Synthesis method of benzo two-hetero five-membered ring

Abstract

The invention provides a synthesis method of a benzo two-hetero five-membered ring, and relates to the technical field of organic synthesis. According to the synthesis method provided by the invention, a 2-substituted aniline compound II reacts with a 2-chloropropene compound III in a solvent environment in the presence of alkali to generate the benzo two-hetero five-membered ring I. The 2-chloropropene compound III structure is adopted to provide a single carbon source, the 2-substituted aniline compound II is subjected to carbon insertion [1 + 4] cyclization to synthesize the benzo two-hetero five-membered ring I, the reaction raw materials are easy to obtain, the reaction conditions are mild, the product is easy to separate, the yield is relatively high, the reaction process is safe and pollution-free, and the method is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing a benzodihetero five-membered ring. Background Art

[0002] According to statistics, among the small molecule drugs approved by the U.S. Food and Drug Administration (FDA), 59% of the drugs contain at least one nitrogen heterocycle. In addition, nitrogen heterocyclic compounds account for almost half of the world's top 200 drugs in terms of sales. Especially benzodiphenylamine five-membered ring compounds, many natural and synthetic organic compounds containing benzodiphenylamine structure skeletons have a wide range of biological activities, including antibacterial, antitumor, antioxidant, antiviral, anti-tuberculosis and anthelmintic properties. Among them, benzothiophene structure derivatives are widely used in pesticides, medicines and other fields, and are also the core skeletons for constructing many functional materials and natural products.

[0003] For example, Mefenacet can effectively remove grass weeds such as barnyard grass. Some 1,3-benzodiazoles also have endothelin antagonist, anti-inflammatory, antibacterial and anti-tumor activities. For example, S-Gboxin is used to treat diffuse midline glioma. The common methods for synthesizing benzodihetero five-membered rings include ring addition with o-aminophenol structure derivatives as substrates and synthesis with o-haloaniline as substrates. For example, o-aminophenol structure and benzyl alcohol are condensed under the conditions of noble metal catalysts to form benzoxazole structure compounds, and base-catalyzed double Michael reactions of allene structure compounds and various nucleophilic reagents are used to obtain benzodihetero five-membered ring compounds.

[0004] However, these methods currently have a series of problems such as harsh reaction conditions, the need for precious metal catalysts, low reaction yields, and pollution in the reaction process; the complexity of the reaction substrates makes it impossible to apply them on a large scale, so there is an urgent need to provide a solution to improve the above problems. Summary of the invention

[0005] The object of the present invention is to provide a method for synthesizing a benzodihetero five-membered ring.

[0006] The present invention provides a method for synthesizing a benzodihetero five-membered ring, wherein a 2-substituted aniline compound II and a 2-chloropropylene compound III react in a solvent environment and with the participation of a base to generate a benzodihetero five-membered ring I;

[0007]

[0008] Wherein, X is one of N, O, S or an amino substituted derivative, R is one of a C1-C6 alkyl or cycloalkyl, phenyl, sulfonyl, benzenesulfonyl, benzoyl, tert-butyloxycarbonyl, benzyl or a substituted derivative thereof, and EWG is one of a sulfone group, sulfonyl fluoride, sulfonyl chloride, ester group, cyano group, trifluoromethyl group, nitro group, phosphate ester, phosphoryl chloride, and phosphoryl fluoride.

[0009] The synthesis method provided by the present invention adopts the structure of 2-chloropropylene compound III to provide a single carbon source, and performs carbon insertion [1+4] cyclization on 2-substituted aniline compound II to synthesize benzodihetero five-membered ring I. The reaction raw materials are easily available and the reaction conditions are mild, the product is easy to separate, the yield is high, and the reaction process is safe and pollution-free, and the method is suitable for large-scale industrial production.

[0010] Optionally, the base includes at least one of DIPEA, DABCO, Et3N, Cs2CO3, Na2CO3, NaHCO3, DBU, DBN, DMAP, NaOH, KOH, t-BuOK, t-BuONa, t-BuOLi, and Li2CO3.

[0011] Optionally, the solvent environment includes at least one of dichloromethane, acetonitrile, ethyl acetate, toluene, tetrahydrofuran, dichloroethane, dioxane, cyclohexane, chloroform, methanol, 2-methyltetrahydrofuran, DMF, and DMSO.

[0012] Optionally, when the 2-substituted aniline compound II is reacted with the 2-chloropropene compound III, the molar ratio of the 2-substituted aniline compound II to the 2-chloropropene compound III is 1:(1-3), preferably the molar ratio is 1:(1.5-2).

[0013] Optionally, the 2-substituted aniline compound II is reacted with the 2-chloropropene compound III at 20-30° C. for 3-6 hours.

[0014] Optionally, after the benzodihetero five-membered ring I is generated by the reaction, it is purified by silica gel flash column chromatography, and then the eluent is used for elution and the effluent is collected, and the pure product of the benzodihetero five-membered ring I is collected after rotary evaporation and drying.

[0015] Optionally, the eluent comprises ethyl acetate and petroleum ether in a volume ratio of 1:(3-20). BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is the H NMR spectrum of the benzodihetero five-membered ring synthesized in Example 1 of the present invention;

[0017] Figure 2 This is the NMR carbon spectrum of the benzodihetero five-membered ring synthesized in Example 1 of the present invention;

[0018] Figure 3 This is the NMR fluorine spectrum of the benzodihetero five-membered ring synthesized in Example 1 of the present invention;

[0019] Figure 4 This is the H NMR spectrum of the benzodihetero five-membered ring synthesized in Example 2 of the present invention;

[0020] Figure 5 This is the NMR carbon spectrum of the benzodihetero five-membered ring synthesized in Example 2 of the present invention;

[0021] Figure 6 This is the NMR fluorine spectrum of the benzodihetero five-membered ring synthesized in Example 2 of the present invention;

[0022] Figure 7 This is the H NMR spectrum of the benzodihetero five-membered ring synthesized in Example 3 of the present invention;

[0023] Figure 8 This is the NMR carbon spectrum of the benzodihetero five-membered ring synthesized in Example 3 of the present invention;

[0024] Fig. 9 This is the NMR fluorine spectrum of the benzodihetero five-membered ring synthesized in Example 3 of the present invention;

[0025] Fig.10 This is the H NMR spectrum of the benzodihetero five-membered ring synthesized in Example 4 of the present invention;

[0026] Fig.11 This is the NMR carbon spectrum of the benzodihetero five-membered ring synthesized in Example 4 of the present invention;

[0027] Fig.12 This is the NMR fluorine spectrum of the benzodihetero five-membered ring synthesized in Example 4 of the present invention;

[0028] Fig.13 This is the H NMR spectrum of the benzodihetero five-membered ring synthesized in Example 5 of the present invention;

[0029] Fig.14 This is the NMR carbon spectrum of the benzodihetero five-membered ring synthesized in Example 5 of the present invention;

[0030] Fig.15 This is the NMR fluorine spectrum of the benzodihetero five-membered ring synthesized in Example 5 of the present invention;

[0031] Fig.16 This is the H NMR spectrum of the benzodihetero five-membered ring synthesized in Example 6 of the present invention;

[0032] Fig.17 This is the NMR carbon spectrum of the benzodihetero five-membered ring synthesized in Example 6 of the present invention;

[0033] Fig.18 This is the NMR fluorine spectrum of the benzodihetero five-membered ring synthesized in Example 6 of the present invention;

[0034] Fig.19 The present invention provides a reaction formula for the synthesis of a benzodihetero five-membered ring. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise defined, the technical terms or scientific terms used herein should be the common meanings understood by people with general skills in the field to which the present invention belongs.

[0036] The present invention provides a method for synthesizing a benzodihetero five-membered ring, comprising reacting a 2-substituted aniline compound II with a 2-chloropropene compound III in a solvent environment and with the participation of a base to generate a benzodihetero five-membered ring I. In fact, during the reaction, the electron-deficient structure of the 2-chloropropene compound III provides a single carbon source, and the 2-substituted aniline compound II undergoes carbon insertion [1+4] cyclization.

[0037] In fact, see Fig.19 The reaction formula of the synthesis method provided by the present invention is as follows:

[0038]

[0039] Wherein, X is one of N, O, S or an amino substituted derivative, R is one of a C1-C6 alkyl or cycloalkyl, phenyl, sulfonyl, benzenesulfonyl, benzoyl, tert-butyloxycarbonyl, benzyl or a substituted derivative thereof, and EWG is one of a sulfone group, sulfonyl fluoride, sulfonyl chloride, ester group, cyano group, trifluoromethyl group, nitro group, phosphate ester, phosphoryl chloride, and phosphoryl fluoride.

[0040] In some embodiments, the base used includes at least one of DIPEA, DABCO, Et3N, Cs2CO3, Na2CO3, NaHCO3, DBU, DBN, DMAP, NaOH, KOH, t-BuOK, t-BuONa, t-BuOLi, and Li2CO3, and the solvent environment used includes at least one of dichloromethane, acetonitrile, ethyl acetate, toluene, tetrahydrofuran, dichloroethane, dioxane, cyclohexane, chloroform, methanol, 2-methyltetrahydrofuran, DMF, and DMSO.

[0041] Specifically, when the 2-substituted aniline compound II reacts with the 2-chloropropene compound III, the molar ratio of the 2-substituted aniline compound II to the 2-chloropropene compound III is 1:(1-3), preferably 1:(1.5-2). In fact, setting the 2-chloropropene compound III in excess is beneficial to improving the conversion rate of the 2-substituted aniline compound II and the yield of the benzodihetero five-membered ring I.

[0042] In some embodiments, 2-substituted aniline compound II and 2-chloropropylene compound III are reacted at 20-30°C for 3-6 hours. Specifically, after the reaction generates benzodihetero five-membered ring I, it is purified by silica gel flash column chromatography, and then washed with an eluent and the effluent is collected, and the pure benzodihetero five-membered ring I is collected after rotary evaporation and drying. In fact, the eluent includes ethyl acetate and petroleum ether in a volume ratio of 1: (3-20).

[0043] Example 1

[0044] This embodiment 1 provides a method for synthesizing a benzodihetero five-membered ring, comprising the following steps:

[0045] S1. Add 10 mmol (2-hydroxyphenyl)-4-methylbenzenesulfonamide (CAS: 3897-39-0), 20 mmol 2-chloropropylenesulfonyl fluoride (CAS: 2137642-41-0), 30 mmol sodium bicarbonate (CAS: 144-55-8) and 50 mL methanol into a reaction vessel, and stir and react for 3 hours at 25°C in an air atmosphere;

[0046] S2. After purification by silica gel flash column chromatography, the product was eluted with an eluent prepared by mixing ethyl acetate and petroleum ether in a volume ratio of 1:6, and the effluent was collected and evaporated to remove the solvent, and then vacuum dried to obtain a benzodihetero five-membered ring with a calculated yield of 95%.

[0047] In fact, the structure of the benzodihetero five-membered ring prepared in Example 1 is shown below:

[0048]

[0049] The benzodihetero five-membered ring prepared in Example 1 was characterized by H NMR spectroscopy. Figure 1 As shown, the NMR carbon spectrum characterization was performed as Figure 2 As shown, NMR fluorine spectrum characterization was performed as Figure 3 As shown, and the NMR characterization data are as follows: 1H NMR(CDCl3,400MHz)δ7.78(d,J=8.4Hz,2H),7.44(m,J=7.5Hz,1H),7.30(d,J=8.2Hz,2H),7 .03–6.94(m,2H),6.85(m,J=7.4,Hz,1H),4.21(d,J=3.2Hz,2H),2.42(s,3H),2.03(s,3H). 13 C NMR (CDCl3, 100MHz) δ147.5,145.2,137.0,130.2,128.6,127.0,124.9,122.6,113.5,110.3,99.2,58.9,58.7,23.5,21.7. 19 F NMR (CDCl3, 376MHz) δ 64.46.

[0050] Example 2

[0051] A method for synthesizing a benzodihetero five-membered ring provided in Example 2 comprises the following steps:

[0052] S1. Add 10 mmol (2-hydroxyphenyl)benzamide (CAS: 3743-70-2), 15 mmol 2-chloropropylenesulfonyl fluoride (CAS: 2137642-41-0), 20 mmol cesium carbonate (CAS: 534-17-8) and 50 mL tetrahydrofuran into a reaction vessel, and stir the reaction at 25°C in an air atmosphere for 3 h;

[0053] S2. After purification by silica gel flash column chromatography, the product was eluted with an eluent prepared by mixing ethyl acetate and petroleum ether in a volume ratio of 1:5, and the effluent was collected and evaporated to remove the solvent, and then vacuum dried to obtain a benzodihetero pentacyclic ring with a calculated yield of 97%.

[0054] In fact, the structure of the benzodihetero five-membered ring obtained in Example 2 is shown below:

[0055]

[0056] The benzodihetero five-membered ring prepared in Example 2 was characterized by H NMR spectroscopy. Figure 4 As shown, the NMR carbon spectrum characterization was performed as Figure 5 As shown, NMR fluorine spectrum characterization was performed as Figure 6 As shown, and the NMR characterization data are as follows: 1H NMR(CDCl3,400MHz)δ7.52(m,J=7.3Hz,3H),7.46–7.40(m,2H),6.83(m,J=8.0Hz,2H),6.51(m, J=7.3Hz,1H),5.67(m,J=8.0Hz,1H),4.85(m,J=4.7Hz,1H),4.15(m,J=1.4Hz,1H),2.02(s,3H). 13 C NMR (CDCl3, 100MHz) δ167.5,131.8,129.1,128.7,127.6,124.9,121.5,114.0,110.4,98.9,54.8,54.6,24.4,24.4. 19 F NMR (CDCl3, 376MHz) δ64.97 (d, J=5.1Hz).

[0057] Example 3

[0058] A method for synthesizing a benzodihetero five-membered ring provided in Example 3 comprises the following steps:

[0059] S1. Add 10 mmol 2-[(dimethylsulfamoyl)amino]phenol (CAS: 105295-03-2), 20 mmol 2-chloropropylenesulfonyl fluoride (CAS: 2137642-41-0), 20 mmol DBU (CAS: 6674-22-2) and 50 mL ethyl acetate into a reaction vessel, and stir the reaction at 25° C. in an air atmosphere for 3 h.

[0060] S2. After purification by silica gel flash column chromatography, the product was eluted with an eluent prepared by mixing ethyl acetate and petroleum ether in a volume ratio of 1:3, and the effluent was collected and evaporated to remove the solvent, and then vacuum dried to obtain a benzodihetero five-membered ring with a calculated yield of 85%.

[0061] In fact, the structure of the benzodihetero five-membered ring obtained in Example 3 is shown below:

[0062]

[0063] The benzodihetero five-membered ring prepared in Example 3 was characterized by H NMR spectroscopy. Figure 7 As shown, the NMR carbon spectrum characterization was performed as Figure 8 As shown, NMR fluorine spectrum characterization was performed as Fig. 9 As shown, and the NMR characterization data are as follows: 1H NMR(CDCl3,400MHz)δ6.98–6.93(m,1H),6.91(m,J=7.6Hz,1H),6.87(m,J=7 .6Hz,1H),6.85–6.79(m,1H),4.25–4.08(m,2H),2.91(s,6H),2.05(s,3H). 13 C NMR (CDCl3, 100MHz) δ147.2,129.4,124.3,122.5,112.7,110.2,99.6,57.4,57.2,37.8,24.5,24.5. 19 F NMR (CDCl3, 376MHz) δ 65.14.

[0064] Example 4

[0065] A method for synthesizing a benzodihetero five-membered ring provided in Example 4 comprises the following steps:

[0066] S1. Add 10 mmol (2-hydroxyphenyl)-4-methylbenzamide (CAS: 57709-82-7), 10 mmol 2-chloropropylenesulfonyl fluoride (CAS: 2137642-41-0), 15 mmol sodium hydroxide (CAS: 1310-73-2) and 50 mL toluene into a reaction vessel, and stir the reaction at 25°C in an air atmosphere for 3 h;

[0067] S2. After purification by silica gel flash column chromatography, the product was eluted with an eluent prepared by mixing ethyl acetate and petroleum ether in a volume ratio of 1:8, and the effluent was collected and evaporated to remove the solvent, and then vacuum dried to obtain a benzodihetero pentacyclic ring with a calculated yield of 88%.

[0068] In fact, the structure of the benzodihetero five-membered ring obtained in Example 4 is shown below:

[0069]

[0070] The benzodihetero five-membered ring prepared in Example 4 was characterized by H NMR spectroscopy. Fig.10 As shown, the NMR carbon spectrum characterization was performed as Fig.11 As shown, NMR fluorine spectrum characterization was performed as Fig.12 As shown, and the NMR characterization data are as follows: 1H NMR(CDCl3,400MHz)δ7.4(d,J=8.2Hz,2H),7.2(d,J=8.0Hz,2H),6.9–6.8(m,2H),6.5(m,J=7.7H z,1H),5.8(m,J=8.0Hz,1H),4.8(m,J=4.4Hz,1H),4.2(m,J=1.7Hz,1H),2.4(s,3H),2.0(s,3H). 13 C NMR (CDCl3, 100MHz) δ167.6,148.4,142.4,129.6,127.8,124.7,121.4,114.1,110.3,98.9,54.8,54.7,24.3,24.3,21.7. 19 F NMR (CDCl3, 376MHz) δ64.93 (d, J=4.6Hz).

[0071] Example 5

[0072] A method for synthesizing a benzodihetero five-membered ring provided in Example 5 comprises the following steps:

[0073] S1. Add 10 mmol 2-(methylamino)phenol (CAS: 611-24-5), 12 mmol 2-chloropropylenesulfonyl fluoride (CAS: 2137642-41-0), 15 mmol cesium carbonate (CAS: 534-17-8), 25 mL acetonitrile and 25 mL dichloromethane into a reaction vessel, and stir the reaction at 25°C in an air atmosphere for 3 h.

[0074] S2. After purification by silica gel flash column chromatography, the product was eluted with an eluent prepared by mixing ethyl acetate and petroleum ether in a volume ratio of 1:6, and the effluent was collected and evaporated to remove the solvent, and then vacuum dried to obtain a benzodihetero pentacyclic ring with a calculated yield of 86%.

[0075] In fact, the structure of the benzodihetero five-membered ring obtained in Example 5 is shown below:

[0076]

[0077] The benzodihetero five-membered ring prepared in Example 5 was characterized by H NMR spectroscopy. Fig.13 As shown, the NMR carbon spectrum characterization was performed as Fig.14 As shown, NMR fluorine spectrum characterization was performed as Fig.15 As shown, and the NMR characterization data are as follows: 1H NMR (CDCl3, 400MHz) δ7.20 (m, J = 8.3Hz, 2H), 6.71 (d, J = 8.4Hz, 1H), 6.70–6.61 (m, 1H), 4.31 (s, 2H), 2.86 (s, 3H), 2.44 (s, 3H). 13 C NMR (CDCl3, 100MHz) δ195.4,141.9,136.1,128.7,122.7,116.4,112.0,60.9,31.3,30.1. 19 F NMR (CDCl3, 376MHz) δ 70.70.

[0078] Example 6

[0079] This embodiment 6 provides a method for synthesizing a benzodihetero five-membered ring, comprising the following steps:

[0080] S1. Add 10 mmol (2-hydroxyphenyl)acetamide (CAS: 714-80-2), 15 mmol 2-chloropropylenesulfonyl fluoride (CAS: 2137642-41-0), 15 mmol DIPEA (CAS: 7087-68-5) and 50 mL chloroform into a reaction vessel, and stir the reaction at 25°C in an air atmosphere for 3 h.

[0081] S2. After purification by silica gel flash column chromatography, the product was eluted with an eluent prepared by mixing ethyl acetate and petroleum ether in a volume ratio of 1:5, and the effluent was collected and evaporated to remove the solvent, and then vacuum dried to obtain a benzodihetero pentacyclic ring with a calculated yield of 80%.

[0082] In fact, the structure of the benzodihetero five-membered ring obtained in Example 6 is shown below:

[0083]

[0084] The benzodihetero five-membered ring prepared in Example 6 was characterized by H NMR spectroscopy. Fig.16 As shown, the NMR carbon spectrum characterization was performed as Fig.17 As shown, NMR fluorine spectrum characterization was performed as Fig.18 As shown, and the NMR characterization data are as follows: 1 H NMR (CDCl3, 400MHz) δ7.09–6.98(m,2H),6.91(m,J=7.8Hz,2H),4.82(m,J=5.0Hz,1H),4.09(m,J=1.5Hz,1H),2.47(s,3H),1.97(s,3H). 13C NMR (CDCl3, 100MHz) δ167.8, 148.8, 128.3, 124.9, 121.9, 113.0, 110.3, 98.6, 55.0 (d, J = 15.0Hz), 25.7, 24.9 (d, J = 2.4Hz). 19 F NMR (CDCl3, 376MHz) δ64.15 (d, J=4.8Hz).

[0085] Although the embodiments of the present invention are described in detail above, it is obvious to those skilled in the art that various modifications and variations can be made to these embodiments. However, it should be understood that such modifications and variations are within the scope and spirit of the present invention as described in the claims. Moreover, the present invention described herein may have other embodiments and may be implemented or realized in a variety of ways.

Claims

1. A method for synthesizing a benzodihetero five-membered ring, characterized in that: In the presence of a solvent and a base, 2-substituted aniline compounds Ⅱ react with 2-chloropropylene compounds Ⅲ to form benzodihetero five-membered ring Ⅰ; Wherein, X is one of N, O, S or an amino substituted derivative, R is one of a C1-C6 alkyl or cycloalkyl, phenyl, sulfonyl, benzenesulfonyl, benzoyl, tert-butyloxycarbonyl, benzyl or a substituted derivative thereof, and EWG is one of a sulfone group, sulfonyl fluoride, sulfonyl chloride, ester group, cyano group, trifluoromethyl group, nitro group, phosphate ester, phosphoryl chloride, and phosphoryl fluoride.

2. The preparation method according to claim 1, characterized in that: The base includes at least one of DIPEA, DABCO, Et3N, Cs2CO3, Na2CO3, NaHCO3, DBU, DBN, DMAP, NaOH, KOH, t-BuOK, t-BuONa, t-BuOLi, and Li2CO3.

3. The preparation method according to claim 1, characterized in that: The solvent environment includes at least one of dichloromethane, acetonitrile, ethyl acetate, toluene, tetrahydrofuran, dichloroethane, dioxane, cyclohexane, chloroform, methanol, 2-methyltetrahydrofuran, DMF, and DMSO.

4. The preparation method according to claim 1, characterized in that: When the 2-substituted aniline compound II is reacted with the 2-chloropropene compound III, the molar ratio of the 2-substituted aniline compound II to the 2-chloropropene compound III is 1:(1-3), preferably the molar ratio is 1:(1.5-2).

5. The preparation method according to claim 1, characterized in that: The 2-substituted aniline compound II and the 2-chloropropylene compound III are reacted at 20-30°C for 3-6 hours.

6. The preparation method according to claim 1, characterized in that: After the benzodihetero five-membered ring I is generated by the reaction, it is purified by silica gel flash column chromatography, and the eluent is used for elution and the effluent is collected, and the pure product of the benzodihetero five-membered ring I is collected after rotary evaporation and drying.

7. The preparation method according to claim 6, characterized in that: The eluent comprises ethyl acetate and petroleum ether in a volume ratio of 1:(3-20).

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