Diisopropylethylamine → 4-[(S)-4-tert-Butoxycarbonyl-2-({5-[2-((S)-4,4-difluoro-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

HRID 1970562Notes

Reaction equation

HRID 1970562 reaction equation
[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](O)=[O:34])[N:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:62][O:63][C:64]([C@@H:66]1[CH2:70][C:69]([F:72])([F:71])[CH2:68][NH:67]1)=[O:65]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:67]3[CH2:68][C:69]([F:72])([F:71])[CH2:70][C@H:66]3[C:64]([O:63][CH3:62])=[O:65])=[O:34])[N:28]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 181649HOAtHCID 45082563methyl (2S)-4,4-difluoropyrrolidine-2-carboxylateHCID 46186284HCID 46186284, compound

Product 1

HCID 668544804-[(S)-4-tert-Butoxycarbonyl-2-({5-[2-((S)-4,4-difluoro-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 1.2 g 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-carboxymethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 35 ml DMF were added 278 mg HOAt, 1.6 g EDC, 1.1 ml DIPEA and 684 mg (S)-4,4-Difluoro-pyrrolidine-2-carboxylic acid methyl ester hydrotrifluoroacetate. After 36 h the mixture was diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was purified by chromatography on silica using heptan/ethyl acetate 40/60 to 33/67 as eluent.

Workup

  1. extractionsubsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and saturated aqueous NaHCO3
  2. dry with materialThe organic layer was dried over MgSO4
  3. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-91b9d79f52424dd1bc6dab44198993f0
Source dataset
uspto-grants-2013_04
Patent number
US08426420B2

Reaction notes

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