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Synthesis process of ezetimibe intermediate

A synthetic process and intermediate technology, which is applied in the field of synthetic process of ezetimibe intermediates, can solve the problems of lack of actual combat experience and synthetic routes that cannot reach large-scale production, and achieve high total yield, low production cost, and easy operation. simple effect

Active Publication Date: 2016-03-30
JIANGSU HANSYN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are currently many laboratories that can synthesize ezetimibe, they lack practical experience in terms of process scale-up. Most of the synthetic routes designed need to be analyzed by column chromatography or the process impurities produced cannot meet the requirements of API declaration. requirements, making these synthetic routes unable to meet the needs of large-scale production

Method used

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  • Synthesis process of ezetimibe intermediate
  • Synthesis process of ezetimibe intermediate
  • Synthesis process of ezetimibe intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] The preparation of embodiment 1 intermediate E3

[0034] (S)-3-oxo-3-(2-oxo-4-phenyloxazolin-3-yl) ethyl propionate, the structural formula is as follows:

[0035]

[0036] In a 500ml three-necked flask, add (s)-4-phenyl-2-oxazolone 20g (0.122mol, 1eq.) and dichloromethane 200ml, cool to between 0 and 10°C, add TMSCl raw material 16g (0.146 mol, 1.2eq.), keep stirring at 0~10℃ for 30 minutes, add 15.4g (0.152mol, 1.25eq.) of triethylamine dropwise, control the material temperature between 0~10℃ during the dropping process, add After completion, continue to stir at 0-10° C. for 2 hours until the reaction of ((s)-4-phenyl-2-oxazolone is detected by TLC (TLC detection condition: petroleum ether / ethyl acetate=2 / 1). Then add 36.8g monoethyl malonate acid chloride (0.245mol, 2eq.), the dropwise addition process controls the temperature of the material between 0~10°C, after the dropwise addition is completed, add 0.2g anhydrous tetrabutylammonium fluoride ( TBAF, 0.6mmol,...

Embodiment 2

[0037] The preparation of embodiment 2 intermediate E4

[0038] 3-(4-(Benzyloxy)phenyl)-3-((4-fluorophenyl)amino)-2-((S)-2-oxo-4-phenyloxazoline-3-carbonyl) Ethyl propionate, the structural formula is as follows:

[0039]

[0040]In a 250ml three-necked flask, 2.5g of the compound (S)-3-oxo-3-(2-oxo-4-phenyloxazolin-3-yl) ethyl propionate (9mmol, 1eq), 3.3g of compound N-(4-fluorophenyl)-4-benzyloxybenzylideneamine (11mmol, 1.2eq) and 100ml of dichloromethane, cooled to -30°C under nitrogen protection, added 1.75g Diisopropylethylamine (13mmol, 1.5eq), after stirring for 10 minutes, add 2.1g of titanium tetrachloride (11mmol, 1.2eq), the reaction solution is reddish brown, continue stirring at -30~-20°C for 3 hours , after the completion of the reaction, add 0.5ml acetic acid to quench the reaction, add 10% aqueous sodium bisulfite solution of 50ml, stir at room temperature for 1 hour, separate the organic phase, and then wash the organic phase twice with 100ml water to o...

Embodiment 3

[0041] The preparation of embodiment 3 intermediate E5

[0042] (2S,3R)-2-(4-(Benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxazetidinone-3-ethyl carbonate, the structural formula is as follows:

[0043]

[0044] In a 250ml three-necked flask, add 30g of the compound 3-(4-(benzyloxy)phenyl)-3-((4-fluorophenyl)amino)-2-((S)-2 prepared in Example 2 -Oxy-4-phenyloxazoline-3-carbonyl)propanoic acid ethyl ester (0.05mol, 1eq), 50gBSA (0.24mol, 4.8eq) and 500ml of dichloromethane, heated to 50°C and refluxed for 3 hours, then added 1g of tetrabutylammonium fluoride, continue to keep reflux for 3 hours, after the reaction is finished, cool down to normal temperature, add 500ml water to wash the organic phase twice, separate the organic phase, and remove the solvent by distilling the organic phase under reduced pressure, and then reapply in 200ml toluene Crystallized, separated and dried to obtain product 15g, yield 75%, MSm / z: 420 (M+H) + .

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Abstract

The invention discloses a synthesis process of an ezetimibe intermediate which is (2S,3S)-2-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxoazetidine-3-carboxaldehyde (an intermediate E6); (s)-4-phenyl-2-oxazolone and ethyl malonyl chloride as raw materials are subjected to condensation through condensation catalysis of TMSCl and TBAF to obtain an intermediate E3, the intermediate E3 and N-(4-fluorophenyl)-4-benzyloxybenzylidene amine are subjected to condensation under catalysis of titanium tetrachloride to obtain an intermediate E4, the intermediate E4 is subjected to cyclization under catalysis of BSA and FBAF to produce beta-lactam intermediate E5, and then the intermediate E5 is reduced by DIBALH into the aldehyde intermediate E6. The raw materials adopted by the process are cheap and easy to obtain, a solvent is single, the reaction time is short, the production cost is low, the yield is high, the operation of production units is simple, and the synthesis process is suitable for industrialized production.

Description

technical field [0001] The invention relates to a synthesis process of an ezetimibe intermediate, belonging to the technical field of drug synthesis. Background technique [0002] The chemical name of Ezetimube is: 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4( S)-(4-hydroxyphenyl)-2-azetidin (azetidin) ketone, the structural formula is as follows: [0003] [0004] Ezetimibe is the first and only selective cholesterol absorption inhibitor approved for clinical use. Since its birth in 1987, it is the first cholesterol-lowering drug with a new mechanism. Cholesterol absorption in the tract, lowering plasma cholesterol levels and hepatic cholesterol reserves. [0005] The report of the synthesis method of ezetimibe has been reported in a large number of literatures at present. In the literature review in Economics and Management, 2012, May, 70-74, you can have a more comprehensive and general understanding of the currently reported synthetic routes. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/08C07D263/22
CPCC07D205/08C07D263/22
Inventor 王希林丁尊良吴华峰张庆云
Owner JIANGSU HANSYN PHARMA
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