Dimethylformamide → HCID 86716512, compound

HRID 1501340Notes

Reaction equation

HRID 1501340 reaction equation
[C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[CH:25][C:24](C(O)=O)=[N:23][N:22]4[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:38][O:39]NC.C1CN([P+](ON2N=N[C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][C:60]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:84][N:85]([CH:87]=[O:88])C>>[CH3:38][O:39][N:85]([CH3:84])[C:87]([C:60]1[CH:61]=[CH:62][C:63]([C:24]2[CH:25]=[CH:26][C:21]3[N:22]([C:30]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[C:19]([C:16]4[CH:15]=[CH:14][C:13]([C:9]5([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:12][CH2:11][CH2:10]5)=[CH:18][CH:17]=4)[N:20]=3)[N:23]=2)=[CH:64][CH:65]=1)=[O:88]

Participants

6

Reactant 5

HCID 6228DimethylformamideHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 70817755HCID 70817755, compound

Product 1

HCID 86716512HCID 86716512, compoundYield 57%

Procedure

A mixture of 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid that was prepared in a manner analgous to that described for Intermediate Example Int-27 (0.40 g, 0.82 mmol), O,N-dimethylhydroxylamine hydrochloride (0.12 g, 1.24 mmol, 1.5 equiv), PYBOP (0.54 g, 1.03 mmol, 1.25 equiv) and N,N-diisopropylethylamine (0.9 mL, 4.95 mmol, 6.0 equiv) in DMF (15 mL) was stirred at room temperature for 21 h. The resulting mixture was added to ice water (50 mL). The aqueous mixture was extracted with EtOAc (4×25 mL). The combined organic phases were sequentially washed with water (25 mL) and a saturated aqueous NaCl solution (25 mL), dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting brown oil (1.48 g) was purified using MPLC (Biotage Isolera; Snap 25 g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 3.0 min, gradient to 50% hexane/50% EtOAc 6.0 min, 50% hexane/50% EtOAc 6.5 min, gradient to 10% hexane/90% EtOAc 6.0 min, gradient to 100% EtOAc 2.7 min, 100% EtOAc 4.5 min) to give tert-butyl {1-[4-(6-{4-[methoxy(methyl)carbamoyl]phenyl}-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.25 g, 57%):

Workup

  1. customwas prepared in a manner analgous to
  2. extractionThe aqueous mixture was extracted with EtOAc (4×25 mL)
  3. washThe combined organic phases were sequentially washed with water (25 mL)
  4. dry with materiala saturated aqueous NaCl solution (25 mL), dried (Na2SO4 anh.)
  5. concentrationconcentrated under reduced pressure
  6. customThe resulting brown oil (1.48 g) was purified
  7. customMPLC (Biotage Isolera; Snap 25 g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 3.0 min, gradient to 50% hexane/50% EtOAc 6.0 min, 50% hexane/50% EtOAc 6.5 min, gradient to 10% hexane/90% EtOAc 6.0 min, gradient to 100% EtOAc 2.7 min, 100% EtOAc 4.5 min)

Sources & evidence

ORD record
ord-624789e2120942bbac49e3eab8e4ed21
Source dataset
uspto-grants-2015_12
Patent number
US09206185B2

Reaction notes

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