Water → HCID 67542367, compound

HRID 1809804Notes

Reaction equation

HRID 1809804 reaction equation
[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:16][CH:17]=2)[C@@H:8]([OH:24])[CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:16][CH:17]=2)[C@@H:8]([O:24][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=2[O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH2:7]1)=[O:5])[CH3:2]

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 59382374HCID 59382374, compoundHCID 67543036HCID 67543036, compound

Product 1

HCID 67542367HCID 67542367, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

A suspension of the title C compound, (3R,4R)-4-biphenyl-3-yl-3-hydroxy-piperidine-1-carboxylic acid ethyl ester (150 mg, 0.45 mmol) and sodium hydride (60% dispersion in mineral oil, 30 mg, 0.68 mmol) in 10 mL of dry DMF is stirred for 10 min at 60° C. under argon. After cooling to room temperature, 1-bromomethyl-2-(3-methoxy-propoxy)-4-methyl-benzene (252 mg, 0.9 mmol) is added and the mixture further stirred for 3 h at 60° C. After addition of H2O, the aqueous layer is extracted twice with ethyl acetate and the combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by preparative HPLC (Macherey-Nagel 250/4 nucleosil 100-10 C18 column, 20:80 CH3CN+0.1% TFA over 11 min, then 100% CH3CN+0.1% TFA for 5.5 min, 40 ml/min). To the combined fractions containing the desired product is added 1M aqueous sodium carbonate solution and the acetonitrile is removed under reduced pressure. The resulting aqueous suspension is extracted twice with ethyl acetate. The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound. MS 535.2 [M+18]; Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 7.29 min.

Workup

  1. temperatureAfter cooling to room temperature
  2. stirringthe mixture further stirred for 3 h at 60° C
  3. extractionthe aqueous layer is extracted twice with ethyl acetate
  4. dry with materialthe combined organic extracts are dried over anhydrous sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customThe residue is purified by preparative HPLC (Macherey-Nagel 250/4 nucleosil 100-10 C18 column, 20:80 CH3CN+0.1% TFA over 11 min
  7. wait100% CH3CN+0.1% TFA for 5.5 min
  8. additionTo the combined fractions containing the desired product
  9. additionis added 1M aqueous sodium carbonate solution
  10. customthe acetonitrile is removed under reduced pressure
  11. extractionThe resulting aqueous suspension is extracted twice with ethyl acetate
  12. dry with materialThe combined organic layers are dried over anhydrous sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-9ea48ea314a2418ab81d68f4871911de
Source dataset
uspto-grants-2013_01
Patent number
US08362040B2

Reaction notes

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