Synthetic method of boceprevir intermediate namely 2-hydroxy-3-amino-4-cyclobutane amide hydrochloride

[0037] Example 1

[0038] At room temperature, add 50 g (0.43 mol) cyclobutyl acetic acid, 73.4 g (0.47 mol) of potassium monomethyl malonate, and 300 mL of tetrahydrofuran to the three-necked reaction flask, and continue to add 103.7 g (0.64 mol) of carbonyl diimidazole under stirring. ), 15g of magnesium chloride to form a reaction solution. After the addition, the reaction solution was reacted at room temperature for 12 hours, and then 100 mL of water was added to the reaction solution, stirring was continued for 0.5 hours, and the layers were separated. The organic phase was washed once with 50 mL of saturated brine and dried. Concentrated to obtain 66.5 g of 4-cyclobutyl-3-oxo-butyric acid ethyl ester compound of formula A, with a yield of 89.2%.

[0039] Add 200 mL of formic acid to the three-necked reaction flask, add 33.2 g (0.2 mol) of sodium percarbonate, 66.5 g (0.39 mol) of ethyl 4-cyclobutyl-3-oxo-butyrate, and iodine at 15-20°C. Benzene 4g (0.02mol) forms a reaction sol

[0042] Example 2

[0043] At room temperature, add 30 g (0.26 mol) of cyclobutyl acetic acid, 44 g (0.28 mol) of potassium monomethyl malonate, and 300 mL of 2-methyltetrahydrofuran to the three-necked reaction flask. After stirring, continue to add cyanuric chloride 47.8 g(0.26mol) and 10g of magnesium chloride form a reaction solution. After the addition, the reaction solution is reacted at room temperature for 10 hours, and then 100mL of water is added to the reaction solution, stirring is continued for 0.4h, and the liquids are separated. The organic phase is washed with 50mL of saturated brine Once, dry and concentrate to obtain 39.5 g of 4-cyclobutyl-3-oxo-butyric acid ethyl ester compound of formula A, with a yield of 88.5%.

[0044] Add 150 mL of formic acid to the three-necked reaction flask, add 35.8 g (0.23 mol) of sodium perborate, 39.5 g (0.23 mol) of ethyl 4-cyclobutyl-3-oxo-butyrate, and iodine at 15-20°C. Benzene 3g (0.02mol) forms a reaction solution. After the addit

[0047] Example 3

[0048] At room temperature, add 18 g (0.16 mol) of cyclobutyl acetic acid, 24.6 g (0.16 mol) of potassium monomethyl malonate, and 200 mL of ethylene glycol dimethyl ether to a three-necked reaction flask. After stirring, continue to add dicarbonate. 35.04g (0.16mol) of tert-butyl ester and 10g of magnesium chloride form a reaction solution. After the addition, the reaction solution is reacted at room temperature for 11 hours, and then 100 mL of water is added to the reaction solution. Stirring is continued for 0.6 hours, and the organic phase is continuously saturated with Wash once with 50 mL of brine, dry, and concentrate to obtain 22.3 g of 4-cyclobutyl-3-oxo-butyric acid ethyl ester compound of formula A, with a yield of 83.1%.

[0049] Add 150mL of formic acid to the three-necked reaction flask, add 4.4g (0.13mol) of hydrogen peroxide, 13.78g (0.13mol) of sodium carbonate and 22g of ethyl 4-cyclobutyl-3-oxo-butyrate at 15-20℃. (0.13mol), 2g (0.01mol) of iodob