Sulfuric Acid → (4aR,11bS)-2-amino-10-((3-chloro-1,7-naphthyridin-8-yl)amino)-11b-(fluoromethyl)-3,3-dimethyl-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazine 4,4-dioxide

HRID 627744Notes

Reaction equation

HRID 627744 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:35][CH2:34][CH2:33][C@H:9]3[S:10](=[O:32])(=[O:31])[C:11]([CH3:30])([CH3:29])[C:12]([N:14](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:13][C@:8]3([CH2:36][F:37])[C:6]=2[CH:7]=1.[Cl:38][C:39]1[CH:40]=[N:41][C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[N:44][C:43]=2Cl.C(O)(C)C.OS(O)(=O)=O>[OH-].[Na+].C(Cl)Cl.CO>[NH2:14][C:12]1[C:11]([CH3:29])([CH3:30])[S:10](=[O:31])(=[O:32])[C@@H:9]2[CH2:33][CH2:34][O:35][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:43]4[N:44]=[CH:45][CH:46]=[C:47]5[C:42]=4[N:41]=[CH:40][C:39]([Cl:38])=[CH:48]5)=[CH:7][C:6]=3[C@@:8]2([CH2:36][F:37])[N:13]=1

Participants

8

Reactant 4

HCID 1118Sulfuric AcidHCID 3776IsopropanolHCID 722135953,8-Dichloro-1,7-naphthyridineHCID 90307377tert-butyl N-[(4aR,11bS)-10-amino-11b-(fluoromethyl)-3,3-dimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate

Product 1

HCID 90308662(4aR,11bS)-2-amino-10-((3-chloro-1,7-naphthyridin-8-yl)amino)-11b-(fluoromethyl)-3,3-dimethyl-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazine 4,4-dioxideYield 81.6%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 14798Sodium HydroxideSolvent

Conditions

Temperature
90 °C

Procedure

To a 15-mL reaction vial was added tert-butyl N-[(4aR,11bS)-10-amino-11b-(fluoromethyl)-3,3-dimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (103 mg, 0.190 mmol), 3,8-dichloro-1,7-naphthyridine (41.6 mg, 0.209 mmol), isopropanol (3 mL) and a couple of β-drops of H2SO4. The vial was closed and heated at 90° C. for 1 h. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with 1N NaOH (5 mL) and extracted with DCM (8 mL×3). The organic extracts were dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 2% 2M NH3.MeOH in DCM, to provide (4aR,11bS)-2-amino-10-((3-chloro-1,7-naphthyridin-8-yl)amino)-11b-(fluoromethyl)-3,3-dimethyl-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazine 4,4-dioxide (78 mg, 0.155 mmol, 81% yield) as yellow solid. MS m/z=503.9 (M+H).

Workup

  1. customTo a 15-mL reaction
  2. customThe vial was closed
  3. temperatureto cool to room temperature
  4. extractionextracted with DCM (8 mL×3)
  5. dry with materialThe organic extracts were dried over Na2SO4
  6. filtrationThe solution was filtered
  7. concentrationconcentrated in vacuo
  8. customto give the crude material
  9. customThe crude material was absorbed onto a plug of silica gel
  10. custompurified by chromatography through a Redi-Sep pre-packed silica gel column (12 g)
  11. washeluting with a gradient of 0% to 2% 2M NH3

Sources & evidence

ORD record
ord-428ea6cc1b754b4e9b91c2612962c2c8
Source dataset
uspto-grants-2016_04
Patent number
US09309263B2

Reaction notes

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