4-Methylmorpholine → 4-(2-Fluoro-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide

HRID 2361341Notes

Reaction equation

HRID 2361341 reaction equation
[C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:22]2[C:23]([F:40])=[C:24]([NH:28][CH2:29][C:30]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:31]=4[C:32]([OH:34])=O)[CH:25]=[CH:26][CH:27]=2)=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=3)(=[O:3])[NH2:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[F:40][C:23]1[C:24]([N:28]2[CH2:29][C:30]3[C:31](=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[C:32]2=[O:34])=[CH:25][CH:26]=[CH:27][C:22]=1[C:7]1[C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 679947772-((3-(1-Carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-fluorophenylamino)methyl)-5-methylbenzoic acid

Product 1

HCID 706509274-(2-Fluoro-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamideYield 7.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A homogeneous, orange solution of 2-((3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-fluorophenylamino)methyl)-5-methylbenzoic acid (0.105 g, 0.194 mmol), BOP (0.257 g, 0.582 mmol), DIPEA (0.119 mL, 0.679 mmol) and N-methylmorpholine (0.192 mL, 1.746 mmol) in DMF (1.940 mL) under nitrogen was heated at 45° C. After 45 min, the reaction was cooled to room temperature, dissolved in EtOAc (75 mL) and washed with water (4×30 mL) and brine (30 mL), successively. The organic solution was dried over MgSO4 and concentrated in vacuo. It was diluted with DMF (0.3 mL) and MeOH (2 mL) and purified by reverse phase HPLC. The appropriate fractions were combined, basified with NaHCO3 (solid), and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combined extract was dried over MgSO4, and concentrated in vacuo to give the desired product (0.00758 g, 0.0144 mmol, 7.4%) as a light tan solid. LC/MS (M+H)=525.30; 1H NMR (500 MHz, DMSO-d6) δ ppm 11.69 (s, 1H), 8.31 (d, J=2.2 Hz, 1H), 7.89 (dd, J1=7.6, J2=1.7 Hz, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.61-7.66 (m, 2H), 7.54-7.59 (m, 2H), 7.50-7.54 (m, 2H), 7.47 (dd, J1=8.7 Hz, J2=1.8 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 6.77 (dd, J1=8.9 Hz, J2=2.2 Hz, 1 H), 5.03 (d, J=16.1 Hz, 1H), 4.95 (d, J=16.6 Hz, 1H), 4.15-4.19 (m, 2H), 3.69-3.74 (m, 2H), 3.33 (s, 3H), 2.44 (s, 3 H).

Workup

  1. washwashed with water (4×30 mL) and brine (30 mL)
  2. dry with materialThe organic solution was dried over MgSO4
  3. concentrationconcentrated in vacuo
  4. additionIt was diluted with DMF (0.3 mL) and MeOH (2 mL)
  5. custompurified by reverse phase HPLC
  6. concentrationconcentrated in vacuo
  7. extractionThe residue was extracted with CH2Cl2 (3×)
  8. extractionThe combined extract
  9. dry with materialwas dried over MgSO4
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-08daedcd0bfd4bb6ad61cb7047ea4934
Source dataset
uspto-grants-2014_04
Patent number
US08685969B2

Reaction notes

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