4-Aminopyridine → 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide

HRID 2239897Notes

Reaction equation

[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2)[N:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:51][C:52]1[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:5]2[N:6]([C:8]([C:11]([NH:51][C:52]3[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=3)=[O:13])=[CH:9][N:10]=2)[N:7]=1

Participants

Conditions

Temperature: 25 °C

Procedure

To a 2 dram vial was added 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)-imidazo[1,2-b]pyridazine-3-carboxylic acid (0.025 g, 0.06 mmol) from (1a), EDCI (0.018 g, 0.09 mmol), HOBT (0.012 g, 0.09 mmol), 4-aminopyridine (8.46 mg, 0.09 mmol), TEA (0.025 ml, 0.18 mmol) and CH3CN (1.0 ml). The reaction was stirred at 25° C. for 48 hours then concentrated to give crude 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide. To this residue was added trans-1,4-cyclohexyldiamine (0.5 g, 4.3 mmol) and the resulting mixture was allowed to heat at 165° C. for 5 hrs. Upon cooling, the sample was dissolved in methylene chloride, and washed with water. The organics were separated, then dried over Na2SO4, filtered and concentrated in vacuo. To this residue was added a 1:1 mixture of CH2Cl2/TFA (2 ml). The solution was stirred at 25° C. for 3 hours, concentrated, diluted with MeOH and purified by preparative HPLC to provide the titled compound (0.008 g, 22%) as a TFA salt. 1H NMR (500 MHz, MeOH) δ ppm 8.74 (2H, d, J=7.15 Hz), 8.30 (2H, d, J=7.15 Hz), 8.19 (1H, s), 7.41-7.50 (2H, m), 7.31-7.41 (2H, m), 7.17-7.26 (1H, m), 6.26-6.33 (1H, m), 3.71-3.87 (1H, m), 3.10-3.23 (1H, m), 2.25-2.39 (2H, m), 2.06-2.24 (2H, m), 1.53-1.66 (2H, m), 1.35-1.52 (2H, m). LC/MS, m/z 443 (M+1). HPLC Rt, 2.34 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.

Workup

concentrationthen concentrated

Sources & evidence

ORD record: ord-92c7b71ed74d413d993ea82bdf1b70a1
Source dataset: uspto-grants-2010_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07723336B2

Reaction notes

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