N,N'-Dicyclohexylurea → 2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)piperidine-1-yl]-ethanone

HRID 2357491Notes

Reaction equation

HRID 2357491 reaction equation
ON1C2C=CC=CC=2N=N1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH2:12]1.CN1CCOCC1.[CH3:33][N:34]([CH3:51])[C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:40][CH2:39][C:38](=[CH:41][C:42](O)=[O:43])[CH2:37][CH2:36]1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O.[OH-].[Na+]>CN(C)C=O.O>[CH3:51][N:34]([CH3:33])[C:35]1([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:40][CH2:39][C:38](=[CH:41][C:42]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:12]2)=[O:43])[CH2:37][CH2:36]1

Participants

10

Reactant 7

HCID 4277N,N'-DicyclohexylureaHCID 79724-MethylmorpholineHCID 10868DicyclohexylcarbodiimideHCID 14798Sodium HydroxideHCID 757711-HydroxybenzotriazoleHCID 153894433-(Piperidin-3-YL)-1H-indoleHCID 574382874-Dimethylamino-4-phenylcyclohexylidene-acetic acid

Product 1

HCID 99567182-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)piperidine-1-yl]-ethanoneYield 30%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

1-hydroxybenzotriazole (675 mg, 5.0 mmole), 3-piperidine-3-yl-1H-indole (500 mg, 2.5 mmole) and N-methylmorpholine (0.555 ml, 5.0 mmole) were added in succession under argon to a solution of (4-dimethylamino-4-phenylcyclohexylidene)-acetic acid (739 mg, 2.5 mmole) in dry dimethylformamide (10 ml). The solution was cooled in an ice bath and dicyclohexylcarbodiimide (1.03 g, 5.0 mmole) was added. The reaction mixture was stirred for 5 days at RT, the dicyclohexylurea precipitating out little by little. The reaction mixture was worked up by separating the precipitated urea and adding the filtrate to a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Further urea together with 2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)-piperidine-1-yl]-ethanone thereupon precipitated out (1.5 g). The aqueous phase was diluted with water (300 ml), 5M sodium hydroxide (7 ml, 35 mmole) was added, and the whole was kept for 16 hours at 5° C. The crude product thereupon precipitated out as a colourless solid (464 mg). The crude product of 2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)-piperidine-1-yl]-ethanone was purified chromatographically on silica gel (60 g) with EE/methanol (4:1) and (2:1) and obtained in a yield of 30% (322 mg)—2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)-piperidine-1-yl]-ethanone was obtained as a diastereoisomer mixture. A separation was not possible.

Workup

  1. temperatureThe solution was cooled in an ice bath
  2. customby separating the precipitated urea
  3. additionadding the filtrate
  4. additionto a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml)
  5. customFurther urea together with 2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)-piperidine-1-yl]-ethanone thereupon precipitated out (1.5 g)
  6. additionwas added
  7. waitthe whole was kept for 16 hours at 5° C
  8. customThe crude product thereupon precipitated out as a colourless solid (464 mg)
  9. customThe crude product of 2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)-piperidine-1-yl]-ethanone was purified chromatographically on silica gel (60 g) with EE/methanol (4:1) and (2:1)

Sources & evidence

ORD record
ord-b5b7c10c44e04ab9b41d9f2bbb0ccff9
Source dataset
uspto-grants-2010_07
Patent number
US07759385B2

Reaction notes

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