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Stereselective synthesis method for lipid-lowering drug ezetimibe

A hypolipidemic drug, stereoselective technology, applied in the production of bulk chemicals, organic chemistry and other directions, can solve the problem of no reported product optical purity, etc., and achieve the effects of improving optical purity, improving yield and purity, and improving chemical purity.

Active Publication Date: 2014-08-06
SHANGHAI FANGNAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield for this step was 65%, but the optical purity of the product was not reported

Method used

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  • Stereselective synthesis method for lipid-lowering drug ezetimibe
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  • Stereselective synthesis method for lipid-lowering drug ezetimibe

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Experimental program
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Effect test

Embodiment 1

[0040] The synthesis of ezetimibe when the chiral prosthetic group is (S)-4-phenyl-2-oxazolidinone comprises the following steps:

[0041] Step (a), the reaction formula is as follows:

[0042]

[0043] Into a 500 mL three-neck round bottom flask was added compound II p-fluorobenzoyl butyric acid (20 g, 95.15 mmol), dichloromethane (100 mL) and triethylamine (23 mL, 165 mmol), and the mixture was stirred at room temperature for 5 min . Pivaloyl chloride (11.3 mL, 91.75 mmol) was added slowly over 30 minutes and stirring was continued for 1 hour. Add chiral prosthetic compound IIIa(S)-4-phenyl-2-oxazolidinone (10g, 61.3mmol), 4-(N,N-dimethylamino)pyridine (1.6g, 13mmol) and dry N,N-Dimethylformamide (10 mL), heated to reflux of dichloromethane for about 7 hours. After cooling to room temperature, the entire batch was slowly transferred to a flask containing 2N sulfuric acid (80 mL) with stirring, and stirring was continued for 30 min, the layers were separated, and the mi...

Embodiment 2

[0054] The synthesis of ezetimibe when the chiral prosthetic group is (S)-4-phenyl-2-thiazolidinone comprises the following steps:

[0055] Step (a), the reaction formula is:

[0056]

[0057] Into a 500 mL three-neck round bottom flask were added p-fluorobenzoylbutyric acid (20 g, 95.15 mmol), dichloromethane (100 mL) and triethylamine (23 mL, 165 mmol), and the mixture was stirred at room temperature for 5 minutes. Pivaloyl chloride (11.3 mL, 91.75 mmol) was added slowly over 30 minutes and stirring was continued for 1 hour. Add the chiral prosthetic group (S)-4-phenyl-2-thiazolidinone (with (S)-4-phenyl-1,3-thiazolidine-2-thione as raw material, according to the literature Phosphorus, Sulfur and Silicon and the Related Elements, 2011, 186(7), prepared by the method provided in 1563–1571) (11g, 61.3mmol), 4-(N,N-dimethylamino)pyridine (1.6g, 13mmol) and dry N,N-Dimethylformamide (10 mL), heated to reflux of dichloromethane for about 8 hours. After cooling to room tempe...

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Abstract

The invention provides a stereselective synthesis method for a lipid-lowering drug ezetimibe shown in formula I. The method comprises the following steps: a, P-fluorobenzoyl butyric acid shown in formula II reacts with a chiral auxiliary shown in formula III to obtain ketone shown in formula IV; b, under the existence of a chiral catalyst, the ketone shown in formula IV is reduced to chiral alcohol shown in formula V; c, chiral alcohol shown in formula V reacts with a silicyl protective agent to obtain a protected compound shown in formula VI, and then the compound shown in formula VI and imine shown in formula VII are subjected to addition and protecting groups are removed, so that a compound shown in formula VIII and a diastereomer thereof shown in formula IX are obtained, and through recrystallization with an appropriate solvent, an optically pure compound shown in formula VIII is obtained; d, the compound shown in formula VIII is protected with an acylation reagent, so that a compound shown in formula X is obtained, and amide shown in formula X is cyclized with a fluorinion catalyst, so that protected lactam shown in formula XI is obtained; then protecting groups are removed, and the ezetimibe shown in formula I is obtained.

Description

technical field [0001] The invention relates to a method for synthesizing the blood lipid-lowering drug ezetimibe, in particular to a stereoselective method for synthesizing the blood fat-lowering drug ezetimibe (I). Background technique [0002] US Patent No. 5,767,115 reported the synthesis method of ezetimibe for the first time. Chinese patent CN1329592 reports a more convenient stereoselective synthesis method, the steps are shown in the following formula: [0003] [0004] In step (c), both the chiral alcohol and the imine are protected with a suitable hydroxyl protecting group such as a silyl protecting group, and the alcohol (1 equivalent) and the imine (preferably 1 to 3 equivalents) are added without In a water solvent such as dichloromethane, cool the reaction mixture to minus 10°C to minus 15°C, add a tertiary amine base such as DIPEA (preferably 2 to 4 equivalents), add a sufficient amount of alcohol to react with imine A silylating agent (for example, 2 to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/08C07D263/26C07D277/14
CPCC07D205/08C07D263/26C07D277/14Y02P20/55
Inventor 张席妮
Owner SHANGHAI FANGNAN PHARMA
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