Cesium carbonate → N-(6-((4R,6S)-2-benzamido-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-chloropicolinamide

HRID 930361Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 930361
CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[N:49]=[C:48]([C@@:50]2([CH:69]([F:71])[F:70])[CH2:55][C@@H:54]([C:56]([F:59])([F:58])[F:57])[O:53][C:52]([NH:60][C:61](=[O:68])[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[N:51]2)[C:47]([F:72])=[CH:46][CH:45]=1.[Cl:73][C:74]1[CH:75]=[CH:76][C:77]([C:80]([NH2:82])=[O:81])=[N:78][CH:79]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:61]([NH:60][C:52]1[O:53][C@H:54]([C:56]([F:59])([F:58])[F:57])[CH2:55][C@@:50]([C:48]2[N:49]=[C:44]([NH:82][C:80](=[O:81])[C:77]3[CH:76]=[CH:75][C:74]([Cl:73])=[CH:79][N:78]=3)[CH:45]=[CH:46][C:47]=2[F:72])([CH:69]([F:71])[F:70])[N:51]=1)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1

Komponenten

6

Edukt 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 218831585-Chloropyridine-2-carboxamideHCID 86732181N-((4R,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide

Produkt 1

HCID 86732182N-(6-((4R,6S)-2-benzamido-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-chloropicolinamideAusbeute 71,4 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysator

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

A round-bottomed flask was charged with Pd2(dba)3 (2.91 mg, 3.17 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (7.35 mg, 0.013 mmol), N-((4R,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (21 mg, 0.042 mmol), 5-chloropicolinamide (9.61 mg, 0.061 mmol), and cesium carbonate (34.5 mg, 0.106 mmol). The flask was evacuated under vacuum and then flushed with nitrogen. Dioxane (0.5 mL) was then added and the reaction was stirred in a 90° C. oil bath for 10 h. The reaction mixture was cooled to RT, filtered through celite and washed with EtOAc. The filtrate was concentrated and the residue was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide N-(6-((4R,6S)-2-benzamido-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-chloropicolinamide (17 mg, 0.030 mmol, 70.2% yield) as white solid. MS m/z=572, 574 M+, Calculated for C24H16ClF6N5O3: 571.86.

Aufarbeitung

  1. customThe flask was evacuated under vacuum
  2. customflushed with nitrogen
  3. additionDioxane (0.5 mL) was then added
  4. temperatureThe reaction mixture was cooled to RT
  5. filtrationfiltered through celite
  6. washwashed with EtOAc
  7. concentrationThe filtrate was concentrated
  8. customthe residue was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g)
  9. washeluting with a gradient of 0% to 30% EtOAc in hexane

Quellen und Nachweise

ORD-Eintrag
ord-20dc069f7f6848b8b013bc490e896eae
Quelldatensatz
uspto-grants-2016_03
Patentnummer
US09296734B2

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