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

HRID 718404Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 718404
O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][C:30]([O:34][CH3:35])([CH3:33])[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][C:30]([O:34][CH3:35])([CH3:33])[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 118307809Isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate

Produkt 1

HCID 118307887(S)-isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetateAusbeute 95 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 1140TolueneLösungsmittel

Reaktionsbedingungen

Temperatur
-15 °C

Versuchsvorschrift

The 1.55 mL of benzo[d][1,3,2]dioxaborole (870 mg, 7.25 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (1.55 g, 3.63 mmol) and 1.45 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (402 mg, 1.45 mmol) in toluene (30 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, diluted with EtOAc, and stirred for 30 min. The organic layer was washed with sat'd Na2CO3 solution, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-30% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate 1.48 g (95%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 5.89 (br. s, 1H), 4.95-4.92 (m, 1H), 3.78 (t, J=11.0 Hz, 1H), 3.53 (t, J=10.6 Hz, 1H), 3.37-3.35 (m, 1H), 3.25 (br. s, 1H), 3.14 (s, 3H), 2.52 (s, 3H), 2.37 (s, 3H), 1.75-1.69 (m, 2H), 1.64-1.52 (m, 2H), 1.15-1.16 (m, 6H). 1.07 (d, J=6.2 Hz, 3H). UPLC (M+H)=431.3.

Aufarbeitung

  1. custombefore being placed in the freezer overnight
  2. customThe reaction was quenched with 1M Na2CO3
  3. additiondiluted with EtOAc
  4. washThe organic layer was washed with sat'd Na2CO3 solution, brine
  5. dry with materialdried (MgSO4)
  6. additionThe crude product was charged (DCM)
  7. washto a 80 g ISCO silica gel cartridge and gradient elution (0-30% EtOAc/hexanes)

Quellen und Nachweise

ORD-Eintrag
ord-d4877fb51eb4400ab115ede00168b793
Quelldatensatz
uspto-grants-2015_11
Patentnummer
US09193720B2

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