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

HRID 1970564Notes

Reaction equation

HRID 1970564 reaction equation
[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][C:38]([F:41])([F:40])[CH2:37][C@H:36]3[C:42]([OH:44])=O)=[O:34])[N:28]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=[N:76][C:71]2[CH:72]=[CH:73][CH:74]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCC1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:51])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][C:38]([F:40])([F:41])[CH2:37][C@H:36]3[C:42](=[O:44])[NH:76][CH:71]3[CH2:72][CH2:73][CH2:74]3)=[O:34])[N:28]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]

Participants

7

Reactant 4

HCID 75645CyclobutylamineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66855209HCID 66855209, compound

Product 1

HCID 668550324-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-4,4-difluoro-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 100 mg 4-[(S)-4-tert-Butoxycarbonyl-2-({5-[2-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 5 ml DMF were added 24 μl DIPEA, 53 mg HATU and 12 μl cyclobutylamine. After stirring for 4 h the mixture was dissolved in ethyl acetate and washed with aqueous LiCl (4% w/w) and saturated aqueous NaHCO3. The solvent was evaporated, the residue dissolved in 1.5 ml dichloromethane and treated with 300 μl TFA. After stirring for 34 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. Yield: 43 mg MS (ES+): m/e=718.

Workup

  1. washwashed with aqueous LiCl (4% w/w) and saturated aqueous NaHCO3
  2. customThe solvent was evaporated
  3. dissolutionthe residue dissolved in 1.5 ml dichloromethane
  4. additiontreated with 300 μl TFA
  5. stirringAfter stirring for 34 h the solvents
  6. customwere removed under reduced pressure
  7. customthe residue purified by preparative HPLC (
  8. washC18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA)
  9. additionThe fractions containing the product
  10. customto yield the pure product

Sources & evidence

ORD record
ord-2b4651bd326748978d2a66b156dcdea6
Source dataset
uspto-grants-2013_04
Patent number
US08426420B2

Reaction notes

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