A kind of synthetic new method of telaprevir intermediate
A synthetic method and compound technology, applied in the field of medicine and chemical industry, can solve the problems of unstable intermediates, high toxicity of reagents, and high production costs, and achieve the effects of increased yield, elimination of toxic and harmful reagents, and reduced production costs
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Embodiment 1
[0068] Ethyl 2-chloro-3-oxohexanoate (compound 2):
[0069] Add 15.8 g (100 mmol) of ethyl butyryl acetate and 200 ml of dichloromethane into the reaction flask, cool down to 0-10°C, add 16.2 g (120 mmol) of sulfonyl chloride dropwise, raise to room temperature after the addition, and keep the temperature for 4 h , TLC monitored the complete conversion of the reactant to the product (developing solvent: ethyl acetate: n-hexane = 1:3). After the reaction is complete, cool down to about 0°C, add 150mL of 1M K 3 PO 4 Aqueous solution, separated into several layers, the aqueous layer was extracted twice by adding 50ml of dichloromethane, the organic layers were combined, washed with water until neutral, dried with 20g of anhydrous magnesium sulfate, filtered off the desiccant, and concentrated under reduced pressure until no slip-outs were obtained. 19.2 g of oily matter, yield 100%, was directly used in the next step reaction without refining. ESI-MS (m / z ) : 193 [M+1] + .
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Embodiment 2
[0085] Ethyl 2-chloro-3-oxohexanoate (compound 2):
[0086] Add 15.8 g (100 mmol) of ethyl butyroacetate and 100 ml of methyl tert-butyl ether into the reaction flask, cool down to 0-10°C, and dissolve 14.6 g (110 mmol) of N-chlorosuccinimide in 100 ml of formic acid In tert-butyl ether, add dropwise to the above reaction solution, keep warm for 6 h after the addition, and monitor the complete conversion of the reactant to the product by TLC (developer: ethyl acetate: n-hexane = 1:3). After the reaction is complete, cool down to about 0°C, add 70mL of 1M K 3 PO 4 Aqueous solution, separate the organic layer, add 50ml of methyl tert-butyl ether to the aqueous layer to extract twice, combine the organic layers, wash with water until neutral, dry with 20g of anhydrous magnesium sulfate, filter off the desiccant, concentrate under reduced pressure until there is no slip-out , to obtain 18.6g of oily substance, yield 97%, directly used for next step reaction without refining. ES...
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