Synthetic method of key intermediate of rosuvastatin calcium side chain

Abstract

The invention discloses a preparation method of a key intermediate of rosuvastatin calcium side chains. (S)-3-hydroxy-4-chlorine-butyronitrile is taken as a starting material and subject to four steps condensation, reduction, hydroxyl protection and condensation reactions to obtain the intermediate. The method has simple operation during the reaction, products in the steps are easily separated and purified, no silica gel column is needed for purification and separation, the yield is above 80%, an intermediate with high chemical purity and optical purity can be obtained, and conclusion of GC determination is that the chemical purity is not less than 99.4%, and the optical purity is not less than 99.3%ee.

Description

technical field [0001] The invention relates to a preparation method of a blood lipid-lowering drug, in particular to a synthesis method of a statin drug rosuvastatin calcium side chain key intermediate. Background technique [0002] Rosuvastatin calcium (rosuvastatin calcium) is a clinically used blood lipid-lowering drug, chemical name: bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (Methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxy-6-heptenoic acid]calcium salt, the chemical structural formula is as follows: [0003] [0004] It is a new generation of statins with a fully synthesized single enantiomer, which belongs to HMG-CoA reductase inhibitors, and can reduce the elevated concentrations of low-density cholesterol, total cholesterol, triglycerides and apoprotein B, while increasing High concentration of HDL cholesterol. It can be used for the comprehensive treatment of primary hypercholesterolemia, mixed lipodystrophy and homozygous familial hyperchol...

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Problems solved by technology

[0008] US5278313, EP0319847, US5399722, US5481009, US5998633, US6140527, EP0104750, WO0307733 all provide or relate to the synthesis of side chain intermediates, but most of them have long synthetic routes, up to 7 to 9 steps, and most of the intermediates are viscous, which requires Multi-step high vacuum (0.1mmHg) distillation and silica gel column purification, using highly toxic potassium cyanide or sodium cyanide, resulting in poor product purity, instability, and difficulty in industrial production

[0009] JP5-32680 and J.Org.Chem, 1994,59 (25) 7849-7854, the side chain synthetic method, there is synthetic difficulty route long, and each step intermediate is mostly viscous liquid, and separation and purification difficulty (necessary many times Step silica gel column purification), poor product purity, instability, low yield when docking side chains and mother cores, poor product purity, etc.

[0010] In the preparation method of rosuvastatin calcium disclosed in WO2004052867, the synthesis method of the side chain intermediate is not provided, and the yield is low when the side chain and the mother nucleus are docked , subject to multi-step silica gel column purification

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