4-Morpholinecarbonyl chloride → 2,2,2-trichloro-ethyl (3RS,4RS)-4-[4-[2-(morpholin-4-ylcarbonyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate

HRID 1858651Notes

Reaction equation

HRID 1858651 reaction equation
[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:13][CH:12]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:7][CH:6]=1.[N:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[N:37]1([C:43]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:22])([Cl:23])[Cl:24])=[O:18])[CH2:13][CH:12]3[O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[CH:9][CH:10]=2)=[O:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1

Participants

6

Reactant 3

HCID 848104-Morpholinecarbonyl chloride2×HCID 9798523Di-n-butyl diacetoxy tinHCID 538370512,2,2-trichloroethyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate

Product 1

HCID 866044052,2,2-trichloro-ethyl (3RS,4RS)-4-[4-[2-(morpholin-4-ylcarbonyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylateYield 14%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalyst2×HCID 1140TolueneSolvent

Procedure

A solution of 250 mg (0.56 mmol) of 2,2,2-trichloroethyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 20 ml of toluene was treated in succession with 250 ml (2.8 mmol, 5.0 eq.) of morpholine-4-carbonyl chloride, 375 mg (3.08 mmol, 5.5 eq.) of 4-dimethylaminopyridine and 20 μl (0.075 mmol, 0.13 eq.) of dibutyltin diacetate. This mixture was boiled under reflux for 64 hours. In the course of the reaction a further 125 ml (1.40 mmol, 5.0 eq.) of morpholine-4-carbonyl chloride and 188 mg (1.56 mmol, 2.3 eq.) of 4-dimethylaminopyridine were added and the mixture was boiled under reflux for a further 24 hours. The reaction mixture, cooled to room temperature, was poured into 100 ml of an ice/water mixture, stirred for 5 minutes and extracted three times with methylene chloride. The organic phases were each washed once with water and saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The crude product (546 mg) was separated on silica gel using a 9:1 mixture of hexane and acetone as the eluent. There were obtained 42 mg (14% of theory) of 2,2,2-trichloro-ethyl (3RS,4RS)-4-[4-[2-(morpholin-4-ylcarbonyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 665.3, 667 (M+H)+.

Workup

  1. temperatureunder reflux for 64 hours
  2. additionwere added
  3. temperatureunder reflux for a further 24 hours
  4. extractionextracted three times with methylene chloride
  5. washeach washed once with water and saturated sodium chloride solution
  6. dry with materialdried over magnesium sulphate
  7. customevaporated under reduced pressure
  8. customdried in a high vacuum
  9. customThe crude product (546 mg) was separated on silica gel using
  10. additiona 9:1 mixture of hexane and acetone as the eluent

Sources & evidence

ORD record
ord-b00568fc517043f5b68cc3f8cb830056
Source dataset
uspto-grants-2000_11
Patent number
US06150526

Reaction notes

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