1593543-00-0Relevant articles and documents
Preparation method of ezetimibe and intermediate thereof
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Paragraph 0057-0059; 0066; 0067; 0069, (2020/03/03)
The invention discloses a preparation method of ezetimibe and an intermediate thereof. The invention provides a preparation method of an ezetimibe intermediate IV. The preparation method comprises thefollowing steps: an ezetimibe intermediate II and an ezetimibe intermediate III are subjected to a cyclization reaction to obtain the ezetimibe intermediate IV in the presence of a trialkylchlorosilane, an organic base, a chiral catalyst and lithium diisopropylamide in an organic solvent, wherein R is methyl, ethyl or propyl. The preparation method is short in route steps, mild in reaction conditions and simple in post-treatment steps, and avoids the connection of a substrate with a chiral group, and the obtained product is high in purity, achieves the standard of bulk drugs, is high in yield, low in production cost, high in atomic utilization rate, and suitable for industrial production.
Preparation method of ezetimibe optical isomer
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Paragraph 0049-0066, (2020/06/05)
The invention relates to a preparation method of an ezetimibe optical isomer, and concretely relates to a method for synthesizing an ezetimibe impurity L by using a compound 03. The method comprises the following steps: 1) mixing the compound 03 with a silyl ether protecting group, 2) adding methyl tert-butyl ether, and 3) adding alcohol and acid.
Structural Correction and Process Improvement for Control of a Critical Process Impurity of Ezetimibe
Mannam, Madhava Rao,Sankareswaran, Srimurugan,Gaddam, Venugopal Reddy,Natarajan, Senthilkumar,Kottapalli, Rajasekhara Prasad,Kumar, Pramod
, p. 919 - 925 (2019/05/08)
A new process-related impurity of ezetimibe was identified and characterized. The impurity is critical and common to most of the manufacturing routes of ezetimibe. Structural characterization using HMBC indicated the presence of a six-membered ring rather than a nine-membered ring as proposed by the innovator of ezetimibe. Prominently, the existing pharmacopoeial methods for ezetimibe are not capable of detecting this impurity. A control strategy was established by appropriate process control that is capable of purging the impurity to levels comfortably below the regulatory requirement. The formation of the diastereomer impurity during the demonstration of a scale-up batch under the optimized conditions is attributed to epimerization of ezetimibe induced by thermal degradation of the silylating agent.