Diisopropylethylamine → (R)-4-{(S)-4-Carboxy-2-[(5-{2-[(S)-2-(2-fluoro-ethylcarbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-2-methyl-piperazine-1-carboxylic acid ethyl ester

HRID 1970531Notes

Reaction equation

HRID 1970531 reaction equation
C([O:5][C:6](=[O:42])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:35])[NH:31][CH2:32][CH2:33][F:34])=[O:24])[N:18]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.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.[CH2:76]([O:78][C:79]([N:81]1[CH2:86][CH2:85][NH:84][CH2:83][C@H:82]1[CH3:87])=[O:80])[CH3:77]>CN(C=O)C>[CH2:76]([O:78][C:79]([N:81]1[CH2:86][CH2:85][N:84]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:35])[NH:31][CH2:32][CH2:33][F:34])=[O:24])[N:18]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:42])=[O:5])[CH2:83][C@H:82]1[CH3:87])=[O:80])[CH3:77]

Participants

6

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 45099581(R)-2-Methyl-piperazine-1-carboxylic acid ethyl esterHCID 86650477(S)-2-({5-[2-((S)-2-(2-Fluoro-ethylcarbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester

Product 1

HCID 86650479(R)-4-{(S)-4-Carboxy-2-[(5-{2-[(S)-2-(2-fluoro-ethylcarbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-2-methyl-piperazine-1-carboxylic acid ethyl ester

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 81 mg (S)-2-({5-[2-((S)-2-(2-Fluoroethyl-carbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 22 μl DIPEA, 52 mg HATU and 24 mg (R)-2-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 24 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 300 μl TFA. After stirring for 16 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.

Workup

  1. concentrationwas concentrated
  2. dissolutionthe residue dissolved in 1.5 ml dichloromethane
  3. additiontreated with 300 μl TFA
  4. stirringAfter stirring for 16 h the solvents
  5. customwere removed under reduced pressure
  6. customthe residue 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

Sources & evidence

ORD record
ord-9c3f08186d0744b494193065f9be8395
Source dataset
uspto-grants-2013_04
Patent number
US08426420B2

Reaction notes

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