Potassium Phosphate, Tribasic → 4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine

HRID 872056Notes

Reaction equation

HRID 872056 reaction equation
Br[C:2]1[C:3]([O:9][CH2:10][C@H:11]2[CH2:13][C@@H:12]2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]2[CH2:13][C@@H:11]2[CH2:10][O:9][C:3]2[C:2]([C:26]3[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=3)=[CH:7][N:6]=[C:5]([CH3:8])[N:4]=2)=[N:15][CH:16]=1

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 710613855-bromo-4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidine

Product 1

HCID 710611064-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 5-bromo-4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-2-methylpyrimidine (MM3) (400 mg, 1.1 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (420 mg, 2.0 mmol), tripotassium phosphate (600 mg, 2.8 mmol), S-Phos (46 mg, 0.1 mmol), and Pd(OAc)2 (12.6 mg, 0.6 mmol) in THF (4.8 mL) and water (0.8 mL) was heated at 100° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and then diluted with EtOAc (10 mL), washed with sodium bicarbonate (2 mL) and brine (2 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-45% acetonitrile in water with 0.1% TFA modifier) to afford the title compound as a colorless gum. 1H NMR (500 MHz, DMSO): δ 8.73 (s, 1 H), 8.14 (s, 1 H), 8.11 (s, 1 H), 7.97 (s, 1 H), 7.31-7.24 (m, 2 H), 4.54 (dd, J=11.2, 6.8 Hz, 1 H), 4.33 (dd, J=11.3, 7.7 Hz, 1 H), 3.82 (s, 3 H), 3.78 (s, 3 H), 2.50 (s, 3 H), 2.22 (dd, J=8.6, 4.7 Hz, 1 H), 1.79 (s, 1 H), 1.22-1.17 (m, 1 H), 1.10-1.05 (m, 1 H); HRMS m/z (M+H) 352.1761 found, 352.1768 required.

Workup

  1. temperatureto cool to room temperature
  2. washwashed with sodium bicarbonate (2 mL) and brine (2 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-45% acetonitrile in water with 0.1% TFA modifier)

Sources & evidence

ORD record
ord-7bca30b7b88e4861bfbce0dc95dc9fe2
Source dataset
uspto-grants-2015_03
Patent number
US08975261B2

Reaction notes

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