Ethylmorpholine → 4-[2-({5-[2-((2S,4R)-2-Cyclobutylcarbamoyl-4-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-acetyl]-piperazine-1-carboxylic acid butyl ester

HRID 1970644Notes

Reaction equation

HRID 1970644 reaction equation
[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26](O)=[O:27])[N:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].FC1C(O)=C(F)C(F)=C(F)C=1F.[CH:48]1([NH:52][C:53]([C@@H:55]2[CH2:59][C@@H:58]([OH:60])[CH2:57][NH:56]2)=[O:54])[CH2:51][CH2:50][CH2:49]1.C(N1CCOCC1)C>CN(C=O)C.C(Cl)Cl.C(Cl)CCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:35])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([N:56]3[CH2:57][C@H:58]([OH:60])[CH2:59][C@H:55]3[C:53](=[O:54])[NH:52][CH:48]3[CH2:51][CH2:50][CH2:49]3)=[O:27])[N:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]

Participants

8

Reactant 4

HCID 7525EthylmorpholineHCID 13041PentafluorophenolHCID 66855041(2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid cyclobutylamideHCID 668555664-{2-[(5-Carboxymethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester

Product 1

HCID 668554924-[2-({5-[2-((2S,4R)-2-Cyclobutylcarbamoyl-4-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-acetyl]-piperazine-1-carboxylic acid butyl ester

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 700 mg 4-{2-[(5-Carboxymethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 10 ml DMF were added 317 mg pentafluorophenol and 330 mg EDC. The mixture was stirred under exclusion of moisture until LCMS indicated complete conversion to the corresponding pentafluorophenolester. (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid cyclobutylamide hydrotrifluoroacetate (455 mg) was mixed with 0.55 ml N-ethylmorpholine and 5 ml DMF and this mixture added dropwise to the solution of the pentafluorophenolester. After 12 h the reaction mixture was diluted with DCM and washed with aqueous LiCl (4%), saturated aqueous NaHCO3 and brine. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were immediately lyophilized to yield the pure product which was taken up in dichloromethane and washed once with aqueous NaHCO3. The residue obtained after evaporation of the solvent was lyophilized again to give the title compound. Yield: 454 mg MS (ES+): m/e=654.

Workup

  1. additionthis mixture added dropwise to the solution of the pentafluorophenolester
  2. washwashed with aqueous LiCl (4%), saturated aqueous NaHCO3 and brine
  3. customThe crude product obtained
  4. customafter evaporation of the solvent
  5. customwas purified by preparative HPLC (
  6. washC18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA)
  7. additionThe fractions containing the product
  8. customto yield the pure product which
  9. washwashed once with aqueous NaHCO3
  10. customThe residue obtained
  11. customafter evaporation of the solvent

Sources & evidence

ORD record
ord-458a1fdff03c48109803b6f45d93a97b
Source dataset
uspto-grants-2013_04
Patent number
US08426420B2

Reaction notes

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