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(WO2017211293) CRYSTALLINE FORM OF SUCCINATE USED AS DIPEPTIDYL PEPTIDASE-4 INHIBITOR
XUANZHU PHARMA CO., LTD. [CN/CN]; 2518, Tianchen Street, National High-Tech Development Zone Jinan, Shandong 250101 (CN)
SHU, Chutian; (CN)
|The present invention relates to a crystalline form of a succinate used as a dipeptidyl peptidase-4 inhibitor, and a manufacturing method, pharmaceutical composition, and application thereof. The invention specifically relates to a dipeptidyl peptidase-4 inhibitor compound as represented by formula (1), a crystalline form of a succinate, wherein the succinate is an (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo(4,5-b)pyridin-1-yl)methyl)benzonitrile, and a manufacturing method, pharmaceutical composition, and application thereof.
Example 1: Preparation of the succinate salt form I of the compound of formula (1)
The compound of formula (1) (44.6 g, 0.12 mol) was added to a 2 L round bottom flask and suspended in 1593 mL of acetonitrile. The mixture was heated to 80 ° C. and dissolved in free form. Immediately after the addition of 15.4 g A white solid precipitated, maintained at 80 ℃ for 1 hour and then cooled to room temperature, filtered and the filter cake was dried in vacuo at 40 ℃ for 10 hours, weighed 57.6g, yield 98.3%. The succinate salt Form I was tested by XRPD.
Example 2: Preparation of the succinate salt form I of the compound of formula (1) II
A quantity of succinate salt of the compound of formula (1) was weighed into glass vials in a total of 26 parts. A total of 26 vials of methanol, ethanol, isopropanol, isobutanol, 2-butanone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, acetone, water, toluene, Isopropyl acetate, n-propanol, isoamyl alcohol, butyl acetate, ethyl formate, 1,4-dioxane, n-butanol, pentane, heptane, cyclohexane, Ketone, xylene, isobutyl acetate, diethyl ether). After stirring, ultrasound and other means to make the sample fully dissolved. Subsequently, about 2 mL of liquid was removed from each bottle and filtered into 26 reagent tubes numbered 1-26. The resulting 26 filtrates were distributed in two 96-well plates. One or two of the above 1-13 solvents are sequentially added into the first 96-well plate, one or two of the above-mentioned 14-26 kinds of solvents are sequentially added into the second 96-well plate, Zha Kong sealing film sealed, placed in a fume hood, the natural environment to dry. Wherein Form I is obtained in the following mixed solvent, and Form I is also precipitated in the methyl isobutyl ketone in the remaining solution after plating.
The solvent used to prepare succinate salt Form I was prepared
Example 3: Preparation of the succinate salt form II of the compound of formula (1)
Take 8 parts of the compound of formula (1), 200mg each, placed in a 10mL round bottom flask, add the solvent in the following table to each solvent, warmed until the solvent is refluxed, after dissolving it, add 69mg (1.1eq) succinic acid and cool to At room temperature, the solid precipitated and was filtered. The resulting solid was subjected to XRPD testing as succinate crystal form II.