1,1-Dichloroethane → Butyl-{3-[4-(tert-butylamino-methyl)-3-fluoro-phenyl]-imidazo[1,2-b]pyridazin-6-yl}-amine

HRID 870644Notes

Reaction equation

HRID 870644 reaction equation
[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([F:23])[CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].ClC(Cl)C.[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:17]([F:23])[CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]

Participants

5

Reactant 4

HCID 63651,1-DichloroethaneHCID 6385Tert-ButylamineHCID 5049666Sodium triacetoxyborohydrideHCID 866963384-(6-Butylamino-imidazo[1,2-b]pyridazin-3-yl)-2-fluorobenzaldehyde

Product 1

HCID 86696339Butyl-{3-[4-(tert-butylamino-methyl)-3-fluoro-phenyl]-imidazo[1,2-b]pyridazin-6-yl}-amineYield 86.6%

Procedure

A mixture of 4-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-2-fluoro-benzaldehyde (30 mg, 0.10 mmol) and dichloroethane (DCE, 1 mL) was treated with tert-butyl amine (0.011 mL, 0.11 mmol) and the resulting reaction mixture was maintained at RT for 20 min. The reaction was then treated with sodium triacetoxyborohydride (23 mg, 0.11 mmol) and the resulting mixture was maintained until LCMS indicated complete consumption of the aldehyde. The reaction was quenched with saturated aqueous sodium bicarbonate, the layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), then dried (MgSO4), filtered and concentrated to afford a residue that was purified by reverse phase HPLC to afford butyl-{3-[4-(tert-butylamino-methyl)-3-fluoro-phenyl]-imidazo[1,2-b]pyridazin-6-yl}-amine (32 mg, 86%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.21 (dd, J=12.3, 1.5 Hz, 1H), 7.93 (dd, J=8.0, 1.7 Hz, 1H), 7.82 (s, 1H), 7.58 (d, J=9.7 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 6.68 (d, J=9.7 Hz, 1H), 4.02 (s, 2H), 3.34 (t, J=7.2 Hz, 2H), 1.60-1.73 (m, 2H), 1.39-1.51 (m, 2H), 1.24-1.35 (m, 10H), 0.91-1.00 (m, 3H); LCMS (ESI) m/e 370.2 [(M+H)+, calcd for C21H29FN5 370.2].

Workup

  1. customthe resulting reaction mixture
  2. temperaturethe resulting mixture was maintained until LCMS
  3. customconsumption of the aldehyde
  4. customThe reaction was quenched with saturated aqueous sodium bicarbonate
  5. customthe layers were separated
  6. extractionthe aqueous layer was extracted with dichloromethane (3×10 mL)
  7. washThe combined organic layers were washed with water (20 mL) and brine (20 mL)
  8. dry with materialdried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto afford a residue that
  12. customwas purified by reverse phase HPLC

Sources & evidence

ORD record
ord-8a78c4c98b8f453b94f976d0b9d6b452
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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