Water → 5-[3-(cyanomethyl)-3-[4-(3,5-dimethyl-1H-pyrazol-4-yl)pyrazol-1-yl]azetidin-1-yl]-N-propan-2-ylpyrazine-2-carboxamide

HRID 1049145Notes

Reaction equation

HRID 1049145 reaction equation
[C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=[N:21]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].Br[C:35]1[C:36]([CH3:41])=[N:37][NH:38][C:39]=1[CH3:40].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:35]3[C:36]([CH3:41])=[N:37][NH:38][C:39]=3[CH3:40])[CH:22]=[N:21]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:16][CH:17]([CH3:18])[CH3:19])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]

Participants

7

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 769374-bromo-3,5-dimethyl-1H-pyrazoleHCID 1317359985-{3-(Cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide

Product 1

HCID 1177001435-[3-(cyanomethyl)-3-[4-(3,5-dimethyl-1H-pyrazol-4-yl)pyrazol-1-yl]azetidin-1-yl]-N-propan-2-ylpyrazine-2-carboxamideYield 42%

Reagents, catalysts & solvents 2

HCID 178439015HCID 178439015, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
53 °C

Procedure

A mixture of 5-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide (256 mg, 0.567 mmol, from Example 2, step 2), 4-bromo-3,5-dimethyl-1H-pyrazole (119 mg, 0.681 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (67 mg, 0.085 mmol) and cesium carbonate (550 mg, 1.7 mmol) in 1,4-dioxane (2 mL)/water (1 mL) was purged with nitrogen three times. The reaction was heated to 53° C. for 2 h. The mixture was diluted with EtOAc, washed with brine, concentrated. The resulting reside was purified first on silica gel (eluting with 0-100% EtOAc/hexanes followed by 10% methanol/dichloromethane), and then by prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.1 g, 40%). 1H NMR (500 MHz, DMSO-d6) δ 8.64 (1H, d, J=1.5 Hz), 8.12 (1H, s), 8.06 (1H, d, J=8.0 Hz), 7.96 (1H, d, J=1.0 Hz), 7.71 (1H, s), 4.72 (2H, d, J=9.5 Hz), 4.49 (1H, d, J=9.5 Hz), 4.08 (1H, m), 3.68 (2H, s), 2.22 (6H, s), 1.16 (6H, d, J=6.5 Hz) ppm. LCMS calculated for C21H26N9O (M+H)+: m/z=420.2. Found: 420.0.

Workup

  1. customwas purged with nitrogen three times
  2. additionThe mixture was diluted with EtOAc
  3. washwashed with brine
  4. concentrationconcentrated
  5. customThe resulting reside was purified first on silica gel (eluting with 0-100% EtOAc/hexanes followed by 10% methanol/dichloromethane)
  6. washby prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min)

Sources & evidence

ORD record
ord-476ef727f6c947c99c41e913dd818622
Source dataset
uspto-grants-2016_07
Patent number
US09382231B2

Reaction notes

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