Preparation method of dipeptidyl peptidase ⅳ inhibitor
A dipeptidyl peptidase and inhibitor technology, applied in the field of preparation and purification of dipeptidyl peptidase IV inhibitors, can solve the problems of high equipment requirements, long reaction time, low product yield and purity, etc.
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Embodiment 1
[0032] 7.27g 2-cyano-5-fluorobenzyl bromide (R 1 for F,R 2 For Br), 6.00g of 3-methyl-6-chlorouracil, 5.10g of potassium carbonate were dissolved in a mixed solution of 78ml of DMSO and THF, the temperature was raised to 50°C and the reaction was stirred for 1h, the reaction was cooled to room temperature, and slowly added dropwise 80ml of ice water was added, stirred in an ice bath for 1 hour after the dripping, and filtered with suction to obtain 8.84g of crude compound III, with a yield of 88.60%. At 20°C, the crude compound III was slurried with 17.7 ml of n-heptane, filtered, washed, and dried to obtain 8.54 g of pure compound III, with a purification yield of 96.61%. The total yield of compound Ⅲ was 85.59%, and the purity was 99.20%.
Embodiment 2
[0034] 6.34g of 2-cyano-5-fluorobenzyl chloride (R 1 for F,R 2 For Cl), 6.00g of 3-methyl-6-chlorouracil, 4.40g of sodium carbonate were dissolved in 78ml of DMSO solution, the temperature was raised to 60°C and the reaction was stirred for 1h, the reaction was cooled to room temperature, and 80ml of ice water was slowly added dropwise, After the drop was completed, the mixture was stirred in an ice bath for 1 h, and filtered with suction to obtain 9.73 g of crude compound III, with a yield of 88.66%. At 35°C, the crude compound III was slurried with a mixed solvent of 48.6 ml of petroleum ether and 48.7 ml of isopropyl acetate, filtered, washed, and dried to obtain 8.96 g of pure compound III, with a purification yield of 92.09%. The total yield of compound Ⅲ was 81.64%, and the purity was 99.00%.
Embodiment 3
[0036] 8.42g 2-cyano-5-fluorobenzyl bromide (R 1 for F,R 2 For Br), 6.00g of 3-methyl-6-chlorouracil, 3.50g of sodium bicarbonate were dissolved in 78ml of NMP solution, heated to 65°C and stirred for 1h, the reaction was cooled to room temperature, and 80ml of ice water was slowly added dropwise , stirring in an ice bath for 1 h after dropping, and suction filtration to obtain 9.77 g of crude compound III, with a yield of 89.02%. At 25°C, the crude compound III was slurried with 39.0 ml of ethyl acetate, filtered, washed, and dried to obtain 9.56 g of pure compound III, with a purification yield of 97.85%. The total yield of compound Ⅲ was 87.11%, and the purity was 99.5%.
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