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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 1025495
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1025495
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
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

8

Edukt 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

Produkt 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)-carboxylate
Ausbeute 103,4 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittelHCID 21584169Diethylether ethylacetateLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

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)+.

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-b2dc29e797064332939a60e902b49b54
Quelldatensatz
uspto-grants-2014_05
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08729084B2

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