Potassium Phosphate, Tribasic → 4-((3R,4S)-4-methoxy-1-(methylsulfonyl)pyrrolidin-3-ylamino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877825Notes

Reaction equation

HRID 877825 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([O:16][CH3:17])[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][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=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>[CH3:17][O:16][C@H:15]1[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][C@H:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:25]=[C:2]([C:31]3[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:22]([NH2:24])=[O:23]

Participants

6

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2734368(6-Methoxypyridin-3-yl)boronic acidHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 682910436-bromo-4-(((3R,4S)-4-methoxy-1-(methylsulfonyl)pyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide

Product 1

HCID 682914664-((3R,4S)-4-methoxy-1-(methylsulfonyl)pyrrolidin-3-ylamino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamideYield 37.8%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of 6-bromo-4-(((3R,4S)-4-methoxy-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 (6-methoxypyridin-3-yl)boronic acid (3.54 mg, 0.023 mmol), X-Phos (0.85 mg, 1.16 μmol) and potassium phosphate (2M, 0.040 mL, 0.081 mmol). The mixture was heated at 100° C. for 3 h. 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 (4.0 mg, 37% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.41 (d, J=2.0 Hz, 1H), 8.21-8.10 (m, 1H), 7.96-7.90 (m, 1H), 7.89-7.85 (m, 1H), 7.59 (s, 2H), 7.16-6.99 (m, 1H), 6.88-6.79 (m, 1H), 5.13-4.90 (m, 1H), 4.12 (br. s., 1H), 4.00-3.90 (m, 4H), 3.74-3.67 (m, 1H), 3.58 (dd, J=11.6, 2.2 Hz, 1H), 3.50 (br. s., 3H), 3.42-3.34 (m, 1H), 2.90 (s, 3H), 2.64 (s, 1H); MS (ES+) m/z: 461.2 (M+H); LC retention time: 2.09 min (analytical HPLC Method H).

Workup

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

Sources & evidence

ORD record
ord-3d341b7773c94870ad219a34a61a69de
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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