Sodium Carbonate → (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)acetate

HRID 718389Notes

Reaction equation

HRID 718389 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[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:34][C:35]1[CH:52]=[CH:51][C:38]([CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:45]2[CH:44]=[CH:43][C:42]([O:41][CH2:40][CH2:39][C:38]3[CH:37]=[CH:36][C:35]([F:34])=[CH:52][CH:51]=3)=[CH:47][CH:46]=2)[C:3]=1[N:22]1[CH2:23][CH2:24][CH:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:26][CH2:27]1)[C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])([CH3:20])([CH3:19])[CH3:21]

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 118307820(S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetateHCID 123643410(4-(4-Fluorophenethoxy)phenyl)boronic acid

Product 1

HCID 118307870(S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)acetateYield 52%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

The Pd(Ph3P)4 (33.5 mg, 0.029 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.29 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (83 mg, 0.32 mmol), and sodium carbonate (184 mg, 1.74 mmol) in dioxane (4.5 mL) and water (0.9 mL) and stirred in a screw-capped pressure vessel for 4 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2SO4). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-65% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)acetate 98 mg (52%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.42-7.39 (m, 2H), 7.29-7.23 (m, 3H), 7.17-7.13 (m, 5H), 7.06-7.02 (m, 3H), 6.07 (s, 1H), 4.98-4.93 (m, 1H), 4.25 (t, J=7.0 Hz, 2H), 3.08 (t, J=6.2 Hz, 2H), 2.78-2.72 (m, 1H), 2.62-2.58 (m, 1H), 2.47 (br. s, 1H), 2.46 (s, 3H), 2.28 (br. s, 1H), 2.05 (s, 3H), 1.94-1.90 (m, 1H), 1.77-1.66 (m, 2H), 1.57 (br. s, 2H), 1.18 (br. s, 12H), 1.14 (d, J=5.5 Hz, 3H). UPLC (M+H)=653.5.

Workup

  1. custompurged
  2. temperatureto cool
  3. washthe organic layer was washed with brine
  4. dry with materialdried (Na2SO4)
  5. additionThe crude product was charged (DCM)
  6. washto a 24 g ISCO silica gel cartridge and gradient elution (5-65% EtOAc/hexanes)

Sources & evidence

ORD record
ord-5429e501bc0246ca8dd028709db948d4
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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