Potassium Phosphate, Tribasic → 2-[4-(2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl]ethanol

HRID 872053Notes

Reaction equation

HRID 872053 reaction equation
Br[C:2]1[C:3]([O:12][CH2:13][C@H:14]2[CH2:16][C@@H:15]2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=2)=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH2:39][OH:40])[CH:37]=2)O1.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]>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:15]2[CH2:16][C@@H:14]2[CH2:13][O:12][C:3]2[C:2]([C:33]3[CH:34]=[N:35][N:36]([CH2:38][CH2:39][OH:40])[CH:37]=3)=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][N:9]=3)[N:4]=2)=[N:18][CH:19]=1

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 457888552-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olHCID 1176891283-bromo-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-1,5-naphthyridine

Product 1

HCID 710627192-[4-(2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl]ethanol

Reagents, catalysts & solvents 4

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

Conditions

Temperature
100 °C

Procedure

A mixture of 3-bromo-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-1,5-naphthyridine (LL2) (130 mg, 0.3 mmol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanol (97 mg, 0.4 mmol), tripotassium phosphate (133 mg, 0.6 mmol), S-Phos (12.8 mg, 0.03 mmol), and Pd(OAc)2 (3.5 mg, 0.02 mmol) in THF (1.3 mL) and water (0.3 mL) was heated at 100° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (10 mL), washed with sodium bicarbonate (2 mL) and brine (2 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-60% acetonitrile in water with 0.1% TFA modifier) to afford the title compound as a white solid. 1H NMR (500 MHz, DMSO): δ 8.78 (d, J=4.1 Hz, 1 H), 8.55 (s, 1 H), 8.35 (s, 1 H), 8.22 (s, 1 H), 8.15-8.10 (m, 2 H), 7.61 (dd, J=8.4, 4.3 Hz, 1 H), 7.29 (s, 2 H), 4.94-4.91 (m, 1 H), 4.69-4.65 (m, 1 H), 4.47 (d, J=9.5 Hz, 1 H), 4.14-4.09 (m, 2 H), 3.79 (s, 3 H), 3.73 (d, J=6.5 Hz, 2 H), 2.31-2.27 (m, 1 H), 1.90 (s, 1 H), 1.26-1.22 (m, 1 H), 1.14 (s, 1H); HRMS m/z (M+H) 418.1871 found, 418.1874 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 in vacuo
  6. customThe resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-60% acetonitrile in water with 0.1% TFA modifier)

Sources & evidence

ORD record
ord-eacf8e856ac842469f174070f2bd5b40
Source dataset
uspto-grants-2015_03
Patent number
US08975261B2

Reaction notes

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