Methanesulfonic Acid → methyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate

Beteiligte Stoffe

Reaktionsbedingungen

Reaktionsschritte

Method A A solution of 3-chloropropanol (14.74 kg, 98.4% pure, 153.4 mole) in dichloromethane (67 L) was cooled to -17° C. In a second vessel dichloromethane (68 L), methyl indole-3-carboxylate (13.5 kg, 99.8% pure, 76.9 mole) and 1,4-diazabicyclo[2.2.2]octane (4.75 kg, assumed 100% pure, 42.3 mole) were cooled to 0° C. N-Clorosuccinimide (11.3 kg, 99.5% pure, 84.2 mole) was added to the second vessel and stirred at 0° C. for 10 minutes. In the meantime methane sulphonic acid (0.59 L, 99.7% pure, 6.14 mole) was added to the first vessel. The solution in the second vessel was added to the first vessel over 49 minutes at -15 to 3° C. and the resulting mixture stirred for a further 31 minutes at -5 to 0° C. 10% Sodium carbonate solution (147 L), made from sodium carbonate (42.2 kg, 398 mole) and process water (422 L), was added over 14 minutes and stirred. The organic layer was separated and washed twice with 10% sodium carbonate solution (147 L each wash). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure below 30° C. The concentrate was dissolved in acetone (101 L) at about 18° C. and potassium carbonate (14.9 kg) added. The mixture was stirred at 18 to 28° C. for 18 hours. Analysis of the reaction showed it to be complete. The inorganic salts were filtered off, the filtrate concentrated under reduced pressure below 30° C. and dissolved in dichloromethane (101 L). The dichloromethane solution was washed twice with 5% sodium bicarbonate solution (85 L each wash), made from sodium bicarbonate (8.3 kg) and water (167 L) and dried over anhydrous sodium sulfate. After filtration the filtrate was concentrated under reduced pressure to a base temperature of about 95° C. and diluted with toluene (12 L). The toluene solution was cooled, causing the product to crystallise and cooling continued to about 0° C. overnight. The product was collected by filtration, washed on the filter with cold (0° C.) toluene (7 L) and dried in vacuo at 30° C. for 21 hours to give the title compound (9.654 kg, 98.9% pure, 53.7%).

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