Lithium Hydroxide → HCID 70664567, compound

HRID 468632

Reaction equation

HRID 468632 reaction equation
[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

Participants

8

Reactant 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

Product 1

HCID 70664567HCID 70664567, compoundYield 74%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
75 °C

Procedure

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, 3H) 2.18 (ddd, J=13.17, 10.24, 5.07 Hz, 1H) 2.41-2.45 (m, 1H) 3.10-3.19 (s, 3H) 3.87-4.08 (m, 2H) 6.47 (d, J=7.02 Hz, 1H) 7.42 (dd, J=8.39, 1.95 Hz, 1H) 7.48-7.56 (m, 1H) 7.60 (dd, J=9.95, 1.95 Hz, 1H) 8.06 (d, J=6.05 Hz, 1H).

Workup

  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

Sources & evidence

ORD record
ord-58146aba062a45ceb898400231c32116
Source dataset
uspto-grants-2014_01
Patent number
US08624034B2

Linked notes

Loading…