Potassium Carbonate → tert-Butyl 4-(7-fluoro-2-(4-hydroxy-1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-2,3-dihydrobenzofuran-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

HRID 1025495Notes

Reaction equation

HRID 1025495 reaction equation
Br[C:2]1[CH:3]=[C:4]([F:27])[C:5]2[O:9][CH:8]([C:10]3([OH:25])[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[CH2:7][C:6]=2[CH:26]=1.CC1(C)C(C)(C)OB([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:4]1[C:5]2[O:9][CH:8]([C:10]3([OH:25])[CH2:11][CH2:12][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:14][CH2:15]3)[CH2:7][C:6]=2[CH:26]=[C:2]([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)[CH:3]=1

Participants

8

Reactant 3

HCID 11430Potassium CarbonateHCID 4642098Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 674657744-(5-Bromo-7-fluoro-2,3-dihydrobenzofuran-2-yl)-1-(5-propylpyrimidin-2-yl)piperidin-4-ol

Product 1

HCID 67468836tert-Butyl 4-(7-fluoro-2-(4-hydroxy-1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-2,3-dihydrobenzofuran-5-yl)-5,6-dihydropyridine-1(2H)-carboxylateYield 103.4%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolventHCID 21584169Diethylether ethylacetateSolvent

Conditions

Temperature
100 °C

Procedure

To a degassed solution of 4-(5-bromo-7-fluoro-2,3-dihydrobenzofuran-2-yl)-1-(5-propylpyrimidin-2-yl)piperidin-4-ol (0.122 g, 0.280 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.112 g, 0.363 mmol), and K2CO3 (97 mg, 0.699 mmol) in dioxane (2.9 mL) and H2O (1 mL) was added Pd(Ph3P)4 (16 mg, 0.014 mmol). Upon completion of addition, the reaction mixture was stirred at 100° C. for 15 hour under argon. At the conclusion of this period, the reaction mixture was cooled to room temperature and then diluted with EtOAc/Et2O (5 mL, 1:1 v/v). The organic layer was washed with aqueous NaHCO3 (saturated, 6 mL) and aqueous NaCl (saturated, 6 mL), dried (Na2SO4), filtered, and then concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 60% EtOAc) to afford Compound 1I as a light yellow solid (0.156 g, 97% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.15 (s, 2 H), 6.96 (s, 1 H), 6.91 (d, J=12.1 Hz, 1 H), 5.90 (br. s., 1 H), 4.67 (t, J=9.1 Hz, 1 H), 4.50-4.63 (m, 2 H), 4.03 (d, J=2.8 Hz, 2 H), 3.60 (t, J=5.6 Hz, 2 H), 3.26-3.40 (m, 3 H), 3.11 (dd, J=15.7, 9.1 Hz, 1 H), 2.33-2.48 (m, 4H), 1.92-2.00 (m, 2 H), 1.68-1.81 (m, 1 H), 1.52-1.67 (m, 4 H), 1.44-1.52 (m, 9H), 0.90-0.97 (t, J=7.3 Hz, 3 H). LC/MS (m/z)=539 (M+H)+.

Workup

  1. additionUpon completion of addition
  2. temperatureAt the conclusion of this period, the reaction mixture was cooled to room temperature
  3. washThe organic layer was washed with aqueous NaHCO3 (saturated, 6 mL) and aqueous NaCl (saturated, 6 mL)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto yield a residue
  8. customThe residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 60% EtOAc)

Sources & evidence

ORD record
ord-b2dc29e797064332939a60e902b49b54
Source dataset
uspto-grants-2014_05
Patent number
US08729084B2

Reaction notes

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