Fudan University

Jiangxi Boya Seehot Pharmaceutical Co., Ltd.

Fangjun Xiong

Yan Wu

Fener Chen

Minjie Liu

Zedu Huang

Ge Meng

Haihui Peng

Jie Li

Dang Cheng

Zhining Li

Yuan Tao

Zexu Wang

Xiayun Huang

Guanxin Huang

Pingping Zhan

Lingjun Xu

Qiuqin He

Wenxue Chen

The present disclosure relates to the technical field of biochemical engineering and particularly discloses a preparation method for (R)-3-hydroxyl-5-hexenoate. In the method of the present disclosure, the (R)-3-hydroxyl-5-hexenoate is prepared by catalytic reduction of 3-carbonyl-5-hexenoate by ketoreductase with 3-carbonyl-5-hexenoate as the substrate. The amino acid sequence of ketoreductase is shown in SEQ ID NO.1. In the present disclosure, the (R)-3-hydroxyl-5-hexenoate having a very high chiral purity is obtained by asymmetric reduction by ketoreductase as the biocatalyst. The present disclosure has the advantages of easy operation, mild reaction conditions, high reaction yield and good practical industrial application value.

Preparation method for (R)-3-hydroxyl-5-hexenoate

The present disclosure belongs to the technical field of organic synthesis and particularly relates to a preparation method for 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate. The 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate is a key chiral intermediate for preparation of statin antilipemic agents. In the present disclosure, the 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate is obtained by bromination and cyclization of 3-((substituted oxycarbonyl)oxy)-5-hexenoate as raw material with hypochlorite and bromide in an organic solvent in the presence of CO. The method of the present disclosure has the advantages of readily available raw material, mild reaction conditions, easy operation, low cost, excellent atomic economy and less by-products, and is applicable to industrial production.

Preparation method for 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate

The present invention belongs to the technical field of organic chemistry, and specifically relates to a method for preparing rosuvastatin sodium. The method of the invention comprises: reducing 4-p-fluorophenyl-6-isopropyl-2-(N-methyl-methylsulfonylamino)pyrimidine-5-carboxylic acid (VII) in the presence of a borohydride, an alkyl-substituted chlorosilane and an assistance in an organic solvent to prepare 4-p-fluorophenyl-5-hydroxymethyl-6-isopropyl-2-(N-methyl-methylsulfonylamino) pyrimidine (VIII); then performing a reaction of the compound VIII with a triphenyl phosphonium salt in an organic solvent to prepare a ((4-p-fluorophenyl-6-isopropyl-2-(N-methyl-methylsulfonylamino)-5-pyridyl)-methyl)triphenyl phosphonium salt (IX); performing a stereoselective Michael addition reaction of (S)-trans-4,5-dihydroxy-pent-2-olefine acid ester (II) with furfural (III) to prepare a 2-((4R,6S)-2-(furan-2-yl)-6-hydroxymethyl-1,3-dioxane-4-yl)acetate (IV); oxidizing the compound IV to prepare a 2-((4R,6S)-2-(furan-2-yl)-6-formacyl-1,3-dioxane-4-yl)acetate (V); performing an olefination reaction of the compound V with the (4-p-fluorophenyl-6-isopropyl-2-(N-methyl-methylsulfonylamino)pyrimid-5-yl)-methyl triphenyl substituted phosphonium salt (IX) or phosphate to prepare 2-((4R,6S)-6-(trans-2-(4-p-fluorophenyl-6-isopropyl-2-(N-methyl-methylsulfonylamino)pyrimid-5-yl)vinyl)-2-(furan-2-yl)-1,3-dioxane-4-yl)acetate (VI); and performing deprotection and sodium salt formation of compound VI to prepare rosuvastatin sodium (I). The method has easily obtainable raw materials, and is simple to operate and suitable for industrial productions.

Method for preparing rosuvastatin sodium

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Shanghai, China

Fangjun Xiong