Potassium Hydroxide → 5-Nitro-3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-indole

A solution of 5-nitroindole (38) (0.2 g, 1.233 mmol) in dry methanol (5 mL) was treated with KOH (0.56 g) at room temperature. After stirring for 10 min., 1,4-cyclohexanedione monoethylene ketal (0.48 g, 3.083 mmol) was added and the resulting solution was refluxed for 36 h. The reaction was brought to room temperature and solvent was evaporated. The crude product was diluted with water (25 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude material was purified by flash-column chromatography (ethyla acetate) to obtain compound 78 (0.25 g, 68%) as a solid. mp 175-177° C.; 1H NMR (CDCl3) δ 1.91 (t, 2H, J=6.6 Hz), 2.49 (brs, 2H), 2.49-2.66 (m, 2H), 3.96-4.00 (m, 4H), 6.12 (t, 1H, J=3.9 Hz), 7.22 (d, 1H, J=2.4 Hz), 7.32 (d, 1H, J=8.7 Hz), 8.05 (dd, 1H, J=2.1, 9.0 Hz), 8.36 (brs, 1H), 8.78 (d, 1H, J=2.1 Hz); ESI-MS m/z (%): 301 (M+, 100). 4-(5-Nitro-1H-indol-3-yl)cyclohex-3-enone (79): A solution of compound 78 (0.1 g, 0.332 mmol) in acetone (5 mL) was treated with 10% aq. HCl (5 mL) at room temperature and stirred for 6 h. Acetone was evaporated and crude was basified using NH4OH solution (20 mL). The product was extracted into CH2Cl2 (2×20 mL), washed with brine (10 mL) and dried (Na2SO4). The CH2Cl2 layer was evaporated to obtain compound 79 (0.075 g, 88%) as a solid. mp 210-212° C.; 1H NMR (DMSO-d6) δ 2.59 (t, 2H, J=6.9 Hz), 2.90 (t, 2H, J=6.6 Hz), 3.11-3.12 (m, 2H), 6.24 (t, 1H, J=3.6 Hz), 7.57 (d, 1H, J=9.0 Hz), 7.76 (d, 1H, J=2.1 Hz), 8.03 (dd, 1H, J=2.1, 9.0 Hz), 8.71 (d, 1H, J=2.1 Hz), 11.95 (s, 1H); ESI-MS m/z (%): 257 (M+, 100). N-Methyl-4-(5-nitro-1H-indol-3-yl)cyclohex-3-enamine (80): A solution of compound 79 (0.07 g, 0.273 mmol) in 1,2-dichloroethane (3 mL) was treated with AcOH (0.015 mL, 0.273 mmol), methylamine hydrochloride (0.018 g, 0.273 mmol), NaBH(OAC)3 (0.086 g, 0.409 mmol) at room temperature and stirred for over night (14 h). The reaction was basified with 2 N NaOH (25 mL) and product was extracted into ethyl acetate (2×20 mL). The combined ethyl acetate layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 80 (0.074 g, quantitative) as a solid. mp 208-210° C.; 1H NMR (DMSO-d6) δ 1.44-1.53 (m, 1H), 1.97-2.01 (m, 2H), 2.35 (s, 3H), 2.40-2.57 (m, 3H), 2.60-2.70 (m, 1H), 6.13 (brs, 1H), 7.54 (d, 1H, J=9.0 Hz), 7.63 (s, 1H), 8.00 (d, 1H, J=7.5 Hz), 8.67 (s, 1H), 11.85 (brs, 1H); ESI-MS m/z (%): 272 (M+, 100). tert-Butyl methyl(4-(5-nitro-1H-indol-3-yl)cyclohex-3-enyl)carbamate (81): A A solution of compound 80 (0.1 g, 0.368 mmol) in dry 1,4-dioxane (3 mL) was treated with Et3N (0.1 mL, 0.737 mmol) followed by (Boc)2O (0.084 g, 0.387 mmol) at room temperature and the resulting solution was stirred for over night (16 h). Solvent was evaporated and crude was purified by column chromatography (EtOAc: Hexanes, 1:1) to obtain compound 81 (0.135 g, quantitative) as a solid. mp 224-226° C.; 1H NMR (DMSO-d6) δ 1.42 (s, 9H), 1.81-1.87 (m, 2H), 2.29-2.45 (m, 2H), 2.60-2.70 (m, 2H), 2.74 (s, 3H), 4.10-4.16 (m, 1H), 6.17 (brs, 1H), 7.55 (d, 1H, J=9.0 Hz), 7.66 (s, 1H), 8.01 (dd, 1H, J=2.4, 9.0 Hz), 8.68 (d, 1H, J=2.1 Hz), 11.87 (s, 1H); ESI-MS m/z (%): 394 (M.Na+, 100), 316 (44), 272 (82). tert-Butyl 4-(5-amino-1H-indol-3-yl)cyclohex-3-enyl(methyl)carbamate (82): A solution of compound 81 (0.5 g, 1.364 mmol) in 2 M NH3 in methanol (20 mL) was treated with Pd—C (0.05 g) and flushed with hydrogen gas. The reaction was stirred at room temperature for over night (16 h) under hydrogen atm. (balloon pressure). The solution was filtered using celite bed and washed with CH2Cl2: methanol (1:1, 3×20 mL). The solvent was evaporated and crude was purified by column chromatography (EtOAc: Hexanes, 1:1) to obtain compound 82 (0.46 g, quantitative) as a solid in 1:2 ratio of diastereomers. 1H NMR (DMSO-d6) δ 1.38, 1.41 (2s, 9H), 1.46-1.84 (m, 6H), 2.02-2.17 (m, 2H), 2.53-2.57 (m, 1H), 2.60-2.72 (2s, 3H), 3.82-3.85 (m, 1H), 4.41 (brs, 2H), 6.42-6.50 (m, 1H), 6.66-6.68 (m, 1H), 6.85-6.87, 6.99-7.06 (2m, 2H), 10.23, 10.28 (2s, 1H); ESI-MS m/z (%): 366 (M.Na+, 8), 344 (MH+, 10), 288 (100). tert-Butyl methyl(4-(5-(thiophene-2-carboximidamido)-1H-indol-3-yl)cyclohexyl)carbamate (83): A solution of compound 82 (0.44 g, 1.281 mmol) in dry ethanol (20 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.73 g, 2.562 mmol) at room temperature and stirred for 24 h. The solvent was evaporated and product was precipitated with ether (100 mL). The solid was dissolved into sat. NaHCO3 sol.:CH2Cl2 (50 mL, 1:1). The org. layer was separated and aqueous layer was extracted with CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 83 (0.425 g, 73%) as a foam in 1:2 ration of diastereomers. 1H NMR (DMSO-d6) δ 1.38-1.56 (m, 1H), 1.64-1.82 (m, 4H), 2.06-2.18 (m, 2H), 2.62-2.70 (m, 4H), 3.80-3.90 (m, 1H), 6.27 (brs, 1H), 6.62-6.66 (m, 1H), 6.95-7.11 (m, 3H), 7.22-7.29 (m, 1H), 7.59 (d, 1H, J=5.1 Hz), 7.71 (d, 1H, J=3.6 Hz), 10.59, 10.63 (2s, 1H); ESI-MS m/z (%): 453 (MH+, 100). Di hydrochloride salt of N-(3-(4-(methylamino)cyclohexyl)-1H-indol-5-yl)thiophene-2-carboximidamide (84): Compound 83 (0.2 g, 0.441 mmol) was treated with 1 N HCl solution at room temperature and the resulting solution was refluxed for 2 h. The reaction was brought to room temperature, filtered and washed with water (5 mL). The solvent was evaporated and crude was recrystallised from ethanol/ether to obtain compound 84 (0.175 g, 94%) as a solid in 1:2 ratio of diastereomers. 1H NMR (DMSO-d6) δ 1.52-1.56 (m, 2H), 1.81-2.16 (m, 6H), 2.50 (s, 3H), 2.75-2.80 (m, 1H), 3.00-3.05 (m, 1H), 7.08 (d, 1H, J=8.1 Hz), 7.24-7.40 (m, 2H), 7.50 (d, 1H, J=8.7 Hz), 7.70-7.72 (m, 1H), 8.15-8.19 (m, 2H), 8.58 (brs, 1H), 9.19 (brs, 2H), 9.65 (brs, 1H), 11.21, 11.26 (2s, 1H), 11.43 (s, 1H); ESI-MS m/z (%): 353 (MH+ for free base, 100) 322 (85); ESI-HRMS calculated for C20H25N4S (MH+ for free base), Calculated: 353.1808; Observed: 353.1794.

1. temperaturethe resulting solution was refluxed for 36 h
2. customwas brought to room temperature
3. customsolvent was evaporated
4. additionThe crude product was diluted with water (25 mL) and product
5. extractionwas extracted into ethyl acetate (2×25 mL)
6. washThe combined ethyl acetate layer was washed with brine (20 mL)
7. dry with materialdried (Na2SO4)
8. customThe solvent was evaporated
9. customcrude material was purified by flash-column chromatography (ethyla acetate)

ORD record

ord-f0ab100ee1bb460cb419a05c33c1811f

Source dataset

uspto-grants-2008_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07375219B2