Catecholborane → (S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate

HRID 718377

Reaktionsgleichung

Reaktionsgleichung von HRID 718377
O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:28][C:29]([F:32])([F:31])[CH2:30]2)=[C:13]([C@H:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]

Komponenten

5

Edukt 3

HCID 67506CatecholboraneHCID 9838490(R)-2-Methyl-CBS-oxazaborolidineHCID 118307859Isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate

Produkt 1

HCID 118307708(S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetateAusbeute 51,4 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 1140TolueneLösungsmittel

Reaktionsbedingungen

Temperatur
-15 °C

Versuchsvorschrift

The 0.33 mL of benzo[d][1,3,2]dioxaborole (166 mg, 1.38 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (360 mg, 0.920 mmol) and 0.28 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (77 mg, 0.28 mmol) in toluene (10 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3 (5 mL), diluted with EtOAc, and stirred for 20 min. The organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (5-60% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate 186 mg (51%). 1H NMR (500 MHz, DMSO-d6) δ 5.24 (s, 1H), 4.97-4.94 (m, 1H), 4.74-4.71 (m, 2H), 4.54-4.51 (m, 2H), 2.50 (s, 3H), 2.33 (s, 3H), 1.19 (d, J=5.9 Hz, 3H), 1.13 (d, J=5.9 Hz, 3H). LCMS (M+H)=395.1.

Aufarbeitung

  1. custombefore being placed in the freezer overnight
  2. customThe reaction was quenched with 1M Na2CO3 (5 mL)
  3. additiondiluted with EtOAc
  4. washThe organic layer was washed with brine
  5. dry with materialdried (MgSO4)
  6. additionThe crude product was charged (DCM)
  7. washto a 40 g ISCO silica gel cartridge and gradient elution (5-60% EtOAc/hexanes)

Quellen und Nachweise

ORD-Eintrag
ord-7e0fdd39bb3249319f7a843a6e863d90
Quelldatensatz
uspto-grants-2015_11
Patentnummer
US09193720B2

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