Potassium Phosphate, Tribasic → 4-(((1R)-1-(1-fluorocyclopropyl)ethyl)amino)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 1507925Notes

Reaction equation

P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]2[C:17]([NH:18][C@@H:19]([C:21]3([F:24])[CH2:23][CH2:22]3)[CH3:20])=[C:16]([C:25]([NH2:27])=[O:26])[CH:15]=[N:14][N:13]2[CH:28]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:24][C:21]1([C@H:19]([NH:18][C:17]2[C:12]3[N:13]([CH:28]=[C:10]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:11]=3)[N:14]=[CH:15][C:16]=2[C:25]([NH2:27])=[O:26])[CH3:20])[CH2:23][CH2:22]1

Participants

Conditions

Temperature: 140 °C

Procedure

Potassium phosphate (2M aqueous solution, 0.11 mL, 0.22 mmol) was added in one portion to a stirred solution of (R)-6-bromo-4-(1-(1-fluorocyclopropyl)ethylamino)-pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 6, 10 mg, 0.029 mmol), phenyl boronic acid (5.4 mg, 0.044 mmol), X-Phos ligand (1.4 mg, 0.0029 mmol) and palladium acetate (0.3 mg, 0.0015 mmol) in anhydrous 1,4-dioxane (0.12 mL). The resulting biphasic mixture was then heated in the CEM microwave at 140° C. for 30 min. The reaction was allowed to cool to rt and the phases separated. The aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organics were then dried (MgSO4) and evaporated in vacuo before purifying by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to afford 2 mg (20%) of the title compound as a white solid. HPLC (condition B): retention time=4.00 min. LCMS (condition B): MH+ m/z 339.2. 1H NMR (400 MHz, MeOD) δ ppm 8.20 (1 H, s), 8.02 (1 H, d, J=1.76 Hz), 7.71 (1 H, dd, J=8.36, 1.10 Hz), 7.57 (1 H, d, J=1.98 Hz), 7.45 (2 H, t, J=7.70 Hz), 7.31 (2 H, t, J=7.37 Hz), 5.07 (1 H, br. s.), 1.40-1.64 (4 H, m), 1.35 (3 H, br. s.).

Workup

temperatureto cool to rt
customthe phases separated
extractionThe aqueous phase was extracted with ethyl acetate (2×5 mL)
dry with materialThe combined organics were then dried (MgSO4)
customevaporated in vacuo
custombefore purifying by reverse-phase Prep HPLC (condition A)
additionThe fraction containing the major product
concentrationwas concentrated on the rotovap

Sources & evidence

ORD record: ord-fb3514e958c04c34bb7f3a5a0fe34c69
Source dataset: uspto-grants-2015_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09221826B2

Reaction notes

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