CN115819406B - Synthesis method of 3- (4-pyrimidine) -1H-indole compound - Google Patents
Synthesis method of 3- (4-pyrimidine) -1H-indole compound Download PDFInfo
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Abstract
The invention belongs to the technical field of indole compounds, and particularly relates to a synthetic method of 3- (4-pyrimidine) -1H-indole compounds. The method comprises the following steps: adding indole and 2, 4-dichloropyrimidine into a reaction vessel, adding a Lewis acid catalyst, adding a solvent, and heating for reaction; wherein: the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride with the mol ratio of 1 (0.2-8.5). The indole is one of 5-fluoroindole, 5-methoxyindole and 5-nitroindole. The solvent is one or two of hexafluoroisopropanol, 1, 2-dichloroethane, 2-trifluoroethanol and ethylene glycol dimethyl ether. The 3- (4-pyrimidine) -1H-indole compound with high reaction yield is obtained by controlling the conditions of catalyst type, substrate reaction site, reaction solvent type, reaction temperature, reaction duration and the like.
Description
Technical Field
The invention belongs to the technical field of indole compounds, and particularly relates to a synthetic method of 3- (4-pyrimidine) -1H-indole compounds.
Background
Indoles are a common and important class of organic intermediates whose structure is widely found in many natural products as well as bioactive molecules. Due to their unique molecular structure, they have been widely used in the field of functional medicines, agricultural chemicals, foods, additives, and the like in recent years. In the medical field, many natural products with good physiological activity and small molecules of drugs have indole derivative structures, such as alkaloid reserpine (reserpine), which exists in various plants of Rauvolfia, and has the effects of reducing blood pressure, slowing down heart rate and the like; the Indomethacin (Indomethacin) can be used as a medical intermediate for synthesizing antipyretic analgesic, antihypertensive drugs, vasodilators and the like, is a non-steroidal anti-inflammatory drug, has good antipyretic, anti-inflammatory and analgesic effects, and has remarkable curative effect when used for Batter syndrome; in the pesticide field, it is widely used as a high-efficiency plant growth regulator, a bactericide, etc., such as amisulbenum, which is an indole structure-containing bactericide, which has a good effect mainly on killing oomycetes and deformed fungi, and thus is widely used in the agricultural field. The 3- (4-pyrimidine) -1H-indole derivatives are compounds containing indole structures. In recent years, 3- (4-pyrimidine) -1H-indole compounds are widely applied to the research and development of medicaments due to the unique structure and good anti-inflammatory, analgesic, anti-tumor and antihypertensive activities, and are particularly embodied in the research and development of anti-tumor medicaments. If the third-generation EGFR inhibitor, namely, the oxtinib is used as a third-generation targeting drug, the EGFR 19del and L858R mutation can be inhibited, the EGFR T780M which is a first-generation EGFR targeting drug resistant mutation and a second-generation EGFR targeting drug resistant mutation can be overcome, the side effect is milder, and the adverse reaction of the oxtinib is less than 1%; SY-1365 (Mevociclib), a CDK7 inhibitor as disclosed earlier, and SY-5609, as disclosed in 2022, both showed good anti-cancer activity.
The current synthetic routes of such compounds mainly include the following three types:
the first synthetic route is a traditional synthetic route, and the synthesis of the compounds is generally carried out by adopting the thought of C-C coupling. Indole derivatives and 2, 4-dichloropyrimidine are used as raw materials, a halogen atom is introduced into the 3 rd position of indole, the halogen atom is converted into boric acid ester, and finally Suzuki coupling is carried out on the boric acid ester and the 2, 4-dichloropyrimidine, so that the 3- (4-pyrimidine) -1H-indole derivatives are obtained. The synthetic route has the defects of more reaction steps, longer reaction time, expensive palladium catalyst and the like.
The second synthetic route is to take indole derivatives and dichloropyrimidine derivatives as raw materials, and to make the indole derivatives and dichloropyrimidine derivatives in CH 3 MgBr (1 eq), indole (1 eq), tetrahydrofuran and 0-60 ℃ to produce the 3- (4-pyrimidine) -1H-indole derivative, however, the reaction yield of the synthetic route is lower.
The third synthetic route is to use indole derivatives and 2, 4-dichloropyrimidine as raw materials. Firstly, the indole derivative raw material and aluminum chloride are stirred in 1, 2-dichloroethane at 0-25 ℃ for 30min, then the temperature is raised to 55 ℃,2, 4-dichloropyrimidine is added for continuous reaction for 1.5H, and 3- (4-pyrimidine) -1H-indole derivatives are generated, wherein the reaction yield of the synthetic route is still only about 30%.
The three synthetic paths have lower reaction yields, and how to improve the synthetic reaction yields of the 3- (4-pyrimidine) -1H-indole derivatives is a problem to be solved urgently.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a synthesis method of 3- (4-pyrimidine) -1H-indole compounds, which can realize one-step reaction, shorten the steps required by the reaction, save the cost and time of the reaction, and has higher reaction yield, wherein the reaction process is shown in figure 1.
The synthesis method of the 3- (4-pyrimidine) -1H-indole compound comprises the following steps: introducing nitrogen to replace water and oxygen in a reaction vessel, then adding indole and 2, 4-dichloropyrimidine into the reaction vessel, adding a Lewis acid catalyst, adding a solvent, heating to react, controlling the TLC until the reaction is finished, adding ethyl acetate for dilution, adding purified water, carrying out liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain the 3- (4-pyrimidine) -1H-indole compound.
Wherein:
the Lewis acid catalyst is a mixture of trifluoromethanesulfonic acid and indium chloride.
The molar ratio of the trifluoromethanesulfonic acid to the indium chloride is 1 (0.2-8.5).
The indole is one of 5-fluoroindole, 5-methoxyindole and 5-nitroindole.
The solvent is one or two of hexafluoroisopropanol, 1, 2-dichloroethane, 2-trifluoroethanol and ethylene glycol dimethyl ether.
Preferably, the solvent is two of hexafluoroisopropanol, 1, 2-dichloroethane, 2-trifluoroethanol and ethylene glycol dimethyl ether, and the volume ratio of the two solvents is 1 (0.1-10).
The temperature is raised to 70-85 ℃.
The reaction time of the reaction is 1.5-2.5h.
The molar ratio of the indole to the 2, 4-dichloropyrimidine is 1 (1-5).
The molar ratio of the Lewis acid catalyst to the 2, 4-dichloropyrimidine is 1 (0.33-5.00).
The solvent is added in an amount of 10-100ml per 1mmol indole.
Compared with the prior art, the invention has the following beneficial effects:
(1) According to the invention, the trifluoro methanesulfonic acid and the indium chloride are used as Lewis acid catalysts, so that the reaction yield is greatly improved.
(2) The invention determines that the highest reaction yield can be achieved when fluorine atoms, methoxy groups and nitro groups are at the 5 th position of indole.
(3) The invention determines that the reaction yield is highest when one or two of hexafluoroisopropanol, 1, 2-dichloroethane, 2-trifluoroethanol and ethylene glycol dimethyl ether are used as solvents.
(4) The invention provides a synthetic method of 3- (4-pyrimidine) -1H-indole compounds, which can react indole derivatives with 2, 4-dichloropyrimidine to generate 3- (4-pyrimidine) -1H-indole compounds in one step. The synthetic method can greatly shorten the steps required by the reaction, and save the reaction cost and the reaction time.
Drawings
FIG. 1 is a reaction scheme of a synthetic pathway according to the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of 3- (2-chloropyrimidin-4-yl) -5-fluoro-1H-indole prepared in example 1;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of 3- (2-chloropyrimidin-4-yl) -5-methoxy-1H-indole prepared in example 2;
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of 3- (2-chloropyrimidin-4-yl) -5-nitro-1H-indole prepared in example 3;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of 3- (2-chloropyrimidin-4-yl) -7-nitro-1H-indole prepared in comparative example 5;
FIG. 6 is a nuclear magnetic resonance hydrogen spectrum of 3- (2-chloropyrimidin-4-yl) -6-fluoro-1H-indole prepared in comparative example 6;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of 3- (2-chloropyrimidin-4-yl) -7-methoxy-1H-indole prepared in comparative example 7.
Detailed Description
The present invention is further illustrated by the following examples, but the scope of the present invention is not limited thereto.
All materials used in the examples are commercially available, except as specified.
Example 1
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 5-fluoroindole and 0.1mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.3mmol of Lewis acid catalyst, adding 1ml of solvent, heating to 70 ℃, reacting for 1.5H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 2:1), adding 3ml of ethyl acetate for dilution, adding 3ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -5-fluoro-1H-indole with the yield of 77%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:0.2.
The solvent is a mixture of hexafluoroisopropanol and 1, 2-dichloroethane in a volume ratio of 1:0.1.
Mass spectrometry and nmr hydrogen spectrometry were performed on the resulting 3- (2-chloropyrimidin-4-yl) -5-fluoro-1H-indole to obtain the following results: MS (ESI) M/z calcd 247.66 (M+H), found 248.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.21 (s, 1H), 8.57 (dd,J= 18.7, 4.3 Hz, 2H), 8.13 (dd,J= 10.4, 2.7 Hz, 1H), 7.92 (d,J= 5.5 Hz, 1H), 7.53 (dd,J= 8.9, 4.7 Hz, 1H), 7.11 (td,J=9.1, 2.6 Hz, 1H). As shown in fig. 2.
Example 2
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 5-methoxyindole and 0.5mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.1mmol of Lewis acid catalyst, adding 10ml of solvent, heating to 85 ℃, reacting for 2.5H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 2:1), adding 30ml of ethyl acetate for dilution, adding 30ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -5-methoxy-1H-indole with the yield of 74%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:8.5.
The solvent is a mixture of ethylene glycol dimethyl ether and 2, 2-trifluoroethanol in a volume ratio of 1:10.
Mass spectrometry and nmr hydrogen spectrometry were performed on the obtained 3- (2-chloropyrimidin-4-yl) -5-methoxy-1H-indole to obtain the following results: MS (ESI) M/z calcd 259.69 (M+H), found 260.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.88 (s, 1H), 8.51 (d,J= 5.5 Hz, 1H), 8.39 (d,J= 3.0 Hz, 1H), 8.28 (d,J= 8.8 Hz, 1H), 7.88 (d,J= 5.5 Hz, 1H), 6.99 (d,J= 2.3 Hz, 1H), 6.88 (dd,J=8.8, 2.4 Hz, 1H), 3.81 (s, 3H). As shown in fig. 3.
Example 3
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 5-nitroindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 80 ℃, reacting for 2H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 1:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -5-nitro-1H-indole with the yield of 78%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:1.
The solvent is hexafluoroisopropanol.
Mass spectrometry and nmr hydrogen spectrometry were performed on the obtained 3- (2-chloropyrimidin-4-yl) -5-nitro-1H-indole to obtain the following results: MS (ESI) M/z calcd 274.66 (M+H), found 275.10. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.70 (s, 1H), 9.39 (d,J= 2.3 Hz, 1H), 8.80 (s, 1H), 8.65 (d,J= 5.4 Hz, 1H), 8.15 (dd,J= 9.0, 2.4 Hz, 1H), 8.02 (d,J= 5.4 Hz, 1H), 7.71 (d,J=9.0 Hz, 1H). As shown in fig. 4.
Example 4
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 5-nitroindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 80 ℃, reacting for 2H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 1:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -5-nitro-1H-indole with the yield of 74%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:4.
The solvent is a mixture of hexafluoroisopropanol and 1, 2-dichloroethane in a volume ratio of 1:1.
Example 5
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 5-nitroindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 80 ℃, reacting for 2H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 1:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -5-nitro-1H-indole with the yield of 77%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:1.
The solvent is a mixture of hexafluoroisopropanol and 2, 2-trifluoroethanol in a volume ratio of 1:1.
Comparative example 1
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 5-nitroindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 80 ℃, reacting for 2H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 1:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -5-nitro-1H-indole with the yield of 67%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:1.
The solvent is isopropanol.
Comparative example 2
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 5-nitroindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 80 ℃, reacting for 2H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 1:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -5-nitro-1H-indole with the yield of 61%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:1.
The solvent is dichloromethane.
Comparative example 3
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 5-nitroindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 80 ℃, reacting for 2H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 1:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -5-nitro-1H-indole with the yield of 66%.
Wherein:
the Lewis acid catalyst is ferric chloride.
The solvent is hexafluoroisopropanol.
Comparative example 4
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 5-nitroindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 80 ℃, reacting for 2H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 1:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -5-nitro-1H-indole, wherein the yield is 69%.
Wherein:
the Lewis acid catalyst is aluminum chloride.
The solvent is hexafluoroisopropanol.
Comparative example 5
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 7-nitroindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 80 ℃, reacting for 2H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 1:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -7-nitro-1H-indole with the yield of 61%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:1.
The solvent is hexafluoroisopropanol.
Mass spectrometry and nmr hydrogen spectrometry were performed on the obtained 3- (2-chloropyrimidin-4-yl) -7-nitro-1H-indole to obtain the following results: MS (ESI) M/z calcd 274.66 (M+H), found 275.20. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.92 (s, 1H), 8.21 – 8.02 (m, 2H),7.54 (t,J= 2.8 Hz, 1H), 7.24 (t,J= 7.9 Hz, 1H), 6.75 (dd,J=3.2, 1.9 Hz, 1H). As shown in fig. 5.
Comparative example 6
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 6-fluoroindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 80 ℃, reacting for 2H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 2:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidin-4-yl) -6-fluoro-1H-indole with the yield of 48%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:1.
The solvent is hexafluoroisopropanol.
Mass spectrometry and nmr hydrogen spectrometry were performed on the resulting 3- (2-chloropyrimidin-4-yl) -6-fluoro-1H-indole to obtain the following results: MS (ESI) M/z calcd 247.66 (M+H), found 248.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.12 (s, 1H), 8.64 – 8.50 (m, 2H), 8.42 (dd,J= 8.8, 5.6 Hz, 1H), 7.93 (d,J= 5.4 Hz, 1H), 7.30 (dd,J= 9.6, 2.4 Hz, 1H), 7.11 (ddd,J=9.8, 8.8, 2.4 Hz, 1H). As shown in fig. 6.
Comparative example 7
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 7-methoxyindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 80 ℃, reacting for 2H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 2:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidin-4-yl) -7-methoxy-1H-indole with the yield of 38%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:1.
The solvent is hexafluoroisopropanol.
Mass spectrometry and nmr hydrogen spectrometry were performed on the obtained 3- (2-chloropyrimidin-4-yl) -7-methoxy-1H-indole to obtain the following results: MS (ESI) M/z calcd 259.69 (M+H), found 260.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.22 (s, 1H), 8.52 (d,J= 5.5 Hz, 1H), 8.41 (d,J= 3.2 Hz, 1H), 8.01 (d,J= 8.1 Hz, 1H), 7.93 (d,J= 5.4 Hz, 1H), 7.15 (t,J= 8.0 Hz, 1H), 6.83 (d,J=7.8 Hz, 1H), 3.96 (s, 3H). As shown in fig. 7.
Comparative example 8
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 5-nitroindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 60 ℃, reacting for 2H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 1:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -5-nitro-1H-indole with the yield of 55%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:1.
The solvent is hexafluoroisopropanol.
Comparative example 9
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 5-nitroindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring at a rotating speed of 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 100 ℃, reacting for 2H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 1:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -5-nitro-1H-indole with a yield of 50%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:1.
The solvent is hexafluoroisopropanol.
Comparative example 10
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 5-nitroindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring, rotating at 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 80 ℃, reacting for 1H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 1:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -5-nitro-1H-indole with the yield of 45%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:1.
The solvent is hexafluoroisopropanol.
Comparative example 11
Introducing nitrogen to replace water and oxygen in a reaction vessel, repeating for three times, adding 0.1mmol of 5-nitroindole and 0.12mmol of 2, 4-dichloropyrimidine into the reaction vessel, starting stirring at a rotating speed of 300r/min, adding 0.04mmol of Lewis acid catalyst, adding 5ml of solvent, heating to 80 ℃, reacting for 3H, performing TLC until the reaction is finished (the volume ratio of ethyl acetate to petroleum ether is 1:1), adding 15ml of ethyl acetate for dilution, adding 15ml of purified water, performing liquid separation operation, collecting an organic phase, concentrating the organic phase, and separating by column chromatography to obtain 3- (2-chloropyrimidine-4-yl) -5-nitro-1H-indole with a yield of 59%.
Wherein:
the Lewis acid catalyst is a mixture of trifluoro methane sulfonic acid and indium chloride in a molar ratio of 1:1.
The solvent is hexafluoroisopropanol.
In summary, when the trifluoromethanesulfonic acid and the indium chloride are used as Lewis acid catalysts, and the fluorine atom, the methoxy group and the nitro group are at the 5-position of the indole, and the solvent is one or two of hexafluoroisopropanol, 1, 2-dichloroethane, 2-trifluoroethanol and ethylene glycol dimethyl ether, the higher yield can be achieved.
Claims (5)
1. The synthesis method of the 3- (4-pyrimidine) -1H-indole compound is characterized by comprising the following steps: adding indole and 2, 4-dichloropyrimidine into a reaction vessel, adding a Lewis acid catalyst, adding a solvent, and heating for reaction;
wherein:
the Lewis acid catalyst is a mixture of trifluoromethanesulfonic acid and indium chloride;
the molar ratio of the trifluoromethanesulfonic acid to the indium chloride is 1 (0.2-8.5);
the indole is one of 5-fluoroindole, 5-methoxyindole and 5-nitroindole;
the solvent is one or two of hexafluoroisopropanol, 1, 2-dichloroethane, 2-trifluoroethanol and ethylene glycol dimethyl ether;
the temperature is raised to 70-85 ℃;
the reaction time of the reaction is 1.5-2.5h.
2. The method for synthesizing 3- (4-pyrimidine) -1H-indole compounds according to claim 1, wherein the solvent is two of hexafluoroisopropanol, 1, 2-dichloroethane, 2-trifluoroethanol and ethylene glycol dimethyl ether, and the volume ratio of the two solvents is 1 (0.1-10).
3. The method for synthesizing 3- (4-pyrimidine) -1H-indole compounds according to claim 1, wherein the molar ratio of indole to 2, 4-dichloropyrimidine is 1 (1-5).
4. The method for synthesizing 3- (4-pyrimidine) -1H-indole according to claim 1, wherein the molar ratio of the Lewis acid catalyst to 2, 4-dichloropyrimidine is 1 (0.33-5.00).
5. The method for synthesizing 3- (4-pyrimidine) -1H-indole compounds according to claim 1, wherein the amount of the solvent is 10-100ml per 1mmol of indole.
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