Morpholine → Racemic 4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-morpholino-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine

HRID 455642Notes

Reaction equation

HRID 455642 reaction equation
FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:27]4[C:28]([F:33])=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:16][C:17]=3[C:18]32[N:25]=[C:24]([NH2:26])[CH2:23][O:22][CH2:21]3)=[C:9]([F:34])[CH:8]=1)(=O)=O.BrC1C=C2[C:51]3([N:56]=[C:55](N)[CH2:54][O:53][CH2:52]3)C3C=C(Cl)N=CC=3OC2=CC=1.N1CCOCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:34][C:9]1[C:10]2[O:11][C:12]3[C:17](=[CH:16][C:15]([C:27]4[C:28]([F:33])=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:14][CH:13]=3)[C:18]3([N:25]=[C:24]([NH2:26])[CH2:23][O:22][CH2:21]3)[C:19]=2[CH:20]=[C:7]([N:56]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)[CH:8]=1

Participants

6

Reactant 4

HCID 8083MorpholineHCID 2733832Lithium HexamethyldisilazideHCID 584659017-Bromo-3-chloro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amineHCID 867619685-Amino-5'-fluoro-2'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthene]-7'-yl trifluoromethanesulfonate

Product 1

HCID 67439029Racemic 4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-morpholino-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amineYield 550%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A re-sealable vial was charged with 5-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7′-yl trifluoromethanesulfonate (200 mg, 0.379 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-isopropoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) 1 (27.6 mg, 0.038 mmol) and 0.5 ml of THF. The mixture was stirred at RT until all solids were dissolved. Morpholine (66.1 μL, 0.758 mmol) and LiHMDS (1M in THF) (1138 pt, 1.138 mmol) were added and the vial was sealed and stirred at RT for 20 minutes. The reaction was quenched by addition of water (1 ml) and diluted with EtOAc (2 ml). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×2 ml). The combined organic fractions were concentrated and purified by chromatography (10-80% DCM/MeOH/NH4OH in DCM) to provide racemic 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-morpholino-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (97 mg, 0.209 mmol, 55.1% yield).

Workup

  1. dissolutionwere dissolved
  2. customthe vial was sealed
  3. stirringstirred at RT for 20 minutes
  4. customThe reaction was quenched by addition of water (1 ml)
  5. additiondiluted with EtOAc (2 ml)
  6. customThe organic layer was separated
  7. extractionthe aqueous layer was extracted with EtOAc (2×2 ml)
  8. concentrationThe combined organic fractions were concentrated
  9. custompurified by chromatography (10-80% DCM/MeOH/NH4OH in DCM)

Sources & evidence

ORD record
ord-7248f8aa93b54b7fa1bf43961d2878f4
Source dataset
uspto-grants-2013_07
Patent number
US08497264B2

Reaction notes

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