Synthetic method of key intermediate of rosuvastatin calcium side chain

A technology of rosuvastatin calcium and its intermediates, which is applied in the field of preparation of blood lipid-lowering drugs, can solve the problems of low yield of side chain and mother nucleus, long synthetic route, instability, etc., and achieve convenient industrial production and high product yield High, easy-to-operate effect

Active Publication Date: 2009-12-30
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 metho

Method used

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  • Synthetic method of key intermediate of rosuvastatin calcium side chain
  • Synthetic method of key intermediate of rosuvastatin calcium side chain
  • Synthetic method of key intermediate of rosuvastatin calcium side chain

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Embodiment 1

[0041] The preparation of embodiment 1 (S)-6-chloro-5-hydroxyl-3-oxohexanoic acid tert-butyl ester III:

[0042] Under nitrogen protection, 46g of zinc powder was added to 400mL of tetrahydrofuran, stirred for 20min, then 34.5g of (S)-3-hydroxy-4-chloro-butyronitrile was added, and then 56.2g of tert-butyl bromoacetate was slowly added dropwise at room temperature. After the temperature was raised to reflux for 3 hours, 2 mol / L hydrochloric acid was slowly added dropwise to adjust the pH to 5-6, and the reaction was stirred at room temperature for 2 hours. Add 200mL of ethyl acetate and 200mL of water for extraction, extract the aqueous layer with 100mL of ethyl acetate, combine the organic phases, wash once with 100mL of water, dry the organic phase over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain 50.6g of oily substance III.

Embodiment 2

[0043] The preparation of embodiment 2 (S)-6-chloro-5-hydroxyl-3-oxohexanoic acid tert-butyl ester III:

[0044] Under nitrogen protection, add 69.0g of zinc powder to 400mL of dimethoxyethane, stir for 20min, then add 69g of (S)-3-hydroxy-4-chloro-butyronitrile, then slowly add 112.4g of bromoacetic acid dropwise at room temperature For tert-butyl ester, heat up to reflux for 3.5 hours, slowly add 2 mol / L hydrochloric acid dropwise, adjust the pH to 5-6, and stir at room temperature for 2.5 hours. Add 450mL of ethyl acetate and 450mL of water for extraction, extract the aqueous layer with 200mL of ethyl acetate, combine the organic phases, wash once with 150mL of water, dry the organic phase over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain 97.5g of oily substance III.

Embodiment 3

[0045] The preparation of embodiment 3 (R, S)-6-chloro-3,5-dihydroxyhexanoic acid tert-butyl ester IV

[0046] Dissolve 93.8g of compound III in 1.25L of dry tetrahydrofuran and 600mL of methanol, cool to -80°C under the protection of nitrogen, add 427mL of diethylmethoxyborane (1mol / L solution in tetrahydrofuran), stir the reaction for 20min, then add Sodium borohydride 16.5g, react at this temperature for 3h, add 200mL acetone and 80mL30% hydrogen peroxide, react at -50°C for 30min, pour the reaction system into 800mL water, extract with ethyl acetate (400mL×3), combine the organic phase , the organic phase was washed with water (100 mL×3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain solid IV, which was recrystallized from n-hexane to obtain 74.6 g of a pale yellow solid, with a yield of 79.5%.

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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...

Claims

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Application Information

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IPC IPC(8): C07D319/06C07C69/675C07C67/31
Inventor 赵志全邓义
Owner LUNAN PHARMA GROUP CORPORATION
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