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Preparation method of ezetimibe and its intermediate

A technology for ezetimibe and intermediates, which is applied in the field of preparation of ezetimibe and its intermediates, can solve the problems of unsuitability for industrial production, harsh reaction conditions, low optical purity, etc., and achieve d.e. value and yield High efficiency, mild reaction conditions and high catalytic efficiency

Inactive Publication Date: 2013-03-06
CHIRAL QUEST (SUZHOU) CO LTD
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Problems solved by technology

[0012] The technical problem to be solved by the present invention is to overcome the defects of harsh reaction conditions, low optical purity, low yield or unsuitable for industrial production in the existing preparation method of ezetimibe intermediate compound II, and provides A kind of preparation method of ezetimibe and its intermediate compound

Method used

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  • Preparation method of ezetimibe and its intermediate
  • Preparation method of ezetimibe and its intermediate
  • Preparation method of ezetimibe and its intermediate

Examples

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Embodiment 17

[0062] Example 17 Synthesis of Ezetimibe

[0063] Add 3 g of palladium carbon (10% Pd / C) to the reaction solution obtained in Example 8, add 5 psi of hydrogen at room temperature, stir for 5 to 8 hours, then filter and concentrate to obtain a crude solid, which is then recrystallized with tert-butanol and water , 3.8 g of pure ezetimibe can be obtained with a purity of 99% and a two-step yield of 92%.

[0064] 1 H NMR (400MHz, DMSO-d6): δ9.82(s, 1H), 9.16(s, 1H), 7.57-7.55(m, 2H), 7.31-7.29(m, 2H), 7.14-7.10(m, 4H), 7.0-6.95(m, 2H), 6.66-6.63(m, 2H), 5.22(d, J=4.4, 1H), 4.50-4.49(m, 1H), 2.80-2.75(m, 1H), 1.64-1.52 (m, 4H).

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Abstract

The invention discloses a preparation method of an ezetimibe intermediate compound as shown in formula II. The method includes the step of: in an organic solvent, in the absence of water and oxygen, and under the effects of an asymmetric hydrogenation catalyst and an organic alkali, subjecting compound I and hydrogen to an asymmetric catalytic hydrogenation reaction as shown in the following. Specifically, R is a conventional protecting group in the field, can protect a phenolic hydroxyl group and is stable under alkaline conditions. The asymmetric hydrogenation catalyst is a ruthenium-diphosphine-diamine catalyst invented by Ryoji Noyori, a Japanese scientist and a Nobel Prize winner. The preparation method provided in the invention has mild reaction conditions, can prepare products with high optical purity, yield and purity, and has after-treatment that is convenient to operate, thus being easy to realize industrialized production.

Description

technical field [0001] The present invention specifically relates to a preparation method of ezetimibe and its intermediates. Background technique [0002] Ezetimibe (Ezetimibe, formula III), chemical name (3R,4S)-1-4-(4-fluorophenyl)-3-(3S)-3-[3-(4-fluorophenyl) )-3-hydroxyphenylpropyl]-4-(4-hydroxyphenyl)-2-azetidinone is a novel hypolipidemic drug jointly developed by Schering-Plough and Merck. Approved by the US FDA at the end of 2002, the trade name is Zetia. [0003] Patents US5631365 and US6627757 report that ezetimibe can be obtained from compound I-a by reduction with borane in the presence of a catalytic amount of Corey reagent, followed by debenzylation with palladium carbon (route 1). In this method, the product obtained after reduction contains 8-10% isomers as shown in formula II-b. Among them, II-a is the required intermediate of ezetimibe, and II-b is the configuration of the unwanted intermediate, and the intermediate of this configuration is difficult to...

Claims

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Application Information

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IPC IPC(8): C07D205/08
CPCY02P20/55
Inventor 白君林张晓娟熊飞李文革
Owner CHIRAL QUEST (SUZHOU) CO LTD
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