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

HRID 1091569Notes

Reaction equation

OC(C(F)(F)F)=O.[CH:8]1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:45](OC(C)(C)C)=[O:46])=[CH:19][C:20]=3[N:21]3[CH2:27][C:26]([C:28]([N:30]4[CH:35]5[CH2:36][CH2:37][CH:31]4[CH2:32][N:33]([CH3:38])[CH2:34]5)=[O:29])=[CH:25][C:24]4[CH:39]=[C:40]([O:43][CH3:44])[CH:41]=[CH:42][C:23]=4[C:22]=23)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:64][N:65]1[CH:69]=[C:68]([S:70]([NH2:73])(=[O:72])=[O:71])[N:67]=[CH:66]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:8]1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:45]([NH:73][S:70]([C:68]4[N:67]=[CH:66][N:65]([CH3:64])[CH:69]=4)(=[O:72])=[O:71])=[O:46])=[CH:19][C:20]=3[N:21]3[CH2:27][C:26]([C:28]([N:30]4[CH:31]5[CH2:37][CH2:36][CH:35]4[CH2:34][N:33]([CH3:38])[CH2:32]5)=[O:29])=[CH:25][C:24]4[CH:39]=[C:40]([O:43][CH3:44])[CH:41]=[CH:42][C:23]=4[C:22]=23)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1

Participants

Conditions

Temperature: 60 °C

Procedure

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.

Workup

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

Sources & evidence

ORD record: ord-ba8b9032e1074fc6a8f7342c4df22ccc
Source dataset: uspto-grants-2012_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08129367B2

Reaction notes

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