A method of synthesizing a triphenob[d,f]azepine derivative

Abstract

The application relates to a method for synthesizing triphenobenzo[b, d, f] azepine from a cyclic diaryliodonium salt, and belongs to the field of chemical synthesis. Under proper reaction conditions, triphenobenzo[b, d, f] azepine is obtained in one step by taking isatin anhydride derivatives and a cyclic diaryliodonium salt as substrates. The application provides a more economical and simple synthesis method for the synthesis of triphenobenzo[b, d, f] azepine, has the advantages of simple steps, high atom economy and excellent yield, and is expected to realize industrialized scale production.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis and relates to a method for synthesizing tribenzo[b,d,f]azepine derivatives by using cyclic diaryliodonium salts and isatoic anhydride compounds, which is simple to operate and has economical steps. Background Art

[0002] Benzazaheterocyclic compounds are an important class of seven-membered nitrogen heterocyclic compounds, which are widely used in biologically active natural products [see: (a) JA Salpekar, JA Conry, W. Doss, S. Cushner-Weinstein, Pearl, PL; SL Weinstein and WD Gaillard, Clinical Experience with Anticonvulsant Medication in Pediatric Epilepsy and Comorbid Bipolar Spectrum Disorder, Epilepsy Behav., 2006, 9, 327-334. (b) B. Renfroe, C. Harrington and GR Proctor, Heterocyclic Compounds: Azepines, Wiley & Interscience, New York, 1984.] and functional materials such as organic light-emitting diodes [see: (a) O. Hisashi and S. Tadahisa, JP 2000282025 A, 2000. (b) C S Kim, S.Eum, Y J Cho, H J Kwon, B O Kim, S M Kim and S SYoon, WO 2011010839 A1, 2011.] have been widely used. Although a large number of works have focused on the synthesis of benzazepines, the synthesis of tribenzo[b,d,f]azepines is rare.

[0003] The construction of tribenz[b,d,f]azepine reported so far usually requires a multi-step synthesis with low synthesis efficiency. For example, Cann et al. reported an example of a multi-step synthesis via Diels-Alder reaction in 1991 [see: HCAxtell, WMHowell, LGSchmid and MCCann, Preparation of 9H-tribenz[b,d,f]azepine and Its 1-methoxy derivative, J.Org.Chem., 1991, 56, 3906-3908.] In 2009, Martin et al. recorded an example of an intramolecular coupling synthesis of 9H-tribenz[b,d,f]azepine via Buchwald-Hartwig reaction [see: M.Buden, V.A.Vaillard, SEMartin and RARossi, Synthesis of Carbazoles by Intramolecular Arylation of Diarylamide Anions, J. Org. Chem., 2009, 74, 4490-4498.] In 2014, Taylor et al. successfully synthesized tribenzazepine heterocycles through two-fold Suzuki-Miyaura coupling reactions, but the reaction required multiple steps and had a low overall yield [see: E. Dimitrijevic, M. Cusimano and MS Taylor, Synthesis of Benzannulated Heterocycles by Twofold Suzuki–Miyaura Couplings of Cyclic Diarylborinic Acids, Org. Biomol. Chem., 2014, 12, 1391-1394.]. Therefore, it is necessary to develop a more novel and efficient method for assembling tribenzazepine compounds. Summary of the Invention

[0004] The present invention aims to provide a method for preparing tribenzo[b,d,f]azepine derivatives with mild reaction conditions, high yield, simple process, convenient operation, low cost and low environmental pollution, which is expected to achieve industrial large-scale production.

[0005] The idea of ​​the present invention is as follows: Figure 1 As shown, isocyanic anhydride compounds and cyclic diaryliodonium salts are used as substrates, a catalyst, an additive and a solvent are added to a reactor, the reaction is started, and after the reaction is completed, the solvent is removed and the product is obtained by column chromatography.

[0006] in:

[0007] (1) The molar ratio of the cyclic diaryliodonium salt to the isatoic anhydride in the reaction system is 1:0.25 to 1:10, preferably 1:1.5.

[0008] (2) The additive may be an organic base or an inorganic base, preferably Na2CO3.

[0009] (3) The metal catalyst can be a palladium catalyst, preferably Pd(PPh3)4.

[0010] (4) The amount of the metal catalyst used in the reaction can be 0.01 to 2 equivalents (relative to the cyclic diaryl iodonium salt), preferably 0.1 equivalent.

[0011] (5) The reaction temperature can be 0°C to 200°C, preferably 140°C.

[0012] (6) The reaction time can be 0.1 to 48 hours, preferably 1 hour.

[0013] Compared with the prior art, the present invention has the advantages of simple process, low cost and less waste residue generated, and provides a new method for the synthesis of tribenzo[b,d,f]azepine, which is expected to achieve industrial-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 The present invention provides a synthetic reaction formula for preparing tribenzo[b,d,f]azepine 3.

[0015] Figure 2 The present invention provides a hydrogen nuclear magnetic resonance spectrum of the product 9-methyl-9H-tribenzo[b,d,f]azepine (3a). DETAILED DESCRIPTION

[0016] The specific embodiments of the present invention are described in detail below, but it should be understood that the protection scope of the present invention is not limited by the specific embodiments.

[0017] Example 1: Synthesis of 9-methyl-9H-tribenzo[b,d,f]azepine (Product 3a): 1-Methyl-1H-benzo[d][1,3]oxazine-2,4-dione (53 mg) and cyclic diphenyliodonium triflate (86 mg) were weighed at a feed ratio of 1.5:1. Pd(PPh3)4 (23 mg) (0.1 equivalent relative to cyclic diphenyliodonium triflate) was then added. Sodium carbonate (42 mg) was then added. Aprotic dimethyl sulfoxide (2 ml) was then added as the reaction solvent. The reaction was incubated at 140°C in an air atmosphere for 1 hour. After completion of the reaction, the solvent was removed and the product was purified by column chromatography to obtain a white solid, which was dried to give the pure product 9-methyl-9H-tribenzo[b,d,f]azepine in a yield of 97%. H NMR spectrum: Figure 2 As shown: (deuterated chloroform as solvent, BRUKER Ascend500 nuclear magnetic resonance instrument) 1 H NMR (500MHz, CDCl3): δ=7.50-7.46(m,6H),7.32(t,J=7.5Hz,2H),7.20(d,J=8.0Hz,2H),7.15(t,J=7.0Hz,2H),3.31(s,3H)ppm. 13 CNMR (125 MHz, CDCl3) δ = 154.47, 139.79, 134.85, 129.91, 129.68, 128.32, 127.70, 124.11, 117.41, 37.99 ppm. High resolution mass spectrometry (ESI) ([M+H]) calculated value C 19 H 16 N,258.1283,,test value,258.1280.

[0018] Example 2: Synthesis of 9-methyl-6-nitro-9H-tribenzo[b,d,f]azepine (Product 3b): The method was the same as in Example 1, except that the substrate 1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione was replaced with 1-methyl-6-nitro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione. The yield was 86%. H NMR spectrum (BRUKER Ascend 500 NMR spectrometer) 1 H NMR (500MHz, CDCl3): δ = 8.34 (d, J = 2.5Hz, 1H), 8.18 (dd, J = 9.0Hz, 2.5Hz, 1H), 7.52-7.46 (m, 5H), 7.37-7.34 (m, 1H), 7.24-7.19 (m, 3H), 3.36 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ = 160.54, 152.66, 144.04, 139.69, 137.89, 135.49, 134.45, 130.22, 130.19, 129.71, 128.91, 128.77, 128.20, 125.25, 125.17, 123.73, 118.35, 117.60, 38.48 ppm. High-resolution mass spectrometry (ESI) ([M+H]) calculated for C 19 H 15 N2O2, 303.1134,, test value, 303.1133.

[0019] Example 3: Synthesis of 6-methoxy-9-methyl-9H-tribenzo[b,d,f]azepine (Product 3c): The method was the same as in Example 1, except that the substrate 1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione was replaced with 1-methyl-6-methoxy-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione. The yield was 52%. H NMR spectrum (BRUKER Ascend 500 NMR spectrometer) 1 H NMR(500MHz, CDCl3):7.54-7.44(m,5H),7.31(t,J=7.5Hz,1H),7.18(d,J=8.0Hz,1H),7.14- 7.11(m,2H),7.00(d,J=2.0Hz),6.86(dd,J=8.8Hz,1.8Hz,1H),3.80(s,3H),3.26(s,3H)ppm. 13 C NMR (125 MHz, CDCl3): δ = 156.22, 154.88, 147.83, 139.93, 139.58, 135.90, 134.74, 129.93, 129.83, 129.39, 128.36, 127.83, 127.70, 123.96, 118.14, 117.03, 115.14, 113.51, 55.73, 38.08 ppm. High-resolution mass spectrometry (ESI) ([M+H]) calculated for C 20 H 18 NO, 288.1388, test value, 288.1385.

[0020] Example 4: Synthesis of 2,7,9-trimethyl-9H-tribenzo[b,d,f]azepine (Product 3d): The method was the same as in Example 1, except that the substrate, cyclic diphenyliodonium triflate, was replaced with bis(p-methyl)phenyliodonium triflate. The yield was 87%. H NMR Spectrum (BRUKER Ascend 500 NMR Spectrometer) 1H NMR (500 MHz, CDC13): δ = 7.44 (dd, J = 7.5 Hz, 1.5 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.31-7.24 (m, 3H, cover the solvent), 7.20-7.17 (m, 1H), 7.12 (td, J = 7.5 Hz, 1.0 Hz, 1H), 6.99 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 3.23 (s, 3H), 2.45 (s, 3H), 2.36 (s, 3H) ppm. 13 C NMR (125 MHz, CDC13): δ = 154.41, 154.11, 139.45, 138.02, 137.13, 136.97, 135.04, 131.95, 130.29, 129.87, 129.44, 129.41, 128.60, 128.21, 124.85, 123.99, 118.17, 117.34, 38.04, 21.41, 21.37 ppm. High resolution mass spectrum (ESI) ([M+H]) calculated for C 21 H 20 N, 286.1596, found, 286.1599.

[0021] Example 5: Synthesis of 2,7-dichloro-9-methyl-9H-triphenobenzo[b,d,f]azepine (product 3e): The procedure of Example 1 was followed, replacing the substrate cyclic diphenyliodonium triflate with bis(p-chloro)phenyliodonium triflate, in 69% yield. Nuclear magnetic resonance hydrogen spectrum (BRUKER Ascend 500 type nuclear magnetic resonance instrument) 1 H NMR (500 MHz, CDC13): δ = 7.47 (d, J = 2.0 Hz, 1H), 7.41 (t, J = 8.3 Hz, 2H), 7.36-7.34 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.20-7.15 (m, 3H), 7.11 (dd, J = 8.3 Hz, 1.8 Hz, 1H), 3.27 (s, 3H) ppm. 13 C NMR (125 MHz, CDC13): δ = 155.16, 153.74, 141.20, 137.24, 134.82, 133.80, 133.56, 132.37, 130.86, 130.46, 129.90, 129.44, 129.09, 127.80, 124.71, 124.36, 118.28, 117.86, 38.00 ppm. High resolution mass spectrum (ESI) ([M+H]) calculated for C 19H 14 Cl2N, 326.0503, tested, 326.0500.

[0022] Example 6: Synthesis of 2,12-dimethoxy-9-methyl-9H-tribenzo[b,d,f]azepine (Product 3f): The method was the same as in Example 1, except that the substrate cyclic diphenyliodonium trifluoromethanesulfonate was replaced with bis(m-methoxy)phenyliodonium trifluoromethanesulfonate. The yield was 41%. H NMR (BRUKER Ascend 500 NMR spectrometer) 1 H NMR (500MHz, CDCl3): δ=7.43-7.40(m,2H),7.29-7.27(m,1H),7.16(d,J=8.0Hz,1H),7.13-7.09(m,2H),7.05( d,J=2.5Hz,1H),7.03-7.00(m,2H),6.86(dd,J=9.0Hz,3.0Hz,1H),3.90(s,3H),3.80(s,3H),3.26(s,3H)ppm. 13 C NMR (125 MHz, CDCl3): δ = 159.10, 156.18, 154.24, 147.63, 140.64, 135.91, 134.48, 132.63, 131.11, 129.52, 127.82, 123.92, 118.25, 116.96, 115.17, 114.26, 114.02, 113.59, 55.76, 55.61, 38.16 ppm. High resolution mass spectrometry (ESI) ([M+H]) calculated for C 21 H 20 NO2, 318.1494, test value, 318.1492.

[0023] Example 7: Synthesis of 2,7,9-trimethyl-12-nitro-9H-tribenzo[b,d,f]azepine (Product 3g): The method was the same as in Example 6, except that the substrate 1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione was replaced with 1-methyl-6-nitro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione, and the substrate cyclic diphenyliodonium triflate was replaced with bis(p-methyl)phenyliodonium triflate. The yield was 68%. H NMR spectrum (BRUKER Ascend 500 NMR spectrometer) 1H NMR (500MHz, CDCl3): δ = 8.32 (d, J = 2.5Hz, 1H), 8.16 (dd, J = 8.8Hz, 2.8Hz, 1H), 7.40-7.38 (m, 1H), 7.3 4-7.31(m,2H),7.22(d,J=9.0Hz,1H),7.01-6.99(m,2H),3.34(s,3H),2.47(s,3H),2.37(s,3H)ppm. 13 C NMR (125 MHz, CDCl3): δ = 160.51, 152.27, 143.94, 138.60, 137.84, 137.50, 136.82, 135.71, 131.48, 130.75, 129.80, 129.73, 129.44, 125.92, 125.20, 123.63, 119.06, 117.54, 38.54, 21.37, 21.31 ppm. High resolution mass spectrometry (ESI) ([M+H]) calculated for C 21 H 19 N2O2, 331.1447, test value, 331.1445.

[0024] Example 8: Synthesis of 2,7-dichloro-9-methyl-12-nitro-9H-tribenzo[b,d,f]azepine (Product 3h): The method was the same as in Example 1, except that the substrate diphenyliodonium fluoroborate was replaced with bis(2-thiophene)iodonium fluoroborate. The yield was 32%. H NMR spectrum (BRUKER Ascend 500 NMR spectrometer) 1 H NMR (500MHz, CDCl3): δ = 8.30 (d, J = 2.5Hz, 1H), 8.22 (dd, J = 8.5Hz, 2.3Hz, 1H), 7.48 -7.46(m,2H),7.38(d,J=8.0Hz,1H),7.34(d,J=8.5Hz,1H),7.26-7.25(m,1H,cover the solvent),7.19-7.17(m,2H),3.33(s,3H)ppm. 13 C NMR (125 MHz, CDCl3): δ = 159.67, 153.32, 144.40, 139.17, 137.12, 135.31, 134.42, 134.27, 131.93, 130.94, 130.75, 129.91, 129.06, 125.45, 125.22, 124.35, 119.17, 118.24, 38.49 ppm. High resolution mass spectrometry (ESI) ([M+H]) calculated value C 19 H 13Cl2N2O2, 371.0354, found, 371.0355.

[0025] Example 9: The procedure of Example 1 was followed except that the catalyst Pd(PPh3)4 was replaced by Pd(OAc)2 and the additive PPh3 (0.1 equivalent) was added and the solvent was replaced by N,N-dimethylformamide. The yield was 70%.

[0026] Example 10: The procedure of Example 1 was followed except that the catalyst Pd(PPh3)4 was replaced by PdCl2 and the additive PPh3 (0.1 equivalent) was added and the solvent was replaced by N,N-dimethylformamide. The yield was 40%.

[0027] Example 11: The procedure of Example 1 was followed except that the catalyst Pd(PPh3)4 was replaced by Pd2(dba)3 and the additive PPh3 (0.1 equivalent) was added and the solvent was replaced by N,N-dimethylformamide. The yield was 90%.

[0028] Example 12: The procedure of Example 1 was followed except that the base Na2CO3 was replaced by NaOAc and the solvent was replaced by N,N-dimethylformamide. The yield was 69%.

[0029] Example 13: The procedure of Example 1 was followed except that the base Na2CO3 was replaced by K2CO3 and the solvent was replaced by N,N-dimethylformamide. The yield was 77%.

[0030] Example 14: The procedure of Example 1 was followed except that the solvent dimethylsulfoxide was replaced by N-methylpyrrolidinone. The yield was 78%.

[0031] Example 15: The procedure of Example 1 was followed except that the solvent dimethylsulfoxide was replaced by dimethylacetamide. The yield was 80%.

[0032] Example 16: The procedure of Example 1 was followed except that the catalyst Pd(PPh3)4 was replaced by 0.01 equivalent. The yield was 10%.

[0033] Example 17: The procedure of Example 1 was followed except that the catalyst Pd(PPh3)4 was replaced by 0.2 equivalent. The yield was 97%.

[0034] Example 18: The procedure of Example 1 was followed except that the temperature was changed to 100°C. The yield was 75%.

[0035] Example 19: The procedure of Example 1 was followed except that the temperature was changed to 160°C. The yield was 88%.

Claims

1. A method for synthesizing tribenzo[b,d,f]azepine derivatives from isatoic anhydride compounds and cyclic diaryliodonium salts, characterized in that The specific steps are: In an air atmosphere, raw materials are weighed according to a molar feed ratio of a cyclic diaryliodonium salt to an isatoic anhydride compound of 1:1.2 to 1:5, and a metal catalyst is added in an amount of 0.1 to 0.2 equivalents relative to the cyclic diaryliodonium salt. An additive is then added, and a reaction solvent is added. The reaction is carried out at 140° C. for 1 hour. After the reaction is completed, the mixture is separated and purified by column chromatography to obtain a tribenzo[b,d,f]azepine derivative; The isatoic anhydride compound is 1-methylisatoic anhydride, 1-methyl-6-nitro-[2,4]-dihydro-1H-[3,1]-benzoxazine-[2,4]-dione or 1-methyl-6-methoxy-[2,4]-dihydro-1H-[3,1]-benzoxazine-[2,4]-dione; The cyclic diaryl iodonium salt is cyclic diphenyl iodonium trifluoromethanesulfonate, cyclic bis(p-methyl)phenyl iodonium trifluoromethanesulfonate, cyclic bis(p-chloro)phenyl iodonium trifluoromethanesulfonate, cyclic bis(m-methoxy)phenyl iodonium trifluoromethanesulfonate, cyclic bis(2-thiophene) iodonium fluoroborate; The metal catalyst is Pd(PPh3)4; The additive is Na2CO3; The reaction solvent is dimethyl sulfoxide.

2. A method for synthesizing a tribenzo[b,d,f]azepine derivative as claimed in claim 1, characterized in that: The molar feed ratio of the isatoic anhydride compound to the cyclic diaryl iodonium salt is 1.5:1; the amount of the metal catalyst used is 0.1 equivalent relative to the amount of the cyclic diaryl iodonium salt used.

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