Hydrogensulfate salt of 2-acetoxy-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and its preparation
A technology of fulminate bisulfate and crystal form, which is applied in the field of platelet aggregation inhibitors, and can solve problems affecting drug stability, dissolution rate, bioavailability, and ability to influence
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[0041] In the preparation method of crystalline form I of prasugrel hydrogensulfate, due to the cooling of the solution, crystals of crystalline form I of prasugrel hydrogensulfate can grow after adding seeds. This is because at higher temperatures the seeds may dissolve and prasugrel bisulfate may thus remain in solution.
[0042] When the temperature of the solution has reached a value at which the seeds remain crystalline for a sufficient time, for example about 30° C. or less, seeds are added to promote crystallization. The seeds may be pure Form I of prasugrel bisulphate or may be prasugrel bisulphate seeds prepared as described in Example 1 of the present application.
[0043] The seed crystals obtained from Example 1 were a mixture of amorphous prasugrel hydrogen sulfate and crystalline form I of prasugrel hydrogen sulfate.
[0044] After the temperature has been lowered to the desired temperature, the reaction mixture is brought to that temperature so that crystalliza...
Embodiment 1
[0108] Embodiment 1: the preparation of seed crystal
[0109] 1 ml of ethyl acetate was added to 1.2 equivalents (18 μl) of concentrated sulfuric acid (95-97%), and the solution was stirred at room temperature. After addition of 100.0 mg prasugrel, a sticky coagulated mass of amorphous prasugrel bisulfate was obtained. The solvent was removed and the solid was dried under vacuum at room temperature for 2 hours. This material was added to a solution of 1.2 equivalents (18 μl) of concentrated sulfuric acid (95-97%) and 100.0 mg of prasugrel in 800 μl of acetone. The solution was stored without stirring at -25°C for about 20 hours to grow white to off-white crystals. The solvent was removed and the crystals were vacuum dried at room temperature to obtain a mixture of amorphous prasugrel hydrogen sulfate and crystalline form I of prasugrel hydrogen sulfate.
[0110] It should be noted that the time required to obtain seeds in the initial experiments was significantly longer, ar...
Embodiment 2
[0112] Example 2: Preparation of Form I of Prasugrel Hydrogen Sulfate
[0113] 250.0 mg of prasugrel and 1.2 equivalents (44 μl) of concentrated sulfuric acid (95-97%) were dissolved in 2 ml of acetone at 40°C. The solution was cooled slowly to room temperature and seeded with prasugrel bisulfate obtained in Example 1. After stirring at room temperature for 17.5 hours, the precipitate was filtered off, washed with acetone and dried under vacuum at room temperature to obtain 199.1 mg (63% yield) of crystalline form I of prasugrel hydrogensulfate.
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