Triethylamine → 4-[(S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-4-(2,2-dimethyl-propionyloxymethoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

HRID 1970520Notes

Reaction equation

HRID 1970520 reaction equation
[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:41][CH2:40][CH2:39]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].ClC[CH2:52][C:53]([CH3:58])([CH3:57])[C:54]([O-:56])=[O:55].[C:59](=O)([O-])[O-].[Cs+].[Cs+].C(N(CC)CC)C>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:39][CH2:40][CH2:41]3)=[O:30])[N:24]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:59][O:56][C:54](=[O:55])[C:53]([CH3:58])([CH3:57])[CH3:52])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]

Participants

7

Reactant 4

HCID 8471Triethylamine2×HCID 10796Cesium carbonate2×HCID 217530474-Chloro-2,2-dimethylbutanoate2×HCID 668558244-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

Product 1

HCID 668547874-[(S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-4-(2,2-dimethyl-propionyloxymethoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalyst2×HCID 180AcetoneSolvent

Procedure

To a solution of 150 mg 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 7 ml acetone were added 40 mg chloromethylpivalate, 8 mg tetrabutylammonium iodide, 72 mg cesium carbonate and 61 μl triethylamine. The reaction mixture was refluxed for 4 h under argon. Additional 40 mg chloromethylpivalate, 8 mg tetrabutylammonium iodide, 72 mg cesium carbonate and 61 μl triethylamine were added and the suspension refluxed for another 7 h. The reaction mixture was concentrated and the residue 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 lyophilized to yield the pure product. Yield: 75 mg MS (ES+): m/e=796.

Workup

  1. temperatureThe reaction mixture was refluxed for 4 h under argon
  2. temperaturethe suspension refluxed for another 7 h
  3. concentrationThe reaction mixture was concentrated
  4. customthe residue was purified by preparative HPLC (
  5. washC18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA)
  6. additionThe fractions containing the product
  7. customto yield the pure product

Sources & evidence

ORD record
ord-eed8256df9f449448f31238aae9a4ae3
Source dataset
uspto-grants-2013_04
Patent number
US08426420B2

Reaction notes

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