Cesium carbonate → (S)-7-bromo-1-fluoro-3-morpholino-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine

HRID 455694Notes

Reaction equation

HRID 455694 reaction equation
[NH2:1][C:2]1[CH2:7][O:6][CH2:5][C@:4]([C:22]2[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:23]=2[OH:29])([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([F:20])[C:9]=2Cl)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>[Cu](Cl)Cl>[Br:28][C:26]1[CH:27]=[C:22]2[C@:4]3([N:3]=[C:2]([NH2:1])[CH2:7][O:6][CH2:5]3)[C:8]3[CH:13]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[N:11]=[C:10]([F:20])[C:9]=3[O:29][C:23]2=[CH:24][CH:25]=1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 707002,2,6,6-Tetramethyl-3,5-heptanedioneHCID 67438929(S)-2-(5-amino-3-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-bromophenol

Product 1

HCID 67436134(S)-7-bromo-1-fluoro-3-morpholino-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amineYield 31.4%

Reagents, catalysts & solvents 1

HCID 24014Cupric ChlorideCatalyst

Conditions

Temperature
120 °C

Procedure

A sealable vial was charged with (S)-2-(5-amino-3-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-bromophenol (234 mg, 0.482 mmol), cesium carbonate (471 mg, 1.445 mmol) and copper chloride (9.54 mg, 0.096 mmol The vial was evacuated and back-filled with nitrogen. NMP (1.5 mL) was added and the vial was evacuated and backfilled with nitrogen. 2,2,6,6-Tetramethyl-3,5-heptanedione (0.080 mL, 0.385 mmol) was added and the reaction mixture was heated to 120° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with EtAOc and filtered through a pad of silica gel. The solvent was removed under reduced pressure and the residue was purified by preparative reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min to obtain 68 mg of (S)-7-bromo-1-fluoro-3-morpholino-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine.TFA.

Workup

  1. customwas evacuated
  2. additionback-filled with nitrogen
  3. additionNMP (1.5 mL) was added
  4. customthe vial was evacuated
  5. temperatureThe reaction mixture was cooled to room temperature
  6. additiondiluted with EtAOc
  7. filtrationfiltered through a pad of silica gel
  8. customThe solvent was removed under reduced pressure
  9. customthe residue was purified by preparative reversed-phase preparative HPLC
  10. customover 20 min

Sources & evidence

ORD record
ord-01c54eb2471643518f4b09b64171304f
Source dataset
uspto-grants-2013_07
Patent number
US08497264B2

Reaction notes

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