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Synthetic method of ezetimibe, and intermediate used in synthetic method

一种化合物、苄基的技术，应用在依泽替米贝的合成领域，能够解决成本高、不经济环保等问题

Active Publication Date: 2014-02-12
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the methods reported so far, for the construction of the chirality of the key C-4 in the four-membered ring of the lactam, an equivalent amount of chiral prosthetic oxazolidinone or chiral starting material (S)- Hydroxy-butyrolactone, uneconomical and environmentally friendly, high cost

Method used

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  • Synthetic method of ezetimibe, and intermediate used in synthetic method
  • Synthetic method of ezetimibe, and intermediate used in synthetic method
  • Synthetic method of ezetimibe, and intermediate used in synthetic method

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preparation example Construction

[0129] The preparation method of formula I compound of the present invention comprises the following steps:

[0130] (a) In the presence of a base, the compound of formula 1 and p-fluoroaniline undergoes an allyl amination reaction to prepare the compound of formula 2;

[0131]

[0132] (b) Addition reaction occurs between the compound of formula 2 and the compound of formula 3 under the action of base to prepare the compound of formula I having the structure shown in formula 4A; and optionally,

[0133]

[0134] (c) the compound of formula I having the structure shown in formula 4A removes the ester group at the β-position of the ketone carbonyl to generate the compound of formula I having the structure shown in formula 5A,

[0135]

[0136] Among the various types, P, R 1 , R 2 , The definition of LG is as mentioned above.

[0137] In another preferred example, the step (a) uses a complex formed between a phosphine ligand and a transition metal catalyst precursor...

Embodiment 1

[0197] Example 1 Preparation of compound (R)-2a.

[0198] The reaction is as follows: under argon atmosphere, [Pd(C 3 h 5 )Cl] 2 (54.8mg, 0.15mmol) and (S, S, S)-Lc (193mg, 0.25mmol) were added to a Schlenk tube, and anhydrous CH 2 Cl 2 (50mL), after stirring at room temperature for 10 minutes, successively added substrate 1a (3.54g, 10mmol), K 2 CO 3(1.0M aqueous solution, 30mL, 30mmol) and p-fluoroaniline (3.33g, 30mmol). After stirring at room temperature for three hours, separate the layers, extract the aqueous phase with dichloromethane (3×50 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by column chromatography to obtain the asymmetric aminated product ( R)-2a. The reaction formula is as follows:

[0199]

[0200] (R)-2a, white solid, 87% yield. Mp72-73°C, [α] D 20 =-111.0(c1.00, CHCl 3 ),95%ee[Determined by high performance liquid chromatography, chiral AD-H column, n-hexane / isopropanol=95:5,1.0mL / mi...

Embodiment 2

[0202] In this embodiment, different phosphine ligands (S, S, S)-L and metal salt [Pd(η-C 3 h 5 )Cl] 2 Catalysts were prepared on site to catalyze the allyl amination reaction of substrate 1a to prepare compound (R)-2a (reaction formula is as follows):

[0203]

[0204] The reaction is as follows: under argon atmosphere, [Pd(C 3 h 5 )Cl] 2 (54.8mg, 0.15mmol) and (S, S, S)-L (0.25mmol) were added to a Schlenk tube, and anhydrous CH 2 Cl 2 (50mL), after stirring at room temperature for 10 minutes, successively added substrate 1a (3.54g, 10mmol), K 2 CO 3 (1.0M aqueous solution, 30mL, 30mmol) and p-fluoroaniline (3.33g, 30mmol). After stirring at room temperature for three hours, separate the layers, extract the aqueous phase with dichloromethane (3×50 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and purify by column chromatography to obtain the asymmetric aminated product ( R)-2a.

[0205] Table 1: Results of asymmetric...

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Abstract

The invention discloses a synthetic method of ezetimibe, and an intermediate used in the synthetic method. According to the synthetic method, allyl amination of Morita-Baylis-Hillman adducts is performed so as to realized production of a chiral beta-aromatic amido alpha-methylene carboxylic acid derivative with high activity and selectivity, and the chiral ezetimibe synthetic intermediate is obtained via simple conversion reaction; and chiral medicament ezetimibe can be synthesized further. According to the synthetic method, chirality of ezetimibe is realized via chiral catalysis, so that the use of chiral auxiliary base oxazolidinone is avoided, cost is low, and the synthetic method is friendly to the environment.

Description

technical field [0001] The invention relates to a synthesis method of ezetimibe and an intermediate used in the method. Background technique [0002] Ezetimibe containing a β-lactam structure is a novel cholesterol-lowering drug developed by Schering Plough and approved by the US Food and Drug Administration (FDA) for marketing at the end of 2002. It reduces the concentration of low-density lipoprotein-cholesterol and total cholesterol in plasma by inhibiting the absorption of exogenous cholesterol in the small intestine. Clinically, it can reduce low-density lipoprotein-cholesterol (LDL-C) and total cholesterol significantly. Reduced; combined with statins can achieve a cholesterol-lowering level equivalent to 8 times the dose of statin alone. [0003] European patent EP720599 first disclosed the synthesis method of ezetimibe: [0004] [0005] [0006] Since the synthesis method was first reported, several synthesis routes of ezetimibe have been reported, such as d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/34C07C227/18C07C227/32C07C227/08C07C69/734C07C67/08C07C69/96C07C68/00C07F7/18C07D205/08
CPCC07C68/00C07C227/18C07C227/32C07C229/34C07D205/08C07C227/08C07C67/08C07F7/18C07C69/734C07C69/96C07C227/16C07F9/5045C07F15/0033C07C67/343C07C2601/16C07D205/04C07C67/31C07C229/30
Inventor 丁奎岭王晓明王正
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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