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A kind of purification method of rosuvastatin calcium intermediate

A technology of rosuvastatin calcium and a purification method, which is applied in the field of drug synthesis, can solve problems such as many synthesis steps, unqualified products, and difficulty in removal, and achieve high purification selectivity

Active Publication Date: 2019-12-06
ZHEJIANG HAIZHOU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The structure of rosuvastatin calcium is complicated, and there are many synthetic steps, especially the cis isomer and the product produced when the trans olefin intermediate (formula III) is synthesized by the wittig reaction have similar properties, are difficult to remove, and will In the subsequent preparation of rosuvastatin calcium, it is easy to cause unqualified products

Method used

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  • A kind of purification method of rosuvastatin calcium intermediate
  • A kind of purification method of rosuvastatin calcium intermediate
  • A kind of purification method of rosuvastatin calcium intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0021] 1) preparation of crude product containing intermediate shown in formula (III)

[0022] Under the protection of nitrogen, place 8.76g of the compound represented by formula (II) in a four-necked reaction flask at room temperature, add 70mL of dimethyl sulfoxide, stir to dissolve completely, then add 20g of the compound represented by formula (I) and 12.2g Anhydrous potassium carbonate solid powder, the solution was heated to 70°C for reaction, TLC detection and tracking, after the reaction was completed, the solution was cooled to room temperature, 200mL ethyl acetate was added to the solution and stirred for several minutes, filtered, and the filtrate was washed with pure water (100mL for 3 times), saturated brine washing (100mL washing 2 times), the organic phase was separated, dried overnight with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 17g of crude product containing the intermediate shown i...

Embodiment 2

[0026] 1) preparation of crude product containing intermediate shown in formula (III)

[0027] Under nitrogen protection, place 8g of the compound shown in formula (II) in a four-necked reaction flask at room temperature, add 60mL of dimethyl sulfoxide, stir to dissolve completely, add successively 14g of the compound shown in formula (I) and 11.1g of Potassium carbonate water solid powder, the solution is heated to 70-75°C for reaction, after about 3 hours of reaction, TLC detects that the reaction is complete, the solution is cooled to room temperature, add 80mL ethyl acetate to the solution and stir for several minutes, filter, and the filtrate is washed with pure water in turn (80mL washed 3 times), saturated brine (50mL washed 1 time), the organic phase was separated, dried overnight with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 12.5 containing the intermediate shown in formula (III). g.

...

Embodiment 3

[0031] 1) preparation of crude product containing intermediate shown in formula (III)

[0032] Under the protection of nitrogen, put 3.7g of the compound of formula (II) in a four-necked reaction flask at room temperature, add 35mL of dimethyl sulfoxide, stir to dissolve completely, then add 7.8g of the compound of formula (I) and 4.76g of anhydrous carbonic acid Potassium solid powder, the solution is heated to 70-75°C for reaction, after 3 hours of reaction, TLC detects that the reaction is complete, the solution is cooled to room temperature, add 100mL ethyl acetate to the solution and stir for several minutes, filter, and the filtrate is washed with pure water (60mL washing 3 times), washed with saturated brine (1 time with 40 mL), separated the organic phase, dried overnight with anhydrous magnesium sulfate, filtered, and concentrated the filtrate under reduced pressure to obtain 7.5 g of the crude product containing the intermediate represented by formula (III).

[0033]...

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Abstract

The invention discloses a purification method of a rosuvastatin calcium intermediate shown as Formula (III) as shown in the specification. The purification method is characterized by comprising the steps of heating and mixing a crude product of the rosuvastatin calcium intermediate shown as Formula (III) and a mixed solution of normal hexane and absolute ethyl alcohol till complete dissolution, and then performing cooling and crystallization. According to the method, the mixed solution of absolute ethyl alcohol and normal hexane serves as a recrystallization solvent for purification of the crude product of the rosuvastatin calcium intermediate shown as Formula (III); the purity of the rosuvastatin calcium intermediate shown as Formula (III) in a prepared product is greater than 99%; the maximum purity is 99.8%; the minimum purity is 99.3%; an effect of removing a cis-isomer is obvious; a cis-isomer content is less than 0.1%; and the purification selectivity is high.

Description

technical field [0001] The invention relates to a method for purifying an intermediate of rosuvastatin calcium, belonging to the technical field of pharmaceutical synthesis. Background technique [0002] Rosuvastatin Calcium (Rosuvastatin Calcium) was developed by Shionogi Co., Ltd. of Japan. It belongs to the HMG-CoA reductase inhibitor, which can reduce the elevated LDL cholesterol, total cholesterol, triglyceride and apoprotein B concentration , while increasing the concentration of high-density cholesterol. It can be used for the comprehensive treatment of primary hypercholesterolemia, mixed lipodystrophy and homozygous familial hypercholesterolemia, and is called a super statin. Rosuvastatin Calcium Chemical Name: [0003] (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonamido)-5-pyrimidine]-3, Calcium 5-dihydroxy-6-heptenate, its structural formula is as follows: [0004] [0005] The structure of rosuvastatin calcium is complicated, and th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/06
CPCC07D405/06
Inventor 宋卫马刚怀哲明陈昌略
Owner ZHEJIANG HAIZHOU PHARMA CO LTD
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