(R)-2-Methyl-CBS-oxazaborolidine → Isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-1-YL)-2,6-dimethylpyridin-3-YL)-2-hydroxyacetate

HRID 718368Notes

Reaction equation

HRID 718368 reaction equation
[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C:10](=[O:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[B]1OC2C(=CC=CC=2)O1.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]

Participants

7

Reactant 3

HCID 9838490(R)-2-Methyl-CBS-oxazaborolidineHCID 118307729Isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetateHCID 131734165Catecholborane toluene

Product 1

HCID 118307841Isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-1-YL)-2,6-dimethylpyridin-3-YL)-2-hydroxyacetateYield 84%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolventHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
-30 °C

Procedure

To a yellow solution of isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (7.7 g, 18.72 mmol) and (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (7.5 mL, 7.50 mmol) in anhydrous toluene (100 mL) was added drop wise 50% catecholborane/toluene (6 mL, 28.0 mmol) over 5 min at −50° C. Then, the reaction mixture was slowly warmed to −30° C. over 1 h and left in refrigerator (−20° C.) for 3 days. Then, the reaction mixture was diluted with EtOAc (100 mL) and 20 mL of 1M Na2CO3, and vigorously stirred for 30 min. Aqueous layer separated and organic layer washed with sat'd Na2CO3 (2×25 mL) by vigorously stirring for 15 each time, then dried (MgSO4), filtered and concentrated to give crude product as light purple paste which was purified by flash chromatography using 0 to 40% EtOAc/hex to afford (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (6.7 g, 15.72 mmol, 84% yield) as colorless thick paste. 1H NMR (500 MHz, CDCl3) δ 5.85 (d, J=5.7 Hz, 1H), 5.59 (d, J=7.4 Hz, 1H), 5.08 (dt, J=12.5, 6.3 Hz, 1H), 3.98-3.88 (m, 1H), 3.88-3.78 (m, 1H), 2.76-2.68 (m, 1H), 2.67 (s, 3H), 2.64-2.58 (m, 1H), 2.57 (s, 3H), 1.73 (td, J=12.8, 4.8 Hz, 1H), 1.65-1.59 (m, 1H), 1.47-1.35 (m, 2H), 1.27 (d, J=6.3 Hz, 3H), 1.17 (d, J=6.1 Hz, 3H), 1.09 (s, 3H), 1.04 (s, 3H). LCMS (M+H)=414.6.

Workup

  1. customAqueous layer separated
  2. washorganic layer washed with sat'd Na2CO3 (2×25 mL)
  3. stirringby vigorously stirring for 15 each time
  4. dry with materialdried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give crude product as light purple paste which
  8. customwas purified by flash chromatography

Sources & evidence

ORD record
ord-b823606ad8ed41be9240912bf69ca6a1
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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