Preparation method of linagliptin intermediate
An intermediate and system technology, which is applied in the field of preparation of the intermediate of hypoglycemic drug linagliptin, can solve the problems of complex production process, difficult subsequent purification process, increased production cost, etc., achieves improved yield and purity, and reduced production Cost and effect of shortening response time
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Embodiment 1
[0021] 8-bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1H-purine-2,6-dione 100mmol and 2-chloromethyl-4-methylquin Add 120mmol of oxazoline to 300mL of N-methylpyrrolidone, add 200mmol of potassium carbonate and 2.5mL of PEG400, stir and react at 50°C for 5 hours to obtain a reaction mixture, and add (R)-3-tert Butoxycarbonylaminopiperidine 120mmol, stirred and reacted at 60°C for 8 hours, the reaction was completed, 500mL of water was added to the reaction liquid, and the solid was precipitated, filtered, the wet filter cake was dissolved in dichloromethane, washed with water, dried with anhydrous sodium sulfate, filtered , concentrated under reduced pressure, added n-hexane, precipitated solid, filtered, and dried to obtain linagliptin intermediate 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7 -(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dione-2,3,6, 7-tetrahydro-1H-purine, the yield is 93.3%, and the purity is 99.5%.
Embodiment 2
[0023] 8-bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1H-purine-2,6-dione 100mmol and 2-chloromethyl-4-methylquin Add 120mmol of oxazoline to 200mL of N-methylpyrrolidone and 100mL of acetonitrile, add 200mmol of potassium carbonate and 2.5mL of PEG400, stir and react at 50°C for 6 hours to obtain a reaction mixture, and add (R)- 3-tert-butoxycarbonylaminopiperidine 120mmol, stirred and reacted at 60°C for 8 hours, the reaction was completed, 500mL of water was added to the reaction solution, and the solid precipitated, filtered, and the wet filter cake was dissolved in dichloromethane, washed with water and then washed with anhydrous sodium sulfate Dry, filter, concentrate under reduced pressure, add n-hexane, precipitate a solid, filter, and dry to obtain linagliptin intermediate 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl Base-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dione-2,3 , 6,7-tetrahydro-1H-purine, the yield was 95.1%, and the purity was...
Embodiment 3
[0025] 8-bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1H-purine-2,6-dione 100mmol and 2-chloromethyl-4-methylquin Add 120mmol of oxazoline to 300mL of N-methylpyrrolidone, add 200mmol of potassium carbonate and 1.5mL of PEG400, stir and react at 60°C for 8 hours to obtain a reaction mixture, and add (R)-3-tert Butoxycarbonylaminopiperidine 120mmol, stirred and reacted at 60°C for 8 hours, the reaction was completed, 500mL of water was added to the reaction liquid, and the solid was precipitated, filtered, the wet filter cake was dissolved in dichloromethane, washed with water, dried with anhydrous sodium sulfate, filtered , concentrated under reduced pressure, added n-hexane, precipitated solid, filtered, and dried to obtain linagliptin intermediate 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7 -(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dione-2,3,6, 7-tetrahydro-1H-purine, the yield is 89.6%, and the purity is 99.2%.
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