Oxalyl chloride → HCID 16113114, compound

HRID 1498619Notes

Reaction equation

HRID 1498619 reaction equation
[CH3:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([OH:6])=O.[C:15](Cl)(=[O:19])[C:16](Cl)=O.Cl.[CH3:22][NH2:23]>C(Cl)Cl>[OH:19][C:15]1[CH:16]=[CH:4][C:3]([C:22]2[NH:23][C:4](=[O:6])[C:3]3[C:2]([CH:1]=2)=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])=[CH:2][CH:1]=1

Participants

5

Reactant 3

HCID 65578Oxalyl chlorideHCID 6072872,4-Dimethoxy-6-methylbenzoic acidHCID 6364545Methylamine hydrochloride

Product 1

HCID 16113114HCID 16113114, compoundYield 61.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a suspension of 2-methyl-4,6-dimethoxy benzoic acid (2.8 g, 14.3 mmol) in CH2Cl2 (30 mL), oxalyl chloride (3.62 g, 28.5 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent and excess oxalyl chloride were removed at reduced pressure. The solid was dissolved in CH2Cl2 (10 mL) and methyl amine hydrochloride (1.33 g, 42.81 mmol) was added on cooling and the mixture was stirred at room temperature for 4 h. The solvent was removed and the crude product was purified by chromatography using 5% methanol in CH2Cl2, to give 1.3 g of the amide intermediate (43% yield). To a solution of the amide intermediate (1.29 g, 6.16 mmol) in THF (30 mL), n-butyl lithium (5.6 mL, 14.18 mmol, 2.5 M solution in hexane) was added slowly under nitrogen with cooling (ice-salt bath), maintaining the temperature below 20° C. The mixture was stirred for 1 h at 0° C., then cooled to −50° C. and a solution of 4-O-TBDMS-benzonitrile (1.58 g, 6.78 mmol) in THF (10 mL) was added quickly. The cooling bath was removed and the mixture was stirred at room temperature for 16 h. Saturated aqueous NH4Cl solution was added with cooling, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give the crude intermediate, which was purified by chromatography using 5% methanol in CH2Cl2, to give two products (1) 678 mg of isoquinoline in 26% yield and (2) 780 mg of quinalone product in 27% yield. To a suspension of the above quinalone product (780 mg, 1.65 mmol) in ethanol (20 mL), conc. HCl (2 mL) was added and the mixture was heated at 70° C. for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed and purified by chromatography to give 3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (215 mg, 44%). Selected data: MS (ES) m/z: 297.93; MP 245-247° C.

Workup

  1. additionwas added
  2. customThe solvent and excess oxalyl chloride were removed at reduced pressure
  3. dissolutionThe solid was dissolved in CH2Cl2 (10 mL)
  4. temperatureon cooling
  5. stirringthe mixture was stirred at room temperature for 4 h
  6. customThe solvent was removed
  7. customthe crude product was purified by chromatography

Sources & evidence

ORD record
ord-9913c70905ed41b0aefcc6dbae56f08a
Source dataset
uspto-grants-2015_12
Patent number
US09199990B2

Reaction notes

Loading…