H)，7.35(d，J＝6.8Hz，4H)，7.25(t，J＝8.0Hz，1H)，7.07-6.98(m，3H)，6.90(d，J＝7.6Hz，1H)，6.69(t，J＝7.2Hz，1H)，6.41(d，J＝8.0Hz，2H)，4.65(s，1H)；13C NMR(100MHz，CDCl3)：179.1，145.0，140.1，140.0，130.6，129.3，129.0(2)，128.7，126.5，125.5，123.2，119.2，115.3，110.7，68.3；HRMS m/z(ESI)calcd for C20H17N2O([M+H]+)301.1335，found301.1337。
example 14 Compounds
Synthesis of (2)
To a Schlenk reaction flask having a volume of 20mL were added 0.3mmol of 6-methyl-3-phenyl-2-indolone, 0.6mmol of morpholine, and 0.06mmol of I20.6mmol of TBHP and dichloroethane (2mL), placing a reaction bottle at 60 ℃ under the condition of air atmosphere, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials completely react (4 hours), concentrating the reaction solution after the reaction is finished under reduced pressure, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product.
White solid (91% yield);1H NMR(400MHz，CDCl3)：9.10(s，1H)，7.58(d，J＝7.2Hz，2H)，7.35-7.28(m，3H)，7.09(s，1H)，7.03(d，J＝8.0Hz，1H)，6.81(d，J＝8.0Hz，1H)，3.71(t，J＝7.6Hz，4H)，2.65(t，J＝7.6Hz，4H)，2.31(s，3H)；13C NMR(100MHz，CDCl3)：178.3，138.3(2)，132.2，129.3，129.2，128.6，128.0，127.7，126.8，110.2，74.7，67.5，47.6，21.3；HRMS m/z(ESI)calcd for C19H21N2O2([M+H]+)309.1598，found 309.1596。
example 15 Compounds
Synthesis of (2)
To a Schlenk reaction flask having a volume of 20mL were added 0.3mmol of 6-chloro-3-phenyl-2-indolone, 0.6mmol of morpholine, and 0.06mmol of I20.6mmol of TBHP and dichloroethane (2mL), placing a reaction bottle at 60 ℃ under the condition of air atmosphere, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials completely react (4 hours), concentrating the reaction solution after the reaction is finished under reduced pressure, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product.
White solid (63% yield);1H NMR(400MHz，CDCl3)：8.74(s，1H)，7.56(d，J＝6.8Hz，2H)，7.38-7.30(m，4H)，7.22(d，J＝8.0Hz，1H)，6.85(d，J＝8.0Hz，1H)，3.72(t，J＝7.6Hz，4H)，2.65(t，J＝8.0Hz，4H)；13C NMR(100MHz，CDCl3)：177.7，139.1，137.4，131.1，129.0，128.9，128.5，128.3，127.5，126.4，111.3，74.8，67.4，47.6；HRMS m/z(ESI)calcd forC18H18ClN2O2([M+H]+)329.1051，found 329.1053。
example 16 Compounds
Synthesis of (2)
To a Schlenk reaction flask having a volume of 20mL were added 0.3mmol of 3-methyl-2-indolone, 0.6mmol of morpholine, 0.06mmol of I20.6mmol of TBHP and dichloroethane (2mL), placing a reaction bottle at 60 ℃ under the condition of air atmosphere, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials completely react (4 hours), concentrating the reaction solution after the reaction is finished under reduced pressure, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product.
White solid (92% yield);1H NMR(400MHz，CDCl3)：8.71(s，1H)，7.30(d，J＝7.2Hz，1H)，7.23(t，J＝8.0Hz，1H)，7.06(t，J＝7.6Hz，1H)，6.90(d，J＝7.6Hz，1H)，3.69(t，J＝4.4Hz，4H)，2.70(t，J＝4.8Hz，4H)，1.54(s，3H)；13C NMR(100MHz，CDCl3)：180.3，140.3，131.7，128.7，124.2，122.8，110.1，67.4，66.6，47.1，21.5；HRMS m/z(ESI)calcd forC13H17N2O2([M+H]+)233.1285，found 233.1287。
example 17 Compounds
Synthesis of (2)
To a Schlenk reaction flask having a volume of 20mL were added 0.3mmol of N-methyl-3-phenyl-2-indolone, 0.6mmol of morpholine, and 0.06mmol of I20.6mmol of TBHP and dichloroethane (2mL), placing a reaction bottle at 60 ℃ under the condition of air atmosphere, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials completely react (4 hours), concentrating the reaction solution after the reaction is finished under reduced pressure, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain the target product.
White solid (49% yield);1H NMR(400MHz，CDCl3)：7.56(d，J＝7.6Hz，2H)，7.36-7.30(m，5H)，7.09(t，J＝7.6Hz，1H)，6.87(d，J＝8.0Hz，1H)，3.70(t，J＝6.8Hz，4H)，3.23(s，3H)，2.59(t，J＝8.0Hz，4H)；13C NMR(100MHz，CDCl3)：177.4，143.5，138.3，129.0，128.6，128.1，127.7，127.2，125.9，122.8，108.4，74.2，67.5，47.6，26.2；HRMS m/z(ESI)calcd for C19H21N2O2([M+H]+)309.1598，found 309.1594。
Claims (9)
1. the preparation method of the 3-amino-2-indolone compound is characterized in that the 2-indolone compound and amine are used as raw materials and are prepared by the following steps: adding a 2-indolone derivative shown in a formula 1a, an amine compound shown in a formula 2a and a catalyst I into a Schlenk reaction bottle2Placing a reaction bottle at 60 ℃ in an air atmosphere, stirring the reaction bottle in an oil bath for reaction, monitoring the reaction process by TLC or GC until the raw materials react completely, and carrying out aftertreatment to obtain a target product 3-amino-2-indolone compound shown in the formula I; the reaction formula is shown as follows:
in the raw material 2-indolone compound represented by the formula 1a and the product 3-amino-2-indolone compound represented by the formula I, R is1Represents 1 or more substituents on the phenyl ring to which it is attached, each R1Independently of one another, from hydrogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Acyl radical, C1-C6Ester group, halogen, cyano, nitro, C3-C6Cycloalkyl radical, C5-C14Aryl radical, C5-C14Heteroaryl, -NRaRb(ii) a Wherein R isa，RbIndependently of one another, from C1-C6Alkyl or hydrogen; the heteroatom of the heteroaryl group is selected from O, S or N;
R2is represented by C1-C6Alkyl, halogen, cyano, C3-C6Cycloalkyl radical, C5-C14Aryl radical, C5-C14A heteroaryl group; the heteroatom of the heteroaryl group is selected from O, S or N;
R3represents hydrogen, tert-butyloxycarbonyl (Boc), C1-C6Alkyl radical, C1-C6Acyl radical, C3-C6Cycloalkyl radical, C5-C14Aryl radical, C5-C14aryl-C1-C6Alkyl radical, C5-C14A heteroaryl group, the heteroatom of which is selected from O, S or N;
wherein each of the above alkyl, alkoxy, cycloalkyl, aryl and heteroaryl groups may be further substituted with a substituent selected from halogen or C1-C6Alkyl groups of (a);
the compound represented by the above formula 2a represents various amine compounds.
2. The method of claim 1, wherein R is1Represents 1 or more substituents on the phenyl ring to which it is attached, each R1Independently of one another, from hydrogen, C1-C6Alkyl, halogen, C1-C6Alkoxy, nitro, C5-C14An aryl group;
R2is represented by C1-C6Alkyl, halogen, cyano, C5-C14An aryl group;
R3represents hydrogen, tert-butyloxycarbonyl (Boc), C1-C6Alkyl radical, C1-C6Acyl, phenyl, benzyl; wherein said C1-C6Alkyl, phenyl, benzyl and/or C5-C14The aryl group may be further substituted, said substituents being selected from halogen or C1-C6Alkyl group of (1).
3. The method according to claim 1, wherein the organic solvent is selected from one or more of dichloroethane, dichloromethane, acetonitrile, tetrahydrofuran.
4. The method of claim 3, wherein the organic solvent is dichloroethane.
5. The method of claim 1, wherein the air atmosphere pressure is 1 atm.
6. The method according to claim 5, characterized in that the replacement of the air atmosphere is a nitrogen atmosphere.
7. The method according to claim 1, wherein the amine compound of formula 2a is added in an amount of 150 to 300 mol% based on the 2-indolone derivative of formula 1 a.
8. The method according to claim 7, wherein the amine compound of formula 2a is added in an amount of 200 mol% based on the amount of the 2-indolone derivative of formula 1 a.
9. The method of claim 1, wherein the post-processing operation is as follows: concentrating the reaction solution after the reaction is finished under reduced pressure, and separating the residue by column chromatography, wherein the elution solvent is as follows: ethyl acetate/n-hexane to obtain the target product 3-amido-2-indolone compound.
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