Potassium Phosphate, Tribasic → (+/-)-4-(((1S,2S)-2-hydroxy-2-methylcyclohexyl)amino)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 1408958Notes

Reaction equation

Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@@:12]3([OH:18])[CH3:17])=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=[N:6][N:5]2[CH:22]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:18][C@@:12]1([CH3:17])[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:22]=[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:19]([NH2:21])=[O:20]

Participants

Conditions

Temperature: 130 °C

Procedure

A mixture of 6-bromo-4-((1S,2S)-2-hydroxy-2-methylcyclohexylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (31 mg, 0.084 mmol), phenylboronic acid (21 mg, 0.17 mmol), Pd(OAc)2 (1.0 mg, 0.004 mmol), and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (X-Phos, 4 mg, 0.0084 mmol) in DMF (0.5 mL) were added 2M K3PO4 (0.13 mL, 0.25 mmol) and the solution degassed via N2 sparging. The mixture was sealed and heated at 130° C. for 30 min. The reaction was cooled and the product was isolated via preparative HPLC to afford the title compound (17.5 mg, 52% yield) as a pale yellow solid. LCMS: 365.15 (M+H)+; HPLC (condition L): retention time=8.34 min; 1H NMR (methanol-d4, 400 MHz) δ 8.16 (s, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.70 (m, 2H), 7.41 (t, J=7.5 Hz, 2H), 7.27 (m, 2H), 4.35 (m, 1H), 2.21 (m, 2H), 1.50-1.88 (m, 6H), 1.35 (s, 3H).

Workup

customthe solution degassed via N2 sparging
customThe mixture was sealed
temperatureThe reaction was cooled
customthe product was isolated via preparative HPLC

Sources & evidence

ORD record: ord-f61ac4a8e2f94659aa3ceaeb835943e5
Source dataset: uspto-grants-2014_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08921368B2

Reaction notes

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