Sodium Carbonate → (R)-3',5'-Dichloro-3-fluoro-4'-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carbonitrile

HRID 1692076Notes

Reaction equation

HRID 1692076 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[F:41][C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][C:47]=1[C:48]#[N:49].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.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:1][C:2]1[CH:3]=[C:4]([C:44]2[CH:45]=[CH:46][C:47]([C:48]#[N:49])=[C:42]([F:41])[CH:43]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:15][CH2:16][CH:17]([O:20][Si:21]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:23])[CH3:24])[CH:28]([CH3:30])[CH3:29])[CH2:18][CH2:19]2)[C:10]1=[O:31]

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 2783130(4-Cyano-3-fluorophenyl)boronic acidHCID 86630019trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenyl ester

Product 1

HCID 66905381(R)-3',5'-Dichloro-3-fluoro-4'-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carbonitrileYield 87.2%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

Purge with nitrogen for 10 minutes a mixture of (R)-trifluoro-methanesulfonic acid 3,5-dichloro-4-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (0.18 g, 0.28 mmol), 3-fluoro-4-cyanophenylboronic acid (0.055 g, 0.33 mmol), sodium carbonate (0.089 g, 0.84 mmol) in THF (10 mL) and water (3 mL). Add Pd(PPh3)4 (0.016 g, 0.01 mmol) to the mixture. Stir the reaction at 80° C. for 1 hour. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 0% to 50% ethyl acetate in hexanes gradient to afford 0.151 g of the titled product. MS (m/z): 617 (M+).

Workup

  1. customPurge with nitrogen for 10 minutes
  2. customthe reaction at 80° C. for 1 hour
  3. temperatureCool
  4. customthe reaction
  5. washwash with water and brine
  6. dry with materialDry the organic layer (Na2SO4)
  7. customremove the solvent in vacuo
  8. customto afford crude product
  9. custompurify on silica gel column with 0% to 50% ethyl acetate in hexanes gradient

Sources & evidence

ORD record
ord-75d4af8d9c624af9972bad9d78f98d01
Source dataset
uspto-grants-2012_04
Patent number
US08153807B2

Reaction notes

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