Sodium Hydroxide → 4-(1-(8-(5,6-Dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamoyl)benzoic acid

HRID 1755409Notes

Reaction equation

HRID 1755409 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:36]=[CH:37][N:38]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=4)=[O:25])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:36]=[CH:37][N:38]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=4)=[O:25])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]

Participants

5

Reactant 2

HCID 14798Sodium HydroxideHCID 86682750Methyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamoyl)benzoate

Product 1

HCID 715265334-(1-(8-(5,6-Dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamoyl)benzoic acidYield 10%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of methyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamoyl)benzoate (100 mg, 0.19 mmol) and sodium hydroxide (100 mg) in 1,4-dioxane (5 mL) and water (5 mL) was stirred at 40° C. for 2 h. The residue was concentrated to ˜5 mL in vacuo and adjusted pH=2 with 1M HCl. The crude mixture was concentrated and 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 45% acetonitrile/55% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamoyl)benzoic acid (9.5 mg, 10%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.29 (s, 1H), 8.80 (d, 1H, J=5.4 Hz), 8.13 (s, 1H), 8.00-7.92 (m, 5H), 7.51-7.40 (m, 2H), 6.98-6.92 (m, 2H), 4.58 (brs, 2H), 3.99 (s, 3H), 3.85 (s, 3H), 2.28-1.98 (m, 5H). LC-MS: [M+H]+, 504, tR=1.236 min, HPLC: 98.3% at 214 nm, 98.4% at 254 nm, tR=4.52 min.

Workup

  1. concentrationThe residue was concentrated to ˜5 mL in vacuo and adjusted pH=2 with 1M HCl
  2. concentrationThe crude mixture was concentrated
  3. custompurified by prep-HPLC (Gemini 5u C18 150×21.2 mm
  4. waitgradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% TFA, v/v) in a linear fashion over 9 min

Sources & evidence

ORD record
ord-e6a8501368ea4968becb4901521e82cd
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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