A preparation method of N-aminoindole

Abstract

The present invention discloses a method for synthesizing N-aminoindole, belonging to the field of chemical synthesis. This method uses arylhydrazines substituted with di-tert-butyl dicarbonate (Boc) groups and calcium carbide as raw materials, divalent ruthenium as a catalyst, silver hexafluoroantimonate as a co-catalyst, divalent copper as an oxidant, and acetic acid as an additive to prepare N-aminoindole through catalytic oxidation. This method uses inexpensive, abundant, and easy-to-handle solid calcium carbide instead of flammable and explosive gaseous acetylene as the primary alkyne source, reducing operational difficulty and safety risks. It also offers advantages such as good substrate compatibility, mild reaction conditions, and high yield.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and particularly relates to a method for preparing N-aminoindole. Background Art

[0002] N-aminoindole is a very important and versatile chemical raw material. The indole skeleton is found in many natural products and in the essential amino acid tryptophan. Indole derivatives exhibit diverse biological activities and are therefore considered advantageous structures in drug research. The indole nucleus is a key component of many biologically important natural and synthetic molecules. It is one of the "privileged structures" of the pharmaceutical industry because this fragment plays a central role in drug discovery.

[0003] Currently, the preparation process of N-aminoindole mainly uses 2-halogenated-phenylacetylene and N,N-disubstituted hydrazine as raw materials and is prepared by a transition metal catalysis method. For example, the Chinese invention patent document with publication number CN101657422A discloses a preparation method of N-aminoindole. Using palladium as a catalyst, 2-halogenated-phenylacetylene and N,N-disubstituted hydrazine as raw materials are used to prepare a variety of N-aminoindole compounds. However, the preparation of 2-halogenated-phenylacetylene is complex and costly, which is not conducive to industrial development. As shown in reaction formula (1):

[0004]

[0005] In 2015, Frank Glorius et al. reported a rhodium-catalyzed nucleophilic addition reaction for the preparation of N-NHBoc indole compounds. This reaction used N-Boc aryl imines and olefins as raw materials to prepare a variety of N-NHBoc indole compounds [see: Angew. Chem. Int. Ed. 2015, 54, 1657]. This reaction has the advantages of high yield and a wide substrate range. However, the reaction uses expensive rhodium as a catalyst and silver acetate as an oxidant, which is costly and not conducive to industrial production. As shown in reaction formula (2):

[0006] Summary of the Invention

[0007] The present invention aims to provide a method for preparing N-aminoindole, which has the advantages of simple and readily available raw materials, high yield, mild reaction conditions, good substrate compatibility and low production cost.

[0008] To achieve the object of the present invention, the present invention provides a technical solution for the preparation of N-aminoindole, comprising the following steps:

[0009] A solution A is prepared by mixing arylhydrazine substituted with di-tert-butyldicarbonate (Boc), a catalyst, silver hexafluoroantimonate, an oxidant, acetic acid, and a solvent. Calcium carbide and a solvent are prepared into a solution B. Solution B is added dropwise to solution A at 50-90°C for 0.5-1 hour and kept warm for 5-12 hours, with the holding temperature being the same as the temperature at the time of addition. After the holding period, the organic phase is washed with water until neutral, and distilled under reduced pressure to remove the solvent to obtain a crude N-aminoindole product, which is then separated by column chromatography and dried to obtain N-aminoindole. The reaction formula is as follows:

[0010]

[0011] wherein R is selected from one of hydrogen, an alkyl group, and a halogen. Furthermore, the solvent is one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dimethyl carbonate, and N,N-dimethylformamide; the solvent in solution A and solution B is the same solvent; the molar ratio of the arylhydrazine substituted with a di-tert-butyl dicarbonate group to the solvent in solution A is 1:5-20; the molar ratio of calcium carbide to the solvent in solution B is 1:5-10; and the molar ratio of the arylhydrazine substituted with a di-tert-butyl dicarbonate group to calcium carbide is 1:1.1-1.5.

[0012] Furthermore, the catalyst is one of ruthenium chloride, ruthenium acetate, ruthenium acetylacetonate, and (1,5-cyclooctadiene)ruthenium chloride, and the molar ratio of the catalyst to the arylhydrazine substituted with di-tert-butyl dicarbonate (Boc) group is 2 to 10:100.

[0013] Furthermore, the oxidant is one of copper acetate, copper chloride, and copper oxide, and the molar ratio of the oxidant to the arylhydrazine substituted with di-tert-butyl dicarbonate (Boc) group is 2 to 5:1.

[0014] Furthermore, the molar ratio of acetic acid to calcium carbide is 2 to 4:1.

[0015] Furthermore, the molar ratio of silver hexafluoroantimonate to arylhydrazine substituted with di-tert-butyl dicarbonate (Boc) group is 0.1-0.3:1.

[0016] The beneficial effects of the present invention are:

[0017] 1. The technical solution provided by this invention utilizes calcium carbide as the alkyne source instead of acetylene, which not only reduces production costs but also significantly minimizes safety risks. Using Boc-substituted arylhydrazines as starting materials not only offers good functional group compatibility but also allows for easy removal of the Boc group, enabling other functionalization reactions.

[0018] 2. The technical solution provided by this invention utilizes divalent ruthenium as a catalyst, silver hexafluoroantimonate as a co-catalyst, and acetic acid as an additive. This method enhances catalytic activity by in situ generating an active ruthenium catalyst containing hexafluoroantimonate. Compared to metallic palladium and rhodium, this method is more affordable and more amenable to industrial production. Acetic acid reacts with calcium carbide to generate acetylene in situ, accelerating the reaction. The resulting calcium acetate then promotes the carbon-hydrogen bond activation step of the reaction.

[0019] 3. The technical solution provided by the present invention has cheap and readily available raw materials, is simple to operate, can complete the reaction in one step, has mild reaction conditions, the reaction temperature is between 50 and 90°C, and has a high reaction yield of 85.8 to 92.1%. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 N-NHBoc indole of Example 1 1 H-NMR spectrum;

[0021] Figure 2 is the N-NHBoc indole of Example 1 13 C-NMR spectrum. DETAILED DESCRIPTION

[0022] To help those skilled in the art better understand the technical solutions of the present invention, the following clearly and completely describes the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only a portion of the embodiments of the present invention, not all of them. All other embodiments derived by those skilled in the art based on the embodiments of the present invention without creative effort should fall within the scope of protection of the present invention. Example 1

[0023]

[0024] In a 1L four-necked flask equipped with a stirrer, a dropping funnel, and a thermometer, N-Boc-N'-phenylhydrazine (0.1 mol), ruthenium chloride (2 mmol), silver hexafluoroantimonate (0.01 mol), copper acetate (0.2 mol), acetic acid (0.22 mol), and dichloromethane (2 mol) were prepared into solution A. Calcium carbide (0.11 mol) and dichloromethane (1.1 mol) were prepared into solution B. Solution B was added dropwise to solution A at 50°C for 0.5 h. After the addition was completed, the temperature was maintained for 5 h. After the temperature was maintained, the reaction solution was washed with water until neutral, the solvent was removed under reduced pressure, and petroleum ether / ethyl acetate was used as the eluent. The product was separated on a silica gel column and dried to obtain 20.1 g of N-NHBoc indole in a yield of 86.8%. Example 2

[0025]

[0026] In a 1L four-necked flask equipped with a stirrer, a dropping funnel, and a thermometer, N-Boc-N'-(4-methylphenyl)hydrazine (0.1 mol), ruthenium acetate (10 mmol), silver hexafluoroantimonate (0.03 mol), copper chloride (0.5 mol), acetic acid (0.6 mol), and 1,2-dichloroethane (0.5 mol) were prepared to form solution A. Calcium carbide (9.6 g, 0.15 mol) and 1,2-dichloroethane (0.75 mol) were prepared to form solution B. Solution B was added dropwise to solution A at 90°C for 1 h. After the addition was completed, the mixture was kept warm for 12 h. After the end of the warming period, the reaction mixture was washed with water until neutral. The solvent was removed under reduced pressure, and petroleum ether / ethyl acetate was used as the eluent. The mixture was separated on a silica gel column and dried to obtain 22.2 g of N-NHBoc-6-methylindole in a yield of 90.2%. Example 3

[0027]

[0028] In a 1L four-necked flask equipped with a stirrer, a dropping funnel, and a thermometer, N-Boc-N'-(4-tert-butylphenyl)hydrazine (0.1 mol), ruthenium acetylacetonate (5 mmol), silver hexafluoroantimonate (0.02 mol), copper oxide (0.3 mol), acetic acid (0.36 mol), and tetrahydrofuran (1 mol) were prepared to form solution A. Calcium carbide (0.12 mol) and tetrahydrofuran (1.2 mol) were prepared to form solution B. Solution B was added dropwise to solution A at 80°C for 0.7 h. After the addition was complete, the temperature was maintained for 10 h. After the temperature was reached, the reaction solution was washed with water until neutral. The solvent was removed under reduced pressure, and petroleum ether / ethyl acetate was used as the eluent. The product was separated on a silica gel column and dried to obtain 24.7 g of N-NHBoc-6-tert-butylindole in a yield of 85.8%. Example 4

[0029]

[0030] In a 1L four-necked flask equipped with a stirrer, a dropping funnel, and a thermometer, N-Boc-N'-(3-methylphenyl)hydrazine (0.1 mol), (1,5-cyclooctadiene)ruthenium chloride (5 mmol), silver hexafluoroantimonate (0.03 mol), copper chloride (0.5 mol), acetic acid (0.26 mol), and dimethyl carbonate (0.8 mol) were prepared to form solution A. Calcium carbide (0.13 mol) and dimethyl carbonate (0.91 mol) were prepared to form solution B. Solution B was added dropwise to solution A at 70°C for 1 h. After the addition was completed, the solution was kept warm for 10 h. After the end of the warming, the reaction solution was washed with water until neutral, the solvent was removed under reduced pressure, and petroleum ether / ethyl acetate was used as the eluent. The product was separated on a silica gel column and dried to obtain 22.7 g of N-NHBoc-7-methylindole in a yield of 92.1%. Example 5

[0031]

[0032] In a 1L four-necked flask equipped with a stirrer, a dropping funnel, and a thermometer, N-Boc-N'-(4-chlorophenyl)hydrazine (0.1 mol), (1,5-cyclooctadiene)ruthenium chloride (5 mmol), silver hexafluoroantimonate (0.03 mol), copper chloride (0.2 mol), acetic acid (0.26 mol), and N,N-dimethylformamide (1.5 mol) were prepared to form solution A. Calcium carbide (0.13 mol) and N,N-dimethylformamide (1.1 mol) were prepared to form solution B. Solution B was added dropwise to solution A at 80°C for 0.8 h. After the addition was completed, the solution was kept warm for 8 h. After the end of the warming, the reaction mixture was washed with water until neutral. The solvent was removed under reduced pressure, and petroleum ether / ethyl acetate was used as the eluent. The product was separated on a silica gel column and dried to obtain 24.4 g of N-NHBoc-6-chloroindole in a yield of 91.4%. Example 6

[0033]

[0034] In a 1L four-necked flask equipped with a stirrer, a dropping funnel, and a thermometer, N-Boc-N'-(4-isopropylphenyl)hydrazine (0.1 mol), (1,5-cyclooctadiene)ruthenium chloride (5 mmol), silver hexafluoroantimonate (0.03 mol), copper chloride (0.2 mol), acetic acid (0.26 mol), and dichloromethane (2 mol) were prepared to form solution A. Calcium carbide (0.13 mol) and dichloromethane (0.78 mol) were prepared to form solution B. Solution B was added dropwise to solution A at 90°C for 1 h. After the addition was completed, the temperature was maintained for 8 h. After the temperature was maintained, the reaction mixture was neutralized with water, the solvent was removed under reduced pressure, and petroleum ether / ethyl acetate was used as the eluent. The mixture was separated on a silica gel column and dried to obtain 24.8 g of N-NHBoc-6-isopropylindole in a yield of 90.6%. Example 7

[0035]

[0036] In a 1L four-necked flask equipped with a stirrer, a dropping funnel, and a thermometer, N-Boc-N'-(4-fluorophenyl)hydrazine (0.1 mol), (1,5-cyclooctadiene)ruthenium chloride (5 mmol), silver hexafluoroantimonate (0.03 mol), copper chloride (0.5 mol), acetic acid (0.6 mol), and 1,2-dichloroethane (1 mol) were prepared to form solution A. Calcium carbide (0.15 mol) and 1,2-dichloroethane (1.1 mol) were prepared to form solution B. Solution B was added dropwise to solution A at 80°C for 1 h. After the addition was completed, the solution was kept warm for 10 h. After the end of the warming, the reaction solution was washed with water until neutral, the solvent was removed under reduced pressure, and petroleum ether / ethyl acetate was used as the eluent. The product was separated on a silica gel column and dried to obtain 21.6 g of N-NHBoc-6-fluoroindole in a yield of 87.1%. Example 8

[0037]

[0038] In a 1L four-necked flask equipped with a stirrer, a dropping funnel, and a thermometer, N-Boc-N'-(3-bromophenyl)hydrazine (0.1 mol), (1,5-cyclooctadiene)ruthenium chloride (5 mmol), silver hexafluoroantimonate (0.02 mol), copper chloride (0.3 mol), acetic acid (0.6 mol), and dimethyl carbonate (1 mol) were prepared to form solution A. Calcium carbide (0.15 mol) and dimethyl carbonate (0.75 mol) were prepared to form solution B. Solution B was added dropwise to solution A at 90°C for 1 h. After the addition was completed, the solution was kept warm for 12 h. After the end of the warming, the reaction solution was washed with water until neutral, the solvent was removed under reduced pressure, and petroleum ether / ethyl acetate was used as the eluent. The product was separated on a silica gel column and dried to obtain 27.4 g of N-NHBoc-7-bromoindole in a yield of 88.4%.

[0039] In addition to the above embodiments, the present invention also includes other implementation methods. Any technical solutions formed by equivalent transformation or equivalent replacement should fall within the scope of protection of the claims of the present invention.

[0040] Figure 1 is the hydrogen spectrum of the product of Example 1, from Figure 1 It can be seen that the 9 hydrogens with a chemical shift of 1.50 are the peaks of the 3 methyl groups in the Boc group of the product, the 2 hydrogens with chemical shifts of 6.47 and 7.06 are Hb and Ha on the indole ring of the product, respectively, the 2 hydrogens with chemical shifts of 7.58 and 7.14 are Hc and Hd on the indole ring of the product, respectively, and the 3 hydrogens with chemical shifts of 7.24-7.28 are Hc, Hd and hydrogen on the amino group on the indole ring of the product, respectively.

[0041] Figure 2 is the carbon spectrum of the product of Example 1, from Figure 1 It can be seen that the carbon with a chemical shift of 28.14 is the peak of the three methyl groups in the Boc group of the product, the carbon with a chemical shift of 82.4 is the Cg in the Boc group of the product, the carbon with a chemical shift of 136.0 is the Ch in the Boc group of the product, the two carbons with chemical shifts of 101.33 and 108.44 are Cb and Ca on the indole ring of the product, respectively, and the carbons with chemical shifts of 128.68, 126.46, 122.73, 121.18, and 120.58 are the carbons of the benzene ring in the indole ring of the product.

[0042] from Figure 1 Proton spectrum combination Figure 2 The carbon spectrum of the product N-NHBoc indole was successfully synthesized.

Claims

1. A method for preparing an N-aminoindole compound, characterized in that: The steps include: Solution A is prepared by mixing a Boc-substituted arylhydrazine, a catalyst, silver hexafluoroantimonate, an oxidant, acetic acid, and a solvent. Solution B is prepared by mixing calcium carbide and a solvent. Solution B is added dropwise to solution A at a temperature of 50 to 90°C for 0.5 to 1 hour and the temperature is kept constant for 5 to 12 hours. The temperature is kept constant at the same temperature as the addition temperature. After the insulation is completed, the reaction solution is washed with water until neutral, and the solvent is removed by distillation under reduced pressure to obtain a crude N-aminoindole compound, which is then separated by a silica gel column and dried to obtain an N-aminoindole compound. The reaction formula is as follows: ； Wherein: R is selected from one of hydrogen, alkyl, fluorine, chlorine and bromine; The oxidant is one of copper acetate, copper chloride, and copper oxide; The catalyst is one of ruthenium chloride, ruthenium acetate, ruthenium acetylacetonate, and (1,5-cyclooctadiene)ruthenium chloride, and the molar ratio of the catalyst to the Boc-substituted arylhydrazine is 2 to 10:

100.

2. The method for preparing N-aminoindole compounds according to claim 1, wherein The solvent is one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dimethyl carbonate, and N,N-dimethylformamide. The solvent in solution A and solution B is the same solvent. The molar ratio of Boc-substituted arylhydrazine to the solvent in solution A is 1:5-20, the molar ratio of calcium carbide to the solvent in solution B is 1:5-10, and the molar ratio of tert-butyloxycarbonyl-substituted arylhydrazine to calcium carbide is 1:1.1-1.

5.

3. The method for preparing N-aminoindole compounds according to claim 1, wherein The molar ratio of the oxidant to the Boc-substituted arylhydrazine is 2 to 5:

1.

4. The method for preparing N-aminoindole compounds according to claim 1, wherein The molar ratio of the acetic acid to the calcium carbide is 2 to 4:

1.

5. The method for preparing N-aminoindole compounds according to claim 1, wherein The molar ratio of the silver hexafluoroantimonate to the Boc-substituted arylhydrazine is 0.1 to 0.3:1.

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