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Crystal Forms of Linagliptin Intermediates

IP.com Disclosure Number: IPCOM000234982D
Publication Date: 2014-Feb-21
Document File: 5 page(s) / 88K

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Crystal Forms of Linagliptin Intermediates

1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)-xanthine, known as Linagliptin has the following chemical structure:

The present disclosure provides processes for preparing and crystallizing its intermediates: 3-methyl- 7-(2-butyn-1-yl)-8-bromoxanthine, 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8- bromoxanthine and 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-[(tert- butoxycarbonyl)amino]piperidin-1-yl)xanthine.

Example 1: Preparation of 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine

1-Bromo-2-butyne (2.26 g, 16.98 mmol, 1.04 equivalents) was added to a solution of 3-methyl-8- bromo-xanthine (4 g, 16.32 mmol, 1.00 equivalents) and Hünig's base (2.66 g, 3.58 mL, 20.58 mmol,


1.26 equivalents) in N,N-dimethylformamide (49 mL). The mixture was stirred at ambient temperature for 4.5 hours, and then heated to 40ºC over 30 mins. After a further 1.5 hours at this temperature HPLC analysis of an aliquot indicated complete conversion and the mixture was cooled with a cold water bath. Water (40 mL) was added to the mixture over 1 hour while maintaining the temperature below 30ºC. The precipitate was collected by filtration and washed first with water (5 ml) and then with ethanol (5 mL). The product was dried at 40ºC under atmospheric pressure to obtain 4.30 g


(14.47 mmol, 88.7% yield) of 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine as white solid. Powder XRD analysis gave the diffractogram shown in figure 1.

Example 2: Preparation of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8- bromoxanthine:


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3-Methyl-7-(2-butyn-1-yl)-8-bromoxanthine (4.0 g, 13.46 mmol, 1.0 equivalents), 2-chloromethyl-4- methylquinazoline (2.85 g, 14.81 mmol, 1.10 equivalents), anhydrous sodium carbonate (1.57 g,


14.81 mmol) and N-methyl-2-pyrrolidone (12 mL) were charged to a 100 mL round bottomed flask equipped with a magnetic stirrer, and the suspension was stirred at 25ºC for 15 minutes. The reaction mixture was heated with stirring to 138-140ºC and the reaction progress was monitored by HPLC of aliquots. After the reaction was complete (about 3 hours), the mixture was cooled to 80ºC, and ethanol (96%, 24 mL) was added, followed by at 70ºC, water (22 mL). Finally, the suspension was cooled to 60ºC and acetic acid (1.62 g, 26.92 mmol, 2.0 equivalents) was added. The resulting suspension was stirred at 60ºC for 30 minutes, then was cooled to 25ºC over 1 hour and stirred for a further 30 minutes. The solid was collected by filtration and washed twice with a mixture of 1:1 ethanol-water (first with 16 mL and then with 32 mL). The product was dried at 40ºC and atmospheric pressure to obtain 5.53 g (12.20 mmol, 90.7% yield) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl- 7-(2-butyn-1-yl)-8-bromo-xanthine as an off-white solid. Powder XRD analysis gave the diffractogram shown in figure 2.

Example 3: Prepara...