Acetic acid methylene chloride → 4-(Benzyloxy)-1-(2-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

HRID 474917Notes

Reaction equation

HRID 474917 reaction equation
Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[CH2:30][NH:29][CH2:28][CH2:27][CH2:26][C:21]=4[N:22]([CH3:25])[C:23]=3[CH:24]=2)[C:12](=[O:31])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:32](Cl)[Cl:33].[CH3:35][C:36](O)=O>CC(C)=O>[ClH:33].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[CH2:30][N:29]([CH:36]([CH3:35])[CH3:32])[CH2:28][CH2:27][CH2:26][C:21]=4[N:22]([CH3:25])[C:23]=3[CH:24]=2)[C:12](=[O:31])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1

Participants

4

Reactant 2

HCID 21922555Acetic acid methylene chlorideHCID 498686694-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

Product 1

HCID 668735084-(Benzyloxy)-1-(2-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochlorideYield 38%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent2×

Procedure

Acetone (2.81 mL) and picoline borane complex (59 mg, 0.55 mmol) were added to a suspension of 4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (80 mg, 0.18 mmol) in 10:1 CH2Cl2/AcOH (3.1 mL) and the resulting solution was stirred at reflux for 18 h. Acetone (1.0 mL) and picoline borane complex (50 mg, 0.46 mmol) were added to the solution and the resulting mixture was stirred for 48 h. The mixture was partitioned with H2O (5 mL) and CH2Cl2 (20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes to 0:100 over 20 column volumes) followed by preparative TLC (Analtech, 20×20 cm, 1000 microns, 50:50 (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH) provided a white solid that upon concentration with 1.25 M HCl in MeOH (2.0 mL) afforded the title compound (33 mg, 38%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 9.92 (br s, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.50-7.35 (m, 6H), 7.02 (dd, J=8.0, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.65-4.53 (m, 2H), 3.72 (s, 3H), 3.57-3.47 (m, 3H), 3.11 (t, J=6.0 Hz, 2H), 2.24-2.07 (m, 2H), 1.34-1.30 (m, 6H); ESI MS m/z 442 [M+H]+; HPLC (Method A, 223 nm) 98.4% (AUC), tR=15.7 min.

Workup

  1. temperatureat reflux for 18 h
  2. stirringthe resulting mixture was stirred for 48 h
  3. customThe mixture was partitioned with H2O (5 mL) and CH2Cl2 (20 mL)
  4. extractionextracted with CH2Cl2 (2×20 mL)
  5. dry with materialThe combined organic extracts were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated to dryness under reduced pressure
  8. customprovided a white solid
  9. concentrationthat upon concentration with 1.25 M HCl in MeOH (2.0 mL)

Sources & evidence

ORD record
ord-8cbc5a4fce084d039281b26f400c3884
Source dataset
uspto-grants-2014_01
Patent number
US08637501B2

Reaction notes

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