CN112979648B - Synthesis method of gamma-carboline derivative - Google Patents

Synthesis method of gamma-carboline derivative Download PDF

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CN112979648B
CN112979648B CN202110281530.8A CN202110281530A CN112979648B CN 112979648 B CN112979648 B CN 112979648B CN 202110281530 A CN202110281530 A CN 202110281530A CN 112979648 B CN112979648 B CN 112979648B
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CN112979648A (en
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王亮
李鹏杰
肖标
王泽田
周春妮
郑子昂
余凡
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Jianghan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The embodiment of the invention provides a synthesis method of a gamma-carboline derivative, which comprises the following steps: will beC-H alkenyl reaction is carried out on the compound I and R2-alkenyl borate to obtain a compound II; removing pyrimidine groups from the compound II to obtain a compound III; formylating the compound III to obtain a compound IV; carrying out serial imidization and cyclization reaction on the compound IV to obtain a gamma-carboline derivative shown in the compound V; the reaction formula is shown as follows, R 1 Selected from C1-C6 alkyl, methoxy, alkoxy, benzyloxy, ester, acetyl, cyano and halogen, R 2 Selected from the group consisting of C1-C6 alkyl, aryl substituted alkyl, naphthalene ring, aromatic heterocycle, phenyl and substituted phenyl. Indole is used as a starting material for construction from the beginning, and the source of the raw material is wide; the steps are simple; the reaction efficiency is high; and the nitrogen atom of the gamma-carboline is not provided with a substituent group, so that the later structural modification of the nitrogen atom is facilitated.

Description

Synthesis method of gamma-carboline derivative
Technical Field
The embodiment of the invention relates to the technical field of organic synthesis, in particular to a synthesis method of a gamma-carboline derivative.
Background
The carboline derivative is an important natural nitrogenous alkaloid, the molecular structure of the carboline derivative is composed of a tricyclic structure of indolopyridine, and the carboline derivative has a large planar aromatic system. Has important biological activity and pharmacological activity of resisting bacteria, viruses, tumors, central nervous system and the like. According to the difference of the nitrogen atom positions of pyridine in the molecule, the pyridine is divided into alpha-carboline, beta-carboline, gamma-carboline and delta-carboline. Among them, β -carbolines inhibit synthesis of topoisomerase, cyclin-dependent kinase and DNA due to their most widespread presence in nature. And can be embedded in DNA, all of which make them have strong antitumor activity. However, gamma-carbolines have less of a relevant study relative to the widely studied beta-carbolines. In recent years, as bioisosteres of beta-carbolines, gamma-carboline derivatives have also received increasing attention from researchers, who have conducted a series of studies and structural optimization. The research shows that the gamma-carboline derivative has no strong anti-tumor activity like the beta-carboline derivative. Their biological activity is manifested as an inhibition of the 5-HT receptor.
At present, the synthesis method of the gamma-carboline derivative mainly comprises the following steps: (1) The gamma-carboline containing special functional groups (such as amino groups) is used as a raw material for derivatization and structural modification. (2) Is prepared by utilizing indolimine or indoloxime ether and alkene or alkyne through metal-catalyzed cyclization reaction. (3) The N-phenylpyridine amine is used as a raw material and prepared through a metal-catalyzed intramolecular cyclization reaction. (4) Prepared by a three component tandem reaction of functionalized indole-3-carbaldehyde with an aldehyde and ammonium acetate. However, the existing methods have some disadvantages: (1) Raw materials are not widely available, and indole is needed to be prepared through multi-step reactions. (2) complex synthesis steps and severe conditions. (3) The reaction efficiency is low, the regioselectivity is poor, and the method has no amplification reaction prospect. (4) The nitrogen atom of the gamma-carboline is provided with a substituent group, which is unfavorable for the later structural modification of the nitrogen atom.
Therefore, a synthesis method which is constructed from the head, is generally applicable and has a certain amplifying application prospect is developed by utilizing simple and easily available raw materials, so that various substituted-carboline derivatives can be efficiently prepared, and the method has important significance for meeting the requirement of screening the activity of a large number of medicine molecules and rapidly developing gamma-carboline candidate medicines.
Disclosure of Invention
The embodiment of the invention aims to provide a synthesis method of a gamma-carboline derivative, which is characterized in that indole which is simply and easily obtained is used as a starting material in a 'de novo construction' manner, and the source of the raw material is wide; the synthesis steps are simpler; the reaction efficiency is high; and the nitrogen atom of the gamma-carboline is not provided with a substituent group, so that the later structural modification of the nitrogen atom is facilitated.
The embodiment of the invention aims to provide a synthesis method of a gamma-carboline derivative, which comprises the following steps:
compounds I and R 2 -alkenyl borate is subjected to C-H alkenylation to obtain compound II;
removing pyrimidine groups from the compound II to obtain a compound III;
formylating the compound III to obtain a compound IV;
carrying out serial imidization and cyclization reaction on the compound IV to obtain a gamma-carboline derivative shown in the compound V;
wherein, the reaction formula is as follows:
substituent R 1 Selected from the group consisting of C1-C6 alkyl, methoxy, alkoxy, benzyloxy, ester, acetyl, cyano and halogen, and the position of the substituent R1 is selected from the group consisting of the 3,4,5,6 positions on the indole ring;
substituent R 2 Selected from the group consisting of C1-C6 alkyl, aryl substituted alkyl, naphthalene ring, aromatic heterocycle, phenyl and substituted phenyl wherein the substituents in the substituted phenyl are selected from the group consisting of trifluoromethoxy, trifluoromethyl, fluoro, chloro, formate, C1-C6 alkyl, benzyloxy and phenoxy and the positions of the substituents in the substituted phenyl are selected from the group consisting of para and/or meta positions on the benzene ring.
Further, the compound I is obtained by carrying out N substitution reaction on indole and 2-chloropyrimidine.
Further, in the C-H alkenylation reaction, a catalyst and an organic solvent are added, wherein the catalyst comprises AgOAc and [ RhCp ] Cl 2 ] 2 The organic solvent is MeOH.
Further, the molar mass ratio of the catalyst, the compound I and the alkenyl borate is: agOAc: [ RhCp ] Cl 2 ] 2 : alkenyl borate: compound i= (1.5-4): (0.01-0.3): (1.5-4): 1.
further, the temperature of the C-H alkenyl reaction is 25-100 ℃, and the time of the C-H alkenyl reaction is 4-30H.
Further, the removing pyrimidine groups from the compound II to obtain a compound III, which comprises:
and (3) reacting the compound II with sodium ethoxide or sodium methoxide to remove pyrimidine groups to obtain a compound III.
Further, the molar ratio of the compound II to the sodium ethoxide is 1: (3-5); the molar ratio of the compound II to the sodium methoxide is 1: (3-5).
Further, POCl is added in the formylation reaction 3 DMF and NaOH, said compound III, POCl 3 The mol ratio of NaOH is as follows: compound III: POCl (Point of care testing) 3 ：NaOH＝1：(2～4)：(4～8)。
Further, hydroxylamine hydrochloride, sodium acetate and 1, 4-dioxane are added in the cascade imidization and cyclization reaction, and the molar ratio of the compound IV to the hydroxylamine hydrochloride to the sodium acetate is that of the compound IV: hydroxylamine hydrochloride: sodium acetate = 1: (1-4): (1-4).
One or more technical solutions in the embodiments of the present invention at least have the following technical effects or advantages:
the embodiment of the invention provides a synthesis method of a gamma-carboline derivative, which comprises the following steps: compounds I and R 2 -alkenyl borate is subjected to C-H alkenylation to obtain compound II; removing pyrimidine groups from the compound II to obtain a compound III; formylating the compound III to obtain a compound IV; carrying out serial imidization and cyclization reaction on the compound IV to obtain a gamma-carboline derivative shown in the compound V; the method is constructed from the head, uses simple and easily obtained indole as a starting raw material, has wide raw material sources, has the characteristics of universal application and a certain amplification application prospect, and has a certain significance for quickly finding gamma-carboline medicine pesticide candidate molecules and shortening the research period; the synthesis steps are simpler; the reaction efficiency is high; no substituent group is arranged on the nitrogen atom of the gamma-carboline, which is favorable for the later structural repair of the nitrogen atomAnd (5) decoration.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the description of the embodiments will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a flow chart of a method for synthesizing a gamma-carboline derivative according to an embodiment of the present invention;
FIG. 2 is an H NMR spectrum of a terminal 1, 2-disubstituted indole ethylene derivative prepared in example 1 of the present invention;
FIG. 3 is a C NMR spectrum of a terminal 1, 2-disubstituted indole ethylene derivative prepared in example 1 of the present invention;
FIG. 4 is a high resolution mass spectrum of the terminal 1, 2-disubstituted indole ethylene derivatives prepared in example 1 of the present invention;
FIG. 5 is an H NMR spectrum of a terminal 1, 2-disubstituted indole ethylene derivative prepared in example 6 of the present invention;
FIG. 6 is a C NMR spectrum of a terminal 1, 2-disubstituted indole ethylene derivative prepared in example 6 of the present invention;
FIG. 7 is a high resolution mass spectrum of the terminal 1, 2-disubstituted indole ethylene derivatives prepared in example 6 of the present invention.
Detailed Description
The advantages and various effects of the embodiments of the present invention will be more clearly apparent from the following detailed description and examples. Those skilled in the art will appreciate that these specific implementations and examples are provided to illustrate, but not limit, examples of the present invention.
Throughout the specification, unless specifically indicated otherwise, the terms used herein should be understood as meaning as commonly used in the art. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the invention belong. In case of conflict, the present specification will control.
Unless otherwise specifically indicated, the various raw materials, reagents, instruments, equipment and the like used in the examples of the present invention are commercially available or may be prepared by existing methods.
The technical scheme provided by the embodiment of the invention aims to solve the technical problems, and the overall thought is as follows:
according to an exemplary embodiment of the present invention, there is provided a method for synthesizing a γ -carboline derivative, as shown in fig. 1, the method comprising:
s1, mixing the compound I and R 2 -alkenyl borate is subjected to C-H alkenylation to obtain compound II;
in this embodiment, compound I is commercially available, or can be obtained by N-substitution of indole with 2-chloropyrimidine; and adding an organic solvent DMF and a catalyst NaH into the N substitution reaction, wherein the reaction temperature is 0-130 ℃. The molar ratio of the indole to the 2-chloropyrimidine is (1-1.2): (1-1.2). Too high or too low a ratio is detrimental to the reaction completion;
the R is 2 -alkenyl borates comprising: one of styrylboronic acid pinacol ester, styrylboronic acid pinacol, 4-methylphenylboronic acid pinacol ester and 4-phenyl Ding Xiji boronic acid pinacol ester, and may further comprise substituent R 2 Substituted other alkenyl borates, substituent R 2 Selected from the group consisting of C1-C6 alkyl, aryl substituted alkyl, naphthalene ring, aromatic heterocycle, phenyl and substituted phenyl wherein the substituents in the substituted phenyl are selected from the group consisting of trifluoromethoxy, trifluoromethyl, fluoro, chloro, formate, C1-C6 alkyl, benzyloxy and phenoxy and the positions of the substituents in the substituted phenyl are selected from the group consisting of para and/or meta positions on the benzene ring.
In step S1, a catalyst comprising AgOAc and [ RhCp ] Cl and an organic solvent are added 2 ] 2 The organic solvent is MeOH.
The molar mass ratio of the catalyst, the compound I and the alkenyl borate is as follows: agOAc: [ RhCp ] Cl 2 ] 2 : alkenyl borate: compound i= (1.5-4): (0.01-0.3): (1.5-4): 1. too high or too low a ratio is detrimental to the reaction completion;
the temperature of the C-H alkenyl reaction is 20-100 ℃, and the time of the C-H alkenyl reaction is 4-30H. Either too low or too high a reaction temperature is detrimental to the progress or completion of the reaction.
S2, removing pyrimidine groups from the compound II to obtain a compound III;
in the step S2, the compound II reacts with sodium ethoxide or sodium methoxide to remove pyrimidine groups, and a compound III is obtained.
The molar ratio of the compound II to the sodium ethoxide is 1: (3-5); the molar ratio of the compound II to the sodium methoxide is 1: (3-5). Too high or too low a ratio is detrimental to the reaction completion;
s3, formylating the compound III to obtain a compound IV;
in the step S3, the catalyst POCl is added in the formylation reaction 3 DMF and NaOH;
specifically, DMF was added, and POCl3 was added dropwise thereto under ice-bath cooling. Stirring for 10-30min, adding the compound III into a reaction bottle, heating to room temperature, continuously stirring for 0.2-1h, adding ice water, then adding 1mol/L NaOH solution, and performing post-treatment purification:
said compound III, POCl 3 The mol ratio of NaOH is as follows: compound III: POCl (Point of care testing) 3 : naoh=1: (2-4): (4-8); too high or too low a ratio is detrimental to complete formylation;
the ratio of the volume of DMF to the number of moles of compound III is (3-5): (0.5-2); too high or too low a ratio is detrimental to complete formylation;
s4, carrying out serial imidization and cyclization reaction on the compound IV to obtain a gamma-carboline derivative shown in the compound V;
in the step S4, hydroxylamine hydrochloride, sodium acetate and 1, 4-dioxane are added, wherein the molar ratio of the compound IV to the hydroxylamine hydrochloride to the sodium acetate is as follows: hydroxylamine hydrochloride: sodium acetate = 1: (1-4): (1-4). Too high or too low a ratio is detrimental to the reaction completion;
wherein, the reaction formula is specifically shown as follows:
substituent R 1 Selected from the group consisting of C1-C6 alkyl, methoxy, alkoxy, benzyloxy, ester, acetyl, cyano and halogen, and the position of the substituent R1 is selected from the group consisting of the 3,4,5,6 positions on the indole ring;
substituent R 2 Selected from the group consisting of C1-C6 alkyl, aryl substituted alkyl, naphthalene ring, aromatic heterocycle, phenyl and substituted phenyl wherein the substituents in the substituted phenyl are selected from the group consisting of trifluoromethoxy, fluoro, chloro, formate, methyl, benzyloxy and phenoxy and the substituents in the substituted phenyl are selected from the group consisting of para-and/or meta-positions on the phenyl ring.
The applicant finds that the gamma-carboline derivative shown in the compound V is successfully obtained by using simple and easily available indole as a starting material through N substitution reaction, C-H alkenylation reaction, radical removal reaction, formylation reaction, cascade imidization and cyclization reaction; the method is constructed from the head, uses simple and easily obtained indole as a starting raw material, has wide raw material sources, has the characteristics of universal application and a certain amplification application prospect, and has a certain significance for quickly finding gamma-carboline medicine pesticide candidate molecules and shortening the research period; the synthesis steps are simpler; the reaction efficiency is high; and the nitrogen atom of the gamma-carboline is not provided with a substituent group, so that the later structural modification of the nitrogen atom is facilitated.
The following will describe in detail the synthesis method of a gamma-carboline derivative according to the present application with reference to examples and experimental data.
Example 1
1. Synthetic Compound (1-1)
To a 25mL reaction flask were added indole (5 mmol), DMF (10 mL) and NaH (5 mmol). The reaction mixture was stirred at 0deg.C for 10 min, then 2-chloropyrimidine (6 mmol) was added and then allowed to warm to 130deg.C for reaction, and TLC detected completion. And (3) carrying out post-treatment purification: quench with water (20 mL), extract with EA (20 mL. Times.3), combine the organic phases and wash with saturated NaCl (20 mL. Times.2). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1 ], to give pure product, white solid, yield: 85%.
Compound (1-1) was detected:
1 H NMR(400MHz,CDCl 3 ):δ8.81(d,J＝8.3Hz,1H),8.71(d,J＝4.8Hz,2H),8.26(d,J＝3.8Hz,1H),7.62(d,J＝7.7Hz,1H),7.35(dd,J＝9.1,6.5Hz,1H),7.24(t,J＝6.1Hz,1H),7.02(m,1H),6.70(d,J＝3.7Hz,1H).
13 C NMR(100MHz,CDCl 3 )δ158.1,157.7,135.5,131.4,126.0,123.8,122.2,120.7,116.3,116.0,107.1.
2. synthetic compound (1-2)
In a 15mL schlenk tube, compound (1-1) (1 mmol), styrylboronic acid pinacol ester (2 mmol), agOAc (2 mmol), and [ RhCp. Times. Cl were added 2 ] 2 (0.02 mmol), meOH (5.0 mL), the mixture was reacted at 60℃for 24h, and TLC (thin layer chromatography) detected the completion of the reaction. And (3) carrying out post-treatment purification: cooled to room temperature and concentrated under pressure. The crude product was purified by column chromatography on silica gel [ V (petroleum ether): v (ethyl acetate)]=50:1 to 30:1, to give pure product, white solid, yield: 88%.
Compound (1-2) was detected:
1 H NMR(400MHz,CDCl 3 )δ8.47(d,J＝4.8Hz,2H),8.22(d,J＝8.2Hz,1H),7.66(d,J＝7.7Hz,1H),7.30(t,J＝7.6Hz,1H),7.26(d,J＝6.1Hz,1H),7.23–7.17(m,2H),7.14–7.01(m,3H),6.89(s,1H),6.83(t,J＝4.8Hz,1H),5.69(s,1H),5.60(s,1H).
13 C NMR(100MHz,CDCl 3 )δ157.7,157.2,143.1,140.4,140.0,137.2,128.9,127.8,127.3,126.7,123.7,122.0,120.6,116.7,115.1,113.5,109.8.
HRMS m/z:calcd for C 20 H 16 N 3 [M+H + ]298.1339,found 298.1337.
3. synthetic Compound (1-3)
In a 25mL reaction flask, compound (1-2) (1 mmol), sodium ethoxide (4 mmol), and DMSO (10 mL) were added. The reaction mixture was left to react at 100℃and TLC detected complete reaction. And (3) carrying out post-treatment purification: the reaction mixture was quenched with water (20 mL), extracted with EA (20 mL. Times.2), and the organic phases were combined and washed with saturated NaCl (20 mL. Times.1). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1 ], to give pure product, white solid, yield: 64%.
Compound (1-3) was tested:
1 H NMR(400MHz,CDCl 3 )δ10.30(br,1H),7.50-7.46(m,3H),7.38-7.35(m,4H),7.12(m,1H),6.96(m,1H),6.32(dd,J＝2.3,0.8Hz,1H),5.73(s,1H),5.32(d,J＝0.6Hz,1H).
13 C NMR(100MHz,CDCl 3 )δ143.0,141.6,138.7,138.4,129.5,129.3,129.1,129.0,123.0,121.1,120.1,112.5,111.9,104.1.
4. synthetic compound (1-4)
DMF (4 mL) was added to a 50mL reaction flask, and POCl was added dropwise thereto under ice-bath cooling 3 (2 mmol). After stirring for 15min, the reaction flask was charged with compound (1-3) (1 mmol) and then liftedTo room temperature. After stirring was continued for 0.5h, ice water (20 mL) was added to the reaction flask, followed by 1mol/L NaOH solution (4 mL) to the reaction flask. And (3) carrying out post-treatment purification: the reaction mixture was extracted with EA (20 mL. Times.2), the organic phases were combined and washed with saturated NaCl (20 mL. Times.1). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1]Pure product was obtained as white solid, yield: 85%.
Compound (1-4) was tested:
1 H NMR(400MHz,CDCl 3 )δ9.96(s,1H),8.67(s,1H),8.47–8.35(m,1H),7.38(d,J＝5.4Hz,5H),7.37–7.33(m,1H),7.33–7.28(m,2H),5.99(s,1H),5.70(s,1H).
13 C NMR(100MHz,CDCl 3 )δ186.4,148.4,138.8,138.7,135.1,129.1,128.9,127.7,125.7,124.6,123.1,122.3,121.6,116.8,111.1.
HRMS m/z:calcd for C 17 H 14 NO[M+H + ]248.1070,found 248.1063.
5. synthetic compound (1-5)
In a 25mL reaction flask, compound (1-4) (1 mmol), hydroxylamine hydrochloride (2 mmol), sodium acetate (2 mmol), and 1, 4-dioxane (10 mL) were added, and the reaction mixture was refluxed and the reaction was complete by TLC. And (3) carrying out post-treatment purification: quench with water (20 mL), extract with EA (20 mL. Times.3), combine the organic phases and wash with saturated NaCl (20 mL. Times.2). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =20:1 ], to give pure product, white solid, yield: 99%.
Compound (1-5) was tested:
1 H NMR(400MHz,DMSO)δ11.71(s,1H),9.35(s,1H),8.37(d,J＝80.0Hz,2H),7.90–7.12(m,8H).
13 C NMR(100MHz,DMSO)δ143.6,141.8,141.1,140.3,135.6,129.2,128.6,128.0,126.7,120.8,120.7,120.3,119.7,112.0.
HRMS m/z:calcd for C 17 H 13 N 2 [M+H + ]245.1073,found 245.1074.
example 2
1. Synthetic Compound (2-1)
In a 25mL reaction flask were added 4-benzylindole (5 mmol), DMF (10 mL) and NaH (5 mmol). The reaction mixture was stirred at 0deg.C for 10 min, then 2-chloropyrimidine (6 mmol) was added and then allowed to warm to 130deg.C for reaction, and TLC detected completion. And (3) carrying out post-treatment purification: quench with water (20 mL), extract with EA (20 mL. Times.3), combine the organic phases and wash with saturated NaCl (20 mL. Times.2). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1 ], to give pure product, white solid, yield: 80%.
2. Synthetic compound (2-2)
In a 15mL schlenk tube, compound (2-1) (1 mmol), styrylboronic acid pinacol (2 mmol), agOAc (2 mmol), and [ RhCp. Times. Cl were added 2 ] 2 (0.02 mmol), meOH (5.0 mL), the mixture was reacted at 60℃for 24h, and TLC (thin layer chromatography) detected the completion of the reaction. And (3) carrying out post-treatment purification: cooled to room temperature and concentrated under pressure. The crude product was purified by column chromatography on silica gel [ V (petroleum ether): v (ethyl acetate)]=50:1 to 30:1, to give pure product, white solid, yield: 66%.
3. Synthetic compound (2-3)
In a 25mL reaction flask, compound (2-2) (1 mmol), sodium ethoxide (4 mmol), and DMSO (10 mL) were added. The reaction mixture was left to react at 100℃and TLC detected complete reaction. And (3) carrying out post-treatment purification: the reaction mixture was quenched with water (20 mL), extracted with EA (20 mL. Times.2), and the organic phases were combined and washed with saturated NaCl (20 mL. Times.1). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1 ], to give pure product, white solid, yield: 70%.
4. Synthetic compound (2-4)
DMF (4 mL) was added to a 50mL reaction flask, and POCl was added dropwise thereto under ice-bath cooling 3 (2 mmol). After stirring for 15min, compound (2-3) (1 mmol) was added to the reaction flask, which was then warmed to room temperature. After stirring was continued for 0.5h, ice water (20 mL) was added to the reaction flask, followed by 1mol/L NaOH solution (4 mL) to the reaction flask. And (3) carrying out post-treatment purification: the reaction mixture was extracted with EA (20 mL. Times.2), the organic phases were combined and washed with saturated NaCl (20 mL. Times.1). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1]Pure product was obtained as white solid, yield: 80%.
5. Synthetic compound (2-5)
In a 25mL reaction flask, compound (2-4) (1 mmol), hydroxylamine hydrochloride (2 mmol), sodium acetate (2 mmol), and 1, 4-dioxane (10 mL) were added, and the reaction mixture was refluxed and the reaction was complete by TLC. And (3) carrying out post-treatment purification: quench with water (20 mL), extract with EA (20 mL. Times.3), combine the organic phases and wash with saturated NaCl (20 mL. Times.2). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =20:1 ], to give pure product, white solid, yield: 96%.
Example 3
1. Synthetic Compound (3-1)
In a 25mL reaction flask was added 5-methylindole (5 mmol), DMF (10 mL) and NaH (5 mmol). The reaction mixture was stirred at 0deg.C for 10 min, then 2-chloropyrimidine (6 mmol) was added and then allowed to warm to 130deg.C for reaction, and TLC detected completion. And (3) carrying out post-treatment purification: quench with water (20 mL), extract with EA (20 mL. Times.3), combine the organic phases and wash with saturated NaCl (20 mL. Times.2). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1 ], to give pure product, white solid, yield: 84%.
2. Synthetic compound (3-2)
In a 15mL schlenk tube, compound (3-1) (1 mmol), styrylboronic acid pinacol (2 mmol), agOAc (2 mmol), and [ RhCp. Times. Cl were added 2 ] 2 (0.02 mmol), meOH (5.0 mL), the mixture was reacted at 60℃for 24h, and TLC (thin layer chromatography) detected the completion of the reaction. And (3) carrying out post-treatment purification: cooled to room temperature and concentrated under pressure. The crude product was purified by column chromatography on silica gel [ V (petroleum ether): v (ethyl acetate)]=50:1 to 30:1, to give pure product, white solid, yield: 76%.
3. Synthetic Compound (3-3)
In a 25mL reaction flask, compound (3-2) (1 mmol), sodium ethoxide (4 mmol), and DMSO (10 mL) were added. The reaction mixture was left to react at 100℃and TLC detected complete reaction. And (3) carrying out post-treatment purification: the reaction mixture was quenched with water (20 mL), extracted with EA (20 mL. Times.2), and the organic phases were combined and washed with saturated NaCl (20 mL. Times.1). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1 ], to give pure product, white solid, yield: 67%.
4. Synthetic compound (3-4)
DMF (4 mL) was added to a 50mL reaction flask, and POCl was added dropwise thereto under ice-bath cooling 3 (2 mmol). After stirring for 15min, compound (3-3) (1 mmol) was added to the reaction flask, which was then warmed to room temperature. After stirring was continued for 0.5h, ice water (20 mL) was added to the reaction flask, followed by 1mol/L NaOH solution (4 mL) to the reaction flask. And (3) carrying out post-treatment purification: the reaction mixture was extracted with EA (20 mL. Times.2), the organic phases were combined and washed with saturated NaCl (20 mL. Times.1). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1]Pure product was obtained as white solid, yield: 87%.
5. Synthetic compound (3-5)
In a 25mL reaction flask, compound (3-4) (1 mmol), hydroxylamine hydrochloride (2 mmol), sodium acetate (2 mmol), and 1, 4-dioxane (10 mL) were added, and the reaction mixture was refluxed and the reaction was complete by TLC. And (3) carrying out post-treatment purification: quench with water (20 mL), extract with EA (20 mL. Times.3), combine the organic phases and wash with saturated NaCl (20 mL. Times.2). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =20:1 ], to give pure product, white solid, yield: 98%.
Example 4
1. Synthetic Compound (4-1)
In a 25mL reaction flask was added 6-bromoindole (5 mmol), DMF (10 mL) and NaH (5 mmol). The reaction mixture was stirred at 0deg.C for 10 min, then 2-chloropyrimidine (6 mmol) was added and then allowed to warm to 130deg.C for reaction, and TLC detected completion. And (3) carrying out post-treatment purification: quench with water (20 mL), extract with EA (20 mL. Times.3), combine the organic phases and wash with saturated NaCl (20 mL. Times.2). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1 ], to give pure product, white solid, yield: 78%.
2. Synthetic compound (4-2)
In a 15mL schlenk tube, compound (4-1) (1 mmol), styrylboronic acid pinacol (2 mmol), agOAc (2 mmol), and [ RhCp. Times. Cl were added 2 ] 2 (0.02 mmol), meOH (5.0 mL), the mixture was reacted at 60℃for 24h, and TLC (thin layer chromatography) detected the completion of the reaction. And (3) carrying out post-treatment purification: cooled to room temperature and concentrated under pressure. The crude product was purified by column chromatography on silica gel [ V (petroleum ether): v (ethyl acetate)]=50:1 to 30:1, to give pure product, white solid, yield: 64%.
3. Synthetic Compound (4-3)
In a 25mL reaction flask, compound (4-2) (1 mmol), sodium ethoxide (4 mmol), and DMSO (10 mL) were added. The reaction mixture was left to react at 100℃and TLC detected complete reaction. And (3) carrying out post-treatment purification: the reaction mixture was quenched with water (20 mL), extracted with EA (20 mL. Times.2), and the organic phases were combined and washed with saturated NaCl (20 mL. Times.1). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1 ], to give pure product, white solid, yield: 60%.
4. Synthetic Compound (4-4)
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DMF (4 mL) was added to a 50mL reaction flask, and POCl was added dropwise thereto under ice-bath cooling 3 (2 mmol). After stirring for 15min, compound (4-3) (1 mmol) was added to the reaction flask, which was then warmed to room temperature. After stirring was continued for 0.5h, ice water (20 mL) was added to the reaction flask, followed by 1mol/L NaOH solution (4 mL) to the reaction flask. And (3) carrying out post-treatment purification: the reaction mixture was extracted with EA (20 mL. Times.2), the organic phases were combined and washed with saturated NaCl (20 mL. Times.1). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1]Pure product was obtained as white solid, yield: 77%.
5. Synthetic compound (4-5)
In a 25mL reaction flask, compound (4-4) (1 mmol), hydroxylamine hydrochloride (2 mmol), sodium acetate (2 mmol), and 1, 4-dioxane (10 mL) were added, and the reaction mixture was refluxed and the reaction was complete by TLC. And (3) carrying out post-treatment purification: quench with water (20 mL), extract with EA (20 mL. Times.3), combine the organic phases and wash with saturated NaCl (20 mL. Times.2). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =20:1 ], to give pure product, white solid, yield: 90%.
Example 5
1. Synthetic Compound (5-2)
In a 15mL schlenk tube, compound (1-1) (1 mmol), 4-methylphenylboronic acid pinacol ester (2 mmol), agOAc (2 mmol), rhCp Cl was added 2 ] 2 (0.02 mmol), meOH (5.0 mL), the mixture was reacted at 60℃for 24h, and TLC (thin layer chromatography) detected the completion of the reaction. And (3) carrying out post-treatment purification: cooled to room temperature and concentrated under pressure. The crude product was purified by column chromatography on silica gel [ V (petroleum ether): v (ethyl acetate)]=50:1 to 30:1, to give pure product, white solid, yield: 76%.
2. Synthetic Compound (5-3)
In a 25mL reaction flask, compound (5-2) (1 mmol), sodium ethoxide (4 mmol), and DMSO (10 mL) were added. The reaction mixture was left to react at 100℃and TLC detected complete reaction. And (3) carrying out post-treatment purification: the reaction mixture was quenched with water (20 mL), extracted with EA (20 mL. Times.2), and the organic phases were combined and washed with saturated NaCl (20 mL. Times.1). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1 ], to give pure product, white solid, yield: 80%.
3. Synthetic Compound (5-4)
DMF (4 mL) was added to a 50mL reaction flask, and POCl was added dropwise thereto under ice-bath cooling 3 (2 mmol). After stirring for 15min, the reaction flask was charged with compound (5-3) (1 mmol) and then liftedTo room temperature. After stirring was continued for 0.5h, ice water (20 mL) was added to the reaction flask, followed by 1mol/L NaOH solution (4 mL) to the reaction flask. And (3) carrying out post-treatment purification: the reaction mixture was extracted with EA (20 mL. Times.2), the organic phases were combined and washed with saturated NaCl (20 mL. Times.1). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1]Pure product was obtained as white solid, yield: 88%.
4. Synthetic Compound (5-5)
In a 25mL reaction flask, compound (5-4) (1 mmol), hydroxylamine hydrochloride (2 mmol), sodium acetate (2 mmol), and 1, 4-dioxane (10 mL) were added, and the reaction mixture was refluxed and the reaction was complete by TLC. And (3) carrying out post-treatment purification: quench with water (20 mL), extract with EA (20 mL. Times.3), combine the organic phases and wash with saturated NaCl (20 mL. Times.2). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =20:1 ], to give pure product, white solid, yield: 99%.
Example 6
1. Synthetic compound (6-2)
In a 15mL schlenk tube, compound (1-1) (1 mmol), pinacol 4-phenyl Ding Xiji borate (2 mmol), agOAc (2 mmol), rhCp Cl was added 2 ] 2 (0.02 mmol), meOH (5.0 mL), the mixture was reacted at 60℃for 24h, and TLC (thin layer chromatography) detected the completion of the reaction. And (3) carrying out post-treatment purification: cooled to room temperature and concentrated under pressure. The crude product was purified by column chromatography on silica gel [ V (petroleum ether): v (ethyl acetate)]=50:1 to 30:1, to give pure product, white solid, yield: 50%.
2. Synthetic Compound (6-3)
In a 25mL reaction flask, compound (6-2) (1 mmol), sodium ethoxide (4 mmol), and DMSO (10 mL) were added. The reaction mixture was left to react at 100℃and TLC detected complete reaction. And (3) carrying out post-treatment purification: the reaction mixture was quenched with water (20 mL), extracted with EA (20 mL. Times.2), and the organic phases were combined and washed with saturated NaCl (20 mL. Times.1). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1 ], to give pure product, white solid, yield: 71%.
3. Synthetic Compound (5-4)
DMF (4 mL) was added to a 50mL reaction flask, and POCl was added dropwise thereto under ice-bath cooling 3 (2 mmol). After stirring for 15min, compound (6-3) (1 mmol) was added to the reaction flask, which was then warmed to room temperature. After stirring was continued for 0.5h, ice water (20 mL) was added to the reaction flask, followed by 1mol/L NaOH solution (4 mL) to the reaction flask. And (3) carrying out post-treatment purification: the reaction mixture was extracted with EA (20 mL. Times.2), the organic phases were combined and washed with saturated NaCl (20 mL. Times.1). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =15:1]Pure product was obtained as white solid, yield: 81%.
4. Synthetic Compound (5-5)
In a 25mL reaction flask, compound (6-4) (1 mmol), hydroxylamine hydrochloride (2 mmol), sodium acetate (2 mmol), and 1, 4-dioxane (10 mL) were added, and the reaction mixture was refluxed and the reaction was complete by TLC. And (3) carrying out post-treatment purification: quench with water (20 mL), extract with EA (20 mL. Times.3), combine the organic phases and wash with saturated NaCl (20 mL. Times.2). After separating the liquid, drying the liquid with anhydrous magnesium sulfate, removing the organic solvent under reduced pressure, and separating and purifying [ V (petroleum ether) by silica gel column chromatography: v (ethyl acetate) =20:1 ], to give pure product, white solid, yield: 92%.
Finally, it is also noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. It is therefore intended that the following claims be interpreted as including the preferred embodiment and all such alterations and modifications as fall within the scope of the embodiments of the invention.
It will be apparent to those skilled in the art that various modifications and variations can be made to the embodiments of the present invention without departing from the spirit or scope of the embodiments of the invention. Thus, the embodiments of the present invention are intended to include such modifications and alterations insofar as they come within the scope of the embodiments of the invention as claimed and the equivalents thereof.

Claims (5)

1. A method of synthesizing a gamma-carboline derivative, the method comprising:
compounds I and R 2 -alkenyl borate is subjected to C-H alkenylation to obtain compound II;
removing pyrimidine groups from the compound II to obtain a compound III;
formylating the compound III to obtain a compound IV;
carrying out serial imidization and cyclization reaction on the compound IV to obtain a gamma-carboline derivative shown in the compound V;
wherein, the reaction formula is as follows:
substituent R 1 Selected from C1-C6 alkyl, alkoxy, benzyloxy, acetyl, cyano and halogen, and the substituent R 1 Is selected from the group consisting of positions 3,4,5,6 on the indole ring;
substituent R 2 Selected from the group consisting of C1-C6 alkyl, aryl substituted alkyl, naphthalene ring, phenyl, and substituted phenyl, wherein the substituents in the substituted phenyl are selected from the group consisting of trifluoromethoxy, trifluoromethyl, fluoro, chloro, formate, C1-C6 alkyl, benzyloxy, and phenoxy, and the positions of the substituents in the substituted phenyl are selected from the group consisting of para-and/or meta-positions on the phenyl ring;
the compound I is obtained by carrying out N substitution reaction on indole and 2-chloropyrimidine;
in the C-H alkenylation reaction, a catalyst is added, wherein the catalyst is AgOAc and [ RhCp ] Cl 2 ] 2 The molar ratio of the catalyst, the compound I and the alkenyl borate is: agOAc: [ RhCp ] Cl 2 ] 2 : alkenyl borate: compound i= (1.5-4): (0.01-0.3): (1.5-4): 1, a step of;
said removing pyrimidine groups from said compound II to obtain a compound III comprising:
reacting the compound II with sodium ethoxide or sodium methoxide to remove pyrimidine groups to obtain a compound III;
the molar ratio of the compound II to the sodium ethoxide is 1: (3-5); the molar ratio of the compound II to the sodium methoxide is 1: (3-5).
2. The method for synthesizing a gamma-carboline derivative according to claim 1, wherein an organic solvent is added in the C-H alkenylation reaction, and the organic solvent is MeOH.
3. The method for synthesizing a gamma-carboline derivative according to claim 1, wherein the temperature of the C-H alkenylation reaction is 25-100 ℃, and the time of the C-H alkenylation reaction is 4-30H.
4. The method for synthesizing a gamma-carboline derivative according to claim 1, wherein POCl is added in the formylation reaction 3 DMF and NaOH, said compound III, POCl 3 The mol ratio of NaOH is as follows: compound III: POCl (Point of care testing) 3 ：NaOH=1：（2～4）：（4～8）。
5. The method for synthesizing the gamma-carboline derivative according to claim 1, wherein hydroxylamine hydrochloride, sodium acetate and 1, 4-dioxane are added in the cascade imidization and cyclization reaction, and the molar ratio of the compound IV to the hydroxylamine hydrochloride to the sodium acetate is the compound IV: hydroxylamine hydrochloride: sodium acetate = 1: (1-4): (1-4).
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106928201A (en) * 2017-02-22 2017-07-07 江汉大学 The method for synthesizing 2 vinyl indole derivativeses

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106928201A (en) * 2017-02-22 2017-07-07 江汉大学 The method for synthesizing 2 vinyl indole derivativeses

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* Cited by examiner, † Cited by third party
Title
Efficient synthetic route toward biologically activeγ-carboline derivatives;Dattatray G. Hingane等;synthetic communications;第46卷(第2期);160-164 *

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