N,N-Dimethylglycine → 6-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

HRID 60422

Reaktionsgleichung

Reaktionsgleichung von HRID 60422
[OH:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.Br[C:39]1[CH:40]=[N:41][CH:42]=[C:43]([F:45])[CH:44]=1>O1CCOCC1.CC(=O)OCC.O.[Cu]I>[F:45][C:43]1[CH:44]=[C:39]([O:1][C:2]2[CH:24]=[N:23][C:5]3[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][O:16]4)[C:9](=[O:10])[C:4]=3[CH:3]=2)[CH:40]=[N:41][CH:42]=1

Komponenten

9

Edukt 4

HCID 673N,N-DimethylglycineHCID 10796Cesium carbonateHCID 8202063-Bromo-5-fluoropyridineHCID 1188754886-hydroxy-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione2×

Produkt 1

HCID 1188755406-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneAusbeute 38,9 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 962WaterLösungsmittelHCID 8857Ethyl AcetateLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
140 °C

Versuchsvorschrift

To a mixture of 6-hydroxy-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 36, step 2, 300 mg, 0.90 mmol), CuI (22.5 mg, 0.19 mmol), Cs2CO3 (583.5 mg, 1.79 mmol) and 2-(dimethylamino)acetic acid (46.5 mg, 0.45 mmol) in dioxane (20 mL) was added 3-bromo-5-fluoropyridine (394 mg, 2.24 mmol). The reaction was heated at 140° C. for 5 h followed by heating at 100° C. for 18 h, cooled to RT then diluted with EA (25 mL) and water (10 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 6-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (150 mg, 38.9% yield) as a white solid. LCMS: [MH+-THP] 347 and TR=1.482 min.

Aufarbeitung

  1. temperatureby heating at 100° C. for 18 h
  2. temperaturecooled to RT
  3. washThe organic layer was washed with water (20 mL) and brine (20 mL)
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated to a residue which
  6. customwas purified by chromatography
  7. washeluted with PE/EA (10:1 to 1:1)

Quellen und Nachweise

ORD-Eintrag
ord-5c5ba2ab3e134f108c041acd25c0f0b3
Quelldatensatz
uspto-grants-2016_09
Patentnummer
US09440972B2

Verknüpfte Notizen

Wird geladen…