Reaction #792226

Reaction equation

1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

thionyl chloride

2-methoxy-2-oxoethanaminium chloride

triethylamine

hydrochloric acid

sodium bicarbonate

sodium hydroxide

methyl 1-oxo-1,2-dihydroisoquinoline-4-carboxylate

→

Methyl N-[(1-oxo-1,2-dihydroisoquinolin-4-yl)carbonyl]glycinate

Solvents

dichloromethane

dichloromethane

N,N-dimethylformamide

methanol

Conditions

Workup

1. 1
   Temperaturecooled to room temperature and, with ice bath
2. 2
   Temperaturecooling
3. 3
   FiltrationThe resulting precipitate was filtered off through a Büchner funnel
4. 4
   Washwashed with cold methanol
5. 5
   OtherThe filter cake was air-dried
6. 6
   OtherThe solvent was then removed under reduced pressure
7. 7
   workup.DISSOLUTIONdissolved in 5 ml of dichloromethane
8. 8
   ExtractionThe solution was extracted with ethyl acetate
9. 9
   Otherthe phases were separated
10. 10
    Dryingthe organic phase was dried over magnesium sulphate
11. 11
    Otherthe solvent was removed under reduced pressure
12. 12
    OtherThe crude product was purified by chromatography (ethyl acetate:n-heptane 2:1)

Procedure

6.00 g (29.53 mmol) of methyl 1-oxo-1,2-dihydroisoquinoline-4-carboxylate were dissolved in 20 ml of methanol, and 20 ml of 6 N aqueous sodium hydroxide solution were added. The solution was heated at 80° C. for 3 h, cooled to room temperature and, with ice bath cooling, adjusted to pH=3 using concentrated hydrochloric acid. The resulting precipitate was filtered off through a Büchner funnel and washed with cold methanol. The filter cake was air-dried. This gave 5.65 g (99% of theory) of the desired 1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 12.69 (br. s, 1H), 11.78 (br. s, 1H), 8.83 (d, 1H), 8.02 (d, 1H), 7.79 (t, 1H), 7.56 (t, 1H). Under an atmosphere of inert nitrogen gas, 0.200 g (1.057 mmol) of 1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid were dissolved in 5 ml of dichloromethane and, with 0.093 ml (1.269 mmol) of thionyl chloride and a drop of N,N-dimethylformamide, heated at the boil for 1 h. The solvent was then removed under reduced pressure and the residue was, under an atmosphere of inert nitrogen gas, dissolved in 5 ml of dichloromethane. To this solution, a solution of 0.245 mg (2.750 mmol) of 2-methoxy-2-oxoethanaminium chloride and 0.383 ml (2.750 mmol) of triethylamine in 5 ml of dichloromethane was added dropwise over a period of 10 min. The suspension was stirred overnight, and 5% strength sodium bicarbonate solution was then added. The solution was extracted with ethyl acetate, the phases were separated, the organic phase was dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by chromatography (ethyl acetate:n-heptane 2:1). This gave 120 mg (40% of theory) of the desired methyl N-[(1-oxo-1,2-dihydroisoquinolin-4-yl)carbonyl]glycinate. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.62 (br. s, 1H), 8.81 (t, 1H), 8.24-8.21 (m, 2H), 7.73 (t, 1H), 7.55-7.52 (m, 2H), 3.99 (d, 2H), 3.68 (s, 3H).

Source