Cesium carbonate → methyl 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate

HRID 2193466Notes

Reaction equation

HRID 2193466 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[N:36][CH:37]=1)=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:36][CH:37]=[C:32]([CH:33]=4)[C:30]([O:29][CH3:28])=[O:31])=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 22309460(5-(Methoxycarbonyl)pyridin-3-yl)boronic acidHCID 59532370(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxy-propyl)-1,3-oxazinan-2-one

Product 1

HCID 59532372methyl 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinateYield 74.4%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (250 mg, 0.6 mmol), 5-(methoxycarbonyl)pyridin-3-ylboronic acid (163 mg, 0.9 mmol), PdCl2(PPh3)2 (50 mg, 20%) and aqueous Cs2CO3 solution (2 M, 2 mL) in 1,4-dioxane (6 mL) was heated to reflux at 100° C. overnight under N2. The mixture was filtered, and the filtrate was extracted with EtOAc for 3 times. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to the crude product, which was purified by preparative HPLC to give methyl 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate (220 mg, crude).

Workup

  1. temperaturewas heated
  2. filtrationThe mixture was filtered
  3. extractionthe filtrate was extracted with EtOAc for 3 times
  4. washThe combined organic layer was washed with brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated to the crude product, which
  7. customwas purified by preparative HPLC

Sources & evidence

ORD record
ord-1725aa114be943248b998ff89707fc64
Source dataset
uspto-grants-2012_12
Patent number
US08329897B2

Reaction notes

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