Cesium carbonate → 4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-2-methyl-5-(2-methyl-1,3-thiazol-5-yl)pyrimidine

HRID 872062Notes

Reaction equation

HRID 872062 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.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:46]1[S:50][C:49]([CH3:51])=[N:48][CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+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:46]3[S:50][C:49]([CH3:51])=[N:48][CH:47]=3)=[CH:7][N:6]=[C:5]([CH3:8])[N:4]=2)=[N:15][CH:16]=1

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 132286635-Bromo-2-methyl-1,3-thiazoleHCID 710613855-bromo-4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidine

Product 1

HCID 714887054-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-2-methyl-5-(2-methyl-1,3-thiazol-5-yl)pyrimidine

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
120 °C

Procedure

A mixture of 5-bromo-4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-2-methylpyrimidine (MM3) (35 mg, 0.10 mmol), bis(pinacolato)diboron (27.9 mg, 0.11 mmol), potassium acetate (39 mg, 0.40 mmol) and PdCl2(dppf) (14.6 mg, 0.020 mmol) in dioxane (0.6 mL) under N2 was heated at 120° C. for 2 hours. A solution of 5-bromo-2-methyl-1,3-thiazole (26.7 mg, 0.15 mmol) in dioxane (0.2 mL) was added followed by aqueous cesium carbonate (2 M, 0.15 mL, 0.30 mmol). The resulting mixture was heated at 120° C. for 14 hours. The mixture was cooled to ambient temperature, diluted with EtOAc (5 mL), washed with sodium bicarbonate (1 mL) and brine (1 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 white, gummy solid. 1H NMR (500 MHz, DMSO): δ 8.83 (s, 1 H), 8.20 (s, 1 H), 8.14 (d, J=2.9 Hz, 1 H), 7.31-7.25 (m, 2 H), 4.56 (dd, J=11.2, 6.9 Hz, 1 H), 4.37 (dd, J=11.2, 7.6 Hz, 1 H), 3.78 (s, 3 H), 2.62 (s, 3 H), 2.54 (s, 3 H), 2.22 (dt, J=8.6, 4.6 Hz, 1 H), 1.78 (s, 1 H), 1.24-1.18 (m, 1 H), 1.11-1.05 (m, 1 H); HRMS m/z (M+H) 369.1386 found, 369.1380 required.

Workup

  1. temperatureThe resulting mixture was heated at 120° C. for 14 hours
  2. temperatureThe mixture was cooled to ambient temperature
  3. washwashed with sodium bicarbonate (1 mL) and brine (1 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. 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-84b8d71ba46c4cdcbac1e48df49d08dc
Source dataset
uspto-grants-2015_03
Patent number
US08975261B2

Reaction notes

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