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Novel preparation method of ezetimibe

A technology of ezetimibe and compounds, applied in the preparation of cholesterol absorption inhibitors, in the field of ezetimibe, which can solve problems such as high cost, unsuitable for industrial production, and weak hydroxyl activity

Inactive Publication Date: 2009-05-06
杜焕达
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Wo20061157080 et al. synthesized β-lactam ring by staudinger reaction. In the subsequent steps, expensive tetrakistriphenylphosphine palladium catalyst was used, and anhydrous and oxygen-free Grignard reaction was carried out. The reaction conditions were harsh and the cost was high. Not suitable for industrial production
[0007] Wo2005 / 049592 et al. first reduced the carbonyl group next to the benzene ring to a hydroxyl group, and then used chlorosilane reagents to protect the hydroxyl group. Due to the weak activity of the hydroxyl group, it cannot react well with chlorosilane reagents, and the protection effect is poor.

Method used

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  • Novel preparation method of ezetimibe
  • Novel preparation method of ezetimibe
  • Novel preparation method of ezetimibe

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Mix 71.4 g of aluminum trichloride and 200 ml of fluorobenzene, add a solution of glutaric anhydride (28.6 g) in fluorobenzene (100 ml) dropwise at 20°C, and react at 30°C for 3 hours after dropping. Cool to about 0°C, add dropwise 200ml of 1M hydrochloric acid, the temperature does not exceed 20°C. Add a large amount of ice water after dropping, stir, filter, and wash the filter cake. Add the filter cake to 800 ml of saturated sodium bicarbonate solution, stir at room temperature for 1 h, filter, and add activated carbon to the filtrate for decolorization. Add concentrated hydrochloric acid to adjust the pH value to 1, filter and wash the filter cake, and dry to obtain a white solid. Namely compound I. Yield 71%.

Embodiment 2

[0034] Mix 47g of compound I, 60ml of triethylamine and 250ml of dichloromethane, dropwise add 27.6ml of pivaloyl chloride, react for 3h, add (4s)-4-phenyl-2-oxazolidinone 38g, DMF25ml, 4, 4-Dimethylaminopyridine 4g, reflux reaction for 10h, after cooling, add 200ml of 5M hydrochloric acid dropwise, oscillate and mix well, then let stand, and separate the organic layer. It was washed successively with saturated sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness to obtain a white solid, namely compound II, 49 g in total, with a yield of 61%.

Embodiment 3

[0036] Put 15g of compound II and 200ml of toluene in a mixing tank equipped with a water separator, add 2ml of titanium tetrachloride and 4.2ml of thiodiethanol in sequence, stir, and heat up to reflux. After reacting for 6 hours, it was cooled to room temperature and washed with an equal volume of saturated brine. Then cooled to -10°C for crystallization. Dry to obtain a white solid, which is Compound III, 14.9 g in total, with a yield of 88%.

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PUM

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Abstract

The invention provides a novel method for synthesizing ezetimibe. The method uses fluorobenzene as an initial raw material to react with glutaric anhydride and 4(s)-4-phenyl oxazolidone in sequence under the action of a catalyst, and generates the ezetimibe via condensation, cyclization, deprotection, reduction and other conventional methods after carbonyl is protected by thiol. The method has the advantages of high yield and few side reactions, and is applicable to industrial production.

Description

technical field [0001] The present invention also relates to a preparation method of a cholesterol absorption inhibitor, specifically, relates to ezetimibe, namely 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl) A new preparation method of -3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone Background technique [0002] Ezetimibe (Ezetimibe), the chemical name is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S )-(4-hydroxyphenyl)-2-azetidinone, its structural formula is: [0003] [0004] Ezetimibe is a new cholesterol-lowering drug jointly developed by Merck and Schering-Plough and launched in October 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. , Elevate high-density lipoprotein (HDL-C); combined with st...

Claims

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Application Information

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IPC IPC(8): C07D413/06
Inventor 杜焕达郑力陈学军
Owner 杜焕达
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