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

HRID 1531478Notes

Reaction equation

HRID 1531478 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-butyl ester in 40 ml of N,N-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 (90.00 mmol) of potassium carbonate. This mixture was stirred at 120° C. for 26 hours. Subsequently, the salts were filtered off and washed with dichloromethane. The filtrate was concentrated in a high vacuum to eliminate most of the N,N-dimethylformamide, poured into 300 ml of an ice/water mixture and the aqueous phase was extracted three times with 100 ml of dichloromethane. 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 thus-obtained crude product (31.64 g) was separated on silica gel using a 99:1 mixture of dichloromethane and methanol as the eluent and yielded 25.4 g (53.85 mmol, 95.8% of theory) of (3R,4R)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a slightly yellow oil; MS: 489 (M+NH4+)+.

Workup

  1. filtrationSubsequently, the salts were filtered off
  2. washwashed with dichloromethane
  3. concentrationThe filtrate was concentrated in a high vacuum
  4. additionpoured into 300 ml of an ice/water mixture
  5. extractionthe aqueous phase was extracted three times with 100 ml of dichloromethane
  6. washThe combined organic phases were washed once with a small amount of water
  7. dry with materialdried over magnesium sulphate
  8. customevaporated under reduced pressure
  9. customdried in a high vacuum
  10. customThe thus-obtained crude product (31.64 g)
  11. customwas separated on silica gel using
  12. additiona 99:1 mixture of dichloromethane and methanol as the eluent

Sources & evidence

ORD record
ord-c6f8569f84014fbdbf9da50371cca576
Source dataset
uspto-grants-2001_03
Patent number
US06197959B1

Reaction notes

Loading…