Diisopropylethylamine → 2-Oxo-1-(3-((3-((4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)carbamoyl)benzyl)thio)phenyl)-6,9,12-trioxa-3-azapentadecan-15-oic acid

HRID 2409873Notes

Reaction equation

HRID 2409873 reaction equation
[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=3)[CH2:19][S:20][C:21]3[CH:22]=[C:23]([CH2:27][C:28]([OH:30])=O)[CH:24]=[CH:25][CH:26]=3)=[O:15])=[C:9]([C:34](=[O:51])[NH:35][C:36]3[CH:40]=[CH:39][N:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=4)[N:37]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C[NH:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][C:74]([O:76]C(C)(C)C)=[O:75].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[O:30]=[C:28]([NH:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][C:74]([OH:76])=[O:75])[CH2:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:20][CH2:19][C:18]2[CH:31]=[CH:32][CH:33]=[C:16]([C:14](=[O:15])[NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][C:9]=3[C:34](=[O:51])[NH:35][C:36]3[CH:40]=[CH:39][N:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:48])([F:49])[F:50])[CH:42]=4)[N:37]=3)[CH:17]=2)[CH:22]=1

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 53662991Methylamino-PEG3-t-butyl ester2×HCID 566445522-(3-((3-((4-(Piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)carbamoyl)benzyl)thio)phenyl)acetic acid

Product 1

HCID 566445542-Oxo-1-(3-((3-((4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)carbamoyl)benzyl)thio)phenyl)-6,9,12-trioxa-3-azapentadecan-15-oic acidYield 33.9%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

Into a round bottom flask was placed a solution of 2-(3-((3-((4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)carbamoyl)benzyl)thio)-phenyl)acetic acid 23 (0.119 mmol, 1 equiv) in acetonitrile (0.5 mL), and DIPEA (78.9 mg, 0.612 mmol, 4 equiv). To this was added a solution of tert-butyl 3-(2-(2-(2-(methylamino)ethoxy)ethoxy)ethoxy)propanoate 8b (33.08 mg, 0.127 mmol, 1.1 equiv) in acetonitrile (0.5 mL), followed by HATU (57.9 mg, 0.153 mmol, 1.2 equiv). The mixture was stirred at room temperature. The reaction progress was monitored by LCMS. After 1 h, more 8b (15 mg) was added to the solution, and the solution was stirred another 30 min. The solvent was removed by evaporation at reduced pressure. The residue was dissolved in DCM (1 mL). To this was added TFA (0.5 mL). The solution was stirred for 1 h and then the solvent was evaporated at reduced pressure. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. Lyophilization gave 37 mg of product. 1H NMR (400 MHz, dmso) δ 11.55 (s, 1H), 11.46 (s, 1H), 8.65 (d, J=2.6 Hz, 1H), 8.33 (d, J=8.5 Hz, 1H), 8.16 (s, 1H), 8.12 (d, J=7.9 Hz, 1H), 8.05 (t, J=5.2 Hz, 1H), 7.94 (s, 1H), 7.78-7.67 (m, 3H), 7.61 (d, J=7.5 Hz, 2H), 7.55 (d, J=7.4 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.22 (s, 1H), 7.17 (d, J=4.9 Hz, 3H), 7.01 (s, 3H), 4.30 (s, 3H), 3.54 (t, J=6.4 Hz, 4H), 3.43 (s, 14H), 3.41-3.16 (m, 15H), 3.16-3.09 (m, 3H), 2.39 (t, J=6.4 Hz, 3H), 1.76-1.66 (m, 4H), 1.61-1.52 (m, 2H). MS (ES, m/z) 917 [M+H]+.

Workup

  1. customInto a round bottom flask was placed
  2. stirringthe solution was stirred another 30 min
  3. customThe solvent was removed by evaporation at reduced pressure
  4. dissolutionThe residue was dissolved in DCM (1 mL)
  5. additionTo this was added TFA (0.5 mL)
  6. stirringThe solution was stirred for 1 h
  7. customthe solvent was evaporated at reduced pressure
  8. customThe crude product was purified by reverse phase HPLC
  9. washeluting with a water/CH3CN gradient
  10. additioncontaining 0.05% TFA

Sources & evidence

ORD record
ord-c77cde6df2c745fcb524aef7b1620a13
Source dataset
uspto-grants-2014_08
Patent number
US08815910B2

Reaction notes

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