Potassium Phosphate, Tribasic → (+/-)-4-(4,4-dimethyl-1-(methylsulfonyl)pyrrolidin-3-ylamino)-6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877815Notes

Reaction equation

HRID 877815 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[C:15]([CH3:17])([CH3:16])[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12]3)=[C:8]([C:22]([NH2:24])=[O:23])[CH:7]=[N:6][N:5]2[CH:25]=1.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30](B(O)O)[CH:29]=[N:28]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][C:15]1([CH3:17])[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:25]=[C:2]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[C:31]=3[CH3:32])[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:22]([NH2:24])=[O:23]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 532165971,5-Dimethylpyrazole-4-boronic acidHCID 68350406(+/-)-6-Bromo-4-((4,4-dimethyl-1-(methylsulfonyl)pyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide

Product 1

HCID 68291884(+/-)-4-(4,4-dimethyl-1-(methylsulfonyl)pyrrolidin-3-ylamino)-6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamideYield 35.1%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
90 °C

Procedure

A solution of (+/−)-6-bromo-4-((4,4-dimethyl-1-(methylsulfonyl)pyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (10 mg, 0.023 mmol) in 1,4-dioxane (0.5 mL), was added (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (3.25 mg, 0.023 mmol), palladium (II) acetate (0.52 mg, 2.32 μmol), X-Phos (2.22 mg, 4.7 μmol), potassium phosphate (0.04 mL, 0.08 mmol. The reaction vial was purged with nitrogen, sealed and heated at 90° C. overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (3.6 mg, 35% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.12 (s, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.63-7.56 (m, 3H), 6.84 (d, J=1.5 Hz, 1H), 4.50 (t, J=5.0 Hz, 1H), 4.32 (br. s., 1H), 3.97 (dd, J=10.9, 5.9 Hz, 1H), 3.83 (s, 3H), 3.44 (dd, J=10.9, 4.5 Hz, 1H), 3.39-3.33 (m, 2H), 2.97-2.80 (m, 3H), 2.43 (s, 3H), 1.27 (d, J=5.4 Hz, 6H). MS (ES+) m/z: 446.2 (M+H); LC retention time: 1.25 min (analytical HPLC Method I).

Workup

  1. customThe reaction
  2. customvial was purged with nitrogen
  3. customsealed
  4. customThe crude material was purified via preparative LC/MS with the following conditions
  5. customa 5-minute hold
  6. additionFractions containing the desired product
  7. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-1ce2b9525c2b4f769464970e8931ef14
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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