Preparation method of (R)-6-cyan-5-hydroxy-3-tert-butyl carbonyl hexanoate

Abstract

The invention discloses a preparation method of (R)-6-cyan-5-hydroxy-3-tert-butyl carbonyl hexanoate. The preparation method comprises the following steps: under the protection of nitrogen, adding tert-butyl acetate and 1,8-diazabicyclo-undecenoic-7-alkene into 2-methyltetrahydrofuran to prepare a solution A; dissolving (R)-4-cyan-3-ethyl hydroxybutyrate into 2-methyltetrahydrofuran to obtain a solution B; adding the solution A and the solution B into a small amount of 2-methyltetrahydrofuran dropwise, controlling the reaction temperature to be 20 to 30 DEG C, and performing stirring reactionfor 1 to 5 hours after adding the solution A and the solution B dropwise and simultaneously; adding water into the reaction system dropwise, standing and layering; performing reduced-pressure concentration on organic phase to obtain the (R)-6-cyan-5-hydroxy-3-tert-butyl carbonyl hexanoate, recovering a solvent simultaneously, and concentrating aqueous phase to recover the 1,8-diazabicyclo-undecenoic-7-alkene. According to the preparation method, low-temperature liquid nitrogen is not needed, energy consumption is low, dangerous reagents such as metal lithium and sodium are not used, the process is safe, the solvent and the reagents can be recovered after reaction, and environmental friendliness is achieved.

Description

technical field [0001] The invention belongs to the field of preparation of atorvastatin calcium intermediates, in particular to a preparation method of (R)-6-cyano-5-hydroxy-3-carbonylhexanoic acid tert-butyl ester. Background technique [0002] (R)-tert-butyl 6-cyano-5-hydroxy-3-carbonylhexanoate, English name: Hexanoic acid,6-cyano-5-hydroxy-3-oxo-,1,1-dimethylethyl ester,(5R )-, CAS No.: 125988-01-4, the structural formula is as follows: [0003] [0004] (R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate is a key intermediate in the synthesis of HMG-CoA reduction inhibitor atorvastatin calcium. The existing synthesis techniques mainly include: [0005] CN105567655 discloses the catalytic synthesis of recombinant halohydrin dehalogenase. [0006] [0007] The raw materials of this synthetic method are not easy to obtain. [0008] CN103420871 discloses that tert-butyl bromoacetate is prepared into zinc reagent and further reacted to obtain (R)-6-cyano-5-hydroxyl-3-...

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Problems solved by technology

The low temperature of the above method needs to be cooled by liquid nitrogen, which is difficult to recycle during use, resulting in high energy consumption; whether it is metallic lithium, metallic sodium, or sodium hydrogen, it will ignite when it meets water, and the process is very dangerous; all of the above processes exist Wastes that produce a large amount of salt, subsequent treatment is difficult, and the environment is polluted

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