Trifluoroacetic acid → (S)-N7'-(3-ethoxypyridin-2-yl)-4'-fluoro-2'-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9'-xanthene]-2,7'-diamine

HRID 931634Notes

Reaction equation

HRID 931634 reaction equation
[CH2:1]([O:3][C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].C(OC(=O)[NH:17][C:18]1[S:19][CH2:20][CH2:21][C@@:22]2([N:40]=1)[C:35]1[CH:34]=[C:33]([O:36][CH3:37])[CH:32]=[C:31]([F:38])[C:30]=1[O:29][C:28]1[C:23]2=[CH:24][C:25](Br)=[CH:26][CH:27]=1)(C)(C)C.CC(C)([O-])C.[Na+].C(O)(C(F)(F)F)=O>O.C(Cl)Cl.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].C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:5]([NH:10][C:25]2[CH:24]=[C:23]3[C:28]([O:29][C:30]4[C:31]([F:38])=[CH:32][C:33]([O:36][CH3:37])=[CH:34][C:35]=4[C@@:22]43[CH2:21][CH2:20][S:19][C:18]([NH2:17])=[N:40]4)=[CH:27][CH:26]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]

Participants

9

Reactant 4

HCID 6422Trifluoroacetic acidHCID 5866303-ethoxypyridin-2-amineHCID 23676156Sodium t-butoxideHCID 117624180(S)-tert-butyl(7'-bromo-4'-fluoro-2'-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9'-xanthen]-2-yl)carbamate

Product 1

HCID 89473217(S)-N7'-(3-ethoxypyridin-2-yl)-4'-fluoro-2'-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9'-xanthene]-2,7'-diamineYield 21.84%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Procedure

A 2-5 ml resealable tube was charged with 3-ethoxypyridin-2-amine (26.0 mg, 0.188 mmol), (S)-tert-butyl(7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-yl)carbamate (80 mg, 0.157 mmol), Pd2 dba3 (15.82 mg, 0.017 mmol), t-BuXPhos (14.67 mg, 0.035 mmol) and sodium t-butoxide (33.2 mg, 0.346 mmol). Toluene (6280 was added, and the mixture was stirred for 2 min at RT, then was heated to 80° C. for 20 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with saturated NaCl and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as a orange oil. The crude material was purified by chromatography eluting with a gradient of 0% to 15% to 30% DCM/MeOH/NH4OH in DCM, to provide Boc-protected product as yellow solid. The Boc protected product was dissolved in 1 mL of DCM and 1 mL of TFA was added. The reaction mixture was stirred at rt for 40 mins. Then the solvent was reduced and crude product was purified by chromatography eluting with a gradient of 20% to 35% to 50% DCM/MeOH/NH4OH in (40% EtOAc in Heptane), to provide (S)—N7′-(3-ethoxypyridin-2-yl)-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthene]-2,7′-diamine (16 mg, 0.034 mmol, 21.84% yield) as light-yellow solid.

Workup

  1. temperaturewas heated to 80° C. for 20 min
  2. extractionextracted with EtOAc
  3. extractionThe organic extract
  4. washwas washed with saturated NaCl
  5. dry with materialdried over MgSO4
  6. filtrationThe solution was filtered
  7. concentrationconcentrated in vacuo
  8. customto give the crude material as a orange oil
  9. customThe crude material was purified by chromatography
  10. washeluting with a gradient of 0% to 15% to 30% DCM/MeOH/NH4OH in DCM
  11. customto provide Boc-
  12. stirringThe reaction mixture was stirred at rt for 40 mins
  13. customcrude product was purified by chromatography
  14. washeluting with a gradient of 20% to 35% to 50% DCM/MeOH/NH4OH in (40% EtOAc in Heptane)

Sources & evidence

ORD record
ord-06ff534079f0442781a572a9c47bb165
Source dataset
uspto-grants-2016_03
Patent number
US09296759B2

Reaction notes

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