Diisopropylethylamine → Methyl 4-(4-(dibutylcarbamoyl)-1-phenethyl-1H-imidazol-2-yl)-3-((S)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate

HRID 529011Notes

Reaction equation

HRID 529011 reaction equation
[CH2:1]([N:5]([CH2:34][CH2:35][CH2:36][CH3:37])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][C:22]=2[C:23](O)=[O:24])[N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:62]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH2:65][C@@H:64]([CH2:72][OH:73])[NH:63]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:34]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][C:22]=2[C:23]([N:63]2[C@H:64]([CH2:72][OH:73])[CH2:65][C:66]3[C:71](=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH2:62]2)=[O:24])[N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1)=[O:7])[CH2:35][CH2:36][CH3:37]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 776757[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]methanolHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 710622442-(4-(Dibutylcarbamoyl)-1-phenethyl-1H-imidazol-2-yl)-5-(methoxycarbonyl)benzoic acid

Product 1

HCID 71086503Methyl 4-(4-(dibutylcarbamoyl)-1-phenethyl-1H-imidazol-2-yl)-3-((S)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoateYield 69.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-(4-(dibutylcarbamoyl)-1-phenethyl-1H-imidazol-2-yl)-5-(methoxycarbonyl)benzoic acid (130 mg, 0.25 mmol) in DMF (5 mL) was added HATU (293 mg, 0.77 mmol), (S)-1,2,3,4-tetrahydroisoquinoline-3-yl-methanol (84 mg, 0.51 mmol) and diisopropylethylamine (269 μL, 1.54 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with water and extracted with MTBE (3×). The combined organic layer was dried over Na2SO4 and concentrated to give crude product. The crude material was purified by flash chromatography (gradient from 0% to 50% EtOAc/hexanes) to provide the title compound (113 mg, 61%) as a light yellow oil. 1H NMR (DMSO-d6, 1:1 mixture amide rotamers) δ 8.14-8.01 (m, 2H), 7.64 (s, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.26-7.21 (m, 3H), 7.17-7.03 (m, 5.5H), 6.98 (d, J=6.8 Hz, 0.5H), 5.03 (d, J=18.4 Hz, 0.5H), 4.91 (br s, 1H), 4.39 (br s, 0.5H), 4.24 (d, J=18.4 Hz, 0.5H), 4.16-4.07 (m, 2.5H), 3.91 (s, 3H), 3.88-3.85 (m, 0.5H), 3.76-3.73 (m, 0.5H), 3.65-3.55 (m, 1H), 3.39-3.34 (m, 2H), 3.24-3.00 (m, 2H), 2.96-2.85 (m, 3H), 2.70-2.65 (m, 2H), 1.50-1.11 (m, 8H), 0.88-0.76 (m, 6H); MS(ESI+) m/z 651.4 (M+H)+.

Workup

  1. extractionextracted with MTBE (3×)
  2. dry with materialThe combined organic layer was dried over Na2SO4
  3. concentrationconcentrated
  4. customto give crude product
  5. customThe crude material was purified by flash chromatography (gradient from 0% to 50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-bbd8f9c2210048e8a6769c7db69127b0
Source dataset
uspto-grants-2016_05
Patent number
US09346795B2

Reaction notes

Loading…