1,1'-Carbonyldiimidazole → 13-Cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-n-((1-methyl-1h-imidazol-4-yl)sulfonyl)-7h-indolo[2,1-a][2]benzazepine-10-carboxamide

온도

60 °C

tert-Butyl 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine -10-carboxylate TFA (200 mg, 0.30 mmol) was dissolved into THF (1.5 mL) and stirred under nitrogen. CDI (80 mg, 0.49 mmol) was added and the reaction mixture was heated at 60° C. for 2 h. The reaction was cooled to rt and then ⅓ (˜0.55 mL) of the reaction solution was added to a stirring solution of 1-methyl-1H-imidazole-4-sulfonamide (60.0 mg, 0.37 mmol) in DBU (0.20 mL, 1.3 mmol) and THF (0.20 mL). The reaction was stirred at rt ON (˜75% conv. by LCMS), concentrated to an oil, quenched with 1N HCl (˜1 mL) (prec. formed) and extracted with EtOAc (2×1 mL) and DCM (2×1 mL). The combined organics were concentrated, dissolved into MeOH (1.5 mL) and purified by preparative HPLC (CH3CN/H2O with 10 mM NH4OAc) to yield 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-N-((1-methyl-1H-imidazol-4-yl)sulfonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (15.6 mg, 0.023 mmol, 22% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.08-2.77 (m, 22H), 2.78-2.92 (m, 1H), 3.81 (s, 1H), 3.93 (s, 3H), 4.26-4.65 (m, 2H), 5.08-5.31 (m, 1H), 7.01 (s, 1H), 7.10 (d, J=2.6 Hz, 1H), 7.15 (dd, J=8.4, 2.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.67 (s, 1H), 7.81 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 8.17 (s, 1H). LC-MS retention time: 2.15 min; m/z 681 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

1. temperatureThe reaction was cooled to rt
2. stirringThe reaction was stirred at rt ON (˜75% conv. by LCMS)
3. concentrationconcentrated to an oil
4. customquenched with 1N HCl (˜1 mL) (prec. formed)
5. extractionextracted with EtOAc (2×1 mL) and DCM (2×1 mL)
6. concentrationThe combined organics were concentrated
7. dissolutiondissolved into MeOH (1.5 mL)
8. custompurified by preparative HPLC (CH3CN/H2O with 10 mM NH4OAc)

ORD 기록

ord-ba8b9032e1074fc6a8f7342c4df22ccc

출처 데이터셋

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08129367B2