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Formaldehyde → 7-Fluoro-6-{6-[1-(1-methyl-azetidin-3-yl)-1H-pyrazol-4-yl]-imidazo[1,2-b]pyridazin-3-yl methyl}-quinoline

HRID 69183
Notes
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Reaction equation

HRID 69183 reaction equation
CO.[NH:3]1[CH2:6][CH:5]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]4[N:16]([C:18]([CH2:21][C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][C:31]=5[F:32])[N:28]=[CH:27][CH:26]=[CH:25]6)=[CH:19][N:20]=4)[N:17]=3)[CH:9]=[N:8]2)[CH2:4]1.C=O.[BH3-][C:36]#N.[Na+]>C(Cl)Cl.C(O)(=O)C>[F:32][C:31]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[CH2:21][C:18]1[N:16]2[N:17]=[C:12]([C:10]3[CH:9]=[N:8][N:7]([CH:5]4[CH2:4][N:3]([CH3:36])[CH2:6]4)[CH:11]=3)[CH:13]=[CH:14][C:15]2=[N:20][CH:19]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 712FormaldehydeHCID 887MethanolHCID 5003444Sodium cyanoborohydrideHCID 686314996-[6-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-7-fluoro-quinoline

Product 1

HCID 579174527-Fluoro-6-{6-[1-(1-methyl-azetidin-3-yl)-1H-pyrazol-4-yl]-imidazo[1,2-b]pyridazin-3-yl methyl}-quinoline

Reagents, catalysts & solvents

2
HCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent

Procedure

A flask was charged with MeOH (1 mL). 6-[6-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-7-fluoro-quinoline (Stage 146.1, 26 mg, 0.065 mmol), formaldehyde (9.7 μL, 0.130 mmol) and NaBH3CN (20 mg, 0.325 mmol) were then added. The pH was adjusted to 5-6 with a drop of acetic acid and the RM was stirred at rt for 2 h. The mixture was then diluted with DCM, washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100)). The residue crystallized in DCM. The solid was filtered off, and dissolved in EtOAc. The solution was washed again with NaHCO3, dried over Na2SO4, filtered and concentrated to afford the title compound as a foam (tR 2.93 min (conditions 3), MH+=414.1, 1H-NMR in DMSO-d6: 8.85 (m, 1H); 8.60 (s, 1H); 8.35 (m, 1H); 8.09 (m, 3H); 7.77 (m, 1H); 7.58 (m, 2H); 7.47 (m, 1H); 5.01 (m, 1H); 4.55 (s, 2H); 3.71 (m, 2H); 3.40 (m, 2H); 2.34 (s, 3H))

Workup

  1. washwashed with NaHCO3 and brine
  2. dry with materialThe organic layer was dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by flash chromatography (CombiFlash® Companion System®
  6. customThe residue crystallized in DCM
  7. filtrationThe solid was filtered off
  8. dissolutiondissolved in EtOAc
  9. washThe solution was washed again with NaHCO3
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-d7db261cf07346c18aa7a6a50df3ea6b
Source dataset
uspto-grants-2014_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08822468B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes