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Structure of 106266-06-2 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium carbonate In acetonitrile for 32 h; Heating / reflux
A mixture of 4.75 g of 3- (2-chloroethyl)-6, 7,8, 9-tetrahydro-2-methyl-4H-pyrido [[1,] [2-A] PYRIMIDIN-4-ONE] hydrochloride, 5.1 g of [4- (2,] 4-difluorobenzoyl) piperidine oxime hydrochloride, 0.46 g of potassium iodide, 5 g of anhydrous sodium carbonate and 30 ml of acetonitrile was stirred and refluxed for 32 hours. The reaction mixture was cooled and water (120 ml) was added under stirring. Separated solid stirred at [5° FOR 1] hour, filtered, washed with water and crystallized from ethyl acetate yielding 6 g (81percent) of [3- [2- [4- (6-FLUORO-] [1,] [2-BENZISOXAZOLE-3-YL) PIPERIDINO] ETHYL]-6,] 7,8, [9-TETRAHYDRO-2-METHYL-4H-PYRIDO [ 1,] 2-a] [PYRIMIDIN-4-ONE.]
79%
With potassium carbonate In acetonitrile for 30 h; Heating / reflux
A mixture of 4.75 g of [3-(2-CHLOROETHYL)-6,] 7,8, 9-tetrahydro-2-methyl-4H-pyrido [1, 2-a] pyrimidin-4-one hydrochloride, 5. 1 g of [4- (2, 4-DIFLUOROBENZOYL)] piperidine oxime hydrochloride, 0.46 g of potassium iodide, 6.5 g of anhydrous powdered potassium carbonate and 30 ml of acetonitrile was stirred and refluxed for 30 hours. Reaction monitoring by HPLC analysis indicated in situ formation of risperidone. After the completion of reaction, the reaction mixture was cooled and water (120 ml) was added under stirring. Separated solid stirred at [5°C] for [1] hour, filtered, washed with water and crystallized from ethyl acetate yielding 6 g [(81percent) OF 3- [2- [4- (6-FLUORO-L,] 2-benzisoxazole-3-yl) piperidino] [ETHYL-6,] 7,8, 9- [TETRAHYDRO-2-METHYL-4H-PYRIDO [1,] 2-a] pyrimidin-4-one. Example-5 A mixture of 4.75 g of [3- (2-CHLOROETHYL)-6,] 7,8, 9-tetrahydro-2-methyl-4H-pyrido [[1,] 2-a] [PYRIMIDIN-4-ONE,] 6.0 g [OF 4- (2,] 4-difluorobenzoyl) piperidine oxime hydrochloride, [0.] 46 g of potassium iodide, 6.1 g of anhydrous powdered potassium carbonate and 40 ml of acetonitrile was stirred and refluxed for 30 hours. The reaction mixture was cooled and water (120 [ML)] was added under stirring. Separated solid stirred at [5°C] for 1 hour, filtered, washed with water. Crude product was purified by crystallization in ethyl acetate to afford 6. [8] g (79percent) of [3- [2- [4- (6-FLUORO-1, 2-BENZISOXAZOLE-3-YL) PIPERIDINO] ETHYL]-6,] 7,8, 9-tetrahydro-2- methyl-4H-pyrido [1, 2-a] [PYRIMIDIN-4-ONE.]
77%
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 95 - 100℃; for 18 h;
A mixture of 4.75 g of [3.] [(2-CHLOROETHYL)-6,] 7,8, 9-tetrahydro-2-methyl-4H-pyrido [[1,] 2-a] [PYRIMIDIN-4-ONE] hydrochloride, [5.] [1] g of 4- (2, 4-difluorobenzoyl) piperidine oxime hydrochloride, 0.46 g of potassium iodide, 6.5 g of anhydrous powdered potassium carbonate and 30 ml [OF N, N-DIMETHYLFORMAMIDE] was stirred at [95-100°C] for 18 hours. The reaction mixture was cooled and water (120 [ML)] was added under stirring. Separated solid stirred at [5°C] for 1 hour, filtered, washed with. water and crystallized from ethyl acetate yielding 5.7 g [(77percent)] of [3- [2- [4- (6-FLUORO-1,] 2-benzisoxazole-3-yl) piperidino] ethyl]-6, 7,8, 9-tetrahydro-2- [METHYL-4H-PYRIDO [1, 2-A] PYRIMIDIN-4-ONE.]
73%
With potassium carbonate In 4-methyl-2-pentanone at 100 - 105℃; for 30 h;
A mixture of 4.75 g of [3- (2-CHLOROETHYL)-6,] 7,8, [9-TETRAHYDRO-2-METHYL-4H-PYRIDO] [[1,] 2-a] pyrimidin-4-one hydrochloride, 5.1 g of 4-(2, 4-difluorobenzoyl) piperidine oxime hydrochloride, 0.46 g of potassium iodide, 6.5 g of anhydrous powdered potassium carbonate and 30 ml [OF MIBK] was stirred at [100105°C] for 30 hours. The reaction mixture was cooled and water (150 ml) was added under stirring. Separated solid stirred at [5°C] for 1 hour, filtered, washed with water and crystallized from ethyl acetate yielding 5.4 g (73percent) of [3- [2- [4- (6-FLUORO-1, 2-BENZISOXAZOLE-3-YL) PIPERIDINO] ETHYL]-6,] 7,8, 9-tetrahydro-2-methyl-4H- [PYRIDO] [[1,] 2-a] [PYRIMIDIN-4-ONE.]
With sodium cyanoborohydride; acetic acid In ethanol at 20℃; for 2.5 h;
Example : 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl)- piperidin-1-yl]-ethyl}-2-methyl-6, 7,8, 9-tetrahydro-4H- pyrido [1, 2-a] pyrimidin-4-one (I); To a suspension of 1.39 g (3,42 mmoles) of 3- {2- [4- (6- fluorobenzo [d] isoxazol-3-yl)-piperidin-1-yl]-vinyl}-2- methyl-6,7, 8,9-tetrahydro-pyrido [1, 2-a] pyrimidin-4-one (III) in 22 mL of absolute ethanol and 1 mL of glacial acetic acid under stirring at room temperature and in a protective atmosphere, 0.254 g (4.04 mmoles) of sodium cyanoborohydride in small portions was added for 1 hour. After 1.5 hour, the solvent was evaporated and the crude product obtained was dissolved in 250 mL of ethyl acetate. The organic phase was successively washed with 50 mL of 1M aqueous sodium bicarbonate solution, 50 mL of water and 50 mL of saturated sodium chloride solution and dried over anhydrous magnesium sulphate. The resultant solution was filtered and the solvent was evaporated to yield 1.17 g of a residual solid (83percent), which was diluted in methylene chloride and purified by column chromatography (silica gel). Elution of the column was with methylene chloride, methanol and triethylamine (95: 5: 1). The pure fractions were collected and the solvent was evaporated under reduced pressure to give 0.83 g (70. 9percent) of 3- {2- [4- (6-fluoro- benzo [d] isoxazol-3-yl)-piperidin-1-yl]-ethyl}-2-methyl- 6,7, 8, 9-tetrahydro-4H-pyrido- [1, 2-a] pyrimidin-4-one (I). Optionally, the reaction crude product was purified by crystallization from a suitable organic solvent, preferably ethanol or 4-methyl-2-pentanone. 1H-NMR (CDCl3), No. (ppm) : 7.71 dd, J1=8. 8 Hz, J2=5. 2 Hz, 1H, CH aromatic; 7.23 dd, J1=8. 6 Hz, J2=2. 2 Hz, 1H, CH aromatic; 7,05 ddd, J1=8. 8 Hz, J2=8. 6 Hz, J3=2. 2 Hz, 1H, CH aromatic; 3.93 t, J=6.2 Hz, 2H, CH2 ; 3.18 d, J=11.6 Hz, 2H, CH2 ; 3.08 m, 1H, CH; 2.87 t, J=6.6 Hz, 2H, CH2 ; 2.77 m, 2H, CH2 ; 2.55 m, 2H, CH2 ; 2.31 s, 3H, CH3 ; 2.27 m, 2H, CH2 ; 2.09 m, 4H, 2xCH2 ; 1.96 m, 2H, CH2; 1.89 m, 2H, CH2. 13C-NMR (CDC13), No. (ppm): 165.26-166, 77, d, JC-F=249 Hz, C aromatic; 163.88-163. 75, d, JC-F=14 Hz, C aromatic; 162.56 ; 161.09 C aromatic; 158.39 C aromatic; 155.87 C aromatic; 122.67-122. 55 d, JC-F=11 Hz, CH aromatic; 119.27 C aromatic; 117.28 C aromatic; 112.35-112. 10 d, JC-F=25 Hz, CH aromatic; 97.48-97. 21 d, JC-F=27 Hz, CH aromatic; 56.68 CH2 ; 53.35 CH2 ; 42.66 CH2 ; 34.59 CH; 31.41 CH2 ; 30.53 CH2 ; 23.74 CH2; 21.95 CH2 ; 21. 24 CH3 ; 19.20 CH2.
With sodium carbonate In methanol at 73 - 75℃; for 4 - 4.5 h;
Example 2; Preparation of risperidone of the formula (I) from 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido [ 1,2-a]pyrirnidine-4-one and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole bases of the formulae (II) and (III).Starting from 11.45 g of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, 12.45 g of 3-(2-cWoroemyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-4-one and 11.8 g of dry sodium carbonate the same method as described in Example 1 is followed, to give 19.8 g (92.8 percent) of risperidone.Mp: 171-172 °C; purity is at least 99 percent, determined by HPLC
77.8%
With N-ethyl-N,N-diisopropylamine In methanol at 45 - 50℃; for 70 - 100 h;
6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (20.0 grams), 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (22.6 grams) and diisopropyl ethylamine (14.1 grams) were dissolved in methanol (90.0 ml). The resulting reaction mixture was maintained at 45-50° C. for about 70-100 hours. The reaction mass was then cooled to 25-35° C. and then separate solid product. The solid mass was filtered and washed with methanol (20.0 ml) followed by water (120.0 ml). The wet product was dried at 70-80° C. to get 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-A]pyrimidin-4-one. (Yield: 29.0 g; 77.8percent; purity by HPLC is 99.93percent)6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10 Kg), 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (11.3 Kg) and diisopropyl ethylamine (7 Kg) were dissolved in methanol (45 Lt). The resulting reaction mixture was maintained at 45-50° C. for about 70 to 100 hours. The reaction mass was then cooled to 25-35° C. and then separate solid product. The solid mass was filtered and washed with methanol (10 Lt) followed by water (60 Lt). The wet product was dried at 70-80° C. to get 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-A]pyrimidin-4-one. (Yield: 18 Kg, purity by HPLC is 99.93percent).
73%
With sodium carbonate In water at 85 - 90℃; for 4 h;
[2.27G OF 4- (6-FLUORO-1, 2-BENZISOXAZOL-3-YL) -PIPERIDINE OBTAINED IN STEP A)] and 2.26g of 3- (2-chloroethyl)-6, 7,8, 9-tetrahydro-2-methyl-4H-pyrido [1, 2- [A] PYRIMIDIN-4-ONE] obtained in Preparation Example 2 were added to a solution of 2.25g of [NA2C03] in [12ML] of water. The resulting mixture was stirred at 85 to [90 °C] for 4 hours, cooled to room temperature, and filtered. The resulting solid was added to [16ML] of N, N- dimethylformamide. The resulting suspension was heated to [80 °C,] left at that temperature for 5 minutes, and then slowly cooled to room temperature. The crystal was filtered, washed with [5ML] of water and dried to obtain 3.02g of the title compound as a white crystal (yield: 73percent). The melting point [ANDAPOS;H-NMR] data were the same as in Example 1.
With potassium hydroxide In water at 120 - 130℃; for 1.5 h;
2.77g of 2,4-difluorophenyl (4-piperidinyl) methanone oxime hydrochloride obtained in Preparation Example 1 and 2.26g of 3- (2-chloroethyl)- 6,7, 8,9-tetrahydro-2-methyl-4H-pyrido [1, 2-a] pyrimidin-4-one obtained in Preparation Example 2 were added to [27ML] of 30percent aqueous potassium hydroxide, and then the resulting mixture was stirred at 120 to 130°C for 90 minutes. The reaction mixture was cooled to room temperature, filtered, and the obtained solid was added to [16ML] of N, N-dimethylformamide. The resulting suspension was heated to [80 °C,] left at that temperature for 5 minutes, and then slowly cooled to room temperature. The resulting crystal was filtered, washed with 5ml of water and dried to obtain 3.39g of the title compound as a white crystal (yield: 82percent). Melting point: 167-169°C ; Purity: 99.7percent (by HPLC); [H-NMR] [(300MHZ,] [CDC13)] : [6] 7.65-7. 61 (m, 1H), 7.18-7. 14 (m, 1H), 7.00-6. 94 (m, 1H), 3.87-3. 83 (m, 2H), 3.12-3. 07 (m, 2H), 2.97-3. 02 (m, 1H), 2.81-2. 76 (m, 2H), 2.71-2. 66 (m, 2H), 2.48-2. 43 (m, 2H), 2.23 (s, 3H), 2.34-2. 19 (m, 2H), 2.05-2. 01 (m, 4H), 1.87-1. 79 (m, 4H).
With potassium carbonate In acetone for 6 h; Heating / reflux
Example 2; Production of risperidone of formula (I) from 3-(2-iodoethyl)-2-methyl-6,7,8,9-tetrahydro-4H- pyrido [ 1 ,2-a]pyrimidine-4-one; 2.56 g (10 mmol) of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole HCl, 2.56 g (10 mmol) 3-(2-iodoemyl)-2-memyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidme-4- one, 2.76 g (20 mmol) of potassium carbonate and 50 ml of acetone are added into a distilling flask equipped with reflux condenser. The suspension is boiled for 6 hours during stirring and then 100 ml of water is added to the suspension and the acetone is distilled off under reduced pressure. The suspension is cooled down to 20 °C and stirred for 1 hour, filtered, washed with 50 ml of water, dried at 60 0C. 3.77 g (92 percent) product is obtained which is recrystallized from 2-propanol.Dry weight: 3.58 g (87.4percent). Melting point: 171-172 0C. Purity: 99.86 percent (determined by HPLC).
Stage #1: With sodium carbonate; potassium iodide In isopropyl alcohol at 20 - 82℃; for 4.16667 h; Heating / reflux Stage #2: With potassium hydroxide In water; isopropyl alcohol at 30 - 40℃; for 6 h;
In one liter four neck round bottom flask 250 ml of isopropyl alcohol was taken at room temperature i. e. 20 to 35degree;C. To the reaction flask, 25 gm of (2,4-difluorophenyl) (4-piperidinyl) methanone oxime was added followed by addition of 30 gm of3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2a] pyrimidin-4-one hydrochloride and 75 gm of sodium Carbonate. To it 3.75 gm of Potassium lodide was added. Reaction mixture was stirred for 5-10 minutes. The reaction mixture was slowly heated to reflux (80-82degree;C), and the temperature maintained for next 4 hours. The reaction mixture was then cooled to room temperature (20-35degree;C). Potassium hydroxide solution (30 gm KOH in 60ml water) was prepared separately and cooled to15degree;C. Potassium hydroxide solution was added slowly to the reaction mixture and stirred at30-40degree;C for 6 hours. The reaction mixture is quenched slowly by addition of the reaction mixture in a 5 lit. 4-neck round bottom flask containing 2 lit. water at room temperature (20-35degree;C). The mixture stirred at room temperature (20-35degree;C) for 1 hour and 30 minutes. The product filtered and washed with 500 ml of water till neutral pH to get 43 gm of wet resperidone, which was further dried at 65degree;C for 6hours to get 32.0 gm of dry respiredone with 99.4percent purity (by HPLC).
With borax; sodium hydroxide In ethanol at 70℃; for 0.5 h;
85 ml of ethanol, 6.97 g of sodium hydroxide, 3.32 g of borax and 50.0 g of the Z-oxime (7) are agitated for 30 min. at 70° C. The reaction mixture is diluted with 200 ml of water at 40° C. and the suspension is agitated for 2 hours at room temperature. The crystals are filtered off, washed with 25 ml of water and dried. Yield: 45.26 g (94.9percent of the theoretical yield) of crude risperidone. Purity (HPLC): 97.2percent
83.9%
With borax; potassium hydroxide In ethanol at 40 - 70℃; for 0.5 h;
1.7 ml of ethanol, 0.40 g of 50percent solution of potassium hydroxide, 0.07 g of borax and 1.00 g of oxime (7) Z-isomer base are agitated at 40° C. for 15 min. The temperature is increased to 70° C. and the suspension agitated for 15 minutes. The reaction mixture is diluted with 8.0 ml of water and the suspension agitated for 1 hour at room temperature. The crystals are filtered off, washed with 10 ml of water and dried. Yield: 0.8 g (83.9percent of theoretical yield) of risperidone.
With sodium carbonate In methanol at 73 - 75℃; for 4 - 4.5 h;
Example 1; Preparation of the risperidone of the formula (I) from the hydrochlorid salt of 3-(2-cUoroemyl)-2-methyl-6,7,8,9-te1xahydro-4H-pyrido[l,2-a]pyrimidme-4-one of the formula (II) and the hydrochloride salt of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of the formula (III). In a pressure vessel into a mixture of 13.3 g (0.052 mol) of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, 15.0 g (0.057 mol) of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-4-one hydrochloride, 20.67 g of dry sodium carbonate and 200 ml of dry methanol nitrogen is introduced and the mixture is stirred for 4-4.5 hours at 73-75 °C. Then the pressure is brought to atmospheric level, the mixture is concentrated to about 150 g, 100 ml of ion exchanged water is added, then the mixture is cooled to a temperature between 0 °C and 5 °C and filtered. To the filter cake 100 ml of ion exchanged water is added, stirred for an hour at 23-25 °C and filtered. The crystals arewashed with ion exchanged water (3 x 20 ml), filtered and dried at a temperature below 60 °C to yield 20.0 g of risperidone (93.6 percent based on the starting benzisoxazole derivative).Mp: 171-172 °C; purity is at least 99 percent, determined by HPLC
With sodium carbonate In water at 110 - 120℃; for 0.666667 h;
Example 9; Preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (risperidone)In a 50-ml reaction flask, 2.56 g of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride and 2.95 g of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one are placed, then a sodium carbonate solution or suspension (dissolved or suspended 8.5 g of sodium carbonate in 25 ml water) is added. The mixture is put into heating bath at 110-120° C. with stirring for 40 min, then cooled with continuous stirring to the room temperature and the precipitate solid is filtered, washed with pure water, and dried to give 3.82 g of the product in 93.2percent yield. The product is purified to obtain a purity of 99.5percent (determined by HPLC) with DMF and isopropanol.
With potassium iodide; sodium carbonate In N,N-dimethyl-formamide
EXAMPLE 1 A mixture of 5.3 parts of 3-(2-chloromethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride, 4.4 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 8 parts of sodium carbonate, 0.1 part of potassium iodide, and 90 parts of DMF is stirred overnight at 80°-90° C. After cooling, the reaction mixture is poured into water. The product is filtered off and crystallized from a mixture of DMF and 2-propanol. The product is filtered off and dried, yielding 3.8 parts (46percent) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 170.0° C.
Reference：
[1] Patent: US5688801, 1997, A,
12
[ 84163-77-9 ]
[ 106266-06-2 ]
Yield
Reaction Conditions
Operation in experiment
46%
With potassium iodide; sodium carbonate In N,N-dimethyl-formamide
EXAMPLE 5 A mixture of 5.3 parts of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride, 4.4 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 8 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide was stirred overnight at 85°-90° C. After cooling, the reaction mixture was poured into water. The product was filtered off and crystallized from a mixture of N,N-dimethylformamide and 2-propanol. The product was filtered off and dried, yielding 3.8 parts (46percent) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 170.0° C. (compound 1).
With sodium carbonate; In methanol; at 73 - 75℃; for 4 - 4.5h;Product distribution / selectivity;
Example 2; Preparation of risperidone of the formula (I) from 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido [ 1,2-a]pyrirnidine-4-one and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole bases of the formulae (II) and (III).Starting from 11.45 g of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, 12.45 g of 3-(2-cWoroemyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-4-one and 11.8 g of dry sodium carbonate the same method as described in Example 1 is followed, to give 19.8 g (92.8 percent) of risperidone.Mp: 171-172 °C; purity is at least 99 percent, determined by HPLC
77.8%
With N-ethyl-N,N-diisopropylamine; In methanol; at 45 - 50℃; for 70 - 100h;Product distribution / selectivity;
6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (20.0 grams), <strong>[63234-80-0]3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one</strong> (22.6 grams) and diisopropyl ethylamine (14.1 grams) were dissolved in methanol (90.0 ml). The resulting reaction mixture was maintained at 45-50° C. for about 70-100 hours. The reaction mass was then cooled to 25-35° C. and then separate solid product. The solid mass was filtered and washed with methanol (20.0 ml) followed by water (120.0 ml). The wet product was dried at 70-80° C. to get 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-A]pyrimidin-4-one. (Yield: 29.0 g; 77.8percent; purity by HPLC is 99.93percent)6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10 Kg), <strong>[63234-80-0]3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one</strong> (11.3 Kg) and diisopropyl ethylamine (7 Kg) were dissolved in methanol (45 Lt). The resulting reaction mixture was maintained at 45-50° C. for about 70 to 100 hours. The reaction mass was then cooled to 25-35° C. and then separate solid product. The solid mass was filtered and washed with methanol (10 Lt) followed by water (60 Lt). The wet product was dried at 70-80° C. to get 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-A]pyrimidin-4-one. (Yield: 18 Kg, purity by HPLC is 99.93percent).
73%
With sodium carbonate; In water; at 85 - 90℃; for 4h;
[2.27G OF 4- (6-FLUORO-1, 2-BENZISOXAZOL-3-YL) -PIPERIDINE OBTAINED IN STEP A)] and 2.26g of 3- (2-chloroethyl)-6, 7,8, 9-tetrahydro-2-methyl-4H-pyrido [1, 2- [A] PYRIMIDIN-4-ONE] obtained in Preparation Example 2 were added to a solution of 2.25g of [NA2C03] in [12ML] of water. The resulting mixture was stirred at 85 to [90 °C] for 4 hours, cooled to room temperature, and filtered. The resulting solid was added to [16ML] of N, N- dimethylformamide. The resulting suspension was heated to [80 °C,] left at that temperature for 5 minutes, and then slowly cooled to room temperature. The crystal was filtered, washed with [5ML] of water and dried to obtain 3.02g of the title compound as a white crystal (yield: 73percent). The melting point [ANDAPOS;H-NMR] data were the same as in Example 1.
With potassium iodide; sodium carbonate; In water; isopropyl alcohol;
Example 1 Synthesis of Risperidone Isopropanol (20 mL), 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one (Compound II)("the chlorine derivative")(2.63 g, 10 mmoles, 1 eq.), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I)("the piperidine derivative") (2.17 g, 10 mmoles, 1 eq.), sodium carbonate (3.18 g, 30 mmoles, 3 eq.), and potassium iodide (66 mg) were added to a 100 mL round bottom flask and stirred with a magnetic stir bar. The flask was placed in an oil bath at 80° C. and allowed to reflux for 9 hours. The flask was then cooled in an ice bath and the contents was filtered. The filter cake was washed in the filter with a small amount of isopropanol. The filter cake was then slurried 3 times in 20 mL of water and filtered. The resulting slurry was dried to give 3 g of material in 73percent yield. The slurry was recrystallized by dissolving in 37 mL of boiling isopropanol, filtered hot and allowed to cool and filtered to give material which had a purity of 99.7percent and an overall yield of 60percent.
2,4-difluorophenyl-(4-piperidinyl)methanone oxime hydrochloride[ No CAS ]
[ 106266-06-2 ]
Yield
Reaction Conditions
Operation in experiment
40 - 91%
With potassium hydroxide; In water; at 120 - 130℃; for 1.5h;
2.77g of 2,4-difluorophenyl (4-piperidinyl) methanone oxime hydrochloride obtained in Preparation Example 1 and 2.26g of 3- (2-chloroethyl)- 6,7, 8,9-tetrahydro-2-methyl-4H-pyrido [1, 2-a] pyrimidin-4-one obtained in Preparation Example 2 were added to [27ML] of 30percent aqueous potassium hydroxide, and then the resulting mixture was stirred at 120 to 130°C for 90 minutes. The reaction mixture was cooled to room temperature, filtered, and the obtained solid was added to [16ML] of N, N-dimethylformamide. The resulting suspension was heated to [80 °C,] left at that temperature for 5 minutes, and then slowly cooled to room temperature. The resulting crystal was filtered, washed with 5ml of water and dried to obtain 3.39g of the title compound as a white crystal (yield: 82percent). Melting point: 167-169°C ; Purity: 99.7percent (by HPLC); [H-NMR] [(300MHZ,] [CDC13)] : [6] 7.65-7. 61 (m, 1H), 7.18-7. 14 (m, 1H), 7.00-6. 94 (m, 1H), 3.87-3. 83 (m, 2H), 3.12-3. 07 (m, 2H), 2.97-3. 02 (m, 1H), 2.81-2. 76 (m, 2H), 2.71-2. 66 (m, 2H), 2.48-2. 43 (m, 2H), 2.23 (s, 3H), 2.34-2. 19 (m, 2H), 2.05-2. 01 (m, 4H), 1.87-1. 79 (m, 4H).
3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride[ No CAS ]
[ 84163-46-2 ]
[ 106266-06-2 ]
Yield
Reaction Conditions
Operation in experiment
99.4%Chromat.
In one liter four neck round bottom flask 250 ml of isopropyl alcohol was taken at room temperature i. e. 20 to 35°ree;C. To the reaction flask, 25 gm of (2,4-difluorophenyl) (4-piperidinyl) methanone oxime was added followed by addition of 30 gm of3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2a] pyrimidin-4-one hydrochloride and 75 gm of sodium Carbonate. To it 3.75 gm of Potassium lodide was added. Reaction mixture was stirred for 5-10 minutes. The reaction mixture was slowly heated to reflux (80-82°ree;C), and the temperature maintained for next 4 hours. The reaction mixture was then cooled to room temperature (20-35°ree;C). Potassium hydroxide solution (30 gm KOH in 60ml water) was prepared separately and cooled to15°ree;C. Potassium hydroxide solution was added slowly to the reaction mixture and stirred at30-40°ree;C for 6 hours. The reaction mixture is quenched slowly by addition of the reaction mixture in a 5 lit. 4-neck round bottom flask containing 2 lit. water at room temperature (20-35°ree;C). The mixture stirred at room temperature (20-35°ree;C) for 1 hour and 30 minutes. The product filtered and washed with 500 ml of water till neutral pH to get 43 gm of wet resperidone, which was further dried at 65°ree;C for 6hours to get 32.0 gm of dry respiredone with 99.4% purity (by HPLC).
In 250 ml four neck round bottom flask 100 mi of isopropyl alcohol was taken at room temperature i. e. 20 to 35°ree;C. To the reaction flask, 10 gm of (2,4-difluorophenyl-)(4-piperidinyl) methanone, oxime was added followed by addition of 11 gm of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride and 15 gm of sodium carbonate. To it 1.0 gm of Potassiumlodide was added. Reaction mixture was stirred for 5-10 minutes. The reaction mixture was slowly heated toreflux (80-82°ree;C), and maintained the temperature for next 5 hours. The reaction mixture was then cooled to room temperature (20-35°ree;C). Piperidine 18 gm was charged slowly to the reaction mixture and stirred at 25-30°ree;C for 12 hours. Quench the reaction mixture slowly by addition of the reaction mixture in a 5 lit. 4-neck round bottom flask containing 750 mi water at room temperature (20-35°ree;C). Stirred the mixture at room temperature (20-35°ree;C) for 2 hour and 30 minutes. Filtered the product and washed with 240 ml of water till neutral pH to get 8.3 gm of wet crude Risperidone, which was further dried at 65°ree;C for 6 hours to get 7.5 gm of dry Risperidone.
In 250 ml four neck round bottom flask, 100 mi of isopropyl alcohol (IPA) was taken at room temperature i. e. 25 to 30°ree;C. To the reaction flask, 10 gm of (2,4-difluorophenyl-)(4-piperidinyl) methanone, oxime was added followed by addition of 11 gm of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a] pyrimidin-4-one hydrochloride and 15 gm of sodium carbonate. To it 1.0 gm of potassium iodide was added. Reaction mixture was stirred for 5-10 minutes. The reaction mixture was slowly heated to reflux (80-82°ree;C), and maintained the temperature for next 5 hours. The reaction mixture was then cooled to room temperature (20-35°ree;C). Sodium hydroxide solution (8.5 gm NaOH in 8.5 ml water) was prepared separately and cooled to15°ree;C. Sodium hydroxide solution was added slowly to the reaction mixture and stirred at25-30°ree;C for 12 hours. Quench the reaction mixture slowly by addition of the reaction mixture in a 5 lit. 4-neck round bottom flask containing 750 ml water at room temperature(20-35°ree;C). Stirred the mixture at room temperature (20-35°ree;C) for 2 hour and 30 minutes. Filtered the product and washed with 240 ml of water till neutral pH to get 12.2 gm of wet crude Risperidone, which was further dried at 65°ree;C for 6 hours to get 11.5 gm of dry Risperidone. HPLC PURITY = 97.5%
In 250 ml four neck round bottom flask 100 ml of Isopropyl alcohol was taken at room temperature i. e. 20 to 35°ree;C. To the reaction flask, 10 gm of (2,4-difluorophenyl-)(4-piperidinyl) methanone, oxime was added followed by addition of 11 gm of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a] pyrimidin-4-one hydrochloride and 5.9 gm of sodium hydroxide. To it 1.0 gm of Potassium lodide was added. Reaction mixture was stirred for 5-10 minutes. The reaction mixture was slowly heated to reflux(80-82°ree;C), and maintained the temperature for next 5 hours. The reaction mixture was then cooled to room temperature (20-35°ree;C). Sodium hydroxide solution (8.5 gm NaOH in 8.5 ml water) was prepared separately and cooled to15°ree;C. Sodium hydroxide solution was added slowly to the reaction mixture and stirred at 25-30°ree;C for 12 hours. Quench the reaction mixture slowly by addition of the reaction mixture in a 5 lit. 4-neck round bottom flask containing 750 ml water at room temperature (20-35°ree;C). Stirred the mixture at room temperature (20-35°ree;C) for 2 hour and 30 minutes. Filtered the product and washed with 240 ml of water till neutral pH to get 8.5 gm of wet crude Risperidone, which was further dried at 65°ree;C for 6 hours to get 7.0 gm of dry Risperidone. HPLC PURITY= 94.74%
With water; acetic acid; In hexane; acetone; at 20℃; for 1h;
Example 6-<strong>[106266-06-2]Risperidone</strong> acetate monohydrate 5.00 g of risperidone base was suspended in a mixture of 15 ml of n-hexane, 1.5 ml of acetone and 0.22 ml of water. Under stirring, 0.73 g of acetic acid was added dropwise. The paste formed in the solution was triturated and after several minutes it turned to crystals. The suspension was stirred for 1 hour at room temperature. The crystals were filtered off and washed with 2x 5ml of n-hexane. Product was air dried at room temperature to constant weight. Yield: 5.25 g, mp. 161.5-164. 5C Water content (by K. Fischer): correspond to monohydrate.
With L-malic acid; In ethanol; at 25 - 63℃; for 20.5h;
Example 7A-<strong>[106266-06-2]Risperidone</strong> hemimalate 14.10 g risperidone was stirred with 250 ml ethanol and heated to 63C in 20 minutes affording a clear solution. A solution of 2.32 g (L) -malic acid in 25 ml ethanol was added in 10 minutes. The solution was allowed to cool to room temperature in 105 minutes. Crystallization was induced by scratching in the flask at 25C. After further stirring at room temperature for 19 h, the crystals were filtered off, washed twice with ethanol and dried in vacuo at 40C for 24h, affording 14.11 g risperidone hemimalate (86%), mp. 183-184C Water content: 0.40%
51%
With L-malic acid; In ethanol; at 20℃;
Example 7-<strong>[106266-06-2]Risperidone</strong> hemimalate 0.99 g of risperidone was suspended in 30 ml ethanol, affording a white suspension. 323 mg (L)- (-)-malic acid was added and after short heating, a pale yellow clear solution was obtained. The solution was allowed to cool to room temperature, resulting in crystallisation. The crystals were filtered off, washed once with ethanol and dried in vacuo at 40C, affording 582 mg risperidone hemimalate (51%), mp. 183-185C NMR. : confirmed the structure Water: 0.9%
With hydrogenchloride; In propan-1-ol; ethanol; for 0.0166667h;
1.98 g <strong>[106266-06-2]Risperidone</strong> base was suspended in 50 ml ethanol, affording a white suspension. 2 ml of an FIICL solution (5-6 N in i-propanol) was added, resulting in an almost clear solution. After one minute, the solution changed into a milky white suspension. Then, the suspension was filtered off, washed twice with ethanol and dried in VACUO at 40C, affording 1.95 g risperidone dihydrochloride (91%) water content: 0.22% NMR: confirmed the structure Acid titration: confirmed the di-salt
87%
With hydrogenchloride; In ethanol; water; at 20℃; for 20h;
Example 1A-<strong>[106266-06-2]Risperidone</strong> dihydrochloride 1.98 g <strong>[106266-06-2]Risperidone</strong> base was suspended in 30 ml ethanol, affording a white suspension and heated until a clear solution was obtained. 1 ml concentrated HC1 solution (12 M; 2.5 equiv. ) was added. A white precipitate was formed immediately. The mixture was then further stirred for 20 h at room temperature. The precipitate was filtered off, washed once with ethanol and dried in vacuo at 40C for 5 days, affording 2.03g risperidone dihydrochloride (87%), mp. 285-291C water content: 0.16% water content after exposure to air under ambient conditions for 3 weeks : 0.30% Acid titration: confirms dihydrochloride salt
With maleic acid; In ethanol; at 20 - 60℃; for 21h;
Example 3-<strong>[106266-06-2]Risperidone</strong> HYDROGENMALEATE 14.00 g <strong>[106266-06-2]Risperidone</strong> base was stirred with 250 ml ethanol and heated to 60C, affording a clear solution. A solution of 4.00 g maleic acid in 25 ml ethanol was added in 5 minutes. The solution was allowed to cool to room temperature. Crystallization was induced by seeding at 40C. After further stirring at room temperature for 21 h, the crystals were filtered off, washed twice with ethanol and dried in vacuo at 40C for 3 days, affording 15.65 g risperidone HYDROGENMALEATE (87%), mp. 185-186C water content: <0. 1%
82%
With maleic acid; In ethanol;
0.99 g risperidone was suspended in 30 ml ethanol, affording a white suspension. 279 mg maleic acid was added, resulting in a pale yellow clear solution. After a few minutes a white solid precipitated. The precipitate was filtered off, washed with cold ethanol and dried in vacuo at 40C, affording 1.04 g risperidone HYDROGENMALEATE (82%) mp. 190-195C NMR: confirmed the structure
Example 4-<strong>[106266-06-2]Risperidone</strong> mesylate 1. 98 g risperidone was suspended in 50 ml ethanol, affording a white suspension and heated until a clear solution was obtained 0. 7 ML METHANESULFONIC acid was added and stirred for 22 h. The solution was concentrated at reduced pressure, affording a yellow oil. Diethyl ether was added, giving rise to a white precipitate. The crystals were filtered off and dried in vacuo at 40C for 3 days, affording 2.14 g risperidone mesylate (yield: 87%), mp 208-212C. water content: 0. 41% water content after exposure to air under ambient conditions for 2 weeks: 1.38% water content after exposure to 40C/75% humidity for 2 weeks: 8. 51% Drying experiment with the hydrated product: Water is released starting from 30C, yielding the anhydrate.
Example 5-<strong>[106266-06-2]Risperidone</strong> hemitartrate 1.98 g risperidone was dissolved by heating in 30 ml ethanol. A solution of 1.45 g (L) -tartaric acid in 20ML ethanol was added, resulting in a pale yellow clear solution, which was allowed to cool to room temperature. After a few minutes, a precipitation was formed. After stirring at room temperature for 20 hours, the precipitate was filtered off, washed once with ethanol and dried in vacuo at 40C for 3 days, affording 1. 85 G risperidone hemitartrate (79%), mp. 224-227C. NMR : confirmed the structure Water content: 0.28%
3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride[ No CAS ]
[ 135634-18-3 ]
[ 106266-06-2 ]
Yield
Reaction Conditions
Operation in experiment
81%
With sodium carbonate;potassium iodide; In acetonitrile; for 32h;Heating / reflux;
A mixture of 4.75 g of 3- (2-chloroethyl)-6, 7,8, 9-tetrahydro-2-methyl-4H-pyrido [[1,] [2-A] PYRIMIDIN-4-ONE] hydrochloride, 5.1 g of [4- (2,] 4-difluorobenzoyl) piperidine oxime hydrochloride, 0.46 g of potassium iodide, 5 g of anhydrous sodium carbonate and 30 ml of acetonitrile was stirred and refluxed for 32 hours. The reaction mixture was cooled and water (120 ml) was added under stirring. Separated solid stirred at [5 FOR 1] hour, filtered, washed with water and crystallized from ethyl acetate yielding 6 g (81%) of [3- [2- [4- (6-FLUORO-] [1,] [2-BENZISOXAZOLE-3-YL) PIPERIDINO] ETHYL]-6,] 7,8, [9-TETRAHYDRO-2-METHYL-4H-PYRIDO [ 1,] 2-a] [PYRIMIDIN-4-ONE.]
79 - 81%
With potassium carbonate;potassium iodide; In acetonitrile; for 30h;Heating / reflux;
A mixture of 4.75 g of [3-(2-CHLOROETHYL)-6,] 7,8, 9-tetrahydro-2-methyl-4H-pyrido [1, 2-a] pyrimidin-4-one hydrochloride, 5. 1 g of [4- (2, 4-DIFLUOROBENZOYL)] piperidine oxime hydrochloride, 0.46 g of potassium iodide, 6.5 g of anhydrous powdered potassium carbonate and 30 ml of acetonitrile was stirred and refluxed for 30 hours. Reaction monitoring by HPLC analysis indicated in situ formation of risperidone. After the completion of reaction, the reaction mixture was cooled and water (120 ml) was added under stirring. Separated solid stirred at [5C] for [1] hour, filtered, washed with water and crystallized from ethyl acetate yielding 6 g [(81%) OF 3- [2- [4- (6-FLUORO-L,] 2-benzisoxazole-3-yl) piperidino] [ETHYL-6,] 7,8, 9- [TETRAHYDRO-2-METHYL-4H-PYRIDO [1,] 2-a] pyrimidin-4-one. Example-5 A mixture of 4.75 g of [3- (2-CHLOROETHYL)-6,] 7,8, 9-tetrahydro-2-methyl-4H-pyrido [[1,] 2-a] [PYRIMIDIN-4-ONE,] 6.0 g [OF 4- (2,] 4-difluorobenzoyl) piperidine oxime hydrochloride, [0.] 46 g of potassium iodide, 6.1 g of anhydrous powdered potassium carbonate and 40 ml of acetonitrile was stirred and refluxed for 30 hours. The reaction mixture was cooled and water (120 [ML)] was added under stirring. Separated solid stirred at [5C] for 1 hour, filtered, washed with water. Crude product was purified by crystallization in ethyl acetate to afford 6. [8] g (79%) of [3- [2- [4- (6-FLUORO-1, 2-BENZISOXAZOLE-3-YL) PIPERIDINO] ETHYL]-6,] 7,8, 9-tetrahydro-2- methyl-4H-pyrido [1, 2-a] [PYRIMIDIN-4-ONE.]
77%
With potassium carbonate;potassium iodide; In DMF (N,N-dimethyl-formamide); at 95 - 100℃; for 18h;
A mixture of 4.75 g of [3.] [(2-CHLOROETHYL)-6,] 7,8, 9-tetrahydro-2-methyl-4H-pyrido [[1,] 2-a] [PYRIMIDIN-4-ONE] hydrochloride, [5.] [1] g of 4- (2, 4-difluorobenzoyl) piperidine oxime hydrochloride, 0.46 g of potassium iodide, 6.5 g of anhydrous powdered potassium carbonate and 30 ml [OF N, N-DIMETHYLFORMAMIDE] was stirred at [95-100C] for 18 hours. The reaction mixture was cooled and water (120 [ML)] was added under stirring. Separated solid stirred at [5C] for 1 hour, filtered, washed with. water and crystallized from ethyl acetate yielding 5.7 g [(77%)] of [3- [2- [4- (6-FLUORO-1,] 2-benzisoxazole-3-yl) piperidino] ethyl]-6, 7,8, 9-tetrahydro-2- [METHYL-4H-PYRIDO [1, 2-A] PYRIMIDIN-4-ONE.]
73%
With potassium carbonate;potassium iodide; In 4-methyl-2-pentanone; at 100 - 105℃; for 30h;
A mixture of 4.75 g of [3- (2-CHLOROETHYL)-6,] 7,8, [9-TETRAHYDRO-2-METHYL-4H-PYRIDO] [[1,] 2-a] pyrimidin-4-one hydrochloride, 5.1 g of 4-(2, 4-difluorobenzoyl) piperidine oxime hydrochloride, 0.46 g of potassium iodide, 6.5 g of anhydrous powdered potassium carbonate and 30 ml [OF MIBK] was stirred at [100105C] for 30 hours. The reaction mixture was cooled and water (150 ml) was added under stirring. Separated solid stirred at [5C] for 1 hour, filtered, washed with water and crystallized from ethyl acetate yielding 5.4 g (73%) of [3- [2- [4- (6-FLUORO-1, 2-BENZISOXAZOLE-3-YL) PIPERIDINO] ETHYL]-6,] 7,8, 9-tetrahydro-2-methyl-4H- [PYRIDO] [[1,] 2-a] [PYRIMIDIN-4-ONE.]
A mixture of 5.58 g of [3- (2-CHLOROETHYL)-6,] 7,8, [9-TETRAHYDRO-2-METHYL-4H-PYRIDO] [1, 2-a] [PYRIMIDIN-4-ONE] hydrochloride, 5.1 g of 4- (2, 4-difluorobenzoyl) piperidine oxime hydrochloride, 0.46 g of potassium iodide, 6.76 g of anhydrous powdered potassium carbonate and 40 [ML] of acetonitrile was stirred and refluxed for 30 hours. Reaction monitoring by HPLC analysis indicated the formation of N-alkylated product, oxime, which subsequently [SLOWLY CYCLIZED IN SITU] to give risperidone. Thereafter, the reaction mixture was cooled and filtered. Residue was washed with cold water (50 [ML)] to remove the inorganics. Further washed with chilled ethyl acetate (5 [ML).] The product was crystallized from ethyl acetate yielding 6 g (81%) of [3- [2- [4- (6-FLUORO-1, 2-BENZISOXAZOLE-3-YL) PIPERIDINO] ETHYL]-] 6,7, 8, [9-TETRAHYDRO-2-METHYL-4H-PYRIDOF1, 2-A] PYRIMIDIN-4-ONE.]
With potassium hydroxide; oxygen; In water; toluene; at 80℃; for 4 - 5h;
In particular, the process comprises the steps of a) charging a reaction vessel with toluene and KOH; b) adding water to the suspension obtained in a) while keeping the temperature between 30 and 40 C; c) adjusting the concentration of oxygen in the atmosphere of the reaction vessel to between 1 and 8 %; d) adding an intermediate of formula (IV) while keeping the temperature above 30 0C; e) heating the reaction mixture to a temperature above 80 0C for 4 to 5 hours; f) diluting the reaction mixture with water at a temperature of 80 0C; g) separating the water phase; h) extracting the organic layer three times with water at a temperature of 80 0C; i) cooling the organic layer to a temperature between 0 and 10 0C while stirring for at least 2 hours; j) collecting the precipitated risperidone (I); k) washing the precipitated risperidone (I) with acetone; and1) drying the risperidone (I) at a temperature between 50 and 60 0C for 16 to 20 hours.Risperidone (I) prepared according to the above process does not contain the contaminant product (V) and thus is useful for the preparation of drug product such as risperi- done long acting injection.
Example 3 Synthesis of Risperidone The same materials and method as in Example 1 with the exception being that 20 mL of acetonitrile was used instead of 20 mL of isopropanol. The flask was put in an oil bath for 17 hours at 79-83 C., then put in the freezer for 2 hours, filtered, and the filter cake washed with acetone until the filtrate had no color. The filter cake was then slurried in 25 mL water 3 times and filtered and dried to give 3.03 g, 74% yield, of crude risperidone. The crude risperidone was recrystallized from 35 mL of isopropanol, filtered hot, cooled, filtered and dried to give 2.47 g of risperidone, 60% overall yield, 99.8% pure by HPLC.
93.11%
Purification / work up;
5.08 g of risperidone is dissolved at room temperature in 10.2 ml of water and 0.81 g of acetic acid. The solution is filtered and diluted with 20.3 ml of water and 10.2 ml of isopropanol. To the stirred solution is added dropwise a solution of 1.52 g of 50% sodium hydroxide solution in 10.2 ml of water. Upon completion, stirring was continued for 1 hour at 70 C. The crystals are filtered off and washed with 2.0 ml of water. The product is dried in air. Yield: 4.73 g (93.11% of theory). DSC: Form A
92%
Purification / work up;
5.00 g of crude risperidone is suspended in 10 ml of water and 0.80 g of acetic acid is added. After dissolving, the solution is filtered. The clear solution is diluted with 30 ml of methanol. The solution is alkalized dropwise during 20 minutes with a solution of 1.5 g of 50% sodium hydroxide in 10 ml of water at 35-40 C. (pH=9.5-10). The suspension is agitated at 22 C. for 1 hour. The product is filtered off and was washed with 5 ml of distilled water (neutral reaction). Yield: 4.61 g (92% of the theoretical yield).
91.6%
Purification / work up;
5 g of risperidone is dissolved in 20 ml of ethanol at reflux. The solution is cooled spontaneously to ambient temperature and agitated for 1 hour. The crystals are filtered off and dried. Yield: 4.58 g (91.6% of the theoretical yield). DSC: Form A.
81.85%
Purification / work up;
5.62 g of risperidone is dissolved at 78 C. in 82.0 ml of 2-propanol. The solution is cooled to 20 C. The mixture is stirred for I hour. The crystals are filtered off and washed with 2×3 ml of 2-propanol. The product is dried. Yield: 4.60 g (81.85% of theory). DSC: Form A.
80%
Purification / work up;
6 g of risperidone is dissolved in 21.8 ml of methanol at reflux. The solution is cooled spontaneously to ambient temperature and agitated for 1 hour. The crystals are filtered off and dried. Yield: 4.77 g (80% of the theoretical yield). DSC: Form A.
78 - 92.67%
Purification / work up;
5.05 g of risperidone is dissolved at room temperature in 10.1 ml of water and 0.81 g of acetic acid. The solution is filtered and diluted with 20.2 ml of water. The solution is poured dropwise into a solution of 1.52 g of 50% sodium hydroxide solution in 10.1 ml of water and 10.1 ml of ethanol. Upon completion, stirring is continued for 1 hour at 25 C. temperature. The crystals are filtered off and washed with 2.0 ml of water. The product is dried in air. Yield: 4.68 g (92.67% of theory). DSC: Form A.; Example 14 Crystallization of Risperidone from Ethanol/Water [0067] 5.00 g of crude risperidone is suspended in 10 ml of water and 0.80 g of acetic acid is added. After dissolving, the solution is filtered. The clear solution diluted with 30 ml of ethanol and then alkalized dropwise during 20 minutes with a solution of 1.5 g of 50% sodium hydroxide in 10 ml of water at 35-40 C. (pH=9.5-10). The suspension is agitated at 20 C. for 1 hour. The product is filtered off and washed with 5 ml of distilled water (neutral reaction). Yield: 3.91 g (78% of the theoretical yield)
70.29%
Purification / work up;
5.62 g of risperidone is dissolved at 78 C. in 62.0 ml of N,N-dimethylformamide. The solution is cooled to 20 C. The mixture is stirred for 1 hour. The crystals are filtered off and washed with 2×3 ml of 2-propanol. The product is dried. Yield: 3.95 g (70.29% of theory). DSC: Form A.
63%
Example 4 Synthesis of Risperidone The same materials and method as in Example 1 with the exception being that 20 mL of iso-butanol was used instead of 20 mL of isopropanol followed by stirring in an oil bath at 78 C. over night. Risperidone was isolated in 63% yield.
53%
Example 2 Synthesis of Risperidone The same materials and method as in Example 1 with the exception being that methyl ethyl ketone (MEK) (15 mL) was used instead of 20 mL of isopropanol. The flask was put in an oil bath at 79-83 C. overnight, cooled, filtered and washed with acetone and water to give 2.19 g, 53% yield.
Example 12 Preparation of Risperidone Form A Risperidone (5.1 g) was dissolved in 30 mL dichloromethane. n-Hexane (150 ml) was added to the solution to facilitate precipitation until a cloudy dispersion was formed. The resulting suspension was filtered. The filtrate, analyzed by PXRD, contained risperidone Form A and a minor quantity of risperidone Form B.
claim 23 , wherein the atypical antipsychotic agent or pharmaceutically acceptable salt thereof is selected from: ... olanzapine 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine; perospirone cis-2-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-hexahydro-1H-isoindole-1,3(2H)-dione; risperidone 3-[2-[4-(6-fluoro-1,2-benzaisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-alpha]pyrimidin-4-one; sertindole 1-[2-[4-[5-chloro-1-(4-fluorophenyl-1H-indol-3yl]-1-piperidinyl]ethyl]imidiazolidin-2-one; ...
With benzoyl chloride; triethylamine; In N,N-dimethyl-formamide; at 60 - 65℃; for 1h;Purification / work up;
Example 2: Purification of Risperidone; Risperidone crude (20 g) and N,N-dimethylformamide (160 mL) followed by triethylamine (1.48 gm) were added in a reaction vessel and were heated to 60 0C to 650C to get a clear solution to which benzoyl chloride (1.37 g) was added. The reaction mixture was stirred at the same temperature for 1 hr and then to room temperature to obtain the solid material, which was stirred for 3 hrs at 100C to 150C, filtered and washed with isopropyl alcohol to get solid which is dried at 600C to 65C for 6 hrs to get highly pure Risperidone having HPLC purity more than 99.70%.
Example 4; Purification of Risperidone:; Risperidone crude (20 g) and N,N-dimethylformamide (16OmL) followed by triethylamine (1.48 g) were added in a reaction vessel and were heated to 60 0C to 650C to get a clear solution to which benzoyl chloride (1.37 g) was added. The reaction mixture was stirred at the same temperature for 1 hr and then to room temperature to obtain the solid material, which was stirred for 3 hrs at 10-150C, filtered and washed with isopropyl alcohol to get crude Risperidone which is taken in another reaction vessel and isopropyl alcohol (120 mL) and N,N-dimethylformamide (3.2 mL) added and heated the solution to 70 to 800C to get a clear solution. Carbon (2 g) was added to the solution and stirred for 20 to30 min., filtered the carbon through highflo, washed the bed with isopropyl alcohol (40 mL) and heated the suspension to 70 to 800C to get the clear solution. Cooled the reaction mass to 10 to 150C and stirred for 3 hrs., filtered the solid, washed with isopropyl alcohol (40 mL) and dried the solid at 60 to70C for 2 hrs. Micronized the material and dried at 80 to 85C for 12 hrs to get Risperidone. (13.5 g) having HPLC Purity more than 99.70 %.
13
[ 132961-05-8 ]
[ 106266-06-2 ]
Yield
Reaction Conditions
Operation in experiment
94.9%
With borax; sodium hydroxide; In ethanol; at 70℃; for 0.5h;
85 ml of ethanol, 6.97 g of sodium hydroxide, 3.32 g of borax and 50.0 g of the Z-oxime (7) are agitated for 30 min. at 70 C. The reaction mixture is diluted with 200 ml of water at 40 C. and the suspension is agitated for 2 hours at room temperature. The crystals are filtered off, washed with 25 ml of water and dried. Yield: 45.26 g (94.9% of the theoretical yield) of crude risperidone. Purity (HPLC): 97.2%
83.9%
With borax; potassium hydroxide; In ethanol; at 40 - 70℃; for 0.5h;
1.7 ml of ethanol, 0.40 g of 50% solution of potassium hydroxide, 0.07 g of borax and 1.00 g of oxime (7) Z-isomer base are agitated at 40 C. for 15 min. The temperature is increased to 70 C. and the suspension agitated for 15 minutes. The reaction mixture is diluted with 8.0 ml of water and the suspension agitated for 1 hour at room temperature. The crystals are filtered off, washed with 10 ml of water and dried. Yield: 0.8 g (83.9% of theoretical yield) of risperidone.
With potassium hydroxide; In ethanol; water; at 80℃; for 1 - 5h;Product distribution / selectivity;
0.2 g of essentially pure Z- or E-isomer of the oxime (7) is attempted to be converted into risperidone by dissolving in 2 ml of ethanol, adding 0.1 g of 50% aqueous KOH and heating the mixture under stirring at 80 C. Samples of the reaction mixture are taken and analyzed by HPLC.; Observations; [0058] Sub a): Adding another KOH and prolonged heating did not lead to an increase of risperidone in the reaction mixture. [0059] Sub b): One hour is sufficient to perform a conversion. Prolonged heating leads to an increased amount of by-products
With potassium hydroxide; In ethanol; water; at 80℃; for 1 - 5h;Product distribution / selectivity;
0.2 g of essentially pure Z- or E-isomer of the oxime (7) is attempted to be converted into risperidone by dissolving in 2 ml of ethanol, adding 0.1 g of 50% aqueous KOH and heating the mixture under stirring at 80 C. Samples of the reaction mixture are taken and analyzed by HPLC.; Observations; [0058] Sub a): Adding another KOH and prolonged heating did not lead to an increase of risperidone in the reaction mixture. [0059] Sub b): One hour is sufficient to perform a conversion. Prolonged heating leads to an increased amount of by-products
3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride[ No CAS ]
[ 84163-13-3 ]
[ 106266-06-2 ]
Yield
Reaction Conditions
Operation in experiment
93.6%
With sodium carbonate; In methanol; at 73 - 75℃; for 4 - 4.5h;Product distribution / selectivity;
Example 1; Preparation of the risperidone of the formula (I) from the hydrochlorid salt of 3-(2-cUoroemyl)-2-methyl-6,7,8,9-te1xahydro-4H-pyrido[l,2-a]pyrimidme-4-one of the formula (II) and the hydrochloride salt of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of the formula (III). In a pressure vessel into a mixture of 13.3 g (0.052 mol) of <strong>[84163-13-3]6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride</strong>, 15.0 g (0.057 mol) of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-4-one hydrochloride, 20.67 g of dry sodium carbonate and 200 ml of dry methanol nitrogen is introduced and the mixture is stirred for 4-4.5 hours at 73-75 C. Then the pressure is brought to atmospheric level, the mixture is concentrated to about 150 g, 100 ml of ion exchanged water is added, then the mixture is cooled to a temperature between 0 C and 5 C and filtered. To the filter cake 100 ml of ion exchanged water is added, stirred for an hour at 23-25 C and filtered. The crystals arewashed with ion exchanged water (3 x 20 ml), filtered and dried at a temperature below 60 C to yield 20.0 g of risperidone (93.6 % based on the starting benzisoxazole derivative).Mp: 171-172 C; purity is at least 99 %, determined by HPLC
With sodium carbonate; In water; at 25 - 55℃; for 9h;Product distribution / selectivity;
Example 1 : Condensation reaction in water medium 6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hyrochloride (Formula - 2.HCl, 100G) IS added to a solution of sodium carbonate (180g) in 400ml water at 25- 30C. STOW . Y THE REACTION mass is warmed to 50-55C and then a SOLUTON of 3- (2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one HYDROCHLORIDE (FORMULA-3. HCI, 150G) IN water (300MT) is added graduaty over a period of 5 hours at 50-55C. THE REACTION mass temperature is maintained further for another 4 hours. The reaction mass is cooled to room temperature and diluted VFI (200ML) WATER THE PRECIPITATED RISPERIDONE IS SEPARATED by filtration, washed with water (50ml) and dried to get crude risperidone. Crude nsperidone weight = 135gm PURITR-90-95% (HPLC); Example 2: Condensation reaction in water medium 6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (Formula - 2.HCl, LONG) is added to a SOTUTION of sodium carbonate(180g) in 400ml water at 25- 30C. Slowly the reaction mass is warmed to 50-55C and then a solution of 3- (2-chloroethyl)-6, 7,8, 9-tetrahydro-2-methyl-4H-pyrido[]1, 2-ALPYRIMIDIN-4-ONE HYDROCHIOHDE (Formula-3. HCl, 150g) in water (300ml) is added gradually over a period of 5 hours at 50-55C. The reaction mass temperature is maintained further for another 4 hours. The reaction mass is cooled to room temperature and diluted with (200ml) water the precipitated risperidone is extracted with DICHLOROMETHANE (3X450ML). The dichloromethane extract is used for further work-up according to Method A or Method B, as given below to get crude risperidone.
With sodium carbonate; In water; acetonitrile; at 25 - 75℃; for 8h;Product distribution / selectivity;
Example 3 : Condensation reaction in mixture of water and water-miscible solvents 6-Fluoro-3-(4-iperidinyl)-1, 2 benzisoxazole hydrochloride (100G) is added to a suspension of sodium carbonate (180G) in ACETONITRITE (500ml) at 25-30C. Slowly, the reaction mass is warmed TO 70-75"C and then a solution of 3-(2- CHLOROETHO)-6. 7, 8, 9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride (1109) IN water (200ML) is added gradually over a period of 4 hours at 70-75C. The reaction mass is maintained at the same temperature for an ADDITIONAL 4 hours. The reaction mass is then cooled to room temperature and diluted with water (500ML). The resulting mixture is extracted with dichloromethane (3X450M .). The dichloromethane extract is worked up as EXP . AINED TOR METHOD A in Example 1 to produce crude risperidone
With sodium cyanoborohydride; acetic acid; In ethanol; at 20℃; for 2.5h;
Example : 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl)- piperidin-1-yl]-ethyl}-2-methyl-6, 7,8, 9-tetrahydro-4H- pyrido [1, 2-a] pyrimidin-4-one (I); To a suspension of 1.39 g (3,42 mmoles) of 3- {2- [4- (6- fluorobenzo [d] isoxazol-3-yl)-piperidin-1-yl]-vinyl}-2- methyl-6,7, 8,9-tetrahydro-pyrido [1, 2-a] pyrimidin-4-one (III) in 22 mL of absolute ethanol and 1 mL of glacial acetic acid under stirring at room temperature and in a protective atmosphere, 0.254 g (4.04 mmoles) of sodium cyanoborohydride in small portions was added for 1 hour. After 1.5 hour, the solvent was evaporated and the crude product obtained was dissolved in 250 mL of ethyl acetate. The organic phase was successively washed with 50 mL of 1M aqueous sodium bicarbonate solution, 50 mL of water and 50 mL of saturated sodium chloride solution and dried over anhydrous magnesium sulphate. The resultant solution was filtered and the solvent was evaporated to yield 1.17 g of a residual solid (83%), which was diluted in methylene chloride and purified by column chromatography (silica gel). Elution of the column was with methylene chloride, methanol and triethylamine (95: 5: 1). The pure fractions were collected and the solvent was evaporated under reduced pressure to give 0.83 g (70. 9%) of 3- {2- [4- (6-fluoro- benzo [d] isoxazol-3-yl)-piperidin-1-yl]-ethyl}-2-methyl- 6,7, 8, 9-tetrahydro-4H-pyrido- [1, 2-a] pyrimidin-4-one (I). Optionally, the reaction crude product was purified by crystallization from a suitable organic solvent, preferably ethanol or 4-methyl-2-pentanone. 1H-NMR (CDCl3), No. (ppm) : 7.71 dd, J1=8. 8 Hz, J2=5. 2 Hz, 1H, CH aromatic; 7.23 dd, J1=8. 6 Hz, J2=2. 2 Hz, 1H, CH aromatic; 7,05 ddd, J1=8. 8 Hz, J2=8. 6 Hz, J3=2. 2 Hz, 1H, CH aromatic; 3.93 t, J=6.2 Hz, 2H, CH2 ; 3.18 d, J=11.6 Hz, 2H, CH2 ; 3.08 m, 1H, CH; 2.87 t, J=6.6 Hz, 2H, CH2 ; 2.77 m, 2H, CH2 ; 2.55 m, 2H, CH2 ; 2.31 s, 3H, CH3 ; 2.27 m, 2H, CH2 ; 2.09 m, 4H, 2xCH2 ; 1.96 m, 2H, CH2; 1.89 m, 2H, CH2. 13C-NMR (CDC13), No. (ppm): 165.26-166, 77, d, JC-F=249 Hz, C aromatic; 163.88-163. 75, d, JC-F=14 Hz, C aromatic; 162.56 ; 161.09 C aromatic; 158.39 C aromatic; 155.87 C aromatic; 122.67-122. 55 d, JC-F=11 Hz, CH aromatic; 119.27 C aromatic; 117.28 C aromatic; 112.35-112. 10 d, JC-F=25 Hz, CH aromatic; 97.48-97. 21 d, JC-F=27 Hz, CH aromatic; 56.68 CH2 ; 53.35 CH2 ; 42.66 CH2 ; 34.59 CH; 31.41 CH2 ; 30.53 CH2 ; 23.74 CH2; 21.95 CH2 ; 21. 24 CH3 ; 19.20 CH2.
3-(2-chloromethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride[ No CAS ]
[ 84163-77-9 ]
[ 106266-06-2 ]
Yield
Reaction Conditions
Operation in experiment
3.8 parts (46%)
With potassium iodide; sodium carbonate; In N,N-dimethyl-formamide;
EXAMPLE 1 A mixture of 5.3 parts of 3-(2-chloromethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride, 4.4 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 8 parts of sodium carbonate, 0.1 part of potassium iodide, and 90 parts of DMF is stirred overnight at 80-90 C. After cooling, the reaction mixture is poured into water. The product is filtered off and crystallized from a mixture of DMF and 2-propanol. The product is filtered off and dried, yielding 3.8 parts (46%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 170.0 C.
With potassium carbonate; In acetone; for 6h;Heating / reflux;
Example 2; Production of risperidone of formula (I) from 3-(2-iodoethyl)-2-methyl-6,7,8,9-tetrahydro-4H- pyrido [ 1 ,2-a]pyrimidine-4-one; 2.56 g (10 mmol) of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole HCl, 2.56 g (10 mmol) 3-(2-iodoemyl)-2-memyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidme-4- one, 2.76 g (20 mmol) of potassium carbonate and 50 ml of acetone are added into a distilling flask equipped with reflux condenser. The suspension is boiled for 6 hours during stirring and then 100 ml of water is added to the suspension and the acetone is distilled off under reduced pressure. The suspension is cooled down to 20 C and stirred for 1 hour, filtered, washed with 50 ml of water, dried at 60 0C. 3.77 g (92 %) product is obtained which is recrystallized from 2-propanol.Dry weight: 3.58 g (87.4%). Melting point: 171-172 0C. Purity: 99.86 % (determined by HPLC).
3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride[ No CAS ]
[ 84163-77-9 ]
[ 106266-06-2 ]
Yield
Reaction Conditions
Operation in experiment
3.8 parts (46%)
With potassium iodide; sodium carbonate; In N,N-dimethyl-formamide;
EXAMPLE 5 A mixture of 5.3 parts of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride, 4.4 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 8 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide was stirred overnight at 85-90 C. After cooling, the reaction mixture was poured into water. The product was filtered off and crystallized from a mixture of N,N-dimethylformamide and 2-propanol. The product was filtered off and dried, yielding 3.8 parts (46%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 170.0 C. (compound 1).
3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride[ No CAS ]
[ 106266-06-2 ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate;potassium iodide; In water; 4-methyl-2-pentanone; at 20 - 90℃; for 12h;Product distribution / selectivity;
Example 1: Preparation of Risperidone; Water (300 mL), methyl isobutyl ketone (400 mL) and 6-fluoro-3-(4- piperidinyl)-l, 2-benzisoxazole monohydrochloride (97.5 g) were taken in a reaction vessel and NaOH solution (30.40 g in 300 mL water) was slowly added, stirred the reaction mass for 5 to 10 min. the organic layer separated and washed with water (150 mL). Water (300 mL), methyl isobutyl ketone (200 mL) were taken in another reaction vessel and 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride (100 g) and KI (5.0 g) were added to the reaction vessel. Sodium carbonate (100.70 g) was slowly added to the reaction mass and then methyl isobutyl ketone layer of 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole base was added to the reaction mass and then the contents were heated up to 85 to 900C and maintained up to 8 hrs. Cooled the reaction mass to room temperature and stirred at room temperature for 4 hrs. Water (300 mL) was added and stirred for 10 min., filtered <n="9"/>the solid and washed with water (200 mL) followed by methyl isobutyl ketone (200 mL) to get the Crude Risperidone, which was taken in another reaction vessel and isopropyl alcohol (1800 mL) was added and the solution was heated to 70 to 8O0C to get a clear solution. Carbon (10 g) was added to the solution and stirred for 20 to30 min., filtered the carbon through highflo. washed the bed with isopropyl alcohol (300 mL) and distilled the filtrate up to residual volume 7 times the 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyriniidin-4-one monohydrochloride quantity. Heated the suspension to 70 to 8O0C to get the clear solution and dimethylformamide (70 mL) was added. Cooled the reaction mass to room temperature' and stirred at room temperature for 3 to 6 hrs., filtered the solid, washed with isopropyl alcohol (100 mL) and dried the solid at 60 to70°C for 2 hrs. Micronized the material and dried at 80 to 850C for 12 hrs to get Risperidone. (80 g) having HPLC Purity more than 99.70 percent.; Example 3: Preparation of Risperidone Water (300 mL), methyl isobutyf ketone (400 mL) and 6-fluoro-3-(4- piperidinyl)-l, 2-benzisoxazole monohydrochloride (97.5 g) were taken in a reaction vessel and NaOH solution (30.40 g in 300 mL water) was slowly added, stirred the reaction mass for 5 to 10 min., the organic layer was separated and washed with water (150 mL). Water (300 mL), methyl isobutyl ketone (200 mL) were taken in another reaction vessel and 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride (100 g), potassium iodide (5.0 g) were added to the reaction vessel. Sodium carbonate (100.70 g) slowly added in to the reaction mass and then methyl isobutyl ketone layer of 6-fluoro-3-(4-pirhoeridinyl)-l, 2-benzisoxazole <n="10"/>base was added to the reaction mass and then heated the contents up to 85 to 900C and maintained up to 8 hrs. Cooled the reaction mass to room temperature and stirred at room temperature for 4 hrs. Water (300 mL) was added and stirred for 10 min. filtered the solid and washed with water (200 mL) followed by methyl isobutyl ketone (200 mL) to get the solid which is dried at 60 to70°C under vacuum for 2 hrs to get crude Risperidone 80g.
With sodium carbonate; In water; at 110 - 120℃; for 0.666667h;Product distribution / selectivity;
Example 9; Preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (risperidone)In a 50-ml reaction flask, 2.56 g of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride and 2.95 g of <strong>[63234-80-0]3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one</strong> are placed, then a sodium carbonate solution or suspension (dissolved or suspended 8.5 g of sodium carbonate in 25 ml water) is added. The mixture is put into heating bath at 110-120° C. with stirring for 40 min, then cooled with continuous stirring to the room temperature and the precipitate solid is filtered, washed with pure water, and dried to give 3.82 g of the product in 93.2percent yield. The product is purified to obtain a purity of 99.5percent (determined by HPLC) with DMF and isopropanol.
76.9%
With sodium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 10h;
In a 1000 mL sealed four-mouth reaction bottle,Add 6-fluoro-3-(4-piperidinyl)-1,2-benzisazole hydrochloride (IV 51.3 g,<strong>[63234-80-0]3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one</strong> (V) 45.3 g,Potassium iodide 6.6 g,Anhydrous sodium carbonate 42.4 g andN,N-dimethylformamide 250mL,Stir and heat to 80 ° C for 10 h.The reaction solution is cooled to 5 to 10 ° C,Add 250 grams of ice water mixture,A large amount of white solid precipitated,Stop stirring,Filtration of a pale yellow solid risperidone (I) 63.1 g,The yield was 76.9percent.
A 50 mL two-necked round bottomed flask is connected to a compressed air cylinder (GC grade, H2O < 5 ppm) via an empty Drechsel bottle. <strong>[106266-06-2]Risperidone</strong> (500 mg, 1.22 mmol) is charged under an argon atmosphere. Dry dichloromethane (20 mL) is added and the solution is cooled to -78 C. Trimethyl phosphite (97%, 197 muL, 1.58 mmol) and LiHMDS (2.69 ml, 1.83 mmol) were added. After 5 minutes stirring, air is slowly bubbled through the solution (about 1 bubble per second) for 6-7 hours keeping the temperature at -78 C. The reaction is monitored by TLC (elution with dichloromethane/methanol/ammonia 95:5:1 v/v, UV visualization and ninhydrin). The reaction is stopped by quenching with NH4Cl (saturated solution in water, 5 mL) and K2CO3 (saturated solution in water, 5 ml). The product is extracted in dichloromethane from pH 10-11. The organic phase is washed with brine, dried over Na2SO4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography on silica gel (20 g) with gradient elution dichloromethane/methanol (90:10 to 86:14) obtaining the ketone by-product (43 mg, 8%) in the forerunning fractions as a yellow oil, followed by Paliperidone (342 mg, 66%) as a white foam. The product was further purified by crystallization from ethyl acetate/hexanes, providing a product with m.p. 162.2-162.4 C. 1H NMR (300 MHz, CDCl3, 298K) delta 1.77 (1H, centre ofm); 1.89-2.04 (1H, m); 2.07-2.21 (6H, m); 2.25-2.42 (2H, m); 2.36 (3H, s); 2.55 and 2.79 (4H, A and X part of an AA'XX' system); 3.10 (1H, centre of m); 3.18 (2H, broad d, J 11.4 Hz); 3.87-4-03 (2H, m); 4..12 (1H, broad s); 4.51 (1H, dd, J 6.3 and 10.2 Hz); 7.07 (1H, dt, J 2.1 and 15.3 Hz); 7.25 (1H, dd, J 2.4 and 9.0 Hz); 7.72 (1H, dd, J 5.4 and 9.0 Hz). 13C NMR (75.4 MHz, CDCl3, 298K) delta 18.5; 21.2; 23.9; 27.0; 34.6; 42.4; 53.4; 56.6; 67.1; 97.5 (d, 2JC-F 27.0 Hz), 112.4 (d, 2JC-F 25.3 Hz), 117.4; 120.5; 122.7 (d, 3JC-F 11.5 Hz); 157.5; 157.9; 161.1; 162.1; 163.8; 164.0 (d, 1JC-F 248.5 Hz); 163.9 (d, 3JC-F 13.2 Hz)
Example 3b Preparation of s-NHS activated 4-({6-[8-Chloro-11-(4-methyl-piperazin-1-yl)-dibenzo[b,e]-[1,4]diazepin-5-yl]6-oxo-hexanoylamino}-methyl)-benzoic acid [9] Clozapine derivative [8], example 2, scheme 2 (25.0 mg) was dissolved in 2.5 mL of DMSO to which was added s-NHS (19.9 mg) and EDC (17.6 mg). The reaction mixture was stirred for 20 hours at ambient temperature under a nitrogen atmosphere to produce the s-NHS activated ester of clozapine [9]. The reaction mixture was used directly in example 5b.
In ethanol; N,N-dimethyl-formamide; at 25 - 30℃; for 5h;
700 ml of dimethyl formamide and 16.6 gm of pamoic acid were charged in the flask. The reaction mixture was stirred for 10 minutes at 25-30°C to obtain clear solution. 35 gm Risperidone solution in 1050 ml ethanol was added to the reaction mixture at 25-30°C. The reaction mixture was stirred further for 5 hours at 25-30°C. The solid was filtered off, washed with 70 ml ethyl alcohol and dried under vacuum at 50-55°C for 12 hours.Dry weight: 42.10 gmDSC: 188°C1 H NMR in accord with structure (400 MHz, DMSO-d6+D20) 8(ppm): 8.22 (2H) s; 8.14-8.16 (2H) d; 8.00-8.03 (2H) d of d; 7.67-7.69 (4H) m; 7.29-7.33 (2H) d of t; 7.14- 7.18 (2H) t; 7.05-7.09 (2H) t; 4.77 (2H) s; 3.81 (4H) t; 3.54 (2H) m; 3.16 3.74 (12 H) m; 2.89-2.91 (4H) m; 2.75-2.78 (4H) t; 2.10-2.15 2.36-2.42 (8H) m; 2.28 (6H) s; 1.75- 1. (8H) m.Elemental analysis (wt percent) calculated for C69H70F2N8O10: C, 68.53; H, 5.83; N, 9.27. Found: C, 68.37; H, 6.00; N, 9.65.The structural characteristics were also confirmed by BRUKER' s SMART APEX Single crystal X-ray CCD Diffractometer.
[(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid[ No CAS ]
3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one L(-)-camphorsulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; at 25 - 30℃; for 5h;
15 ml methanol and 2.8 gm of L (-) camphor sulfonic acid were charged in flask. The reaction mixture was stirred for 10 minutes at 25-30C to obtain clear solution. 5 gm <strong>[106266-06-2]Risperidone</strong> solution in 80 ml methanol was added to the reaction mixture within 15-20 minutes at 25-30C. The reaction mixture was stirred for 5 hours and was distilled out completely under vacuum at 50-55C. 20 ml of acetone was added further and stirred for 10 minutes at 40-45C. The reaction mixture was cooled to -5 to -10C and stirred for 4 hours. The solid was filtered off, washed with 5 ml acetone and dried in vacuo at 50-55C for 12 hours.Dry weight: 5.1 gmDSC: 120.4C
3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one decanate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 25 - 55℃;
150 ml of ethanol and 5 gm <strong>[106266-06-2]Risperidone</strong> were charged in the flask. The reaction mixture was heated at 50-55C and stirred for 10 minutes to get clear solution. 2.1 gm decanoic acid solution in 30 ml ethanol was added to the reaction mixture at 40-45C. The reaction mixture was further cooled to 25-30C, stirred for 18-20 hours and distilled out completely under vacuum at 50-55C. The solid was dried under vacuum at 40-45C. Dry weight: 5.3 gm
In methanol; at 20℃; for 0.75h;Equilibrium constant;
General procedure: The six risperidone solid charge transfer complexes with general formula [(Ris)(pi-acceptor)] were synthesized as a solid colours, by mixing a (0.25 mmol, 0.103 g) of risperidone drug in 20 ml methanol to a 0.25 mmol of each acceptors; PA (0.06 g), DDQ (0.06 g), TCNQ (0.051 g), TCNE (0.032 g), p-BL (0.105 g) and p-CL (0.061 g) in 20 ml methanol solvent. All mixtures were stirred for 45 min at room temperature and the solid products were filtered off, washed with minimum amounts of chloroform and dried under vacuum over anhydrous CaCl2
In methanol; at 20℃; for 0.75h;Equilibrium constant;
General procedure: The six risperidone solid charge transfer complexes with general formula [(Ris)(pi-acceptor)] were synthesized as a solid colours, by mixing a (0.25 mmol, 0.103 g) of risperidone drug in 20 ml methanol to a 0.25 mmol of each acceptors; PA (0.06 g), DDQ (0.06 g), TCNQ (0.051 g), TCNE (0.032 g), p-BL (0.105 g) and p-CL (0.061 g) in 20 ml methanol solvent. All mixtures were stirred for 45 min at room temperature and the solid products were filtered off, washed with minimum amounts of chloroform and dried under vacuum over anhydrous CaCl2
In methanol; at 20℃; for 0.75h;Equilibrium constant;
General procedure: The six risperidone solid charge transfer complexes with general formula [(Ris)(pi-acceptor)] were synthesized as a solid colours, by mixing a (0.25 mmol, 0.103 g) of risperidone drug in 20 ml methanol to a 0.25 mmol of each acceptors; PA (0.06 g), DDQ (0.06 g), TCNQ (0.051 g), TCNE (0.032 g), p-BL (0.105 g) and p-CL (0.061 g) in 20 ml methanol solvent. All mixtures were stirred for 45 min at room temperature and the solid products were filtered off, washed with minimum amounts of chloroform and dried under vacuum over anhydrous CaCl2
In methanol; at 20℃; for 0.75h;Equilibrium constant;
General procedure: The six risperidone solid charge transfer complexes with general formula [(Ris)(pi-acceptor)] were synthesized as a solid colours, by mixing a (0.25 mmol, 0.103 g) of risperidone drug in 20 ml methanol to a 0.25 mmol of each acceptors; PA (0.06 g), DDQ (0.06 g), TCNQ (0.051 g), TCNE (0.032 g), p-BL (0.105 g) and p-CL (0.061 g) in 20 ml methanol solvent. All mixtures were stirred for 45 min at room temperature and the solid products were filtered off, washed with minimum amounts of chloroform and dried under vacuum over anhydrous CaCl2
In methanol; at 20℃; for 0.75h;Equilibrium constant;
General procedure: The six risperidone solid charge transfer complexes with general formula [(Ris)(pi-acceptor)] were synthesized as a solid colours, by mixing a (0.25 mmol, 0.103 g) of risperidone drug in 20 ml methanol to a 0.25 mmol of each acceptors; PA (0.06 g), DDQ (0.06 g), TCNQ (0.051 g), TCNE (0.032 g), p-BL (0.105 g) and p-CL (0.061 g) in 20 ml methanol solvent. All mixtures were stirred for 45 min at room temperature and the solid products were filtered off, washed with minimum amounts of chloroform and dried under vacuum over anhydrous CaCl2
In methanol; at 20℃; for 0.75h;Equilibrium constant;
General procedure: The six risperidone solid charge transfer complexes with general formula [(Ris)(pi-acceptor)] were synthesized as a solid colours, by mixing a (0.25 mmol, 0.103 g) of risperidone drug in 20 ml methanol to a 0.25 mmol of each acceptors; PA (0.06 g), DDQ (0.06 g), TCNQ (0.051 g), TCNE (0.032 g), p-BL (0.105 g) and p-CL (0.061 g) in 20 ml methanol solvent. All mixtures were stirred for 45 min at room temperature and the solid products were filtered off, washed with minimum amounts of chloroform and dried under vacuum over anhydrous CaCl2
In methanol; at 20℃; for 0.75h;Equilibrium constant;
General procedure: The six risperidone solid charge transfer complexes with general formula [(Ris)(pi-acceptor)] were synthesized as a solid colours, by mixing a (0.25 mmol, 0.103 g) of risperidone drug in 20 ml methanol to a 0.25 mmol of each acceptors; PA (0.06 g), DDQ (0.06 g), TCNQ (0.051 g), TCNE (0.032 g), p-BL (0.105 g) and p-CL (0.061 g) in 20 ml methanol solvent. All mixtures were stirred for 45 min at room temperature and the solid products were filtered off, washed with minimum amounts of chloroform and dried under vacuum over anhydrous CaCl2
In methanol; at 20℃; for 0.75h;Equilibrium constant;
General procedure: The six risperidone solid charge transfer complexes with general formula [(Ris)(pi-acceptor)] were synthesized as a solid colours, by mixing a (0.25 mmol, 0.103 g) of risperidone drug in 20 ml methanol to a 0.25 mmol of each acceptors; PA (0.06 g), DDQ (0.06 g), TCNQ (0.051 g), TCNE (0.032 g), p-BL (0.105 g) and p-CL (0.061 g) in 20 ml methanol solvent. All mixtures were stirred for 45 min at room temperature and the solid products were filtered off, washed with minimum amounts of chloroform and dried under vacuum over anhydrous CaCl2
In methanol; at 20℃; for 0.75h;Equilibrium constant;
General procedure: The six risperidone solid charge transfer complexes with general formula [(Ris)(pi-acceptor)] were synthesized as a solid colours, by mixing a (0.25 mmol, 0.103 g) of risperidone drug in 20 ml methanol to a 0.25 mmol of each acceptors; PA (0.06 g), DDQ (0.06 g), TCNQ (0.051 g), TCNE (0.032 g), p-BL (0.105 g) and p-CL (0.061 g) in 20 ml methanol solvent. All mixtures were stirred for 45 min at room temperature and the solid products were filtered off, washed with minimum amounts of chloroform and dried under vacuum over anhydrous CaCl2
In methanol; at 20℃; for 0.75h;Equilibrium constant;
General procedure: The six risperidone solid charge transfer complexes with general formula [(Ris)(pi-acceptor)] were synthesized as a solid colours, by mixing a (0.25 mmol, 0.103 g) of risperidone drug in 20 ml methanol to a 0.25 mmol of each acceptors; PA (0.06 g), DDQ (0.06 g), TCNQ (0.051 g), TCNE (0.032 g), p-BL (0.105 g) and p-CL (0.061 g) in 20 ml methanol solvent. All mixtures were stirred for 45 min at room temperature and the solid products were filtered off, washed with minimum amounts of chloroform and dried under vacuum over anhydrous CaCl2
In methanol; at 20℃; for 0.75h;Equilibrium constant;
General procedure: The six risperidone solid charge transfer complexes with general formula [(Ris)(pi-acceptor)] were synthesized as a solid colours, by mixing a (0.25 mmol, 0.103 g) of risperidone drug in 20 ml methanol to a 0.25 mmol of each acceptors; PA (0.06 g), DDQ (0.06 g), TCNQ (0.051 g), TCNE (0.032 g), p-BL (0.105 g) and p-CL (0.061 g) in 20 ml methanol solvent. All mixtures were stirred for 45 min at room temperature and the solid products were filtered off, washed with minimum amounts of chloroform and dried under vacuum over anhydrous CaCl2
In methanol; at 20℃; for 0.75h;Equilibrium constant;
General procedure: The six risperidone solid charge transfer complexes with general formula [(Ris)(pi-acceptor)] were synthesized as a solid colours, by mixing a (0.25 mmol, 0.103 g) of risperidone drug in 20 ml methanol to a 0.25 mmol of each acceptors; PA (0.06 g), DDQ (0.06 g), TCNQ (0.051 g), TCNE (0.032 g), p-BL (0.105 g) and p-CL (0.061 g) in 20 ml methanol solvent. All mixtures were stirred for 45 min at room temperature and the solid products were filtered off, washed with minimum amounts of chloroform and dried under vacuum over anhydrous CaCl2
Example-3 Preparation of <strong>[106266-06-2]Risperidone</strong> Decanoate 150 ml of ethanol and 5 gm <strong>[106266-06-2]Risperidone</strong> were charged in the flask. The reaction mixture was heated at 50-55 C. and stirred for 10 minutes to get clear solution. 2.1 gm decanoic acid solution in 30 ml ethanol was added to the reaction mixture at 40-45 C. The reaction mixture was further cooled to 25-30 C., stirred for 18-20 hours and distilled out completely under vacuum at 50-55 C. The solid was dried under vacuum at 40-45 C. Dry weight: 5.3 gm
In ethanol; N,N-dimethyl-formamide; at 25 - 30℃; for 5.16h;
Preparation of Risperidone Hemipamoate 700 ml of dimethyl formamide and 16.6 gm of pamoic acid were charged in the flask. The reaction mixture was stirred for 10 minutes at 25-30° C. to obtain clear solution. 35 gm Risperidone solution in 1050 ml ethanol was added to the reaction mixture at 25-30° C. The reaction mixture was stirred further for 5 hours at 25-30° C. The solid was filtered off, washed with 70 ml ethyl alcohol and dried under vacuum at 50-55° C. for 12 hours. Dry weight: 42.10 gm DSC: 188° C. 1 H NMR in accord with structure (400 MHz, DMSO-d6+D2O) delta(ppm): 8.22 (2H) s; 8.14-8.16 (2H) d; 8.00-8.03 (2H) d of d; 7.67-7.69 (4H) m; 7.29-7.33 (2H) d of t; 7.14-7.18 (2H) t; 7.05-7.09 (2H) t; 4.77 (2H) s; 3.81 (4H) t; 3.54 (2H) m; 3.16 & 3.74 (12 H) m; 2.89-2.91 (4H) m; 2.75-2.78 (4H) t; 2.10-2.15 & 2.36-2.42 (8H) m; 2.28 (6H) s; 1.75-1. (8H) m. Elemental analysis (wt percent) calculated for C69H70F2N8O10: C, 68.53; H, 5.83; N, 9.27. Found: C, 68.37; H, 6.00; N, 9.65.
Preparation of <strong>[106266-06-2]Risperidone</strong> Camphor Sulfonate 15 ml methanol and 2.8 gm of L (-) camphor sulfonic acid were charged in flask. The reaction mixture was stirred for 10 minutes at 25-30 C. to obtain clear solution. 5 gm <strong>[106266-06-2]Risperidone</strong> solution in 80 ml methanol was added to the reaction mixture within 15-20 minutes at 25-30 C. The reaction mixture was stirred for 5 hours and was distilled out completely under vacuum at 50-55 C. 20 ml of acetone was added further and stirred for 10 minutes at 40-45 C. The reaction mixture was cooled to -5 to -10 C. and stirred for 4 hours. The solid was filtered off, washed with 5 ml acetone and dried in vacuo at 50-55 C. for 12 hours. Dry weight: 5.1 gm DSC: 120.4 C.
3-(2-(4-(6-fluoro-5-iodobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one trifluoroacetic acid[ No CAS ]
With lithium aluminium tetrahydride; In tetrahydrofuran; at 68℃; for 6h;Inert atmosphere;
(a) In a 50ml single-necked round bottom flask, add 0.30mmol risperidone, add 0.30mmol lithium aluminum hydride and 10ml anhydrous THF, under nitrogen protection, reflux at 68 for 6 hours;Stop the reaction, add 3.4ml of sodium hydroxide solution with a mass fraction of 38% after cooling, adjust pH = 8, filter and spin dryAn oily product was obtained; the product was further purified by column chromatography TLC; the chromatographic liquid was ethyl acetate, the product specific shift value Rf = 0.3-0.5; the yield was 85%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 6h; Reflux; Darkness;
1 Preparation of compound 2:
risperidone (4.1g, 0.01mol) was added to a 250mL single-necked flask, 150mL carbon tetrachloride, benzoyl peroxide (0.24g, 0.001mol) and NBS (3.9g, 0.022mol) were added ), the system was refluxed in the dark for 6 hours, the TLC detection reaction ended, and the system was cooled to room temperature. Pour the reaction solution into 200 mL of water for extraction, separate the organic phase, extract the aqueous phase with dichloromethane three times, the amount of dichloromethane is 50 mL each time, combine the organic phases, dry with anhydrous sodium sulfate, filter, and evaporate to obtain a crude product . The crude product was purified by column chromatography to obtain 1.8 g of compound 2 (yield 32%).
3.4. Preparation of the Solid Inclusion Complexes and Physical Mixtures
The inclusion complexes of RSP with DM-β-CD and TM-β-CD were prepared using the kneadingmethod in a 2:1 guest:host molar ratio. For RSP/DM-β-CD KP preparation 0.1908 g RSP and 0.3093 βCD were weighed and their mixture was pulverized in an agate mortar and triturated with 0.5 gethanol:HCl 0.1Msolution (1:1,m/m). To obtain the RSP/TM-β-CD inclusion complex 0.1824 g RSP and0.3174 g TM-β-CD were accurately weighed and the resulted mixture was pulverized and trituratedwith 0.50 g ethanol: HCl 0.1 M solution (1:1, m/m) until a homogeneous paste was obtained. The pastewas kneaded for 45 min and during this process an appropriate quantity of solvent was added tomaintain the paste consistency. The final product was dried at room temperature and then in theoven, at 40 °C for 24 h. The obtained kneaded products were pulverized and passed through a 75-msize sieve.
3.4. Preparation of the Solid Inclusion Complexes and Physical Mixtures
The inclusion complexes of RSP with DM-β-CD and TM-β-CD were prepared using the kneadingmethod in a 2:1 guest:host molar ratio. For RSP/DM-β-CD KP preparation 0.1908 g RSP and 0.3093 βCD were weighed and their mixture was pulverized in an agate mortar and triturated with 0.5 gethanol:HCl 0.1Msolution (1:1,m/m). To obtain the RSP/TM-β-CD inclusion complex 0.1824 g RSP and0.3174 g TM-β-CD were accurately weighed and the resulted mixture was pulverized and trituratedwith 0.50 g ethanol: HCl 0.1 M solution (1:1, m/m) until a homogeneous paste was obtained. The pastewas kneaded for 45 min and during this process an appropriate quantity of solvent was added tomaintain the paste consistency. The final product was dried at room temperature and then in theoven, at 40 °C for 24 h. The obtained kneaded products were pulverized and passed through a 75-msize sieve.
Stage #1: Risperidone With potassium carbonate In N,N-dimethyl-formamide at 25℃;
Stage #2: 3-mercaptopropionic acid In N,N-dimethyl-formamide at 100℃;
1.1.1-1.1.2; 2.1.1-2.1.2; 3.1.1-3.1.2; 4.1.1-4.1.2 (1) Preparation of artificial hapten III
(1) Weigh risperidone 150mg (0.37mmol) in a 50mL single-mouth round bottom flask, add 5mLN, N-dimethylformamide to dissolve, add potassium carbonate powder 303mg (2.20mmol), stir at 25 °C for 0.5 hours, then add 96μL (1.10mmol) of mercaptopropionic acid, transfer to an oil bath at 100 °C and stir and reflux for 18 hours, at which time it is yellow suspension liquid;TLC (chromatography is dichloromethane: 95% ethanol: 1,4-dioxane: ammonia = 10: 8: 1: 1 (v/v), product Rf = 0.1) detects most of the raw materials after the reaction, ends the reaction, naturally cools the reaction solution to room temperature, filters, collects the filtrate, and evaporates the filtrate under reduced pressure at 60 °C to obtain yellow solids. Add 15mL of purified water to the yellow solid residue, adjust the pH = 3 of the solution with 10% hydrochloric acid, at this time a large amount of yellow precipitate is generated, 30mL ×3 ethyl acetate is extracted, the organic phase is combined, the organic phase is washed with 20mL of 5% sodium bicarbonate solution and 20mL of saturated saline, the organic phase is collected, dried with anhydrous magnesium sulfate for 5 minutes, filtered, and evaporated under reduced pressure to obtain yellow solid.(2) The yellow solid was passed by thin layer chromatography (chromatography is dichloromethane: 95% ethanol: 1,4-dioxane: ammonia = 10: 8: 1: 1 (v/v), solvent and eluent are absolute ethanol, product Rf = 0.1, the point is obvious color at 254nm, iodine smoking does not develop. Isolated to obtain a yellowish solid 127 mg (0.26 mmol), that is, risperidone artificial hapten III.;
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