Method for synthesizing important ezetimibe intermediate-(4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1, 3-oxazolidine-2-ketone

A technology of oxacyclopentane and ezetimibe, which is applied to an important intermediate of ezetimibe (4S)-3-[(5S)-5-(4-fluorophenyl)-5- The field of synthesis of hydroxyvaleryl]-4-phenyl-1,3-oxazacyclopentan-2-one can solve the problems of large environmental pollution, high cost and high cost

Inactive Publication Date: 2013-06-26
北京京卫燕康药物研究所有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In this method, the pivaloyl chloride used in the synthesis of compound (I) and the borane dimethyl sulfide used in the synthesis of compound (II) have certain toxicity, and the pollution to the environment is large, and the operation and post-treatment are more loaded down with trivial details during use, and (R )-2-phenyl-CBS-oxazoboridine is expensive, and the cost of using (R)-2-phenyl-CBS-oxazoboridine is higher, but nonetheless, there is still no effective technical means to solve the problem in the prior art above question

Method used

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  • Method for synthesizing important ezetimibe intermediate-(4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1, 3-oxazolidine-2-ketone
  • Method for synthesizing important ezetimibe intermediate-(4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1, 3-oxazolidine-2-ketone
  • Method for synthesizing important ezetimibe intermediate-(4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1, 3-oxazolidine-2-ketone

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example 1

[0022] Under nitrogen, add 20 grams of p-fluorobenzoyl butyric acid, 10 grams of S-4-phenyl-2-oxazolidinone, 20.1 grams of EDCI, 1.6 grams of DMAP, and 100ml of dichloromethane into a 250ml single-necked flask at room temperature. After stirring for 24 hours, TLC monitored the reaction to be complete. Add 100ml of 1N hydrochloric acid, separate the liquids, wash and dry with water, and concentrate to obtain 19 grams of off-white solid. Recrystallize with isopropanol to obtain 16 grams of white solid, which is the compound. Melting point: 91.6-92.4°C, purity 99.9% (HPLC).

[0023] MS(ESI): 356(M+H), 1 H-NMR(CDCl 3 -d1): δ-2.0~2.1(m,2H), 2.94~2.99(m,2H), 3.03~3.03(m,2H), 4.27~4.31(m,1H), 4.67~4.73(m,1H) , 5.41 ~ 5.45 (m, 1H), 7.01 ~ 7.13 (m, 2H), 7.29 ~ 7.39 (m, 5H), 7.90 ~ 7.95 (m, 2H).

example 2

[0025] Under nitrogen, add 19.5g (55mmol) of compound I and 200ml of dichloromethane to a three-necked flask, cool to -20°C, dropwise add 32ml of homemade isopinylchloroborane (60% n-hexane solution, concentration 1.7mol) / L), control the internal temperature not to be higher than -20°C, stir at -20°C for 1 hour after the dropwise addition is completed, then stir at 0°C for 1 hour, and naturally rise to room temperature and stir until the conversion is complete. After quenching by adding a small amount of potassium carbonate solution dropwise, 200 ml of potassium carbonate solution was added to separate the layers, the organic layer was dried and concentrated to obtain a colorless oil, and the compound II was obtained by column chromatography with a mixture of n-hexane and ethyl acetate.

[0026] MS(ESI): 380(M+Na + ), 1 H-NMR (CDCl3-d1): δ-1.60~1.82(m,4H), 2.96~3.02(m,2H), 4.26~4.30(m,1H), 4.61~4.65(m,1H), 4.66~4.71 (m, 1H), 5.40 to 5.42 (m, 1H), 6.98 to 7.01 (m, 2H), 7.25 to 7....

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Abstract

The invention provides a method for synthesizing an important ezetimibe intermediate-(4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1, 3-oxazolidine-2-ketone. The method comprises the following steps of: 1, enabling fluorobenzoicacid butanoic acid and (S)-4-phenyl-2 oxazolidone to react under the action of a condensing agent to generate a compound (I); and 2, reducing the compound (I) through a chiral reducing agent so as to obtain a compound (II).

Description

Technical field [0001] The present invention relates to an important intermediate of ezetimibe (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxyvaleryl]-4-phenyl-1,3-oxazepine Synthesis method of cyclopentane-2-one. Background technique [0002] Ezetimibe is a new cholesterol absorption inhibitor developed by Schering in the United States. It was first marketed in the United States in 2002. It is the first FDA-approved cholesterol absorption inhibitor and is used in the treatment of primary hypercholesterolemia. China Patent CN99814140.2 has reported the synthesis method of this compound, in which (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxyvaleryl]-4-phenyl-1,3 The -oxazolane-2-one intermediate is the most important intermediate in the synthesis of ezetimibe. The method for synthesizing compound (II) in CN99814140.2 is to react fluorobenzyl butyric acid with pivaloyl chloride, and then react with (S)-4-phenyl-2-oxazolidinone to obtain compound (I), and then Compound (I) is reacted with ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/22
Inventor 葛志敏王德平吴龙昊张盈盈
Owner 北京京卫燕康药物研究所有限公司
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