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

HRID 651695Notes

Reaction equation

HRID 651695 reaction equation
[CH2:1]([N:8]([CH3:15])[S:9]([CH2:12][C:13]#[N:14])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:22]([N:29]1[C:37]2[C:32](=[CH:33][C:34](Br)=[CH:35][CH:36]=2)[C:31]([CH2:39][C@H:40]2[CH2:44][CH2:43][CH2:42][N:41]2[CH3:45])=[CH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1(C)C=CC=CC=1.[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>[CH2:1]([N:8]([CH3:15])[S:9]([CH:12]([C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:30]=[C:31]2[CH2:39][C@H:40]1[CH2:44][CH2:43][CH2:42][N:41]1[CH3:45])[C:13]#[N:14])(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 962WaterHCID 12179009Methanesulfonamide, 1-cyano-N-methyl-N-(phenylmethyl)-HCID 23665647Potassium tert-butoxideHCID 54492095(r)-1-Benzyl-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1h-indole

Product 1

HCID 59966110N-Benzyl-1-[(R)-1-benzyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-1-cyano-N-methylmethanesulfonamideYield 80%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 1140TolueneSolvent2×

Procedure

To a stirred solution of N-benzyl-1-cyano-N-methylmethanesulfonamide (from step (c), 643 mg, 2.9 mmol) in toluene (5 ml) at 0° C. under a nitrogen atmosphere was added potassium tert-butoxide (615 mg, 5.5 mmol) portionwise, maintaining the temperature below 5° C. The brown solution was then warmed to ambient temperature over a 10 min period, before tetrakis(triphenylphosphine) palladium(0) (181 mg, 0.16 mmol) was added in one portion. A solution of (R)-1-benzyl-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (from step (d), 1.0 g, 2.6 mmol) in toluene (5 ml) was then added dropwise to the yellow slurry and the mixture was warmed to reflux. Reflux was maintained for 1.5 hr after which time the dark brown solution was cooled to ambient temperature. The reaction mixture was then poured into water (25 ml) and extracted with ethyl acetate (3×25 ml). The combined organic extracts were evaporated in vacuo to yield a brown oil. This was purified by flash column chromatography (ethyl acetate:hexane:diethylamine 1:1:0.1 as eluant) to give the title compound (1.09 g, 80%) as a brown oil.

Workup

  1. temperaturemaintaining the temperature below 5° C
  2. additionwas added in one portion
  3. temperaturethe mixture was warmed to reflux
  4. temperatureReflux
  5. temperaturewas maintained for 1.5 hr after which time the dark brown solution
  6. extractionextracted with ethyl acetate (3×25 ml)
  7. customThe combined organic extracts were evaporated in vacuo
  8. customto yield a brown oil
  9. customThis was purified by flash column chromatography (ethyl acetate:hexane:diethylamine 1:1:0.1 as eluant)

Sources & evidence

ORD record
ord-9a2318a698a343539edc5d6a88e45d66
Source dataset
uspto-grants-2001_08
Patent number
US06281357B1

Reaction notes

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