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Preparation method of key intermediate of rosuvastatin calcium side chain

A technology of rosuvastatin calcium and intermediates, which is applied in the field of preparation of hypolipidemic drugs, can solve the problems of low yield of side chain and parent nucleus, long synthesis route, instability and the like, and achieves convenient industrial production and product yield. High, easy-to-use effect

Active Publication Date: 2010-01-13
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 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

Method used

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

Examples

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Embodiment 1

[0042] Embodiment 1 Preparation of (S)-6-chloro-5-hydroxyl-3-oxohexanoic acid tert-butyl ester III:

[0043] N 2Under protection, 225mL (1.61mol, 4.0eq) of diisopropylamine was dissolved in 1400mL of dried tetrahydrofuran, cooled to -78°C, and 64mL (4.0eq, 2.5mol / L) of tetrahydrofuran solution of n-butyllithium was slowly added dropwise. After reacting at this temperature for 30 min, 217.5 mL (1.61 mol, 4.0 eq) of tert-butyl acetate was slowly added dropwise, and then reacted at -78°C for 1 h. Slowly add 66.76g (402.2mmol, 1eq) II solution in 300mL tetrahydrofuran to the reaction system, the temperature is controlled at -78°C, after reacting at this temperature for 1h, the mixture is poured into 500mL10% hydrochloric acid, ethyl acetate (150mL×3 ), combined the organic phases, washed the organic phases with water (100 mL×2), dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure to obtain 93.8 g of oily matter.

Embodiment 2

[0044] Embodiment 2 Preparation of (S)-6-chloro-5-hydroxyl-3-oxohexanoic acid tert-butyl ester III:

[0045] N 2 Under protection, 168.8mL (1.21mol, 3.0eq) of diisopropylamine was dissolved in 1200mL of dried tetrahydrofuran, cooled to -65°C, and 483mL (3.0eq, 2.5mol / L), after reacting at this temperature for 30min, slowly add 163.1mL (1.21mol, 3.0eq) tert-butyl acetate dropwise, and then react at -55°C for 1h. Slowly add 66.76g (402.2mmol, 1eq) II solution in 300mL tetrahydrofuran to the reaction system, the temperature is controlled at -78°C, after reacting at this temperature for 1h, the mixture is poured into 500mL10% hydrochloric acid, ethyl acetate (150mL×3 ), combined the organic phases, washed the organic phases with water (100 mL×2), dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure to obtain 83.5 g of oily matter.

Embodiment 3

[0046] Example 3 Preparation of (R, S)-6-chloro-3,5-dihydroxyhexanoic acid tert-butyl ester IV:

[0047] Dissolve 93.8 g of compound III in 1.5 L of dry tetrahydrofuran and 400 mL of methanol, cool to -80°C under nitrogen protection, add 427 mL of diethylmethoxyborane (1 mol / L tetrahydrofuran solution), stir for 20 minutes, and then add Sodium borohydride 16.5g, react at this temperature for 3h, add 200mL acetone and 80mL30% hydrogen peroxide, react at -60°C for 30min, pour the reaction system into 800mL water, extract with ethyl acetate (400mL×3), and combine the organic phases , 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 77.6 g of a pale yellow solid, with a yield of 82.7%.

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Abstract

The invention provides a preparation method of a key intermediate of a rosuvastatin calcium side chain, comprising the following steps: using (S)-4-chlorine-3-hydroxybutanoate as an initial raw material; and preparing the key intermediate through four-step reactions of condensation, reduction, hydroxy group protection and condensation. The reaction process is simple to operate, the products in each step are easy to separate and purify, the purification and separation step is carried out without a silicagel column, and the yield is more than 80 percent, therefore, the intermediate with higher chemical purity and optical purity can be obtained. The GC determination shows that the chemical purity is more than or equal to 99.5 percent and the optical purity is more than or equal to 99.2 percent ee.

Description

technical field [0001] The invention relates to a preparation method of a blood lipid-lowering drug, in particular to a preparation 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 hyperch...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D319/06C07C69/675C07C67/31
Inventor 赵志全邓义
Owner LUNAN PHARMA GROUP CORPORATION
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