Lithium Hydroxide → (3R)-3-[(3,5-Dichloro-4′-fluoro[1,1′-biphenyl]-4-yl)methyl]-1-(4,5,6,7-tetrahydro-1H-indazol-6-yl)-2-pyrrolidinone

HRID 1013850Notes

Reaction equation

HRID 1013850 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:22][C:21]3[N:20](S(C(F)(F)F)(=O)=O)[N:19]=[CH:18][C:17]=3[CH2:16][CH2:15]2)[C:10]1=[O:30].ClC1C=C(OS(C(F)(F)F)(=O)=O)C=C(Cl)C=1C[C@@H]1CCN(C2CC3C(=CN(S(C(F)(F)F)(=O)=O)N=3)CC2)C1=O.[F:79][C:80]1[CH:85]=[CH:84][C:83](B(O)O)=[CH:82][CH:81]=1.C(=O)([O-])[O-].[Na+].[Na+].[Li+].[OH-]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:83]2[CH:84]=[CH:85][C:80]([F:79])=[CH:81][CH:82]=2)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:22][C:21]3[NH:20][N:19]=[CH:18][C:17]=3[CH2:16][CH2:15]2)[C:10]1=[O:30]

Participants

9

Reactant 5

HCID 3939Lithium HydroxideHCID 10340Sodium CarbonateHCID 2856454-Fluorophenylboronic acidHCID 57671367HCID 57671367, compoundHCID 86629989HCID 86629989, compound

Product 1

HCID 57671356(3R)-3-[(3,5-Dichloro-4′-fluoro[1,1′-biphenyl]-4-yl)methyl]-1-(4,5,6,7-tetrahydro-1H-indazol-6-yl)-2-pyrrolidinoneYield 57%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

Purge a solution of trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)-pyrrolidin-3-ylmethyl]-phenyl ester and trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(2-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 83) (0.573 g, 0.89 mmol), 4-fluorophenylboronic acid (0.149 g, 1.06 mmol), and 2M sodium carbonate (1.3 mL) in THF (22 mL) with nitrogen. Treat the reaction with tetrakis(triphenylphosphine)palladium(0) (0.051 g, 0.044 mmol) and heat the reaction to 80° C. and stir for 1 hr. Cool to room temperature and treat the reaction with 2N LiOH (4.5 mL) and stir for 1 hr. Dilute the reaction with water and extract with ethyl acetate. The organic layer is dried (Na2SO4) and the solvent is removed to afford crude product that is purified first with 0 to 10% methanol in CH2Cl2 and then with a Varian 10 g SCX column with 9/1 CH2Cl2/MeOH and then 2:1 CH2Cl2/2M NH3 in MeOH to afford 0.233 g (57%) of the titled product. MS (m/z): 458 (M+1).

Workup

  1. additionTreat
  2. temperatureheat
  3. customthe reaction to 80° C.
  4. additiontreat
  5. stirringstir for 1 hr
  6. additionDilute
  7. extractionextract with ethyl acetate
  8. dry with materialThe organic layer is dried (Na2SO4)
  9. customthe solvent is removed
  10. customto afford crude product that
  11. customis purified first with 0 to 10% methanol in CH2Cl2

Sources & evidence

ORD record
ord-1148bde5341641539997e9be3eb65ec6
Source dataset
uspto-grants-2011_07
Patent number
US07981918B2

Reaction notes

Loading…