5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole → HCID 10439569, compound

HRID 2357503Notes

Reaction equation

HRID 2357503 reaction equation
C1([O:7][C:8](=O)[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1>O1CCOCC1>[CH3:24][N:23]([CH3:25])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:40]2[CH2:39][CH:38]=[C:37]([C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([Cl:27])[CH:29]=4)[NH:33][CH:32]=3)[CH2:42][CH2:41]2)=[O:7])[CH2:12][CH2:13]1

Participants

4

Reactant 2

HCID 30505325-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoleHCID 67531743(4-Dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester

Product 1

HCID 10439569HCID 10439569, compoundYield 9%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (705 mg, 2 mmole) was added to a solution of 5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (465.4 mg, 2 mmole) in dioxane (12 ml). The reaction mixture was then boiled under reflux for 20 hours. The reaction mixture was a suspension at RT. The solid was filtered off, washed with cold dioxane (3×2 ml) and dried. The solid was the polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (259 mg, m.p. 120°-130° C., 26%). The reaction solution (filtrate and wash phases) was concentrated by evaporation and water (10 ml) was added to the residue. The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The combined EE extracts were washed with 1M NaOH (1×5 ml) and dried with Na2SO4. The solvent was distilled off in vacuo. The residue contained phenol and mainly the non-polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (80 g). Ethanol (1000 ml) was used as eluent. The non-polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (304 mg, m.p. 216°-222° C., 31%) and a further part of the polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (85 mg, m.p. 108°-111° C., 9%) were thereby isolated.

Workup

  1. temperatureunder reflux for 20 hours
  2. customat RT
  3. filtrationThe solid was filtered off
  4. washwashed with cold dioxane (3×2 ml)
  5. customdried
  6. washThe reaction solution (filtrate and wash phases)
  7. concentrationwas concentrated by evaporation and water (10 ml)
  8. additionwas added to the residue
  9. extractionextracted with EE (3×20 ml)
  10. washThe combined EE extracts were washed with 1M NaOH (1×5 ml)
  11. dry with materialdried with Na2SO4
  12. distillationThe solvent was distilled off in vacuo
  13. customThe diastereoisomers were separated
  14. custompurified by flash chromatography on silica gel (80 g)

Sources & evidence

ORD record
ord-c06aa6080f0a4098b6106e062beebf66
Source dataset
uspto-grants-2010_07
Patent number
US07759385B2

Reaction notes

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