Methanol → HCID 70817965, compound

HRID 1501335Notes

Reaction equation

HRID 1501335 reaction equation
FC(F)(F)S(O[C:7]1[C:8]2[N:9]([C:13]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:15]=2)[N:10]=[CH:11][CH:12]=1)(=O)=O.C1[CH2:46][O:45][CH2:44]C1.C(N(CC)CC)C.C[OH:55]>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:30]([O:29][C:27]([NH:26][C:22]1([C:19]2[CH:18]=[CH:17][C:16]([C:14]3[N:15]=[C:8]4[C:7]([C:44]([O:45][CH3:46])=[O:55])=[CH:12][CH:11]=[N:10][N:9]4[C:13]=3[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24][CH2:25]1)=[O:28])([CH3:31])([CH3:32])[CH3:33]

Participants

6

Reactant 4

HCID 887MethanolHCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 86716503HCID 86716503, compound

Product 1

HCID 70817965HCID 70817965, compoundYield 63%

Reagents, catalysts & solvents 1

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

Procedure

To a solution of 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazin-8-yl trifluoromethanesulfonate that was prepared in a manner analgous to that described for Intermediate Example Int-15 (0.15 g, 0.25 mmol) in MeOH (0.4 mL) and THF (0.04 mL) in an autoclave was added 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.040 g, 0.050 mmol, 0.20 equiv) and triethylamine (0.040 mL, 0.27 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 10 g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 2.5 min, gradient to 70% hexane/30% EtOAc 3.0 min, 70% hexane/30% EtOAc 2.5 min, gradient to 50% hexane/50% EtOAc 3.5 min, 50% hexane/50% EtOAc 4.0 min, gradient to 100% EtOAc 1.0 min, 100% EtOAc 5.8 min) to give methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-8-carboxylate (0.081 g, 63%):

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 10 g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 2.5 min, gradient to 70% hexane/30% EtOAc 3.0 min, 70% hexane/30% EtOAc 2.5 min, gradient to 50% hexane/50% EtOAc 3.5 min, 50% hexane/50% EtOAc 4.0 min, gradient to 100% EtOAc 1.0 min, 100% EtOAc 5.8 min)

Sources & evidence

ORD record
ord-278eb5d57fc545ce8f7a5699cf666564
Source dataset
uspto-grants-2015_12
Patent number
US09206185B2

Reaction notes

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