Cesium carbonate → tert-Butyl (S)-1-(5-(3-fluoroisoquinolin-6-yl)-1,3,4-thiadiazol-2-ylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate

HRID 2075393Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2075393
[F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[S:16][C:15]([NH:17][C:18](=O)OC(C)(C)C)=[N:14][N:13]=1)=[CH:7][CH:6]=2.C(=O)([O-])[O-].[Cs+].[Cs+].[F:31][C:32]([F:55])([F:54])[C:33]1[CH:53]=[CH:52][C:36]([CH2:37][C@H:38]2COS(=O)(=O)[N:39]2[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[CH:35][CH:34]=1.C(OC(N[C@@H](CC1C=NC(C(F)(F)F)=CC=1)CN1N=C(C2C=C3C(=CC=2)C=NC(F)=C3)S/C/1=N\C(=O)OC(C)(C)C)=O)(C)(C)C.[Cl-].[Li+].[NH4+].[Cl-]>CN(C=O)C.CS(C)=O.O>[F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[S:16][C:15]([NH:17][CH2:18][C@@H:38]([NH:39][C:45](=[O:46])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])[CH2:37][C:36]3[CH:35]=[CH:34][C:33]([C:32]([F:55])([F:54])[F:31])=[CH:53][CH:52]=3)=[N:14][N:13]=1)=[CH:7][CH:6]=2

Komponenten

10

Edukt 6

HCID 10796Cesium carbonateHCID 25517Ammonium ChlorideHCID 433294Lithium ChlorideHCID 57634052tert-Butyl (4S)-4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxideHCID 68360231tert-Butyl 5-(3-fluoroisoquinolin-6-yl)-1,3,4-thiadiazol-2-ylcarbamateHCID 87263879tert-butyl (NZ)-N-[5-(3-fluoroisoquinolin-6-yl)-3-[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[6-(trifluoromethyl)-3-pyridinyl]propyl]-1,3,4-thiadiazol-2-ylidene]carbamate

Produkt 1

HCID 57991856tert-Butyl (S)-1-(5-(3-fluoroisoquinolin-6-yl)-1,3,4-thiadiazol-2-ylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamateAusbeute 30 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 679Dimethyl SulfoxideLösungsmittelHCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
55 °C

Versuchsvorschrift

tert-Butyl 5-(3-fluoroisoquinolin-6-yl)-1,3,4-thiadiazol-2-ylcarbamate (0.30 g, 0.860 mmol) and cesium carbonate (0.56 g, 1.72 mmol) in DMF (5.0 mL) were stirred under nitrogen at 55° C. for 10 minutes. tert-Butyl (4S)-4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.362 g, 0.946 mmol) as prepared in Schemes 1a and 1b for Example 1 was added as a solid. The resulting reaction mixture was stirred at 55° C. for 1.5 hours. The solvent was removed and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3×140 mL), the combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was partially purified by chromatography on silica gel (0-35% EtOAc:hexane) to provide the product contaminated with tert-butyl ((2Z)-3-((2S)-2-((tert-butoxycarbonyl)amino)-3-(6-(trifluoromethyl)-3-pyridinyl)propyl)-5-(3-fluoro-6-isoquinolinyl)-1,3,4-thiadiazol-2(3H)-ylidene)carbamate. The mixture was taken up in DMSO (6 mL) and water (0.019 mL). Lithium chloride (0.15 g, 3.5 mmol) was added and the mixture was heated at 100° C. with stirring 16 hours. Saturated NH4Cl was added, and the mixture was extracted with EtOAc (120 mL×3). The organic extracts were washed with water (3×100 mL), brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel (0-3% MeOH-DCM) to provide the product as an off-white solid (57 mg, 30%). LCMS (API-ES) m/z: 548 (M+H+).

Aufarbeitung

  1. additionwas added as a solid
  2. customThe resulting reaction mixture
  3. customThe solvent was removed
  4. customthe residue was partitioned between water and EtOAc
  5. extractionThe aqueous layer was extracted with EtOAc (3×140 mL)
  6. washthe combined organic extracts were washed with brine
  7. dry with materialdried over sodium sulfate
  8. customevaporated
  9. customThe residue was partially purified by chromatography on silica gel (0-35% EtOAc:hexane)
  10. customto provide the product
  11. temperaturethe mixture was heated at 100° C.
  12. stirringwith stirring 16 hours
  13. extractionthe mixture was extracted with EtOAc (120 mL×3)
  14. washThe organic extracts were washed with water (3×100 mL), brine
  15. dry with materialdried over sodium sulfate
  16. customevaporated
  17. customThe residue was purified by chromatography on silica gel (0-3% MeOH-DCM)

Quellen und Nachweise

ORD-Eintrag
ord-4b1448fb546f4bf3a0e5b3223b56a6a7
Quelldatensatz
uspto-grants-2011_04
Patentnummer
US07919504B2

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