Sodium Carbonate → (R)-Methyl 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonamido)propanoate

HRID 83846

Reaktionsgleichung

Reaktionsgleichung von HRID 83846
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([OH:35])(=[O:34])=O)=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].S(Cl)(Cl)=O.[CH3:43][O:44][C:45](=[O:49])[C@@H:46]([CH3:48])[NH2:47].C([O-])([O-])=O.[Na+].[Na+].S(Cl)(Cl)(=O)=O>C(Cl)Cl.CN(C=O)C.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([NH:47][C@H:46]([CH3:48])[C:45]([O:44][CH3:43])=[O:49])(=[O:35])=[O:34])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38]

Komponenten

9

Edukt 5

HCID 10340Sodium CarbonateHCID 24386Thionyl ChlorideHCID 24648Sulfuryl chlorideHCID 89020methyl D-alaninateHCID 866622244-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzenesulfonic acid

Produkt 1

HCID 68070481(R)-Methyl 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonamido)propanoateAusbeute 95 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 6228DimethylformamideLösungsmittelHCID 6342AcetonitrileLösungsmittel2×HCID 6344DichloromethaneLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

To a solution of 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzenesulfonic acid (650 mg, 1.11 mol) in DCM (7 mL) and DMF (cat.) was added thionyl chloride (1.32 g, 11.1 mol, 10 eq.) and heated to reflux for 1.5 h with stirring. The reaction mixture was concentrated to dryness and the residue was diluted with 1,2-dichloroethane, co-evaporated (3×2 mL) and dried under high vacuum. Meanwhile a mixture of D-alanine methyl ester (622 mg, 4.44 mol, 4.0 eq.), MeCN (1.2 mL) and 2M Na2CO3 (6 mL) was stirred for 30 min and then cooled to 0° C. with an ice-water bath. A solution of the above sulfonyl chloride in MeCN (6 mL) then was added dropwise to the chilled aqueous mixture over 15 min with vigorously stirring. After complete addition, the ice-water bath was removed and the reaction slurry was stirred vigorously another 15 min. The reaction mixture was transferred into a separatory funnel with MeCN and the organic layer was collected. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with water/brine (1:1), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting product was purified by chromatography (silica, Hex/EtOAc, 1:1) to afford (R)-methyl 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonamido)propanoate (709 mg, 95%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 2H), 7.18 (s, 1H), 7.13-7.15 (d, 1H), 6.76-6.80 (t, 2H), 6.46-6.48 (m, 2H), 6.36-6.39 (m, 2H), 5.37 (d, 1H), 4.06 (s, 2H), 3.93-4.03 (m, 1H), 3.73 (s, 3H), 3.60 (s, 3H), 1.46 (s, 6H), 1.39-1.41 (d, 3H).

Aufarbeitung

  1. temperatureheated
  2. temperatureto reflux for 1.5 h
  3. concentrationThe reaction mixture was concentrated to dryness
  4. additionthe residue was diluted with 1,2-dichloroethane
  5. customdried under high vacuum
  6. stirringwas stirred for 30 min
  7. stirringwith vigorously stirring
  8. additionAfter complete addition
  9. customthe ice-water bath was removed
  10. stirringthe reaction slurry was stirred vigorously another 15 min
  11. customThe reaction mixture was transferred into a separatory funnel with MeCN
  12. customthe organic layer was collected
  13. extractionThe aqueous layer was extracted with DCM (2×10 mL)
  14. washThe combined organic layers were washed with water/brine (1:1)
  15. dry with materialdried over MgSO4
  16. filtrationfiltered
  17. concentrationconcentrated under reduced pressure
  18. customThe resulting product was purified by chromatography (silica, Hex/EtOAc, 1:1)

Quellen und Nachweise

ORD-Eintrag
ord-e074aaa73e6a41db8d9b30fe0a24894d
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08846739B2

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