A method for preparing 5H-pyrazino[2,3-b]indole compounds

Abstract

The application provides a preparation method of 5H-pyrazino[2,3-b]indole compounds and relates to the technical field of organic synthesis. The preparation method comprises the following steps: in the presence of an alkali as a promoter and under a non-oxidizing gas, an o-iodoaniline compound I and a pyrazine compound II firstly undergo an alkali-promoted homolytic aryl substitution reaction, then undergo an intramolecular nucleophilic addition elimination reaction, and after dehydrogenation, a 5H-pyrazino[2,3-b]indole compound III is obtained. The preparation method can prepare the 5H-pyrazino[2,3-b]indole compound III in a one-pot method, avoids the use of expensive transition metals, has relatively mild preparation reaction conditions, high product yield, high atomic economy and step economy.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and in particular to a preparation method of 5H-pyrazino[2,3-b]indole compounds. BACKGROUND

[0002] Heterocyclic compounds are the largest number of organic compounds in nature, widely exist in nature, such as nucleic acids, some vitamins, antibiotics, hormones, pigments and alkaloids, etc. In addition, people have synthesized a variety of heterocyclic compounds with various properties, some of which can be used as drugs, pesticides, herbicides, dyes, plastics, etc.

[0003] The inventors have previously developed a metal-free intramolecular arylamine and pyridine dehydroamination reaction (Org. Chem. Front. 2023, 10, 3045-3051.), which provides a new synthetic method for the synthesis of α-carboline skeleton, and further develops a metal-free dehydroamination reaction of electron-deficient heterocycle C(sp 2 )-H. However, this method still has obvious defects. The intermediate of the intramolecular arylamine and pyridine dehydroamination reaction needs to be pre-prepared, and a noble metal such as palladium needs to be used. Therefore, it is of great significance to develop a more efficient and green direct dehydroamination reaction of intermolecular arylamine and pyridine without using pre-prepared reaction intermediates.

[0004] 5H-pyrazino[2,3-b]indole is a heterocyclic compound, and also an important structural unit, which can be used as a structural skeleton in the fields of drug synthesis, organic polymer synthesis, new material synthesis and total synthesis of natural products. Therefore, there are many studies on the synthesis method of 5H-pyrazino[2,3-b]indole. However, the existing synthesis of 5H-pyrazino[2,3-b]indole mostly adopts the strategy of reconstituting a pyridine ring on an indole ring.

[0005] However, the above preparation method using the above synthesis strategy often has defects such as complex synthesis of reaction substrates, unsatisfactory yield, generation of N-substituted products, use of expensive transition metals, and residual noble metals after reaction, which is not conducive to atom economy. Therefore, it is urgent to provide a solution to improve the above problems. SUMMARY

[0006] The purpose of the present application is to provide a preparation method of 5H-pyrazino[2,3-b]indole compounds, which can prepare 5H-pyrazino[2,3-b]indole compounds in one pot, avoid the use of expensive transition metals, and have relatively mild preparation reaction conditions, high product yield, high atom economy and step economy.

[0007] The application provides a preparation method of 5H-pyrazino[2,3-b]indole compounds, which comprises the following steps: controlling the temperature of a reaction system at 80-110 DEG C under a non-oxidizing gas, and then performing the following reaction of o-iodoaniline compounds I and pyrazine compounds II in the presence of an alkali as a promoter to obtain 5H-pyrazino[2,3-b]indole compounds III.

[0008]

[0009] wherein X is C or N, R 1 and R 2 are independently of each other hydrogen, a C1-C 15 aliphatic radical, a C4-C 15 aromatic radical, alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, alkyl, hydroxy, carboxy, aldehyde, carbonyl, amino, sulfo, amide or halogen.

[0010] The application provides a preparation method of 5H-pyrazino[2,3-b]indole compounds, which comprises the following steps: controlling the temperature of a reaction system at 80-110 DEG C under a non-oxidizing gas, and then performing the following reaction of o-iodoaniline compounds I and pyrazine compounds II in the presence of an alkali as a promoter to obtain 5H-pyrazino[2,3-b]indole compounds III.

[0011] Optionally, the o-iodoaniline compounds I are reacted with excess pyrazine compounds II.

[0012] Optionally, when the o-iodoaniline compounds I are reacted with excess pyrazine compounds II, the molar ratio of the o-iodoaniline compounds I to the pyrazine compounds II is 1:(20-100).

[0013] Optionally, after the reaction of the o-iodoaniline compounds I and the pyrazine compounds II, the reaction product is separated by column chromatography to obtain the 5H-pyrazino[2,3-b]indole compounds III.

[0014] Optionally, when the column chromatography is performed, the eluent is a mixture of petroleum ether and acetic acid in a volume ratio of 0.1-10.

[0015] Optionally, the non-oxidizing gas comprises an inert gas and / or nitrogen.

[0016] Optionally, the alkali comprises an organic alkali and / or an inorganic alkali, and the molar ratio of the alkali to the o-iodoaniline compounds I is (3-9):1.

[0017] Optionally, the organic base comprises t-BuOK or t-BuONa; and the inorganic base comprises KOH, NaOH or K2CO3.

[0018] Optionally, the C1-C 40 alkyl group comprises methyl, ethyl, propyl, isopropyl, butyl or benzyl; and the C4-C 60 aromatic group comprises pyridine derivative group, phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl; and the halogen comprises fluorine, chlorine, bromine or iodine. DETAILED DESCRIPTION

[0019] In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are only some but not all of the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the scope of the present application. Unless otherwise defined, the technical terms or scientific terms used herein should be understood as the common meanings thereof by those of ordinary skill in the art to which the present application belongs. The words “comprise” and similar words in this text mean that the elements or objects before the words encompass the elements or objects listed after the words and their equivalents, and do not exclude other elements or objects.

[0020] The embodiments of the present application provide a preparation method of 5H-pyrazino[2,3-b]indole compounds, comprising the following steps: controlling the temperature of a reaction system to be 80-110°C under a non-oxidizing gas, and using a base as a promoter to perform the following reaction of an o-iodoaniline compound I and a pyrazine compound II, so as to obtain a 5H-pyrazino[2,3-b]indole compound III.

[0021]

[0022] wherein X is C or N, R 1 and R 2 are independently hydrogen, C1-C 15 alkyl group, C4-C 15 aromatic group, alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, alkyl, hydroxyl, carboxyl, aldehyde, carbonyl, amino, sulfo, amide or halogen.

[0023] Specifically, in the reaction process of the o-iodoaniline compound I and the pyrazine compound II, first, a base-promoted homolytic aryl substitution reaction occurs, so that the aniline group is coupled with the pyrazine ring, then an intramolecular nucleophilic addition elimination reaction occurs, so that the dehydrogenation is performed to obtain the 5H-pyrazino[2,3-b]indole compound III.

[0024] In fact, the specific o-iodoaniline compound I and the pyrazine compound II participating in the reaction are all commercially available conventional products, and can be used after purification by means known in the art if necessary. Further, the specific o-iodoaniline compound I and the pyrazine compound II used can also be synthesized in the laboratory by means known in the art, and used after purification if necessary.

[0025] In fact, the by-product generated after the reaction of the o-iodoaniline compound I and the pyrazine compound II is green and environmentally friendly hydrogen.

[0026] In some embodiments, the reaction of the o-iodoaniline compound I and the pyrazine compound II is continuously stirred, so as to facilitate the mixing of the o-iodoaniline compound I and the pyrazine compound II, thereby improving the reaction rate.

[0027] In some embodiments, the reaction of the o-iodoaniline compound I and the pyrazine compound II is carried out after mixing the o-iodoaniline compound I with an excess of the pyrazine compound II, so as to promote the forward reaction, thereby improving the yield of the 5H-pyrazino[2,3-b]indole compound III.

[0028] Specifically, the molar ratio of the o-iodoaniline compound I to the pyrazine compound II is controlled to be 1:(20-100) during the reaction of the o-iodoaniline compound I and the pyrazine compound II.

[0029] In fact, since the melting point of the pyrazine compound II is 50-56°C at normal pressure, and the boiling point is greater than 110°C, the reaction temperature is controlled to be 80-110°C, and after the pyrazine compound II is completely dissolved, the o-iodoaniline compound I is dissolved in the pyrazine compound II, so as to improve the mixing uniformity of the two raw materials, and no additional organic solvent is added into the reaction system, thereby further saving cost.

[0030] In some embodiments, the temperature of the reaction system is controlled to be 80-110°C during the reaction of the o-iodoaniline compound I and the pyrazine compound II, and then the mixing system of the o-iodoaniline compound I and the pyrazine compound II is stirred, so as to further improve the mixing uniformity of the two raw materials.

[0031] In some embodiments, the base used as the promoter includes an organic base and / or an inorganic base, i.e., an organic base can be used as the promoter, or an inorganic base can be used as the promoter, or a mixture of an organic base and an inorganic base in any ratio can be used as the promoter, all of which can achieve good promotion effect.

[0032] In some embodiments, the organic base includes t-BuOK or t-BuONa. That is, when an organic base is used as the accelerator of the reaction system, t-BuOK can be specifically selected as the accelerator, or t-BuONa can be specifically selected as the accelerator, or a mixture of t-BuOK and t-BuONa in any proportion can be used as the accelerator.

[0033] In some embodiments, the inorganic base includes KOH, NaOH or K2CO3. That is, when an inorganic base is used as the accelerator of the reaction system, KOH can be specifically selected as the accelerator, or NaOH can be specifically selected as the accelerator, or K2CO3 can be specifically selected as the accelerator, or a mixture of any two or three of KOH, NaOH and K2CO3 in any proportion can be used as the accelerator.

[0034] In fact, when an inorganic base is used as the accelerator of the reaction system, Cs2CO3 or a mixture of Cs2CO3 and other inorganic bases in any proportion can also be used as the inorganic base.

[0035] In some embodiments, when the base is used as the accelerator to promote the reaction system of the o-iodoaniline compound I and the pyrazine compound II, the molar ratio of the base to the o-iodoaniline compound I is (3-9): 1.

[0036] Specifically, when t-BuOK is used as the accelerator and the o-iodoaniline compound I is 2-iodoaniline, the molar ratio of t-BuOK to 2-iodoaniline is (3-9): 1.

[0037] In some embodiments, the non-oxidizing gas includes an inert gas and / or nitrogen. The non-oxidizing gas can protect the reaction from oxidation of the raw materials and products during the high-temperature process.

[0038] Further, when the non-oxidizing gas is used, it needs to be filled in the reaction container in which the reaction system is located in advance before the reaction system is reacted, so that the non-oxidizing gas can be used to replace the gas in the reaction container multiple times, thereby increasing the concentration of the non-oxidizing gas in the reaction container.

[0039] Specifically, the inert gas can be helium, neon, argon, nitrogen, xenon or radon. Therefore, when the o-iodoaniline compound I and the pyrazine compound II are reacted, the non-oxidizing gas can be one of helium, neon, argon, nitrogen, xenon, radon and nitrogen, or a mixture of any of them in any proportion.

[0040] Specifically, using t-BuOK as a promoter, under a nitrogen atmosphere and with the reaction temperature controlled at 80-110℃, o-iodoaniline compound I and pyrazine compound II undergo the following reaction to obtain 5H-pyrazino[2,3-b]indole compound III;

[0041]

[0042] In some embodiments, when performing the reaction of o-iodoaniline compound I with pyrazine compound II, the reaction time of the reaction system can be controlled to be 8-16 hours.

[0043] In some embodiments, after the reaction of o-iodoaniline compound I with pyrazine compound II is completed, deionized water is added to the reaction system for quenching treatment, the reaction product is extracted with an organic solvent, and then column chromatography is performed to obtain pure 5H-pyrazino[2,3-b]indole compound III.

[0044] Specifically, when using an organic solvent to extract the reaction product, the organic solvent used can be dichloromethane, ethyl acetate, or diethyl ether, and the amount of organic solvent used is 20-100 equivalents of o-iodoaniline compound I.

[0045] Specifically, when performing column chromatography, silica gel or neutral alumina is used as the stationary phase, and a mixture of petroleum ether and ethyl acetate is used as the eluent. Furthermore, when using a mixture of petroleum ether and ethyl acetate as the eluent, the volume ratio of petroleum ether to ethyl acetate is 1 / 10-10.

[0046] In some embodiments, after the reaction of o-iodoaniline compound I with pyrazine compound II is completed, the product is directly packed into a column for column chromatography separation to obtain pure 5H-pyrazino[2,3-b]indole compound III.

[0047] Specifically, when performing column chromatography separation by direct packing, the mixture after the reaction can be directly added to silica gel powder or neutral alumina powder, stirred, and then packed into the column, using a mixture of petroleum ether and ethyl acetate as the eluent. Furthermore, when using a mixture of petroleum ether and ethyl acetate as the eluent, the volume ratio of petroleum ether to ethyl acetate in the eluent is 1 / 10-10.

[0048] In some embodiments, C1-C 40 The aliphatic groups include methyl, ethyl, propyl, isopropyl, butyl, or benzyl; C4-C 60 The aromatic groups include pyridine derivatives, phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl; the halogens include fluorine, chlorine, bromine or iodine.

[0049] Examples 1-14

[0050] The present embodiments 1-14 provide a method for preparing 5H-pyrazino[2,3-b]indole compounds III, comprising the following steps:

[0051] S1, 0.2 mmol of o-iodoaniline compound I, 8 mmol of pyrazine and 1.2 mmol of t-BuOK were added to a Schlenk tube, the Schlenk tube was replaced with nitrogen three times, and then the reaction was stirred at a temperature of 100°C for 16h;

[0052] S2, the reaction product in S1 was directly added to silica gel powder for sample mixing and column packing, and column chromatography was performed using an eluent of petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain the pure 5H-pyrazino[2,3-b]indole compound III.

[0053] In the embodiments 1-14, the specific name and structural formula of the o-iodoaniline compound I, the structural formula of the product 5H-pyrazino[2,3-b]indole compound III and the yield are shown in Table 1.

[0054] Table 1 Name and structural formula of raw materials in embodiments 1-14 and structural formula of product and yield

[0055]

[0056]

[0057]

[0058] The product (5H-pyrazino[2,3-b]indole) in Example 1 was characterized by the following spectrum:

[0059] 1 H NMR (400 MHz, DMSO-d6): δ 12.15 (s, 1H), 8.46 (dd, J = 21.2, 2.6 Hz, 2H), 8.23 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 3.6 Hz, 2H), 7.32 (dt, J = 8.1, 4.1 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 145.9, 140.7, 140.3, 136.9, 135.6, 129.4, 121.4, 120.9, 119.7, 112.5. HRMS (ESI) m / z calcd for C 10 H7N3[M+H] + : 170.0713, Found: 170.0713.

[0060] The spectral data for the product (7-methyl-5H-pyrazino[2,3-b]indole) in Example 2 are as follows:

[0061] 1 H NMR (400 MHz, DMSO-d6): δ 12.00 (s, 1H), 8.41 (d, J = 2.7 Hz, 1H), 8.35 (d, J = 2.7 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 2.48 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 146.0, 141.2, 139.7, 139.6, 136.6, 135.9, 122.5, 121.2, 117.4, 112.4, 22.3. HRMS (ESI) m / z calcd for C 11 H9N3[M+H] + : 184.0870, Found: 184.0872.

[0062] The spectral data for the product (8-(tert-butyl)-5H-pyrazino[2,3-b]indole) in Example 3 are as follows:

[0063] 1 H NMR (400 MHz, DMSO-d6): δ 12.00 (s, 1H), 8.46 (d, J = 2.6 Hz, 1H), 8.40 (d, J = 2.7 Hz, 1H), 8.18 (s, 1H), 7.68 (dt, J = 8.7, 1.6 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 1.38 (s, 9H). 13 C NMR (100 MHz, DMSO-d6): δ 146.3, 143.4, 140.1, 138.9, 136.6, 135.9, 127.5, 119.4, 117.0, 112.2, 34.9, 32.0. HRMS (ESI) m / z calcd for C 14 H 15 N3[M+H] + : 226.1338, Found: 226.1340.

[0064] The spectral data for the product (7-methoxy-5H-pyrazino[2,3-b]indole) in Example 4 are as follows:

[0065] 1H NMR (400 MHz, DMSO-d6): δ 12.00 (s, 1H), 8.39 (d, J = 2.7 Hz, 1H), 8.30 (d, J = 2.8 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 6.93 (dd, J = 8.6, 2.2 Hz, 1H), 3.89 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 161.3, 146.1, 142.6, 138.6, 136.6, 136.2, 122.6, 113.2, 110.6, 95.6, 55.9. HRMS (ESI) m / z calcd for C 11 H9N3O [M+H] + : 200.0816, Found: 200.0821.

[0066] The spectral data for the product (9-methoxy-5H-pyrazino[2,3-b]indole) in Example 5 are as follows:

[0067] 1 H NMR (400 MHz, DMSO-d6): δ 12.00 (s, 1H), 8.39 (d, J = 2.7 Hz, 1H), 8.30 (d, J = 2.8 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 6.93 (dd, J = 8.6, 2.2 Hz, 1H), 3.89 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 161.3, 146.1, 142.6, 138.6, 136.6, 136.2, 122.6, 113.2, 110.6, 95.6, 55.9. HRMS (ESI) m / z calcd for C 11 H9N3O [M+H] + : 200.0816, Found: 200.0821.

[0068] The spectral data for the product (7-(trifluoromethoxy)-5H-pyrazino[2,3-b]indole) in Example 6 are as follows:

[0069] 1H NMR (400 MHz, DMSO-d6): δ 12.39 (s, 1H), 8.55 (d, J = 2.7 Hz, 1H), 8.49 (d, J = 2.6 Hz, 1H), 8.34 (d, J = 8.6 Hz, 1H), 7.52 (s, 1H), 7.30 (ddd, J = 8.5, 2.2, 1.0 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 149.0 (d, J = 1.8 Hz), 146.5, 140.9, 137.7, 134.8, 123.2, 121.9, 119.4, 118.8, 114.2, 105.0. HRMS (ESI) m / z calcd for C 11 H6F3N3O [M+H] + : 254.0535, Found: 254.0538.

[0070] The spectral data for the product (8-(trifluoromethoxy)-5H-pyrazino[2,3-b]indole) in Example 7 are as follows:

[0071] 1 H NMR (400 MHz, DMSO-d6): δ 12.41 (s, 1H), 8.55 (d, J = 2.6 Hz, 1H), 8.51 (d, J = 2.6 Hz, 1H), 8.15 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.61-7.56 (m, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 146.7, 142.6 (q, J = 2.1 Hz), 141.5, 139.0, 137.5, 134.9, 123.0, 122.1, 120.1, 119.6, 114.0 (d, J = 13.3 Hz). HRMS (ESI) m / z calcd for C 11 H6F3N3O [M+H] + : 254.0535, Found: 254.0540.

[0072] The spectral data for the product (6-fluoro-5H-pyrazino[2,3-b]indole) in Example 8 are as follows:

[0073] 1H NMR (400 MHz, DMSO-d6): δ 12.67 (s, 1H), 8.58-8.48 (m, 2H), 8.04 (d, J = 7.8 Hz, 1H), 7.47 (dd, J = 11.2, 8.0 Hz, 1H), 7.33-7.25 (m, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 150.4, 148.0, 146.2, 141.3, 137.7, 135.2 (d, J = 3.8 Hz), 128.4 (d, J = 13.9 Hz), 123.2 (d, J = 5.3 Hz), 121.3 (d, J = 5.7 Hz), 117.4 (d, J = 3.7 Hz), 114.5 (d, J = 16.1 Hz). HRMS (ESI) m / z calcd for C 10 H6FN3 [M+H] + : 188.0619, Found: 188.0620.

[0074] The spectral data for the product (7-fluoro-5H-pyrazino[2,3-b]indole) in Example 9 are as follows:

[0075] 1 H NMR (400 MHz, DMSO-d6): δ 12.29 (s, 1H), 8.49 (d, J = 2.7 Hz, 1H), 8.42 (d, J = 2.7 Hz, 1H), 8.24 (dd, J = 8.6, 5.6 Hz, 1H), 7.35 (dd, J = 9.8, 2.3 Hz, 1H), 7.21-7.13 (m, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 164.4, 162.0, 146.4, 141.6 (d, J = 13.3 Hz), 140.0, 137.3, 123.3 (d, J = 10.8 Hz), 116.5 (d, J = 1.4 Hz), 109.4 (d, J = 24.3 Hz), 99.1 (d, J = 36.2 Hz). HRMS (ESI) m / z calcd for C 10 H6FN3 [M+H] + : 188.0619, Found: 188.0622.

[0076] The spectral data for the product (8-fluoro-5H-pyrazino[2,3-b]indole) in Example 10 are as follows:

[0077] 1H NMR (400 MHz, DMSO-d6): δ 12.22 (s, 1H), 8.49 (dt, J = 12.6, 2.4 Hz, 2H), 7.97 (dd, J = 8.7, 2.5 Hz, 1H), 7.60 (ddd, J = 8.9, 4.3, 2.2 Hz, 1H), 7.47 (tt, J = 9.1, 2.4 Hz, 1H). 13 CNMR (100 MHz, DMSO-d6): δ 158.8, 156.4, 146.7, 141.1, 137.0 (d, J = 5.8 Hz), 135.1 (d, J = 4.6 Hz), 120.1 (d, J = 9.4 Hz), 117.4 (d, J = 25.5 Hz), 113.9 (d, J = 8.9 Hz), 106.7 (d, J = 23.7 Hz). HRMS (ESI) m / z calcd for C 10 H6FN3 [M+H] + : 188.0619, Found: 188.0617.

[0078] The spectral data for the product (9-fluoro-5H-pyrazino[2,3-b]indole) in Example 11 are as follows:

[0079] 1 H NMR (400 MHz, DMSO-d6): δ 12.44 (s, 1H), 8.54 (d, J = 2.7 Hz, 1H), 8.51-8.45 (m, 1H), 7.63-7.55 (m, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.14-7.06 (m, 1H). 13 CNMR (100 MHz, DMSO-d6): δ 159.2, 156.7, 145.5, 142.5 (d, J = 8.9 Hz), 140.6, 137.6, 133.6 (d, J = 2.6 Hz), 130.5 (d, J = 8.4 Hz), 108.8 (d, J = 3.8 Hz), 106.6 (d, J = 18.5 Hz). HRMS (ESI) m / z calcd for C 10 H6FN3 [M+H] + : 188.0619, Found: 188.0624.

[0080] The spectral data for the product (7-(trifluoromethyl)-5H-pyrazino[2,3-b]indole) in Example 12 are as follows:

[0081] 1H NMR (400 MHz, DMSO-d6): δ 12.57 (s, 1H), 8.59 (dd, J = 15.7, 2.6 Hz, 2H), 8.44 (d, J = 8.2 Hz, 1H), 7.88 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 146.7, 142.1, 139.6, 138.1, 134.3, 129.8 (t, J = 31.3 Hz), 122.7, 122.5, 117.1 (q, J = 3.7 Hz), 112.4, 109.6 (q, J = 3.8 Hz). HRMS (ESI) m / z calcd for C 11 H6F3N3[M+H] + : 238.0586, Found: 238.0587.

[0082] The spectral data for the product (5H-pyrido[3',2':4,5]pyrrolo[2,3-b]pyrazine) in Example 13 are as follows:

[0083] 1 H NMR (400 MHz, DMSO-d6): δ 12.72 (s, 1H), 8.64-8.59 (m, 2H), 8.56 (d, J = 2.7 Hz, 1H), 8.51 (d, J = 2.7 Hz, 1H), 7.38 (dd, J = 7.7, 4.9 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 152.6, 149.9, 145.8, 141.4, 138.0, 134.0, 130.2, 117.4, 113.0. HRMS (ESI) m / z calcd for C9H6N4[M+H] + : 171.0665, Found: 171.0666.

[0084] The spectral data for the product (9H-pyrido[2',3':4,5]pyrrolo[2,3-b]pyrazine) in Example 14 are as follows:

[0085] 1 H NMR (400 MHz, DMSO-d6): δ 12.36 (s, 1H), 8.69-8.62 (m, 2H), 8.56 (q, J = 1.0 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.58 (dd, J = 8.2, 4.8 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 146.2, 144.0, 142.1, 138.4, 137.8, 134.8, 134.1, 123.4, 120.2. HRMS (ESI) m / z calcd for C9H6N4 [M+H] + : 171.0665, Found: 171.0668.

[0086] As can be seen from Table 1, the method provided by the present application has a yield of 60-80% in preparing 5H-pyrazino[2,3-b]indole compounds, and the overall reaction conditions are mild and green, avoiding the introduction of expensive transition metals into the reaction system.

[0087] Examples 15-18

[0088] Examples 15-18 provide a method for preparing 5H-pyrazino[2,3-b]indole compounds III, which is different from Example 1 in that 8 mmol of pyrazine compound II is added to the Schlenk tube in step S1.

[0089] In the examples 15-18, the specific names and structural formulas of the pyrazine compounds II, the structural formulas of the products 5H-pyrazino[2,3-b]indole compounds III, and the yields are shown in Table 2.

[0090] Table 2 Names and structural formulas of raw materials in examples 15-18 and structural formulas of products and yields

[0091]

[0092] The spectral characterization of the product (6H-indolo[2,3-b]quinoxaline) in Example 15 is as follows:

[0093] 1 H NMR (400 MHz, DMSO-d6): δ 12.01 (s, 1H, NH), 8.36 (d, 1H, J = 7.5 Hz, 1H), 8.26 (d, J = 8 Hz, 1H), 8.08 (d, 1H, J = 8.5 Hz, 2H), 7.81 (t, J = 7.5 Hz, 1H), 7.70-7.75 (m, 2H), 7.59 (d, J = 8.5 Hz, 1H), 7.37 (t, J = 8.5 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 145.8, 143.9, 140.1, 139.7, 138.5, 131.2, 129.0, 128.6, 127.4, 125.8, 122.1, 120.6, 118.9, 111.9.

[0094] The spectral data for the product (6H-pyrido[3',4':5,6]pyrazino[2,3-b]indole) in Example 16 are as follows:

[0095] 1 H NMR (400 MHz, DMSO-d6): δ 12.30 (s, 1H), 9.49 (s, 1H), 8.68 (d, J = 4.8 Hz, 1H), 8.32 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 4.8, 1.6 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.37 (dd, J = 8.6, 1.6 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 153.0, 147.5, 144.3, 143.2, 141.6, 134.1, 132.0, 122.5, 121.3, 120.3, 118.7, 112.2.

[0096] The spectral data for the product (9H-pyrido[2,3-b]indole) in Example 17 are as follows:

[0097] 1 H NMR (400 MHz, DMSO-d6): δ 11.82 (s, 1H), 8.47 (dt, J = 7.7, 1.6 Hz, 1H), 8.43 (dt, J = 4.8, 1.6 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.24 - 7.16 (m, 2H). 13 C NMR (100 MHz, DMSO-d6): δ 152.4, 146.5, 139.3, 128.8, 127.0, 121.5, 120.8, 119.8, 115.6, 115.4, 111.7.

[0098] The spectral data for the product (2-methoxy-9H-pyrido[2,3-b]indole) in Example 18 are as follows:

[0099] 1H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.35-7.29 (m, 1H), 7.16 (t, J = 7.4 Hz, 1H), 6.62 (dd, J = 8.3, 0.9 Hz, 1H), 3.94 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 163.0, 150.7, 138.1, 132.0, 124.9, 121.5, 120.1, 119.8, 111.5, 108.9, 102.4, 53.7.

[0100] Example 19

[0101] The preparation method of 5H-pyrazino[2,3-b]indole provided in the embodiment 19 of the present application comprises the following steps:

[0102] S1, 2.19 g (10 mmol) of o-iodoaniline, 6.84 g (60 mmol) of t-BuOK and 32 g (400 mmol) of pyrazine were added to a Schlenk tube, the Schlenk tube was replaced with nitrogen for three times, and then the reaction was stirred at a temperature of 100°C for 16 h;

[0103] S2, the reaction product in S1 was directly added with silica gel powder for sample mixing and column loading, and column chromatography was performed using an eluent of petroleum ether and ethyl acetate in a volume ratio of 1:1, and 1.31 g of pure 5H-pyrazino[2,3-b]indole was obtained by weighing, and the yield was 78%.

[0104] The preparation reaction formula of 5H-pyrazino[2,3-b]indole in the embodiment 19 is as follows:

[0105]

[0106] As can be seen from the embodiment 19, the preparation method provided by the present application can prepare 5H-pyrazino[2,3-b]indole compound III in a kilogram scale, and the preparation reaction condition is mild and green and environmentally friendly, without using expensive transition metals, and the reaction cost is low, which is conducive to large-scale industrialized preparation of 5H-pyrazino[2,3-b]indole compound III, and is conducive to further application of 5H-pyrazino[2,3-b]indole compound III in the field of drug synthesis.

[0107] While the embodiments of the application have been illustrated and described in detail, it will be readily apparent to those skilled in the art that various modifications and changes can be made to the embodiments without departing from the scope and spirit of the application, as described in the claims. Moreover, the application described is not limited in its application to the details set forth in the description or illustrated in the drawings. The application is capable of other embodiments and of being practiced or carried out in various ways.

Claims

1. A method for preparing a 5H-pyrazino[2,3-b]indole compound, characterized by, The method comprises the following steps: reacting o-iodoaniline compound I with pyrazine compound II in a molar ratio of 1:(20-100) under the promotion of a base and in a non-oxidizing gas, and without adding an organic solvent into the reaction system, to obtain 5H-pyrazino[2,3-b]indole compound III, wherein the base is t NaOt-Bu, and the molar ratio of the base to the o-iodoaniline compound I is (3-9):

1. ； wherein X is C or N, R 1 and R 2 are independently of each other hydrogen, a C1-C 15 aliphatic radical, alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxy, carboxy, aldehyde, carbonyl, sulfonamide or fluorine.

2. The production method according to claim 1, characterized by, After performing the reaction of o-iodoaniline compound I with pyrazine compound II, the reaction product is separated by column chromatography to obtain 5H-pyrazino[2,3-b]indole compound III.

3. The production method according to claim 2, characterized by, When performing the column chromatography separation, the eluent is a mixture of petroleum ether and acetic acid in a volume ratio of 0.1-10.

4. The method of claim 1, wherein, The non-oxidizing gas is selected from the group consisting of inert gas and / or nitrogen.

5. The preparation method according to claim 1, characterized in that, said C1-C4alkyl group is selected from methyl, ethyl, propyl, or butyl. 15 said C1-C4alkyl group is selected from methyl, ethyl, propyl, or butyl.

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