Potassium Phosphate, Tribasic → (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-({5-[5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl]-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one

HRID 531277

Reaktionsgleichung

Reaktionsgleichung von HRID 531277
[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:33][CH3:34])=[N:28][CH:29]=[C:30](Cl)[CH:31]=4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:43][C:44]1[C:48](B2OC(C)(C)C(C)(C)O2)=[C:47]([CH3:58])[NH:46][N:45]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[Na+].O.C(OCC)(=O)C>[Pd](Cl)Cl.O.C1COCC1>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:33][CH3:34])=[N:28][CH:29]=[C:30]([C:48]5[C:44]([CH3:43])=[N:45][NH:46][C:47]=5[CH3:58])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Komponenten

8

Edukt 4

HCID 62657Potassium Phosphate, TribasicHCID 162177133,5-Dimethylpyrazole-4-boronic acid, pinacol esterHCID 90009178(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-oneHCID 131718255Brine ethyl acetate

Produkt 1

HCID 72192733(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-({5-[5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl]-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 24290Palladium ChlorideKatalysatorHCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 1, 0.2 g, 0.323 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0717 g, 0.323 mmol), potassium phosphate (0.103 g, 0.484 mmol), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (XPHOS Biphenyl Precatalyst) (0.0254 g, 0.032 mmol), THF (2.40 mL), and H2O (0.80 mL) were sealed in a microwave vessel and subject to microwave irradiation at 120 C for 1.5 hours. The resulting reaction mixture was worked up with brine/ethyl acetate. The combined extracts were dried over Na2SO4, filtered and evaporated to afford a dark mixture. This dark mixture was purified by flash chromatography (SiO2, ISCO, RediSep 12 g Cartridge). The column was eluted by an ethyl acetate/hexanes mixture (0% to 50% ethyl acetate). Related fractions were pooled and evaporated under reduced pressure to afford an off-white solid of 113 mg as the titled compound. LCMS (M+H)+: 680.4. 1H NMR (CDCl3, 500 MHz): δ 8.19-8.11 (m, 2H), 7.85 (s, 1H), 7.73 (s, 2H), 7.42-7.36 (m, 1H), 5.72-5.66 (d, J=8.5 Hz, 1H), 5.53 (s, 1H), 5.41 (s, 1H), 4.72-4.66 (m, 1H), 4.54-4.40 (m, 2H), 4.38-4.26 (m, 3H), 4.00 (s, 3H), 2.51 (m, 1H), 2.42 (s, 3H), 2.30-2.10 (m, 4H), 0.52 (d, J=6.5 Hz, 3H). RTA IC50: 5 nM.

Aufarbeitung

  1. customsubject to microwave irradiation at 120 C for 1.5 hours
  2. customThe resulting reaction mixture
  3. dry with materialThe combined extracts were dried over Na2SO4
  4. filtrationfiltered
  5. customevaporated
  6. customto afford a dark mixture
  7. customThis dark mixture was purified by flash chromatography (SiO2, ISCO, RediSep 12 g Cartridge)
  8. washThe column was eluted by an ethyl acetate/hexanes mixture (0% to 50% ethyl acetate)
  9. customevaporated under reduced pressure

Quellen und Nachweise

ORD-Eintrag
ord-93e002c93c5045f693ea1fb14910251b
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09353101B2

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