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Method for preparing Rosuvastatin Calcium and key intermediate

A technology for rosuvastatin calcium and intermediates, which is applied in the field of preparation of key intermediates, and can solve problems such as increased impurity content, affecting the completeness of stereoselective reactions, and large content

Inactive Publication Date: 2006-12-06
SHANGHAI SINE PHARMA LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Experiments show that the unrefined compound I-XI has a spot at Rf=0.64 and Rf=0.40 in addition to the main spot at Rf=0.48 on the TLC plate (developing agent sherwood oil: ethyl acetate=2:1). Impurity spots, these impurities enter the reaction of compound I-XII in the next step, and then produce a variety of impurities, and the amount is large, which will affect the completeness of the stereoselective reaction and cause unnecessary pairing of the 3-position of the dihydroxyheptenoic acid group. Increased content of enantiomer impurities
And once the reaction to generate compound I-XII is completed, because the by-product is similar to the target product I-XII in structure, Rf is similar, and there are many types of impurities and large content, it is difficult to remove them even if they are passed through a silica gel column.
In this way, in order to achieve the purpose of purification, such as reaching a purity of more than 90%, it is necessary to use a very high chromatographic column with column efficiency (i.e. the ratio of the length of the chromatographic column to the cross-sectional diameter), which not only prolongs the production cycle, but also increases the operating cost. overall reduced productivity

Method used

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  • Method for preparing Rosuvastatin Calcium and key intermediate
  • Method for preparing Rosuvastatin Calcium and key intermediate
  • Method for preparing Rosuvastatin Calcium and key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Compounds I-X were prepared as described in EP 0,521,471 A1. Weigh 16 g of compound I-X and dissolve it in 100 ml of acetonitrile to obtain solution 1. Under ice-bath conditions, 20ml of 48% (w / v) HF aqueous solution was added to 380ml of acetonitrile to obtain solution 2. Solution 1 was added dropwise to solution 2 in an ice bath. After the dropwise addition was completed, it was heated to room temperature and stirred for 1.5 hr. Then use Na 2 CO 3 Neutralize and extract with ether. The organic layer was separated and harvested, washed with sodium chloride, dried, and the solvent was evaporated under reduced pressure to obtain 14.6 ml of a concentrated solution. To the concentrated solution was added 14.6 ml of toluene / diethyl ether 3:2 (v / v) mixture, and the ratio of concentrated solution:mixed solution (w / v) was 1:1. Stir at room temperature until dissolved. Cool to 0-4 ° C to crystallize. Filter the reaction solution after crystallization, and spot the filtr...

Embodiment 2

[0031] 30 g of compound I-X was dissolved in 800 ml of acetonitrile, 20 ml of 48% (w / v) HF solution was added, and reacted at room temperature for 10 hr. Add NaHCO under ice-salt cooling 3 , adjust the pH to 7, and extract with ether. The organic layer was separated and harvested, washed with saturated brine, washed with anhydrous Na 2 SO 4 Dry, filter, and distill off the solvent under reduced pressure to obtain 26.8 g of an oily concentrate. Add 40.2ml of toluene / diethyl ether 2:1 (v / v) mixture to the concentrated solution, the ratio of concentrated solution:mixed solution (w / v) is 2:3, stir at room temperature until dissolved. Cool to 0-4 ° C to fully crystallize. After filtration, the filter cake was vacuum-dried to obtain 22.5 g of compound I-XI in the form of yellow crystals. As mentioned above, the purity was 98.8% as determined by HPLC.

[0032] HNMR (CDCl 3 )δ: 1.28(d, 6H), 2.52(m, 2H), 2.73(m, 2H), 3.36(hept, 1H), 3.51(s, 3H), 3.59(s, 3H), 3.72(s, 3H ), 4.48 ...

Embodiment 3

[0034] 20 g of compound I-X was dissolved in 125 ml of acetonitrile to obtain solution 1. Under ice-bath conditions, 25ml of 48% (w / v) HF aqueous solution was added to 475ml of acetonitrile to obtain solution 2. Solution 1 was added dropwise to solution 2 in an ice bath, heated to room temperature after the dropwise addition, and stirred for 1.5 hr. use Na 2 CO 3 Neutralize and extract with ether. The organic layer was separated and harvested, washed with sodium chloride, dried, and the solvent was evaporated under reduced pressure to obtain 18.3 g of a concentrated solution. Add 27.5ml of toluene:diethyl ether 3:1 (v / v) mixture to the concentrated solution, the ratio of concentrated solution:mixed solution (w / v) is 1:1.5, and dissolve at room temperature. Then cool to 0-4 ° C to fully crystallize. After filtration, the filter cake was vacuum-dried to obtain compound I-XI in the form of yellow crystals, 16.1 g. As mentioned above, the purity was 98.9% as determined by HP...

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Abstract

This invention provides a method for preparing rosuvastatin intermediate compound I-XI. The method can ensure a high purity of I-XI, thus ensuring the completeness of the stereoselectivity in subsequent reactions. Although the yield of I-XII from I-X in this invention is a little lower than that in the invention EP 0,521,471 A1, the purification of I-XII only needs a low-efficiency chromatographic column. The method thus has such advantages as low cost and high efficiency.

Description

technical field [0001] The present invention relates to the preparation of rosuvastatin calcium (Rosuvastatin), especially the preparation method of one of the key intermediates. Background technique [0002] The compound of structure I shown below is an HMG-CoA reductase inhibitor used in the treatment of atherosclerosis, hyperlipidemia, familial hypercholesterolemia and similar diseases. [0003] [0004] Among them, R 1 for C 1-6 Alkyl, aryl or aralkyl (C1-C6); R 2 and R 3 for hydrogen, C 1-6 Alkyl or aralkyl (C1-C6); R 4 for hydrogen, C 1-6 Alkyl (C1-C6) or a non-toxic salt that does not affect pharmacological effects; X is sulfur, oxygen or sulfonyl or imino with substituents. [0005] Structure I compounds include lovastatin (mevinolin) (disclosed by U.S. Patent 4,231,938), pravastatin (pravatatin) (disclosed by U.S. Patent 4,346,227), simvastatin (simvastatin) (disclosed by U.S. Patent 4,444,784), fluvastatin ( fluvastatin) (dis...

Claims

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Application Information

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IPC IPC(8): C07D239/42
Inventor 戴健张跃良项春丽黄河
Owner SHANGHAI SINE PHARMA LAB
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