Lithium Hydroxide → (2R)-4-[4-(4-Chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid

HRID 1625028Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1625028
[F:1][C:2]1[C:3](I)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13]CC)=[O:12])[CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([F:33])[CH:25]=1.CC1CCCO1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Li+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:3]2[C:2]([F:1])=[CH:7][N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:17])=[O:18])[C:11]([OH:13])=[O:12])[C:5](=[O:21])[CH:4]=2)=[C:26]([F:33])[CH:25]=1

Komponenten

8

Edukt 5

HCID 3939Lithium HydroxideHCID 73012-MethyltetrahydrofuranHCID 62657Potassium Phosphate, TribasicHCID 4193595(4-Chloro-2-fluorophenyl)boronic acid2×HCID 67249679Ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate

Produkt 1

HCID 70664567(2R)-4-[4-(4-Chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acidAusbeute 74 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 962WaterLösungsmittel

Reaktionsbedingungen

Temperatur
75 °C

Versuchsvorschrift

To a 3 L flask with mechanical stirring was added ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate, T2 (100 g, 225 mmol), (4-chloro-2-fluorophenyl)boronic acid (25.5 g, 146 mmol) and Pd(dppf)2Cl2 (4.93 g, 6.74 mmol). The flask was purged with N2, then degassed 2-methyltetrahydrofuran (1 L) and 3 M aq K3PO4 (225 mL, 674 mmol) were added. The reaction mixture was heated to 75° C. and stirred at this temperature for 30 min. Additional (4-chloro-2-fluorophenyl)boronic acid (25.5 g, 146 mmol) was added and the reaction was allowed to heat for 1.5 h. The mixture was allowed to cool to rt and the aqueous layer was separated. The organic layer was passed through a celite pad and placed back in the reaction vessel. Lithium hydroxide (28 g, 667 mmol) in water (700 mL) was added and the mixture was heated to 50° C. and stirred at this temperature for 1 h. The mixture was allowed to cool and the aqueous layer separated. Celite was added to the aqueous layer and the mixture was filtered through a plug of celite. The filtrate was placed in a flask with overhead stirrer and carefully acidified with 4 M aq HCl and heated to 50° C. with stirring until a precipitate formed. The solid was collected via filtration and dried under vacuum to afford the title compound as a tan solid (68.7 g, 74%). MS (LCMS) m/z 420.6 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (s, 3 H) 2.18 (ddd, J=13.17, 10.24, 5.07 Hz, 1 H) 2.41-2.45 (m, 1 H) 3.10-3.19 (s, 3 H) 3.87-4.08 (m, 2 H) 6.47 (d, J=7.02 Hz, 1 H) 7.42 (dd, J=8.39, 1.95 Hz, 1 H) 7.48-7.56 (m, 1 H) 7.60 (dd, J=9.95, 1.95 Hz, 1 H) 8.06 (d, J=6.05 Hz, 1 H).

Aufarbeitung

  1. customThe flask was purged with N2
  2. stirringstirred at this temperature for 30 min
  3. temperatureto heat for 1.5 h
  4. temperatureto cool to rt
  5. customthe aqueous layer was separated
  6. temperaturethe mixture was heated to 50° C.
  7. stirringstirred at this temperature for 1 h
  8. temperatureto cool
  9. customthe aqueous layer separated
  10. additionCelite was added to the aqueous layer
  11. filtrationthe mixture was filtered through a plug of celite
  12. customThe filtrate was placed in a flask with overhead stirrer
  13. temperatureheated to 50° C.
  14. stirringwith stirring until a precipitate
  15. customformed
  16. filtrationThe solid was collected via filtration
  17. customdried under vacuum

Quellen und Nachweise

ORD-Eintrag
ord-917cdee4402d4ff48fd839695cfdef16
Quelldatensatz
uspto-grants-2014_07
Patentnummer
US08779148B2

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