2-(2-oxopropyl)cyclohexane-1,3-dione

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 2-(2-oxopropyl)cyclohexane-1,3-dione (prepared by evaporation of an ethanolic solution to dryness under vacuum) (20.0 g, 119 mmol) and glycine (17.9 g, 238 mmol) in acetic acid (100 mL) was heated under reflux for 1.5 h then allowed to cool to r.t. Water (100 mL) was then added and the mixture evaporated to a thick oil in vacuo. Acetone (200 mL) and water (40 mL) were added to the residue and the mixture stirred for 30 mins at r.t., after which the solid was collected by filtration and the filtrates retained. The solid was slurried with further acetone (100 mL) and water (20 mL) at r.t. then removed by filtration. The combined filtrates were concentrated in vacuo then dissolved in aqueous sodium hydroxide (1M, 200 mL), adding a small amount of 10M sodium hydroxide to bring the pH to 14. After washing with ethyl acetate (2×100 mL), the mixture was acidified by the addition of aqueous hydrochloric acid (5M, 60 mL) then sodium chloride (50 g) was added. After stiffing for 4 h, the solid product was collected by filtration, washed with acetone (2×25 mL) then dried under vacuum at 40° C. to afford the title compound as an orange-brown solid; 7.45 g (30%); purity 99.1 area % by HPLC; m/z: 208 (MH+); 1H-NMR: 13.2 (1H, br s), 6.02 (1H, s), 4.67 (2H, s), 2.65 (2H, t, J=6.2 Hz), 2.29-2.24 (2H, m), 2.10 (3H, s), 2.02-1.95 (2H, m). was heated under reflux for 1.5 h the mixture evaporated to a thick oil in vacuo Acetone (200 mL) and water (40 mL) were added to the residue after which the solid was collected by filtration was slurried with further acetone (100 mL) and water (20 mL) at r.t. then removed by filtration The combined filtrates were concentrated in vacuo then dissolved in aqueous sodium hydroxide (1M, 200 mL) adding a small amount of 10M sodium hydroxide After washing with ethyl acetate (2×100 mL) the mixture was acidified by the addition of aqueous hydrochloric acid (5M, 60 mL) sodium chloride (50 g) was added After stiffing for 4 h the solid product was collected by filtration washed with acetone (2×25 mL) then dried under vacuum at 40° C.

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In reaction vessel 1, potassium hydroxide (11.78 g, 10.0 g corrected for assay, 178 mmol)) was dissolved in water (72 mL) with stirring (highly exothermic) then the solution was cooled back to 20° C. 1,3-cyclohexanedione (20.0 g, 178 mmol) was added (exothermic addition) and the resulting dark red solution was stirred at 20° C. for 5 mins. Redistilled chloroacetone (18.9 g, 17.0 g corrected for assay, 184 mmol) was added in one portion, rinsing in with ethanol (18 mL) and the reaction mixture was stirred overnight at 20° C. The resulting solution of 2-(2-oxopropyl)cyclohexane-1,3-dione, volume 124 mL, was split into 4 equal portions. Glycine ethyl ester hydrochloride (6.85 g, 49.0 mmol), anhydrous sodium acetate (4.02 g, 49.0 mmol), water (26.5 mL) and ethanol (5.0 mL) were charged to reaction vessel 2 and stirring started. One portion of the solution of 2-(2-oxopropyl)cyclohexane-1,3-dione prepared above (31 mL) was then added to the contents of reaction vessel 2 with stirring and the resulting mixture was heated to 75° C., held at this temperature for 2 h, then cooled to 20° C. over 55 mins. After stirring overnight at 20° C., the solid was collected by filtration, washed with water (10 mL), tert-butyl methyl ether (2×10 mL) and then dried in vacuo 40° C. for 20 h to provide (2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)-acetic acid ethyl ester as a beige solid, 5.88 g (56.0% yield). MP 101.2 to 103.5° C. Assay by 1H-NMR 95.3% w/w. Purity by GC 99.25 area %. (exothermic addition) the resulting dark red solution was stirred at 20° C. for 5 mins rinsing in with ethanol (18 mL) the reaction mixture was stirred overnight at 20° C The resulting solution of 2-(2-oxopropyl)cyclohexane-1,3-dione, volume 124 mL, was split into 4 equal portions stirring was then added to the contents of reaction vessel 2 with stirring the resulting mixture was heated to 75° C. cooled to 20° C. over 55 mins After stirring overnight at 20° C. the solid was collected by filtration washed with water (10 mL), tert-butyl methyl ether (2×10 mL) dried in vacuo 40° C. for 20 h

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of potassium hydroxide (23.58 g, 20.0 g corrected for assay, 357 mmol) in water (36 mL) at r.t. was added to a solution of 1,3-cyclohexanedione (39.97 g, 356 mmol) in ethanol (144 mL) with stirring (exothermic addition). After stirring for 15 mins at 20° C., redistilled chloroacetone (37.62 g, 33.9 g corrected for assay, 366 mmol) was added in one portion and the reaction mixture stirred for 20 h at 20° C. The inorganic by products were removed by filtration, washing the filter cake with ethanol (40 mL) and the filtrates were combined to provide 2-(2-oxo-propyl)cyclohexane-1,3-dione as a solution in aqueous ethanol. To this solution were added glycine ethyl ester hydrochloride (54.73 g, 392 mmol) and anhydrous sodium acetate (32.19 g, 392 mmol). The reaction mixture was heated to reflux (75° C. internal temperature) for 1 h then cooled to 20° C. and stirred for 19 h. The mixture was heated to reflux (internal temperature 75° C.) and water (116 mL) added, then cooled to 20° C. over 30 mins. A small amount of 2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)-acetic acid, ethyl ester was added as a seed (10 mg) and, after a few minutes, crystallization of the product was observed. The slurry was stirred for 30 mins, then cooled to 5° C. and stirred for 18 h. The solid was collected by filtration, washed with water (2×80 mL) followed by tert-butyl methyl ether (2×80 mL) and then dried in vacuo at 40° C. for 20 h to provide ethyl(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)acetate as a pale yellow crystalline solid, 41.77 g (49.8% yield). MP 105.1 to 105.4° C. Assay by 1H-NMR 99.3% w/w. Purity by GC 100 area %. (exothermic addition) After stirring for 15 mins at 20° C. was added in one portion the reaction mixture stirred for 20 h at 20° C The inorganic by products were removed by filtration washing the filter cake with ethanol (40 mL)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of KOH (2.54 kg, 2.26 kg corrected for assay, 40.2 moles) in water (4.0 L) was added over 30 mins to a solution of cyclohexane-1,3-dione (4.53 kg, 4.51 kg corrected for assay, 40.2 moles) in EtOH (16.2 L), while maintaining the temperature below 30° C. After stirring for 15 mins at r.t., freshly distilled chloroacetone (4.39 kg, 3.83 kg corrected for assay, 41.4 mol) was then added slowly to the mixture, maintaining a temperature of 25-28° C. The resulting slurry was stirred at r.t. for 19 h. Inorganic by-products were then removed by filtration and were washed on the filter with EtOH (4.5 L). The filtrates were combined to provide 2-(2-oxopropyl)cyclo-hexane-1,3-dione as a solution in EtOH. Assay by GC 26.5% w/w; purity by GC: 82.3 area %). This solution was transferred to a reactor and glycine ethyl ester hydrochloride salt (6.41 kg, 6.17 kg corrected for assay, 44.2 moles) was added at r.t. with stirring followed by sodium acetate trihydrate (6.04 kg, 6.02 kg corrected for assay, 44.3 moles). The mixture was diluted with ethanol (28.9 L) then heated under reflux for 2 h. EtOH was removed in vacuo (−0.850 to −0.900 bar) at 30° C. until 40 L of distillate had been collected. After cooling the residue to 0° C., water (15 L) was added, while maintaining a temperature of 0-5° C. After stirring for a further 1 h at this temperature, the solid that separated out was collected by filtration and was then dried in vacuo at 35° C. with a nitrogen bleed to give the title compound as a solid; 6.7 kg; assay by 1H NMR: 86.6% w/w; weight corrected for assay: 5.80 kg (61% over 2 steps); purity by GC: 96.0 area %; m/z: 235 (MH+); 1H NMR: (CDCl3) 1.27-1.32 (3H, t), 2.10-2.17 (2H, m), 2.19 (3H, s), 2.42-2.46 (2H, t), 2.65-2.69 (2H, t), 4.21-4.28 (2H, m), 4.51 (2H, s) and 6.27 (1H, s). while maintaining the temperature below 30° C maintaining a temperature of 25-28° C The resulting slurry was stirred at r.t. for 19 h Inorganic by-products were then removed by filtration were washed on the filter with EtOH (4.5 L)