Hydrochloric Acid → (E)-N-(cyclopropylmethoxy)-1-[3-[1-(5,7-difluoroquinolin-6-yl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]ethanimine

HRID 1959774Notes

Reaction equation

HRID 1959774 reaction equation
[CH:1]1([CH2:4][O:5][N:6]2C(=O)C3[C:8](=CC=CC=3)[C:7]2=O)[CH2:3][CH2:2]1.O.NN.[F:20][C:21]1[C:30]([CH:31]([C:33]2[N:37]3[N:38]=[C:39](C(=O)C)[CH:40]=[CH:41][C:36]3=[N:35][N:34]=2)[CH3:32])=[C:29]([F:45])[CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2.Cl.[OH-].[Na+]>CO>[CH:1]1([CH2:4][O:5]/[N:6]=[C:7](/[C:39]2[CH:40]=[CH:41][C:36]3[N:37]([C:33]([CH:31]([C:30]4[C:21]([F:20])=[C:22]5[C:27](=[CH:28][C:29]=4[F:45])[N:26]=[CH:25][CH:24]=[CH:23]5)[CH3:32])=[N:34][N:35]=3)[N:38]=2)\[CH3:8])[CH2:3][CH2:2]1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 24654Hydrazine hydrate (1:1)HCID 14843102-(cyclopropylmethoxy)-1H-isoindole-1,3(2H)-dioneHCID 581904661-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone

Product 1

HCID 58190494(E)-N-(cyclopropylmethoxy)-1-[3-[1-(5,7-difluoroquinolin-6-yl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]ethanimineYield 92.2%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

2-(cyclopropylmethoxy)isoindoline-1,3-dione (300 mg, 1.42 mmol), and hydrazine monohydrate (35 μL, 0.71 mmol) in methanol (5 mL) was heated at 75° C. for 3 hr. The reaction mixture was cooled, and the precipitate was filtered off, and washed twice with minimum methanol. To the combined methanol solution was added 1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (53.6, 100 mg, 0.28 mmol), followed by hydrochloride (1 N in dioxane) dropwise to give a clear solution. The reaction mixture was stirred at rt overnight, LCMS showed the reaction was complete. 1N NaOH aqueous solution was added until pH 8-9. The mixture was concentrated, and purified by column chromatography to afford 109 mg (91% yield) of the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.93 (dd, 1H), 8.33 (d, 1H), 7.96 (d, 1H), 7.75 (d, 1H), 7.59 (d, 1H), 7.41 (dd, 1H), 5.28 (q, 1H), 4.03 (d, 2H), 2.19 (d, 3H), 2.02 (s, 3H), 1.13-1.22 (m, 1H), 0.52-0.62 (m, 2H), 0.22-0.31 (m, 2H). LCMS (method A): [MH]+=423, tR=5.49 min.

Workup

  1. temperatureThe reaction mixture was cooled
  2. filtrationthe precipitate was filtered off
  3. washwashed twice with minimum methanol
  4. customto give a clear solution
  5. concentrationThe mixture was concentrated
  6. custompurified by column chromatography

Sources & evidence

ORD record
ord-3f02e6e07c414a4aa4f799cf8cc37d90
Source dataset
uspto-grants-2013_04
Patent number
US08410264B2

Reaction notes

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