Cesium carbonate → 5-chloro-N-(5-fluoro-6-((4S,6S)-4-methyl-2-(4-nitrobenzamido)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)pyridin-2-yl)picolinamide

HRID 930311Notes

Reaction equation

HRID 930311 reaction equation
Br[C:2]1[N:7]=[C:6]([C@:8]2([CH3:30])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[N:9]2)[C:5]([F:31])=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([NH2:41])=[O:40])=[N:37][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([NH:41][C:2]2[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@:8]3([CH3:30])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:29])[C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=4)=[N:9]3)[N:7]=2)=[O:40])=[N:37][CH:38]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 218831585-Chloropyridine-2-carboxamide2×HCID 86732139N-((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)-4-nitrobenzamide

Product 1

HCID 867321385-chloro-N-(5-fluoro-6-((4S,6S)-4-methyl-2-(4-nitrobenzamido)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)pyridin-2-yl)picolinamide

Reagents, catalysts & solvents 2

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

Conditions

Temperature
110 °C

Procedure

A mixture of A sealable vial was charged with N-((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)-4-nitrobenzamide (8a, 0.297 g, 0.588 mmol), 5-chloropicolinamide (intermediate 18, 0.101 g, 0.647 mmol), cesium carbonate (0.479 g, 1.470 mmol, Aldrich), Pd2(dba)3 (0.040 g, 0.044 mmol, Strem), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.102 g, 0.176 mmol, Aldrich), and 1,4-dioxane (4 mL). The reaction was purged with Argon and heated to 110° C. overnight. The reaction mixture was filtered through celite and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via silica gel flash chromatography (gradient 0-35% EtOAc in hexanes) to afford the title compound as a light yellow solid. MS m/z=581 [M+H]+. Calculated for C24H17ClF4N6O5: 580.

Workup

  1. additionA mixture of A sealable vial
  2. customThe reaction was purged with Argon
  3. filtrationThe reaction mixture was filtered through celite
  4. washthe filter cake was washed with EtOAc
  5. washThe filtrate was washed with water and brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated under reduced pressure
  8. customThe crude material was purified via silica gel flash chromatography (gradient 0-35% EtOAc in hexanes)

Sources & evidence

ORD record
ord-30126cafbf714a03b5d19193fec02a04
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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