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

HRID 1970642Notes

Reaction equation

HRID 1970642 reaction equation
[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][C@@H:25]([C:27]([OH:29])=O)[CH3:26])[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:70]1([NH:74][C:75]([C@@H:77]2[CH2:81][CH2:80][CH2:79][NH:78]2)=[O:76])[CH2:73][CH2:72][CH2:71]1>CN(C=O)C.ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:36])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][C@H:25]([CH3:26])[C:27]([N:78]3[CH2:79][CH2:80][CH2:81][C@H:77]3[C:75](=[O:76])[NH:74][CH:70]3[CH2:71][CH2:72][CH2:73]3)=[O:29])[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 62415949(2S)-N-cyclobutylpyrrolidine-2-carboxamideHCID 668560214-(2-{[5-((R)-1-Carboxy-ethoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-acetyl)-piperazine-1-carboxylic acid butyl ester

Product 1

HCID 668569494-[2-({5-[(R)-2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-acetyl]-piperazine-1-carboxylic acid butyl ester

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 1.00 g 4-(2-{[5-((R)-1-Carboxy-ethoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-acetyl)-piperazine-1-carboxylic acid butyl ester in 40 ml DMF were added 521 μl DIPEA and 758 mg HATU. After 20 minutes 336 mg (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide were added and the reaction mixture stirred for 3 h. After evaporation of the solvent the crude product was dissolved in dichloromethane and extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3. 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: 517 mg MS (ES+): m/e=652.

Workup

  1. customAfter evaporation of the solvent the crude product
  2. dissolutionwas dissolved in dichloromethane
  3. extractionextracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3
  4. customThe crude product obtained
  5. customafter evaporation of the solvent
  6. customwas purified by preparative HPLC (
  7. washC18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA)
  8. additionThe fractions containing the product
  9. customto yield the pure product which
  10. washwashed once with aqueous NaHCO3
  11. customThe residue obtained
  12. customafter evaporation of the solvent

Sources & evidence

ORD record
ord-775902e94c274a80a8e44fbc02bb977d
Source dataset
uspto-grants-2013_04
Patent number
US08426420B2

Reaction notes

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