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

HRID 718390

Reaktionsgleichung

Reaktionsgleichung von HRID 718390
O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[O:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[N:34]=3)[CH2:29][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[CH2:32][CH2:31][CH:30]([C:33]3[O:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[N:34]=3)[CH2:29][CH2:28]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 118307821Isopropyl 2-(5-bromo-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate

Produkt 1

HCID 118307876(S)-isopropyl 2-(5-bromo-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetateAusbeute 58 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 1140TolueneLösungsmittel

Reaktionsbedingungen

Temperatur
-15 °C

Versuchsvorschrift

The 1.6 mL of benzo[d][1,3,2]dioxaborole (416 mg, 3.47 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (950 mg, 1.93 mmol) and 0.6 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (160 mg, 0.58 mmol) in toluene (20 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 filtered, and 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-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate 550 mg (58%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 5.98/5.87 (s, 1H), 4.95-4.92 (m, 1H), 3.75-3.71 (m, 1H), 3.08-3.01 (m, 3H), 2.88-2.86 (m, 1H), 2.54 (s, 3H), 2.39 (s, 3H), 2.06-2.00 (m, 3H), 1.90-1.83 (m, 2H), 1.27 (d, J=6.6 Hz, 6H), 1.14 (d, J=5.9 Hz, 3H), 1.08 (d, J=5.9 Hz, 3H). UPLC (M+H)=497.2.

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. filtrationThe crude product was filtered
  7. additioncharged (DCM)
  8. washto a 40 g ISCO silica gel cartridge and gradient elution (5-60% EtOAc/hexanes)

Quellen und Nachweise

ORD-Eintrag
ord-bd635da1f0314e1b995287f0c2c5dcfd
Quelldatensatz
uspto-grants-2015_11
Patentnummer
US09193720B2

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