Pyridine → HCID 54766565, compound

HRID 2361304Notes

Reaction equation

HRID 2361304 reaction equation
[NH2:1][C:2]1[C:3]([CH3:30])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH:22]5[CH2:26][CH2:25][O:24][CH2:23]5)=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31](Cl)(=O)[O:32]C1C=CC([N+]([O-])=O)=CC=1.N1C=CC=CC=1.Cl.[F:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[CH2:57][NH:56][CH2:55]2.C(N(CC)C(C)C)(C)C>ClCCl>[F:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[CH2:57][N:56]([C:31]([NH:1][C:2]1[C:3]([CH3:30])=[C:4]([C:8]3[C:20]4[C:19]5[C:14](=[CH:15][C:16]([O:21][CH:22]6[CH2:26][CH2:25][O:24][CH2:23]6)=[CH:17][CH:18]=5)[NH:13][C:12]=4[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=1)=[O:32])[CH2:55]2

Participants

7

Reactant 5

HCID 1049PyridineHCID 81531DiisopropylethylamineHCID 821294-Nitrophenyl chloroformateHCID 179862865-fluoro-2,3-dihydro-1H-isoindole hydrochlorideHCID 67994518HCID 67994518, compound

Product 1

HCID 54766565HCID 54766565, compoundYield 55.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
50 °C

Procedure

To a heterogeneous mixture of 4-(3-amino-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indole-1-carboxamide (38 mg, 0.081 mmol) and 4-nitrophenyl carbonochloridate (19.64 mg, 0.097 mmol) in dichloromethane (2 mL) at room temperature was added pyridine (0.013 mL, 0.162 mmol). The resulting homogeneous mixture was stirred at room temperature for 1 hr before 5-fluoroisoindoline hydrocloride (35.2 mg, 0.203 mmol) and N,N-diisopropylethylamine (0.053 mL, 0.305 mmol) was added. The mixture was heated at 50° C. for 1 hr. It was concentrated under vacuum, diluted with MeOH (1.8 mL), and was purified by 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 (26.4 mg, 0.045 mmol, 54.9% yield) as a yellow solid. LCMS (M+H)+=566.34. 1H NMR (500 MHz, DMSO-d6) δ: 11.67 (s, 1H), 8.36 (m, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 7.79 (s, 1H), 7.64 (d, J=6.9 Hz, 1H), 7.46-7.39 (m, 3H), 7.29 (dd, J1=9.0 Hz, J2=2.4 Hz, 1H), 7.23-7.17 (m, 2H), 7.08 (d, J=8.6 Hz, 1H), 6.70 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 5.10 (m, 1H), 4.85 (s, 2H), 4.82 (s, 2H), 3.99 (dd, J1=10.5 Hz, J2=4.2 Hz, 1H), 3.92-3.83 (m, 2H), 3.84 (m, 1H), 2.32 (m, 1H), 2.09 (m, 1H), 2.01 (s, 3H).

Workup

  1. additionwas added
  2. concentrationIt was concentrated under vacuum
  3. additiondiluted with MeOH (1.8 mL)
  4. customwas purified by reverse phase HPLC
  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-4999a7465e414acfa6004d1d5ebd893b
Source dataset
uspto-grants-2014_04
Patent number
US08685969B2

Reaction notes

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