Patent Application
20080076825
175.0 g of 5-nitrovanillin and 135.1 g of aluminum chloride were suspended in 774.2 g of chlorobenzene to form an orange-red suspension. 319.9 g of pyridine were then added dropwise in such a way that the internal temperature did not exceed 25° C. The deep red suspension obtained after the addition was heated to an internal temperature of 70-80° C. When the reaction was complete, a solution of 525 g of water and 603.75 g of 32% hydrochloric acid (semiconcentrated hydrochloric acid) was added slowly to the reaction mixture. The hydrolysis initially produced a deep red two-phase mixture, from which a yellow solid precipitated out towards the end. When the addition of the semi-concentrated hydrochloric acid had ended, the suspension was concentrated to half the volume under vacuum. 475 g of water were then added to the suspension and the mixture was heated to the boil, during which the solid dissolved. After 5-10 min under reflux, the solution was left to cool slowly and a solid then precipitated out. The suspension was cooled to 20-25° C., stirred at this temperature and then filtered with suction. The solid was washed with 1000 g of water and dried at 60° C. under vacuum (yield: 152.47 g).
25.0 g of cyanoacetic acid were dissolved in 163.08 g of ethyl acetate. 21.70 g of diethylamine were added slowly to the resulting colorless solution in such a way that the internal temperature did not exceed 25° C. A solution of 61.10 g of dicyclohexylcarbodiimide in 54.06 g of ethyl acetate was then added dropwise and a solid precipitated out slowly. After the addition the suspension was stirred overnight at 35-40° C. When the reaction had ended, the suspension was cooled to 20-25° C. and filtered with suction. The solid was rinsed with 64.87 g of ethyl acetate. The combined filtrates were concentrated under vacuum and a solid precipitated out. The suspension was taken up in 45.05 g of ethyl acetate, the mixture was stirred at 20-25° C. and the solid was filtered off and rinsed with 45.05 g of ethyl acetate. The combined filtrates were concentrated under vacuum again. The residue was taken up in 18.02 g of ethyl acetate, the mixture was filtered, the material on the filter was rinsed with 13.52 g of ethyl acetate and the filtrate was concentrated under vacuum. The crude product obtained was then distilled under vacuum (vapor temperature: 107-110° C., pressure: 4×10−1-2×10−2 Torr) to give 39.25 g (89%) of 2-cyanoacetic acid diethylamide in the main fraction.
A mixture of 120 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 94.56 g of N,N-diethyl-2-cyanoacetamide, 3.76 g of acetic acid and 4.58 g of diethylamine in 432 g of toluene was heated in a water separator. When the reaction was almost complete (E/Z isomer ratio=70/30), 109 g of acetonitrile and 38.4 g of active charcoal were added and the mixture was refluxed for 0.5-4 h. While still hot, the suspension was filtered on 14.0 g of Célite and the solid was then rinsed with 66.1 g of acetonitrile. The solution was placed in a receiver with 432 g of toluene. The temperature was not supposed to exceed 20° C. When the addition was complete, 43.2 g of a 33% solution of HBr in acetic acid were added and the mixture was stirred overnight at room temperature. The suspension was then cooled to 0-5° C. and filtered with suction. The moist crude product was elutriated in a mixture of 67.2 g of isopropanol and 100.8 g of water and washed with 200 g of water. The yield was 143.21 g (73.8%, corrected for content).
Instruction 1: 131.72 g of the product obtained under 3.1. were dissolved in 381.8 g of acetone and 38.2 g of water, with heating to 58° C. While still hot, this solution was added to a cold (0° C.) mixture of 1211.2 g of water, 37.5 g of acetone and 0.3 g of entacapone (polymorphous form D) in such a way that the internal temperature was maintained at 0-12° C. The suspension was then filtered with suction and the product was elutriated in 1300 g of water for 5-10 min at 0° C. After a repeat filtration, the product was washed with 130 g of water. The yield was 126.45 g (95.9%, corrected for content).
Instruction 2: 5.00 g of the product obtained under 3.1. were dissolved in 14.3 g of THF in a round-bottom flask at the boiling point. While still hot at a temperature just below the boiling point, this solution was poured into 124 g of ice-water, the flask was then rinsed with 4.0 g of THF and this solution was also added to the ice-water. The suspension was filtered at an internal temperature of 10° C. and the filter cake was washed with 15 g of ice-water and dried for 15 h at 50° C. The yield was 4.93 g (97.7%, corrected for content).
Instruction 3: 5.00 g of the product obtained under 3.1. were dissolved in 12.0 g of n-propanol at the boiling point. While still hot at a temperature just below the boiling point, this solution was poured into 40.0 g of ice-water. The suspension was filtered at an internal temperature of 23° C. and the filter cake was washed with 10 g of ice-water and dried for 15 h at 70° C. The yield was 4.64 g (93.1%, corrected for content).
5.00 g of entacapone were dissolved in 189.3 g of toluene, with heating, and added at 95° C. to 267 g of hot n-heptane, causing immediate crystallization. Half of the suspension was filtered hot at 90° C. to give 2.23 g of entacapone in the polymorphous form C. The second half of the suspension was cooled to room temperature and filtered after 14 h to give 2.57 g of entacapone, likewise in the polymorphous form C.
Instruction 1: 10.00 g of entacapone were dissolved in 28.0 g of THF, with heating, and, while still hot, added to 120 g of cold n-hexane so that the internal temperature did not exceed 10° C., causing immediate crystallization. The suspension was filtered and dried for 15 h at 50° C. to give 9.69 g of entacapone in the polymorphous form E.
Instruction 2: 10.00 g of entacapone were dissolved in 28.0 g of THF, with heating, and, while still hot, added to 120 g of cold n-pentane so that the internal temperature did not exceed 10° C., causing immediate crystallization. The suspension was filtered and dried for 15 h at 50° C. to give 9.72 g of entacapone in the polymorphous form E.
Instruction 3: 10.00 g of entacapone were dissolved in 28.0 g of THF, with heating, and, while still hot, added to 120 g of cold cyclohexane so that the internal temperature did not exceed 10° C., causing immediate crystallization. The suspension was filtered and dried for 15 h at 50° C. to give 9.56 g of entacapone in the polymorphous form E.
Instruction 4: 5.00 g of entacapone were dissolved in 41.4 g of isopropanol at the boiling point. This solution was cooled to 68° C. and poured into 126.0 g of n-hexane (internal temperature: 68° C.). The suspension was immediately filtered and the filter cake was dried for 20 h at 50° C. The yield was 4.08 g (83.2%, corrected for content).
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/CH03/00853 | Dec 2003 | CH | national |
| 940/04 | Jun 2004 | CH | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/CH04/00754 | 12/27/2004 | WO | 00 | 4/3/2007 |
