Preparation method of (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazacyclolan-2-one _Kain Industrial Additives

Background and overview^[1]

Ezetimibe was jointly developed by Schering-Plough and Merck for the treatment of hyperlipidemia. It was approved by the US FDA for marketing in 2002 under the trade name Zetia. Its chemical name is: 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl) -2-propionolactam. Hyperlipidemia is an important risk factor for the occurrence of cardiovascular diseases such as atherosclerosis. Lowering the total cholesterol level in plasma can reduce the risk of cardiovascular diseases. Current clinical drugs for the treatment of hyperlipidemia mainly include cholesterol synthesis inhibitors, phenoxy acids, and bile acid sequestrants. Ezetimibe selectively inhibits the absorption of cholesterol from the biliary tract and food by acting on the brush border of small intestinal cells without affecting the absorption of fat-soluble vitamins, triglycerides, and bile acids. The characteristics of ezetimibe are: after oral absorption, it enters the enterohepatic circulation and repeatedly enters the intestinal tract. Its glycolipid metabolites also have pharmaceutical activity, further preventing the absorption of cholesterol. The existing technical route for the preparation of ezetimibe is as follows: using methyl chloroformylbutyrate as the starting material, after reacting with a chiral auxiliary agent, it undergoes Michael addition and cyclization with the Schiff base intermediate to obtain nitrogen. The heterofour-membered ring intermediate is then subjected to hydrolysis, acylation, Grignard reaction, and asymmetric reduction reaction to prepare ezetimibe. This route has the disadvantages of complicated preparation steps, low yield and high cost, and is not suitable for large-scale industrial production. (4S)-3-[(5S)-5-(4-Fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazalan-2-one as Eze Good yields were obtained for the preparation of timibe intermediates.

Preparation^[1]

(4S)-3-[(5S)-5-(4-Fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazacyclopentan-2-one Preparation is as follows: under nitrogen protection, add 41.1g of 2mol/L tetrahydrofuran solution of borane dimethyl sulfide into the reaction bottle, then add 173.2g of methylene chloride, cool to 0-~5°C, add 1mol/L ( 3R)-1-Methyl-3,3-diphenyl-1H,3H-tetrahydropyrro[1,2-C][1,3,2]oxazoborane [R-MeCBS] in toluene 5.1g, stir for 15 minutes. Control the temperature below 0°C, and add dropwise the dichloromethane solution of (4S)-3-[5-(4-fluorophenyl)-5oxopentanoyl]-4-phenyl-2-oxazolidinone (25.95 g+58.9g), complete the dropwise addition within 2-3 hours, and continue stirring for 1 hour. Control the temperature below 0°C, add 8.2g of methanol dropwise, then add 52.8g of 5% hydrogen peroxide solution, control the temperature to 20±5°C, and stir for 20 minutes. Then add 4.2g of 2mol/L sulfuric acid solution and stir for 20 minutes, perform liquid separation extraction, add 58.9g of methylene chloride to the water phase for back extraction, and combine the organic phases. Then add 70.5g of 1mol/L sulfuric acid solution and stir for 5 minutes, perform liquid-separation extraction. Add 44.8g of 5% sodium sulfite aqueous solution to the organic phase, stir for 5 minutes, and perform liquid-separation extraction. Then add 89.7g of saturated sodium chloride aqueous solution to the organic phase, stir for 5 minutes, and perform liquid separation extraction. Add 25.95g anhydrous sodium sulfate to the organic phase, dry for 0.5 hours, filter, and concentrate the filtrate under reduced pressure at 40±5°C with a vacuum degree of -0.08~-0.1Mpa until no droplets flow out to obtain a viscous oily substance, namely (4S)- 3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazacyclolan-2-one.

Main reference materials

[1] CN201810147417.9 Crystal form and preparation method of key intermediate of ezetimibe