Phosphorus oxychloride → 4-(1-Chloro-6-methoxyisoquinolin-3-yl)morpholine

HRID 1852101Notes

Reaction equation

HRID 1852101 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)=[N:8][C:7]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:6]2.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:8]=1

Participants

3

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 178487762HCID 178487762, compound

Product 1

HCID 222501304-(1-Chloro-6-methoxyisoquinolin-3-yl)morpholineYield 95.8%

Procedure

A solution of 6-methoxy-3-morpholinoisoquinolin-1-ol (315 mg, 1.210 mmol) in POCl3 (1692 μl, 18.15 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in Hexanes as eluent. The product fractions were collected and the solvent removed under vacuum to give 4-(1-chloro-6-methoxyisoquinolin-3-yl)morpholine (323 mg, 95% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.01 (d, J=9.3 Hz, 1H), 6.97 (dd, J=9.3, 2.5 Hz, 1H), 6.86 (d, J=2.5 Hz, 1H), 6.59 (s, 1H), 3.92 (s, 3H), 3.90-3.85 (m, 4H), 3.56-3.50 (m, 4H); MS: MS m/z 279.1 (M++1).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. dissolutionThe residue was dissolved in DCM
  3. customThe organic phase was collected
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customThe crude material was purified by silica gel chromatography
  8. customThe product fractions were collected
  9. customthe solvent removed under vacuum

Sources & evidence

ORD record
ord-39036b679b664870bd8e2e0ab4467166
Source dataset
uspto-grants-2015_02
Patent number
US08957203B2

Reaction notes

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