Cesium carbonate → tert-butyl 4-{3-[(3R)-3-({1-[5-fluoro-4'-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)biphenyl-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate

HRID 526386Notes

Reaction equation

HRID 526386 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:46])[NH:25][CH:26]([C:32]3[CH:33]=[C:34]([C:39]4[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=4)[CH:35]=[C:36]([F:38])[CH:37]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:53]1([CH3:76])[CH:58]=[CH:57][C:56]([S:59]([O:62][CH2:63][CH2:64]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:61])=[O:60])=[CH:55][CH:54]=1>CN(C)C=O>[F:38][C:36]1[CH:37]=[C:32]([CH:26]([NH:25][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[CH2:19]2)=[O:46])[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:33]=[C:34]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH2:64][CH2:63][O:62][S:59]([C:56]3[CH:57]=[CH:58][C:53]([CH3:76])=[CH:54][CH:55]=3)(=[O:61])=[O:60])=[CH:43][CH:44]=2)[CH:35]=1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 228289Ethylene glycol ditosylateHCID 71268075HCID 71268075, compound

Product 1

HCID 89412830tert-butyl 4-{3-[(3R)-3-({1-[5-fluoro-4'-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)biphenyl-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylateYield 11.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

178.0 mg (0.28 mmol) 4-(3-{(R)-3-[1-(5-fluoro-4′-hydroxy-biphenyl-3-yl)-2-methoxycarbonyl-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester (example 17d) were dissolved in 10.7 ml N,N-dimethylformamide. 272 mg (0.84 mmol) cesium carbonate and 154.6 mg (0.42 mmol) ethylene glycol bis-p-toluenesulfonate were added. The mixture was stirred at room temperature for 70 hours and concentrated. The remainder was taken up with saturated ammonium chloride solution and ethyl acetate. The aqueous phase was extracted with 3×20 ml ethyl acetate. The extracts were dried over sodium sulfate and concentrated. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5) gave 167 mg which were further purified by HPLC to yield 27 mg (11%) tert-butyl 4-{3-[(3R)-3-({1-[5-fluoro-4′-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)biphenyl-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.

Workup

  1. concentrationconcentrated
  2. extractionThe aqueous phase was extracted with 3×20 ml ethyl acetate
  3. dry with materialThe extracts were dried over sodium sulfate
  4. concentrationconcentrated
  5. customChromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5) gave 167 mg which
  6. customwere further purified by HPLC

Sources & evidence

ORD record
ord-7ed0fbab17de44088ce92c84fd377e90
Source dataset
uspto-grants-2016_05
Patent number
US09345793B2

Reaction notes

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