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

HRID 1091567Notes

Reaction equation

C1N=CN(C(N2C=NC=C2)=O)C=1.OC(C(F)(F)F)=O.[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:57](OC(C)(C)C)=[O:58])=[CH:31][C:32]=3[N:33]3[CH2:39][C:38]([C:40]([N:42]4[CH:47]5[CH2:48][CH2:49][CH:43]4[CH2:44][N:45]([CH3:50])[CH2:46]5)=[O:41])=[CH:37][C:36]4[CH:51]=[C:52]([O:55][CH3:56])[CH:53]=[CH:54][C:35]=4[C:34]=23)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[CH2:64]([C:66]1([S:69]([NH2:72])(=[O:71])=[O:70])[CH2:68][CH2:67]1)[CH3:65].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:57]([NH:72][S:69]([C:66]4([CH2:64][CH3:65])[CH2:68][CH2:67]4)(=[O:71])=[O:70])=[O:58])=[CH:31][C:32]=3[N:33]3[CH2:39][C:38]([C:40]([N:42]4[CH:43]5[CH2:49][CH2:48][CH:47]4[CH2:46][N:45]([CH3:50])[CH2:44]5)=[O:41])=[CH:37][C:36]4[CH:51]=[C:52]([O:55][CH3:56])[CH:53]=[CH:54][C:35]=4[C:34]=23)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1

Participants

Conditions

Temperature: 60 °C

Procedure

CDI (80 mg, 0.49 mmol) was added to a solution of 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) in THF (1.5 mL) 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-ethylcyclopropane-1-sulfonamide (40 mg, 0.27 mmol) in DBU (0.20 mL, 1.3 mmol) and THF (0.20 mL). The reaction was stirred at rt ON (˜75% conversion 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 to dryness, dissolved into MeOH (1.5 mL) and purified by preparative HPLC (CH3CN/H2O with 10 mM NH4OAc) to yield 13-cyclohexyl-N-((1-ethylcyclopropyl)sulfonyl)-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (30.9 mg, 0.046 mmol, 45% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.97-2.35 (m, 29H), 2.56-2.73 (m, 1H), 2.80-2.94 (m, 1H), 3.38-3.58 (m, 1H), 3.94 (s, 3H), 4.29-4.64 (m, 2H), 5.14-5.31 (m, 1H), 7.05 (s, 1H), 7.09-7.20 (m, 2H), 7.57 (d, J=8.4 Hz, 1H), 7.65 (dd, J=8.4, 1.5 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 8.16 (br s, 1H). LC-MS retention time: 2.91 min; m/z 669 (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
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 to dryness
dissolutiondissolved into MeOH (1.5 mL)
custompurified by preparative HPLC (CH3CN/H2O with 10 mM NH4OAc)

Sources & evidence

ORD record: ord-d4178f63bae741868af7031dd6edd00f
Source dataset: uspto-grants-2012_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08129367B2

Reaction notes

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