Synthesis method of asymmetric thiourea compound

Abstract

The invention relates to the technical field of organic synthesis, and discloses a synthesis method of an asymmetric thiourea compound. The asymmetric thiourea compound is prepared by taking an indole-2-methylamine compound and N, N '-diaryl thiourea as reaction substrates and reacting in the presence of organic alkali under the conditions of inert gas atmosphere and ultraviolet irradiation. The synthesis method disclosed by the invention avoids the use of a highly toxic substance of isothiocyanate required in a traditional synthesis method, and meanwhile, a traditional heating reaction is replaced by an illumination reaction, so that the requirement of green synthesis is met.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing an asymmetric thiourea compound. Background Art

[0002] Nitrogen-containing fused heterocyclic compounds are a class of heterocyclic compounds with complex and diverse structures. They are not only used in medicine, agriculture, and fine chemicals, but also play an important role in the fields of dyes and organic functional materials. Therefore, developing a simple, green, and efficient method for synthesizing nitrogen-containing fused heterocyclic compounds has become the goal of many researchers.

[0003] Compounds A, B and C are indole derivatives among nitrogen-containing fused heterocyclic compounds and have various biological activities. The structural formulas of compounds A, B and C are as follows: Asymmetric thiourea compounds, such as thiourea compound D, are key intermediates for synthesizing compounds A, B and C, and they themselves also exhibit certain biological activities.

[0004] At present, the above-mentioned thiourea compound D is mainly synthesized by traditional methods using amine and isothiocyanate as raw materials, and the synthesis process is as follows: The above-mentioned traditional method for synthesizing thiourea compound D has the following problems: isothiocyanate is highly toxic, and highly toxic substances such as thiophosgene and methyl chloroformate are often used in the synthesis process, which makes the synthesis process relatively dangerous; at the same time, isothiocyanate is sensitive to water, which will lead to low synthesis efficiency. Summary of the invention

[0005] In order to solve the above-mentioned problem of synthesizing asymmetric thiourea compounds, the present invention provides a method for synthesizing asymmetric thiourea compounds.

[0006] The specific technical scheme of the present invention is: The present invention provides a method for synthesizing an asymmetric thiourea compound. The method comprises: using an indole-2-methylamine compound and N,N'-diarylthiourea as reaction substrates, reacting in the presence of an organic base, in an inert gas atmosphere, and under ultraviolet light irradiation to obtain an asymmetric thiourea compound; The structural formula of the indole-2-methylamine compound is shown in formula (II), the structural formula of the N,N'-diarylthiourea is shown in formula (III), and the structural formula of the asymmetric thiourea compound is shown in formula (I): Among them, R 1is selected from H, C1-C8 alkyl, C1-C2 alkoxy, F, Cl, Br, NO2 and CN; R 2 is one or more substituents, each independently selected from C1-C8 alkyl, C1-C4 alkoxy, F, Cl, Br, NO2 and CF3.

[0007] In the present invention, the thiourea compound is a compound containing a thiourea group. Asymmetric thiourea compounds are compounds in which the groups connected to the two ends of the thiourea group are different. Specifically, the present invention provides a method for synthesizing an asymmetric thiourea compound as shown in formula (I).

[0008] The present invention uses indole-2-methylamine compounds and N,N'-diarylthiourea as reaction substrates, reacts in the presence of an organic base, in an inert gas atmosphere, and under ultraviolet light irradiation conditions to prepare an asymmetric thiourea compound. The synthesis method of the present invention avoids the use of highly toxic substances such as isothiocyanates required in traditional synthesis methods, and at the same time, replaces traditional heating reactions with light irradiation reactions, meeting the requirements of green synthesis.

[0009] As a preferred method for the above synthesis, R 1 is selected from H, Br, Cl, methyl and methoxy.

[0010] As a preferred embodiment of the above synthesis method, the reaction is carried out in an organic solvent.

[0011] More preferably, the organic solvent is one or more of tetrahydrofuran, acetonitrile, dichloroethane and dimethyl sulfoxide.

[0012] As a preferred embodiment of the above synthesis method, the molar ratio of the indole-2-methylamine compound to the N,N'-diarylthiourea is 1:1-3.

[0013] More preferably, the molar ratio of the indole-2-methylamine compound to the N,N'-diarylthiourea is 1:1.5-2.5.

[0014] As a preferred embodiment of the above synthesis method, the organic base is one or more of pyridine, triethylamine, DABCO, DBU, tributylamine and diisopropylethylamine.

[0015] As a preferred embodiment of the above synthesis method, the wavelength of the ultraviolet light is 360-405 nm.

[0016] More preferably, the wavelength of the ultraviolet light is one of the ranges of 360-385 nm, 380-385 nm and 400-405 nm.

[0017] As a preferred embodiment of the above synthesis method, the reaction temperature of the reaction is 20 to 35° C. and the reaction time is 6 to 14 hours.

[0018] More preferably, the reaction time of the reaction is 10 to 13 hours.

[0019] As a preferred embodiment of the above-mentioned synthesis method, the structural formula of the asymmetric thiourea compound is selected from the structural formulas shown in (3-1) to (3-29):

[0020] As a preferred embodiment of the above synthesis method, after the reaction is completed, the solvent is evaporated under reduced pressure, and then column chromatography is performed, using a mixed solution of ethyl acetate / petroleum ether in a volume ratio of 1:5 as an eluent, collecting the eluate containing the target compound, and evaporating the solvent to obtain the product asymmetric thiourea.

[0021] Compared with the prior art, the present invention has the following technical effects: (1) Isothiocyanates required in traditional synthesis methods are not used, thus avoiding the use of highly toxic substances.

[0022] (2) The traditional heating reaction is replaced by light reaction, which can save energy. DETAILED DESCRIPTION

[0023] The present invention provides a method for synthesizing an asymmetric thiourea compound, which comprises: using an indole-2-methylamine compound and N,N'-diarylthiourea as reaction substrates, reacting in the presence of an organic base, in an inert gas atmosphere and under ultraviolet light irradiation to obtain an asymmetric thiourea compound; The structural formula of the indole-2-methylamine compound is shown in formula (II), the structural formula of the N,N'-diarylthiourea is shown in formula (III), and the structural formula of the asymmetric thiourea compound is shown in formula (I): Among them, R 1 is selected from H, C1-C8 alkyl, C1-C2 alkoxy, F, Cl, Br, NO2 and CN; R 2 is one or more substituents, each independently selected from C1-C8 alkyl, C1-C4 alkoxy, F, Cl, Br, NO2 and CF3.

[0024] As a preferred method for the above synthesis, R 1 is selected from H, Br, Cl, methyl and methoxy.

[0025] As a preferred embodiment of the above synthesis method, the reaction is carried out in an organic solvent.

[0026] More preferably, the organic solvent is one or more of tetrahydrofuran, acetonitrile, dichloroethane and dimethyl sulfoxide. The recommended amount of the organic solvent is 15 to 50 times the mass of the indole-2-methylamine compound.

[0027] As a preferred embodiment of the above synthesis method, the molar ratio of the indole-2-methylamine compound to the N,N'-diarylthiourea is 1:1-3.

[0028] More preferably, the molar ratio of the indole-2-methylamine compound to the N,N'-diarylthiourea is 1:1.5-2.5.

[0029] As a preferred embodiment of the above synthesis method, the organic base is one or more of pyridine, triethylamine, DABCO, DBU, tributylamine and diisopropylethylamine, preferably triethylamine.

[0030] As a preferred embodiment of the above synthesis method, the wavelength of the ultraviolet light is 360-405 nm.

[0031] More preferably, the wavelength of the ultraviolet light is one of the ranges of 360-385 nm, 380-385 nm and 400-405 nm.

[0032] As a preferred embodiment of the above synthesis method, the reaction temperature of the reaction is 20 to 35° C. and the reaction time is 6 to 14 hours.

[0033] More preferably, the reaction time of the reaction is 10 to 13 hours.

[0034] As a preferred embodiment of the above-mentioned synthesis method, the structural formula of the asymmetric thiourea compound is selected from the structural formulas shown in (3-1) to (3-29):

[0035] Based on the synthesis method of the asymmetric thiourea compound provided by the present invention, the compounds shown in the structural formulas (3-1) to (3-29) are obtained. This proves the wide applicability of the synthesis method of the present invention, and the synthesis method of the present invention can synthesize more asymmetric thiourea compounds shown in formula (I).

[0036] As a preferred embodiment of the above synthesis method, after the reaction is completed, the solvent is evaporated under reduced pressure, and then column chromatography is performed, using a mixed solution of ethyl acetate / petroleum ether in a volume ratio of 1:5 as an eluent, collecting the eluate containing the target compound, and evaporating the solvent to obtain the product asymmetric thiourea.

[0037] Based on the above, the synthesis method of the asymmetric thiourea compound of the present invention is specifically recommended as follows: The method for synthesizing asymmetric thiourea by using indole-2-methylamine compounds and N,N'-diaryl thiourea as reaction substrates is carried out according to the following steps: adding indole-2-methylamine compounds, N,N'-diaryl thiourea and triethylamine into tetrahydrofuran solvent, reacting for 10-13 hours under normal pressure nitrogen atmosphere and irradiation of ultraviolet lamp of 360-385 nm at room temperature, distilling off the solvent under reduced pressure, and then performing column chromatography separation, using a mixed solution of ethyl acetate / petroleum ether in a volume ratio of 1:5 as eluent, collecting the eluate containing the target compound, and distilling off the solvent to obtain the product asymmetric thiourea; the molar ratio of the reaction substrate indole-2-methylamine compounds to the N,N'-diaryl thiourea is 1:1.5-2.5; and the molar ratio of the triethylamine to the indole-2-methylamine compounds is 1:2-3.

[0038] The present invention will be further described below in conjunction with embodiments. Those of ordinary skill in the art will be able to implement the present invention based on these descriptions. In addition, the embodiments of the present invention involved in the following description are generally only embodiments of a part of the present invention, rather than all embodiments. Therefore, based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work should belong to the scope of protection of the present invention.

[0039] The following combined embodiments specifically synthesize the asymmetric thiourea compounds represented by the structural formulas shown in formulas (3-1) to (3-29) above using indole-2-methylamine compounds represented by structural formulas (1-1) to (1-5) and N,N'-diarylthioureas represented by formulas (2-1) to (2-25) as reaction substrates.

[0040] The indole-2-methylamine compounds represented by formula (1-1) to (1-5) are as follows:

[0041] The N,N'-diarylthiourea compounds represented by formulas (2-1) to (2-25) are as follows:

[0042] Example 1 Preparation of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-1)) In a 15 mL sealed tube equipped with a magnetic stirrer, 0.2 mmol of indole-2-methylamine (Formula (1-1)) and 0.4 mmol of N,N'-diphenylthiourea (Formula (2-1)) were added, the air in the sealed tube was replaced with nitrogen, the bottle mouth was sealed with a rubber stopper, and then 0.4 mmol of triethylamine and 2 mL of tetrahydrofuran were injected into the sealed tube. After the reaction was carried out under ultraviolet light (irradiation with ultraviolet light of a wavelength of 360 to 385 nm) for 11 hours, the solvent was evaporated under reduced pressure, and then column chromatography was performed, using a mixed solution of ethyl acetate / petroleum ether in a volume ratio of 1:5 as an eluent, the eluate containing the target compound was collected, and the solvent was evaporated to obtain the product 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea, and the separation yield was 91%.

[0043] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ11.03(br,NH,1H),9.69(br,NH,1H),8.13(br,NH,1H),7.49(d,J=8.6Hz,3H),7.38-7.32 13C NMR (100MHz, DMSO-d6): δ181.0,139.6,136.8,136.5,129.1,128.3,124.8,123.7,121.3,120.1,119.4,111.6,100.0,42.0. Example 2 Preparation of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-1)) The difference between this embodiment and embodiment 1 is that the reaction time is changed to 8 hours. Other operations are the same as those in embodiment 1.

[0044] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea was 73%.

[0045] Example 3 Preparation of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-1)) The difference between this example and Example 1 is that the reaction time is changed to 8 hours. The other operations are the same as in Example 1.

[0046] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea was 73%.

[0047] Example 4 Preparation of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-1)) The difference between this example and example 1 is that the reaction time is changed to 6 hours. The other operations are the same as in example 1.

[0048] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea was 65%.

[0049] Example 5 Preparation of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-1)) The difference between this example and Example 1 is that the reaction time is changed to 6 hours and the wavelength of the ultraviolet lamp is changed to 380-385 nm. The other operations are the same as in Example 1.

[0050] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea was 67%.

[0051] Example 6 Preparation of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-1)) The difference between this example and Example 1 is that the wavelength of the ultraviolet lamp is changed to 400-405 nm. The implementation operation is the same as that of Example 1. Other operations are the same as those of Example 1.

[0052] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea was 80%.

[0053] Example 7 Preparation of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-1)) The difference between this example and Example 1 is that the reaction solvent is changed to acetonitrile. The other operations are the same as in Example 1.

[0054] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea was 69%.

[0055] Example 8 Preparation of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-1)) The difference between this example and example 1 is that the amount of N,N'-diphenylthiourea is changed to 3 mmol. The other operations are the same as in example 1.

[0056] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea was 75%.

[0057] Example 9: Preparation of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-1)) The difference between this example and Example 1 is that the amount of N,N'-diphenylthiourea is changed to 6 mmol. The other operations are the same as in Example 1.

[0058] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea was 93%.

[0059] Example 10 Preparation of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-1)) The difference between this example and Example 1 is that the reaction time is changed to 6 h and the amount of N,N'-diphenylthiourea is changed to 6 mmol. Other operations are the same as in Example 1.

[0060] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea was 72%.

[0061] Example 11 Preparation of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-1)) The difference between this example and Example 1 is that the organic base is changed to DABCO. The other operations are the same as in Example 1.

[0062] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea was 93%.

[0063] Example 12 Preparation of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-1)) The difference between this example and Example 1 is that the organic base is replaced by pyridine. The other operations are the same as those in Example 1.

[0064] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-phenylthiourea was 89%.

[0065] Example 13 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(2-methoxyphenyl)thiourea (Formula (3-2)) The difference between this example and Example 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(2-methoxyphenyl)thiourea (Formula (2-2). Other operations are the same as in Example 1.

[0066] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(2-methoxyphenyl)thiourea was 54%.

[0067] The separated product was subjected to NMR detection, and the results were as follows: 1HNMR (400MHz, DMSO-d6): δ11.02(br,NH,1H),9.10(br,NH,1H),8.30(br,NH,1H),7.93(d,J=8.0Hz,1H),7.49(d,J=7.8Hz,1H),7. 13C NMR (100MHz, DMSO-d6): δ181.1,152.1,136.7,136.5,128.3,128.2,126.0( d, J=11.7Hz),121.3,120.3,119.4,120.1,111.9,111.6,100.2,56.0,42.0. Example 14 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(3-methoxyphenyl)thiourea (Formula (3-3)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(3-methoxyphenyl)thiourea (Formula (2-3). Other operations are the same as those in embodiment 1.

[0068] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(3-methoxyphenyl)thiourea was 75%.

[0069] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ11.02(br,NH,1H),9.73(br,NH,1H),8.15(br,NH,1H),7.50(d,J=8.9Hz,1H ),7.38(d,J=9.2Hz,1H),7.27-7.22(m,2H),7.09-7.07(m,1H),7.00-6.98(m,2H),6.73-6.70(m,1H), 6.37 (s, 1H), 4.90 (dd, J1=8.2Hz, J2=1.2Hz, 1H), 3.73 (s, 3H); 13CNMR (100MHz, DMSO-d6): δ180.7,159 .9,140.8,136.8,136.6,130.0,128.3,121.3,120.2,120.1,119.4,111.6,110.3,100.0,55.5,42.0. Example 15 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(4-methoxyphenyl)thiourea (Formula (3-4)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(4-methoxyphenyl)thiourea (Formula (2-4). Other operations are the same as those in embodiment 1.

[0070] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(3-methoxyphenyl)thiourea was 48%.

[0071] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ10.99(br,NH,1H),9.52(br,NH,1H),7.90(br,NH,1H),7.50(d,J=9.4Hz,1H),7.44(d,J=5. 13C NMR (100MHz, DMSO-d6): δ181.4,157.1,157.0,137.2,136.5,128.3,126.6(d,J=8.9Hz),121.2,120.9,119.4,114.5,114.1,111.6,55.7,42.0. Example 16 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(2-bromophenyl)thiourea (Formula (3-5)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(2-bromophenyl)thiourea (Formula (2-5). Other operations are the same as those in embodiment 1.

[0072] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(2-bromophenyl)thiourea was 85%.

[0073] The separated product was subjected to NMR detection, and the results were as follows: 1HNMR (400MHz, DMSO-d6): δ11.08(br,NH,1H),9.28(br,NH,1H),8.43(br,NH,1H),7.75(d,J=7.5Hz,1H),7.78(dd,J1=8.0Hz,J2=1.5Hz,1H) 13C NMR (100MHz, DMSO-d6): δ186.7, 142.8, 141.3 (d, J = 4.4Hz), 137.8, 134.8, 133.1, 133.0, 132.7, 126.1, 124.9, 124.2, 116.4, 105.0, 47.0. Example 17 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(3-bromophenyl)thiourea (Formula (3-6)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(3-bromophenyl)thiourea (Formula (2-6). Other operations are the same as those in embodiment 1.

[0074] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(3-bromophenyl)thiourea was 82%.

[0075] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ11.05(br,NH,1H),9.81(br,NH,1H),8.30(br,NH,1H),7.79(s,1H),7.50(d,J=7.8Hz,1H),7.44-7.42 13C NMR (100MHz, DMSO-d6): δ185.8, 146.3, 141.3 (d, J = 5.4Hz), 135.7, 133.8, 131.8, 130.3, 126.3, 126.0, 124.9, 124.2, 116.4, 104.9, 46.7. Example 18 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(4-bromophenyl)thiourea (Formula (3-7)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(4-bromophenyl)thiourea (Formula (2-7). Other operations are the same as those in embodiment 1.

[0076] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(4-bromophenyl)thiourea was 85%.

[0077] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR(400MHz,DMSO-d6): δ11.02(br,NH,1H),9.78(br,NH,1H),8.24(br,NH,1H),7.53-7.48(m,5H), 7.37(d,J=8.9Hz,1H),7.09-7.04(m,1H),7.00-6.96(m,1H),6.36(s,1H),4.88(d,J=5.2Hz,2H); 13C NMR (100MHz, DMSO-d6): δ181.0, 139.2, 136.6 (d, J = 5.5Hz), 131.8, 128.3, 125.5, 121.3, 120.1, 119.4, 116.6, 111.6, 100.1, 41.7. Example 19 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(2-fluorophenyl)thiourea (Formula (3-8)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(2-fluorophenyl)thiourea (Formula (2-8). Other operations are the same as those in embodiment 1.

[0078] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(2-fluorophenyl)thiourea was 84%.

[0079] The separated product was subjected to NMR detection, and the results were as follows: 1HNMR (400MHz, DMSO-d6): δ11.04(br,NH,1H),9.40(br,NH,1H),8.33(br,NH,1H),7.81(s,1H),7.50(d,J=7.8Hz,1H),7.37 13C NMR (100MHz, DMSO-d6): δ181.9,156.3(d,J=246.1Hz),136.6,136.5,128.3,127.3,127.2, 127.1,124.6(d,J=3.6Hz),121.3,120.1,119.4,116.2(d,J=20.0Hz),111.6,100.1,42.2. Example 20 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(3-fluorophenyl)thiourea (Formula (3-9)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(3-fluorophenyl)thiourea (Formula (2-9). Other operations are the same as those in embodiment 1.

[0080] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(3-fluorophenyl)thiourea was 88%.

[0081] The separated product was subjected to NMR detection, and the results were as follows: 1HNMR (400MHz, DMSO-d6): δ11.07(br,NH,1H),9.86(br,NH,1H),8.30(br,NH,1H),7.78(d,J=11.8Hz,1H),7.50(d,J=7.8Hz,1 13C NMR (100MHz, DMSO-d6): δ180.9,162.4(d,J=242.7Hz), 141.7(d,J=10.9Hz), 136.6,136,5,130.5(d,J=9. 5Hz),128.3,121.3,120.1,119.4,118.7,111.6,110.9(d,J=21.2Hz),109.8(d,J=25.3Hz),100.2,42.0. Example 21 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(4-fluorophenyl)thiourea (Formula (3-10)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(4-fluorophenyl)thiourea (Formula (2-10). Other operations are the same as those in embodiment 1.

[0082] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(4-fluorophenyl)thiourea was 90%.

[0083] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ11.01(br,NH,1H),9.64(br,NH,1H),8.10(br,NH,1H),7.50-7.47(m,3H),7.38(d,J=11 .6Hz,1H),7.19(q,J=8.8Hz,1H),7.08-7.05(m,1H),6.98(q,J=7.4Hz,1H),6.36(s,1H),4.88(d,J=5.3Hz,2H); 13C NMR (100MHz, DMSO-d6): δ181.5, 159.6 (d, J = 242.3Hz), 136.8, 136.6, 128.3, 126.8 (d, J = 8. 2Hz),121.3,120.1,119.4,115.8(d,J=22.1Hz),115.6(d,J=22.6Hz),111.6,100.0,42.0. Example 22 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(2-chlorophenyl)thiourea (Formula (3-11)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(2-chlorophenyl)thiourea (Formula (2-11). Other operations are the same as those in embodiment 1.

[0084] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(2-chlorophenyl)thiourea was 83%.

[0085] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ11.10(br,NH,1H),9.36(br,NH,1H),8.47(br,NH,1H),7.84(s,1H),7.54-7.50(m,2H),7.42(d,J=2.8Hz, 1H),7.35(q,J=9.2Hz,1H),7.25-7.21(m,1H),7.10(q,J=7.5Hz,1H),7.01(q,J=7.5Hz,1H),6.42(s,1H),4.91(d,J=5.2Hz,2H); 13C NMR (100MHz, DMSO-d6): δ186.6,141.4,134.6,134.1,133.9,133.0,132.3,132,1,126,1,124.9,124.2,116.4,105.1,47.0. Example 23 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(3-chlorophenyl)thiourea (Formula (3-12)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(3-chlorophenyl)thiourea (Formula (2-12). Other operations are the same as those in embodiment 1.

[0086] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(3-chlorophenyl)thiourea was 86%.

[0087] The separated product was subjected to NMR detection, and the results were as follows: 1HNMR (400MHz, DMSO-d6): δ11.04(br,NH,1H),9.82(br,NH,1H),8.31(br,NH,1H),7,82(s,1H),7.50(d,J=7.8Hz,1H),7 13C NMR (100MHz, DMSO-d6): δ185.7,146.2,141.3(d,J=5.7Hz),137.9,135.4,133.1,128.9,127.4,126.0,124.9,124.2,116.4,104.9,46.7. Example 24 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(4-chlorophenyl)thiourea (Formula (3-13)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(4-chlorophenyl)thiourea (Formula (2-13). Other operations are the same as those in embodiment 1.

[0088] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(4-chlorophenyl)thiourea was 89%.

[0089] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ11.02(br,NH,1H),9.75(br,NH,1H),8.21(br,NH,1H),7.54(d,J=8.4Hz,2H),7.48(d,J=7. 13C NMR (100MHz, DMSO-d6): δ180.7, 138.4, 136.2 (d, J = 9.2Hz), 128.5, 127.9, 124.7, 124.8, 120.9, 119.7, 118.9, 111.2, 99.6, 41.5. Example 25 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(4-tert-butylphenyl)thiourea (Formula (3-14)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(4-tert-butylphenyl)thiourea (Formula (2-14). Other operations are the same as those in embodiment 1.

[0090] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(4-tert-butylphenyl)thiourea was 82%.

[0091] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, CDCl3): δ9.58(br,NH,1H),8.42(br,NH,1H),7.57(d,J=7.8Hz,1H),7.46(d,J=8.4Hz,2H),7.38(d,J=7.8 13C NMR (100MHz, CDCl3): δ181.6,151.2,136.3,136.0.132.8,127.4,127.3,125.4,122.2,120.3,119.8,111.4,101.1,42.2,34.7,31.3. Example 26 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(3-methylphenyl)thiourea (Formula (3-15)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(3-methylphenyl)thiourea (Formula (2-15). Other operations are the same as those in embodiment 1.

[0092] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(3-methylphenyl)thiourea was 82%.

[0093] The separated product was subjected to NMR detection, and the results were as follows: 1HNMR (400MHz, DMSO-d6): δ11.01(br,NH,1H),9.66(br,NH,1H),8.09(br,NH,1H),7.50(d,J=7.8Hz,1H),7.38(d,J=7.9 13C NMR (100MHz, DMSO-d6): δ181.0,139.6,138.5,136.9,136.6,129.0,128.3,125.6,124.3,121.3,120.1,119.4,111.6,100.0,42.0,21.5. Example 27 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(4-methylphenyl)thiourea (Formula (3-16)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(4-methylphenyl)thiourea (Formula (2-16). Other operations are the same as those in embodiment 1.

[0094] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(4-methylphenyl)thiourea was 66%.

[0095] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ11.00(br,NH,1H),9.60(br,NH,1H),7.99(br,NH,1H),7.48(d,J=8.0Hz,1H),7.38-7.31(m,3H) 13C NMR (100MHz, DMSO-d6): δ181.1,137.0,136.9,136.5,134.2,129.7,128.3,124.2,121.2,120.1,119.4,111.6,100.0,42.0,21.0. Example 28 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(2-methyl-4-bromophenyl)thiourea (Formula (3-17)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(2-methyl-4-bromophenyl)thiourea (Formula (2-17). Other operations are the same as those in embodiment 1.

[0096] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(2-methyl-4-bromophenyl)thiourea was 82%.

[0097] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, CDCl3): δ9.50(br,NH,1H),8.15(br,NH,1H),7.56(d,J=7.9Hz,1H),7.44(s,1H),7.37(d,J=8.2Hz,2H),7.20(q,J =8.3Hz,1H),7.11(q,J=7.5Hz,1H),7.03(d,J=8.4Hz,1H),6.31(s,1H),6.15(br,NH,1H),4.93(d,J=6.2Hz,2H),2.18(s,3H); 13C NMR (100MHz, CDCl3): δ181.2,138.2,136.2,134.7,133.0,130.8,129.3,127.2,122.3,120.4,119.8,111.4,101.3,42.2,17.7. Example 29 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(2,4-dimethylphenyl)thiourea (Formula (3-18)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(2,4-dimethylphenyl)thiourea (Formula (2-18). Other operations are the same as those in embodiment 1.

[0098] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(2,4-dimethylphenyl)thiourea was 88%.

[0099] The separated product was subjected to NMR detection, and the results were as follows: 1HNMR (400MHz, DMSO-d6): δ10.94(br,NH,1H),9.21(br,NH,1H),7.72(br,NH,1H),7.48(d,J=7.8Hz,1H),7.37(d,J=8. 13C NMR (100MHz, DMSO-d6): δ181.4,137.3,136.5,136.3,135.0,134.8,131.6,128.3,127.4,121.2,120.1,119.3,111.6,99.8,42.2,21.0,18.1. Example 30 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(2-chloro-3-methylphenyl)thiourea (Formula (3-19)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(2-chloro-3-methylphenyl)thiourea (Formula (2-19). Other operations are the same as those in embodiment 1.

[0100] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(2-chloro-3-methylphenyl)thiourea was 90%.

[0101] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ11.04(br,NH,1H),9.72(br,NH,1H),8.21(br,NH,1H),7.74(s,1H),7.50(d,J=7.8Hz,1H),7.40(d,J=8. 13C NMR (100MHz, DMSO-d6): δ181.1,138.9,136.7,136.6,133.2,131.9,131.4(q,J =9.1Hz),128.3,124.4,123.7,123.0,122.4,121.3,119.4,111.6,42.0,19.5. Example 31 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(4-trifluoromethylphenyl)thiourea (Formula (3-20)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(4-trifluoromethylphenyl)thiourea (Formula (2-20). Other operations are the same as those in embodiment 1.

[0102] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(4-trifluoromethylphenyl)thiourea was 90%.

[0103] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ11.09(br,NH,1H),10.03(br,NH,1H),8.44(br,NH,1H),7.85(d,J=8.4Hz,2H),7.70(d,J=8.5Hz,2H),7 13C NMR (100MHz, DMSO-d6): δ181.0,143.8,136.6,136.3,128.4,126.0(d,J=3.8Hz),124.8 (q, J=272.4Hz), 124.1 (d, J=32.1Hz), 123.5, 121.4, 120.1, 119.4, 111.6, 100.3, 42.0. Example 32 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(3,5-difluorophenyl)thiourea (Formula (3-21)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(3,5-difluorophenyl)thiourea (Formula (2-21). Other operations are the same as those in embodiment 1.

[0104] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(3,5-difluorophenyl)thiourea was 90%.

[0105] The separated product was subjected to NMR detection, and the results were as follows: 1HNMR (400MHz, DMSO-d6): δ11.07(br,NH,1H),9.90(br,NH,1H),8.46(br,NH,1H),7.50(d,J=7.8Hz,1 13C NMR (100MHz, DMSO-d6): δ180.7, 162.7 (dd, J1=244.1Hz, J2=15.5Hz), 142.7 (t, J=13.5Hz), 136.6, 136.3, 128.3, 121.4, 120.1, 119.4, 111.6, 105.3 (d, J = 27.4Hz), 100.3, 99.2 (t, J = 26.3Hz), 42.0. Example 33 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(2-methyl-3-chlorophenyl)thiourea (Formula (3-22)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(2-methyl-3-chlorophenyl)thiourea (Formula (2-22). Other operations are the same as those in embodiment 1.

[0106] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(2-methyl-3-chlorophenyl)thiourea was 82%.

[0107] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ10.96(br,NH,1H),9.42(br,NH,1H),8.03(br,NH,1H),7.49(d,J=7.8Hz,1H),7.37(d,J=7.7Hz, 13C NMR (100MHz, DMSO-d6): δ182.0,139.3,137.1,136.5,133.8,134.4,128.3,127.6(d,J=11.2Hz),121.2,120.1,119.4,111.6,99.9,42.3,15.6. Example 34 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(3,5-dimethylphenyl)thiourea (Formula (3-23)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(3,5-dimethylphenyl)thiourea (Formula (2-23). ​​Other operations are the same as those in embodiment 1.

[0108] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(3,5-dimethylphenyl)thiourea was 82%.

[0109] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ11.00(br,NH,1H),9.58(br,NH,1H),8.03(br,NH,1H),7.49(d,J=7.8Hz,1H),7.38(d,J= 13C NMR (100MHz, DMSO-d6): δ180.9,139.3,138.3,137.0,136.5,128.3,126.5,121.6,121.2,120.1,119.4,111.6,100.0,42.0,21.5. Example 35 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(2,4-dichlorophenyl)thiourea (Formula (3-24)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(2,4-dichlorophenyl)thiourea (Formula (2-24). Other operations are the same as those in embodiment 1.

[0110] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(2,4-dichlorophenyl)thiourea was 85%.

[0111] 1HNMR (400MHz, DMSO-d6): δ11.07(br,NH,1H),9.36(br,NH,1H),8.52(br,NH,1H),7.86(d,J=8.8Hz, 1H),7.67(d,J=2.5Hz,1H),7.50(d,J=7.8Hz,1H),7.44-7.37(m,2H),7.09(q,J=8.0Hz,1H),6.99(q, J=7.4Hz, 1H), 6.39 (s, 1H), 4.88 (d, J=4.9Hz, 2H); 13CNMR (100MHz, DMSO-d6): δ181.8, 136.6, 136.3 ,135.8,130.6(d,J=16.1Hz),130.0,129.3,128.3,127.7,121.4,120.2,119.4,111.6,100.3,42.3. Example 36 Preparation of 1-((1H-indazol-2-yl)methyl)-3-(3,5-dichlorophenyl)thiourea (Formula (3-25)) The difference between this embodiment and embodiment 1 is that N,N'-diphenylthiourea is replaced by N,N'-di(2,4-dichlorophenyl)thiourea (Formula (2-25). Other operations are the same as those in embodiment 1.

[0112] Results: The isolated yield of 1-((1H-indazol-2-yl)methyl)-3-(3,5-dichlorophenyl)thiourea was 82%.

[0113] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ11.05(br,NH,1H),9.95(br,NH,1H),8.49(br,NH,1H),7.69(d,J=1.9Hz,1H),7.49(d,J=7.9Hz,1H 13C NMR (100MHz, DMSO-d6): δ180.9,142.6,136.6,136.3,134.2,128.3,123.4,121.4,121.0,120.1,119.4,111.6,100.2,42.0. Example 37 Preparation of 1-((5-chloro-1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-26)) The difference between this embodiment and embodiment 1 is that indole-2-methylamine is replaced by 5-chloroindole-2-methylamine (Formula (1-2). Other operations are the same as those in embodiment 1.

[0114] Results: The isolated yield of 1-((5-chloro-1H-indazol-2-yl)methyl)-3-phenylthiourea was 92%.

[0115] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ11.2(br,NH,1H),9.7(s,NH,1H),8.1(s,NH,1H),7.54(d,J=2.1Hz,1H),7.47(d,J=7.2Hz,2H), 13C NMR (100MHz, DMSO-d6): δ181.1,139.5,139.0,135.0,129.5,129.2,124.9,123.9,123.8,121.1,119.2,113.1,99.7,41.9. Example 38 Preparation of 1-((5-bromo-1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-27)) The difference between this embodiment and embodiment 1 is that indole-2-methylamine is replaced by 5-bromoindole-2-methylamine (Formula (1-3). Other operations are the same as those in embodiment 1.

[0116] Results: The isolated yield of 1-((5-bromo-1H-indazol-2-yl)methyl)-3-phenylthiourea was 82%.

[0117] The separated product was subjected to NMR detection, and the results were as follows: 1HNMR(400MHz,DMSO-d6): δ11.23(br,NH,1H),9.72(br,NH,1H),8.14(br,NH,1H),7 .68(d,J=2.0Hz,1H),7.47(d,J=8.0Hz,2H),7.34(t,J=7.3Hz,3H),7.18-7.13(m,2 H), 6.35 (s, 1H), 4.88 (d, J = 5.3Hz, 2H); 13CNMR (100MHz, DMSO-d6): δ181.2, 139.5, 138.8,135.2,130.3,129.2,124.9,123.8,123.6,122.3,113.6,111.9,99.6,41.8. Example 39 Preparation of 1-((5-methyl-1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-28)) The difference between this embodiment and embodiment 1 is that indole-2-methylamine is replaced by 5-methylindole-2-methylamine (Formula (1-4). Other operations are the same as those in embodiment 1.

[0118] Results: The isolated yield of 1-((5-methyl-1H-indazol-2-yl)methyl)-3-phenylthiourea was 81%.

[0119] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ10.89(br,NH,1H),9.68(br,NH,1H),8.09(br,NH,1H),7.49(d,J=7.8H z,1H),7.34(t,J=7.4Hz,2H),7.26(d,J=9.1Hz,2H),7.13(t,J=7.4Hz,1H),6.89(dd,J1=8.2Hz,J2 =1.7Hz, 1H), 6.27 (s, 1H), 4.86 (d, J = 4.4Hz, 2H), 2.37 (s, 3H); 13CNMR (100MHz, DMSO-d6): δ181.0 ,139.7,136.8,134.9,129.1,128.6,127.8,124.8,123.7,122.9,119.8,111.3,99.6,42.0,21.7. Example 40 Preparation of 1-((5-methoxy-1H-indazol-2-yl)methyl)-3-phenylthiourea (Formula (3-29)) The difference between this embodiment and embodiment 1 is that indole-2-methylamine is replaced by 5-methylindole-2-methylamine (Formula (1-5). Other operations are the same as those in embodiment 1.

[0120] Results: The isolated yield of 1-((5-methoxy-1H-indazol-2-yl)methyl)-3-phenylthiourea was 67%.

[0121] The separated product was subjected to NMR detection, and the results were as follows: 1 HNMR (400MHz, DMSO-d6): δ10.85(br,NH,1H),9.69(br,NH,1H),8.10(br,NH,1H),7.48(d,J=7.2Hz,2H),7.34(t,J=7.4Hz,2H),7.26(d,J=8.6 13C NMR (100MHz, DMSO-d6): δ181.0,153.8,139.6,137.3,131.6,129.1,128.7,124.8,123.7,112.2,111.2,102.0,100.0,55.7,42.0. The raw materials and equipment used in the present invention, unless otherwise specified, are all commonly used raw materials and equipment in the art; the methods used in the present invention, unless otherwise specified, are all conventional methods in the art.

[0122] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any way. Any simple modification, change and equivalent transformation made to the above embodiment based on the technical essence of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for synthesizing an asymmetric thiourea compound, characterized in that: Indole-2-methylamine compounds and N,N'-diarylthiourea are used as reaction substrates, and react in the presence of an organic base, in an inert gas atmosphere, and under ultraviolet light irradiation to obtain an asymmetric thiourea compound; The structural formula of the indole-2-methylamine compound is shown in formula (II), the structural formula of the N,N'-diarylthiourea is shown in formula (III), and the structural formula of the asymmetric thiourea compound is shown in formula (I): Among them, R 1 is selected from H, C1-C8 alkyl, C1-C2 alkoxy, F, Cl, Br, NO2 and CN; R 2 is one or more substituents, each independently selected from C1-C8 alkyl, C1-C4 alkoxy, F, Cl, Br, NO2 and CF3.

2. The method for synthesizing an asymmetric thiourea compound according to claim 1, characterized in that: R 1 is selected from H, Br, Cl, methyl and methoxy.

3. The method for synthesizing an asymmetric thiourea compound according to claim 1, characterized in that: The reaction is carried out in an organic solvent.

4. The method for synthesizing an asymmetric thiourea compound according to claim 3, characterized in that: The organic solvent is one or more of tetrahydrofuran, acetonitrile, dichloroethane and dimethyl sulfoxide.

5. The method for synthesizing an asymmetric thiourea compound according to claim 1, characterized in that: The molar ratio of indole-2-methylamine compounds to N,N'-diarylthiourea is 1:1-3.

6. The method for synthesizing an asymmetric thiourea compound according to claim 1, characterized in that: The organic base is one or more of pyridine, triethylamine, DABCO, DBU, tributylamine and diisopropylethylamine.

7. The method for synthesizing an asymmetric thiourea compound according to claim 1, characterized in that: The wavelength of the ultraviolet light is 360-405 nm.

8. The method for synthesizing an asymmetric thiourea compound according to claim 1, characterized in that: The reaction temperature of the reaction is 20 to 35° C., and the reaction time is 6 to 14 hours.

9. The method for synthesizing an asymmetric thiourea compound according to claim 1, characterized in that: The structural formula of the asymmetric thiourea compound is selected from the structural formulas shown in (3-1) to (3-29):

10. The method for synthesizing an asymmetric thiourea compound according to claim 1, characterized in that: After the reaction is completed, the solvent is evaporated under reduced pressure, and then column chromatography is performed, using a mixed solution of ethyl acetate / petroleum ether in a volume ratio of 1:5 as an eluent, collecting the eluate containing the target compound, and evaporating the solvent to obtain the product asymmetric thiourea.

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