Novel method for preparing dihydroxy acid HMG CoA reductase inhibitor
A hydroxycarboxylate, alkyl technology, applied in the field of preparing dihydroxyacid HMG-CoA reductase inhibitors, can solve problems such as difficult operation, complex structure, difficult synthesis, etc., and achieves less environmental pollution, high yield, easy effect of operation
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[0057] Example 1: Preparation of compound (B) 4-(4-fluorobenzene)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-pyrimidinecarbaldehyde:
[0058]Add 28.0 g of pyridinium chlorochromate (PCC) and 24.6 g of anhydrous sodium acetate to 300 ml of dry dichloromethane, stir, and add compound (A) [4-(4-fluorobenzene)-6-iso] dropwise at 20°C. Propyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]methanol 35.3g and 200ml dichloromethane prepared solution, stirred for 1h, filtered, the filtrate 1N hydrochloric acid 500ml, 1N NaOH 500ml, Wash with 500 ml of saturated brine, dry with anhydrous magnesium sulfate, remove dichloromethane under reduced pressure, column chromatography of the residue, eluent dichloromethane, to obtain 29.1 g of the crystalline target product (yield: 82.9%).
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[0059] Example 2: Preparation of Compound (D):
[0060] Add 13.0 g of trimethyl phosphite to 200 ml of toluene, heat to reflux, and add compound (C) 2-[(4R, 6S)-6-bromomethyl-2,2-dimethyl-1,3-dioxe dropwise A solution of 32.3g of tert-butyl acetate and 200ml of toluene, reflux for 3h, remove toluene under reduced pressure, add 500ml of water, extract with 200ml×3 of chloroform, dry with anhydrous magnesium sulfate, remove chloroform under reduced pressure, The residue was subjected to column chromatography and ethyl acetate as the eluent to obtain 31.7 g of the target product (yield: 90.1%).
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[0061] Example 3: Preparation of Compound (E)
[0062] Under the protection of argon, add 15.3g of LiCl and 42.2g of compound (D) to 300ml of dry dichloromethane, stir, add 12.2g of triethylamine dropwise at 0°C, and then add 35.1g of compound (B) and dichloromethane dropwise. 200ml of the prepared solution, stirred at 20°C for 1 hour, added 300ml of saturated ammonium chloride solution to the reaction solution, separated into layers, extracted with 200ml of dichloromethane in the aqueous phase, combined the organic phases, dried over anhydrous magnesium sulfate, and removed under reduced pressure. Chloromethyl, column chromatography of the residue, eluent (n-hexane: ethyl acetate = 5:1), to obtain 40.7 g of the target product (yield: 70.5%).
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