Ammonia → ethyl 4-cyclohexyl-1-[(R)-2-{3-[3-(3H-imidazol-4-yl)propyl]ureido}-3-(4-methoxyphenyl)propionyl]-piperidine-4-carboxylate

HRID 1855664Notes

Reaction equation

HRID 1855664 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]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.N.FC(F)(F)[C:47]([OH:49])=O.FC(F)(F)C(O)=O.[NH:59]1[CH:63]=[C:62]([CH2:64][CH2:65][CH2:66][NH2:67])[N:61]=[CH:60]1>C(Cl)Cl.CN(C=O)C.C(N(CC)CC)C.O>[CH:16]1([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:47]([NH:67][CH2:66][CH2:65][CH2:64][C:62]3[NH:61][CH:60]=[N:59][CH:63]=3)=[O:49])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH2:6][CH2:7]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1

Participants

9

Reactant 4

HCID 222AmmoniaHCID 821294-Nitrophenyl chloroformateHCID 66987937ethyl 1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylateHCID 178510940HCID 178510940, compound

Product 1

HCID 46194157ethyl 4-cyclohexyl-1-[(R)-2-{3-[3-(3H-imidazol-4-yl)propyl]ureido}-3-(4-methoxyphenyl)propionyl]-piperidine-4-carboxylateYield 19.1%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×HCID 8471TriethylamineSolvent

Procedure

To 100 mg (0.24 mmol) of ethyl 1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate dissolved in 2 ml of DCM immersed in a bath of cold water are added 53 mg (0.26 mmol) of 4-nitrophenyl chloroformate. After warming to room temperature, the reaction medium is stirred for 2 hours and 30 minutes. The reaction is stopped by adding aqueous ammonia solution. The organic phase is then washed with water and then dried over MgSO4, filtered and concentrated. The oil obtained is dissolved in 4 ml of DMF at 80° C., and 110 mg (0.31 mmol) of 3-(1H-imidazol-4-yl)propylamine bis(trifluoroacetate), 0.05 ml of triethylamine are then added. The reaction mixture is left stirring at 80° C. for 15 minutes. After returning to room temperature, dichloromethane is added and the organic phase is washed with 1N sodium hydroxide solution. The organic phase is dried over MgSO4, filtered and concentrated. The crude product obtained is chromatographed on silica gel (eluent: 9/1 DCM/MeOH). 26 mg of ethyl 4-cyclohexyl-1-[(R)-2-{3-[3-(3H-imidazol-4-yl)propyl]ureido}-3-(4-methoxyphenyl)propionyl]-piperidine-4-carboxylate in the form of a colourless oil are obtained in a yield of 11%.

Workup

  1. washThe organic phase is then washed with water
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe oil obtained
  6. waitThe reaction mixture is left
  7. stirringstirring at 80° C. for 15 minutes
  8. customAfter returning to room temperature
  9. washthe organic phase is washed with 1N sodium hydroxide solution
  10. dry with materialThe organic phase is dried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe crude product obtained
  14. customis chromatographed on silica gel (eluent: 9/1 DCM/MeOH)

Sources & evidence

ORD record
ord-dd33c72766274e8eb0d9400b8eb0b41b
Source dataset
uspto-grants-2015_02
Patent number
US08962846B2

Reaction notes

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