Diisopropylethylamine → HCID 57639109, compound

HRID 2111948Notes

Reaction equation

HRID 2111948 reaction equation
[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30](=[O:38])[NH:31][S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21](O)=[O:22])=[CH:18][C:17]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:39]([N:46]1[CH2:51][C@H:50]([CH3:52])[NH:49][C@H:48]([CH3:53])[CH2:47]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.Cl>[CH2:39]([N:46]1[CH2:47][C@H:48]([CH3:53])[N:49]([C:21]([C:19]2[CH2:20][N:14]3[C:13]4[CH:12]=[C:11]([C:30]([NH:31][S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[O:38])[CH:10]=[CH:9][C:8]=4[C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:15]3[C:16]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:17]=3[CH:18]=2)=[O:22])[C@H:50]([CH3:52])[CH2:51]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 12197174(3r,5s)-1-Benzyl-3,5-dimethylpiperazine2×HCID 59682115HCID 59682115, compound

Product 1

HCID 57639109HCID 57639109, compoundYield 14.1%

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of 13-cyclohexyl-10-(((dimethylamino)sulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (200 mg, 0.37 mmol), (3R,5S)-1-benzyl-3,5-dimethylpiperazine (115 mg, 0.56 mmol) and diisopropylethylamine (0.26 mL) in DMF (4 mL) was added HATU (212 mg, 0.56 mmol). The reaction mixture was stirred at rt for 2 h, treated with additional (3R,5S)-1-benzyl-3,5-dimethylpiperazine (100 mg, 0.49 mmol) and stirred at 100° C. for 3 h. The reaction was cooled to rt, diluted with H2O (30 mL) and 1M HCl (aq.) (1.5 mL) and extracted with EtOAc (20 mL). The organic layer was separated, washed with brine (10 mL), dried (MsSO4), filtered and concentrated. The residue was diluted with MeOH (5 mL) and purified by preparative HPLC (H2O/CH3CN with 10 mM NH4OAc buffer) to yield rel-6-(((2R,6S)-4-benzyl-2,6-dimethyl-1-piperazinyl)carbonyl)-13-cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (38 mg, 0.052 mmol, 14%) as an orange solid. 1HNMR (300 MHz, CD3OD) δ 1.02-2.22 (m, 20H), 2.58-3.03 (m, 3H), 3.05 (s, 6H), 3.27-3.40 (m, 2H), 3.92 (s, 3H), 4.34-4.56 (m, 1H), 4.99-5.19 (m, 1H), 6.89 (s, 1H) 7.08 (d, J=2.6 Hz, 1H), 7.14 (dd, J=8.8, 2.6 Hz, 1H), 7.19-7.33 (m, 5H), 7.55 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 8.17 (s, 1H). LCMS: m/e 724 (M+H)+, ret time 3.37 min, column B, 4 minute gradient.

Workup

  1. stirringstirred at 100° C. for 3 h
  2. temperatureThe reaction was cooled to rt
  3. extractionextracted with EtOAc (20 mL)
  4. customThe organic layer was separated
  5. washwashed with brine (10 mL)
  6. customdried (MsSO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. additionThe residue was diluted with MeOH (5 mL)
  10. custompurified by preparative HPLC (H2O/CH3CN with 10 mM NH4OAc buffer)

Sources & evidence

ORD record
ord-b7386e5524ea407aba6d805564eebcb5
Source dataset
uspto-grants-2009_04
Patent number
US07521441B2

Reaction notes

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