Potassium Carbonate → (3R,4R)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester

HRID 650735Notes

Reaction equation

HRID 650735 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C@@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:19]=2)[C@@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 113449261-(3-Chloro-propoxymethyl)-2-methoxy-benzeneHCID 11483231(3R,4R)-tert-Butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate

Product 1

HCID 11305954(3R,4R)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl esterYield 95.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

A solution of 16.50 g (56.24 mmol) of (3R,4R)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butylester in 40 ml of dimethylformamide was treated in succession with 12.68 g (59.06 mmol) of 1-(3-chloro-propoxymethyl)-2-methoxy-benzene (WO 97/09311) and 12.44 g (89.99 mmol) of potassium carbonate. This mixture was stirred at 120° C. for 26 hours. Subsequently, it was filtered, concentrated to a few milliliters, poured into 300 ml of an ice/water mixture and extracted three times with 100 ml of methylene chloride each time. The combined organic phases were washed once with a small amount of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The resulting crude product (31.64 g) was separated on silica gel using a 99:1 mixture of methylene chloride and methanol as the eluent and yielded 25.4 g (95.8% of theory) (3R,4R)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butylester as a slightly yellow oil; MS: 489 (M+NH4+).

Workup

  1. filtrationSubsequently, it was filtered
  2. concentrationconcentrated to a few milliliters
  3. additionpoured into 300 ml of an ice/water mixture
  4. extractionextracted three times with 100 ml of methylene chloride each time
  5. washThe combined organic phases were washed once with a small amount of water
  6. dry with materialdried over magnesium sulphate
  7. customevaporated under reduced pressure
  8. customdried in a high vacuum
  9. customThe resulting crude product (31.64 g) was separated on silica gel using
  10. additiona 99:1 mixture of methylene chloride and methanol as the eluent

Sources & evidence

ORD record
ord-ab764b108a8146aa8dd252d9abf53eb0
Source dataset
uspto-grants-2001_08
Patent number
US06274735B1

Reaction notes

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