Tetrahydrofuran → HCID 178522301, compound

HRID 1943480Notes

Reaction equation

HRID 1943480 reaction equation
Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6](Cl)[CH:7]=1.C1COCC1.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>CO>[CH:27]1([NH:31][C:2]2[C:3]3[N:4]([C:9]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=4[F:21])=[O:13])=[CH:10][N:11]=3)[N:5]=[C:6]([NH:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]3)[CH:7]=2)[CH2:30][CH2:29][CH2:28]1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 75645CyclobutylamineHCID 596244958-Bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamideHCID 178511715HCID 178511715, compound

Product 1

HCID 178522301HCID 178522301, compoundYield 14.8%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
80 °C

Procedure

A 1 dram vial was charged with 8A (25 mg, 0.077 mmol) and THF (1 mL). Cyclobutylamine (8.54 μL, 0.100 mmol) was added and the reaction was heated to 80° C. After 4 hours at 80° C., the reaction was cooled to room temperature and the solvent was removed under a stream of nitrogen. Trans-4-aminocyclohexanol (400 mg, 3.47 mmol) was added and the mixture was heated to 130° C. and then cooled to room temperature after 4 hours. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 40 min gradient, monitored at 220 nm). The product (retention time=39.317 minutes) was isolated and lyophilized to dryness to afford 8-(cyclobutylamino)-N-(3-fluoropyridin-4-yl)-6-((trans)-4-hydroxycyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (5 mg, 11.78%). HPLC Rt=3.971 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=440.28.

Workup

  1. temperaturethe reaction was cooled to room temperature
  2. customthe solvent was removed under a stream of nitrogen
  3. temperaturethe mixture was heated to 130° C.
  4. temperaturecooled to room temperature after 4 hours
  5. customThe crude reaction product
  6. custompurified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 40 min gradient, monitored at 220 nm)
  7. customThe product (retention time=39.317 minutes) was isolated

Sources & evidence

ORD record
ord-7405cc409c7d4bd786682dc5ff0f63a0
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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