Potassium Phosphate, Tribasic → 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-(1-(2-hydroxy-2-methylpropyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 1408974Notes

Reaction equation

HRID 1408974 reaction equation
[OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]1=[O:19].[NH2:22][C@@:23]1([CH3:44])[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]2[C:30]3[N:31]([CH:38]=[C:39](Br)[CH:40]=3)[N:32]=[CH:33][C:34]=2[C:35]([NH2:37])=[O:36])[C:24]1([CH3:43])[CH3:42].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+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:22][C@@:23]1([CH3:44])[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]2[C:30]3[N:31]([CH:38]=[C:39]([C:7]4[CH:8]=[CH:9][N:4]([CH2:3][C:2]([OH:1])([CH3:20])[CH3:21])[C:5](=[O:19])[CH:6]=4)[CH:40]=3)[N:32]=[CH:33][C:34]=2[C:35]([NH2:37])=[O:36])[C:24]1([CH3:43])[CH3:42]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 682910911-(2-hydroxy-2-methylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneHCID 682922884-((1R,3 S)-3-amino-2,2,3-trimethylcyclopentylamino)-6-bromopyrrolo[1,2-b]-pyridazine-3-carboxamide2×

Product 1

HCID 683586034-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-(1-(2-hydroxy-2-methylpropyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of Pd(OAc)2 (0.570 mg, 2.54 μmol), 1-(2-hydroxy-2-methylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (22.3 mg, 0.076 mmol), 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-bromopyrrolo[1,2-b]pyridazine-3-carboxamide (19.3 mg, 0.051 mmol, Intermediate 48), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (2.42 mg, 5.1 μmol), and 2 M K3PO4 (0.08 mL, 0.15 mmol) in dioxane (0.5 mL) was degassed then heated at 95° C. for 18 h. The reaction mixture was cooled to rt, diluted with MeOH and purified directly via preparative HPLC. 1H NMR (CD3OD, 400 MHz) δ 8.24 (s, 1H), 8.16 (d, J=1.5 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.83 (dd, J=7.0, 2.0 Hz, 1H), 4.71 (t, J=9.0 Hz, 1H), 4.10 (s, 2H), 2.52 (dtd, J=13.7, 9.0, 4.6 Hz, 1H), 2.23-2.00 (m, 2H), 1.92-1.73 (m, 1H), 1.61-1.47 (m, 3H), 1.28-1.16 (m, 9H), 1.16-0.98 (m, 3H). MS (ES+) m/z: 467.19 (M+H); LC retention time: 2.63 min (Analytical HPLC conditions: Chromalith Speedrod, C18, 4.6×50 mm, 10% MeOH/water to 90% MeOH/water with 0.2% H3PO4, 4 min gradient, 4 mL/min)

Workup

  1. customwas degassed
  2. temperatureThe reaction mixture was cooled to rt
  3. additiondiluted with MeOH
  4. custompurified directly via preparative HPLC
  5. customLC retention time: 2.63 min (Analytical HPLC conditions: Chromalith Speedrod, C18, 4.6×50 mm, 10% MeOH/water to 90% MeOH/water with 0.2% H3PO4, 4 min gradient, 4 mL/min)

Sources & evidence

ORD record
ord-832512709dbd435eb456a03177d97d54
Source dataset
uspto-grants-2014_12
Patent number
US08921368B2

Reaction notes

Loading…