Potassium Phosphate, Tribasic → HCID 68291383, compound

HRID 877801Notes

Reaction equation

HRID 877801 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][F: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.[CH2:26]([N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1)[CH3:27].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:26]([N:28]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9]([NH:10][C@H:11]4[C@@H:15]([CH2:16][F:17])[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12]4)=[C:8]([C:22]([NH2:24])=[O:23])[CH:7]=[N:6][N:5]3[CH:25]=2)[CH:30]=[N:29]1)[CH3:27]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 113790451-Ethyl-1H-pyrazole-4-boronic acid, pinacol esterHCID 68291868HCID 68291868, compound

Product 1

HCID 68291383HCID 68291383, compoundYield 48.7%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Procedure

A degassed solution of 6-bromo-4-(((3S,4S)-4-(fluoromethyl)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (50 mg, 0.115 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (38.4 mg, 0.173 mmol), 2-(Dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (5.49 mg, 0.012 mmol), Pd(OAc)2 (1.292 mg, 5.76 μmol) and 2 M aq. potassium phosphate solution (0.173 mL, 0.345 mmol) in DMF (0.5 mL) was heated to 105° C. for 2 hrs. The crude reaction mixture 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 (25.2 mg, 48% yield). 1H NMR (500 MHz, 1:1, Chloroform-d3 & METHANOL-d4) δ 8.14 (s, 1H), 7.87 (s, 1H), 7.79 (d, J=1.5 Hz, 1H), 7.76 (s, 1H), 7.00 (d, J=1.5 Hz, 1H), 5.17-5.10 (m, 1H), 4.71-4.64 (m, 1H), 4.42 (s, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.90-3.74 (m, 2H), 3.59-3.45 (m, 2H), 3.13-3.02 (m, 1H), 2.90 (s, 3H), 1.52 (t, J=7.4 Hz, 3H). MS (ES+) m/z: 450.2 (M+H); HPLC: 99%, retention time: 1.739 min (analytical HPLC Method F).

Workup

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

Sources & evidence

ORD record
ord-9159a0bd808249e9a3fe0a8008f2f349
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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