Water → 5-tert-Butyl-2-(2-methyl-3-(4-methyl-6-(4-(morpholine-4-carbonyl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)isoindolin-1-one

HRID 1772073Notes

Reaction equation

HRID 1772073 reaction equation
[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[C:24]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=3)[C:17]=2[CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:12][CH:13]=1)[C:9](=[O:11])[N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[C:24]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[O:38])=[CH:33][CH:32]=4)[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=3)[C:17]=1[CH3:45])[CH2:14]2)([CH3:3])([CH3:4])[CH3:2]

Participants

7

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 666101474-tert-Butyl-2-((2-methyl-3-(4-methyl-6-(4-(morpholine-4-carbonyl)-phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenylamino)methyl)benzoic Acid

Product 1

HCID 569283405-tert-Butyl-2-(2-methyl-3-(4-methyl-6-(4-(morpholine-4-carbonyl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)isoindolin-1-oneYield 48%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To 25 mL round bottom flask charged with acid 101i (97 mg, 0.16 mmol), diisopropyethylamine (0.08 mL, 0.48 mmol) in DMF (5 mL) was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (84 mg, 0.19 mmol). After the reaction was stirred at room temperature for 2 h, H2O (5 mL) and EtOAc (10 mL) were added. The organic phase was extracted with aqueous HCl (1M, 2×5 mL), H2O (5 mL), aqueous Na2CO3 (1M, 5 mL), brine (5 mL), dried with Na2SO4 and concentrated. The residue was chromatographed (gradient, 0%-100% 60:35:5 CH2Cl2:Et2O:MeOH/CH2Cl2) to afford 45 mg (48%) of 101. MH+(m/z): 591.5. 1H NMR (300 MHz, CDCl3) 6 m; 8.44 (s, 1 H), 8.39 (m, 1 H), 7.88 (s, 1 H), 7.82 (s, 1 H), 7.39-7.49 (m, 5 H), 7.31-7.35 (, 2 H), 7.07 (d, J=7.5 Hz, 1 H), 6.81 (s, 1 H), 6.58 (d, J=7.5 Hz, 1 H), 3.69 (broad s, 6 H), 3.62 (s, 3 H), 3.07 (m, 1 H), 2.21 (s, 3 H), 1.35 (s, 3 H), 1.33 (s, 3 H); MS (ESI+) m/z (M+H) 590.58.

Workup

  1. extractionThe organic phase was extracted with aqueous HCl (1M, 2×5 mL), H2O (5 mL), aqueous Na2CO3 (1M, 5 mL), brine (5 mL)
  2. dry with materialdried with Na2SO4
  3. concentrationconcentrated
  4. customThe residue was chromatographed (gradient, 0%-100% 60:35:5 CH2Cl2:Et2O:MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-2e3bfed4ad2b4e7c9c37560ee54a7337
Source dataset
uspto-grants-2016_02
Patent number
US09249123B2

Reaction notes

Loading…