Potassium Phosphate, Tribasic → 4-((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-ylamino)-6-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877823Notes

Reaction equation

HRID 877823 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]([C:18]([C:20]4([C:23]#[N:24])[CH2:22][CH2:21]4)=[O:19])[CH2:12]3)=[C:8]([C:25]([NH2:27])=[O:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[C:23]([C:20]1([C:18]([N:13]2[CH2:14][C@H:15]([O:16][CH3:17])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:28]=[C:2]([C:34]5[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:25]([NH2:27])=[O:26])[CH2:12]2)=[O:19])[CH2:22][CH2:21]1)#[N:24]

Participants

5

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 201262(4-Methoxyphenyl)boronic acidHCID 682909856-bromo-4-(((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide

Product 1

HCID 682914604-((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-ylamino)-6-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazine-3-carboxamideYield 42.1%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

A solution of 6-bromo-4-(((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.045 mmol) in 1,4-dioxane (0.3 mL), was added (4-methoxyphenyl)boronic acid (10.2 mg, 0.07 mmol), [1,1′-(diphenylphosphino)ferrocene]-dichloropalladium (II) (3.27 mg, 4.5 μmol), potassium phosphate (0.08 mL, 0.16 mmol). The reaction vial was purged with N2, sealed and heated at 85° 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 (9 mg 42% yield). 1H NMR (400 MHz, METHANOL-d4) δ 8.19 (d, J=7.0 Hz, 1H), 7.95 (d, J=7.0 Hz, 1H), 7.72-7.65 (m, 2H), 7.28 (d, J=14.5 Hz, 1H), 7.02-6.95 (m, 2H), 5.23-5.11 (m, 1H), 4.57 (dd, J=10.1, 7.0 Hz, 1H), 4.32-4.24 (m, 1H), 4.24-4.16 (m, 1H), 4.14-4.06 (m, 1H), 3.94-3.88 (m, 1H), 3.86 (s, 3H), 3.78-3.71 (m, 1H), 3.60-3.53 (m, 2H), 3.40 (s, 3H), 1.79-1.52 (m, 3H), 1.45-1.35 (m, 1H); MS (ES+) m/z: 475.2 (M+H); LC retention time: 3.49 min (analytical HPLC Method B).

Workup

  1. customThe reaction
  2. customvial was purged with N2
  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-7710a07bc5b44a38a80290e036f6b374
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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