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

HRID 718382Notes

Reaction equation

HRID 718382 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([CH3:27])([CH3:26])[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:28][C:29]1[CH:46]=[CH:45][C:32]([CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[CH:31][CH:30]=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:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:46][CH:45]=3)=[CH:41][CH:40]=2)[C:3]=1[N:22]1[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 118307812(S)-isopropyl 2-(5-bromo-4-(3,3-dimethylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetateHCID 123643410(4-(4-Fluorophenethoxy)phenyl)boronic acid

Product 1

HCID 118307700(S)-isopropyl 2-(tert-butoxy)-2-(4-(3,3-dimethylazetidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetateYield 67.5%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
90 °C

Procedure

The Pd(Ph3P)4 (57.6 mg, 0.05 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-4-(3,3-dimethylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (110 mg, 0.25 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (71.3 mg, 0.27 mmol), and sodium carbonate (185 mg, 1.74 mmol) in dioxane (3 mL) and water (0.6 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-(4-(3,3-dimethylazetidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 97 mg (67.5%). 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.37 (m, 2H), 7.32 (br. s, 1H), 7.14 (t, J=8.4 Hz, 2H), 6.99 (d, J=8.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.78 (br. s, 1H), 5.20 (s, 1H), 5.02-4.97 (m, 1H), 4.20 (t, J=6.2 Hz, 2H), 3.44 (s, 4H), 3.05 (t, J=6.6 Hz, 2H), 1.99 (s, 3H), 1.89 (s, 3H), 1.21-1.18 (m, 6H), 1.11 (s, 9H), 1.02 (s, 6H). UPLC (M+H)=577.5.

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-22e690cd31d740c4876bef62089afdf2
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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