Diisopropylethylamine → Methyl (2s)-1-(4-(5-(4-aminophenyl)-1-(4-(6-morpholinopyridin-3-yl)phenyl)pyrrolidin-2-yl)phenylamino)-3-methyl-1-oxobutan-2-ylcarbamate

HRID 1470983Notes

Reaction equation

HRID 1470983 reaction equation
[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]([C:24]5[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=5)[CH2:22][CH2:21][CH:20]4[C:31]4[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:38][O:39][C:40]([NH:42][C@@H:43]([CH:47]([CH3:49])[CH3:48])[C:44](O)=[O:45])=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CS(C)=O.CO>[NH2:28][C:27]1[CH:29]=[CH:30][C:24]([CH:23]2[N:19]([C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:11]=[N:12][C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)=[CH:8][CH:9]=4)=[CH:18][CH:17]=3)[CH:20]([C:31]3[CH:32]=[CH:33][C:34]([NH:35][C:44](=[O:45])[C@@H:43]([NH:42][C:40](=[O:41])[O:39][CH3:38])[CH:47]([CH3:49])[CH3:48])=[CH:36][CH:37]=3)[CH2:21][CH2:22]2)=[CH:25][CH:26]=1

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 10942966(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acidHCID 672367054,4'-(1-(4-(6-Morpholinopyridin-3-yl)phenyl)pyrrolidine-2,5-diyl)dianiline

Product 1

HCID 59616795Methyl (2s)-1-(4-(5-(4-aminophenyl)-1-(4-(6-morpholinopyridin-3-yl)phenyl)pyrrolidin-2-yl)phenylamino)-3-methyl-1-oxobutan-2-ylcarbamateYield 52.1%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 887MethanolSolvent

Conditions

Temperature
25 °C

Procedure

In an oven-dried 5-mL round bottom flask purged with nitrogen, dissolved the product of Example 108B (70 mg, 0.142 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (26.2 mg, 0.150 mmol) in anhydrous DMSO (1.5 mL), added HATU (58.6 mg, 0.150 mmol) and diisopropylethylamine (0.050 mL, 0.285 mmol), and stirred dark yellow solution at 25° C. for 15 min. Diluted the reaction with MeOH (1.5 mL) and purified by RP-C18 HPLC (Waters Prep LC, 40 mm Module with Nova Pak HR C18 6 μm 40×100 mm Prep Pak cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA in H2O/AcCN to 25:75 0.1% TFA in H2O/AcCN, then 10 min to 100% AcCN at 20 mL/min. Pure fractions were concentrated by rotary evaporation (water bath 35°) to a small volume, partitioned between 20% iPrOH/CHCl3 (50 mL), and sat'd aq NaHCO3 (15 mL), separated layers, dried organic extract over anhydrous MgSO4, filtered, and concentrated by rotary evaporation to afford the title compound as a light yellow solid (48 mg, 52%). 1H NMR showed the material to be ˜3:1 trans:cis mixture; MS (ESI+) m/z 649 (M+H)+, 1297 (2M+H)+.

Workup

  1. customIn an oven-dried 5-mL round bottom flask purged with nitrogen
  2. additionDiluted
  3. custompurified by RP-C18 HPLC (Waters Prep LC, 40 mm Module with Nova Pak HR C18 6 μm 40×100 mm Prep Pak cartridge)
  4. washeluting with a 30 min gradient of 95:5 0.1% TFA in H2O/AcCN to 25:75 0.1% TFA in H2O/AcCN
  5. concentrationPure fractions were concentrated by rotary evaporation (water bath 35°) to a small volume
  6. custompartitioned between 20% iPrOH/CHCl3 (50 mL)
  7. customseparated layers
  8. extractiondried organic extract over anhydrous MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated by rotary evaporation

Sources & evidence

ORD record
ord-9fbcdb9ee09349288cdd03703251e262
Source dataset
uspto-grants-2015_04
Patent number
US09006387B2

Reaction notes

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