7,9-DIMETHOXYCARBONYL-2-ETHOXYCARBONYL-5-METHOXY-1H-PYRROLO-[2,3-F]QUINOLINE synthesis

Yield:133706-80-6 86.1%

Reaction Conditions:

with hydrogenchloride;oxygen;copper acetylacetonate in dichloromethane at 20;

Steps:

1.G; h

Into a 3-L, 3-neck flask equipped with a mechanical stirrer, an addition funnel, a temperature probe, a heating mantle, and a condenser vented to a nitrogen line under static pressure were placed, ethyl 6-amino-5-methoxy-lH-indole-2-carboxylate (8) (213.6 g, 0.912 mol) and 1325 mL of methylene chloride. The green suspension was stirred under nitrogen and a solution of dimethyl 2-oxoglutaconate (12) (175.0 g, 1.02 mol) in 700 mL of methylene chloride was added at room temperature over a 10-min period. An additional 100 mL of EPO methylene chloride was used to rinse all of 12 into the reactor. At the end of the addition, the reaction mixture was nearly black. There was no rise in temperature. The reaction mixture was stirred overnight as a matter of convenience.The reaction mixture was transferred to a 3-L, 1-neck flask and concentrated in vacuo to about one fourth of its original volume. The reaction mixture was then stirred and cooled in cold water for 1 hour. The final temperature was 7 ⁰C. The product was collected by filtration and washed with 350 niL of 1 :5 methylene chloride - heptane. The amber product was partially dried on the filter and then at 50 ⁰C under high vacuum to afford 270.8 g (73.1%) of the 9-hydroxy-5-methoxy-6,7,8,9-tetrahydro-lH-pyrrolo[2,3-f]quinoline-2,7,9- tricarboxylic acid 2-ethyl ester 7,9-dimethyl ester.Into a 22-L, jacketed reactor equipped with a mechanical stirrer, a bottom-drop valve, an addition funnel, a temperature probe, a heating mantle, a dip tube and a condenser were placed, 9-hydroxy-5-methoxy-6,7,8,9-tetrahydro-lH-pyrrolo[2,3-f]quinoline-2,7,9- tricarboxylic acid 2-ethyl ester 7,9-dimethyl ester (270.8 g, 0.666 mol), Cu(OAc)₂-H₂O (146.3 g, 0.733 mol), and 11.50 L of methylene chloride. The reaction mixture was stirred and a stream of air and anhydrous hydrogen chloride were bubbled through the reaction mixture. The reaction was exothermic and the reactor jacket temperature was set for 10 ⁰C to maintain the reaction temperature at about 20 ⁰C. After about 30 min, the reaction mixture became less exothermic and the jacket temperature was set to 20 ⁰C. Bubbling of air and hydrogen chloride was continued for 6 hours. Bubbling of air through the reaction mixture was continued overnight.The reaction was quenched by addition of a solution of 550 g of sodium bicarbonate in 6.0 L of water over a 30-min period. Very little evolution of carbon dioxide was noted. A very dark blue solution and blue-green solids resulted. The demarcation between the organic and aqueous phases was poor. The mixture was stirred 2 hours and filtered. Filtration was slow taking about 7 hours. Evaporation of methylene chloride left black solids in and at the exit of the filter. Near the end, the slimy, essentially all aqueous mixture was poured into a clean filter and allowed to filter. Both filters were filled with methylene chloride and allowed to drain by gravity overnight. The filters were further rinsed with methylene chloride and the combined filtrate was returned to the reaction vessel. Several liters of methylene chloride were added to bring the volume back to approximately the original volume.The two-phase mixture was stirred 5 hours to assure that the product was completely in solution. The methylene chloride layer was separated. There were blue-green solids EPO floating in the upper part of the methylene chloride layer. The upper part of the methylene chloride layer was collected separately and the solids were removed by filtration. The aqueous layer was extracted with 2 L of methylene chloride. The combined methylene chloride solution was washed with 4 L of water and dried by stirring with 750 g of sodium sulfate. The solution was filtered and stripped to a black semi-solid with yellow crystalline highlights. The material was stirred overnight with 1 L of ethyl ether. The slurry was cooled in ice and the product was collected by filtration. The product was then washed with 700 niL of ethyl ether and dried at 50 ⁰C under high vacuum to afford 221.7 g (86.1%) of the title compound (9) as a brassy colored product.; To a reaction vessel charged with ethyl 6-amino-5-methoxy-lH-indole-2 -carboxylate (8) and CH₂Cl₂ was added a solution of dimethyl 2-oxoglutaconate (12) in CH₂Cl₂ (step g). At the end of the addition, the reaction mixture was transferred to a second reaction vessel, EPO stirred in cold water, and vacuum filtered. The product was collected, washed with CH₂Cl₂- heptane, and dried under vacuum to afford 9-hydroxy-5-methoxy-6,7,8,9-tetrahydro-lH- pyrrolo[2,3-fjquinoline-2,7,9-tricarboxylic acid 2-ethyl ester 7,9-dimethyl ester which was combined with copper acetate monohydrate (Cu(OAc)₂ H₂O) and CH₂Cl₂ (step h). The reaction mixture was stirred with a stream of air and anhydrous HCl bubbling through while it was kept at room temperature. Bubbling was continued for six hours and then bubbling of only air was continued overnight. The reaction mixture was quenched by the addition of an aqueous sodium carbonate (Na₂CO₃) solution. The reaction mixture was stirred for two hours and vacuum filtered. Methylene chloride was used to further dilute the resulting filtrate. The mixture was stirred to ensure that the product was completely dissolved in solution. The CH₂Cl₂ layer was separated and the aqueous layer was extracted with CH₂Cl₂. The organic layers were combined, washed with H₂O, dried over Na₂SO₄, filtered and concentrated to afford a solid which was stirred overnight with Et₂O, cooled in an ice bath, filtered, washed with Et₂O and dried at 50 ⁰C under high vacuum to afford 5-methoxy-lH-pyrrolo[2,3- f]quinoline-2,7,9-tricarboxylic acid 2-ethyl ester 7,9-dimethyl ester (9).

References:

WO2006/102642,2006,A1 Location in patent:Page/Page column 9-10; 15-17; 1/6