Ammonia → 1-[(R)-2-(4-butyryl-4-cyclohexylpiperidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1-methyl-1H-imidazol-4-yl)ethyl]urea

HRID 1855658Notes

Reaction equation

HRID 1855658 reaction equation
[NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].Cl[C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].N.[CH3:45][N:46]1[CH:53]=[N:52][C:48]([CH2:49][CH2:50][NH2:51])=[CH:47]1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl.CN(C=O)C>[C:17]([C:8]1([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:32]([NH:51][CH2:50][CH2:49][C:48]2[N:52]=[CH:53][N:46]([CH3:45])[CH:47]=2)=[O:33])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:6][CH2:7]1)(=[O:21])[CH2:18][CH2:19][CH3:20]

Participants

9

Reactant 6

HCID 222AmmoniaHCID 36141-MethylhistamineHCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 821294-Nitrophenyl chloroformateHCID 669876811-{1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidin-4-yl}butan-1-one

Product 1

HCID 461940291-[(R)-2-(4-butyryl-4-cyclohexylpiperidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1-methyl-1H-imidazol-4-yl)ethyl]ureaYield 39.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

75 mg (0.18 mmol) of 1-{1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidin-4-yl}butan-1-one and 40 mg (0.2 mmol) of para-nitrophenyl chloroformate are dissolved in 5 ml of dichloromethane. The mixture is stirred for 1 hour at room temperature and the solution is then stopped by adding 20% aqueous ammonia and extracted with dichloromethane. The organic phase is washed with water and then dried over sodium sulfate, filtered and concentrated to dryness. The oil obtained is diluted in 5 ml of DMF, the mixture is heated to 80° C. and 39 mg (0.2 mmol) of 1-methylhistamine and 0.05 ml (0.36 mmol) of triethylamine are then added, and the solution is stirred for 5 minutes at 80° C. and for 10 minutes at room temperature. The reaction is stopped by adding aqueous 1N sodium hydroxide solution and then extracted with DCM. The organic phase is washed with water and then dried over sulfate, filtered and concentrated. The oil obtained is chromatographed on silica gel (eluent: 90/10 DCM/MeOH). 40 mg of 1-[(R)-2-(4-butyryl-4-cyclohexylpiperidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1-methyl-1H-imidazol-4-yl)ethyl]urea in the form of a colourless oil are obtained in a yield of 39%.

Workup

  1. extractionextracted with dichloromethane
  2. washThe organic phase is washed with water
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated to dryness
  6. customThe oil obtained
  7. temperaturethe mixture is heated to 80° C.
  8. stirringthe solution is stirred for 5 minutes at 80° C. and for 10 minutes at room temperature
  9. extractionextracted with DCM
  10. washThe organic phase is washed with water
  11. dry with materialdried over sulfate
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe oil obtained
  15. customis chromatographed on silica gel (eluent: 90/10 DCM/MeOH)

Sources & evidence

ORD record
ord-bf34b2f1eaaa413d8bb4fc823e4370b1
Source dataset
uspto-grants-2015_02
Patent number
US08962846B2

Reaction notes

Loading…