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XUANZHU PHARMA CO., LTD. [CN/CN]; 2518, Tianchen Street, National High-Tech Development Zone Jinan, Shandong 250101 (CN)

SHU, Chutian; (CN)

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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


[Table 0001]

Mixed solvents Solvent 1 Solvent 2
1 Methyl isobutyl ketone Ether
2 Xylene Ether
3 Isobutyl acetate Ether
4 Ether Ether
5 1,4-dioxane Pentane
6 1,4-dioxane Heptane
7 1,4-dioxane Cyclohexane
8 1,4-dioxane Methyl isobutyl ketone
9 1,4-dioxane Xylene
10 1,4-dioxane Isobutyl acetate
11 Butyl acetate Ether
12 Butyl acetate 1,4-dioxane


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.


[Table 0002]

Feeding amount Solvent and ratio
2mL Tetrahydrofuran
3mL acetone
5.5mL Acetonitrile: water = 10: 1
2mL Methanol
4mL Ethanol
1mL Ethanol: water = 10: 1
2mL Isopropanol: water = 19: 1
2mL Isopropyl alcohol: water = 9: 1

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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