Preparation method of benzothieno tetrahydropyrimidine compound

Abstract

The invention relates to the field of chemical synthesis, in particular to a preparation method of a benzothieno tetrahydropyrimidine compound. According to the invention, 3-aminobenzothiophene and 1, 3, 5-triazinane are used as reactants. According to the method, the tetrahydrobenzothienopyrimidine compound can be simply and efficiently prepared, the raw materials are easy to obtain, the operation is simple, a metal reagent and a catalyst are not used, the yield is medium, inert gas protection is not needed in the preparation process, and the reaction conditions are mild.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemical synthesis, in particular to a preparation method of benzothienotetrahydropyrimidine compounds. BACKGROUND

[0002] Nitrogen-containing heterocycles are ubiquitous in natural products, pharmaceuticals, and bioactive molecules. Pyrimidines and their derivatives are common core structures in medicinal chemistry. A large number of thiophene pyrimidine fungicides, acaricides, and insecticides have been reported in the literature, and they have anticancer, antiviral, antitumor, anti-inflammatory, antihistamine, analgesic, and other effects. Therefore, in the past few decades, synthetic chemists have made continuous efforts to develop new nitrogen-containing structural synthesis units and to develop their applications, synthesizing various nitrogen-containing heterocycles. Among them, the application of 1,3,5-triazinanes for the construction of N-heterocycles has recently developed into a research hotspot. Given our continued interest in 1,3,5-triazinanes, we designed a cyclization reaction of 1,3,5-triazinanes with 3-aminobenzothiophene to obtain a benzothienotetrahydropyrimidine structural unit, an advantageous skeleton that has not been successfully obtained in previous literature.Benzothienopyrimidine related structural unit plays an important role in pharmaceutically active molecules (e.g. recently applied patents and literatures: Pyrimidine-2(lH)-one-fused bicyclic compound having MAT2A inhibitory activity and application, World Intellectual Property Organization, WO2023116390 A1 2023-06-29; Synthesis of certain benzothieno[3,2-d]pyrimidine derivatives as a selective SIRT2 inhibitors, European Journal of Medicinal Chemistry 2020, 187, 111926), and this structural unit is widely used in the field of optoelectronic materials (e.g.: Preparation of pyrimidine derivatives as organic electroluminescence device materials, World Intellectual Property Organization, WO2019098765 A1 2019-05-23; Preparation of heterocyclic compounds as organic optoelectronic device materials, World Intellectual Property Organization, WO2019066282 A1 2019-04-04; Diazadibenzofurane and diazadibenzothiophene derivatives and their use in organic optoelectronic devices, European Patent Organization, EP3056498 A1 2016-08-17). Thus, the present patent method has very important value, which can be used for the development of related functional molecules. SUMMARY

[0003] The application provides a novel benzothiophene tetrahydro pyrimidine compound and a synthesis method.

[0004] The technical scheme adopted by the application is as follows:

[0005] The benzothiophene tetrahydro pyrimidine compound is shown in the following structural formula III:

[0006]

[0007] In the formula, R1 is a substituent group, including a phenyl group, a p-toluenesulfonyl group and a p-nitrophenyl group; R2 is a substituted phenyl group, and the substituent group includes a 4-methyl group, a 4-methoxy group, a 4-bromo group, a 3-methyl group and a 2-methoxy group; and the substituted alkyl group includes a benzyl group and a cyclopropyl group.

[0008] The preparation method of the benzothiophene tetrahydro pyrimidine compound is shown in the following formula:

[0009]

[0010] The preparation method of the target compound III is as follows: the compound I and the compound II are dissolved in dichloromethane, and the reaction is stirred at 60 DEG C; the reaction is stopped after the compound I is completely reacted by thin layer monitoring; the solvent in the reaction mixture is removed under reduced pressure; and the target compound III is obtained by silica gel column chromatography elution.

[0011] Further, the dichloromethane can be replaced by 1,2-dichloroethane, chloroform, ethyl acetate, methanol, toluene, acetonitrile, tetrahydrofuran or N,N-dimethylformamide.

[0012] Further, the molar ratio of the compound I to the compound II is 1:1.5.

[0013] Further, the eluent used in the silica gel column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 50:1 to 10:1.

[0014] The application has the following beneficial effects: the application uses 1,3,5-triazane and 3-amino benzothiophene as reactants; the method can simply and efficiently prepare the benzothiophene tetrahydro pyrimidine compound; the raw material is easy to obtain; the operation is simple; no metal reagent and catalyst are needed; the yield is medium; no inert gas protection is needed in the preparation process; the reaction condition is mild; the benzothiophene tetrahydro pyrimidine synthesis method is rarely reported; the compound has potential life activity; and the compound is expected to be used as a drug lead molecule mother skeleton. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 The hydrogen spectrum of product III-1 obtained by the embodiment of the present application

[0016] Figure 2 The carbon spectrum of product III-1 obtained by the embodiment of the present application. DETAILED DESCRIPTION

[0017] The technical solutions of the present application are further illustrated below by specific examples in combination with the drawings:

[0018] The reaction formula of Example 1, the specific compounds I-1 and II-1 used and the structure of product III-1 are as follows. Experiments show that the best organic solvent used in the present application is dichloromethane, the highest yield of the reaction product is 98%, the best molar ratio of raw materials is compound I-1: compound II-1 = 1 / 1.5, and the best reaction concentration of compound I-1 is 0.1 mol·L -1 .

[0019]

[0020] The specific experimental steps are as follows: 45 mg, 0.2 mmol, 1.0 equivalent of compound I-1 and 165 mg, 0.3 mmol, 1.5 equivalents of compound II-1 are dissolved in 2 mL of dichloromethane, and stirred at room temperature. The reaction is stopped after the reactant I-1 is completely reacted, and the reaction mixture is rotary evaporated under water pump reduced pressure to remove the solvent dichloromethane. The residue is column chromatographed with 200-300 mesh silica gel and eluent (volume ratio V 石油醚 :V 乙酸乙酯 = 50:1~40:1) to obtain 83 mg of the compound shown as III-1, and the product is identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum) and high resolution mass spectrometry.

[0021] Product III-1 is a white solid, and the yield is 98%, and the melting point is 138-140℃. 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 1H), 7.31-7.19 (m, 5H), 7.16 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.06-7.01 (m, 1H), 7.00-6.95 (m, 2H), 6.66-6.57 (m, 2H), 5.07 (s, 2H), 4.64 (s, 2H). 13C NMR (100 MHz, CDC13) δ 147.8, 147.3, 137.5, 135.2, 133.8, 132.0, 129.2, 124.5, 124.0, 123.3, 122.9, 122.3, 121.7, 117.9, 112.1, 71.3, 47.9, 2C merged with other peaks; ESI-HRMS m / z calcd for C 22 H 18 BrN2S [M+H] + 421.0369, found 421.0370.

[0022] The method used in the preparation of other compounds of the application (compounds III-2 to III-9) is the same as in Example 1, and the reaction conditions are as follows: compound I (0.2 mmol), compound II (0.3 mmol) are dissolved in 2 mL of dichloromethane, and heated at 60°C.

[0023] The structure and data characterization of the product obtained are as follows:

[0024]

[0025] III-2 is a yellow solid, yield 51%, melting point 183-184°C. 1 H NMR (400 MHz, CDC13) δ 8.37 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.20 (d, t, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 5.14 (s, 2H), 3.92 (s, 2H), 2.31 (s, 3H), 2.26 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 144.3, 143.7, 137.1, 135.0, 134.4, 130.8, 130.1, 130.0, 129.1, 128.8, 128.1, 125.2, 125.0, 124.2, 122.4, 114.2, 64.4, 46.2, 21.6, 20.5; ESI-HRMS m / z calcd for C 24 H 22 N2O2S2Na [M+Na] + 457.1015, found 457.1015.

[0026] Product III-3

[0027] III-3 is a yellow solid with a yield of 83% and a melting point of 166-168℃. 1 H NMR(400MHz, CDCl3)δ8.03(d,J=9.1Hz,2H),7.83(d,J=8.0Hz,1H),7.36–7.30(m,1H),7.24–7.19(m,1H) ,7.03(d,J=8.0Hz,1H),6.95–6.86(m,4H),6.75(d,J=8.5Hz,2H),5.20(s,2H),4.71(s,2H),2.18(s,3H); 13 C NMR (100MHz, CDCl3) δ152.9,145.4,141.6,137.5,133.2,133.1,131.2,129.8,1 25.1,124.8(2C),124.3,123.2,122.1,119.9,118.1,71.5,48.5,20.5;ESI-HRMS m / zcalcd for C 23 H 19 N3O2SNa[M+Na] + 424.1090, found 424.1089.

[0028] Product III-4

[0029] III-4 is a pale yellow solid with a yield of 88% and a melting point of 103-105℃. 1 H NMR(400MHz, CDCl3)δ7.84–7.79(m,1H),7.34–7.23(m,3H),7.23–7.11(m,2H) ,7.08–6.96(m,5H),6.77–6.71(m,2H),5.09(s,2H),4.66(s,2H),2.25(s,3H); 13 C NMR (100MHz, CDCl3) δ148.0,146.0,137.6,135.2,134.0,129.7,129.6,129.1,124.3 ,123.9,122.99,123.0,122.9,122.4,122.3(2C),116.7,72.2,48.2,20.5; ESI-HRMS m / z calcd for C 23 H 21 N2S[M+H] + 357.1420, found 357.1420.

[0030] Product III-5

[0031] III-5 is an orange-red solid with a yield of 75% and a melting point of 93-95 °C. 1 H NMR (400 MHz, CDC13) δ 7.81 (dt, J = 8.0, 0.9 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.26 - 7.21 (m, 2H), 7.20 - 7.15 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.05 - 7.00 (m, 1H), 7.00 - 6.96 (m, 2H), 6.82 - 6.77 (m, 2H), 6.76 - 6.70 (m, 2H), 5.03 (s, 2H), 4.62 (s, 2H), 3.73 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 154.2, 148.0, 142.3, 137.5, 135.0, 133.9, 129.0, 124.3, 123.8, 122.9, 122.4, 122.3, 121.9, 119.0, 114.5, 73.2, 55.6, 48.7, 22.8; ESI-HRMS m / z calcd for C 23 H 21 N2OS [M+H] + 373.1369, found 373.1370.

[0032] Product III-6

[0033] III-6 is a yellow solid with a yield of 84% and a melting point of 137-139 °C. 1 H NMR (400 MHz, CDC13) δ 7.81 (dt, J = 8.0, 1.0 Hz, 1H), 7.33 - 7.24 (m, 3H), 7.22 - 7.12 (m, 2H), 7.10 - 7.01 (m, 4H), 6.67 - 6.59 (m, 3H), 5.12 (s, 2H), 4.69 (s, 2H), 2.24 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 148.2, 148.0, 139.0, 137.6, 135.2, 134.0, 129.1, 124.4, 123.9, 123.0, 122.9, 122.4, 122.3 (2C), 120.9, 117.0, 113.5, 71.4, 48.0, 21.8; ESI-HRMS m / z calcd for C 23 H 21 N2S [M+H] + 357.1420, found357.1419.

[0034] Product III-7

[0035] III-7 is an orange red oil in 80% yield. 1 H NMR (400 MHz, CDC13) δ 7.77 (dt, J = 8.07, 0.95 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.12 - 7.07 (m, 3H), 7.01 (d, J = 8.02 Hz, 1H), 6.94 (dd, J = 7.84, 1.64 Hz, 1H), 6.88 (dt, J = 7.33, 1.14 Hz, 1H), 6.84 (ddt, J = 7.77, 3.73, 1.74 Hz, 3H), 6.73 (td, J = 7.63, 1.48 Hz, 1H), 6.61 (dd, J = 7.99, 1.45 Hz, 1H), 5.08 (s, 2H), 4.67 (s, 2H), 3.56 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 152.2, 147.8, 137.4, 137.4, 134.8, 133.8, 128.4, 124.2, 123.7, 123.5, 122.9, 122.6, 122.2, 121.3, 120.7, 119.8, 111.3, 71.0, 55.3, 49.4, (1C peak is merged with other peaks); ESI-HRMS m / z calcd for C 23 H 20 N2OSNa [M + Na] + 395.1189, found 395.1189.

[0036] Product III-8

[0037] III-8 is a brown solid in 91% yield, melting point 95-97 °C. 1 H NMR (400 MHz, CDC13) δ 7.77 (dt, J = 8.07, 0.95 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.12 - 7.07 (m, 3H), 7.01 (d, J = 8.02 Hz, 1H), 6.94 (dd, J = 7.84, 1.64 Hz, 1H), 6.88 (dt, J = 7.33, 1.14 Hz, 1H), 6.84 (ddt, J = 7.77, 3.73, 1.74 Hz, 3H), 6.73 (td, J = 7.63, 1.48 Hz, 1H), 6.61 (dd, J = 7.99, 1.45 Hz, 1H), 5.08 (s, 2H), 4.67 (s, 2H), 3.56 (s, 3H); 13C NMR (100 MHz, CDC13) δ 149.1, 138.6, 137.9, 134.2, 134.0, 129.5, 129.3, 128.8, 127.7, 124.5, 124.0, 123.3, 123.2, 122.7, 122.0, 121.0, 72.1, 58.0, 51.1; ESI-HRMS m / z calcd for C 23 H 21 N2S [M+H] + 357.1420, found 357.1420.

[0038] Product III-9

[0039] III-9 is a brown oil in 95% yield. 1 H NMR (400 MHz, CDC13) δ 7.78 (dt, J = 8.06, 0.93 Hz, 1H), 7.28 - 7.20 (m, 3H), 7.16 - 7.11 (m, 1H), 7.05 (d, J = 8.00 Hz, 1H), 7.02 - 6.94 (m, 3H), 4.62 (s, 2H), 4.27 (s, 2H), 2.23 - 2.15 (m, 1H), 0.46 - 0.39 (m, 2H), 0.34 - 0.29 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 148.9, 137.4, 133.9, 133.7, 128.9, 124.0, 123.6, 122.8, 122.8, 121.8, 121.3, 121.0, 72.2, 51.4, 34.7, 7.3; ESI-HRMS m / z calcd for C 19 H 19 N2S [M+H] + 307.1263, found 307.1263.

[0040] It will be obvious to those skilled in the art that the application is not limited to the details of the foregoing exemplary embodiments and can be implemented in other specific forms without departing from the spirit or essential characteristics of the application. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the application being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

1. A method for preparing a benzothiophene tetrahydropyrimidine compound, the structural formula of which is shown in Figure III: in: R 1 Substituents include phenyl, p-toluenesulfonyl, p-nitrophenyl, R 2 The substituted phenyl group includes 4-methyl, 4-methoxy, 4-bromo, 3-methyl, and 2-methoxy; the substituted alkyl group includes benzyl and cyclopropyl. Its characteristic is that the preparation method is as follows: Preparation method of target compound III: Compound I and compound II were dissolved in dichloromethane and stirred under heating conditions. The reaction was stopped after compound I was completely reacted by thin-layer chromatography. The solvent was removed from the reaction mixture under reduced pressure, and target compound III was obtained by silica gel column chromatography.

2. The method for preparing a benzothiophene tetrahydropyrimidine compound according to claim 1, characterized in that: The dichloromethane replacement solvent is 1,2-dichloroethane, chloroform, ethyl acetate, methanol, toluene, acetonitrile, tetrahydrofuran, or N,N-dimethylformamide.

3. The method for preparing a benzothiophene tetrahydropyrimidine compound according to claim 1, characterized in that: The molar ratio of compound I to compound II is I:II = 1:1.

5.

4. The method for preparing a benzothiophene tetrahydropyrimidine compound according to claim 1, characterized in that: The eluent used for the silica gel column chromatography was a mixed solvent of petroleum ether and ethyl acetate, with a volume ratio of V... 石油醚 :V 乙酸乙酯 =50:1~10:1.

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