Method for synthesizing bis-indole ring compound by using di-tert-butyldiaziridone as amine source

Abstract

The invention belongs to the field of organic medicine synthesis, and discloses a method for synthesizing a bis-indole ring compound by taking di-tert-butyldiazidinone as an amine source. The preparation method comprises the following steps: under the protection of inert gas, adding 2-(2-iodophenyl)-indole 1, di-tert-butyldiaziridone 2, a palladium catalyst, a ligand and alkali into an organic solvent according to a ratio, reacting at a heating temperature, preparing the bis-indole ring compound after the reaction, and separating a target product after the reaction is completed. According to the present invention, the di-tert-butyl aziridone is adopted as the nitrogen source, such that the method has advantages of simpleness and novelty, and can synthesize a series of the bisindole ring compounds and the derivatives thereof at the high efficiency. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic drug synthesis, and specifically relates to a method for synthesizing a bisindole cyclic compound by using di-tert-butyldiaziridine ketone as an amine source. Background Art

[0002] As we all know, indole is an important structural skeleton in nature. Indole and its homologues and derivative skeletons are widely present in nature, such as natural flower oils, jasmine, vanilla and other substances. Similarly, as a kind of indole derivatives, bis-indole cyclic compounds and their derivatives are also a very important class of organic nitrogen-containing heterocycles with potential biological and pharmaceutical activities. The synthesis and application of bis-indole cyclic compounds and their derivatives are also receiving more and more attention. In previous studies, the use of di-tert-butyl diaziridine ketone as an amine source to synthesize indole compounds has also been studied to a certain extent. However, previous studies mainly synthesized compounds with a single indole skeleton.

[0003] As far as we know, there is no report on the method of synthesizing the skeleton of bis-indole cyclic compounds using 2-(2-iodophenyl)-indole as the raw material and di-tert-butyl diaziridine ketone as the nitrogen source. Here, we use a new reaction substrate and newly explored optimal conditions to efficiently synthesize a series of corresponding bis-indole cyclic compounds. Summary of the invention

[0004] The present invention provides a novel synthesis method of a bis-indole cyclic compound and its derivatives. The present invention uses 2-(2-iodophenyl)-indole as a raw material, a novel reactant di-tert-butyl diaziridine ketone as a nitrogen source, and a series of bis-indole cyclic compounds and their derivatives can be obtained by amination reaction of 2-(2-iodophenyl)-indole and di-tert-butyl diaziridine ketone under the conditions of metal palladium as a catalyst, cesium carbonate as a base, and various phosphorus ligands as ligands.

[0005] To achieve the above technical objectives and the above technical effects, the present invention intends to implement the following technical solutions:

[0006] A method for synthesizing a bisindole cyclic compound comprises the following steps: under the protection of an inert gas, adding 2-(2-iodophenyl)-indole 1, di-tert-butyldiaziridine ketone 2, metal palladium, a ligand and a base as shown in formula (1) to an organic solvent in proportion, reacting at 90 to 130 degrees Celsius, and preparing a compound 3 as shown in the following formula after several hours of reaction. After the reaction is completed, the target product, the bisindole cyclic compound, is separated.

[0007]

[0008] In the 2-(2-iodophenyl)-indole 1 represented by formula (1), R1 One substituent selected from the group consisting of hydrogen atom, 5-Me, 5-F, 5-Cl, 5-trifluoromethoxy, 4,6-dimethyl, 4,6-dichloro and the like.

[0009] In the 2-(2-iodophenyl)-indole 1 represented by formula (1), R 2 One selected from a hydrogen atom, 4-F, 4-Cl, or a substituent such as 3-Me, 3-Cl.

[0010] In the 2-(2-iodophenyl)-indole 1 represented by formula (1), R 3 Select one of methyl, ethyl, benzyl or 2-methylpentenyl.

[0011] The added components of formula (1) are 2-(2-iodophenyl)-indole 1 (1.0 eq.), di-tert-butyldiaziridinone (1.0 to 3.0 equivalents), a base (1.0 to 3.0 equivalents), various metal palladiums (2.5 mol% to 20.0 mol%), and various phosphine ligands (5 mol% to 20 mol%).

[0012] The organic solvent includes one or more of toluene, 1,4-dioxane, tetrahydrofuran, n-hexane, acetonitrile or NN-dimethylformamide, and NN-dimethylformamide is preferred as the solvent.

[0013] The metal palladium includes one or more of palladium acetate, palladium trifluoroacetate, palladium di(acetylacetonate), palladium chloride, palladium iodide, or palladium hydroxide. Preferably, palladium acetate is used as the catalyst.

[0014] The phosphine ligands include PPh3, (o-tolyl)3P, (pF-Ph)3P, PPh2Cy, PCy3, dppb, dppf, etc. (o-tolyl)3P(L1) is preferred as the ligand.

[0015]

[0016] The structure of the selected di-tert-butyl diaziridine ketone is:

[0017]

[0018] The reaction temperature is 90-130°C, and 130°C is more preferably selected as the reaction temperature.

[0019] The prepared bis-indole cyclic compound is separated by column chromatography.

[0020] Beneficial results of the present invention: The present invention uses metal palladium as a catalyst and various phosphine ligands as ligands, and in the presence of a base, 2-(2-iodophenyl)-indole and di-tert-butyldiaziridine ketone are reacted to obtain corresponding bis-indole cyclic compounds and their derivatives under certain conditions. The synthesis method has simple steps, is easy to operate, has high synthesis efficiency, and is relatively novel. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 5-(tert-butyl)-10-methyl-5,10-dihydroindole[3,2-b]indole (structural formula 3a) synthesized in Example 1 1 H NMR spectrum;

[0022] Figure 2 5-(tert-butyl)-10-methyl-5,10-dihydroindole[3,2-b]indole (structural formula 3a) synthesized in Example 1 13 C NMR spectrum;

[0023] Figure 3 5-(tert-butyl)-10-ethyl-5,10-dihydroindole[3,2-b]indole (structural formula 3b) synthesized in Example 2 1 H NMR spectrum;

[0024] Figure 4 5-(tert-butyl)-10-ethyl-5,10-dihydroindole[3,2-b]indole (structural formula 3b) synthesized in Example 2 13 C NMR spectrum;

[0025] Figure 5 5-benzyl-10-(tert-butyl)-5,10-dihydroindole[3,2-b]indole (structural formula 3c) synthesized in Example 3 1 HNMR spectrum;

[0026] Figure 6 5-benzyl-10-(tert-butyl)-5,10-dihydroindole[3,2-b]indole (structural formula 3c) synthesized in Example 3 13 CNMR spectrum;

[0027] Figure 7 5-(tert-butyl)-10-(3-methylbut-3-en-1-yl)-5,10-dihydroindole[3,2-b]indole (structural formula 3d) synthesized in Example 4 1 H NMR spectrum;

[0028] Figure 85-(tert-butyl)-10-(3-methylbut-3-en-1-yl)-5,10-dihydroindole[3,2-b]indole (structural formula 3d) synthesized in Example 4 13 C NMR spectrum;

[0029] Fig. 9 10-(tert-butyl)-3-fluoro-5-(3-methylbut-3-en-1-yl)-5,10-dihydroindole[3,2-b]indole (structural formula 3e) synthesized in Example 5 1 H NMR spectrum;

[0030] Fig.10 10-(tert-butyl)-3-fluoro-5-(3-methylbut-3-en-1-yl)-5,10-dihydroindole[3,2-b]indole (structural formula 3e) synthesized in Example 5 13 C NMR spectrum;

[0031] Fig.11 5-(tert-butyl)-2,4-dimethyl-10-(3-methylbut-3-en-1-yl)-5,10-dihydroindole[3,2-b]indole (structural formula 3f) synthesized in Example 6 1 H NMR spectrum;

[0032] Fig.12 5-(tert-butyl)-2,4-dimethyl-10-(3-methylbut-3-en-1-yl)-5,10-dihydroindole[3,2-b]indole (structural formula 3f) synthesized in Example 6 13 C NMR spectrum. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the examples. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the scope of protection of the present invention. The raw materials in Examples 1-6 can all be synthesized by the disclosed methods.

[0034] The application principle and implementation examples of the present invention are described in detail below in conjunction with the accompanying drawings.

[0035] Example 1: Synthesis of 5-(tert-butyl)-10-methyl-5,10-dihydroindole[3,2-b]indole (Structural Formula 3a)

[0036]

[0037] Under argon protection, Pd(OAc)2 (0.0034 g, 0.015 mmol), (o-tolyl)3P(L1) (0.0183 g, 0.060 mmol), Cs2CO3 (0.1466 g, 0.45 mmol), 2-(2-iodophenyl)-1-methylindole of structural formula 1a (0.1000 g, 0.3 mmol), 2.0 mL DMF, and di-tert-butyldiaziridine ketone 2 (0.0766 g, 0.45 mmol) were added to the reactor in sequence. After nitrogen was purged from the reaction bottle, the bottle cap was screwed on and sealed. After reacting at 130°C for 48 hours, the mixture was cooled to room temperature and subjected to neutral alumina column chromatography. The specific conditions were as follows: the column was loaded with petroleum ether and the eluent was petroleum ether:ethyl acetate in a ratio of 100:1 to obtain a white solid 3a (0.0812 g, 98% yield) at mp. 92.0-94.4°C;

[0038] The results of 3a structure confirmation are as follows: 1 H NMR (400MHz, CDCl3) δ8.13(d,J=8.4Hz,1H),8.04(d,J=9.2Hz,2H),7.53(d,J=8.0Hz,1 H),7.44-7.37(m,1H),7.34-7.26(m,2H),7.25-7.19(m,1H),4.20(s,3H),2.12(s,9H); 13 C NMR (100MHz, CDCl3) δ141.5,140.5,128.2,125.1,122.0,121.5,121.0,118.3 ,117.8,117.7,115.7,115.3,114.0,109.6,58.1,31.7,31.5; HRMS(ESI)calcd for C 19 H 21 N2(M+H) + :277.1699;found:277.1694.

[0039] For the synthesis of product 3a in Example 1, the reaction results under some other conditions are as follows:

[0040]

[0041]

[0042] aUnless otherwise noted, all reaction conditions were as follows: substrate 1a (0.30 mmol), di-tert-butyldiaziridine ketone 2 (0.45 mmol), palladium catalyst (0.015 mmol), ligand (0.060 mmol, Pd / P=1:4), cesium carbonate (0.45 mmol), in solvent (2.0 mL), reaction at 130 °C for 12 h.

[0043] Example 2: Synthesis of 5-(tert-butyl)-10-ethyl-5,10-dihydroindole[3,2-b]indole (Structural Formula 3b)

[0044]

[0045] Under argon protection, Pd(OAc)2 (0.0034 g, 0.015 mmol), (o-tolyl)3P(L1) (0.0183 g, 0.060 mmol), Cs2CO3 (0.1466 g, 0.45 mmol), 2-(2-iodophenyl)-1-ethylindole of structural formula 1b (0.1042 g, 0.3 mmol), 2.0 mL DMF, and di-tert-butyldiaziridine ketone 2 (0.0766 g, 0.45 mmol) were added to the reactor in sequence. After nitrogen was purged from the reaction bottle, the bottle cap was screwed on and sealed. After reacting at 130°C for 48 hours, the mixture was cooled to room temperature and subjected to neutral alumina column chromatography. The specific conditions were as follows: the column was loaded with petroleum ether and the eluent was petroleum ether:ethyl acetate in a ratio of 150:1 to obtain a white solid 3b (0.0840 g, 96% yield) at mp. 106.3-109.2°C;

[0046] The results of 3b structure confirmation are as follows: 1 H NMR (400MHz, CDCl3) δ8.03(d,J=8.0Hz,1H),7.94(d,J=8.8Hz,1H),7.86(d,J=7.6Hz,1H),7.45(d,J=8.0Hz,1H),7 .31-7.25(m,1H),7.24-7.17(m,2H),7.16-7.10(m,1H),4.55(q,J=7.2Hz,2H),2.02(s,9H),1.49(t,J=7.2Hz,3H); 13 CNMR (100MHz, CDCl3) δ140.5,140.4,127.2,125.4,121.9,121.5,121.1,118.2,117.9,117.8,115.8,115.1,114.0,109.5,58.1,39.6,31.7,15.3.

[0047] Example 3: Synthesis of 5-benzyl-10-(tert-butyl)-5,10-dihydroindole[3,2-b]indole (Structural Formula 3c)

[0048]

[0049] Under argon protection, Pd(OAc)2 (0.0034 g, 0.015 mmol), (o-tolyl)3P(L1) (0.0183 g, 0.060 mmol), Cs2CO3 (0.1466 g, 0.45 mmol), 2-(2-iodophenyl)-1-benzylindole of structural formula 1c (0.1227 g, 0.3 mmol), 2.0 mL DMF, and di-tert-butyldiaziridine ketone 2 (0.0766 g, 0.45 mmol) were added to the reactor in sequence. After nitrogen was purged from the reaction bottle, the bottle cap was screwed on and sealed. After reacting at 130°C for 48 hours, the mixture was cooled to room temperature and subjected to neutral alumina column chromatography. The specific conditions were as follows: the column was loaded with petroleum ether and the eluent was petroleum ether:ethyl acetate in a ratio of 100:1 to obtain a white solid 3c (0.1027 g, 97% yield) at mp. 113.7-116.3°C;

[0050] The results of 3c structure confirmation are as follows: 1 H NMR (400MHz, CDCl3) δ8.05(d,J=8.0Hz,1H),7.93(d,J=8.8Hz,1H),7.67(d,J=7.6Hz,1H), 7.39(d,J=8.0Hz,1H),7.26-7.10(m,8H),7.01(t,J=7.6Hz,1H),5.68(s,2H),2.03(s,9H); 13 C NMR (100MHz, CDCl3) δ141.3,140.6,138.1,129.0,127.8,127.5,126.6,125.5,122.0,121.8 ,121.1,118.7,118.0,117.8,116.0,115.1,114.0,110.0,58.2,48.5,31.7; HRMS(ESI)calcd for C 25 H 25 N2(M+H) + :353.2012,found353.2011.

[0051] Example 4: Synthesis of 5-(tert-butyl)-10-(3-methylbut-3-en-1-yl)-5,10-dihydroindole[3,2-b]indole (Structural Formula 3d)

[0052]

[0053] Under argon protection, Pd(OAc)2 (0.0034 g, 0.015 mmol), (o-tolyl)3P(L1) (0.0183 g, 0.060 mmol), Cs2CO3 (0.1466 g, 0.45 mmol), 2-(2-iodophenyl)-1-(3-methylpentenyl)indole (0.1162 g, 0.3 mmol) of the structural formula 1d, 2.0 mL DMF, and di-tert-butyldiaziridine ketone 2 (0.0766 g, 0.45 mmol) were added to the reactor in sequence. After nitrogen was purged into the reaction bottle, the bottle cap was screwed on and sealed. After reacting at 130°C for 48 hours, the mixture was cooled to room temperature and subjected to silica gel column chromatography. The specific conditions were as follows: the column was loaded with petroleum ether, and the eluent was petroleum ether: ethyl acetate 50:1, to obtain a light yellow oil 3d (0.0765 g, 77% yield);

[0054] The results of 3D structure confirmation are as follows: 1 H NMR (400MHz, CDCl3) δ8.06(d,J=8.4Hz,1H),7.99(d,J=8.8Hz,1H),7.89(dd,J=7.6,1.2Hz,1H),7.51(d,J=8.4Hz,1H),7.36-7.31 (m,1H),7.28-7.21(m,2H),7.21-7.14(m,1H),4.94-4.89(m,2H),4.69-4.63(m,2H),2.67-2.60(m,2H),2.07(s,9H),1.89(s,3H); 13 C NMR (100MHz, CDCl3) δ142.9,140.7,140.5,127.2,125.5,121.9,121.5,121.2,118.4,117. 9,117.8,115.8,115.1,114.1,112.3,109.6,58.2,44.1,38.0,31.7,23.2; HRMS(ESI)calcd for C 23 H 27 N2(M+H) + 331.2169; found 331.2168.

[0055] Example 5: Synthesis of 10-(tert-butyl)-3-fluoro-5-(3-methylbut-3-en-1-yl)-5,10-dihydroindole[3,2-b]indole (Structural Formula 3e)

[0056]

[0057] Under argon protection, Pd(OAc)2 (0.0034 g, 0.015 mmol), (o-tolyl)3P(L1) (0.0183 g, 0.060 mmol), Cs2CO3 (0.1466 g, 0.45 mmol), 2-(5-fluoro-2-iodophenyl)-1-(3-methylpentenyl)-indole (0.1216 g, 0.3 mmol) of structural formula 1e, 2.0 mL DMF, and di-tert-butyldiaziridine ketone 2 (0.0766 g, 0.45 mmol) were added to the reactor in sequence. After nitrogen was purged from the reaction bottle, the bottle cap was screwed on and sealed. After reacting at 130° C. for 48 hours, the mixture was cooled to room temperature and subjected to silica gel column chromatography. The specific conditions were as follows: the column was loaded with petroleum ether and the eluent was petroleum ether:ethyl acetate in a ratio of 50:1 to obtain a light yellow oil 3e (0.0797 g, 76% yield);

[0058] The results of 3e structure confirmation are as follows: 1 H NMR (400MHz, CDCl3) δ8.05(d,J=8.4Hz,1H),7.88(dd,J=9.6,4.4Hz,1H),7.51-7.46(m,2H),7.37-7.31(m,1H),7.23-7.18( 13C NMR (100MHz, CDCl3) δ156.4 (d, J = 232.8), 142.7, 141.0, 137.2, 127.1, 126.9 (d, J = 4.2 Hz), 122.1, 121.4, 118.5, 115. 7,114.7(d,J=9.6Hz),114.6(d,J=8.8Hz),112.5,109.70(d,J=24.7),109.66,102.6(d,J=23.8Hz); HRMS(ESI)calcd forC 23 H 22 F3N2O2(M+H) + :349.2075;found:349.2072.

[0059] Example 6: Synthesis of 5-(tert-butyl)-2,4-dimethyl-10-(3-methylbut-3-en-1-yl)-5,10-dihydroindole[3,2-b]indole (Structural Formula 3f)

[0060]

[0061] Under argon protection, Pd(OAc)2 (0.0034 g, 0.015 mmol), (o-tolyl)3P(L1) (0.0183 g, 0.060 mmol), Cs2CO3 (0.1466 g, 0.45 mmol), 2-(2-iodophenyl)-4,6-dimethyl-1-(3-methylpentenyl)-indole (0.1246 g, 0.3 mmol) of structural formula 1f, 2.0 mL DMF, and di-tert-butyldiaziridine ketone 2 (0.0766 g, 0.45 mmol) were added to the reactor in sequence. After nitrogen was purged into the reaction bottle, the bottle cap was screwed on and sealed. After reacting at 130°C for 48 hours, the mixture was cooled to room temperature and subjected to silica gel column chromatography. The specific conditions were as follows: the column was loaded with petroleum ether and the eluent was petroleum ether:ethyl acetate 50:1 to obtain a light yellow solid 3f (0.0832 g, 77% yield) with mp. 108.6-109.8°C;

[0062] The results of 3f structure confirmation are as follows: 1 1H NMR (400MHz, CDCl3) δ7.78-7.69(m,2H),7.21-7.13(m,2H),7.07(s,1H),6.82(s,1H),4.89(s,2H 13C NMR (100MHz, CDCl3) δ146.6,143.0,141.1,131.4,130.1,128.5,128.3,123.3,121.2,119.7,118 .8,118.3,117.2,117.0,112.2,107.1,57.9,44.0,37.9,32.3,24.1,23.2,21.9; HRMS(ESI)calcd for C 24 H 26 N2ONa(M+H) + :359.2482;found:359.2480.

[0063] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for synthesizing a bisindole annular compound, characterized in that: Under the protection of an inert gas, 2-(2-iodophenyl)-indole 1, di-tert-butyldiaziridine ketone 2, a palladium catalyst, a phosphine ligand and a base represented by formula (1) are added to an organic solvent in proportion, reacted under heating conditions, and after the reaction is completed, the target product, a bis-indole cyclized compound 3, is isolated; 2. The method for synthesizing the bisindole annular compound according to claim 1, wherein: In the 2-(2-iodophenyl)-indole 1 represented by formula (1), R 1 One selected from the group consisting of hydrogen atom, 5-Me, 5-F, 5-Cl, 5-trifluoromethoxy, 4,6-dimethyl, and 4,6-dichloro substituents.

3. The method for synthesizing the bisindole annular compound according to claim 1, characterized in that: In the 2-(2-iodophenyl)-indole 1 represented by formula (1), R 2 One selected from the group consisting of hydrogen atom, 4-F, 4-Cl, 3-Me, and 3-Cl substituents.

4. The method for synthesizing the bisindole annular compound according to claim 1, characterized in that: In the 2-(2-iodophenyl)-indole 1 represented by formula (1), R 3 One selected from an alkyl group, a benzyl group or a 2-methylpentenyl group.

5. The method for synthesizing the bisindole annular compound according to claim 1, characterized in that: The molar ratio of 2-(2-iodophenyl)-indole 1, di-tert-butyldiaziridine ketone 2, base, palladium catalyst and phosphine ligand is 1:(1-3):(1-3):(0.025-0.2):(0.05-0.2).

6. The method for synthesizing the bisindole annular compound according to claim 1, characterized in that: The organic solvent includes one or more of toluene, 1,4-dioxane, tetrahydrofuran, n-hexane, acetonitrile or NN-dimethylformamide.

7. The method for synthesizing the bisindole annular compound according to claim 1, characterized in that: The palladium catalyst includes one or more of palladium acetate, palladium trifluoroacetate, di(acetylacetonate)palladium, palladium chloride, palladium iodide and palladium hydroxide.

8. The method for synthesizing the bisindole annular compound according to claim 1, characterized in that: The phosphine ligand includes one of PPh3, (o-tolyl)3P, (pF-Ph)3P, PPh2Cy, PCy3, dppb, and dppf ligands.

9. The method for synthesizing the bisindole annular compound according to claim 1, characterized in that: The reaction temperature is 90-130°C.

10. The method for synthesizing the bisindole annular compound according to claim 1, characterized in that: The base is Cs2CO3.

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