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With triethylamine; potassium iodide In N,N-dimethyl-formamide at 90 - 95℃;
4-Amino-5-chloro-2,3-dihydro-N-(4-piperidinyl)-7-benzomrancarboxamide (30 g), triethyl amine (30 ml), l-chloro-3-methoxy-propane (13.8 g) and potassium iodide (4 g) in dimethylformamide (150 ml) were taken into a reaction flask at 25-30°C. The resulting mixture was heated to 90-95°C and then maintained for 4-5 hours at the same temperature. The reaction mass was cooled to 25-30°C, followed by the addition of l-chloro-3- methoxy-propane (5 g) and triethylamine (10 ml) at the same temperature. The reaction mass was heated to 90-95°C and then maintained for 4-5 hours at the same temperature. After completion of reaction, the reaction mass was cooled to 25-30°C, followed by the addition of water (750 ml) and then extracting with dichloromethane (300 ml x 3 times). The layers were separated and the organic layer was washed with water (500 ml). Activated carbon powder (3 g) was added to the organic layer and then stirred for 10 minutes at 25-30°C, followed by filtration through carbon bed. The resulting filtrate was concentrated under vacuum to obtain a residue. To the resulting residue, water (350 ml) was added and then stirred for 30 minutes at 20-25°C. The solid separated was filtered and washed with water (50 ml x 2 times) to produce 31 g of Prucalopride monohydrate (Purity by HPLC: 97.0percent).
b) A solution of 18.4 parts of intermediate 10 and 28.0 parts of potassium hydroxide in 125 parts of 2-propanol was stirred for 4 hours at reflux temperature. The solvent was evaporated and replaced by 100 parts of water. The mixture was evaporated again and the residue was stirred in 100 parts of water for 15 min. while heating on a water-bath. After cooling, the solid was filtered off, washed with water and dissolved in boiling 2-propanol. There were added 400 parts of water to the solution. The product crystallized upon cooling and was filtered off, washed with water and dried, yielding 12.35 parts (83.5%) of 4-amino-5-chloro-2,3-dihydro-N-(4-piperidinyl)-7-benzofurancarboxamide; mp. 190.3 C. (interm. 11).
Ethyl 4-[[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]amino]-l-piperidine carboxylate (40 g) was added to a mixture of sulphuric acid (80 ml) and water (24 ml) at 10-20C. The resulting mass was heated to 90-95C and then stirred for 5-6 hours at the same temperature. After completion of reaction, the resulting mass was poured into a solution of ice (270 g) and water (540 ml) at 10C. The resulting mass was stirred for 1 hour at room temperature. The resulted solid was filtered and then washed with water (30 ml). The wet product was added to water (630 ml), followed by adjusting the pH to 10- 10.5 with 50% aqueous NaOH solution at 10-15C. The reaction mass was stirred for 1 hour at 20-25C and the product obtained was filtered, washed with water (70 ml) and then dried the material at 55-60C for 4 hours to produce 31 g of 4-amino-5-chloro-2,3-dihydro- N-(4-piperidinyl)-7-benzofurancarboxamide (Purity by HPLC: 99.6%; Yield: 96.8%).
With triethylamine; potassium iodide; In N,N-dimethyl-formamide; at 90 - 95℃;
4-Amino-5-chloro-2,3-dihydro-N-(4-piperidinyl)-7-benzomrancarboxamide (30 g), triethyl amine (30 ml), l-chloro-3-methoxy-propane (13.8 g) and potassium iodide (4 g) in dimethylformamide (150 ml) were taken into a reaction flask at 25-30C. The resulting mixture was heated to 90-95C and then maintained for 4-5 hours at the same temperature. The reaction mass was cooled to 25-30C, followed by the addition of l-chloro-3- methoxy-propane (5 g) and triethylamine (10 ml) at the same temperature. The reaction mass was heated to 90-95C and then maintained for 4-5 hours at the same temperature. After completion of reaction, the reaction mass was cooled to 25-30C, followed by the addition of water (750 ml) and then extracting with dichloromethane (300 ml x 3 times). The layers were separated and the organic layer was washed with water (500 ml). Activated carbon powder (3 g) was added to the organic layer and then stirred for 10 minutes at 25-30C, followed by filtration through carbon bed. The resulting filtrate was concentrated under vacuum to obtain a residue. To the resulting residue, water (350 ml) was added and then stirred for 30 minutes at 20-25C. The solid separated was filtered and washed with water (50 ml x 2 times) to produce 31 g of Prucalopride monohydrate (Purity by HPLC: 97.0%).
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