1-Hydroxybenzotriazole → 4-[(S)-6-Benzyloxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-hexanoyl]-piperazine-1-carboxylic acid cyclobutyl ester

HRID 1970612Notes

Reaction equation

HRID 1970612 reaction equation
[CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:50]1([O:54][C:55]([N:57]2[CH2:62][CH2:61][N:60]([C:63](=[O:78])[C@@H:64]([NH2:77])[CH2:65][CH2:66][CH2:67][CH2:68][O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:59][CH2:58]2)=[O:56])[CH2:53][CH2:52][CH2:51]1>CN(C=O)C.C(Cl)CCl>[CH:50]1([O:54][C:55]([N:57]2[CH2:62][CH2:61][N:60]([C:63](=[O:78])[C@@H:64]([NH:77][C:27]([C:18]3[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[C:6](=[O:7])[NH:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)=[O:30])[N:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:19]=3)=[O:28])[CH2:65][CH2:66][CH2:67][CH2:68][O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:59][CH2:58]2)=[O:56])[CH2:53][CH2:52][CH2:51]1

Participants

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 66854150HCID 66854150, compoundHCID 668546955-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid

Product 1

HCID 668552404-[(S)-6-Benzyloxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-hexanoyl]-piperazine-1-carboxylic acid cyclobutyl ester

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 480 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 10 ml DMF were added 232 mg HOBt, 290 mg EDC and 0.48 ml DIPEA. After 5 minutes 470 mg (S)-4-(2-Amino-6-benzyloxy-hexanoyl)-piperazine-1-carboxylic acid cyclobutyl ester were added and the mixture stirred for 12 h. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product was obtained by evaporation of the solvent. An aliquot (80 mg) was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 40 mg MS (ES+): m/e=798.

Workup

  1. concentrationThe reaction mixture was concentrated
  2. additiondiluted with ethyl acetate
  3. washwashed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3
  4. customThe crude product was obtained by evaporation of the solvent
  5. customAn aliquot (80 mg) was purified by preparative HPLC (
  6. washC18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA)

Sources & evidence

ORD record
ord-cd8ed4ac42e845c38145a723cc2d7fb8
Source dataset
uspto-grants-2013_04
Patent number
US08426420B2

Reaction notes

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