Sodium Hydroxide → HCID 71525712, compound

HRID 1755333Notes

Reaction equation

HRID 1755333 reaction equation
[CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])[N:22]=3)[C:14]3[N:15]([CH:17]=[CH:18][N:19]=3)[N:16]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])[N:22]=3)[C:14]3[N:15]([CH:17]=[CH:18][N:19]=3)[N:16]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]

Participants

5

Reactant 2

HCID 14798Sodium HydroxideHCID 86682716HCID 86682716, compound

Product 1

HCID 71525712HCID 71525712, compoundYield 59.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of (S)-2-methyl-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (72 mg, 0.16 mmol) in dioxane (5 mL) and water (4 mL) was added NaOH (64 mg, 1.6 mmol), then the mixture was heated to 40° C. with stirring for 4 h. The solution was concentrated in vacuo, water (10 mL) was added and the solution was washed with dichloromethane (10 mL×3). The aqueous layer was adjusted to pH=4 by the addition of concentrated HCl. The solid formed was collected by filtration and was purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give the final product (S)-2-methyl-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (41 mg, 59%). 1H NMR (300 MHz, DMSO): δ 10.43 (s, 1H), 8.72 (s, 1H), 8.45 (s, 1H), 8.12 (s, 1H), 7.90 (d, 1H, J=7.5 Hz), 7.62-7.42 (m, 3H), 6.68 (d, 1H, J=7.8 Hz), 6.10 (d, 1H, J=8.1 Hz), 4.04-4.00 (m, 2H), 3.40-3.35 (m, 1H), 3.18-3.15 (m, 1H), 2.47 (s, 3H), 1.96-1.88 (m, 2H), 1.55-1.51 (m, 1H), 0.86 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 429, tR=1.619 min, HPLC: 100% at 214 nm, 99.42% at 254 nm, tR=5.838 min.

Workup

  1. concentrationThe solution was concentrated in vacuo, water (10 mL)
  2. additionwas added
  3. washthe solution was washed with dichloromethane (10 mL×3)
  4. additionThe aqueous layer was adjusted to pH=4 by the addition of concentrated HCl
  5. customThe solid formed
  6. filtrationwas collected by filtration
  7. customwas purified by prep-HPLC (Gemini 5u C18 150×21.2 mm
  8. waitgradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min

Sources & evidence

ORD record
ord-e563dbad92134dcbaeb08f12f4988a79
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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