A kind of synthetic method of rosuvastatin calcium chiral isomer impurity

Abstract

The invention relates to a synthesis method of chiral isomer impurities of rosuvastatin calcium. The invention finds that meso compounds IV (3R, 5R) and (3R, 5S), which are obtained after a compound III is reduced by sodium borohydride, differ greatly in chemical properties, (3R, 5S) compounds, adopting hydroxyl cis-structures, on C-3 and C-5 can be hydrolyzed in a very low-temperature alkaline environment, while (3R, 5R) compounds, adopting hydroxyl trans-structures, on the C-3 and the C-5 can be hydrolyzed at a relatively high temperature and cannot be hydrolyzed at a low temperature, and by virtue of a peculiar phenomenon, two chiral isomers of the meso compound IV are separated to obtain a target compound. The synthesis method is short in route; chiral carbon is not required to be introduced from a side chain source; the synthesis method is simple in process and easy to operate; the purity and the yield of the obtained target product are high, the purity can reach 98.8%, the yield can reach 75%, and the purity and the yield are much higher than those in the prior art; a reference substance is provided for the (3R, 5S) chiral isomer impurities of the rosuvastatin calcium; the synthesis method is of a great significance in researching the quality of the rosuvastatin calcium.

Description

technical field [0001] The invention relates to a synthesis method of rosuvastatin calcium chiral isomer impurity, in particular to a synthesis method of rosuvastatin calcium (3R, 5R) chiral isomer impurity. Background technique [0002] Rosuvastatin calcium, chemical name: bis-[E-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5 -base] (3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt (2:1), is a kind of cardiovascular drug, which was first developed by Shionogi Company in Japan. It was released in April 1998. It was transferred to British AstraZeneca in August 2003, and was approved by the US FDA in August 2003. The trade name is Crestor. The drug has extremely strong HMG-COA reductase inhibitory activity, is superior to other statins on the market, and has better tolerance and safety. It is the most powerful lipid-lowering drug so far. Its structural formula is as follows: [0003] [0004] Compound (3R,5R,E)-7-(4-(4-fluorophenyl)-6-is...

AI Technical Summary

Problems solved by technology

[0007] The above-mentioned whole synthetic route has a total of 10 steps of reaction, and the total yield from compound 1 to compound 7 is less than 10%. When compound 7 and 8 react, the cis-isomer of alkene will be produced at the same time, the reaction is complicated, difficult to purify, and finally unable to successfully prepared

[0008] After searching professional databases such as Scifinder and Reaxys, except that patent WO2015 / 071861 mentioned in Example 4 that rosuvastatin calcium (3R, 5R) chiral isomer impurity B was synthesized by biological enzyme method, up to now, there is no Found relevant personnel about the compound (3R,5R,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethanesulfonamide)pyridin-5-yl) -Calcium 3,5-dihydroxyhept-6-enoate, namely (3R,5R) chiral isomer impurity chemical synthesis method, so it is particularly important to develop a new synthetic method for impurity B

Images