Ammonia → HCID 178450012, compound

HRID 333451Notes

Reaction equation

HRID 333451 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.[NH2:45][CH2:46][CH2:47][C:48]1[N:52]=[CH:51][NH:50][CH:49]=1.[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:45][CH2:46][CH2:47][C:48]2[N:52]=[CH:51][NH:50][CH:49]=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

8

Reactant 5

HCID 222AmmoniaHCID 14798Sodium HydroxideHCID 821294-Nitrophenyl chloroformateHCID 669876811-{1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidin-4-yl}butan-1-oneHCID 178419017HCID 178419017, compound

Product 1

HCID 178450012HCID 178450012, compoundYield 67%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

1.24 g (3 mmol) of 1-{1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexyl-piperidin-4-yl}butan-1-one and 660 mg (3.3 mmol) of para-nitrophenyl chloroformate are dissolved in 40 mL of dichloromethane at 0° C. The reaction mixture is stirred for 1 hour at room temperature and the reaction is then stopped by adding 20% aqueous ammonia solution and the organic products are extracted with dichloromethane. The organic phase is washed with water and then dried over sodium sulfate, filtered and concentrated. The white solid obtained is dissolved in 20 mL of DMF, the mixture is heated to 80° C., 0.367 g (3.3 mmol) of histamine is 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 NaOH solution and the reaction medium is extracted with DCM. The organic phase is washed with water and then dried over sodium sulfate, filtered and concentrated. The crude product obtained is chromatographed on silica gel (eluent: 80/20 DCM/MeOH). 1.1 g of 1-[(R)-2-(4-butyryl-4-cyclo-hexylpiperidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1H-imidazol-4-yl)ethyl]urea in the form of a white powder are obtained in a yield of 67%.

Workup

  1. extractionthe organic products are extracted with dichloromethane
  2. washThe organic phase is washed with water
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe white solid 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. extractionthe reaction medium is extracted with DCM
  10. washThe organic phase is washed with water
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe crude product obtained
  15. customis chromatographed on silica gel (eluent: 80/20 DCM/MeOH)

Sources & evidence

ORD record
ord-e64caa9c8bcd4eaf91fc190204cbfa65
Source dataset
uspto-grants-2014_11
Patent number
US08877968B2

Reaction notes

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