Azobisisobutyronitrile → HCID 86701136, compound

HRID 1403084Notes

Reaction equation

HRID 1403084 reaction equation
BrC1C=CC=[C:8]2C=1[CH:4]=[C:5](C)[N+:6]([O-])=[CH:7]2.[Cl:14][C:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:26]=[N:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH3:35])[N:16]=1.C1C(=O)N(Br)C(=[O:39])C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:26]=[N:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH2:35][N:6]2[CH2:7][CH2:8][O:39][CH2:4][CH2:5]2)[N:16]=1

Participants

7

Reactant 4

HCID 6547AzobisisobutyronitrileHCID 67184N-bromobutanimideHCID 86701137HCID 86701137, compoundHCID 86701138HCID 86701138, compound

Product 1

HCID 86701136HCID 86701136, compound

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 5943Carbon TetrachlorideSolvent

Procedure

5-Bromo-3-methylisoquinoline-2-oxide was obtained according to Example 1(1) using 5-bromo-3-methylisoquinoline instead of 5-bromoisoquinoline. 3-(1-Chloro-3-methylisoquinolin-5-yl)quinoline was obtained according to Example 5(1) using the obtained 5-bromo-3-methylisoquinoline-2-oxide instead of compound (3a) and Pd(PPh3)4 instead of PdCl2dppf. A suspension of the obtained 3-(1-chloro-3-methylisoquinolin-5-yl)quinoline (0.151 g), NBS (0.098 g), and AIBN (0.017 g) in carbon tetrachloride (5 ml) was heated to reflux overnight. After cooling, insoluble matter was filtered off using celite. THF (3 ml), morpholine (0.1 ml), and diisopropylethylamine (0.2 ml) were added to the filtrate, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 4-((1-chloro-5-(quinolin-3-yl)isoquinolin-3-yl)methyl)morpholine (25 mg). Compound (31) was obtained as a pale yellow solid (yield based on 7 steps: 1%) according to Example 1(5) using the obtained 4-((1-chloro-5-(quinolin-3-yl)isoquinolin-3-yl)methyl)morpholine instead of compound (1d) and 4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester instead of 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester.

Workup

  1. temperaturewas heated
  2. temperatureto reflux overnight
  3. temperatureAfter cooling
  4. filtrationinsoluble matter was filtered off
  5. additionTHF (3 ml), morpholine (0.1 ml), and diisopropylethylamine (0.2 ml) were added to the filtrate
  6. distillationThe solvent was distilled off
  7. customthe residue was partitioned between ethyl acetate and water
  8. washThe organic layer was washed with brine
  9. washThe organic layer thus washed
  10. dry with materialwas dried over anhydrous sodium sulfate
  11. distillationThen, the solvent was distilled off
  12. customthe residue was purified by neutral silica gel column chromatography (chloroform/methanol)

Sources & evidence

ORD record
ord-3906a115066140d59f9d4da0b93d73ad
Source dataset
uspto-grants-2014_12
Patent number
US08912181B2

Reaction notes

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