Trifluoroacetic acid → 4-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide

HRID 2361278Notes

Reaction equation

HRID 2361278 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]([CH3:40])=[C:24]([NH:28][CH2:29][C:30]4[CH:38]=[CH:37][C:36]([Cl: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].C(O)(C(F)(F)F)=O.C(NC(C)C)(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.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[Cl:39][C:36]1[CH:35]=[C:31]2[C:30]([CH2:29][N:28]([C:24]3[C:23]([CH3:40])=[C:22]([C:7]4[C:8]5[C:16]6[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:14][CH:15]=6)[NH:10][C:9]=5[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=4)[CH:27]=[CH:26][CH:25]=3)[C:32]2=[O:34])=[CH:38][CH:37]=1

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 7912DiisopropylamineHCID 79724-MethylmorpholineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 679950002-((3-(1-Carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-chlorobenzoic acid

Product 1

HCID 547517474-(3-(6-Chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamideYield 68.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
45 °C

Procedure

A mixture of 2-((3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-chlorobenzoic acid, TFA (38 mg, 0.056 mmol), N,N-diisopropylamine (0.015 mL, 0.085 mmol), BOP (32.5 mg, 0.073 mmol), and N-methylmorpholine (0.024 mL, 0.220 mmol) in DMF (4 mL) was heated at 45° C. for 1 hr. The mixture was diluted with ethyl acetate (60 mL), washed sequentially with water (3×25 mL) and brine (25 mL), and dried over anhydrous MgSO4. After the solvent was removed under vacuum, the residue was purified by prep. Reverse phase HPLC. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with CH2Cl2 (3×30 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (21.7 mg, 0.039 mmol, 68.2% yield) as a yellow solid. LCMS (M+H)+=541.33. 1H NMR (500 MHz, DMSO-d6) δ: 11.66 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 7.82 (s, 1H), 7.77-7.73 (m, 3H), 7.67 (m, 1H), 7.54 (m, 1H), 7.45 (m, 1H), 7.36 (d, J=2.2 Hz, 1H), 7.14 (d, J=8.9 Hz, 1H), 6.71 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 5.04 (d, J=17.5 Hz, 1H), 4.95 (d, J=17.5 Hz, 1H), 4.16 (m, 2H), 3.72 (m, 2H), 3.34 (s, 3H), 1.87 (s, 3H).

Workup

  1. washwashed sequentially with water (3×25 mL) and brine (25 mL)
  2. dry with materialdried over anhydrous MgSO4
  3. customAfter the solvent was removed under vacuum
  4. customthe residue was purified by prep
  5. concentrationThe correct fraction was concentrated under vacuum
  6. extractionextracted with CH2Cl2 (3×30 mL)
  7. extractionThe combined extract
  8. washwas washed with brine (30 mL)
  9. dry with materialdried over anhydrous MgSO4
  10. customRemoval of solvent under vacuum

Sources & evidence

ORD record
ord-96503e46c6e44e1383949ba99aca22f2
Source dataset
uspto-grants-2014_04
Patent number
US08685969B2

Reaction notes

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