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 1959775Notes

Reaction equation

HRID 1959775 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-e64f2b2e8f4948acb0b0dd071f986f8a
Source dataset
uspto-grants-2013_04
Patent number
US08410264B2

Reaction notes

Loading…