Diisopropylethylamine → Methyl 13-cyclohexyl-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate

HRID 2111651Notes

Reaction equation

HRID 2111651 reaction equation
CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][C:41]([C:43](O)=[O:44])=[CH:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:65][N:66]1[CH2:72][CH:71]2[NH:73][CH:68]([CH2:69][CH2:70]2)[CH2:67]1>CN(C=O)C>[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][C:41]([C:43]([N:73]4[CH:68]5[CH2:69][CH2:70][CH:71]4[CH2:72][N:66]([CH3:65])[CH2:67]5)=[O:44])=[CH:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 1607274513-cyclohexyl-10-methoxycarbonyl-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acidHCID 229243503-Methyl-3,8-diazabicyclo(3.2.1)octane--hydrogen chloride (1/2)

Product 1

HCID 57639132Methyl 13-cyclohexyl-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

TBTU (115 mg, 0.361 mmol) was added at rt, in one portion, to a solution containing 13-cyclohexyl-10-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (100 mg, 0.241 mmol), DIEA (0.17 mL, 0.964 mmol), 3-Methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride (115 mg, 0.289 mmol), and DMF (2.4 mL). The solution was maintained for 18 h and concentrated. The resultant residue was charged with dichloromethane (30 mL), washed with water (4×15 mL), washed with brine (15 mL), dried (magnesium sulfate), filtered and concentrated to afford a yellow solid which was used without further purification in the next step. LCMS: retention time: 2.272 min LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u 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 4 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% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode: m/z 524 (MH+). Crude 1H NMR (300 MHz, CDCl3) δ ppm: 8.19 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.77 (dd, J=8.78 Hz, J=1.46 Hz, 1H), 7.61 (m, 1H), 7.49 (m, 3H), 6.96 (s, 1H), 5.2 (s, 1H), 4.41 (s, 1H), 2.81 (m, 4H), 2.51 (s, 1H), 1.95 (m, 15H), 1.29 (m, 11H), 0.76 (m, 2H).

Workup

  1. temperatureThe solution was maintained for 18 h
  2. concentrationconcentrated
  3. additionThe resultant residue was charged with dichloromethane (30 mL)
  4. washwashed with water (4×15 mL)
  5. washwashed with brine (15 mL)
  6. dry with materialdried (magnesium sulfate)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto afford a yellow solid which
  10. customwas used without further purification in the next step
  11. customequipped with a Phenomenex-Luna 10u C18 4.6×50 mm column
  12. washThe elution conditions
  13. customa gradient time of 4 min
  14. customa hold time of 1 min
  15. customan analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B

Sources & evidence

ORD record
ord-45129171bd44459b938465596ccf6f1a
Source dataset
uspto-grants-2009_04
Patent number
US07521443B2

Reaction notes

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