Diisopropylethylamine → Methyl (S)-1-((S)-2-(4-(((4-((S)-1-((R)-2-(dimethylamino)-2-phenylacetyl)pyrrolidine-2-carboxamido)benzyl)(phenyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate

HRID 923382Notes

Reaction equation

HRID 923382 reaction equation
[CH3:1][C:2]([CH3:49])([CH3:48])[C@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:4](=[O:42])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:41])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@@H:30]3[CH2:34][CH2:33][CH2:32][NH:31]3)=[O:29])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1.[CH3:50][N:51]([CH3:62])[C@H:52]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:53](O)=[O:54].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH3:50][N:51]([CH3:62])[C@H:52]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:53]([N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:19]([CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:10]([C@@H:6]3[CH2:7][CH2:8][CH2:9][N:5]3[C:4](=[O:42])[C@@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:2]([CH3:49])([CH3:48])[CH3:1])=[O:41])=[CH:17][CH:16]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:22][CH:23]=1)=[O:29])=[O:54]

Participants

7

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 36691413(R)-2-(dimethylamino)-2-phenylacetic acidHCID 59540386Methyl (S)-3,3-dimethyl-1-oxo-1-((S)-2-(4-((phenyl(4-((S)-pyrrolidine-2-carboxamido)benzyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-yl)butan-2-ylcarbamate

Product 1

HCID 59540195Methyl (S)-1-((S)-2-(4-(((4-((S)-1-((R)-2-(dimethylamino)-2-phenylacetyl)pyrrolidine-2-carboxamido)benzyl)(phenyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamateYield 43.8%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Procedure

The product from Example 10A (15 mg, 0.022 mmol) was combined with (R)-2-(dimethylamino)-2-phenylacetic acid (4.82 mg, 0.027 mmol), HATU (9.38 mg, 0.025 mmol) and Hunig's base (0.014 mL, 0.078 mmol) in DMSO (0.5 mL) and the mixture was stirred at room temperature for 45 min. Diluted with water and collected the solid by filtration. The product was purified by chromatography on silica gel, eluting with 0-4% MeOH in CH2Cl2 to give the title compound (8 mg, 43% yield). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.02 (s, 9 H) 1.65-1.73 (m, 1 H) 1.86-1.95 (m, 2 H) 1.99-2.08 (m, 1 H) 2.13-2.20 (m, 2 H) 2.26 (s, 6 H) 2.49 (dd, J=12.21, 6.56 Hz, 1 H) 2.53-2.60 (m, 1 H) 3.32-3.39 (m, 1 H) 3.65-3.68 (m, 1 H) 3.69 (s, 3 H) 3.74-3.80 (m, 1 H) 3.81-3.87 (m, 1 H) 4.01 (s, 1 H) 4.38 (d, J=9.77 Hz, 1 H) 4.56 (s, 4 H) 4.76 (d, J=7.17 Hz, 1 H) 4.80 (dd, J=8.01, 2.52 Hz, 1 H) 5.39 (d, J=9.61 Hz, 1 H) 6.70 (t, J=7.25 Hz, 1 H) 6.73 (d, J=7.93 Hz, 2 H) 7.12-7.19 (m, 6 H) 7.36-7.43 (m, 5 H) 7.47-7.51 (m, 4 H) 9.30 (s, 1 H) 9.71 (s, 1 H).

Workup

  1. customcollected the solid
  2. filtrationby filtration
  3. customThe product was purified by chromatography on silica gel
  4. washeluting with 0-4% MeOH in CH2Cl2

Sources & evidence

ORD record
ord-eca08dc5b74d4ce6b08b65c82cc39f8b
Source dataset
uspto-grants-2016_03
Patent number
US09278922B2

Reaction notes

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