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

HRID 718415Notes

Reaction equation

HRID 718415 reaction equation
O1C2C=CC=CC=2OB1.[CH2:10]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:28]([Br:29])=[C:27]([CH3:30])[N:26]=[C:25]([CH3:31])[C:24]=2[C:32](=[O:39])[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[CH2:10]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:28]([Br:29])=[C:27]([CH3:30])[N:26]=[C:25]([CH3:31])[C:24]=2[C@H:32]([OH:39])[C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1

Participants

5

Reactant 3

HCID 67506CatecholboraneHCID 9838490(R)-2-Methyl-CBS-oxazaborolidineHCID 118307762Isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-oxoacetate

Product 1

HCID 118307743(S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
-15 °C

Procedure

The 1.3 mL of benzo[d][1,3,2]dioxaborole (709 mg, 5.91 mmol) was added to a nitrogen purged solution of isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-oxoacetate (1.4 g, 2.96 mmol) and 1.2 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (328 mg, 1.18 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 (0-50% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate as a mixture of diastereomers 1.4 g (100%). 1H NMR (500 MHz, DMSO-d6) δ 7.30-7.27 (m, 2H), 7.19-7.18 (m, 3H), 5.95/5.93 (s, 1H), 4.97-4.93 (m, 1H), 3.53 (t, J=11.4 Hz, 1H), 3.40-3.38 (m, 1H), 3.31 (t, J=11.7 Hz, 1H), 3.25 (br. s, 1H), 2.87 (d, J=10.3 Hz, 1H), 2.77 (d, J=10.6 Hz, 1H), 2.55/2.54 (s, 3H), 2.38 (s, 3H), 1.60-1.52 (m, 3H), 1.38-1.63 (m, 2H), 1.14 (d, J=5.9 Hz, 3H), 1.05 (d, J=5.9 Hz, 3H). UPLC (M+H)=477.1.

Workup

  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 (0-50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-29f2c2e00a1d4bbabff7d23ae7316d08
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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