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Preparation method of atorvastatin calcium isomer mixture and its intermediate
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A technology of isomer mixtures and compounds, applied in the field of chemical synthesis, can solve problems such as diastereoisomer synthesis and analysis not involved, quality control methods are complicated, etc.
Active Publication Date: 2013-06-05
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 an unresolved problem in this field
[0007] The enantiomers of atorvastatin calcium are disclosed in US Patent No. 5,273,995, but the synthesis and analysis of another group of diastereoisomers do not involve
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[0074] The present invention provides a method for preparing a mixture of isomers as shown in formula 11A, the method comprising the steps:
[0075] (a) Mixing the compound shown in formula 2 and compound RCOX to obtain the compound shown in formula 7A;
[0076] (b) Ring-opening of the compound represented by formula 7A in the presence of an acid to obtain the compound represented by formula 8A;
[0077] (c) mixing the compound shown in formula 8A with an oxidizing agent to obtain an isomer mixture shown in formula 9A;
[0078] (d) reducing the compound shown in formula 9A to obtain an isomer mixture 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, aryl; aryloxy;
[0081] X is fluorine, chlorine, bromine, or iodine.
[0082]
[0083] In a preferred embodiment of the present invention, the...
Embodiment 1
[0152] Compound 2 is reacted with benzoyl chloride to obtain compound 3. The molar ratio of compound 2 to benzoyl chloride is 1:1. Dissolve 2 (10g, 0.037mol) in dichloromethane and add dropwise benzoyl chloride (5.18g, 0.037mol). ), control the temperature not to exceed 40°C, and stir at 30°C for 2h after the addition is complete. Water was added for washing, liquid separation, the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain 10.1 g of the crude product of 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 to compound 3 is 2:1, stir after the dropwise addition for 2-3h, add saturated sodium bicarbonate solution to adjust After the pH reached 6-7, it was concentrated, and dichloromethane was added for liquid separation. 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 atorvastatin calcium isomer mixture and its intermediate 2 isomer mixture. Background technique [0002] Atorvastatin calcium is a statin lipid regulator developed by Burke-Davis (Warner-Lambert branch) and sold jointly with Pfizer. Atorvastatin calcium is a competitive and selective HMG-CoA reductase inhibitor that can block the reduction of HMG-CoA to hydroxymevalonate, thereby greatly reducing the content of total cholesterol and low-density lipoprotein. [0003] As the activity of atorvastatin is better than all the statins before it, and the side effects are small, it has shown an extraordinary upward trend once it is marketed. After 2000, it became the drug with the highest sales in the world, with a market share of 55% of the world's lipid-lowering drugs; in 2004, the global sales revenue reached 12 billion U.S. dollars...
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Application Information
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