Preparation method of rosuvastatin calcium

A technology of rosuvastatin calcium and its compounds, which is applied in the field of drug synthesis, can solve problems such as unfavorable industrial production, and achieve the effects of realizing industrial production, increasing synthesis yield, and avoiding harsh conditions

Active Publication Date: 2019-06-21
ZHEJIANG YONGTAI TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the synthesis of rosuvastatin calcium, it also involves the reaction under harsh conditions of -78°C, which is not conducive to industrial production

Method used

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  • Preparation method of rosuvastatin calcium
  • Preparation method of rosuvastatin calcium
  • Preparation method of rosuvastatin calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048]

[0049]Compound II was prepared according to the method of Bernhard Breit et al. (Org. Lett. 2018, 20, 3286-3290). Add Pd(PPh 3 ) 4 (2.67g, 2.3mmol, 2.0mol%), (S)-(-)-SEGphos (3.52g, 5.77mmol, 5.0mol%) and p-toluenesulfonic acid (1.98g, 11.54mmol, 10mol%), nitrogen After 5min, add formula I compound (18.0g, 115.4mmol, 1.0 equivalent), 37% aqueous formaldehyde solution (18.6mL, 248.4mmol) and freshly distilled toluene (300mL), heat up to 85°C, stir for 10 hours, and cool to room temperature Afterwards, the solvent was removed under reduced pressure, and by flash column chromatography (silica gel column, n-hexane:EtOA C =2:1), to obtain a colorless transparent liquid compound II (20.2g, 94%, d.r.=97:3). 1 H-NMR (400MHz, CDC1 3 ):δ=5.83(ddd,1H),5.26(ddd,1H),5.13(ddd,1H),5.09(d,1H),4.74(d,1H),4.13-4.07(m,2H),3.67( s,3H), 2.61(dd,1H), 2.43(dd,1H), 1.70(m,1H), 1.49(ddd,1H), basically similar to those reported in the literature.

[0050] According to the operating me...

Embodiment 2

[0054]

[0055] Dissolve 2.0g of the compound of formula II in 10ml of ethanol, add 0.2g of heteropolyacid H 3 PW 12 o 40 , dropwise added 30% H 2 o 2 10ml aqueous solution, the reaction temperature was controlled at 35°C, after 6 hours of reaction, the solvent was evaporated, water was added, extracted with ethyl acetate, and the organic phase was Na 2 SO 4 After drying, the solvent was distilled off under reduced pressure to obtain 2.0 g of the compound of formula III with a yield of 99%. 1 H-NMR (400MHz, CDC1 3 ):δ=9.56(d,1H),5.13(m,1H),4.76(d,1H),4.12-4.06(m,2H),3.68(s,3H),2.62(dd,1H),2.44( dd,1H), 1.72(m,1H), 1.50(ddd,1H).

[0056] According to the operation method of embodiment 2, the influence of the selection of oxidation system and catalyzer on this reaction has been studied, and the results are shown in table 2:

[0057] Table 2 The influence of different oxidation systems and reaction conditions on the reaction

[0058] oxidation system catal...

Embodiment 3

[0060]

[0061] Dissolve 6.78g (0.01mol) of the compound of formula IV and 1.88g (0.01mol) of the compound of formula III in 30ml of DMSO, stir to dissolve; raise the temperature to 80°C; add 4.14g (0.03mol) of potassium carbonate, stir, and keep warm at 80°C for 10h After the reaction, 80ml of water was added to precipitate a white solid, which was filtered, washed with saturated brine, washed with 5% ethanol, and dried to obtain 4.72g of white solid compound V with a yield of 93%, E:Z=97:3.

[0062] S(ESI)m / z:508.23(M+H) + ; 1 H-NMR (400MHz, CDC1 3 ):δ=7.62-7.60(m,2H),7.10-7.08(m,2H),6.59(dd,1H),5.44(dd,1H),5.11(d,1H),4.77(d,1H), 4.16-4.06(m,2H),3.69(s,3H),3.57(s,3H),3.50(s,3H),3.34(m,1H),2.63(dd,1H),2.44(dd,1H) ,1.60-1.57(m,1H),1.35(m,1H),1.26(d,6H).

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Abstract

The invention provides a preparation method of rosuvastatin calcium. A rosuvastatin calcium side chain is prepared by using allene as a raw material and is used to synthesize rosuvastatin calcium. According to the method, a hydrogen peroxide-heteropoly acid oxidation system is used to oxidize the side chain from olefin to aldehyde, thereby avoiding harsh conditions of low-temperature reaction in the prior art and being more beneficial to industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of rosuvastatin calcium. Background technique [0002] Rosuvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), which can be used for the treatment of hypercholesterolemia and mixed dyslipidemia. High LDL cholesterol, total cholesterol, triglycerides, and apoprotein B concentrations with elevated HDL cholesterol; can be used in primary hypercholesterolemia and mixed lipodystrophy and homozygous familial forms The comprehensive treatment of hypercholesterolemia is called super statin. [0003] In therapy, rosuvastatin is administered as its calcium salt and is a single enantiomer having the following chemical formula. [0004] [0005] Regarding the synthetic method of rosuvastatin calcium, multiple methods have been reported, for example, EP0521471A1 reports the following synthetic method...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
Inventor 林娇华夏海建向科
Owner ZHEJIANG YONGTAI TECH CO LTD
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