Synthetic method for ezetimibe intermediate

Abstract

The invention discloses a synthetic method for an ezetimibe intermediate. The synthetic method comprises: by taking a compound I as a raw material, mixing the compound I with a reaction solution; under the action of an acid-binding agent, firstly activating the compound I by pivaloyl chloride; then coupling the compound with S-4-phenyl-2-oxazolidinone; then carrying out reduction reaction through (R)-2-mehtyl-CBS-oxazole borane; and then carrying out post-treatment to prepare (4S)-3-[(5S)-5-(4-fluorophenyl-5-hydroxyl valeryl)-4-phenyl-1,3- azacyclocyclopentane-2-(one) (II), wherein the formula is as shown in the description, and the reaction solution comprises tetrahydrofuran, chloroform, dioxane or dichloromethane. The synthetic method for the ezetimibe intermediate disclosed by the invention has the advantages of being simple to operate, short in synthetic line and relatively low in synthetic cost, and is suitable for large-scaled industrial production.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to an ezetimibe intermediate (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl -1,3-Oxazolane-2-one (II) synthesis method. Background technique [0002] Ezetimibe is the first cholesterol absorption inhibitor approved by the U.S. FDA. It was jointly developed by Schering-Plough and Merck. It was first approved for marketing in the U.S. in 2002. There are many kinds of drugs for lowering blood lipids in the market. As a new type of cholesterol absorption inhibitor, ezetimibe not only has remarkable effect, but also has less side effects. It can also be used in combination with statins. The effect is good and the market is huge. [0003] (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolane-2-one (Ⅱ) It is the key intermediate in the route of synthesizing ezetimibe. The existing synthetic routes are two-step synthesis, and the reaction for...

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Problems solved by technology

[0005] It can be seen that in the prior art, the key intermediate for the synthesis of ezetimibe (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1 ,3-Oxazolane-2-one (Ⅱ) usually requires two synthetic steps to prepare the corresponding intermediate, which has the disadvantages of long synthetic route and high synthetic cost

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