Cesium carbonate → (+/-)-tert-butyl (3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate

HRID 921680Notes

Reaction equation

HRID 921680 reaction equation
Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Si:19]([O:26][C@H:27]1[C@H:32]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:31][CH2:30][NH:29][CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:19]([O:26][C@H:27]1[C@H:32]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH2:31][CH2:30][N:29]([C:2]2[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=2)[CH2:28]1)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:20])[CH3:21]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 86708481Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamateHCID 86708549(+/-)-4-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)morpholine

Product 1

HCID 86708551(+/-)-tert-butyl (3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamateYield 75.2%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (116 mg, 0.349 mmol), (+/−)-4-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)morpholine (100 mg, 0.333 mmol), Pd2dba3 (9.14 mg, 9.98 μmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (18.65 mg, 0.030 mmol), and cesium carbonate (217 mg, 0.666 mmol) in Dioxane (2 mL) was evacuated and filled with nitrogen three times and heated at 110° C. overnight. The reaction mixture was diluted with dichloromethane and filtered through Celite, the filtrate was concentrated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 5-25% ethyl acetate/hexanes). (+/−)-tert-butyl (3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate (138 mg) was obtained as a white solid.

Workup

  1. customwas evacuated
  2. additionfilled with nitrogen three times
  3. additionThe reaction mixture was diluted with dichloromethane
  4. filtrationfiltered through Celite
  5. concentrationthe filtrate was concentrated
  6. customthe crude product was purified by flash chromatography on silica gel using
  7. washan automated ISCO system (24 g column, eluting with 5-25% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-6cd3af96d7c74a59938f3a546f19d918
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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