Potassium Phosphate, Tribasic → (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate

HRID 718406Notes

Reaction equation

HRID 718406 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][C:25]([O:29][CH3:30])([CH3:28])[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:31][C:32]1[CH:57]=[CH:56][C:35]([CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42](B3OC(=O)CN(C)CC(=O)O3)=[CH:41][CH:40]=2)=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:42]2[CH:41]=[CH:40][C:39]([O:38][CH2:37][CH2:36][C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:57][CH:56]=3)=[CH:44][CH:43]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][C:25]([O:29][CH3:30])([CH3:28])[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 118307854(S)-isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetateHCID 1317341662-(4-(4-Fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

Product 1

HCID 118307837(S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetateYield 78.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

PD(Ph3P)4 (143 mg, 0.124 mmol) was added to an argon-degassed solution of (S)-isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (300 mg, 0.618 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (177 mg, 0.68 mmol), potassium phosphate tribasic (984 mg, 4.63 mmol) in dioxane (5 ml) and water (1 ml) stirred in a screw-capped pressure vessel for 16 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and 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 (0-50% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate 300 mg (78%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.39-7.37 (m, 2H), 7.21-7.12 (m, 3H), 7.04-7.00 (m, 3H), 5.98 (br. s, 1H), 4.96-4.93 (m, 1H), 4.24-4.21 (m, 2H), 3.42-3.40 (m, 2H), 3.26-3.21 (m, 1H), 3.07-3.05 (m, 2H), 2.90-2.86 (m, 1H), 2.81 (s, 3H), 2.44 (s, 3H), 2.05 (s, 3H), 1.53-1.42 (m, 2H), 1.33-1.25 (m, 2H), 1.18 (d, J=6.2 Hz, 3H), 1.14-1.12 (m, 12H), 1.00/0.81 (s, 3H). UPLC (M+H)=621.6.

Workup

  1. temperatureto cool
  2. washthe organic layer was washed with brine
  3. dry with materialdried (MgSO4)
  4. additionThe crude product was charged (DCM)
  5. washto a 40 g ISCO silica gel cartridge and gradient elution (0-50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-af395a80c3664f56a38ac3b9c2d9ea8e
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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