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

HRID 718392Notes

Reaction equation

HRID 718392 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N: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:36][C:37]1[CH:62]=[CH:61][C:40]([CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47](B3OC(=O)CN(C)CC(=O)O3)=[CH:46][CH:45]=2)=[CH:39][CH:38]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C(O[Pd]OC(=O)C)(=O)C>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:47]2[CH:46]=[CH:45][C:44]([O:43][CH2:42][CH2:41][C:40]3[CH:39]=[CH:38][C:37]([F:36])=[CH:62][CH:61]=3)=[CH:49][CH:48]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=2)[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:20])([CH3:21])[CH3:19]

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 118307888(S)-isopropyl 2-(5-bromo-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-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 118307752(S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetateYield 18.4%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

The diacetoxypalladium (6.11 mg, 0.027 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.272 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (111 mg, 0.299 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (22.30 mg, 0.054 mmol), and potassium phosphate tribasic (432 mg, 2.040 mmol) in dioxane (4.5 mL) and water (0.9 mL) and stirred in a screw-capped pressure vessel for 4 h at 80° 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 (5-85% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate 34.3 mg (18.4%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.41-7.39 (m, 2H), 7.24-7.22 (m, 1H), 7.17-7.13 (m, 2H), 7.03 (br. s, 2H), 6.96-6.94/6.87-6.86/6.80-6.78 (series m, 1H), 5.98 (br. s, 1H), 4.95 (br. s, 1H), 4.24 (t, J=6.2 Hz, 2H), 3.99-3.96 (m, 1H), 3.08 (t, J=6.2 Hz, 2H), 3.02-2.98 (m, 1H), 2.77-2.70 (m, 1H), 2.64-2.58 (m, 1H), 2.46 (s, 3H), 2.31-2.28 (m, 1H), 2.05 (s, 3H), 2.01-1.99 (m, 1H), 1.92-1.88 (m, 1H), 1.80 (br. s, 1H), 1.62-1.47 (m, 2H), 1.23-1.17 (m, 12H), 1.14 (s, 9H). UPLC (M+H)=687.5.

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 (5-85% EtOAc/hexanes)

Sources & evidence

ORD record
ord-b2ca6e1ca33c4efa9f2b3c059f38ffd7
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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