Methylamine → Methyl 4-(4-(dibutylcarbamoyl)-1-(2-(methylamino)-2-oxoethyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate

HRID 529001Notes

Reaction equation

HRID 529001 reaction equation
[CH2:1]([N:5]([CH2:39][CH2:40][CH2:41][CH3:42])[C:6]([C:8]1[N:9]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=2[C:27]([N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:28])[N:11]([CH2:13][C:14]([OH:16])=O)[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:43][N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:1]([N:5]([CH2:39][CH2:40][CH2:41][CH3:42])[C:6]([C:8]1[N:9]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=2[C:27]([N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:28])[N:11]([CH2:13][C:14]([NH:44][CH3:43])=[O:16])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]

Participants

7

Reactant 4

HCID 6329MethylamineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 710623632-(4-(Dibutylcarbamoyl)-2-(4-(methoxycarbonyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-imidazol-1-yl)acetic acid

Product 1

HCID 71062460Methyl 4-(4-(dibutylcarbamoyl)-1-(2-(methylamino)-2-oxoethyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-(4-(dibutylcarbamoyl)-2-(4-(methoxycarbonyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-imidazol-1-yl)acetic acid (180 mg, 0.31 mmol) in dry DMF (5 mL) was added HATU (595 mg, 1.56 mmol), methylamine (Aldrich, 78 μL, 1.56 mmol, 2.0 M in THF) and diisopropylethyl amine (544 μL, 3.13 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature over 30 min and stirring was continued for 16 h. The reaction mixture was diluted with water, and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give crude product. The crude material was purified by flash chromatography (gradient from 20 to 50% EtOAc/hexanes) to provide (85 mg, 46%). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.22-8.19 (m, 1H), 8.10 (dd, J=6.0, 1.6 Hz, 1H), 7.58 (s, 0.5H), 7.56-7.52 (m, 1H), 7.50 (s, 0.5H), 7.36-7.10 (m, 3.5H), 6.94 (d, J=7.6 Hz, 0.5H), 4.76 (br s, 1H), 4.65 (br s, 3H), 3.98 (s, 3H), 3.97-3.95 (m, 1.5H), 3.73 (t, J=5.6 Hz, 1.5H), 3.60-3.30 (m, 3H), 3.00-2.85 (m, 2H), 2.65 (s, 1.5H), 2.64 (s, 1.5H), 1.47-1.24 (m, 6H), 0.96-0.84 (m, 5H), 0.80 (t, J=7.4 Hz, 1.5H), 0.60 (t, J=7.4 Hz, 1.5H); MS(ESI+) m/z 588.4 (M+H)+.

Workup

  1. extractionextracted with EtOAc (3×)
  2. dry with materialThe combined organic layers were dried over Na2SO4
  3. concentrationconcentrated in vacuo
  4. customto give crude product
  5. customThe crude material was purified by flash chromatography (gradient from 20 to 50% EtOAc/hexanes)
  6. customto provide (85 mg, 46%)

Sources & evidence

ORD record
ord-3de02543900d41b1bd5ede8bf508964d
Source dataset
uspto-grants-2016_05
Patent number
US09346795B2

Reaction notes

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