Methanol → HCID 178498530, compound

HRID 1501331Notes

Reaction equation

HRID 1501331 reaction equation
C([O:8][C:9]1[C:10]2[N:11]([C:16]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[N:18]=2)[N:12]=[C:13](Cl)[CH:14]=1)C1C=CC=CC=1.C1[CH2:47][O:46][CH2:45]C1.C(N(CC)CC)C.C[OH:56]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:32]([O:31][C:30]([NH:29][C:25]1([C:22]2[CH:21]=[CH:20][C:19]([C:17]3[N:18]=[C:10]4[C:9]([OH:8])=[CH:14][C:13]([C:45]([O:46][CH3:47])=[O:56])=[N:12][N:11]4[C:16]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:24][CH:23]=2)[CH2:26][CH2:27][CH2:28]1)=[O:36])([CH3:34])([CH3:33])[CH3:35]

Participants

6

Reactant 4

HCID 887MethanolHCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 86716505HCID 86716505, compound

Product 1

HCID 178498530HCID 178498530, compoundYield 44%

Reagents, catalysts & solvents 1

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst

Procedure

To a solution of tert-butyl (1-{4-[8-(benzyloxy)-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-17 (0.91 g, 1.48 mmol) in MeOH (20 mL) and THF (2 mL) in an autoclave was added 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.24 g, 0.30 mmol, 0.20 equiv) and triethylamine (0.23 mL, 1.63 mmol, 1.1 equiv.). The autoclave was flushed with CO (approximately 5 bar) three times, then was pressurized with CO (5.2 bar), stirred at room temperature 30 min., and briefly placed under reduced atmosphere (0.06 bar). The autoclave was then pressurized with CO (5.9 bar at 20° C.), heated to 100° C., and stirred at this temperature for 18 h. The resulting solution was concentrated under reduced pressure. The resulting material 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 26.7 min) to give methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-hydroxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate (0.34 g, 44%):

Workup

  1. customThe autoclave was flushed with CO (approximately 5 bar) three times
  2. customwas then pressurized with CO (5.9 bar at 20° C.)
  3. temperatureheated to 100° C.
  4. stirringstirred at this temperature for 18 h
  5. concentrationThe resulting solution was concentrated under reduced pressure
  6. customThe resulting material 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 26.7 min)

Sources & evidence

ORD record
ord-bbc8f4730c88441b8dca7a7507b1aa48
Source dataset
uspto-grants-2015_12
Patent number
US09206185B2

Reaction notes

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