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Method for synthesizing key intermediate of rosuvastain calcium

A technology for rosuvastatin calcium and intermediates, which is applied in the field of synthesizing rosuvastatin calcium key intermediates, can solve the problems of purification, storage, inconvenience in use, low production efficiency, and high operating costs, and achieves advantages that are beneficial to subsequent reactions, Improve product quality and avoid the effect of rectification

Inactive Publication Date: 2010-01-13
ENANTIOTECH CORP
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  • Claims
  • Application Information

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Problems solved by technology

The technology of patent US5260440 and WO03 / 097614 has the following disadvantages: the yield is low, the intermediate needs to be purified by column chromatography, the operation cost is high, the production efficiency is low, it is difficult to obtain solids, only oily substances can be obtained, the content and purity Not high, inconvenient to purify, store and use

Method used

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  • Method for synthesizing key intermediate of rosuvastain calcium
  • Method for synthesizing key intermediate of rosuvastain calcium
  • Method for synthesizing key intermediate of rosuvastain calcium

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Embodiment 1

[0031] Synthesis of 3-(4-fluorophenyl)-2-isobutyryl methyl acrylate: in a reaction flask, add p-fluorobenzaldehyde (18.4g, 0.15mol), methyl isobutyryl acetate (21.6g, 0.15 mol), acetic acid 2ml, piperidine 2ml, toluene 50ml, heated to reflux for 15h. Cool down to room temperature, add 20 ml of 10% sodium carbonate aqueous solution, stir, and separate the liquids. The organic phase was washed with 20 mL of 10% sodium carbonate aqueous solution, the aqueous phases were combined, the organic phase was extracted with toluene, the obtained organic layer was washed with water, washed with saturated brine, and separated. After concentration, 35.0 g of a brownish-red oil was obtained, which was 3-(4-fluorophenyl)-2-isobutyryl methyl acrylate, which could be put into the next reaction without rectification.

[0032] Compound II (R 1 =R 2 =Me, the salt-forming agent is hydrochloric acid) synthetic: add the compound 3-(4-fluorophenyl)-2-isobutyryl methyl acrylate (35.0g, 0.148mol) tha...

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Abstract

The invention discloses a method for synthesizing a key intermediate [4-(4-fluorophenyl)-6-isopropyl-2-alkylsulfanyl-5-yl] formate III of rosuvastain calcium, which takes fluorobenzaldehydes and ethyl isobutyrylacetate as raw materials, comprises the steps of condensation, cyclization, salification and oxidation, and adopts a reaction route as shown on the right, wherein R1 is selected from C1 to C6 alkyls and C6 to C12 aryls; and R2 is selected from C1 to C6 alkyls and C6 to C12 aryls. The method has the advantages that: as a compound I reacts with an acid to form a solid compound II which is a salt, the product quality is improved, the yield is increased, the package, storage, transportation and use of products are convenient, the consequent reactions are smooth, and low-efficiency, high consumption and trivial operation of rectification, column chromatography and the like is avoided; and a compound III can be obtained in one oxidation process.

Description

technical field [0001] The invention relates to a synthesis method of a key intermediate of rosuvastatin calcium [4-(4-fluorophenyl)-6-isopropyl-2-alkylsulfonyl-5-yl] formate. Background technique [0002] The first research unit of Rosuvastatin Calcium was Shionogi Pharmaceutical Co., Ltd. of Japan, which was later transferred to AstraZeneca. It was first listed in Canada in February 2003, and the generic name is Rosuvastatin calcium. [0003] Patents US5260440 and WO03 / 097614 respectively disclose the synthetic routes of aminopyrimidine derivatives and rosuvastatin calcium, including the following steps: [0004] [0005] Wherein, the key intermediate 2-alkylsulfonylpyrimidine compound [(4-(4-fluorophenyl)-6-isopropyl-2-alkylsulfonyl-5-yl] formate is synthesized from compound I In the process of III, two oxidations are required, and in the preparation of compound III, due to the difficulty in separation and purification of the product, it is difficult to obtain a pure ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/38
Inventor 韩勇黄仲斌戴连华谌淳刘毓宏徐亮
Owner ENANTIOTECH CORP
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