Bromoacetonitrile → (3R,4R)-3-(1-cyanomethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester

HRID 1531508Notes

Reaction equation

HRID 1531508 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]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:47][C:48]#[N:49].P([O-])([O-])(O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CN1CCCC1=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][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][C:48]#[N:49])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 3

HCID 11534BromoacetonitrileHCID 24203Sodium Phosphate, DibasicHCID 57314360(3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butylester

Product 1

HCID 86756520(3R,4R)-3-(1-cyanomethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl esterYield 85.9%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
50 °C

Procedure

A solution of 2.50 g (4.05 mmol) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [example 1(c)] and 0.968 g (8.10 mmol, 2.0 equiv.) of bromoacetonitrile in 15 ml of toluene and 2 ml of N-methyl pyrrolidone was treated with 2.88 g (20.27 mmol, 5.0 equiv.) of anhydrous disodium hydrogen phosphate. The suspension was stirred for 18 h at 50° C., allowed to cool to room temperature, poured into 100 ml of an ice/water mixture and extracted three times with 200 ml of ethyl acetate. The combined organic phases were washed twice with 50 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 10:1 v/v mixture of dichloromethane and ethyl acetate as eluent to yield 2.28 g (3.48 mmol, 85.9% of theory) of (3R,4R)-3-(1-cyanomethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 656 (M+H)+.

Workup

  1. temperatureto cool to room temperature
  2. extractionextracted three times with 200 ml of ethyl acetate
  3. washThe combined organic phases were washed twice with 50 ml of water
  4. customevaporated under reduced pressure
  5. customdried in a high vacuum
  6. customThe thus obtained crude product
  7. customwas purified by chromatography on silica gel using
  8. additiona 10:1 v/v mixture of dichloromethane and ethyl acetate as eluent

Sources & evidence

ORD record
ord-24ae8b791ed446f8948047ba3ecef253
Source dataset
uspto-grants-2001_03
Patent number
US06197959B1

Reaction notes

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