Water → 1-[(R)-1-benzyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide

HRID 651700Notes

Reaction equation

HRID 651700 reaction equation
[C:1]([CH2:3][S:4]([N:7]([CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8])(=[O:6])=[O:5])#[N:2].[H-].[Na+].[CH2:24]([N:31]1[C:39]2[C:34](=[CH:35][C:36](Br)=[CH:37][CH:38]=2)[C:33]([CH2:41][C@H:42]2[CH2:46][CH2:45][CH2:44][N:43]2[CH3:47])=[CH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1.COCCOC.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:24]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([CH:3]([C:1]#[N:2])[S:4]([N:7]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:8])(=[O:5])=[O:6])=[CH:37][CH:38]=2)[C:33]([CH2:41][C@H:42]2[CH2:46][CH2:45][CH2:44][N:43]2[CH3:47])=[CH:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1

Participants

9

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 217091131-Cyano-n-diphenylmethyl-n-methylmethanesulfonamideHCID 54492095(r)-1-Benzyl-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1h-indole

Product 1

HCID 540937701-[(R)-1-benzyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-1-cyano-N-diphenylmethyl-N-methylmethanesulfonamideYield 70.2%

Reagents, catalysts & solvents 4

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 702EthanolSolventHCID 1140TolueneSolvent2×HCID 80711,2-DimethoxyethaneSolvent

Procedure

To a stirred solution of 1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide (from step (c), 18.79 g, 62.6 mmol) in a mixture of toluene (60 ml) and ethylene glycol dimethylether (20 ml) at 0-5° C. under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil) (4.6 g, 115 mmol) portionwise, maintaining the temperature below 5° C. Upon completion of the addition, the dark brown solution was warmed to ambient temperature over a 30 min period, before tetrakis(triphenylphosphine) palladium(0) (3.61 g, 3.1 mmol) was added in one portion. A solution of (R)-1-benzyl-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (from Example 1(d), 19.74 g, 52 mmol) in toluene (20 ml) was then added dropwise to the brown slurry and the mixture was warmed to reflux. Reflux was maintained for 2 hr after which time the dark brown solution was cooled to ambient temperature. The reaction mixture was then poured into water (250ml) and extracted with ethyl acetate (3×100 ml). The organic extracts were combined and evaporated in vacuo to yield a brown oil. This was re-dissolved in absolute ethanol (80 ml) and stirred for 18 hr over which time precipitation occurred. The solid seas filtered and dried in vacuo at 50° C. overnight to yield the subtitle compound (22 g, 70%) as a cream solid. m.p. 152-155° C.

Workup

  1. temperaturemaintaining the temperature below 5° C
  2. additionUpon completion of the addition
  3. additionwas added in one portion
  4. temperaturethe mixture was warmed to reflux
  5. temperatureReflux
  6. temperaturewas maintained for 2 hr after which time the dark brown solution
  7. extractionextracted with ethyl acetate (3×100 ml)
  8. customevaporated in vacuo
  9. customto yield a brown oil
  10. filtrationThe solid seas filtered
  11. customdried in vacuo at 50° C. overnight

Sources & evidence

ORD record
ord-288b5bade8c3413da70886d2ee057a16
Source dataset
uspto-grants-2001_08
Patent number
US06281357B1

Reaction notes

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