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

HRID 718372Notes

Reaction equation

HRID 718372 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][C:25]([CH3:29])([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:30][C:31]1[CH:56]=[CH:55][C:34]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(=O)CN(C)CC(=O)O3)=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:56][CH:55]=3)=[CH:43][CH:42]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][C:25]([CH3:29])([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 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 118307891Isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-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 118307693(S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetateYield 82%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (1.0 g, 2.13 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (0.87 g, 2.434 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.175 g, 0.426 mmol) and 2M K3PO4 (7.99 mL, 15.98 mmol) in 1,4-Dioxane (200 mL) and Water (40.0 mL) was degassed for 10 min. Then, PdOAc2 (0.048 g, 0.213 mmol) was added, degassed for 5 min and mixture was heated at 80° C. for 3 h. After cooling to room temp, water was added and the mixture was extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered and concentrated the residue was then purified by Biotage (5-40% EtOAc/hexane) to afford (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (1.056 g, 82% yield) as white foam. 1H NMR (500 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 7.18-7.14 (m, 1H), 7.09-7.01 (m, 3H), 6.99-6.93 (m, 2H), 6.07 (br. s., 1H), 5.10 (spt, J=6.2 Hz, 1H), 4.28-4.19 (m, 2H), 3.21 (d, J=12.0 Hz, 1H), 3.13 (t, J=6.9 Hz, 2H), 2.87 (t, J=12.1 Hz, 1H), 2.60 (s, 3H), 2.28 (d, J=12.8 Hz, 1H), 2.20 (s, 3H), 2.10-2.01 (m, 1H), 1.60-1.52 (m, 1H), 1.42-1.34 (m, 1H), 1.25 (d, J=6.3 Hz, 3H), 1.23 (d, J=6.3 Hz, 3H), 1.20 (s, 9H), 1.08 (d, J=12.3 Hz, 1H), 0.91 (s, 3H), 0.66 (s, 3H). 1H of piperidine was not resolved. LCMS (M+H)=606.5.

Workup

  1. customwas degassed for 10 min
  2. additionThen, PdOAc2 (0.048 g, 0.213 mmol) was added
  3. customdegassed for 5 min
  4. temperatureAfter cooling to room temp
  5. additionwater was added
  6. extractionthe mixture was extracted with ethyl acetate
  7. washwashed with brine
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated the residue
  11. customwas then purified by Biotage (5-40% EtOAc/hexane)

Sources & evidence

ORD record
ord-69e5637954374b21ac6a1e33c5ea375e
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

Loading…