Clopidogrel active metabolite derivatives and prodrug thereof, and preparation method and application of clopidogrel active metabolite derivatives and prodrugs thereof
A technology of clopidogrel and its derivatives, which can be applied in drug combinations, active ingredients of heterocyclic compounds, blood diseases, etc., and can solve problems such as inactive metabolites, high cost of biological enzymes, low bioavailability of clopidogrel and delayed inhibition
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Embodiment 1
[0095] Synthesis of (R)2-Cl-Deuterated Methyl Mandelate
[0096]
[0097] Add 2-Cl-mandelic acid (2g, 10.7mmol) to a 100ml dry three-necked flask and dissolve it in 10ml of deuterated methanol. During the heating process, slowly add 1.5ml of concentrated sulfuric acid under vigorous stirring through a constant pressure dropping funnel, and reflux for 3h to react Completely, after vacuum spinning, add 30ml of ethyl acetate to dissolve, add 10% citric acid solution (50ml), saturated sodium bicarbonate solution (50ml) and saturated sodium chloride solution (50ml) for extraction, combine the organic layers and use anhydrous sulfuric acid The sodium was dried, the filtrate was spun to remove the solvent, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 2.0 g of 2-Cl-deuterated methyl mandelate as a white solid with a yield of 91.79%.
[0098] Its hydrogen spectrum characterization result is:
[0099] ( 1 H-NMR600MHz...
Embodiment 2
[0101] Synthesis of (R)2-Cl-7-deuteromethyl p-nitrobenzenesulfonylmandelate
[0102]
[0103] In a dry 100ml round bottom flask, 2-Cl-deuteromethyl mandelate (2.0g, 9.8mmol) was dissolved in 20ml of dichloromethane, and triethylamine (1.5ml, 20mmol) was added in an ice-salt bath and stirred for 3min Afterwards p-nitrosulfonyl chloride (2.24 g, 11.7 mmol) was added. The reaction was complete at -10°C for 20 min, and the reaction was completed by vacuum spin-drying to obtain a yellow oily liquid, which was dissolved by adding 30 ml of ethyl acetate, 10% citric acid solution (50 ml), saturated sodium bicarbonate solution (50 ml) and saturated sodium chloride solution ( 50ml), the organic layers were combined and dried over anhydrous sodium sulfate, the filtrate was spun to remove the solvent, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain 2-Cl-7-p-nitrobenzene Deuteromethyl sulfonylmandelic acid white solid 3.6g,...
Embodiment 3
[0107] Synthesis of (3Z)-3-(2-ethoxy-2-oxoethylene)-4-oxopiperidine-1-carboxylate tert-butyl ester
[0108]
[0109]Add boc-4-piperidone (16g, 80mmol) in a 250ml round bottom flask, add 70ml toluene, after fully dissolving, slowly add morpholine (8ml, 91mmol), add p-toluenesulfonic acid (1.0g, 5.8mmol ), the water separator device was heated to reflux for 3h and cooled naturally to room temperature, slowly added dropwise a 50% toluene solution of ethyl glyoxylate (16ml, 80mmol), p-toluenesulfonic acid (4.0g, 23.2mmol) was added, and the water separator device After heating to reflux for 2h and cooling to room temperature, 4M HCl (10ml) was slowly added dropwise under vigorous stirring and stirred at room temperature for 3h, and the reaction was complete. The lower aqueous phase was extracted three times with ethyl acetate (20ml), 10% citric acid solution (50ml), saturated sodium bicarbonate solution (50ml) and saturated sodium chloride solution (50ml) were added to the orga...
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