Potassium Phosphate, Tribasic → HCID 68291653, compound

HRID 877813Notes

Reaction equation

HRID 877813 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C:15]([CH3:17])([CH3:16])[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]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=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>[C:23]([C:20]1([C:18]([N:13]2[CH2:14][C:15]([CH3:17])([CH3:16])[CH:11]([NH:10][C:9]3[C:4]4[N:5]([CH:28]=[C:2]([C:35]5[CH:34]=[CH:33][N:32]=[C:31]([O:30][CH3:29])[CH:36]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:25]([NH2:27])=[O:26])[CH2:12]2)=[O:19])[CH2:21][CH2:22]1)#[N:24]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23546919(2-Methoxypyridin-4-yl)boronic acidHCID 68292348HCID 68292348, compound

Product 1

HCID 68291653HCID 68291653, compoundYield 21.1%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

A solution of (S)-6-bromo-4-(1-(1-cyanocyclopropanecarbonyl)-4,4-dimethylpyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (10 mg, 0.022 mmol) in 1,4-Dioxane (0.5 mL), was added (2-methoxypyridin-4-yl)boronic acid (4.12 mg, 0.027 mmol), palladium (II) acetate (0.25 mg, 1.123 mmol), X-Phos (1.07 mg, 2.25 mmol) and potassium phosphate (2M, 0.04 mL, 0.08 mmol). The reaction vial was purged with nitrogen, sealed and heated at 100° 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 (2.2 mg, 17% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.43 (dd, J=5.4, 2.5 Hz, 1H), 8.23-8.09 (m, 1H), 7.99-7.93 (m, 1H), 7.90 (dd, J=10.4, 1.5 Hz, 1H), 7.61 (s, 2H), 7.17-7.08 (m, 1H), 6.86 (d, J=8.4 Hz, 1H), 4.12 (dd, J=12.9, 6.4 Hz, 1H), 3.96 (s, 3H), 3.95-3.87 (m, 1H), 3.64-3.55 (m, 1H), 3.50-3.44 (m, 1H), 3.01 (s, 1H), 2.88 (s, 1H), 1.75-1.53 (m, 4H), 1.35-1.24 (m, 6H). MS (ES+) m/z: 474.2 (M+H); LC retention time: 1.41 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-bf24f200a8d14b5f9cde04f39ee5d7e7
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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