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

HRID 718410Notes

Reaction equation

HRID 718410 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][C:25]([C:29]#[N: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.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: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]([C:29]#[N:30])([CH3:28])[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])([CH3:20])([CH3:19])[CH3:21]

Participants

8

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 118307757(S)-isopropyl 2-(5-bromo-4-(4-cyano-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 118307880(S)-isopropyl 2-(tert-butoxy)-2-(4-(4-cyano-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetateYield 76%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
90 °C

Procedure

Pd(Ph3P)4 (144 mg, 0.125 mmol) was added to an argon-degassed solution (S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (300 mg, 0.624 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (179 mg, 0.687 mmol), potassium phosphate tribasic (994 mg, 4.68 mmol) in dioxane (4 ml) and water (0.8 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 (0-70% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(4-(4-cyano-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 291 mg (76%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.38-7.3 (m, 2H), 7.19 (br. s, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.08-7.06 (m, 1H), 7.02-7.00 (m, 2H), 5.91 (br. s, 1H), 4.94 (br. s, 1H), 4.28-4.23 (m, 1H), 4.19-4.15 (m, 1H), 3.44-3.40 (m, 4H), 3.05 (t, J=6.2 Hz, 2H), 2.45 (s, 3H), 2.06 (s, 3H), 1.80 (br. s, 1H), 1.69 (br. s, 1H), 1.55 (br. s, 1H), 1.34-1.32 (m, 1H), 1.29 (s, 3H), 1.18 (d, J=6.2 Hz, 3H), 1.15-1.1 (m, 12H). UPLC (M+H)=616.6.

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 (0-70% EtOAc/hexanes)

Sources & evidence

ORD record
ord-1c2f6d0e3e3745d1a45eef5a38b7d9b8
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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