Dichloromethane → N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(2-(piperazin-1-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine hydrochloride

HRID 1755429Notes

Reaction equation

HRID 1755429 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:24]=[C:25]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([N:39]5[CH2:43][CH2:42][CH2:41][CH:40]5[CH3:44])[N:34]=4)[C:26]4[N:27]([CH:29]=[CH:30][N:31]=4)[N:28]=3)[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:45]CCl>>[ClH:45].[CH3:44][CH:40]1[CH2:41][CH2:42][CH2:43][N:39]1[C:35]1[N:34]=[C:33]([NH:32][C:25]2[C:26]3[N:27]([CH:29]=[CH:30][N:31]=3)[N:28]=[C:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=2)[CH:38]=[CH:37][CH:36]=1

Participants

3

Reactant 2

HCID 6344DichloromethaneHCID 86682754Tert-butyl-4-(2-(3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)piperazine-1-carboxylate

Product 1

HCID 86682755N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(2-(piperazin-1-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine hydrochlorideYield 71%

Procedure

tert-butyl-4-(2-(3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)piperazine-1-carboxylate (25 mg, 0.042 mmol) was dissolved in dichloromethane (5 mL) that had been saturated by bubbling HCl gas. The solution was stirred at room temperature for 2 h. The solvent was concentrated in vacuo. The residue was purified by preparative-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: 10% acetonitrile/90% water (0.1% TFA, v/v) initially, proceeding to 60% acetonitrile/40% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(2-(piperazin-1-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine hydrochloride (15 mg, 71%) as a yellow solid. 1H NMR (300 MHz, DMSO+D2O): δ 9.12 (s, 1H), 8.49 (s, 1H), 8.21 (s, 1H), 7.58-7.52 (m, 4 h), 7.27-7.26 (m, 1H), 6.66 (d, 1H, J=7.8 Hz), 6.19 (d, 1H, J=8.4 Hz), 4.51 (brs, 2H), 4.25 (brs, 1H), 3.69-3.37 (m, 12H), 2.08-1.99 (m, 3H), 1.72 (brs, 1H), 1.12 (d, 3H, J=6.3 Hz). LC/MS: 499 [M+H]+, tR=1.08 min. HPLC: 99.25% at 214 nm, 99.12% at 254 nm, tR=4.99 min.

Workup

  1. customby bubbling HCl gas
  2. concentrationThe solvent was concentrated in vacuo
  3. customThe residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm
  4. waitgradient conditions: 10% acetonitrile/90% water (0.1% TFA, v/v) initially, proceeding to 60% acetonitrile/40% water (0.1% TFA, v/v) in a linear fashion over 9 min

Sources & evidence

ORD record
ord-9afeda4380ea4a3e86003bb58f543b4d
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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