Nitrogen → 4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)-6-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877764Notes

Reaction equation

Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=4)[CH2:12]3)=[C:8]([C:25]([NH2:27])=[O:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH3:29][C:30]([OH:47])([CH3:46])[CH2:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.N#N>C(O)(C)(C)C.CO.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([N:13]2[CH2:14][C@H:15]([CH3:16])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:28]=[C:2]([C:35]5[CH:34]=[N:33][N:32]([CH2:31][C:30]([OH:47])([CH3:46])[CH3:29])[CH:36]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:25]([NH2:27])=[O:26])[CH2:12]2)=[N:18][CH:19]=1)#[N:24]

Participants

Conditions

Temperature: 110 °C

Procedure

A solution of 6-bromo-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.045 mmol, from Step 2), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (24.18 mg, 0.091 mmol, from Step 3), potassium phosphate tribasic (28.9 mg, 0.136 mmol), palladium(II) acetate (1 mg, 4.45 μmol) and dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (4.78 mg, 8.90 μmol) in tert-butanol (0.5 mL) was degassed by vacuum-N2 refill cycle twice. The sealed tube was then heated at 110° C. for 2 h. The crude material was diluted with methanol (1.3 mL) and water (0.2 mL) and filtered. The filtrate was purified by preparative RP-HPLC (50-80% solvent B in 30 min, 30 mL/min, Pursuit XRs 10 u C18 30×250 mm) to give the title compound (9.7 mg). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.31 (br. s., 1H), 8.07 (s, 1H), 7.85 (s, 1H), 7.74 (s, 2H), 7.63 (dd, J=8.9, 1.5 Hz, 1H), 6.98 (d, J=1.5 Hz, 1H), 6.49 (d, J=8.9 Hz, 1H), 4.97 (br. s., 1H), 4.10 (s, 2H), 3.99-3.75 (m, 3H), 3.46-3.36 (m, 1H), 2.84 (br. s., 1H), 1.29 (d, J=6.9 Hz, 3H), 1.20 (s, 6H); MS (ES+) m/z: 500.2 (M+H); LC retention time: 1.18 min (analytical LCMS Method I).

Workup

filtrationfiltered
customThe filtrate was purified by preparative RP-HPLC (50-80% solvent B in 30 min, 30 mL/min, Pursuit XRs 10 u C18 30×250 mm)

Sources & evidence

ORD record: ord-de5bb545fe634b7ba81eb6b12c2b3e2a
Source dataset: uspto-grants-2015_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08987268B2

Reaction notes

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