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, poor atom economy, poor product purity, etc., and avoid connecting chiral groups substrate, high total yield, and low production cost

Active Publication Date: 2021-06-29
上海新礼泰药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The technical problem to be solved by the present invention is to overcome the defects in the prior art that the preparation method of ezetimibe has long steps, low yield, poor product purity, poor atom economy, high production cost, and is not suitable for industrialized production. And provide a kind of preparation method of ezetimibe and its intermediate

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

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: Preparation of ezetimibe intermediate IV (R=methyl)

[0049]

[0050] Under nitrogen protection, add 23.0 g (0.102 mol) of ezetimibe intermediate II (5S-5-(4-fluorophenyl)-5-hydroxyvaleric acid methyl ester) and ezetimibe intermediate to 345 mL of tetrahydrofuran Body III (4-[[(4-fluorophenyl)imine]methyl]-phenol) 32.9g (0.153mol), cooled to -10 ℃ ~ 0 ℃, added diisopropylethylamine 39.5g ( 0.306 mol) and 29.9 g (0.275 mol) of trimethylchlorosilane, and stirred at -10°C to 0°C for 2 hours to 3 hours. Add (+)-N-benzyl-(3R,4R)-bis(diphenylphosphine)pyrrolidine 0.54g (0.00102mol), and then slowly add 2.0mol / L lithium diisopropylamide tetrahydrofuran / ethylbenzene / heptane Alkanes solution 102mL (0.204mol), stirred at -10°C to 0°C for 1 hour to 2 hours. Adding mass concentration is 5% ammonium chloride aqueous solution (the described mass concentration refers to the quality of ammonium chloride accounts for the percentage of ammonium chloride aqueous solution t...

Embodiment 2

[0051] Example 2: Preparation of Ezetimibe Intermediate IV (R=Ethyl)

[0052]

[0053] Under nitrogen protection, 23.0 g (0.102 mol) of ezetimibe intermediate II (5S-5-(4-fluorophenyl)-5-hydroxyvaleric acid methyl ester) was added to 230 mL of 2-methyltetrahydrofuran, and Zemibe intermediate III (4-[[(4-fluorophenyl)imine]methyl]-phenol) 26.4g (0.123mol), cooled to 0 ℃ ~ 10 ℃, added 49.2g of tri-n-butylamine ( 0.265mol) and 36.9g (0.245mol) of triethylchlorosilane, stirred at 0°C to 10°C for 1 hour to 2 hours. Add (+)-N-benzyl-(3R,4R)-bis(diphenylphosphine)pyrrolidine 0.27g (0.00051mol), and then slowly add 2.0mol / L lithium diisopropylamide tetrahydrofuran / ethylbenzene / heptane Add 77 mL (0.154 mol) of alkane solution, and stir at 0°C to 10°C for 2 hours to 3 hours. Adding mass concentration is 5% ammonium chloride aqueous solution (the described mass concentration refers to the quality of ammonium chloride accounts for the percentage of ammonium chloride aqueous solution ...

Embodiment 3

[0054] Example 3: Preparation of Ezetimibe Intermediate IV (R=Propyl)

[0055]

[0056] Under nitrogen protection, 23.0 g (0.102 mol ), ezetimibe intermediate III (4-[[(4-fluorophenyl)imine]methyl]-phenol) 39.5g (0.183mol), cooled to -20℃~-10℃, added triethyl 35.0 g (0.346 mol) of amine and 60.9 g (0.316 mol) of tripropylchlorosilane were stirred at -20°C to -10°C for 3 hours to 4 hours. Add (+)-N-benzyl-(3R,4R)-bis(diphenylphosphine)pyrrolidine 1.08g (0.00204mol), and then slowly add 2.0mol / L lithium diisopropylamide tetrahydrofuran / ethylbenzene / heptane Add 102 mL (0.204 mol) of alkane solution, and stir at -20°C to -10°C for 3 hours to 4 hours. Adding mass concentration is 5% ammonium chloride aqueous solution (the described mass concentration refers to the quality of ammonium chloride accounts for the percentage of ammonium chloride aqueous solution total mass) 200mL, vacuum concentration removes most of organic solvent (35 ℃~45 ℃, -0.085MPa~-0.095MPa), extracted thre...

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Abstract

The invention discloses a preparation method of ezetimibe and an intermediate thereof. The invention provides a preparation method of ezetimibe intermediate IV, comprising the following steps: in an organic solvent, in the presence of a trialkylchlorosilane, an organic base, a chiral catalyst and lithium diisopropylamide, the ezetimibe The ezetimibe intermediate II and the ezetimibe intermediate III undergo a ring closure reaction to obtain the ezetimibe intermediate IV; R is methyl, ethyl or propyl. The preparation method of the present invention has short route steps, mild reaction conditions, simple post-treatment steps, avoids substrates connected with chiral groups, and the prepared product has high purity, meets the standard of raw materials, high yield, low production cost, and atom utilization High efficiency, suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of ezetimibe and an intermediate thereof. Background technique [0002] Ezetimibe (I), developed by Merck Sharp & Dohme (MSD), was approved by the U.S. Food and Drug Administration (FDA) on October 25, 2002, and then approved by Japan Pharmaceuticals on April 18, 2007. Approved by the Comprehensive Device Agency (PMDA), marketed by Merck under the trade name [0003] [0004] Ezetimibe is a cholesterol absorption inhibitor. It inhibits the absorption of cholesterol in the small intestine, reduces the content of cholesterol in liver cells, and promotes the increase of cholesterol absorption in the circulation, thereby reducing the content of cholesterol in the blood. It is mainly used as an auxiliary dietary treatment for primary hyperlipidemia, mixed hyperlipidemia, homozygous familial hypercholesterolemia and homozygous sitosterolemia (phytosterolemia). [0005] Ezetimibe comes in oral tablets, eac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D205/08C07F7/18
CPCC07D205/08C07F7/188
Inventor 陈健邹宝勤应述欢
Owner 上海新礼泰药业有限公司
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