Linagliptin crystal form, and preparation method therefor
A technology of linagliptin crystal and linagliptin, which is applied in the field of linagliptin crystal form and preparation thereof, can solve the problems of polymorph transformation, difficulty in ensuring, and polymorph ratio change, and achieves thermal stability. Excellent stability
- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Problems solved by technology
Method used
Image
Examples
preparation example Construction
[0045] Specifically, the preparation method of the linagliptin crystal form includes (1) adding the linagliptin 4-hydroxybenzoate into water or an organic solvent, and then adding a base and then stirring; and (2) filtering the reactant in the step (1), washing the filtered crystal with water and an organic solvent, and drying.
[0046]In the step (1), the solvent may be alcohol such as methanol or ethanol, acetone, water, etc., and water alone is preferably used. The use of water dissolves various bases and in this way avoids the use of various types of organic solvents commonly used to produce known crystalline forms and allows the separation of residual acids. Based on the volume of linagliptin 4-hydroxybenzoate, the solvent can be used in an amount of 5 to 20 times the volume, preferably 8 to 15 times the volume.
[0047] In addition, the base can be basified with linagliptin 4-hydroxybenzoate to form a linagliptin crystal form. The base can be an organic base or an inorg...
Embodiment 1
[0064] Embodiment 1: Preparation of linagliptin 4-hydroxybenzoate
[0065] 30 g of linagliptin (Intercore Corporation) was added to the reactor, and 240 ml of ethanol solvent was added thereto, and the reaction mixture was heated to about 70° C. and completely dissolved by stirring for about 15 minutes. After adjusting the temperature of the dissolved reaction solution to about 60° C., 1 equivalent of 4-hydroxybenzoic acid was added to the clear reaction solution. After stirring at the same temperature for about 4 hours, the resulting crystals were filtered, washed with 90ml of ethanol, and dried under warm air at about 60°C to obtain 34.8g of linagliptin 4-hydroxybenzoate (yield: 90 %, purity: 88.2% (4-hydroxybenzoic acid 11.6%), melting point: 204°C).
[0066] 1H-NMR (DMSO-d6, 300MHz) δ8.22(d, 1H), 7.89(dd, 1H, J=5.4Hz), 7.80-7.74(m, 3H), 7.65(dd, 1H, J=5.4Hz ),6.76(d,2H),5.31(s,2H),4.90(s,2H),3.68(d,2H),3.56(d,2H),3.38(s,3H),3.07-2.99(m, 2H),2.93-2.90(m,1H),2.87(s,3H),1....
Embodiment 2
[0067] Example 2: Preparation of linagliptin crystal form-(1)
[0068] Add 20.0 g of linagliptin 4-hydroxybenzoate prepared in Example 1 to the reactor, dissolve 12.0 g of sodium hydroxide in 300 ml of water to prepare an aqueous solution, and add it to the reactor. After stirring at about 25° C. for 15 minutes, the reaction mixture was filtered, washed with 200 ml of water, and dried under warm air at about 60° C. to obtain 14.0 g of a solid compound (yield: 91%). Then, 10 g of the solid compound was added into the reactor, 100 ml of water was added, and stirred at about 25° C. for 10 minutes. The reaction mixture was filtered, washed with 100 ml of water, and then washed with 50 ml of heptane, and then dried in vacuum at about 60° C. to obtain 9.29 g of linagliptin crystal form. (Yield: 93%, purity: 99.8%, melting point: 202°C).
PUM
Login to View More Abstract
Description
Claims
Application Information
Login to View More