Preparation method of thiopyrano [2, 3-b] indole compound

Abstract

The invention relates to the field of organic chemical synthesis, in particular to a preparation method of a thiopyrano [2, 3-b] indole compound. According to the method, the thiopyrano [2, 3-b] indole compound is simply and efficiently synthesized by a one-pot method by taking indoline-2-thioketone, chromone 3-formaldehyde and halogenated alkane as initial raw materials, sodium bicarbonate, zinc chloride and potassium carbonate as catalysts and dichloromethane as a solvent under the condition of heating reaction at 60 DEG C. The method provided by the invention can be used for simply and efficiently preparing the thiopyrano [2, 3-b] indole compound, the raw materials are easily available, the operation is simple, the yield is excellent, inert gas protection is not needed in the preparation process, and the reaction conditions are mild.

Description

Technical Field

[0001] The present invention relates to the field of organic chemical synthesis, and specifically to a preparation method of thiopyrano[2,3-b]indole compounds. Background Art

[0002] Introducing a sulfur atom into the indole heterocycle and constructing indolo-thiopyran has significant chemical and biological significance. Through its unique electronic effects, such as high polarizability and enhanced conjugated delocalization, the sulfur atom can regulate the energy levels of molecular orbitals, enhance the reactivity and selectivity of the indole aromatic ring. For example, it can promote electrophilic substitution or act as a metal-catalyzed directing group. At the same time, the rigid fused-ring structure of the thiopyrano ring can limit the conformational freedom of the molecule, enhance the hydrophobic or π-π interaction with biological targets, thereby optimizing the binding affinity of drug molecules; the sulfur atom can also improve metabolic stability, reduce oxidative degradation, and prolong the drug half-life.

[0003] Structures such as thiopyranoindole have outstanding potential in the fields of drug design and functional materials. Sulfur-modified indole derivatives exhibit high activities in the fields of anti-tumor, antibacterial, etc., and can expand drug diversity by mimicking natural sulfur-containing alkaloids. In addition, the introduction of a sulfur atom can regulate the optoelectronic properties of materials. For example, it can expand the conjugated system to enhance the carrier mobility of organic semiconductors, or regulate the emission wavelength for the development of OLED materials, realizing multi-dimensional expansion of molecular functions. Therefore, the synthesis of thiopyranoindole is of great significance. Summary of the Invention

[0004] The present invention provides a synthesis method of thiopyrano[2,3-b]indole compounds. This method realizes the one-pot synthesis of thiopyrano[2,3-b]indole compounds in a simple and efficient manner under the conditions of using indoline-2-thione, chromone-3-carbaldehyde and haloalkane as starting materials, sodium bicarbonate, zinc chloride and potassium carbonate as catalysts, dichloromethane as a solvent, and heating at 60 °C.

[0005] The technical solution of the present invention is as follows:[[]]END

[0006] A preparation method of thiopyrano[2,3-b]indole compounds, and the structural formula Ⅳ of the thiopyrano[2,3-b]indole compounds is as follows:[[]]END

[0007]

[0008] Wherein: R 1 is an alkane, specifically including: acetophenone, 4-methoxyacetophenone, 4-chloroacetophenone, 4-bromoacetophenone, ethyl acetate, benzyl acetate or methyl-substituted groups, and the preparation method is as follows:[[]]END

[0009]

[0010] The preparation steps of the target compound Ⅳ include: dissolving compound Ⅰ and compound Ⅱ in dichloromethane, adding zinc chloride and sodium bicarbonate and then reacting. After monitoring by thin layer that compound Ⅰ has reacted completely, adding haloalkane Ⅳ and potassium carbonate to react. Then, the reaction mixture is removed the solvent under reduced pressure, and eluted by silica gel column chromatography to obtain the target compound Ⅳ.

[0011] As a further improvement of the preparation method, the replacement of the dichloromethane solvent includes: 1,2-dichloroethane, chloroform, ethyl acetate, methanol, acetonitrile or tetrahydrofuran.

[0012] As a further improvement of the preparation method, the replacements of zinc chloride include: scandium trifluoromethanesulfonate, tin trifluoromethanesulfonate, indium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, aluminum chloride or magnesium iodide and other Lewis acids.

[0013] As a further improvement of the preparation method, the replacements of sodium bicarbonate include: sodium carbonate, potassium carbonate, sodium methoxide, triethylamine or DABCO.

[0014] As a further improvement of the preparation method, the replacements of potassium carbonate include: sodium carbonate, sodium bicarbonate or sodium hydroxide.

[0015] As a further improvement of the preparation method, the molar ratio of compound I, compound Ⅱ and compound Ⅲ is I∶Ⅱ∶Ⅲ = 2:1:1.2.

[0016] As a further improvement of the preparation method, the eluent used in the silica gel column chromatography is a mixed solvent of petroleum ether and dichloromethane, and the volume ratio V 石油醚 :V 二氯甲烷 = 5:1~1:3.

[0017] As a further improvement of the preparation method, the reaction temperature for preparing the target compound Ⅳ is 25℃ to 80℃.

[0018] As a further improvement of the preparation method, the reaction temperature for preparing the target compound Ⅳ is 60℃.

[0019] The beneficial effects brought by the technical solutions provided in the embodiments of this application at least include the following

[0020] Beneficial effects:

[0021] In the present invention, indoline-2-thione, chromone-3-carbaldehyde and haloalkane are used as starting materials, sodium bicarbonate, zinc chloride and potassium carbonate are used as catalysts, and dichloromethane is used as the solvent. Under the condition of heating reaction at 60℃, the thiochromeno[2,3-b]indole compounds are synthesized by a simple and efficient one-pot method. The reaction substrate range is wide and the functional group tolerance is good. Description of the Drawings

[0022] Figure 1 1H NMR spectrum of the product Ⅳ-1 obtained in the embodiment of the present invention

[0023] Figure 2 This is the carbon spectrum of product Ⅳ-1 obtained in the embodiment of the present invention. Detailed implementation manners

[0024] Next, the technical solutions in the embodiments of the present application will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present application.

[0025] Example 1

[0026] The reaction formula of Example 1. The specific compounds I-1, II-1, and III-1 used and the structure of their product Ⅳ-1 are as follows. Experiments show that the best organic solvent for the reaction of the present invention is dichloromethane, the highest yield of its reaction product is 98%, the best molar ratio of raw materials is the molar ratio of compound I∶compound II∶compound III as I∶II∶III = 2:1:1.2, and the best reaction concentration is 0.1M.

[0027]

[0028] The specific experimental steps are as follows: Dissolve 65 mg (0.4 mmol, 2.0 equivalents) of compound I-1 and 35 mg (0.2 mmol, 1.0 equivalent) of compound II-1 in 2 mL of dichloromethane, add 3 mg of zinc chloride (0.02 mmol, 0.1 equivalent), and 17 mg of sodium bicarbonate (0.2 mmol, 1.0 equivalent), and stir and react at 60 °C. After monitoring the reaction of reactant I-1 by thin-layer chromatography and it is completed, add 48 mg of compound Ⅳ (0.24 mmol, 1.2 equivalents) and 55 mg of potassium carbonate (0.4 mmol, 2.0 equivalents). After reacting for 24 hours, remove the solvent from the reaction mixture under reduced pressure, and elute by silica gel column chromatography to obtain the target compound Ⅳ-1. Rotate and evaporate the solvent dichloromethane from the reaction mixture under reduced pressure with a water pump. The residue is chromatographed on silica gel with 200 - 300 mesh, and the eluent (volume ratio V 石油醚 :V 二氯甲烷 = 5:1 - 1:1) column chromatography to obtain 115 mg of the compound shown as Ⅳ-1. The product is identified by nuclear magnetic resonance (proton spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0029] The product Ⅳ-1 is a yellow oil, and the yield is 96%. 11H NMR (500 MHz, CDCl3) δ 11.09 (s, 1H), 7.91 - 7.87 (m, 2H), 7.76 (s, 1H), 7.69 (dd, J = 7.9, 1.7 Hz, 1H), 7.62 - 7.59 (m, 1H), 7.54 - 7.49 (m, 2H), 7.42 - 7.37 (m, 1H), 7.36 - 7.31 (m, 2H), 7.27 - 7.24 (m, 1H), 7.24 - 7.20 (m, 2H), 7.20 - 7.16 (m, 1H), 7.15 - 7.11 (m, 1H), 6.95 (dd, J = 8.3, 1.1 Hz, 1H), 6.92 (s, 1H), 6.90 - 6.83 (m, 2H), 4.45 (d, J = 15.1 Hz, 1H), 4.40 (d, J = 15.1 Hz, 1H), 3.70 (s, 3H), 3.60 (s, 3H); 13 13C NMR (125 MHz, CDCl3) δ 198.7, 194.8, 161.6, 139.7, 139.0, 138.4, 135.7, 135.5, 134.8, 133.8, 132.1, 128.8, 127.4, 126.7, 125.1, 123.3, 123.3, 122.2, 121.7, 121.0, 120.7, 120.4, 119.9, 118.6, 118.1, 116.9, 110.3, 109.4, 108.6, 43.8, 39.2, 30.8, 30.5, (1C is merged with other peaks); ESI - HRMS m / z calcd for C 36 H 28 N2O3S2Na [M + Na] + 623.1434, found 623.1434.

[0030] The methods used in the examples for preparing other compounds (Compound IV - 2 to Compound IV - 7) of the present invention are the same as those in Example 1, and the reaction conditions are as follows: Compound I (0.4 mmol) and Compound II (0.2 mmol) are dissolved in 2 mL of dichloromethane, 3 mg of zinc chloride (0.02 mmol, 0.1 equivalent) and 17 mg of sodium bicarbonate (0.2 mmol, 1.0 equivalent) are added, and the reaction is stirred at 60 °C. After monitoring the reaction of reactant I by thin - layer chromatography and it is completed, alkyl halide IV (0.24 mmol) and 55 mg of potassium carbonate are added. After reacting for 24 hours, the reaction mixture is rotary - evaporated under reduced pressure with a water pump to remove the solvent dichloromethane. The residue is subjected to column chromatography on silica gel of 200 - 300 mesh, and the eluent (volume ratio V 石油醚 :V 二氯甲烷 = 5:1 to 1:2) gives the compound shown in IV.

[0031] The structure and data characterization of the obtained product are as follows:

[0032]

[0033] Product Ⅳ-2 is a yellow solid with a yield of 98% and a melting point of 191 - 193 °C. 1 H NMR(500MHz,CDCl3)δ11.15(s,1H),7.87 - 7.81(m,2H),7.77(s,1H),7.70(dd,J=7.9,1.7Hz,1H),7.63 - 7.59(m,1H),7.55 - 7.52(m,1H),7.43 - 7.39(m,1H),7.26 - 7.21(m,3H),7.18 - 7.15(m,1H),7.14 - 7.10(m,1H),6.97(dd,J=8.3,1.2Hz,1H),6.93(s,1H),6.91 - 6.84(m,2H),6.75 - 6.70(m,2H),4.41(d,J=14.7Hz,1H),4.28(d,J=14.6Hz,1H),3.76(s,3H),3.67(s,3H),3.59(s,3H); 13 C NMR(125MHz,CDCl3)δ198.7,193.5,164.0,161.6,139.7,138.9,138.3,135.6,134.8,132.1,131.2,128.6,127.5,126.7,125.0,123.3,123.2,122.2,121.7,121.0,120.7,120.4,119.8,118.6,118.1,116.8,113.9,110.3,109.4,108.6,55.6,43.2,39.2,30.8,30.4;ESI - HRMS m / z calcd for C 37 H 30 N2O4S2Na[M + Na] + 653.1539,found 653.1539.

[0034] Product Ⅳ-3 is a yellow solid with a yield of 81% and a melting point of 179 - 181 °C. 11H NMR (500 MHz, CDCl3) δ 11.11 (s, 1H), 7.85 - 7.81 (m, 2H), 7.77 (s, 1H), 7.70 (dd, J = 7.9, 1.7 Hz, 1H), 7.63 - 7.09 (m, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.32 - 7.28 (m, 2H), 7.25 - 7.21 (m, 3H), 7.21 - 7.13 (m, 2H), 6.98 (dd, J = 8.4, 1.2 Hz, 1H), 6.92 (s, 1H), 6.91 - 6.86 (m, 2H), 4.44 (d, J = 15.1 Hz, 1H), 4.36 (d, J = 15.1 Hz, 1H), 3.70 (s, 3H), 3.58 (s, 3H); 13 13C NMR (125 MHz, CDCl3) δ 198.7, 193.6, 161.5, 140.2, 139.7, 138.9, 138.3, 135.8, 134.8, 133.8, 132.0, 130.1, 129.1, 129.0, 127.0, 126.6, 125.0, 123.3, 122.2, 121.7, 121.0, 120.6, 120.5, 119.7, 118.6, 118.1, 116.8, 110.2, 109.4, 108.6, 43.5, 39.1, 30.7, 30.4; ESI-HRMS m / z calcd for C 36 H 27 ClN2O3S2Na [M + Na] + 657.1044, found 657.1044.

[0035] The product Ⅳ-4 is a yellow solid, with a yield of 66%, melting point: 185 - 187 °C. 1 1H NMR (500 MHz, CDCl3) δ 11.06 (s, 1H), 7.78 - 7.76 (m, 1H), 7.76 - 7.72 (m, 2H), 7.68 (dd, J = 7.9, 1.7 Hz, 1H), 7.62 - 7.59 (m, 1H), 7.55 - 7.52 (m, 1H), 7.47 - 7.44 (m, 2H), 7.44 - 7.40 (m, 1H), 7.26 - 7.21 (m, 3H), 7.20 - 7.17 (m, 1H), 7.17 - 7.13 (m, 1H), 6.96 (dd, J = 8.3, 1.2 Hz, 1H), 6.91 - 6.84 (m, 3H), 4.42 (d, J = 15.0 Hz, 1H), 4.34 (d, J = 15.0 Hz, 1H), 3.69 (s, 3H), 3.60 (s, 3H);13 C NMR (125 MHz, CDCl3) δ 198.7, 193.9, 161.6, 139.7, 138.9, 138.4, 135.8, 134.9, 134.3, 132.1, 132.1, 130.3, 129.1, 127.0, 126.7, 125.0, 123.4, 122.3, 121.8, 121.0, 120.7, 120.5, 119.7, 118.7, 118.1, 116.9, 110.3, 109.4, 108.6, 43.5, 39.2, 30.8, 30.5, (1C is merged with other peaks); ESI-HRMS m / z calcd for C 36 H 27 BrN2O3S2Na [M+Na] + 701.0539, found 701.0539.

[0036] Product Ⅳ-5 is a yellow solid, with a yield of 97%, melting point: 178 - 180 °C. 1 H NMR (500 MHz, CDCl3 δ 11.22 (s, 1H), 7.73 (s, 1H), 7.67 (dd, J = 7.8, 1.7 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.29 - 7.21 (m, 4H), 7.19 - 7.15 (m, 1H), 6.98 (dd, J = 8.3, 0.8 Hz, 1H), 6.95 (s, 1H), 6.92 - 6.88 (m, 1H), 6.87 - 6.83 (m, 1H), 4.21 - 4.15 (m, 2H), 3.88 (s, 3H), 3.70 (s, 2H), 3.60 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13 C NMR (125 MHz, CDCl3) δ 198.4, 169.5, 161.5, 139.4, 138.9, 138.4, 135.1, 134.7, 132.0, 127.3, 126.6, 125.0, 123.4, 123.3, 122.1, 121.6, 121.0, 120.6, 120.4, 119.9, 118.5, 118.0, 116.8, 110.3, 109.3, 108.5, 61.8, 39.1, 38.9, 30.7, 30.5, 14.2; ESI-HRMS m / z calcd for C 32 H 28 N2O4S2Na [M+Na]+ 591.1383, found 591.1383.

[0037] Product Ⅳ-6 is a yellow solid with a yield of 80% and a melting point of 194 - 196 °C. 1 H NMR (500 MHz, CDCl3) δ 11.16 (s, 1H), 7.73 (d, J = 0.5 Hz, 1H), 7.65 (dd, J = 7.9, 1.7 Hz, 1H), 7.62 - 7.59 (m, 1H), 7.54 - 7.50 (m, 1H), 7.41 - 7.37 (m, 1H), 7.29 - 7.20 (m, 9H), 7.18 - 7.14 (m, 1H), 6.96 (dd, J = 8.3, 1.1 Hz, 1H), 6.93 - 6.92 (m, 1H), 6.92 - 6.88 (m, 1H), 6.86 - 6.82 (m, 1H), 5.17 (d, J = 12.3 Hz, 1H), 5.13 (d, J = 12.3 Hz, 1H), 3.77 (s, 3H), 3.76 (d, J = 14.8 Hz, 1H), 3.71 (d, J = 14.8 Hz, 1H), 3.57 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 198.4, 169.4, 161.6, 139.4, 138.9, 138.4, 135.3, 135.1, 134.7, 132.0, 128.6, 128.4, 128.4, 127.1, 126.7, 125.0, 123.4, 123.3, 122.2, 121.6, 121.1, 120.6, 120.4, 120.0, 118.5, 118.1, 116.8, 110.4, 109.3, 108.5, 67.4, 39.0, 39.0, 30.7, 30.5; ESI-HRMS m / z calcd for C 37 H 30 N2O4S2Na [M + Na] + 653.1539, found 653.1540.

[0038] Product Ⅳ-7 is a yellow solid with a yield of 98% and a melting point of 208 - 210 °C. 11H NMR (500 MHz, CDCl3) δ 11.24 (s, 1H), 7.73 (s, 1H), 7.67 (dd, J = 7.9, 1.7 Hz, 1H), 7.64 - 7.60 (m, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.42 - 7.38 (m, 1H), 7.28 - 7.21 (m, 4H), 7.18 - 7.13 (m, 1H), 6.98 (dd, J = 8.4, 1.2 Hz, 1H), 6.96 (s, 1H), 6.92 - 6.88 (m, 1H), 6.87 - 6.83 (m, 1H), 3.86 (s, 3H), 3.60 (s, 3H), 2.42 (s, 3H); 13 13C NMR (125 MHz, CDCl3) δ 198.6, 161.6, 139.4, 138.9, 138.2, 134.9, 134.7, 132.0, 130.3, 126.7, 125.0, 122.9, 122.2, 122.1, 121.6, 120.8, 120.7, 120.3, 120.1, 118.5, 118.0, 116.8, 110.1, 109.3, 108.5, 38.8, 30.7, 30.2, 20.2; ESI-HRMS m / z calcd for C 29 H 24 N2O2S2Na [M+Na] + 519.1172, found 519.1171.

[0039] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above-described exemplary embodiments, and the present invention can be implemented in other specific forms without departing from the spirit or basic characteristics of the present invention. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-restrictive. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be encompassed within the present invention.

[0040] In addition, it should be understood that although this specification is described according to embodiments, not every embodiment only contains an independent technical solution. This narrative manner of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for preparing a thiopyrano[2,3-b]indole compound. The thiopyrano[2,3-b]indole compound has a structural formula IV as shown below: in: R 1 is an alkane, specifically including: acetophenone, 4-methoxyacetophenone, 4-chloroacetophenone, 4-bromoacetophenone, ethyl acetate, benzyl acetate or a methyl substituent, characterized in that the preparation method is as follows: The preparation steps of the target compound IV include: dissolving compound I and compound II in dichloromethane, adding zinc chloride and sodium bicarbonate to react, adding halogenated alkane IV and potassium carbonate to react after the reaction of compound I is completed through thin layer monitoring, and then removing the solvent from the reaction mixture under reduced pressure, eluting by silica gel column chromatography to obtain the target compound IV.

2. The method for preparing thiopyrano[2,3-b]indole compounds according to claim 1, characterized in that: The dichloromethane solvent replacement includes: 1,2-dichloroethane, chloroform, ethyl acetate, methanol, acetonitrile or tetrahydrofuran.

3. The method for preparing thiopyrano[2,3-b]indole compounds according to claim 1, characterized in that: The zinc chloride substitutes include scandium trifluoromethanesulfonate, tin trifluoromethanesulfonate, indium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, aluminum chloride or magnesium iodide.

4. The method for preparing thiopyrano[2,3-b]indole compounds according to claim 1, characterized in that: The sodium bicarbonate substitutes include: sodium carbonate, potassium carbonate, sodium methoxide, triethylamine, or DABCO.

5. The method for preparing thiopyrano[2,3-b]indole compounds according to claim 1, characterized in that: Potassium carbonate alternatives include: sodium carbonate, sodium bicarbonate or sodium hydroxide.

6. The method for preparing thiopyrano[2,3-b]indole compounds according to claim 1, characterized in that: The molar ratio of the compound I, compound II and compound III is I:II:III=2:1:1.

2.

7. The method for preparing thiopyrano[2,3-b]indole compounds according to claim 1, characterized in that: The eluent used for the silica gel column chromatography is a mixed solvent of petroleum ether and dichloromethane, and the volume ratio is V 石油醚 :V 二氯甲烷 =5:1~1:

3.

8. The method for preparing thiopyrano[2,3-b]indole compounds according to any one of claims 1 to 7, characterized in that: The reaction temperature for preparing the target compound IV is 25°C to 80°C.

9. The method for preparing thiopyrano[2,3-b]indole compounds according to claim 8, characterized in that: The reaction temperature for preparing the target compound IV is 60°C.

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