Preparation method of atorvastatin calcium isomer mixture and its intermediate
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A technology for isomer mixtures and compounds, which is applied in the field of chemical synthesis and can solve the problems of complex quality monitoring methods and no diastereomer synthesis and analysis involved.
Active Publication Date: 2011-06-22
WUHAN QR PHARMA CO LTD +1
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At present, the quality monitoring method for the intermediate (i.e. the side chain compound) is very complicated, therefore, the chiral analysis and quality control for the intermediate has always been a
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[0074] The present invention provides a method for preparing the isomer mixture shown in formula 11A, the method comprising the steps of:
[0075] (a) mixing the compound shown in formula 2 and compound RCOX to obtain the compound shown in formula 7A;
[0076] (b) ring-opening the compound shown in Formula 7A in the presence of an acid to obtain a compound shown in Formula 8A;
[0077] (c) mixing the compound shown in formula 8A with an oxidizing agent to obtain a mixture of isomers shown in formula 9A;
[0078] (d) reducing the compound shown in formula 9A to obtain a mixture of isomers shown in formula 10A; and
[0079] (e) mixing the isomer mixture of the compound shown in formula 10A, the catalyst, acetone, and 2,2-dimethoxypropane to obtain the isomer mixture shown in formula 11A;
[0080] Wherein R is an ultraviolet emitting group, an aryl group; an aryloxy group;
[0081] X is fluorine, chlorine, bromine, or iodine.
[0082]
[0083] In a preferred example of the...
Embodiment 1
[0152] Compound 2 was reacted with benzoyl chloride to obtain compound 3, the molar ratio of compound 2 and benzoyl chloride was 1:1, 2 (10g, 0.037mol) was dissolved in dichloromethane, and benzoyl chloride (5.18g, 0.037mol) was added dropwise ), control the temperature not to exceed 40°C, and stir at 30°C for 2h after the dropwise addition is completed. Water was added for washing, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain 10.1 g of crude compound 3 with a yield of 72%.
Embodiment 2
[0154] Dissolve compound 3 (10.1g, 0.027mol) in methanol, add dropwise 10% hydrochloric acid, the molar ratio of 10% hydrochloric acid and compound 3 is 2:1, stir for 2-3h after the dropwise addition, add saturated sodium bicarbonate solution to adjust When the pH reached 6-7, concentrated, dichloromethane was added to separate the layers, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 8.5 g of crude isomer mixture 4 with a yield of 93%.
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Abstract
The invention discloses a preparation method of an atorvastatin calcium isomer mixture and its intermediate. The invention discloses a method for determining and controlling the chiral purity of atorvastatin by allowing the mixture of atorvastatin calcium and its isomer as shown in formula 1' and the isomer mixture of materials as shown in formula 2' to perform synthesis reactions. The method comprises the following steps: (1) allowing the racemic mixture of the compound as shown in formula 2 and the compound as shown in formula 12 to perform a condensation reaction so as to obtain an isomer mixture as shown in formula 13; (2) hydrolyzing the isomer mixture as shown in formula 13 by an acid, and allowing the obtained isomer mixture as shown in formula 14 to form an isomer mixture of sodium salts as shown in formula 15; (3) mixing the isomer mixture as shown in formula 15 with calcium acetate to obtain an isomer mixture as shown in formula 1'; (4) determining the chiral content of the atorvastatin calcium as shown in the formula by a HPLC method; preparing the isomer mixture of the compound as shown in formula 2' and performing derivatization to obtain 11', allowing the compound asshown in formula 2 to perform derivatization so as to obtain a compound as shown in formula 7', and determining the chiral content of the compound as shown in formula 7' by a HPLC method so as to obtain the chirality of the compound as shown in formula 2. Therefore, the chiral purity of atorvastatin calcium can be controlled.
Description
technical field [0001] The present invention relates to the field of chemical synthesis, in particular to the preparation and purity determination method of the isomer mixture of atorvastatin calcium isomer mixture and its intermediate 2. Background technique [0002] Atorvastatin Calcium is a statin lipid-regulating drug developed by Burke-Davis (Warner-Lambert Branch) and jointly marketed with Pfizer. Atorvastatin calcium belongs to a competitive and selective HMG-CoA reductase inhibitor, which can block the reduction of HMG-CoA to valonate, thereby greatly reducing the content of total cholesterol and low-density lipoprotein. [0003] Because the activity of atorvastatin is better than that of all statins before it, and its toxic and side effects are small, it has shown an extraordinary upward trend once it is launched. After 2000, it became the drug with the highest sales in the world, with a share of 55% in the world blood lipid-regulating drug market; in 2004, the glo...
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