Hydrochloric Acid → 2-[(E)-1-[3-[1-(5,7-difluoroquinolin-6-yl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]ethylideneamino]oxyacetic acid

HRID 1892422Notes

Reaction equation

HRID 1892422 reaction equation
O=[C:2]1[C:10]2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]([O:16]C)=[O:15].O.NN.[F:21][C:22]1[C:31]([CH:32]([C:34]2[N:38]3[N:39]=[C:40](C(=O)C)[CH:41]=[CH:42][C:37]3=[N:36][N:35]=2)[CH3:33])=[C:30]([F:46])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[N:27]2.Cl>CO>[F:21][C:22]1[C:31]([CH:32]([C:34]2[N:38]3[N:39]=[C:40](/[C:2](=[N:3]/[O:12][CH2:13][C:14]([OH:16])=[O:15])/[CH3:10])[CH:41]=[CH:42][C:37]3=[N:36][N:35]=2)[CH3:33])=[C:30]([F:46])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[N:27]2

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 24654Hydrazine hydrate (1:1)HCID 748410Methyl ((1,3-dioxo-1,3-dihydro-2H-isoindol-2-YL)oxy)acetateHCID 581904661-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone

Product 1

HCID 509914532-[(E)-1-[3-[1-(5,7-difluoroquinolin-6-yl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]ethylideneamino]oxyacetic acidYield 43.6%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
70 °C

Procedure

Methyl 2-(1,3-dioxoisoindolin-2-yloxy)acetate (237 mg, 1.01 mmol) and hydrazine monohydrate (50 mg, 1.0 mmol) were dissolved in methanol (3 mL) and heated at 70° C. for 2 h. After filtration, the solid was washed with EtOAc. The combined solution was concentrated and the residue was diluted with methanol. A solution of NaOH (6 N, 3 mL) was added and the mixture was stirred at 70° C. for 2 h. The solution was concentrated, acidified with 3 N HCl to pH 1 and filtered. The solid was washed with water, and the combined solution was concentrated. The residue was diluted with DCM, then ketone 53.5 (40 mg, 0.113 mmol) and HCl (4 N HCl in dioxane, 0.7 mL) were added. It was stirred at rt for 24 h. After concentration, the residue was purified by prep-HPLC to give 21 mg (34%) of the title compound as white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.90 (s, 1H), 8.97 (d, 1H), 8.45 (d, 1H), 8.26 (d, 1H), 7.70 (d, 1H), 7.60 (d, 1H), 5.27 (q, 1H), 4.76 (s, 2H), 2.03 (d, 3H), 1.94 (s, 3H). LCMS (method B): [MH]+=427, tR=2.259 min. Chiral separation (method L) provided enantiomeric pure compounds example 68-R (tR=7.71 min) and example 68-S (tR=9.99 min).

Workup

  1. filtrationAfter filtration
  2. washthe solid was washed with EtOAc
  3. concentrationThe combined solution was concentrated
  4. additionthe residue was diluted with methanol
  5. additionA solution of NaOH (6 N, 3 mL) was added
  6. concentrationThe solution was concentrated
  7. filtrationfiltered
  8. washThe solid was washed with water
  9. concentrationthe combined solution was concentrated
  10. additionThe residue was diluted with DCM
  11. stirringIt was stirred at rt for 24 h
  12. concentrationAfter concentration
  13. customthe residue was purified by prep-HPLC

Sources & evidence

ORD record
ord-ba64fea2f39146e5ab5da10f4e7485c1
Source dataset
uspto-grants-2013_08
Patent number
US08507676B2

Reaction notes

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