Potassium Phosphate, Tribasic → HCID 118307702, compound

HRID 718420Notes

Reaction equation

HRID 718420 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][C:25]([F: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.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: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]([F: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

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 118307738HCID 118307738, compoundHCID 1317341662-(4-(4-Fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

Product 1

HCID 118307702HCID 118307702, compoundYield 78%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
90 °C

Procedure

The diacetoxypalladium (4.0 mg, 0.018 mmol) was added to a argon purged and degassed solution of (S)-isopropyl 2-(5-bromo-4-(4-fluoro-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (85 mg, 0.18 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (73.3 mg, 0.197 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (14.7 mg, 0.036 mmol), and potassium phosphate tribasic (286 mg, 1.34 mmol) in dioxane (2 mL) and water (0.4 mL) and 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 (0-40% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(4-(4-fluoro-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 85.1 mg (78%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.37 (m, 2H), 7.22-7.20 (m, 1H), 7.14 (t, J=9.2 Hz, 2H), 7.02-7.00 (m, 3H), 5.94 (br. s, 1H), 4.96-4.93 (m, 1H), 4.22 (t, J=7.3 Hz, 2H), 3.41-3.39 (m, 4H), 3.06 (t, J=6.6 Hz, 2H), 2.47 (br. s, 3H), 2.05 (s, 3H), 1.69-1.43 (m, 4H), 1.24 (br. s, 3H), 1.18 (d, J=6.2 Hz, 3H), 1.13 (br. s, 12H). UPLC (M+H)=609.4.

Workup

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

Sources & evidence

ORD record
ord-6196314974e94a0a8be7031d7964a263
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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