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Ezetimibe synthesis intermediate and preparation method and application thereof

A technology of ezetimibe and intermediates, applied in chemical instruments and methods, compounds of Group 4/14 elements of the periodic table, organic chemistry, etc., can solve the difference in the sequence of chiral reduction, low industrial application prospects, The problems of complicated operation in the process can achieve the effect of simple operation, good industrial application prospect and high optical purity of the product.

Active Publication Date: 2015-08-26
ABIOCHEM BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] 4US6207822, WO2007120824, WO2010071358, etc. have also adopted similar routes, the difference is that different ketal protection and hydroxyl reagents are introduced, and the sequence of chiral reduction is slightly different
[0026] The disadvantage of this route is that the air-sensitive metal compounds Li, LDA, TiCl are involved many times in the synthesis process. 4 etc., and the low temperature reaction at -78°C, and the use of Pd / C under high pressure to catalyze the hydrogenation of olefinic bonds, the process is complex and the reaction conditions are harsh
[0027] It can be seen from the existing routes for the synthesis of ezetimibe that the construction of chiral hydroxyl and lactam structures is a key step in the synthesis of ezetimibe, but these routes generally have complex processes, high costs, and poor selectivity , low industrial application prospects and other defects

Method used

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  • Ezetimibe synthesis intermediate and preparation method and application thereof
  • Ezetimibe synthesis intermediate and preparation method and application thereof
  • Ezetimibe synthesis intermediate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] With stirring, 20 g of the substrate Add to the reaction solution containing the following components: 700mL water, 2g of aldehyde and ketone reductase lyophilized powder, 7g of glucose and 500U of glucose dehydrogenase (purchased from sigma), and 0.1mM NADP+, and stirred at 30°C for 16 hours During the period, the pH value of the system was controlled between 6.5-7.5 by using 1M NaOH aqueous solution, and the reaction progress was detected by TLC.

[0064] After the reaction, adjust the pH value to about 9.0, extract 3 times with an equal volume of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, spin down the solvent under reduced pressure to obtain 18.5 g of the product, the yield is 91.8%, and the purity is 97.0 %.

[0065] The structure of the product was confirmed by 1H NMR, electrospray ionization mass spectrometry and e.e. value determination.

[0066]

[0067] 1 H NMR (300MHz, CDCl3): δ6.66-7.02 (4H, m, Ar-H), 5.14 (1H, t, -C...

Embodiment 2-4

[0071] Referring to the method of Example 1, using the substrates listed in Table 1, Examples 2-4 were carried out.

[0072] The results are shown in Table 1.

[0073] Table 1

[0074]

Embodiment 5

[0076] With stirring, 20 g of the substrate Add to the reaction solution containing the following components: 700mL water, 200mL crude enzyme solution and 20mL isopropanol, stir and react at 30°C for 16 hours, during which the pH value of the system is controlled between 6.5-7.5 with 1M NaOH aqueous solution, TLC detects the progress of the reaction.

[0077] After the reaction, adjust the pH value to 9.0, extract 3 times with an equal volume of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, spin down the solvent under reduced pressure to obtain 18.3 g of the product, the yield is 90.8%, and the purity is 96.9% .

[0078] The structure of the product was confirmed by 1H NMR, electrospray ionization mass spectrometry and e.e. value determination.

[0079]

[0080] 1 H NMR (300MHz, CDCl3): δ6.66-7.02 (4H, m, Ar-H), 5.14 (1H, t, -CHOH), 3.67 (3H, s, -OCH 3 ),2.61-2.86(2H,d,-CH 2 CO 2 CH 3 ),2.0(1H,s,-OH),0.08(9H,s,-Si(CH 3 ) 3 ).

[00...

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Abstract

The invention discloses an ezetimibe synthesis intermediate and a preparation method and application thereof, the ezetimibe synthesis intermediate has the structure as shown in formula III, and is synthesized by enzyme-chemical method, a chiral hydroxyl compound is produced by asymmetric reduction reaction of a raw material compound under the catalysis effect of aldehyde ketone reductase, and a product can be obtained by cyclization reaction. The ezetimibe synthesis intermediate is used in the preparation of ezetimibe, the process is simple, the concentration of the obtained product is high, and the product has the advantages of high optical purity, mild reaction conditions, environmental friendliness, simple operation, easy industrial amplification, and very good industrial application prospect.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to an intermediate for synthesizing ezetimibe, a preparation method and application thereof. Background technique [0002] Ezetimibe is a breakthrough in the research of blood lipid-lowering drugs. It was approved by the US FDA in 2002 and became the first lipid-lowering drug with a completely innovative mechanism of action since statins. The drug inhibits the absorption of cholesterol and phytosterols in food and bile at the brush border of the small intestine, reduces the transport of cholesterol from the intestine to the liver, reduces the storage of cholesterol in the liver, and increases the clearance of cholesterol in the blood, thereby reducing plasma cholesterol Level. As of 2011, ezetimibe's original single tablet and compound tablet have been approved by SFDA and launched in China. The structural formula of ezetimibe is shown below: [0003] [0004] The ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18C07D205/08C12P17/10
Inventor 罗煜丁时澄瞿旭东孙传民
Owner ABIOCHEM BIOTECH CO LTD
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