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Stage #1: 3-(N-methyl-N-pentylamino) propionic acid hydrochloride With phosphonic Acid; phosphorus trichloride In silicon oil at 20 - 80℃; for 3.41667 - 9.66667h;
Stage #2: With water for 15 - 22h; Heating / reflux;
1; 2; 3; 4
Example 1: Preparation of Ibandronic acid Form Sl 5; [0074] A 500ml reactor was loaded with silicon oil (21 OmI), 3-N-methyl-N- pentylamino propionic acid hydrochloride ("ibanic acid hydrochloride" or "MPPA HCl") (30g) and H3PO3 (44g) at room temperature. The mixture was heated to 730C and PCI3 (47ml) was added drop-wise to form a reaction mixture over a period of 10 minutes. The reaction mixture was heated to 8O0C and stirred at 8O0C for 9.5 hours. Distilled water (210ml) was then added drop- wise to form a biphasic mixture. The two phases were stirred for 0.5 hour. The lower aqueous phase was separated and hydrolyzed at reflux in a 250ml reactor for 22 hours. Vacuum filtration through hyflo was done. The obtained solution was evaporated until dryness to obtain 64.3g of colorless oil. The oily residue was dissolved in distilled water (10ml) and absolute ethanol (1607ml, ) was added drop- wise over a period of 25 minutes at room temperature. The slurry was stirred for 16 hours at room temperature and then it was cooled to 40C. The product was isolated by vacuum filtration, washed with ethanol 96% (2x50ml) and dried in a vacuum oven at 5O0C for 24 hours to obtain 22.53g of ibandronic acid crystalline Form S 15.; Example 2: Preparation of Ibandronic acid Form Sl 5; [0075] A 500ml reactor was loaded with silicon oil (210ml), Ibanic acid hydrochloride (MPPA HCl) (30g), H3PO3 (44g) and PCl3 (47ml) at room temperature. The mixture was heated to 8O0C over a period of 2 hours. The reaction mixture was stirred for 3 hours. Distilled water (210ml) was then added drop-wise to the reaction mixture to form a biphasic mixture. The two phases were stirred for 10 minutes. The lower aqueous phase was separated and hydrolyzed at reflux in a 250ml reactor for 15 hours. The obtained solution was evaporated until dryness to obtain 75g of colorless oil. Absolute ethanol (1440ml) was added drop-wise over a period of 40 minutes at room temperature. The slurry was stirred for about 72 hours at room temperature. The product was isolated by vacuum filtration, washed with absolute ethanol (2x40ml) and dried in a vacuum oven at 5O0C for 22 hours to obtain 23.5g of ibandronic acid crystalline Form S15.; Example 3: Preparation of Ibandronic acid Form S16; [0076] A 500ml reactor was loaded with silicon oil (105ml), Ibanic acid hydrochloride (MPPA HCl) (15g) and H3PO3 (22g) at room temperature. The mixture was heated to 800C in order to melt H3PO3. The mixture was then cooled to 25°C and PCl3 (23.4ml) was added in one portion. The reaction mixture was heated to 800C over a period of 2 hours and stirred at 8O0C for 7.5 hours. Distilled water (105ml) was then added drop-wise to the reaction mixture to form a biphasic mixture. The two phases were stirred for 10 minutes. The lower aqueous phase was separated and hydrolyzed at reflux in a 250ml reactor during 15.5 hours. The obtained solution was evaporated until dryness to obtain 53.3g of colorless oil. The oily residue was dissolved in distilled water (8ml) and absolute ethanol (1333ml) was added drop-wise over a period of 55 minutes at room temperature. The slurry was stirred for 16 hours at room temperature. The product was isolated by vacuum filtration, washed with absolute ethanol (2x25ml) and dried in a vacuum oven at 5O0C during 20 hours to obtain 22g of ibandronic acid crystalline Form S16.; Example 4: Preparation of Ibandronic acid Form S 16; [0077] A 500ml reactor was loaded with silicon oil (105ml), Ibanic acid hydrochloride (MPPAHCl) (15g), H3PO3 (22g) and PCl3 (19ml) at room temperature. The reaction mixture was heated to 800C during 15 minutes and stirred at this temperature for 3 hours. Distilled water (105ml) was added drop-wise to the reaction mixture to form a biphasic mixture. Then 30% H2O2 solution (3ml) was added gradually to improve phase separation. The two phases were stirred for 30 minutes. The lower aqueous phase was separated and hydrolyzed at reflux in a 250ml reactor during 18 hours. The obtained solution was evaporated until dryness to obtain 44.8g of colorless oil. The oily residue was dissolved in distilled water (9ml) and absolute ethanol (1500ml) was added drop- wise during about 5 minutes at room temperature. The slurry was stirred for about 72 hours at room temperature. The product was isolated by vacuum filtration, washed with absolute ethanol (2x25ml) and dried in a vacuum oven at 5O0C during 24 hours to obtain 20.2g of ibandronic acid crystalline Form S 16.
Stage #1: 3-(N-methyl-N-pentylamino) propionic acid hydrochloride With phosphonic Acid In formaldehyde diethyl acetal at 40℃; for 0.5h;
Stage #2: With phosphorus trichloride at 40 - 58℃; for 5.08333h;
8
Example 8Ibandronic Acid in Formaldehyde Diethyl Acetal; 3 g of (3-methyl-pentyl-amino) propionic acid hydrochloride 4.46 g of H3PO3 and 9 ml of ethylal (formaldehyde diethyl acetal) was stirred at 40° C. for 30 minutes. 4.75 ml of PCl3 was added to the reaction mixture during 5 minutes. Reaction mixture was heated to 58° C. and heating continued 5 hours. Then 29 ml of methanol was added to the reaction mixture. Reaction mixture was heated for 1 hour at reflux and then the solvents were distilled off. 9 ml of toluene was added and distilled off and again 9 ml of toluene was added and distilled off. 24 ml of water was added into the residue and the solution was stirred for 18 hour at 95° C. (in bath). Then the mixture was cooled to 20° C. and neutralized with 5-6 ml of 50% aqueous sodium hydroxide to pH 4.2-4.5. 150 ml of ethanol was added into light solution and it was stirred in ice bath for 2 hours. The precipitated crystals were filtered off and washed with 10 ml of ethanol, 10 ml of acetone:water=5:2, 10 ml of acetone, and 10 ml of ether. The crystals were dried at 50° C. Yield: 1.11 g of the ibandronic acid monohydrate (first crop).The filtrate was stirred overnight. The precipitated crystals were filtered off and washed with 10 ml of ethanol, 10 ml of acetone:water=5:2, 10 ml of acetone, and 10 ml of ether. The crystals were dried at 50° C. Yield: 0.94 g of the ibandronic acid monohydrate (second crop).
Stage #1: 3-(N-methyl-N-pentylamino) propionic acid hydrochloride With phosphonic Acid In sunflower oil at 90 - 95℃;
Stage #2: With phosphorus trichloride In sunflower oil at 70 - 95℃;
Stage #3: With water In sunflower oil at 10 - 15℃; Reflux;
1
Example 1: A reaction vessel is charged with 3-(methylpentylamino)propionic acid hydrochloride (21 g, 100 mmol), phosphorous acid (23 g, 280 mmol) and sunflower oil (170 ml). The suspension is heated. Temperature is adjusted to 90-95°C at which all components of the reaction medium are provided in liquid form. A NaOH trap was mounted to the system to catch the possible HCl emission. The reaction mixture was cooled to 70-75°C and at this temperature phosphorus trichloride (29 ml, 330 mmol) was added dropwise and stirred for further 30 min. And then the temperature was adjusted to 90-95°C and the reaction medium was stirred for 3-4 hours. Then the reaction medium was allowed to cool down to 10-15°C and water (170 ml) slowly added to the reaction mixture. The mixture was stirred for 4 hours at reflux temperature. Phases are separated. The water phase was filtered on celite and allowed to cool down to room temperature. The pH was adjusted to 4.4 using 50% NaOH solution. Methanol (200 ml) was poured into the aqueous phase containing the crude product. This mixture was stirred for 3 hours for obtaining the thus formed white crystals in precipitated form. Ibandronic acid monosodium salt was filtered and dried yielding 25 g of Ibandronic acid monosodium salt.
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