CN109748840B

CN109748840B - Synthetic method of 2-substituted indole derivative

Info

Publication number: CN109748840B
Application number: CN201811266846.4A
Authority: CN
Inventors: 肖志艳; 任龙; 汤雁波; 杨颖�
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2017-11-02
Filing date: 2018-10-29
Publication date: 2021-12-07
Anticipated expiration: 2038-10-29
Also published as: CN109748840A

Abstract

The invention relates to a synthesis method for preparing 2-substituted indole derivatives, which comprises the steps of mixing aromatic amine compounds (I), ketone compounds (II) and drying agents in an organic solvent, adding palladium catalysts, and reacting in an aerobic weak acid environment to obtain indole compounds (III), wherein the formula (I) is

(II) is

(III) is

Wherein R is¹Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted phenyl and pyridyl, and heterocyclic aryl; (I) pyridylamine, pyrimidinamine, pyridazinamine or pyrazinamine which may also be substituted or unsubstituted; the substituent is selected from one or more of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, amino,an amino group; r²Selected from C1-C6 alkyl, formate or C1-C6 alkylamide.

Description

Synthetic method of 2-substituted indole derivative

Technical Field

The invention relates to a method for directly preparing 2-substituted indole derivatives from aromatic amine under normal pressure.

Background

Indoles are one of the most common aromatic heterocyclic structures and synthetic building blocks, widely exist in natural products and human body physiologically active substances, are also important structural units commonly found in medicines and functional materials, and are called as 'dominant structures'. The synthesis of indoles and their functionalization methods have been continuously improving since the last century, given their importance in a variety of fields.

These synthetic methods can be broadly divided into two categories, namely equivalent reactions and catalytic reactions. There are many well-known reactions that fall into the equivalent class, such as Bartoli, Mori-Ban and the well-known Fischer indole synthesis. These methods have their own limitations and they have the common disadvantage that the reaction raw materials are generally not readily available and require a multi-step reaction synthesis.

Catalytic reaction type methods are developed rapidly in recent years, and among the methods, metal-catalyzed cross-dehydrogenation coupling reaction is one of the most convenient methods, and indole compounds can be prepared by taking imine or enamine which is synthesized by simple aniline and is relatively stable as a substrate, such as documents: S.W u rtz, S.Rakshit, J.J.Neumann, T.

Glorius, angelw, chem, int, ed, 2008,47,7230; y.wei, i.deb, n.yoshikai, j.am.chem. soc.2012,134, 9098. However, these methods still have the following limitations: 1. most methods need to use a large amount of copper salt as an oxidant, large-scale synthesis is not economical, and post-treatment is difficult; 2. indole can not be directly synthesized by one-step reaction of simple aromatic amine under aerobic condition, and relatively stable imine or enamine needs to be synthesized firstly; 3. in order to obtain a stable imine or enamine intermediate,often, specific groups introduced at the 2-and 3-positions of the indole are required, most of which are difficult to remove, reducing the flexibility for re-transformation or as a synthetic building block.

Disclosure of Invention

The invention aims to solve the problems in the prior art and provides a method for preparing 2-substituted indole derivatives from simple and easily-obtained aromatic amine in one step, which has the advantages of simple process, high yield, less waste discharge and easy industrialization.

In order to achieve the purpose, the invention provides a catalytic synthesis method for preparing 2-substituted indole derivatives, which is characterized in that an aromatic amine compound (I), a ketone compound (II) and a drying agent are mixed in an organic solvent, a palladium catalyst is added to react in an aerobic weak acid environment to prepare an indole compound (III),

(I) is composed of

(II) is

(III) is

Wherein R is¹Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted phenyl and pyridyl, and heterocyclic aryl; (I) pyridylamine, pyrimidinamine, pyridazinamine or pyrazinamine which may also be substituted or unsubstituted; the substituent is selected from one or more of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl and amino;

R²selected from C1-C6 alkyl, formate or C1-C6 alkanoylamino; the drying agent is a molecular sieve or no drying agent, and the palladium catalyst is palladium acetate, palladium trifluoroacetate or palladium tetratriphenylphosphine;

the organic solvent is dimethyl sulfoxide or N, N-dimethylformamide; the acidic environment is from acetic acid, pivalic acid or benzoic acid or none.

Wherein the reaction temperature is 10-130 ℃, and the preferable temperature is 70 ℃.

Wherein the reaction pressure is 1atm to 3atm, preferably 1 atm.

Wherein the drying agent is molecular sieve or non-molecular sieve, preferably powdery

And (3) a molecular sieve.

Wherein the palladium catalyst is palladium acetate, palladium trifluoroacetate or palladium tetratriphenylphosphine, and is preferably palladium acetate.

Wherein the organic solvent can be dimethyl sulfoxide or N, N-dimethylformamide, and is preferably dimethyl sulfoxide.

Wherein the weak acid is acetic acid, pivalic acid, benzoic acid or none, preferably acetic acid.

Wherein the molar ratio of the aromatic amine compound to the carbonyl compound is 1: 1-1: 10, the molar ratio of the aromatic amine compound to the palladium catalyst is 1: 1-50: 1, and the molar ratio of the aromatic amine compound to the weak acid is 1: 0-1: 20; preferably, the molar ratio of the aromatic amine compound to the carbonyl compound is 1:2, the molar ratio of the aromatic amine compound to the palladium catalyst is 10:1, and the molar ratio of the aromatic amine compound to the weak acid is 1: 4.

Compared with the prior art, the synthesis method of the 2-substituted indole derivative has the following advantages that:

1. the invention realizes the one-step synthesis from simple aromatic amine to 2-substituted indole for the first time in the atmospheric aerobic environment, and compared with the existing synthesis method which needs to form a more stable imine or enamine intermediate, the application range is expanded;

2. the 3-position of the synthesized indole is active hydrogen, and the 2-position is ester group or other groups (such as alkyl group) which are easy to remove and convert, thereby retaining the flexibility of reconversion of the indole or serving as a synthetic building block;

3. compared with the traditional synthetic method, the method has the advantages of simple process, high yield, less waste discharge, easy industrial production and the like, and passes gram-scale synthetic tests with high yield.

Detailed Description

The above and further features and advantages of the present invention are explained in more detail below with reference to examples.

EXAMPLE 15 Synthesis of Ethyl-methoxy-1H-indole-2-carboxylate

a) The method comprises the following steps A25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure 5-methoxy-1H-indole-2-ethyl formate product of 75mg with the yield of 86%.

b) The method comprises the following steps A25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ under atmospheric pressure and air for 18 hours. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain 75mg of a pure 5-methoxy-1H-indole-2-ethyl formate product with the yield of 72%.

c) The method comprises the following steps A25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under two atmospheric pressure oxygen conditions. After the reaction is finished, 15mL of diluted reaction solution is added, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, the water phase is extracted for 1 time by ethyl acetate, the organic phase is combined, and the 5-methoxy-1H-indole-2-ethyl formate pure product of 75mg is obtained through column chromatography separation, wherein the yield is 87%.

d) The method comprises the following steps A25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieve 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under three atmospheric pressure oxygen conditions. After the reaction is finished, 15mL of diluted reaction solution is added, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, the water phase is extracted for 1 time by ethyl acetate, the organic phase is combined, and the 5-methoxy-1H-indole-2-ethyl formate pure product of 75mg is obtained through column chromatography separation, wherein the yield is 91%.

e) The method comprises the following steps A25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 50 ℃ for 18 hours. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure 5-methoxy-1H-indole-2-ethyl formate product of 75mg with the yield of 80%.

f) The method comprises the following steps A25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieve 80mg, injecting ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL, connecting with 200mL oxygen balloon, stirring at 90 deg.CStirring for 18 hours. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure 5-methoxy-1H-indole-2-ethyl formate product of 75mg with the yield of 76%.

g) The method comprises the following steps A25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, followed by stirring at 120 ℃ for 18 hours. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is used for washing for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure 5-methoxy-1H-indole-2-ethyl formate product of 75mg with the yield of 44%.

h) The method comprises the following steps A25 mL Schlenk reaction tube was charged with 49mg of p-anisidine and 9mg of palladium acetate, 93mg of ethyl 2-oxopropionate, 96mg of acetic acid and 2mL of dimethyl sulfoxide were injected, and the mixture was stirred at 70 ℃ for 18 hours in a 200mL oxygen balloon. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of saline is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain 75mg of a pure 5-methoxy-1H-indole-2-ethyl formate product with the yield of 67%.

i) The method comprises the following steps A25 mL Schlenk reaction tube was taken, and 49mg of p-anisidine, 12mg of palladium trifluoroacetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is used for washing for 2 times after the reaction is finished, an organic phase is separated, an aqueous phase is extracted for 1 time by ethyl acetate, the organic phases are combined, and the pure 5-methoxy-1H-indole-2-ethyl formate product is obtained by column chromatography separation, wherein the yield is 66%.

j) The method comprises the following steps A25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg, dimethyl sulfoxide 0.3 mL and N, N-dimethylformamide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200 mL-sized oxygen balloon. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain 75mg of a pure 5-methoxy-1H-indole-2-ethyl formate product with the yield of 21%.

k) The method comprises the following steps A25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, trimethylacetic acid 96mg and dimethylsulphoxide 2mL were injected, followed by a 200mL oxygen balloon and stirred at 70 ℃ for 18 hours. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain 75mg of a pure 5-methoxy-1H-indole-2-ethyl formate product with the yield of 82%.

l): a25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours in a 200mL oxygen balloon. After the reaction is finished, 15mL of diluted reaction solution is added, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, the water phase is extracted for 1 time by ethyl acetate, the organic phase is combined, and the 5-methoxy-1H-indole-2-ethyl formate pure product of 75mg is obtained through column chromatography separation, wherein the yield is 64%.

m): a25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 70 ℃ for 12 hours. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure 5-methoxy-1H-indole-2-ethyl formate product of 75mg with the yield of 80%.

n): a25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 70 ℃ for 24 hours. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain 75mg of a pure 5-methoxy-1H-indole-2-ethyl formate product with the yield of 75%.

o): a25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 90 ℃ for 6 hours. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of saline is used for washing for 2 times after filtration, an organic phase is separated, a water phase is extracted for 1 time by using ethyl acetate, the organic phase is combined, and column chromatography separation is carried out to obtain 75mg of a pure 5-methoxy-1H-indole-2-ethyl formate product with the yield of 76%.

p): a25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieve 80mg, injectingEthyl 2-oxopropionate 55mg, acetic acid 96mg and dimethyl sulfoxide 2mL, followed by a 200mL oxygen balloon were stirred at 70 ℃ for 18 hours. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain 75mg of a pure 5-methoxy-1H-indole-2-ethyl formate product with the yield of 72%.

q): a25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 460mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 70 ℃ for 18 hours. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain 75mg of a pure 5-methoxy-1H-indole-2-ethyl formate product with the yield of 30%.

r): a25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 2mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure 5-methoxy-1H-indole-2-ethyl formate product of 75mg with the yield of 10%.

s): a25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 5mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. After the reaction is finishedAdding 15mL of ethyl acetate to dilute the reaction solution, filtering, washing with 10mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain a pure 5-methoxy-1H-indole-2-ethyl formate product of 75mg with the yield of 63%.

t): a25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 170mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain 75mg of a pure 5-methoxy-1H-indole-2-ethyl formate product with the yield of 74%.

u): gram-scale amplification: a250 mL three-necked flask was charged with p-anisidine 1.23g, palladium acetate 0.22g and

molecular sieves 1.00g, 2.32g of ethyl 2-oxopropionate, 0.6g of acetic acid and 100mL of dimethylsulfinyl ether were charged, followed by stirring with a 200 mL-sized oxygen balloon at 70 ℃ for 18 hours. After the reaction is finished, 200mL of ethyl acetate is added to dilute the reaction solution, 100mL of saline water is washed for 2 times after filtration, an organic phase is separated, a water phase is extracted for 1 time by ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain 1.95g of a pure 5-methoxy-1H-indole-2-ethyl formate product with the yield of 89%.

¹H NMR(400MHz,Chloroform-d)δ:9.05(brs,1H),7.31(d,J＝8.9,1H), 7.16–7.13(m,1H),7.07(d,J＝2.4,1H),6.99(dd,J＝8.9,2.4,1H),4.41(q,J＝ 7.1,2H),3.85(s,3H),1.41(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ: 162.18,154.81,132.39,128.00,127.96,117.08,112.92,108.32,102.66,61.10, 55.80,14.53。

EXAMPLE 27 Synthesis of Ethyl-methoxy-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was charged with 49mg of o-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 74mg of the target product, wherein the yield is 85%.

¹H NMR(400MHz,Chloroform-d)δ:9.17(brs,1H),7.26(d,J＝8.1,1H), 7.19(d,J＝2.2,1H),7.04(t,J＝7.9,1H),6.69(d,J＝7.6,1H),4.39(q,J＝7.1, 2H),3.93(s,3H),1.39(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ: 161.91,146.57,128.74,128.18,127.34,121.23,114.86,108.89,104.16,61.02, 55.45,14.48。

EXAMPLE 35 Synthesis of Ethyl-tert-butyl-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was charged with p-tert-butylaniline 60mg, palladium acetate 9mg and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a target product pure product 74mg with the yield of 76%.

¹H NMR(400MHz,Chloroform-d)δ:9.22(brs,1H),7.67–7.63(m,1H),7.41 (dd,J＝8.8,1.8,1H),7.35(dt,J＝8.8,0.8,1H),7.19(dd,J＝2.1,0.9,1H),4.41(q, J＝7.1,2H),1.41(t,J＝7.1,3H),1.37(s,9H)；¹³C NMR(101MHz,Chloroform-d) δ:162.44,143.72,135.38,127.60,127.47,124.20,118.03,111.59,108.88,61.08, 34.74,31.82,14.52。

EXAMPLE synthesis of 45-methyl-1H-indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was charged with p-methylaniline 43mg, palladium acetate 9mg and

molecular sieves 80mg were charged with 93mg of ethyl 2-oxopropionate, 96mg of acetic acid and 2mL of dimethyl sulfoxide, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 63mg of the target product, wherein the yield is 78%.

3da:white solid；¹H NMR(400MHz,Chloroform-d)δ:9.05(brs,1H),7.47– 7.43(m,1H),7.31(d,J＝8.4,1H),7.17–7.11(m,2H),4.41(q,J＝7.1,2H),2.43 (s,3H),1.41(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ:162.33,135.45, 130.16,127.88,127.60,127.41,121.94,111.68,108.25,61.09,21.54,14.53。

Example Synthesis of ethyl 55-cyclohexyl-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was charged with p-cyclohexylaniline 70mg, palladium acetate 9mg and

molecular sieve 80mg, 93mg of ethyl 2-oxopropionate, 96mg of acetic acid and 2mL of dimethyl sulfoxide were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200 mL-sized oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 81mg of the target product with the yield of 75%.

¹H NMR(400MHz,Chloroform-d)δ:9.00(brs,1H),7.50–7.47(m,1H),7.33 (d,J＝8.5,1H),7.20(dd,J＝8.6,1.6,1H),7.17(dd,J＝2.1,0.9,1H),4.41(q,J＝ 7.1,2H),2.57(td,J＝11.5,3.3,1H),1.89(dd,J＝26.8,11.9,4H),1.76(d,J＝13.8, 1H),1.52–1.36(m,7H),1.33–1.21(m,1H)；¹³C NMR(101MHz,Chloroform-d) δ:162.31,140.86,135.72,127.80,127.61,125.60,119.61,111.70,108.60,61.07, 44.71,35.09,27.18,26.38,14.53。

Example 61 Synthesis of H-indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was taken, and 37mg of aniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of saline is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phase is combined, and column chromatography separation is carried out to obtain a pure product 54mg of a target product, wherein the yield is 71%.

¹H NMR(400MHz,Chloroform-d)δ:8.92(brs,1H),7.69(d,J＝8.2,1H), 7.42(d,J＝8.2,1H),7.32(t,J＝7.7,1H),7.25–7.21(m,1H),7.15(t,J＝7.6,1H), 4.42(q,J＝7.1,2H),1.42(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ: 162.37,137.08,127.60,125.42,122.69,120.86,112.05,112.01,108.76,61.19, 14.51。

EXAMPLE 71 Synthesis of H-benzo [ g ] indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was taken, and 57mg of 1-naphthylamine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 70 ℃ for 24 hours. And after the reaction is finished, 15mL of diluted reaction solution is added, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, a water phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a target product pure product 79mg with the yield of 82%.

¹H NMR(400MHz,Chloroform-d)δ:10.33(brs,1H),8.29(d,J＝7.5,1H), 7.90(d,J＝7.5,1H),7.66(d,J＝8.7,1H),7.56–7.46(m,3H),7.34(d,J＝2.1, 1H),4.50(q,J＝7.1,2H),1.46(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d) δ:162.54,133.20,132.12,128.98,125.98,125.93,125.67,123.94,122.18,122.07, 121.41,120.91,110.35,61.27,14.64。

EXAMPLE synthesis of ethyl 85-hydroxy-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was taken, and 44mg of p-hydroxyaniline, 9mg of palladium acetate and

molecular sieves 80mg were charged with 93mg of ethyl 2-oxopropionate, 96mg of acetic acid and 2mL of dimethyl sulfoxide, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, and an aqueous phase is extracted for 1 time by ethyl acetateAnd combining organic phases, and performing column chromatography separation to obtain a target product pure product of 28mg with a yield of 34%.

¹H NMR(400MHz,Chloroform-d)δ:8.86(brs,1H),7.29(d,J＝8.8,1H), 7.13–7.08(m,1H),7.06(d,J＝2.2,1H),6.93(dd,J＝8.8,2.4,1H),4.82(brs,1H), 4.40(q,J＝7.1,2H),1.41(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ: 162.17,150.28,132.48,128.40,128.25,116.29,112.86,108.03,106.05,61.21, 14.53。

EXAMPLE synthesis of 95-hydroxymethyl-1H-indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was charged with 49mg of 4-hydroxymethylaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 55mg of a target product, wherein the yield is 63%.

¹H NMR(400MHz,DMSO-d₆)δ:11.81(brs,1H),7.58(s,1H),7.41(d,J＝8.5, 1H),7.24(d,J＝8.4,1H),7.12(s,1H),5.10(t,J＝5.6,1H),4.55(d,J＝5.5,2H), 4.34(q,J＝7.0,2H),1.34(t,J＝7.0,3H)；¹³C NMR(101MHz,DMSO-d₆)δ: 161.41,136.67,134.44,127.47,126.60,124.51,119.69,112.29,107.73,63.53, 60.43,14.37。

EXAMPLE 105 Synthesis of Ethyl phenyl-1H-indole-2-carboxylate

Taking a 25mL Schlenk reaction tube, adding68mg of 4-phenylaniline, 9mg of palladium acetate and

molecular sieves 80mg were charged with 93mg of ethyl 2-oxopropionate, 96mg of acetic acid and 2mL of dimethyl sulfoxide, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of saline is used for washing for 2 times after filtration, an organic phase is separated, a water phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product of the target product of 40mg, wherein the yield is 38%.

¹H NMR(400MHz,Chloroform-d)δ:9.05(brs,1H),7.90–7.87(m,1H),7.66 –7.61(m,2H),7.58(dd,J＝8.6,1.7,1H),7.50–7.42(m,3H),7.35–7.30(m,1H), 7.27(dd,J＝2.1,0.9,1H),4.43(q,J＝7.1,2H),1.43(t,J＝7.1,3H)；¹³C NMR (101MHz,Chloroform-d)δ:162.11,141.99,136.44,134.51,128.87,128.28,128.17, 127.46,126.82,125.53,120.96,112.26,109.08,61.25,14.55。

Example Synthesis of ethyl 115-phenoxy-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was charged with 74mg of 4-phenoxyaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 63mg of the target product, wherein the yield is 56%.

¹H NMR(400MHz,Chloroform-d)δ:9.24(brs,1H),7.40(d,J＝8.9,1H), 7.34–7.26(m,3H),7.16(dd,J＝2.1,0.9,1H),7.09(dd,J＝8.9,2.3,1H),7.07– 7.02(m,1H),7.00–6.95(m,2H),4.42(q,J＝7.1,2H),1.42(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ:162.16,158.86,151.01,133.98,129.74,128.67, 128.16,122.53,119.59,117.84,113.14,112.14,108.57,61.28,14.51。

Example Synthesis of 125-Methanesulfonylamino-1H-indole-2-carboxylic acid Ethyl ester

A25 mL Schlenk reaction tube was taken, and 75mg of 4-methanesulfonamidoaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 73mg of the target product, wherein the yield is 65%.

¹H NMR(400MHz,DMSO-d₆)δ:11.93(s,1H),9.44(s,1H),7.52(d,J＝1.8, 1H),7.42(d,J＝8.8,1H),7.18(dd,J＝8.8,2.0,1H),7.14(d,J＝1.4,1H),4.33(q, J＝7.1,2H),2.89(s,3H),1.33(t,J＝7.1,3H)；¹³C NMR(101MHz,DMSO-d₆)δ: 161.24,135.15,130.96,128.28,126.96,121.08,114.68,113.26,107.68,60.57, 38.53,14.36。

Example Synthesis of Ethyl 131, 6-dihydropyrrolo [2,3-e ] indole-2-carboxylate

A25 mL Schlenk reaction tube was taken, and 53mg of 1H-indol-4-amine, 9mg of palladium acetate and

molecular Sieve 80mg, injection of ethyl 2-oxopropionate93mg, acetic acid 96mg and dimethyl sulfoxide 2mL, followed by a 200mL oxygen balloon, were stirred at 70 ℃ for 18 hours. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 14mg of the target product, wherein the yield is 15%.

¹H NMR(400MHz,Chloroform-d)δ:9.29(brs,1H),8.46(brs,1H),7.44(d,J ＝8.7,1H),7.33(d,J＝2.1,1H),7.23(d,J＝8.7,1H),7.21–7.18(m,1H),6.77– 6.73(m,1H),4.43(q,J＝7.1,2H),1.43(t,J＝7.1,3H)；¹³C NMR(101MHz, Chloroform-d)δ:162.41,134.42,131.10,124.46,122.32,121.10,117.06,113.02, 110.59,107.44,99.82,60.80,14.65。

EXAMPLE 145 Synthesis of fluoro-1H-indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was taken, and 44mg of p-fluoroaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product of a target product of 48mg, wherein the yield is 58%.

¹H NMR(400MHz,Chloroform-d)δ:9.24(brs,1H),7.36(dd,J＝8.9,4.4, 1H),7.31(dd,J＝9.2,2.5,1H),7.18(dd,J＝2.1,0.7,1H),7.08(td,J＝9.1,2.5, 1H),4.43(q,J＝7.1,2H),1.42(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d) δ:162.10,158.28(d,J＝236.6),133.66,129.13,127.75(d,J＝10.4),114.55(d,J ＝27.0),112.98(d,J＝9.5),108.56(d,J＝5.4),106.85(d,J＝23.3),61.36,14.49。

Example 157 Synthesis of fluoro-1H-indole-2-carboxylic acid Ethyl ester

A25 mL Schlenk reaction tube was taken, and 44mg of o-fluoroaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product of the target product of 24mg, wherein the yield is 29%.

¹H NMR(400MHz,Chloroform-d)δ:9.34(brs,1H),7.44(d,J＝8.0,1H), 7.27–7.22(m,1H),7.09–6.97(m,2H),4.44(q,J＝7.1,2H),1.43(t,J＝7.1,3H)； ¹³C NMR(101MHz,Chloroform-d)δ:161.81,149.77(d,J＝245.9),130.98(d,J＝ 4.8),128.56(d,J＝1.3),125.88(d,J＝13.8),121.00(d,J＝5.8),118.37(d,J＝ 4.0),109.66(d,J＝15.7),109.08(d,J＝2.6),61.45,14.50。

Example 165 Synthesis of acetyl-1H-indole-2-carboxylic acid Ethyl ester

A25 mL Schlenk reaction tube was taken, and 54mg of p-acetanilide, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 70 ℃ for 24 hours. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, and an aqueous phase is extracted by ethyl acetate1 time, combining organic phases, and performing column chromatography separation to obtain a pure product 23mg of a target product, wherein the yield is 25%.

¹H NMR(400MHz,Chloroform-d)δ:9.48(brs,1H),8.38–8.35(m,1H),7.99 (dd,J＝8.8,1.7,1H),7.47(d,J＝8.8,1H),7.33(dd,J＝2.0,0.9,1H),4.45(q,J＝ 7.1,2H),2.67(s,3H),1.44(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ: 198.01,161.83,139.33,130.99,129.26,127.08,125.24,125.13,112.10,110.20, 61.53,26.72,14.50。

Example Synthesis of 175-chloro-1H-indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was taken, and 51mg of p-chloroaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 55mg of a target product, wherein the yield is 62%.

¹H NMR(400MHz,Chloroform-d)δ:9.19(brs,1H),7.66(s,1H),7.35(d,J＝ 8.8,1H),7.26(dd,J＝8.6,2.2,1H),7.15(dd,J＝2.1,0.9,1H),4.43(q,J＝7.1, 2H),1.42(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ:161.95,135.24, 128.87,128.53,126.57,125.96,121.87,113.14,108.08,61.43,14.50。

Example Synthesis of 187-chloro-1H-indole-2-carboxylic acid Ethyl ester

A25 mL Schlenk reaction tube was taken, and 51mg of o-chloroaniline and palladium acetate were added9mg and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 15mg of the target product, wherein the yield is 17%.

¹H NMR(400MHz,Chloroform-d)δ:9.04(brs,1H),7.59(d,J＝8.1,1H), 7.32(dd,J＝7.6,0.8,1H),7.25(d,J＝2.2,1H),7.11–7.06(m,1H),4.43(q,J＝ 7.1,2H),1.43(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ:161.63, 134.33,128.85,128.39,124.56,121.61,121.29,117.36,109.44,61.43,14.53。

Example Synthesis of ethyl 195-bromo-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was taken, and 69mg of p-bromoaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product of the target product of 50mg, wherein the yield is 47%.

¹H NMR(400MHz,Chloroform-d)δ:9.14(brs,1H),7.84–7.81(m,1H),7.39 (dd,J＝8.8,1.9,1H),7.30(d,J＝8.8,1H),7.15(dd,J＝2.1,0.9,1H),4.42(q,J＝ 7.1,2H),1.42(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ:161.89, 135.46,129.22,128.71,128.44,125.06,114.07,113.51,107.94,61.45,14.51。

Example 201 Synthesis of diethyl H-indole-2, 5-dicarboxylate

A25 mL Schlenk reaction tube was charged with 66mg of ethyl 4-aminobenzoate, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 70 ℃ for 24 hours. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 35mg of the target product, wherein the yield is 34%.

¹H NMR(400MHz,Chloroform-d)δ:9.44(brs,1H),8.49–8.46(m,1H),8.02 (dd,J＝8.7,1.6,1H),7.45(dt,J＝8.7,0.8,1H),7.31(dd,J＝2.1,0.9,1H),4.44(q, J＝7.1,2H),4.41(q,J＝7.1,2H),1.43(t,J＝7.1,3H),1.42(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ:167.32,161.94,139.27,129.05,127.13,126.37, 125.84,123.48,111.77,109.93,61.48,60.94,14.56,14.50。

Example 215 Synthesis of Ethyl-cyano-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was charged with 47mg of 4-aminobenzonitrile, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 139mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was connected, and the mixture was stirred at 70 ℃ for 3 days. After the reaction, 15mL of ethyl acetate was added to dilute the reaction mixture, followed by filtration to give brine 1Washing with 0mL for 2 times, separating out an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain a pure product 19mg of a target product with the yield of 22%.

¹H NMR(400MHz,Chloroform-d)δ:9.27(brs,1H),8.10–8.05(m,1H),7.56 –7.49(m,2H),7.28(d,J＝2.0,1H),4.45(q,J＝7.1,2H),1.44(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ:161.47,138.09,129.91,128.69,127.70,127.26, 120.13,113.10,108.99,104.45,61.77,14.48。

Example Synthesis of 225-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was taken, and 64mg of p-trifluoromethylaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 139mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was connected, and the mixture was stirred at 70 ℃ for 2 days. And after the reaction is finished, adding 15mL of ethyl acetate to dilute the reaction solution, filtering, washing with 10mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain a pure target product of 40mg with the yield of 39%.

¹H NMR(400MHz,Chloroform-d)δ:9.47(brs,1H),8.03–7.98(m,1H),7.56 –7.49(m,2H),7.30(dd,J＝2.0,0.6,1H),4.46(q,J＝7.1,2H),1.44(t,J＝7.1, 3H)；¹³C NMR(101MHz,Chloroform-d)δ:161.94,138.06,129.34,126.80,125.01 (q,J＝282.0),δ:123.50(q,J＝42.5),121.92(q,J＝3.2),120.63(q,J＝4.4), 112.55,109.36,61.63,14.49。

Example 235 Synthesis of Trifluoromethoxy-1H-indole-2-carboxylic acid Ethyl ester

A25 mL Schlenk reaction tube was taken, and 71mg of 4-trifluoromethoxyaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 80 ℃ for 24 hours. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 65mg of the target product with the yield of 60%.

¹H NMR(400MHz,Chloroform-d)δ:9.21(brs,1H),7.56–7.52(m,1H),7.42 (dt,J＝8.9,0.7,1H),7.22(dd,J＝2.1,0.9,1H),7.20(ddd,J＝8.9,2.3,0.8,1H), 4.44(q,J＝7.1,2H),1.43(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ: 161.89,143.72,135.15,129.42,127.64,120.89(q,J＝256.0),119.73,114.76, 112.92,108.85,61.49,14.49。

EXAMPLE 245 Synthesis of carbamoyl-1H-indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was taken, and 54mg of 4-aminobenzamide, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 70 ℃ for 24 hours. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 66mg of the target product, wherein the yield is 71%.

¹H NMR(400MHz,DMSO-d₆)δ:12.10(s,1H),8.31–8.25(m,1H),7.91(s, 1H),7.81(dd,J＝8.7,1.7,1H),7.46(d,J＝8.7,1H),7.23(dd,J＝2.1,0.8,1H), 7.19(brs,1H),4.35(q,J＝7.1,2H),1.34(t,J＝7.1,3H)；¹³C NMR(101MHz, DMSO-d₆)δ:168.53,161.10,138.72,128.63,126.66,126.09,124.20,122.43, 112.01,108.69,60.62,14.29。

Example Synthesis of 256-methoxy-1H-indole-2-carboxylic acid Ethyl ester

A25 mL Schlenk reaction tube was charged with 49mg of 3-methoxyaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 66mg of the target product, wherein the yield is 75%.

¹H NMR(400MHz,Chloroform-d)δ:9.18(brs,1H),7.53(d,J＝8.5,1H), 7.17(s,1H),6.84–6.79(overlap,2H),4.40(q,J＝7.1,2H),3.83(s,3H),1.40(t,J ＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ:162.31,158.94,138.17,126.50, 123.45,121.96,112.38,109.13,93.87,60.93,55.55,14.55。

Example gram Synthesis of 266-methoxy-1H-indole-2-carboxylic acid Ethyl ester

A100 mL three-necked flask was taken, and 0.44g of palladium acetate and

2.00g of molecular sieve, injecting 2.46g of 3-methoxyaniline, 4.64g of ethyl 2-oxopropionate, 1.20g of acetic acid and 20mL of dimethyl sulfoxide, and adding 200mL of sodium bicarbonateA small oxygen balloon was stirred at 70 ℃ for 18 hours. After the reaction is finished, adding 80mL of ethyl acetate to dilute the reaction solution, filtering, washing with 40mL of saline for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain: 3.55g of a pure 6-methoxy-1H-indole-2-ethyl formate product, wherein the yield is 81 percent; the pure product of the 4-methoxy-1H-indole-2-ethyl formate is 0.15g, and the yield is 3 percent.

4-methoxy-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,Chloroform-d)δ:9.26 (brs,1H),7.35(s,1H),7.22(t,J＝8.2,1H),7.01(d,J＝8.3,1H),6.49(d,J＝7.8, 1H),4.41(q,J＝7.1,1H),3.94(s,3H),1.40(t,J＝7.1,2H)；¹³C NMR(101MHz, Chloroform-d)δ:162.24,154.73,138.41,126.46,126.31,119.10,106.49,104.99, 99.83,61.06,55.45,14.50。

EXAMPLE 274 Synthesis of ethyl 6-dimethoxy-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was charged with 61mg of 3, 5-dimethoxyaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 9 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 77mg of a target product, wherein the yield is 77%.

¹H NMR(400MHz,Chloroform-d)δ:9.06(brs,1H),7.26(dd,J＝2.2,0.8, 1H),6.43(dd,J＝1.8,0.8,1H),6.18(d,J＝1.8,1H),4.38(q,J＝7.1,2H),3.90(s, 3H),3.82(s,3H),1.39(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ: 162.20,160.34,155.15,138.76,125.04,113.95,106.92,92.76,86.31,60.80,55.66, 55.49,14.54。

Example 286 Synthesis of tert-butyl-1H-indole-2-carboxylic acid Ethyl ester

A25 mL Schlenk reaction tube was charged with 60mg of 3-tert-butylaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 70 ℃ for 12 hours. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product of the target product of 80mg, wherein the yield is 82%.

¹H NMR(400MHz,Chloroform-d)δ:9.29(brs,1H),7.60(d,J＝8.5,1H), 7.41(s,1H),7.23(d,J＝8.6,1H),7.18(s,1H),4.43(q,J＝7.1,2H),1.42(t,J＝ 7.1,3H),1.37(s,9H)；¹³C NMR(101MHz,Chloroform-d)δ:162.52,149.07, 137.47,127.26,125.31,122.07,119.63,108.52,108.00,61.05,35.14,31.63,14.54。

Example 296 Synthesis of methyl-1H-indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was charged with 43mg of 3-methylaniline, 9mg of palladium acetate and

molecular sieves 80mg were charged with 93mg of ethyl 2-oxopropionate, 96mg of acetic acid and 2mL of dimethyl sulfoxide, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. Adding 15mL of ethyl acetate to dilute the reaction solution after the reaction is finished, filtering, washing with 10mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain a target product, namely a pure product 64mg, wherein the yield is 79％。

¹H NMR(400MHz,Chloroform-d)δ:9.10(brs,1H),7.56(dd,J＝8.2,2.7, 1H),7.22–7.17(m,2H),6.98(d,J＝8.2,1H),4.40(q,J＝7.2,2H),2.46(s,3H), 1.41(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ:162.43,137.50,135.65, 127.03,125.51,123.02,122.29,111.70,108.79,61.06,22.12,14.55。

Example Synthesis of Ethyl 304, 6-dimethyl-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was charged with 48mg of 3, 5-dimethylaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 24mg and dimethyl sulfoxide 3mL were injected, and the mixture was stirred at 70 ℃ for 36 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure target product of 44mg, wherein the yield is 51%.

¹H NMR(400MHz,Chloroform-d)δ＝9.00(brs,1H),7.22(s,1H),7.02(s, 1H),6.78(s,1H),4.41(q,J＝7.1,2H),2.51(s,3H),2.42(s,3H),1.41(t,J＝7.1,3H)； ¹³C NMR(101MHz,Chloroform-d)δ＝162.39,137.41,135.87,131.93,126.36, 125.79,123.03,109.17,107.45,61.00,22.05,18.67,14.56。

Example Synthesis of Ethyl 314, 7-dimethyl-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was charged with 48mg of 2, 5-dimethylaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 70 ℃ for 24 hours. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 14mg of the target product, wherein the yield is 16%.

¹H NMR(400MHz,Chloroform-d)δ:8.80(brs,1H),7.27(d,J＝2.2,1H),7.01 (d,J＝7.1,1H),6.86(d,J＝7.1,1H),4.42(q,J＝7.1,2H),2.53(s,3H),2.48(s, 3H),1.43(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ:162.34,136.57, 129.88,127.43,126.77,125.81,120.98,118.63,107.92,61.13,18.54,16.59,14.59。

Example 326 Synthesis of phenyl-1H-indole-2-carboxylic acid Ethyl ester

A25 mL Schlenk reaction tube was taken and [1,1' -biphenyl ] was added]68mg of 3-amine, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 80 ℃ for 24 hours. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product of the target product of 75mg, wherein the yield is 71%.

¹H NMR(400MHz,Chloroform-d)δ:9.22(brs,1H),7.73(d,J＝8.4,1H), 7.62(t,J＝8.6,3H),7.43(q,J＝8.3,7.9,3H),7.34(t,J＝7.3,1H),7.23(d,J＝7.9, 1H),4.43(q,J＝7.1,2H),1.42(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d) δ:162.24,141.78,138.86,137.58,128.91,128.08,127.50,127.26,126.88,122.91, 121.03,110.29,108.66,61.25,14.54。

EXAMPLE 335 Synthesis of ethyl H- [1,3] methylenedioxo [4,5-f ] indole-6-carboxylate and ethyl 6H- [1,3] methylenedioxo [4,5-e ] indole-7-carboxylate

A25 mL Schlenk reaction tube was charged with 55mg of 3, 4-methylenedioxyaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 9 hours under a 200mL oxygen balloon. After the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of filtered saline is washed for 2 times, an organic phase is separated, an aqueous phase is extracted for 1 time by ethyl acetate, the organic phase is combined, and column chromatography separation is carried out to obtain: 5H- [1,3]Methylenedioxo [4, 5-f)]The pure indole-6-ethyl formate product is 41mg, and the yield is 44%; 6H- [1,3]Methylenedioxo [4,5-e ]]36mg of pure indole-7-ethyl formate, and the yield is 39%.

5H-[1,3]Methylenedioxo [4, 5-f)]Indole-6-carboxylic acid ethyl ester:¹H NMR(400MHz, Chloroform-d)δ:9.17(brs,1H),7.10(s,1H),6.98(s,1H),6.83(s,1H),5.96(s,2H), 4.39(q,J＝7.1,2H),1.40(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ: 162.05,148.01,144.25,132.96,126.32,121.80,109.15,101.13,99.91,91.99,60.91, 14.57；6H-[1,3]methylenedioxo [4,5-e ]]Indole-7-carboxylic acid ethyl ester:¹H NMR(400MHz, Chloroform-d)δ:9.07(brs,1H),7.13(s,1H),6.97(d,J＝8.6,1H),6.90(d,J＝8.6, 1H),6.04(s,2H),4.42(q,J＝7.1,2H),1.41(t,J＝7.1,3H)；¹³C NMR(101MHz, Chloroform-d)δ:161.96,140.48,139.49,135.08,128.93,113.92,108.55,103.77, 103.63,101.28,61.33,14.49。

example 346 Synthesis of Ethyl-nitro-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was charged with 55mg of 3-nitroaniline, 9mg of palladium acetate and

molecular sieves 80mg were charged with ethyl 2-oxopropionate 232mg, acetic acid 96mg and dimethyl sulfoxide 2mL, followed by 200mL oxygen balloon and stirring at 90 ℃ for 48 hours. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of saline is used for washing for 2 times after filtration, an organic phase is separated, a water phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and the pure product 15mg of the target product is obtained through column chromatography separation, wherein the yield is 16%.

¹H NMR(400MHz,Chloroform-d)δ:9.43(brs,1H),8.42(s,1H),8.05(dd,J＝ 8.9,2.0,1H),7.78(d,J＝8.9,1H),7.29(dd,J＝2.0,1.0,1H),4.48(q,J＝7.1,2H), 1.45(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ:161.28,145.73,135.16, 132.63,132.02,123.09,116.05,108.93,108.49,61.99,14.48。

Example 356 Synthesis of Ethyl trifluoromethyl-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was taken, and 64mg of 3-trifluoromethylaniline, 9mg of palladium acetate and

molecular sieves 80mg, 139mg of ethyl 2-oxopropionate, 96mg of acetic acid and 2mL of dimethyl sulfoxide were injected, and the mixture was stirred at 80 ℃ for 36 hours under a 200 mL-sized oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by ethyl acetate, the organic phases are combined, and the pure product 21mg of the target product is obtained through column chromatography separation, wherein the yield is 20%.

¹H NMR(400MHz,Chloroform-d)δ:9.30(brs,1H),7.79(d,J＝8.4,1H), 7.74(s,1H),7.38(dd,J＝8.4,1.0,1H),7.28–7.26(m,1H),4.45(q,J＝7.1,2H), 1.44(t,J＝7.1,3H)；¹³C NMR(101MHz,Chloroform-d)δ:161.74,135.61,130.10, 129.74,127.36(q,J＝32.2),124.84(q,J＝272.5),123.36,117.45(q,J＝3.4), 109.73(q,J＝4.6),108.44,61.64,14.50。

EXAMPLE 366-chloro-1H-indole-2-carboxylic acid ethyl ester Synthesis with 4-chloro-1H-indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was charged with 51mg of 3-chloroaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 70 ℃ for 24 hours. And after the reaction is finished, adding 15mL of ethyl acetate to dilute the reaction solution, filtering, washing with 10mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain: the pure product of the 6-chloro-1H-indole-2-ethyl formate is 33mg, and the yield is 37 percent; the pure product of 4-chloro-1H-indole-2-carboxylic acid ethyl ester is 12mg, and the yield is 13%.

6-chloro-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,Chloroform-d)δ:9.17(brs, 1H),7.59(d,J＝8.6,1H),7.42(s,1H),7.19(dd,J＝2.1,0.9,1H),7.12(dd,J＝8.6, 1.8,1H),4.43(q,J＝7.1,2H),1.42(t,J＝7.1,3H)；¹³c NMR (101MHz, Chloroform-d) delta 162.02,137.22,131.40,128.35,126.15,123.65,121.98,111.86, 108.75,61.40, 14.52; 4-chloro-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz, Chloroform-d)δ:9.15(brs,1H),7.35–7.30(m,2H),7.23(t,J＝7.9,1H),7.16(dd, J＝7.5,0.8,1H),4.43(q,J＝7.1,2H),1.43(t,J＝7.1,3H)；¹³C NMR(101MHz, Chloroform-d)δ:161.89,137.41,128.05,127.98,126.78,125.92,120.60,110.64, 107.14,61.47,14.52。

example 376 Synthesis of ethyl-bromo-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was taken, and 69mg of 3-bromoaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a target product pure product 36mg with the yield of 34%.

¹H NMR(400MHz,Chloroform-d)δ＝9.07(brs,1H),7.59(s,1H),7.54(d, J＝8.6,1H),7.25(dd,J＝8.2,1.8,1H),7.22–7.16(m,1H),4.42(q,J＝7.1,2H),1.42 (t,J＝7.1,3H).¹³C NMR(101MHz,Chloroform-d)δ＝161.95,137.52,128.20, 126.40,124.50,123.94,119.19,114.91,108.76,61.43,14.52。

Example 386 Synthesis of Ethyl-hydroxy-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was charged with 44mg of 3-hydroxyaniline, 9mg of palladium acetate and

molecular sieves 80mg were charged with 93mg of ethyl 2-oxopropionate, 96mg of acetic acid and 2mL of dimethyl sulfoxide, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure target product 67mg with the yield of 82%.

¹H NMR(400MHz,DMSO-d₆)δ:11.42(s,1H),9.36(s,1H),7.42(d,J＝8.6, 1H),7.02(d,J＝1.3,1H),6.78(d,J＝1.9,1H),6.61(dd,J＝8.7,2.1,1H),4.29(q, J＝7.1,2H),1.31(t,J＝7.1,3H)；¹³C NMR(101MHz,DMSO-d₆)δ:161.29, 155.79,138.91,125.59,122.73,120.34,112.06,108.27,96.34,60.00,14.36。

Example Synthesis of Ethyl 394, 6-difluoro-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was charged with 52mg of 3, 5-difluoroaniline, 9mg of palladium acetate and

molecular sieves 80mg, 139mg of ethyl 2-oxopropionate, 96mg of acetic acid and 2mL of dimethyl sulfoxide were injected, and the mixture was stirred at 80 ℃ for 36 hours under a 200 mL-sized oxygen balloon. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 27mg of the target product, wherein the yield is 30%.

¹H NMR(400MHz,Chloroform-d)δ:9.38(brs,1H),7.27(overlap,1H),6.93 (d,J＝8.8,1H),6.65(td,J＝10.0,1.9,1H),4.44(q,J＝7.1,2H),1.43(t,J＝7.1, 3H)；¹³C NMR(101MHz,Chloroform-d)δ:161.70,161.44(dd,J＝243.4,11.7), 157.08(dd,J＝253.2,15.2),138.08(dd,J＝14.9,12.4),128.09,114.22(d,J＝ 22.3),105.00,96.69(dd,J＝29.3,22.8),94.25(dd,J＝26.4,4.8),61.53,14.49。

Example 406 Synthesis of fluoro-1H-indole-2-carboxylic acid ethyl ester and 4-fluoro-1H-indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was taken, and 44mg of 3-fluoroaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 70 ℃ for 24 hours. And after the reaction is finished, adding 15mL of ethyl acetate to dilute the reaction solution, filtering, washing with 10mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain: the pure product of 6-fluoro-1H-indole-2-ethyl formate is 41mg, and the yield is 50%; the pure product of 4-fluoro-1H-indole-2-carboxylic acid ethyl ester is 29mg, and the yield is 35%.

6-fluoro-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,Chloroform-d)δ:9.35(brs, 1H),7.30(d,J＝1.8,1H),7.26–7.19(m,2H),6.80(ddd,J＝10.2,6.8,1.6,1H), 4.44(q,J＝7.1,2H),1.43(t,J＝7.1,3H)；¹³c NMR (101MHz, Chloroform-d) δ 162.05,157.33(d, J equals 250.4),139.17(d, J equals 10.0),127.67,125.97(d, J equals 7.9), 117.45(d, J equals 22.4),108.09(d, J equals 4.1),105.21(d, J equals 18.5),104.74(d, J equals 0.7), 61.46, 14.49; 4-fluoro-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,Chloroform-d)δ: 9.34(brs,1H),7.61(dd,J＝8.8,5.4,1H),7.21(dd,J＝2.0,0.8,1H),7.10(dd,J＝ 9.4,2.0,1H),6.93(td,J＝9.4,2.3,1H),4.43(q,J＝7.1,2H),1.43(t,J＝7.1,3H)； ¹³C NMR(101MHz,Chloroform-d)δ:162.14,161.81(d,J＝242.1),137.12(d,J＝ 12.9),128.16(d,J＝3.6),124.20,123.89(d,J＝10.4),110.50(d,J＝25.3),108.92, 97.95(d,J＝26.1),61.30,14.51。

example 416 Synthesis of acetyl-1H-indole-2-carboxylic acid Ethyl ester with 4-acetyl-1H-indole-2-carboxylic acid Ethyl ester

A25 mL Schlenk reaction tube was charged with 54mg of 3-acetanilide, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 80 ℃ for 24 hours. Reaction ofAnd after the reaction is finished, adding 15mL of ethyl acetate to dilute the reaction solution, filtering, washing with 10mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain: the pure product of the 6-acetyl-1H-indole-2-ethyl formate is 31mg, and the yield is 34%; the pure 4-acetyl-1H-indole-2-carboxylic acid ethyl ester product is 9mg, and the yield is 10%.

6-acetyl-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,Chloroform-d)δ:9.47 br(s,1H),8.14–8.11(m,1H),7.77(dd,J＝8.5,1.4,1H),7.73(d,J＝8.5,1H), 7.24(dd,J＝2.1,0.9,1H),4.46(q,J＝7.1,2H),2.68(s,3H),1.44(t,J＝7.1,3H)； ¹³c NMR (101MHz, Chloroform-d) delta 198.31,161.83,136.33,134.22,130.81, 122.58,120.65,113.30,108.37,61.63,27.02, 14.49; 4-acetyl-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,Chloroform-d)δ:9.21(brs,1H),8.00(dd,J＝2.2,1.0, 1H),7.79(dd,J＝7.4,0.8,1H),7.65(dt,J＝8.3,0.9,1H),7.39(dd,J＝8.2,7.4, 1H),4.44(q,J＝7.1,2H),2.72(s,3H),1.43(t,J＝7.1,3H)；¹³C NMR(101MHz, Chloroform-d)δ:199.21,162.20,137.60,130.99,129.87,125.57,124.45,117.33, 110.15,61.45,27.81,14.51。

example 426 Synthesis of Ethyl-acetamido-1H-indole-2-carboxylate with Ethyl 4-acetamido-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was charged with 60mg of 3-acetaminoaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, adding 15mL of ethyl acetate to dilute the reaction solution, filtering, washing with 10mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain: 23mg of a pure 6-acetamido-1H-indole-2-carboxylic acid ethyl ester product, and the yield is 23%; 4-acetylamino group13mg of pure (E) -1H-indole-2-carboxylic acid ethyl ester and 13% of yield.

6-acetylamino-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,DMSO-d₆)δ:11.73(s, 1H),9.97(s,1H),8.04(s,1H),7.53(d,J＝8.7,1H),7.11(dd,J＝8.7,1.8,1H), 7.07(dd,J＝2.1,0.9,1H),4.31(q,J＝7.1,2H),2.06(s,3H),1.32(t,J＝7.1,3H)； ¹³C NMR(101MHz,DMSO-d₆) Delta 168.15,161.20,137.75,136.62,126.94,122.79, 122.02,113.91,107.86,101.91,60.21,24.09 and 14.32; 4-acetylamino-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,DMSO-d₆)δ:11.89(s,1H),9.74(s,1H),7.78–7.71(m, 1H),7.59(d,J＝1.7,1H),7.20–7.13(m,2H),4.35(q,J＝7.1,2H),2.15(s,3H), 1.35(t,J＝7.1,3H)；¹³C NMR(101MHz,DMSO-d₆)δ:168.63,161.21,138.04, 132.41,126.03,125.09,119.04,110.06,107.86,106.14,60.38,23.87,14.28。

example 431 Synthesis of H-indole-2, 6-dicarboxylic acid 2-ethyl-6-methyl-diester and 1H-indole-2, 4-dicarboxylic acid 2-ethyl-4-methyl-diester

A25 mL Schlenk reaction tube was charged with 60mg of methyl 3-aminobenzoate, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 80 ℃ for 24 hours. And after the reaction is finished, adding 15mL of ethyl acetate to dilute the reaction solution, filtering, washing with 10mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain: 45mg of pure 1H-indole-2, 6-dicarboxylic acid-2-ethyl-6-methyl-diester, yield 46%; the pure 1H-indole-2, 4-dicarboxylic acid-2-ethyl-4-methyl-diester was 5mg, yield 5%.

1H-indole-2, 6-dicarboxylic acid-2-ethyl-6-methyl-diester:¹H NMR(400MHz,DMSO-d₆)δ: 12.30(s,1H),8.12(dt,J＝1.6,0.8,1H),7.77(d,J＝8.5,1H),7.66(dd,J＝8.5,1.5, 1H),7.22(dd,J＝2.2,0.9,1H),4.37(q,J＝7.1,2H),3.87(s,3H),1.35(t,J＝7.1, 3H)；¹³C NMR(101MHz,DMSO-d₆) Delta 166.78,160.99,136.46,130.48,130.07, 125.44,122.14,120.29,114.63,107.45,60.85,52.03 and 14.23; 1H-indole-2, 4-dicarboxylic acid-2-ethyl-4-methyl-diester:¹H NMR(400MHz,Chloroform-d)δ:9.16(brs,1H),7.96(d, J＝7.4,1H),7.87–7.79(m,1H),7.64(d,J＝8.2,1H),7.38(t,J＝8.0,1H),4.44 (q,J＝7.1,2H),4.01(s,3H),1.44(t,J＝7.1,3H)；¹³C NMR(101MHz, Chloroform-d)δ＝167.58,162.10,137.42,129.18,126.74,124.67,124.58,123.66, 116.96,109.68,61.47,52.13,14.53。

EXAMPLE 442 Synthesis of ethoxycarbonyl-1H-indole-6-carboxylic acid and 2-ethoxycarbonyl-1H-indole-4-carboxylic acid

A25 mL Schlenk reaction tube was charged with 55mg of 3-aminobenzoic acid, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 80 ℃ for 24 hours. And after the reaction is finished, adding 15mL of ethyl acetate to dilute the reaction solution, filtering, washing with 10mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain: 5mg of 2-ethoxycarbonyl-1H-indole-6-formic acid pure product, 5% of yield; 9mg of pure 2-ethoxycarbonyl-1H-indole-4-carboxylic acid is obtained, and the yield is 10%.

2-ethoxycarbonyl-1H-indole-6-carboxylic acid:¹H NMR(400MHz,DMSO-d₆)δ:12.24(s,1H), 8.12–8.10(m,1H),7.74(d,J＝8.4,1H),7.65(dd,J＝8.4,1.4,1H),7.21(dd,J＝ 2.1,0.9,1H),4.37(q,J＝7.1,2H),1.35(t,J＝7.1,3H)；¹³C NMR(101MHz, DMSO-d₆)δ:167.85,161.02,136.53,130.17,129.80,126.63,121.90,120.60, 114.72,107.44,60.80,14.27; 2-ethoxycarbonyl-1H-indole-4-carboxylic acid:¹H NMR(400MHz, DMSO-d₆)δ:12.21(s,1H),7.79(dd,J＝7.3,1.0,1H),7.71(dt,J＝8.3,0.9,1H), 7.60(dd,J＝2.3,0.9,1H),7.37(dd,J＝8.2,7.4,1H),4.36(q,J＝7.1,2H),1.36(t, J＝7.1,3H)；¹³C NMR(101MHz,DMSO-d₆)δ:167.86,161.22,137.99,128.85, 125.76,123.92,123.77,123.42,117.57,108.35,60.70,14.27。

example 456 Synthesis of Ethyl hydroxymethyl-1H-indole-2-carboxylate with Ethyl 4-hydroxymethyl-1H-indole-2-carboxylate

A25 mL Schlenk reaction tube was taken, and 49mg of 3-aminobenzol, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 70 ℃ for 12 hours. And after the reaction is finished, adding 15mL of ethyl acetate to dilute the reaction solution, filtering, washing with 10mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain: 53mg of a pure 6-hydroxymethyl-1H-indole-2-carboxylic acid ethyl ester product, with a yield of 60%; the pure 4-hydroxymethyl-1H-indole-2-carboxylic acid ethyl ester product is 6mg, and the yield is 7%.

6-hydroxymethyl-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,DMSO-d₆)δ:11.81(s, 1H),7.58(d,J＝8.3,1H),7.43–7.41(m,2H),7.10(dd,J＝2.1,0.9,1H),7.01(dd, J＝8.3,1.4,1H),4.58(s,2H),4.33(q,J＝7.1,2H),3.69(brs,1H),1.34(t,J＝7.1, 3H)；¹³C NMR(101MHz,DMSO-d₆) Delta 161.38,139.52,137.60,127.15,125.62, 121.61,119.59,109.97,107.69,63.37,60.34 and 14.34; ethyl 4-hydroxymethyl-1H-indole-2-carboxylate:¹H NMR(400MHz,DMSO-d₆)δ:11.86(s,1H),7.34(d,J＝8.3,1H),7.27– 7.18(m,2H),7.05(d,J＝7.2,1H),5.19(t,J＝5.7,1H),4.77(d,J＝5.7,2H),4.34 (q,J＝7.1,2H),1.34(t,J＝7.1,3H)；¹³C NMR(101MHz,DMSO-d₆)δ:161.36, 137.42,135.91,126.82,124.87,124.48,117.47,111.26,106.41,61.38,60.37,14.33。

example 466 Synthesis of carbamoyl-1H-indole-2-carboxylic acid ethyl ester with 4-carbamoyl-1H-indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was taken, and 54mg of 3-aminobenzamide, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached thereto, and the mixture was stirred at 80 ℃ for 24 hours. And after the reaction is finished, adding 15mL of ethyl acetate to dilute the reaction solution, filtering, washing with 10mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain: the pure product of 6-carbamoyl-1H-indole-2-carboxylic acid ethyl ester is 19mg, and the yield is 20%; the pure product of 4-carbamoyl-1H-indole-2-carboxylic acid ethyl ester is 11mg, and the yield is 12%.

6-carbamoyl-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,DMSO-d₆)δ:12.21(s, 1H),8.07–7.95(m,2H),7.68(d,J＝8.5,1H),7.59(dd,J＝8.5,1.5,1H),7.31(brs, 1H),7.18(dd,J＝2.1,0.8,1H),4.36(q,J＝7.1,2H),1.35(t,J＝7.1,3H)；¹³C NMR(101MHz,DMSO-d₆) 168.48,161.11,136.75,130.72,129.48,128.64, 121.49,119.28,112.73,107.41,60.65, 14.28; 4-carbamoyl-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,DMSO-d₆)δ:12.05(s,1H),7.88(brs,1H),7.63–7.57(m,2H), 7.55(d,J＝6.9,1H),7.37–7.25(m,2H),4.35(q,J＝7.1,2H),1.35(t,J＝7.1, 3H)；¹³C NMR(101MHz,DMSO-d₆)δ:168.98,161.30,137.94,128.15,127.96, 125.03,123.80,120.14,115.52,108.60,60.56,14.29。

example 476 Synthesis of methylsulfonylamino-1H-indole-2-carboxylic acid ethyl ester with 4-methylsulfonylamino-1H-indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was charged with 74mg of 3-methanesulfonamidoaniline, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, adding 15mL of ethyl acetate to dilute the reaction solution, filtering, washing with 10mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain: 78mg of a pure 6-methylsulfonylamino-1H-indole-2-carboxylic acid ethyl ester product, and the yield is 69%; the pure product of the 4-methylsulfonylamino-1H-indole-2-carboxylic acid ethyl ester is 1mg, and the yield is 1%.

6-Methylsulfonylamino-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,DMSO-d₆)δ:11.81 (s,1H),9.68(s,1H),7.60(d,J＝8.6,1H),7.40–7.37(m,1H),7.10(dd,J＝2.2, 0.9,1H),6.99(dd,J＝8.6,2.0,1H),4.32(q,J＝7.1,2H),2.95(s,3H),1.33(t,J＝ 7.1,3H)；¹³C NMR(101MHz,DMSO-d₆) δ 161.11,137.72,135.50,127.41,123.68, 122.79,114.97,107.79,103.22,60.33,38.77 and 14.28; 4-methanesulfonylamino-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,DMSO-d₆)δ:11.97(s,1H),9.69(s,1H),7.52(d,J＝ 1.7,1H),7.26–7.26(m,2H),7.04(dd,J＝6.6,1.7,1H),4.34(q,J＝7.1,2H),2.97 (s,3H),1.34(t,J＝7.1,3H)；¹³C NMR(101MHz,DMSO-d₆)δ:161.16,138.36, 131.45,126.79,125.17,121.05,111.63,109.18,106.34,60.49,38.78,14.30。

example Synthesis of 486-methoxycarbonylmethyl-1H-indole-2-carboxylic acid ethyl ester and 4-methoxycarbonylmethyl-1H-indole-2-carboxylic acid ethyl ester

A25 mL Schlenk reaction tube was charged with 66mg of methyl 3-aminophenylacetate, 9mg of palladium acetate and

molecular sieves 80mg, ethyl 2-oxopropionate 93mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and the mixture was stirred at 70 ℃ for 18 hours under a 200mL oxygen balloon. And after the reaction is finished, adding 15mL of ethyl acetate to dilute the reaction solution, filtering, washing with 10mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain: 67mg of a pure 6-methoxycarbonylmethyl-1H-indole-2-carboxylic acid ethyl ester product with a yield of 64%; the pure 4-methoxycarbonylmethyl-1H-indole-2-carboxylic acid ethyl ester content was 6mg, the yield was 6%.

6-Methoxycarbonylmethyl-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,Chloroform-d)δ ＝9.06(brs,1H),7.62(d,J＝8.3,1H),7.34(s,1H),7.19(d,J＝1.8,1H),7.07(d, J＝8.2,1H),4.41(q,J＝7.1,2H),3.73(s,2H),3.70(s,3H),1.41(t,J＝7.1,3H).¹³c NMR (101MHz, Chloroform-d) δ 172.45,162.23,137.26,131.46,127.97,126.79, 122.88,122.68,112.61,108.72,61.26,52.34,41.79, 14.62; 4-methoxycarbonylmethyl-1H-indole-2-carboxylic acid ethyl ester:¹H NMR(400MHz,Chloroform-d)δ＝9.18(brs,1H),7.35 (overlap,1H),7.29(d,J＝1.9,1H),7.26(t,J＝7.5,1H),7.04(overlap,1H),4.42(q, J＝7.1,2H),3.91(s,2H),3.69(s,3H),1.42(t,J＝7.1,3H)。

example 492 Synthesis of methyl-5-methoxy-1H-indole

A25 mL Schlenk reaction tube was charged with 49mg of p-anisidine, 9mg of palladium acetate and

molecular sieves 80mg, acetone 116mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, followed by a 200mL oxygen balloon and stirred at 70 ℃ for 18 hours. After the reaction, ethyl acetate 1 was addedDiluting the reaction solution by 5mL, filtering, washing by 10mL of saline for 2 times, separating an organic phase, extracting a water phase by ethyl acetate for 1 time, combining the organic phases, and carrying out column chromatography separation to obtain a pure product 51mg of a target product, wherein the yield is 79%.

¹H NMR(400MHz,Chloroform-d)δ＝7.73(brs,1H),7.17(d,J＝8.8,1H), 6.99(d,J＝2.4,1H),6.76(dd,J＝8.7,2.4,1H),6.14(brs,1H),3.83(s,3H),2.43(s, 3H)；¹³C NMR(101MHz,Chloroform-d)δ＝154.19,136.05,131.28,129.64, 110.95,110.75,102.04,100.39,56.01,13.86。

EXAMPLE 502 gram-Scale Synthesis of methyl-5-methoxy-1H-indole

A250 mL three-necked flask was charged with p-anisidine 1.23g, palladium acetate 0.22g and

1.00g of molecular sieve, 2.90g of acetone, 0.60g of acetic acid and 100mL of dimethyl sulfoxide were injected, and a 200mL oxygen balloon was attached thereto, followed by stirring at 70 ℃ for 18 hours. After the reaction is finished, 200mL of ethyl acetate is added to dilute the reaction solution, 100mL of saline is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain 1.23g of a pure 2-methyl-5-methoxy-1H-indole product with the yield of 76%.

EXAMPLE 512 Synthesis of isobutyl-5-methoxy-1H-indole

80mg of molecular sieve, injecting 80mg of 4-methyl-pentan-2-one, 96mg of acetic acid and 2mL of dimethyl sulfoxide, connecting with a 200mL oxygen balloon, and stirring at 70 deg.CStirring for 24 hours. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, an aqueous phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product 23mg of the target product, wherein the yield is 28%.

¹H NMR(400MHz,Chloroform-d)δ＝7.73(brs,1H),7.17(d,J＝8.7,1H), 7.01(d,J＝2.4,1H),6.77(dd,J＝8.7,2.4,1H),6.15(brs,1H),3.83(s,3H),2.59 (d,J＝7.1,2H),2.03–1.89(m,1H),0.97(d,J＝6.6,6H)；¹³C NMR(101MHz, Chloroform-d)δ＝154.24,139.91,131.07,129.48,111.06,110.88,102.10,100.48, 56.04,37.98,29.13,22.66。

Example 522 Synthesis of propyl-5-methoxy-1H-indole

molecular sieves 80mg, pentan-2-one 172mg, acetic acid 24mg and dimethyl sulfoxide 8mL were injected, followed by a 200mL oxygen balloon and stirred at 70 ℃ for 18 hours. And after the reaction is finished, 15mL of diluted reaction solution is added, 10mL of brine is washed for 2 times after filtration, an organic phase is separated, a water phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product of 28mg of a target product, wherein the yield is 37%.

¹H NMR(400MHz,Chloroform-d)δ＝7.74(brs,1H),7.16(d,J＝8.7,1H), 7.01(d,J＝2.4,1H),6.76(dd,J＝8.7,2.4,1H),6.16(brs,1H),3.83(s,3H),2.69(t, J＝7.6,2H),1.73(h,J＝7.4,2H),0.99(t,J＝7.3,3H)；¹³C NMR(101MHz, Chloroform-d)δ＝154.22,140.83,131.06,129.45,111.03,110.86,102.12,99.58, 56.05,30.54,22.65,14.04。

EXAMPLE 53 Synthesis of N, N-dibutyl-5-methoxy-1H-indole-2-carboxamide

molecular sieves 80mg, N-dibutyl-2-oxo-propionamide 80mg, acetic acid 96mg and dimethyl sulfoxide 2mL were injected, and a 200mL oxygen balloon was attached and stirred at 80 ℃ for 48 hours. And after the reaction is finished, 15mL of ethyl acetate is added to dilute the reaction solution, 10mL of saline is used for washing for 2 times after filtration, an organic phase is separated, a water phase is extracted for 1 time by using ethyl acetate, the organic phases are combined, and column chromatography separation is carried out to obtain a pure product of the target product of 50mg, wherein the yield is 41%.

¹H NMR(400MHz,Chloroform-d)δ＝9.88(brs,1H),7.34(d,J＝8.9,1H), 7.07(d,J＝2.3,1H),6.94(dd,J＝8.9,2.3,1H),6.68(d,J＝1.6,1H),3.85(s,3H), 3.62(brs,4H),1.72(brs,4H),1.42(h,J＝7.3,4H),0.99(t,J＝7.2,6H)；¹³C NMR (101MHz,Chloroform-d)δ＝162.68,154.53,131.03,130.51,128.26,115.58, 112.83,104.04,102.30,55.83,48.18(d,J＝101.7),30.56(d,J＝109.6),20.37, 14.05。

Example 545 gram-order Synthesis of Methylsulfonylamino-1H-indole-2-carboxylic acid methyl ester

A250 mL three-necked flask was charged with p-methanesulfonamido aniline 1.86g, palladium acetate 0.22g and

molecular sieve 1.00g, 2.04g of 2-oxo-pyruvic acid methyl ester, 0.60g of acetic acid and 100mL of dimethyl sulfoxide were injected, and a 200mL oxygen balloon was attached, and stirred at 70 ℃ for 18 hours. After the reaction is finished, adding 200mL of ethyl acetate to dilute the reaction solution, filtering, washing with 100mL of saline water for 2 times, separating an organic phase, extracting a water phase with ethyl acetate for 1 time, combining the organic phases, and performing column chromatography separation to obtain the 5-methylsulfonylamino-1H-indole2.15g of pure methyl-2-carboxylate, 80% yield.

¹H NMR(400MHz,DMSO-d₆)δ:11.95(s,1H),9.41(s,1H),7.51(d,J＝1.6, 1H),7.41(d,J＝8.8,1H),7.17(dd,J＝8.8,2.1,1H),7.15(d,J＝1.7,1H),3.87(s, 3H),2.89(s,3H)；¹³C NMR(101MHz,DMSO-d₆)δ:161.59,135.11,130.93, 127.91,126.88,121.03,114.57,113.18,107.70,51.82,38.51。

The indole product can be used as a direct raw material for synthesizing anti-HIV drug delavirdine, and refer to the patent: a process for synthesizing delavirdine as anti-AIDS medicine for treating AIDS is disclosed, which is CN 102633778B [ P ]. 2014-04-16.

The above-mentioned embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solution of the present invention by those skilled in the art should fall within the protection scope defined by the claims of the present invention without departing from the spirit of the present invention.

Claims

1. A synthetic method for preparing 2-substituted indole derivatives is characterized in that: mixing an aromatic amine compound (I), a ketone compound (II) and a drying agent in an organic solvent, adding a palladium catalyst, reacting in an aerobic weak acid environment to obtain an indole compound (III),

(I) is composed of

(II) is

(III) is

Wherein R is¹Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted phenylAnd a pyridyl group; the substituent is selected from one or more of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl and amino;

2. The method of synthesis according to claim 1, characterized in that: the reaction temperature is 10-130 ℃.

3. The method of synthesis according to claim 2, characterized in that: the reaction temperature was 70 ℃.

4. The method of synthesis according to claim 1, characterized in that: the reaction pressure is 1 atm-3 atm.

5. The method of synthesis according to claim 4, characterized in that: the reaction pressure is 1 atm.

6. The method of synthesis according to claim 1, characterized in that: the molecular sieve is in powder form

And (3) a molecular sieve.

7. The method of synthesis according to claim 1, characterized in that: the molar ratio of the aromatic amine compound to the ketone compound is 1: 1-1: 10, the molar ratio of the aromatic amine compound to the palladium catalyst is 1: 1-50: 1, and the molar ratio of the aromatic amine compound to the weak acid is 1: 0-1: 20.

8. The method of synthesis according to claim 7, characterized in that: the molar ratio of the aromatic amine compound to the ketone compound is 1:2, the molar ratio of the aromatic amine compound to the palladium catalyst is 10:1, and the molar ratio of the aromatic amine compound to the weak acid is 1: 4.