Synthetic procedure and analysis data
Steps 1 and 2: 2-[2-(Tetrahydropyran-2-yloxy)ethyl]phenylboronic Acid (37)
To a solution of 2-(2-bromophenyl)ethanol (3.10 g) and p-toluenesulfonic acid monohydrate (10.0 mg) in CHCl3 (30.0 mL) was added 3,4-dihydro-2H-pyran (1.70 mL) with cooling by an ice-water bath and the mixture was stirred at room temperature for 1 h. Saturated aqueous NaHCO3 was added to the reaction mixture and the mixture was extracted with CHCl3. The organic layer was washed with brine and dried over Na2SO4. Filtration and concentration in vacuo and purification by silica gel flash chromatography (n-hexane/EtOAc = 30/1 ~ 10/1) gave 3.58 g (81%) of 2-[2-(2-bromophenyl)ethoxy]tetrahydropyran as an oil.
1H-NMR (400 MHz, CDCl3) δ: 7.53 (1H, dd, J = 1.5, 7.7 Hz), 7.30 (1H, dd, J = 1.4, 7.4 Hz), 7.23 (1H, ddd, J =1.4, 7.4, 7.4 Hz), 7.07 (1H, ddd, J = 1.5, 7.7, 7.4 Hz), 4.61 (1H, t, J = 3.7 Hz), 3.95 (1H, td, J = 4.9, 12.8 Hz), 3.79–3.73 (1H, m), 3.65 (1H, td, J = 4.9, 12.8 Hz), 3.47–3.45 (1H, m), 3.07 (2H, t, J = 7.2 Hz), 1.82–1.80 (1H, m), 1.72–1.67 (1H, m), 1.57–1.53 (4H, m).
To a solution of 2-[2-(2-bromophenyl)ethoxy]tetrahydropyran (3.58 g) and triisopropyl borate (3.70 mL) in THF (10.0 mL) was added 1.6 M n-butyllithium in n-hexane (151 mL) dropwise with cooling by a dry ice-acetone bath. The mixture was stirred at 0 ˚C for 2 h. 1 N aqueous HCl was added to the reaction mixture and the mixture was extracted with EtOAc. The organic layer was washed with brine
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and dried over Na2SO4. Filtration and concentration in vacuo and purification by silica gel flash chromatography (n-hexane/EtOAc = 3/1 ~ 2/1) gave 1.77 g (56%) of 37 as an oil.
1H-NMR (400 MHz, CDCl3) δ: 7.67 (1H, d, J = 7.4 Hz), 7.38 (1H, dd, J = 7.4, 7.4 Hz), 7.24–7.23 (2H, m), 6.42 (2H, brs), 4.60–4.58 (1H, m), 4.34–4.31 (1H, m), 3.71–3.66 (1H, m), 3.36–3.33 (2H, m), 3.05–3.01 (2H, m), 1.66–1.26 (4H, m), 0.95–0.90 (2H, m).
Step 3-4: 3-Cyclohexyl-2-[2-(2-hydroxyethyl)phenyl]-1H- indole-6-caboxylic acid methyl ester (38).
To a suspension of 27 49) (2.10 g) and 37 (1.77 g) in DME (20 mL) and water (10 mL) were added tetrakis(triphenylphosphine) palladium(0) (360 mg) and NaHCO3 (2.00 g), and the mixture was heated at reflux temperature for 7 h. After cooling, water was added to the reaction mixture and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, and dried over Na2SO4. Filtration and concentration in vacuo and purification by silica gel flash chromatography (n-hexane/EtOAc = 6/1 ~ 5/1) gave 2.21 g (77%) of 3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethyl]phenyl}-1H- indole-6-carboxylic acid methyl ester as an oil.
MS (FAB) m/z 462 (M + H)+.
To a solution of 3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethyl]phenyl}-1H-indole-6-carboxylic acid methyl ester (2.21 g) in MeOH (10 mL) and THF (10 mL) was added 6 N aqueous HCl (20 mL) and the mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture and the mixture was extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaHCO3 and brine, and dried over Na2SO4. Filtration and concentration in vacuo and purification by silica gel flash chromatography (n-hexane/EtOAc = 5/1~2/1) gave 1.20 g (67%) of 38 as an oil.
1H-NMR (400 MHz, CDCl3) δ: 9.85 (1H, s), 8.10 (1H, brs), 7.84 (1H, d, J = 8.3 Hz), 7.76 (1H, dd, J
= 1.4, 8.3 Hz), 7.46–7.31 (4H, m), 4.01–3.97 (2H, m), 3.94 (3H, s), 2.72–2.69 (3H, m), 1.98–1.80 (7H, m), 1.30–1.26 (3H, m).
Step 5-7: 12-Cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylic Acid (39).
To a solution of 38 (600 mg) obtained above in CHCl3 (6.0 mL) were added CBr4 (790 mg) and triphenylphosphine (497 mg) and the mixture was stirred at room temperature for 5 min. Saturated aqueous NaHCO3 was added to the reaction mixture and the mixture was extracted with CHCl3. The organic layer was washed with brine and dried over Na2SO4. Filtration and concentration in vacuo and purification by silica gel flash chromatography (n-hexane/EtOAc = 7/1 ~ 6/1) gave 500 mg (72%) of 2-[2-(2-bromoethyl)phenyl]- 3-cyclohexyl-1H-indole-6-caboxylic acid methyl ester as an oil.
To a solution of 2-[2-(2-bromoethyl)phenyl]-3-cyclohexyl-1H-indole-6-caboxylic acid methyl ester (500 mg) obtained above in DMF (10 mL) was added NaH (48.0 mg, 60wt% in mineral oil) with cooling by an ice-water bath and the mixture was stirred for 30 min. 2 N aqueous HCl was added to the reaction mixture and the mixture was extracted with EtOAc. The organic layer was washed with
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water and brine, and dried over Na2SO4. Filtration and concentration in vacuo and purification by silica gel flash chromatography (n-hexane/EtOAc = 10/1 ~ 8/1) gave 337 mg (83%) of 12-cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylic acid methyl ester as a solid.
1H-NMR (400 MHz, CDCl3) δ: 8.06 (1H, brs), 7.88 (1H, d, J = 8.3 Hz), 7.71 (1H, d, J = 8.3 Hz), 7.40–7.25 (4H, m), 4.24 (2H, t, J = 6.3 Hz), 3.94 (3H, s), 3.34 (1H, brt, J = 12.3 Hz), 3.11 (2H, t, J = 6.3 Hz), 2.14–2.11 (2H, m), 1.92–1.87 (5H, m), 1.50–1.45 (3H, m).
MS (FAB) m/z 360 (M + H)+.
12-Cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylic acid methyl ester was converted to 39 by hydrolysis using the procedure described for 36 (step 3) in 92% yield.
mp 285–288 ˚C .
1H-NMR (300MHz, DMSO-d6) δ: 12.5 (1H, brs), 8.06 (1H, brs), 7.88 (1H, d, J = 8.2 Hz), 7.68 (1H, d, J = 7.5 Hz), 7.59 (1H, d, J = 8.3 Hz), 7.44–7.42 (1H, m), 7.33 (1H, dd, J = 7.5, 8.2 Hz), 4.27 (2H, brs), 3.08 (2H, brs), 2.57–2.45 (1H, m), 2.08–2.04 (2H, m), 1.85–1.76 (5H, m), 1.46–1.42 (3H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 168.1, 135.1, 134.7, 132.5, 129.6, 128.7, 128.5, 127.5, 127.2, 125.6, 123.0, 120.3, 119.1, 116.9, 111.3, 40.1, 36.4, 32.4, 29.3, 26.6, 25.5.
Anal. (C23H23NO2) calcd C 79.97%, H 6.71%, N 4.05%; found C 79.75%, H 6.72%, N 3.78%.
IR (neat) cm-1: 2918, 2848, 2637, 2509, 1674, 1611, 1603, 1552, 1488, 1467, 1446, 1405, 1384, 1305, 1273, 1261, 1248, 1235, 1138, 1103, 1036, 887, 868, 765, 753, 737, 695, 669, 643, 601, 535, 527, 504, 490, 443.
12-Cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic Acid (43).
Step 1: 3-Cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylic Acid Methyl Ester (41).
Compound 27 49) was converted to 41 by Suzuki-coupling with 40 using the procedure described for 38 in 88%yield.
mp 192–193 ˚C.
1H-NMR (300MHz, DMSO-d6) δ: 11.24 (1H, brs), 9.71 (1H, brs), 7.98 (1H, d, J = 1.5 Hz), 7.78 (1H, d, J = 8.4 Hz), 7.58 (1H, dd, J = 1.5, 8.4 Hz), 7.20-7.31 (2H, m), 7.00 (1H, d, J = 7.5 Hz), 6.92 (1H, t, J = 7.5 Hz), 3.85 (3H, s), 2.60–2.75 (1H, m), 1.62–1.98 (7H, m), 1.14–1.41 (3H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 167.2, 155.4, 135.2, 131.4, 129.8, 129.5, 120.9, 119.6, 119.3, 118.7, 118.3, 118.0, 115.8, 115.8, 112.9, 51.5, 36.0, 32.4, 26.6, 25.6.
Anal. (C22H23NO3) calcd C 75.62%, H 6.63%, N 4.01%; found C 75.62%, H 6.67%, N 4.00%.
Steps 2-4: 12-Cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9- carboxylic Acid (43).
To a solution of 41 (500 mg) in acetone (20 mL) were added K2CO3 (237 mg) and 1-bromo-2-chloroethane (0.14 mL) and the mixture was heated at 50 ˚C for 2 h. K2CO3 (474 mg, 3.44 mmol) and 1-bromo-2-chloroethane (0.28 mL) were added against the mixture and the mixture was heated at 50
˚C for 24 h. After cooling, water was added to the reaction mixture and the mixture was extracted with
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EtOAc. The organic layer was washed with brine and dried over Na2SO4. Filtration and concentration in vacuo and purification by silica gel flash chromatography (n-hexane/EtOAc = 3/1) gave 370 mg (63%) of 2-[2-(2-chloroethoxy)phenyl]-3-cyclohexyl-1H- indole-6-carboxylic acid methyl ester as an oil.
1H-NMR (400 MHz, CDCl3) δ: 9.00(1H, s), 8.06–8.07 (1H, m), 7.85 (1H, d, J = 7.8 Hz), 7.74 (1H, ddd, J = 1.2, 7.8, 8.0 Hz), 7.41 (1H, dd, J = 1.2, 7.8 Hz), 7.37 (1H, ddd, J = 1.8, 7.7, 8.0 Hz), 7.12 (1H, dd, J = 1.8, 7.8 Hz), 6.99 (1H, brd, J = 7.7 Hz), 4.28 (2H, t, J = 5.2 Hz), 3.93 (3H, s), 3.81 (2H, t, J = 5.2 Hz), 2.88–2.95 (1H, m), 1.99–2.10 (2H, m), 1.76–1.87 (5H, m), 1.32–1.41 (3H, m).
To a solution of 2-[2-(2-chloroethoxy)phenyl]-3-cyclohexyl-1H-indole-6-carboxylic acid methyl ester (180 mg) in DMF (6.0 mL) was added NaH (20.0 mg, 60wt% in mineral oil) with cooling by an ice-water bath and the mixture was stirred at room temperature for 24 h. Water was added to the reaction mixture and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4. Filtration and concentration in vacuo gave a solid, which was triturated in diisopropylether and collected by filtration to give 70 mg (42%) of 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid methyl ester as a solid.
1H-NMR (400 MHz, DMSO-d6) δ: 8.20 (1H, d, J = 1.2 Hz), 7.89 (1H, d, J = 8.4 Hz), 7.62 (1H, dd, J
= 1.2, 8.4 Hz), 7.40–7.47 (2H, m), 7.33 (1H, dt, J = 1.2, 7.4 Hz), 7.23 (1H, dd, J = 1.2, 8.0 Hz), 4.33–
4.45 (4H, m), 3.85 (3H, s), 2.83–2.90 (1H, m), 1.95–2.06 (2H, m), 1.67–1.83 (5H, m), 1.24–1.44 (3H, m).
MS (FAB) m/z 376 (M + H)+.
Compound 43 was prepared from 12-Cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9- carboxylic acid methyl ester, which was obtained above, using the hydrolysis procedure described for 36 (step 3) in 85% yield.
mp 295–297 ˚C .
1H-NMR (400 MHz, DMSO-d6) δ: 12.54 (1H, brs), 8.17 (1H, brs), 7.86 (1H, d, J = 8.4 Hz), 7.60 (1H, dd, J = 0.8, 8.4 Hz), 7.40–7.47 (2H, m), 7.33 (1H, dt, J = 0.8, 7.5 Hz), 7.22 (1H, d, J = 7.4 Hz), 4.33–
4.44 (4H, m), 2.83–2.91 (1H, m), 1.95–2.05 (2H, m), 1.68–1.81 (5H, m), 1.25–1.37 (3H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 168.2, 153.5, 136.0, 134.7, 130.3, 130.0, 129.1, 125.7, 124.7, 123.3, 122.9, 120.1, 119.3, 117.9, 111.4, 74.0, 66.9, 40.5, 35.8, 32.6, 26.6, 25.5, 25.1.
Anal. (C23H23NO3) calcd C 76.43%, H 6.41%, N 3.88%; found C 76.32%, H 6.39%, N 3.54%.
IR (neat) cm-1: 2923, 2854, 1668, 1611, 1463, 1449, 1420, 1290, 1252, 1219, 940, 872, 789, 767, 748, 528, 481.
11-Cyclohexyl-5-oxa-6a-azabenzo[a]fluorene-8-carboxylic Acid (42).
To a solution of 41 (150 mg) in DMF (7.5 mL) were added K2CO3 (1.0 g) and dibromomethane (0.15 mL) and the mixture was heated at 70 ˚C for 13 h. After cooling, water was added to the reaction
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mixture and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, and dried over Na2SO4. Filtration and concentration in vacuo and purification by silica gel flash chromatography (n-hexane/EtOAc = 10/1 ~ 5/1) gave 30 mg (26%) of 11-cyclohexyl-5-oxa-6a-azabenzo[a]fluorine-8-carboxylic acid methyl ester as a solid.
1H-NMR (400 MHz, CDCl3) δ: 8.00(1H, d, J = 1.6 Hz), 7.89 (1H, d, J = 8.0 Hz), 7.78 (1H, dd, J = 1.6, 8.0 Hz), 7.75 (1H, dd, J = 1.2, 8.2 Hz), 7.31 (1H, ddd, J = 0.4, 7.6, 8.0 Hz), 7.19 (1H, ddd, J = 1.2, 7.6, 8.2 Hz), 7.15 (1H, dd, J = 0.4, 8.0 Hz), 5.86 (2H, s), 3.95 (3H, s), 3.24–3.34 (1H, m), 2.02–
2.15 (2H, m), 1.81–1.98 (5H, m), 1.36–1.55 (3H, m).
MS (FAB) m/z 362 (M + H)+.
Compound 42 was prepared from 11-cyclohexyl-5-oxa-6a-azabenzo[a]fluorine-8-carboxylic acid methyl ester obtained above using the hydrolysis procedure described for 35 (step 3) in 68% yield.
mp >300 ˚C .
1H-NMR (400 MHz, DMSO-d6) δ: 12.65(1H, brs), 8.19 (1H, d, J = 1.0 Hz), 7.91 (1H, d, J = 8.7 Hz), 7.82 (1H, dd, J = 1.0, 8.7 Hz), 7.63 (1H, dd, J = 1.2, 8.0 Hz), 7.37 (1H, ddd, J = 1.4, 7.8, 8.0 Hz), 7.27 (1H, ddd, J = 1.2, 7.8, 7.8 Hz), 7.21 (1H, dd, J = 1.4, 7.8 Hz), 6.07 (2H, s), 3.21–3.35 (1H, m), 1.99–2.13 (2H, m), 1.72–1.91 (5H, m), 1.37–1.55 (3H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 168.0, 152.7, 133.0, 129.9, 129.3, 128.2, 125.3, 123.9, 123.6, 120.6, 120.0, 119.0, 117.7, 117.5, 111.6, 72.7, 36.2, 32.3, 26.6, 25.5.
Anal. (C22H21NO3) calcd C 76.06%, H 6.09%, N 4.03%; found C 75.92%, H 6.18%, N 3.67%.
IR (neat) cm-1: 2940, 2909, 2849, 1678, 1618, 1499, 1424, 1386, 1300, 1289, 1265, 1242, 1210, 1037, 939, 881, 757, 732, 622, 549, 542.
14-Cyclohexyl-7,8-dihydro-6H-indole[1,2e][1,5]benzoxazocine-11-carboxylic Acid (44).
Compound 44 was prepared from 41 in 54% total yield (3 steps) using the procedure described above for 43, except 1-bromo-3-chloropropane was used instead of 1-bromo-2-chloroethane in step 2.
mp 285–286 ˚C .
1H-NMR (300MHz, DMSO-d6) δ: 12.52 (1H, brs), 8.10 (1H, brs), 7.85 (1H, d, J = 8.4 Hz), 7.65 (1H, d, J = 8.4 Hz), 7.50 (1H, dd, J = 7.5, 7.5 Hz), 7.33–7.20 (3H, m), 4.62 (1H, brd, J = 15.8 Hz), 4.30 (1H, dt, J = 3.5, 12.2 Hz), 3.98 (1H, dt, J = 3.5, 12.2 Hz), 3.63 (1H, dd, J = 8.5, 15.8 Hz), 2.75–2.60 (1H, m), 2.05–1.80 (6H, m), 1.78–1.62 (2H, m), 1.59–1.47 (1H, m), 1.40–1.15 (3H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 168.3, 159.4, 137.0, 134.9, 131.8, 131.1, 129.1, 123.17, 123.11, 122.5, 122.1, 119.8, 119.4, 117.6, 111.4, 72.6, 41.0, 36.1, 32.8, 32.6, 29.8, 26.65, 26.61, 25.5.
Anal. (C24H25NO3) calcd C 76.77%, H 6.71%, N 3.73%; found C 76.88%, H 6.66%, N 3.45%.
IR (neat) cm-1: 2925, 2843, 1669, 1605, 1449, 1420, 1346, 1279, 1267, 1247, 1221, 1046, 947, 788, 768, 745, 544, 470, 430.
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13-Cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic Acid Hydrochloride (49).
Step 1: 2-(4,4,5,5-Tetramethyl[1,3,2]dioxabororan-2-yl)phenylamine (45).
To a solution of 2-bromoaniline (1.0 g) in 1,4-dioxane (15 mL) were added triethylamine (3.24 mL) and PdCl2(dppf)·CH2Cl2 (243 mg). Pinacolborane (2.53 ml) was added to the mixture dropwise and the reaction mixture was heated at 100 ˚C for 3 h. After the reaction mixture was cooled, saturated aqueous NH4Cl was added to the reaction mixture and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4. Filtration and concentration in vacuo and purification by silica gel flash chromatography (n-hexane/EtOAc = 5/1) gave 810 mg (64%) of 45 as a solid.
1H-NMR (400 MHz, CDCl3) δ: 7.59 (1H, dd, J = 1.6, 7.2 Hz), 7.20 (1H, ddd, J = 1.6, 7.2, 7.4 Hz), 6.66 (1H, ddd, J = 1.6, 7.4, 7.4 Hz), 6.58 (1H, dd, J = 1.6, 7.4 Hz), 4.72 (2H, brs), 1.33 (12H, s).
Step 2: 2-(2-Aminophenyl)-3-cyclohexyl-1H-indole-6-carboxylic Acid Methyl Ester (46).
Compound 27 49) was converted to 46 by Suzuki-coupling with 45 using the procedure described for 38 in 96% yield.
mp 178–180 ˚C .
1H-NMR (400 MHz, DMSO-d6) δ: 11.30 (1H, s), 7.95 (1H, d, J = 1.2 Hz), 7.78 (1H, d, J = 8.4 Hz), 7.58 (1H, dd, J = 1.2, 8.4 Hz), 7.14 (1H, ddd, J = 0.8, 7.8, 8.0 Hz), 7.04 (1H, dd, J = 0.8, 7.2 Hz), 6.79 (1H, dd, J = 0.4, 8.0 Hz), 6.65 (1H, ddd, J = 0.4, 7.2, 7.8 Hz), 4.81 (2H, brs), 3.84 (3H, s), 2.53–
2.63 (1H, m), 1.63–1.94 (7H, m), 1.16–1.37 (3H, m).
HRMS (ESI, m/z) calcd for C22H24N2O2 (M+H)+ 349.1911, found 349.1907.
Steps 3–5: 13-Cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a] indole-10-carboxylic Acid Methyl Ester (48).
To a suspension of 46 (6.48 g) and AcONa (1.68 g) in AcOH (1.17 mL) and THF (60 mL) was added chloroacetyl chloride (1.63 mL) dropwise and the mixture was stirred at room temperature for 2 h.
Saturated aqueous NaHCO3 was added to the reaction mixture and the mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine, and dried over MgSO4. Filtration and concentration in vacuo gave 7.90 g (100%) of 2-[2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-caboxylic acid methyl ester as a solid.
1H-NMR (400 MHz, DMSO-d6) δ: 11.44 (1H, s), 9.38 (1H, s), 7.98 (1H, d, J = 1.2 Hz), 7.90 (1H, d, J = 8.0 Hz), 7.82 (1H, d, J = 8.4 Hz), 7.60 (1H, dd, J = 1.0, 8.0 Hz), 7.47 (1H, ddd, J = 1.0, 7.6, 7.8 Hz), 7.36 (1H, dd, J = 1.4, 7.8 Hz), 7.30 (1H, ddd, J = 1.4, 7.6, 8.0 Hz), 4.19 (2H, s), 3.85 (3H, s), 2.42–2.50 (1H, m), 1.61–1.91 (7H, m), 1.11–1.34 (3H, m).
To a solution of 2-[2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-caboxylic acid methyl ester (7.90 g) obtained above in DMF (170 mL) was added NaH (1.67 g, 60wt% in mineral oil) with cooling by an ice-water bath and the mixture was stirred at room temperature for 2 h. To the
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reaction mixture was added water and the precipitates were collected by filtration to give 6.72 g (93%) of 13-cyclohexyl-6-oxo-6,7-dihydro- 5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid methyl ester 47 as a solid.
mp 279–280 ˚C .
1H-NMR (400 MHz, DMSO-d6) δ: 10.34 (1H, s), 8.27 (1H, d, J = 1.2 Hz), 7.96 (1H, d, J = 8.4 Hz), 7.68 (1H, dd, J = 1.2, 8.4 Hz), 7.49–7.53 (2H, m), 7.38 (1H, dd, J = 7.6, 8.0 Hz), 7.28 (1H, d, J = 8.0 Hz), 5.07 (1H, d, J = 15.0 Hz), 4.52 (1H, d, J = 15.0 Hz), 3.89 (3H, s), 2.81–2.91 (1H, m), 1.98–2.11 (3H, m), 1.84–1.94 (1H, m), 1.66–1.78 (2H, m), 1.34–1.56 (3H, m), 1.10–1.27 (1H, m).
HRMS (ESI, m/z) calcd for C24H24N2O3 (M+H)+ 389.1860, found 389.1856.
To a suspension of 47 (6.72 g) obtained above in THF (13 mL) was added 1 M BH3·THF complex THF solution (67 mL) with cooling by an ice-water bath and the mixture was stirred at room temperature for 4 h. To the reaction mixture was added 2N aqueous HCl (40 mL) and the mixture was heated at 70 ˚C for 1 h. After cooling, 2N aqueous NaOH (40 mL) was added to the mixture and the mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3
and brine, and dried over MgSO4. Filtration and concentration in vacuo gave 6.08 g (94%) of 48 as a solid.
mp 234–236 ˚C .
1H-NMR (400 MHz, DMSO-d6) δ: 8.13 (1H, d, J = 1.6 Hz), 7.86 (1H, d, J = 8.8 Hz), 7.61 (1H, dd, J
= 1.6, 8.8 Hz), 7.17–7.21 (2H, m), 6.91 (1H, dd, J = 1.2, 8.0 Hz), 6.83 (1H, dd, J = 7.4, 8.0 Hz), 5.80 (1H, t, J = 4.0 Hz), 4.41 (2H, brs), 3.86 (3H, s), 3.45–3.52 (2H, m), 2.80–2.89 (1H, m), 1.97–2.10 (2H, m), 1.68–1.85 (5H, m), 1.21–1.46 (3H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 167.6, 146.4, 139.4, 134.9, 131.4, 130.1, 129.9, 121.7, 120.4, 119.9, 119.2, 118.2, 118.1, 117.4, 111.3, 52.1, 49.8, 42.7, 36.4, 33.0, 27.1, 26.0, 21.1, 14.4.
HRMS (ESI, m/z) calcd for C24H26N2O2 (M+H)+ 375.2067, found 375.2062.
Step 6: 13-Cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole- 10-carboxylic Acid Hydrochloride (49).
To a solution of 48 (60.0 mg) in MeOH (1.0 mL) and THF (1.0 mL) was added 4N aqueous NaOH (1.0 mL) and the mixture was stirred at room temperature for 36 h. The reaction mixture was neutralized to pH 7 with 1N aqueous HCl (4.0 mL) and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. After filtrating, the solvent was removed by evaporation in vacuo and the residue was dissolved in THF. To the solution was added 4N HCl in EtOAc (1.0 mL). Concentration in vacuo gave a solid, which was triturated in diethyl ether and collected by filtration to give 48.0 mg (76%) of 49 as a solid.
mp 271–275 ˚C .
108
1H-NMR (300MHz, DMSO-d6) δ: 8.18(1H, s), 7.89 (1H, d, J = 8.4 Hz), 7.65 (1H, d, J = 9.9 Hz), 7.18–7.44 (4H, m), 3.46–4.47 (4H, m), 2.81–2.91 (1H, m), 1.96–2.11 (2H, m), 1.68–1.86 (5H, m), 1.22–1.45 (3H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 168.1, 135.2, 130.8, 129.8, 129.4, 123.6, 123.1, 120.3, 119.5, 119.3, 119.2, 111.6, 50.2, 50.1, 40.1, 39.9, 36.0, 32.5, 32.4, 26.6, 25.5.
Anal. (C23H24N2O2·HCl) calcd C 69.60%, H 6.35%, N 7.06%; found C 69.67%, H 6.41%, N 6.76%.
IR (neat) cm-1: 3100, 2923, 2847, 2715, 1704, 1689, 1614, 1569, 1469, 1446, 1382, 1337, 1214, 1198, 792, 760, 748, 723, 630, 587, 494, 412.
12-Cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9-carboxylic Acid (53).
Step 1: 2-[2-(2-Bromophenylsulfanyl)ethoxy]tetrahydropyran (51).
To a solution of 2-bromobenzenethiol (3.0 mL) in DMF (50.0 mL) was added NaH (1.10 g, 60wt%
in mineral oil) with cooling by an ice-water bath and the mixture was stirred at the same temperature for 1h. To the mixture was added 2-(2-bromoethoxy)tetrahydropyran (4.5 ml) with cooling by an ice-water bath and the mixture was stirred at room temperature for 3 h. Aqueous Na2CO3 was added to the reaction mixture and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, and dried over Na2SO4. Filtration and concentration in vacuo and purification by silica gel flash chromatography (n-hexane/EtOAc = 10/1) gave 7.91 g (quantitative yield) of 51 as an oil.
1H-NMR (400 MHz, CDCl3) δ: 7.55 (1H, dd, J = 1.2, 8.1 Hz), 7.36 (1H, dd, J = 1.4, 8.1 Hz), 7.29–
7.25 (1H, m), 7.03 (1H, ddd, J =1.4, 7.7, 8.1 Hz), 4.65 (1H, t, J = 3.5 Hz), 4.00–3.94 (1H, m), 3.91–
3.85 (1H, m), 3.70 (1H, td, J = 6.0, 12.8 Hz), 3.54–3.49 (1H, m), 3.20 (2H, dt, J = 2.0, 6.0 Hz), 1.83–
1.69 (2H, m), 1.63–1.50 (4H, m).
Steps 2-3: 3-Cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethylsulfanyl] phenyl}-1H- indole-6-carboxylic Acid Methyl Ester (52).
To a solution of 27 49) (40.00 g) in 1,4-dioxane (400 mL) were added pinacolborane (51.8 mL), and then triethylamine (66.3 mL) dropwise at room temperature and the mixture was stirred for 3 h. (2-biphenyl)dicyclohexylphosphine (5.01 g) and Pd(OAc)2 (802 mg) were added to the mixture and the reaction mixture was heated at 85 ˚C for 1.5 h. After cooling, saturated aqueous NH4Cl was added to the reaction mixture and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, and dried over Na2SO4. Filtration and concentration in vacuo gave a solid, which was triturated in n-hexane/EtOAc (20/1) and collected by filtration to give 39.2 g (86%) of 50 as a solid.
1H-NMR (400 MHz, DMSO-d6) δ: 11.28 (1H, s), 8.04 (1H, d, J = 1.4 Hz), 7.82 (1H, d, J = 8.6 Hz), 7.53 (1H, dd, J = 1.4, 8.6 Hz), 3.85 (3H, s), 2.53–2.48 (1H, m), 2.00–1.64 (7H, m), 1.45–1.27 (3H, m), 1.35 (12H, s).
109
Compound 52 was synthesized from the pinacolborate 50 obtained in step 2 and 51 obtained in step 1 by Suzuki-coupling using the procedure described for 38 in 74% yield.
1H-NMR (300MHz, CDCl3) δ: 8.86 (1H, s), 8.11 (1H, d, J = 0.7 Hz), 7.82 (1H, d, J = 8.4 Hz), 7.76 (1H, dd, J = 0.7, 8.4 Hz), 7.54 (1H, d, J = 7.7 Hz), 7.41–7.25 (3H, m), 4.50 (1H, t, J = 3.9 Hz), 4.12 (1H, q, J = 7.1 Hz), 3.93 (3H, s), 3.84 (1H, tt, J = 4.7, 11.6 Hz), 3.61 (1H, td, J = 5.9, 11.6 Hz), 3.44 (1H, q, J = 5.6 Hz), 3.05 (1H, td, J = 5.6, 5.9 Hz), 2.96 (1H, dt, J = 6.1, 6.2 Hz), 2.69–2.59 (1H, m), 1.98–1.69 (7H, m), 1.68–1.40 (7H, m), 1.38–1.22 (2H, m).
Step 4: 12-Cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9- carboxylic Acid (53).
Compound 53 was synthesized from 52 in 29% total yield (4 steps) using the procedure described for 39, except mesylate was used instead of bromide as a leaving group in the intramolecular cyclization step.
mp 298–300 ˚C.
1H-NMR (300MHz, DMSO-d6) δ: 12.57 (1H, brs), 8.18 (1H, d, J = 1.5 Hz), 7.89 (1H, d, J = 8.4 Hz), 7.73–7.70 (1H, m), 7.65 (1H, dd, J = 1.5, 8.4 Hz), 7.59 (1H, d, J = 4.4 Hz), 7.49–7.47 (2H, m), 4.93 (1H, dd, J = 4.8, 13.5 Hz), 3.80–3.70 (1H, m), 3.44 (1H, dd, J = 3.7, 13.5 Hz), 3.36–3.28 (1H, m), 2.76–2.73 (1H, m), 1.99–1.89 (4H, m), 1.78–1.71 (2H, m), 1.49–1.24 (4H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 168.1, 138.1, 136.4, 135.1, 134.6, 130.6, 130.5, 129.5, 129.0, 128.9, 123.3, 120.1, 119.3, 117.7, 111.1, 40.3, 40.1, 36.3, 35.8, 32.6, 32.5, 26.5, 25.4.
Anal. (C23H23NO2S) calcd C 73.18%, H 6.14%, N 3.71%; found C 73.07%, H 6.07%, N 3.45%.
IR (neat) cm-1: 2931, 2918, 2847, 2646, 2527, 1677, 1667, 1614, 1497, 1448, 1419, 1386, 1348, 1328, 1295, 1272, 1241, 963, 946, 874, 774, 764, 747, 740, 608, 553, 529, 519, 456, 420.
13-Cyclohexyl-5-Methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic Acid (55).
To a solution of 48 (60.0 mg) in CHCl3 (1.5 mL) and 37% aqueous HCHO (0.2 mL) was added NaBH(OAc)3 (51.0 mg) and the mixture was stirred at room temperature for 24 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4. Filtration and concentration in vacuo gave 13-cyclohexyl-5-methyl –6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10 carboxylic acid methyl ester 54 as a crude oil.
The crude 54 obtained above was converted to compound 55 by using the hydrolysis procedure described for 36 (step 3) in 75% yield from 48.
mp 288–289 ˚C .
1H-NMR (400 MHz, DMSO-d6) δ: 12.51 (1H, s), 8.15 (1H, d, J = 1.2 Hz), 7.84 (1H, d, J = 8.6 Hz), 7.60 (1H, dd, J = 1.2, 8.6 Hz), 7.43 (1H, ddd, J = 1.4, 7.6, 7.6 Hz), 7.28 (1H, dd, J = 1.4, 7.8 Hz), 7.17 (2H, d, J = 7.6 Hz), 7.15 (2H, ddd, J = 1.4, 7.6, 7.8 Hz), 4.90–4.25 (1H, m), 3.95–3.00 (3H, m), 2.79 (1H, brt, J = 12.0 Hz), 2.73 (3H, s), 2.08–1.95 (2H, m), 1.88–1.65 (4H, m), 1.45–1.20 (4H, m).
110
13C-NMR (100 MHz, DMSO-d6) δ: 168.3, 147.7, 138.29, 138.25, 134.2, 129.8, 129.1, 125.2, 122.7, 121.6, 119.9, 119.5, 119.0, 116.9, 111.0, 66.9, 59.6, 40.7, 40.3, 35.7, 32.6, 26.6, 25.5, 25.1.
HRMS (ESI, m/z) calcd for C24H26N2O2 (M+H)+ 375.2067, found 375.2062.
HPLC method A, 97% (16.0 min); HPLC method B, 95% (2.42 min).
IR (neat) cm-1: 2919, 2842, 2523, 1663, 1615, 1497, 1457, 1442, 1421, 1300, 1291, 1272, 1205, 1177, 1037, 773, 747, 573, 540, 506.
5-Acetyl- 13-Cyclohexyl -6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic Acid (57).
To a solution of 48 (60.0 mg) in pyridine (1.0 mL) was added Ac2O (0.023 mL) and the mixture was stirred at room temperature for 24 h. The reaction mixture was added water and the precipitates were collected by filtration to give 56 as a crude solid.
The crude 56 obtained above was converted to compound 57 by using the hydrolysis procedure described for 36 (step 3) in 77% yield from 48.
mp >300 ˚C .
1H-NMR (300 MHz, DMSO-d6) δ: 12.5 (1H, brs), 8.20 (1H, s), 7.87 (1H, d, J = 8.4 Hz), 7.69–7.53 (5H, m), 4.90–4.75 (2H, m), 3.75–3.55 (1H, m), 3.40–3.30 (1H, m), 2.90 (1H, t, J = 11.0 Hz), 2.10–
1.83 (4H, m), 1.80–1.68 (3H, m), 1.55–1.30 (3H, m), 1.50 (3H, s).
13C-NMR (100 MHz, DMSO-d6) δ: 169.4, 168.2, 138.8, 135.8, 134.8, 130.46, 130.41, 130.2, 129.9, 129.2, 129.0, 123.6, 120.2, 119.3, 118.2, 111.5, 78.9, 47.9, 35.8, 33.0, 32.5, 26.6, 26.5, 25.4, 22.3.
Anal. (C25H26N2O3) calcd C 74.60%, H 6.51%, N 6.96%; found C 74.75%, H 6.32%, N 6.67%.
IR (neat) cm-1: 2924, 2849, 1663, 1611, 1463, 1420, 1381, 1327, 1294, 1286, 1258, 1252, 1228, 825, 772, 743, 605, 572, 542, 426.
13-Cyclohexyl-5-(2-piperidin-1-ylethyl)-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic Acid Dihydrochloride (64).
Steps 1–4: 13-Cyclohexyl-5-(2-piperidin-1-ylethyl)-6,7-dihydro-5H-benzo [5,6][1,4]diazepino[7,1-a]indole-10-carboxylic Acid Methyl Ester (62b, R = piperidinyl).
To a solution of 48 (2.00 g) in DMF (16 mL) were added K2CO3 (1.85 g), NaI (800 mg) and bromoacetic acid tert-butyl ester (1.18 mL) and the mixture was heated at 90 ˚C for 12 h. After cooling, the reaction mixture was poured into water and the precipitates were collected by filtration to give 2.47 g (95%) of 5-tert-butoxycarbonyl methyl-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid methyl ester as a solid.
1H-NMR (400 MHz, DMSO-d6) δ: 8.18(1H, d, J = 1.2 Hz), 7.88 (1H, d, J = 8.5 Hz), 7.62 (1H, dd, J
= 1.2, 8.5 Hz), 7.38 (1H, dd, J = 7.6, 7.4 Hz), 7.28 (1H, d, J = 7.6 Hz), 7.14 (1H, dd, J = 7.4, 8.4 Hz),
111
7.02 (1H, d, J = 8.4 Hz), 3.87 (5H, s), 3.51 (2H, brs), 2.75–2.85 (1H, m), 1.95–2.09 (2H, m), 1.66–
1.86 (5H, m), 1.17–1.45 (3H, m), 1.29 (9H, s).
MS (FAB) m/z 489 (M + H)+.
To a solution of 5-tert-butoxycarbonyl methyl-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid methyl ester (2.47 g) obtained above in CHCl3 (17 mL) was added trifluoroacetic acid (17 mL) and the mixture was stirred at room temperature for 5 h. The solvent was removed by evaporation in vacuo and the residue was purified by silica gel flash chromatography (CHCl3/MeOH = 30/1 ~ 15/1) gave 1.34 g (61%) of 13-cyclohexyl-10- methoxycarbonyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-5-yl) acetic acid as a solid.
1H-NMR (400 MHz, DMSO-d6) δ: 12.60 (1H, brs), 8.18 (1H, d, J = 1.2 Hz), 7.87 (1H, d, J = 8.4 Hz), 7.62 (1H, dd, J = 1.2, 8.4 Hz), 7.37 (1H, ddd, J = 1.6, 7.4, 8.0 Hz), 7.27 (1H, dd, J = 1.6, 7.4 Hz), 7.11 (1H, ddd, J = 0.8, 7.4, 7.4 Hz), 7.05 (1H, dd, J = 0.8, 8.0 Hz), 4.40 (2H, brs), 3.88 (2H, brs), 3.87 (3H, s), 3.58 (2H, t, J = 5.4 Hz), 2.76–2.86 (1H, m), 1.94–2.07 (2H, m),1.66–1.86 (5H, m), 1.20–1.45 (3H, m).
MS (FAB) m/z 433 (M + H)+.
To a solution of 13-cyclohexyl-10- methoxycarbonyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-5-yl) acetic acid (200 mg) obtained above, WSC•HCl (106 mg) and HOBt•H2O (75 mg) in DMF (2.0 mL) was added piperidine (0.13 mL) and the mixture was stirred at room temperature for 4 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Filtration and concentration in vacuo and purification by silica gel flash chromatography (n-hexane/EtOAc = 1/1 ~ 1/2) gave 181 mg (78%) of 13-cyclohexyl-5-[2-oxo-2- (piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid methyl ester as a solid.
1H-NMR (400 MHz, DMSO-d6) δ: 8.19 (1H, d, J = 1.2 Hz), 7.87 (1H, d, J = 8.3 Hz), 7.61 (1H, dd, J
= 1.2, 8.3 Hz), 7.39 (1H, dd, J = 7.7, 7.7 Hz), 7.29 (1H, dd, J = 1.6, 7.7 Hz), 7.15 (1H, ddd, J = 1.6, 7.4, 7.7 Hz), 7.09 (1H, d, J = 7.4 Hz), 5.00–4.30 (2H, m), 3.94 (2H, brs), 3.86 (3H, s), 3.45 (2H, brs), 3.35–3.25 (2H, m), 3.08 (2H, brs), 2.81 (1H, tt, J = 3.2, 12.0 Hz), 2.10–1.95 (2H, m), 1.90–1.60 (5H, m), 1.45–1.15 (7H, m), 1.05–0.80 (2H, m).
To a solution of 13-cyclohexyl-5-[2-oxo-2- (piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid methyl ester (120 mg) obtained above in THF (1.0 mL) was added 1 M BH3·THF complex THF solution (1.2 mL) with cooling by an ice-water bath and the mixture was stirred at room temperature for 13 h. To the reaction mixture was added 2N aqueous HCl (3.0 mL) and the mixture was heated at 60 ˚C for 7 h. After cooling, the mixture was made basic by 2N aqueous NaOH (5.5 ml) and the precipitates were collected by filtration to give 111 mg (95%) of 62b (R = piperidinyl) as a solid.
112
1H-NMR (400 MHz, DMSO-d6) δ: 8.17 (1H, d, J = 1.2 Hz), 7.86 (1H, d, J = 8.3 Hz), 7.61 (1H, dd, J
= 1.2, 8.3 Hz), 7.43 (1H, ddd, J = 1.4, 7.7, 7.4 Hz), 7.29 (1H, dd, J = 1.4, 7.4 Hz), 7.25 (1H, d, J = 7.7 Hz), 7.16 (1H, dd, J = 7.4, 7.4 Hz), 3.87 (3H, s), 4.75–4.00 (2H, m), 3.50–3.00 (4H, m), 2.82 (1H, tt, J = 2.8, 12.0 Hz), 2.27 (2H, t, J = 6.8 Hz), 2.20–2.15 (4H, m), 2.05–1.95 (2H, m), 1.85–1.65 (4H, m), 1.40–1.20 (10H, m).
Step 5: 13-Cyclohexyl-5-(2-piperidin-1-ylethyl)-6,7-dihydro-5H-benzo[5,6][1,4] diazepino[7,1-a]indole-10-carboxylic Acid Dihydrochloride (64).
The ester 62b (R =piperidinyl) obtained above was hydrolyzed to give compound 64 by using the hydrolysis procedure described for 49 (step 6) in 72% yield.
mp 196–200 ˚C .
1H-NMR (400 MHz, DMSO-d6) δ: 12.54 (1H, brs), 9.55 (1H, brs), 8.17 (1H, d, J = 1.2 Hz), 7.85 (1H, d, J = 8.6 Hz), 7.60 (1H, dd, J = 1.2, 8.6 Hz), 7.50 (1H, ddd, J = 1.5, 7.7, 7.7 Hz), 7.37 (1H, dd, J = 1.5, 7.7 Hz), 7.32 (1H, d, J = 7.4 Hz), 7.28 (1H, dd, J = 7.4, 7.7 Hz), 4.75 (1H, brs), 3.91–3.53 (5H, m), 3.50–3.30 (1H, m), 3.20–2.90 (5H, m), 2.84 (1H, brt, J = 12.2 Hz), 2.65–2.50 (1H, m), 2.10–1.95 (2H, m), 1.90–1.65 (4H, m), 1.50–1.20 (9H, m), 1.10–0.95 (1H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 168.2, 146.0, 137.6, 134.2, 129.8, 129.7, 128.8, 127.3, 123.3, 122.8, 121.2, 119.8, 119.0, 117.0, 110.9, 56.6, 52.0, 47.8, 43.4, 35.5, 30.8, 26.5, 25.4, 22.0, 21.9, 21.5, 20.8, 13.8.
Anal. (C30H37N3O2·2HCl) calcd C 66.17%, H 7.22%, N 7.72%; found C 66.15%, H 7.49%, N 7.78%.
IR (neat) cm-1: 3375, 2926, 2854, 1694, 1681, 1611, 1485, 1463, 1447, 1385, 1325, 1252, 1219, 1206, 891, 762, 748, 724, 630, 546, 522, 434.
Compounds 59, 60, 61, 65 were prepared from 48 and the corresponding alkyl halides by using the alkylation procedure described for 62b (step1) and the hydrolysis procedure described for compound 49 (step 6).
13-Cyclohexyl-5-iso-propyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10- carboxylic Acid Hydrochloride (59):
Compounds 59 was prepared from 48 with 2-iodo-propane in 14% yield (2 steps).
mp 220–221 ˚C .
1H-NMR (300MHz, DMSO-d6) δ: 8.14 (1H, s), 7.85 (1H, d, J = 8.4 Hz), 7.61 (1H, d, J = 8.4 Hz), 7.45–7.35 (1H, m), 7.35–7.20 (2H, m), 7.20–7.10 (1H, m), 4.60–4.00 (5H, m), 3.70–3.50 (1H, m), 2.83 (1H, t, J = 12.0 Hz), 2.10–1.90 (2H, m), 1.85–1.65 (5H, m), 1.45–1.20 (3H, m), 1.06 (6H, brs).
13C-NMR (125 MHz, DMSO-d6) δ: 168.1, 134.3, 130.7, 130.2, 129.8, 129.3, 126.3, 123.2, 122.9, 122.0, 120.4, 120.1, 119.3, 117.5, 111.4, 51.6, 40.0, 36.4, 35.8, 32.6, 30.9, 26.5, 26.2, 25.5, 20.9, 19.9.
HRMS (ESI, m/z) calcd for C26H30N2O2 (M+H)+ 403.2380, found 403.2377.
113
HPLC method A, 98% (13.9 min); HPLC method B, 96% (2.63 min).
IR (neat) cm-1: 2928, 2872, 2430, 1693, 1612, 1468, 1445, 1382, 1359, 1206, 1184, 1166, 1107, 816, 767, 745, 719, 627, 557.
13-Cyclohexyl-5-benzyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic Acid (60):
Compounds 60 was prepared from 48 with benzylbromide in 89% yield (2 steps).
mp 242–246 ˚C.
1H-NMR (300MHz, DMSO-d6) δ: 12.52 (1H, brs), 8.15 (1H, d, J = 1.5 Hz), 7.88 (1H, d, J = 8.4 Hz), 7.62 (1H, dd, J = 1.5, 8.4 Hz), 7.31 (1H, dd, J = 6.8, 6.8 Hz), 7.30 (1H, d, J = 7.7 Hz), 7.19 (1H, d, J
= 7.7 Hz), 7.13 (1H, d, J = 6.8 Hz), 7.10–6.95 (5H, m), 4.45–4.20 (2H, m), 3.55–3.35 (2H, m), 3.35–
3.25 (2H, m), 2.83 (1H, brt, J = 12.8 Hz), 2.15–1.95 (2H, m), 1.90–1.65 (5H, m), 1.50–1.20 (3H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 168.2, 146.0, 138.5, 138.4, 134.3, 129.7, 129.4, 129.1, 127.8, 127.2, 127.1, 126.4, 122.7, 122.37, 122.33, 121.3, 119.8, 118.9, 116.8, 111.0, 57.8, 55.4, 40.16, 40.10, 35.8, 32.8, 26.5, 25.5.
Anal. (C30H30N2O2·0.2H2O) calcd C 79.34%, H 6.75%, N 6.17%; found C 79.48%, H 6.73%, N 5.96%.
IR (neat) cm-1: 2926, 2852, 2832, 1672, 1611, 1493, 1466, 1448, 1417, 1288, 1268, 1203, 763, 751, 744, 698, 543, 500, 470.
13-Cyclohexyl-5-(2-phenylethyl)-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10- carboxylic Acid Hydrochloride (61):
Compounds 61 was prepared from 48 with 2-phenylethyl bromide in 45% yield (2 steps).
mp 240–243 ˚C.
1H-NMR (400 MHz, DMSO-d6) δ: 8.16 (1H, brs), 7.87 (1H, d, J = 8.3 Hz), 7.62 (1H, dd, J = 1.4, 8.3 Hz), 7.47 (1H, br dd, J = 6.7 Hz), 7.33 (2H, brd, J = 6.7 Hz), 7.25–7.15 (1H, m), 7.05–6.95 (5H, m), 5.50–4.25 (2H, m), 3.62–3.59 (2H, m), 3.55–3.10 (3H, m), 2.83 (1H, tt, J = 3.0, 12.0 Hz), 2.70–2.55 (2H, m), 2.10–1.95 (2H, m), 1.85–1.65 (5H, m), 1.45–1.20 (3H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 168.2, 146.1, 139.6, 138.2, 134.2, 130.0, 129.6, 129.1, 128.4, 128.2, 127.8, 126.6, 125.6, 122.6, 122.3, 122.2, 121.1, 119.8, 118.9, 116.8, 111.0, 57.7, 53.8, 40.0, 35.7, 32.8, 32.6, 26.5, 25.5.
Anal. (C31H32N2O2·HCl) calcd C 74.31%, H 6.64%, N 5.59%; found C 73.97.75%, H 6.61%, N 5.34%.
IR (neat) cm-1: 2929, 2848, 2427, 1698, 1612, 1489, 1456, 1451, 1381, 1359, 1210, 1179, 1122, 1098, 1044, 899, 824, 772, 763, 743, 721, 698, 626, 587, 503, 484, 419.
13-Cyclohexyl-5-(dimethylcarbamoylmethyl)-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic Acid (65):
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Compounds 65 was prepared from 48 with 2-chloro-N,N-dimethylacetamide in 45% yield (2 steps).
mp 241–245 ˚C.
1H-NMR (300MHz, DMSO-d6) δ: 12.46 (1H, brs), 8.16 (1H, brs), 7.86 (1H, d, J = 8.4 Hz), 7.61 (1H, d, J = 8.4 Hz), 7.36 (1H, dd, J = 7.3, 7.9 Hz), 7.28 (1H, d, J = 7.3 Hz), 7.12 (1H, dd, J = 7.3, 7.3 Hz), 7.06 (1H, d, J = 7.9 Hz), 4.60–4.20 (2H, m), 3.98 (2H, brs), 3.50 (2H, t, J = 4.7 Hz), 2.80 (1H, brt, J
= 10.0 Hz), 2.74 (3H, s), 2.71 (3H, s), 2.10–1.90 (2H, m), 1.82–1.70 (5H, m), 1.45–1.20 (3H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 169.0, 168.7, 146.8, 138.7, 134.6, 130.4, 130.0, 129.6, 125.0, 123.1, 122.0, 121.2, 120.3, 119.5, 117.5, 111.4, 57.2, 55.6, 40.5, 40.3, 36.3, 36.2, 35.5, 33.1, 27.0, 25.9.
Anal. (C27H31N3O3) calcd C 72.78%, H 7.01%, N 9.43%; found C 72.89%, H 6.85%, N 9.25%.
IR (neat) cm-1: 2922, 2852, 1668, 1642, 1609, 1488, 1462, 1445, 1398, 1331, 1250, 1229, 1204, 1141, 772, 755, 745, 532.
13-Cyclohexyl-5-(dimethylaminoethyl)-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic Acid Dihydrochloride (63).
Compound 63 was prepared from 62a (R = methyl) in 63% total yield (2 steps) by using the procedure described for 64.
mp 240–244 ˚C.
1H-NMR (400 MHz, DMSO-d6) δ: 12.51 (1H, brs), 10.04 (1H, brs), 8.18 (1H, d, J = 0.9 Hz), 7.85 (1H, d, J = 8.5 Hz), 7.60 (1H, dd, J = 0.9, 8.5 Hz), 7.50 (1H, ddd, J = 1.3, 7.7, 7.5 Hz), 7.35 (1H, dd, J = 1.3, 7.3 Hz), 7.33 (1H, d, J = 7.3 Hz), 7.27 (1H, dd, J = 7.3, 7.5 Hz), 4.76 (1H, brs), 3.85–3.40 (6H, m), 3.20–2.95 (2H, m), 2.80 (1H, brt, J = 11.0 Hz), 2.45 (3H, s), 2.44 (3H, s), 2.10–1.95 (3H, m), 1.90–1.65 (3H, m), 1.50–1.30 (2H, m), 1.30–1.20 (2H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 167.9, 140.4, 138.8, 134.6, 134.4, 130.9, 129.3, 129.1, 128.2, 128.0, 124.0, 121.3, 118.4, 116.5, 113.1, 56.2, 53.3, 43.0, 42.2, 36.7, 34.9, 32.4, 31.8, 26.58, 26.50, 25.4.
HRMS (ESI, m/z) calcd for C27H33N3O2 (M+H)+ 432.2646, found 432.2647.
HPLC method A, 96% (11.5 min); HPLC method B, 99% (2.11 min).
IR (neat) cm-1: 3358, 2924, 2848, 2457, 1694, 1677, 1613, 1462, 1448, 1386, 1300, 1250, 1212, 1112, 970, 889, 760, 748, 724, 632, 614, 552, 507, 418.
2-(13-Cyclohexyl-6,7-dihydrobenzo[6,7][1,4]oxazepino[4,5-a]indole-10-carboxamido)-2-methylpropanoic acid (68).
Step 1
To a solution of Methyl 2-amino-2-methylpropanoate Hydrocloride (184 mg) and 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9- carboxylic Acid (43) (361 mg) obtained above, WSC•HCl (249 mg) and HOBt•H2O (197 mg) in DMF (2.0 mL) was added triethylamine (0.18 mL)
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and the mixture was stirred at room temperature for 12 h. Saturated aqueous NaHCO3 and MeOH was added to the reaction mixture. The precipitated solid was collected on a filter and dried under reduced pressure to give 2-(13-cyclohexyl-6,7-dihydrobenzo[6,7][1,4]oxazepino[4,5-a]indole-10-carboxamido)-2-methylpropanoic acid methyl ester (435 mg, 94%) as a crude solid.
Step 2
To a solution of 2-(13-cyclohexyl-6,7-dihydrobenzo[6,7][1,4]oxazepino[4,5-a]indole-10-carboxamido)-2-methylpropanoic acid methyl ester (432 mg) in MeOH (6.0 mL) and THF (6.0 mL) was added 1N aqueous NaOH (2.0 mL) and the mixture was stirred at room temperature for 24 h. The reaction mixture was neutralized to pH 7 with 1N aqueous HCl (4.0 mL). The precipitated solid was collected on a filter and dried under reduced pressure to give 68 (415 mg, 99 %) as a solid.
mp 217–219 ˚C.
1H-NMR (400 MHz, DMSO-d6) δ: 12.13 (1H, br s), 8.26 (1H, s), 8.13 (1H, d, J = 1.2 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.56 (1H, dd, J = 8.4, 1.2 Hz), 7.49-7.43 (2H, m), 7.36 (1H, ddd, J = 1.2, 7.7, 7.7 Hz), 7.25 (1H, dd, J = 7.7, 1.2 Hz), 4.48 (2H, t, J = 5.5 Hz), 4.38-4.32 (2H, m), 2.89 (1H, tt, J = 12.1, 3.1 Hz), 2.03 (2H, dt, J = 12.1, 12.1 Hz), 1.86-1.69 (5H, m), 1.51 (6H, s), 1.46-1.25 (3H, m).
13C-NMR (100 MHz, DMSO-d6) δ: 175.6, 166.3, 153.3, 135.0, 134.6, 130.1, 129.9, 127.9, 126.8, 125.7, 124.5, 122.8, 119.8, 117.8, 117.6, 108.9, 73.8, 55.2, 40.5, 38.7, 35.8, 32.6, 26.5, 25.4, 25.0.
Anal. (C27H30N2O4) calcd C 72.62%, H 6.77%, N 6.27%; found C 72.24%, H 6.81%, N 6.12%.
IR (neat) cm-1: 3435, 3068, 2931, 2852, 1736, 1622, 1610, 1531, 1467, 1450, 1391, 1351, 1298, 1248, 1210, 1150, 1131, 1029, 882, 835, 816, 795, 762, 741, 612, 591, 513, 481.
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