Diisopropylethylamine → 3-((3-((4-(Piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)carbamoyl)benzyl)thio)benzoic acid

HRID 926891Notes

Reaction equation

HRID 926891 reaction equation
Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:29][C:10]=1[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:15]=1)=[O:12])=[O:7].[SH:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46]([OH:48])=[O:47].C(N(CC)C(C)C)(C)C>O1CCCC1.[I-].[K+]>[N:33]1([C:30]2[CH:31]=[CH:32][C:9]([NH:8][C:6]([C:5]3[CH:4]=[C:3]([CH:41]=[CH:40][CH:39]=3)[CH2:2][S:42][C:43]3[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=3)[C:46]([OH:48])=[O:47])=[O:7])=[C:10]([C:11](=[O:12])[NH:13][C:14]3[CH:18]=[CH:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:15]=3)[CH:29]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 95737Benzoic acid, 3-mercapto-HCID 665882652-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide

Product 1

HCID 566443423-((3-((4-(Piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)carbamoyl)benzyl)thio)benzoic acidYield 63.3%

Reagents, catalysts & solvents 2

HCID 4875Potassium IodideCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
40 °C

Procedure

Into a 250-mL round bottom flask, was placed a solution of 2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 21a (1.6 g, 2.56 mmol, 1.00 equiv) in tetrahydrofuran (100 mL), 3-mercaptobenzoic acid (390 mg, 2.53 mmol, 0.99 equiv), potassium iodide (21.2 mg, 0.13 mmol, 0.05 equiv), and N,N-diisopropylethylamine (660 mg, 5.12 mmol, 2.00 equiv). The resulting solution was stirred for 24 h at 40° C. in an oil bath. The reaction progress was monitored by TLC/LCMS. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O, extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of hydrochloric acid (1 mol/L) and 3×20 mL of brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:1). This resulted in 1.12 g (63%) of product as a yellow to green solid. 1H-NMR (400 MHz, CDCl3, ppm): δ 11.68(s, 1H), 9.75(s, 1H), 8.60-8.56(d, J=9.2 Hz, 1H), 8.00(s, 1H), 7.91(s, 3H), 7.88-7.81(m, 2H), 7.80-7.79(d, J=2.1 Hz, 1H), 7.66-7.65(d, J=2.4 Hz, 4H), 7.53-7.38(m, 2H), 7.33-7.25(m, 1H), 7.10-7.08(m, 1H), 4.20(s, 2H), 3.17(s, 4H), 1.69-1.54(m, 6H). MS (ES, m/z): 700 [M+H]+.

Workup

  1. customInto a 250-mL round bottom flask, was placed
  2. concentrationThe resulting mixture was concentrated under vacuum
  3. additionThe resulting solution was diluted with 20 mL of H2O
  4. extractionextracted with 3×20 mL of ethyl acetate
  5. washThe resulting mixture was washed with 1×20 mL of hydrochloric acid (1 mol/L) and 3×20 mL of brine
  6. dry with materialThe mixture was dried over anhydrous sodium sulfate
  7. washeluted with ethyl acetate/petroleum ether (1:20-1:1)

Sources & evidence

ORD record
ord-b2628f7810c647bf80e035e966f5bd52
Source dataset
uspto-grants-2016_03
Patent number
US09289430B2

Reaction notes

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