Ammonia → [(E)-1-[3-[(1R)-1-(5,7-difluoroquinolin-6-yl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]ethylideneamino] carbamate

HRID 1892443Notes

Reaction equation

HRID 1892443 reaction equation
[F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20](/[C:23](=[N:25]/[OH:26])/[CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH3:13])=[C:10]([F:27])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O=C(Cl)[O:30][C:31](Cl)(Cl)Cl.[NH3:36]>C1COCC1>[C:31]([O:26]/[N:25]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C@@H:12]([C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:27])[N:7]=[CH:6][CH:5]=[CH:4]4)[CH3:13])=[N:15][N:16]=2)[N:19]=1)\[CH3:24])(=[O:30])[NH2:36]

Participants

5

Reactant 3

HCID 222AmmoniaHCID 10426DiphosgeneHCID 136055455(NE)-N-[1-[3-[1-(5,7-difluoroquinolin-6-yl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]ethylidene]hydroxylamine

Product 1

HCID 58190606[(E)-1-[3-[(1R)-1-(5,7-difluoroquinolin-6-yl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]ethylideneamino] carbamateYield 57.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

Previously prepared (E)-1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone oxime (75-R, 100 mg, 0.271 mmol) in anhydrous THF (8 mL) was added diphosgene (0.1 mL, 0.829 mmol) dropwise at 0° C., and the reaction mixture was heated at 50° C. for 4 hr. Oil bath was removed, and the reaction mixture was cooled in an ice-water bath. An ammonia solution (0.5 N in dioxane, 8.0 mL, 4.0 mmol) was added dropwise. The temperature was allowed to rise to rt naturally, and the reaction mixture was stirred at rt overnight. Solvent was evaporated, and the residue was purified by column chromatography (8% methanol in ethyl acetate as eluent) to afford 64 mg (45.8% yield) of title compound as white solid, which was unstable at nucleophiles such as methanol, and was pro to degrade into starting material 75-R. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.96 (d, 1H), 8.44 (d, 1H), 8.34 (d, 1H), 8.10 (d, 1H), 7.56-7.74 (m, 2H), 7.34 (s br, 2H), 5.27 (q, 1H), 2.02 (d, 3H), 2.03 (s, 3H). LCMS (method B): [MH]+=412, tR=2.25 min.

Workup

  1. customOil bath was removed
  2. temperaturethe reaction mixture was cooled in an ice-water bath
  3. customto rise to rt
  4. customSolvent was evaporated
  5. customthe residue was purified by column chromatography (8% methanol in ethyl acetate as eluent)

Sources & evidence

ORD record
ord-4e9b31f9da9f4727817da9d18f57f098
Source dataset
uspto-grants-2013_08
Patent number
US08507676B2

Reaction notes

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