Water → (R)-3-[3,5-Dichloro-4'-(4,4-difluoro-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4-hydroxy-piperidin-1-yl)-pyrrolidin-2-one

HRID 1692100Notes

Reaction equation

HRID 1692100 reaction equation
O.C(O)(C(F)(F)F)=O.[Cl:9][C:10]1[CH:11]=[C:12]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([N:49]3[CH2:54][CH2:53][C:52]([F:56])([F:55])[CH2:51][CH2:50]3)=[O:48])=[CH:43][CH:42]=2)[CH:13]=[C:14]([Cl:40])[C:15]=1[CH2:16][C@@H:17]1[CH2:21][CH2:20][N:19]([N:22]2[CH2:27][CH2:26][CH:25]([O:28][Si](C(C)C)(C(C)C)C(C)C)[CH2:24][CH2:23]2)[C:18]1=[O:39]>C1COCC1>[Cl:40][C:14]1[CH:13]=[C:12]([C:41]2[CH:42]=[CH:43][C:44]([C:47]([N:49]3[CH2:54][CH2:53][C:52]([F:55])([F:56])[CH2:51][CH2:50]3)=[O:48])=[CH:45][CH:46]=2)[CH:11]=[C:10]([Cl:9])[C:15]=1[CH2:16][C@@H:17]1[CH2:21][CH2:20][N:19]([N:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)[C:18]1=[O:39]

Participants

5

Reactant 3

HCID 962WaterHCID 6422Trifluoroacetic acidHCID 66905189(R)-3-[3,5-Dichloro-4'-(4,4-difluoro-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one

Product 1

HCID 24864210(R)-3-[3,5-Dichloro-4'-(4,4-difluoro-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4-hydroxy-piperidin-1-yl)-pyrrolidin-2-oneYield 97%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Add water (60 mL) and TFA 20 mL) to a solution of (R)-3-[3,5-dichloro-4′-(4,4-difluoro-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one in THF (60 mL). Stir the mixture at room temp for 12 hours. Partition the reaction with ethyl acetate (200 mL) and sodium bicarbonate (sat. solution, 150 mL), separate the organic layer, extract the aqueous with another 200 mL of ethyl acetate, and combine the organic solutions. Dry over sodium sulfate, filter and concentrate. Dissolve the residue in 40 mL of dichloromethane and load on a Biotage Si 65M 1385-1 column, flash with ethyl acetate for 30 minutes, switch to 8% methanol in dichloromethane to afford 8.02 grams (97%) of the desired product as white solid. MS (m/z): 566 (M+).

Workup

  1. customPartition
  2. customthe reaction with ethyl acetate (200 mL) and sodium bicarbonate (sat. solution, 150 mL)
  3. customseparate the organic layer
  4. extractionextract the aqueous with another 200 mL of ethyl acetate
  5. dry with materialDry over sodium sulfate
  6. filtrationfilter
  7. concentrationconcentrate
  8. dissolutionDissolve the residue in 40 mL of dichloromethane
  9. waitload on a Biotage Si 65M 1385-1 column, flash with ethyl acetate for 30 minutes

Sources & evidence

ORD record
ord-3ecde93ef9a44642aa315f348856220f
Source dataset
uspto-grants-2012_04
Patent number
US08153807B2

Reaction notes

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