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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 1091569
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1091569
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
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Komponenten

6

Edukt 4

HCID 682631,1'-CarbonyldiimidazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 27368851-methyl-1H-imidazole-4-sulfonamideHCID 131727454HCID 131727454, Verbindung

Produkt 1

HCID 5769506213-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
Ausbeute 22 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel2×

Reaktionsbedingungen

Temperatur
60 °C

Versuchsvorschrift

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.

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-ba8b9032e1074fc6a8f7342c4df22ccc
Quelldatensatz
uspto-grants-2012_03
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08129367B2

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