Lithium Hydroxide → HCID 24762809, compound

HRID 1013853Notes

Reaction equation

HRID 1013853 reaction equation
C(OC([N:8]1[C:16]2[CH2:15][CH2:14][CH2:13][C@@H:12]([N:17]3[CH2:21][CH2:20][CH:19]([CH2:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26](OS(C(F)(F)F)(=O)=O)=[CH:25][C:24]=4[Cl:38])[C:18]3=[O:39])[C:11]=2[CH:10]=[N:9]1)=O)(C)(C)C.C(OC(N1C=C2C(CCC[C@H]2N2CCC(CC3C(Cl)=CC(OS(C(F)(F)F)(=O)=O)=CC=3Cl)C2=O)=N1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[F:85][C:86]1[CH:91]=[CH:90][C:89](B(O)O)=[CH:88][CH:87]=1.[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>[Cl:38][C:24]1[CH:25]=[C:26]([C:89]2[CH:90]=[CH:91][C:86]([F:85])=[CH:87][CH:88]=2)[CH:27]=[C:28]([Cl:29])[C:23]=1[CH2:22][C@@H:19]1[CH2:20][CH2:21][N:17]([CH:12]2[CH2:13][CH2:14][CH2:15][C:16]3[NH:8][N:9]=[CH:10][C:11]2=3)[C:18]1=[O:39]

Participants

8

Reactant 5

HCID 3939Lithium HydroxideHCID 10340Sodium CarbonateHCID 2856454-Fluorophenylboronic acidHCID 86629992HCID 86629992, compoundHCID 86629993HCID 86629993, compound

Product 1

HCID 24762809HCID 24762809, compoundYield 89%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (R)-4-[3-(2,6-dichloro-4-trifluoromethanesulfonyloxy-benzyl)-2-oxo-pyrrolidin-1-yl]-4,5,6,7-tetrahydro-indazole-1-carboxylic acid tert-butyl ester and (R)-4-[3-(2,6-dichloro-4-trifluoromethanesulfonyloxy-benzyl)-2-oxo-pyrrolidin-1-yl]-4,5,6,7-tetrahydro-indazole-2-carboxylic acid tert-butyl ester (Preparation 105) (0.90 g, 1.39 mmol) in THF (35 mL), add 2M sodium carbonate (2.1 mL, 2.78 mmol) and 4-fluorophenylboronic acid (0.23 g, 1.64 mmol). Degas the mixture using a nitrogen gas dispenser for 5 minutes. Add Tetrakis(triphenylphosphine)palladium (0.081 g, 0.070 mmol), bring the reaction mixture to 80° C., and stir under nitrogen for 1 hour. Cool the reaction to room temperature and then treat with 2M aqueous LiOH (14 mL) and stir at room temperature for 1 hour. Partition the mixture between ethyl acetate and water; separate the organic, dry over sodium sulfate, filter and concentrate to afford crude product, and then purify by flash chromatography (gradient, 0 to 10% methanol in dichloromethane) to afford 0.57 g (89%) of the desired product as a mixture of regioisomers. LCMS: 458 (M+H).

Workup

  1. customDegas the mixture
  2. customfor 5 minutes
  3. customto 80° C.
  4. temperatureCool
  5. customthe reaction to room temperature
  6. stirringstir at room temperature for 1 hour
  7. customPartition the mixture between ethyl acetate and water
  8. customseparate the organic,
  9. dry with materialdry over sodium sulfate
  10. filtrationfilter
  11. concentrationconcentrate
  12. customto afford crude product
  13. custompurify by flash chromatography (gradient, 0 to 10% methanol in dichloromethane)

Sources & evidence

ORD record
ord-d430aafa4c50475899d58e8a5315fd50
Source dataset
uspto-grants-2011_07
Patent number
US07981918B2

Reaction notes

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