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Rosuvastatin calcium preparation intermediate, and method for preparing rosuvastatin calcium from intermediate

A technology for rosuvastatin calcium and intermediates, which is applied in the field of preparation of intermediate compounds of rosuvastatin calcium and its preparation, can solve the problems of increasing the difficulty of controlling impurities in intermediates and finished products, and achieve the effect of reducing difficulty

Active Publication Date: 2016-10-05
PKU HEALTHCARE CORP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still diastereoisomers produced during removal of the isopropylidene protection group under acidic conditions, which increases the difficulty of controlling impurities in intermediates and finished products.

Method used

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  • Rosuvastatin calcium preparation intermediate, and method for preparing rosuvastatin calcium from intermediate
  • Rosuvastatin calcium preparation intermediate, and method for preparing rosuvastatin calcium from intermediate
  • Rosuvastatin calcium preparation intermediate, and method for preparing rosuvastatin calcium from intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Synthesis of Example 1 Compound 3-b (R=tert-butyl, X=Br)

[0053]

[0054] In a 100ml three-neck round bottom flask, compound 3-a 6.5g (22.5mmol), pyridine 11.2g (138mmol) were dissolved in 25ml of dichloromethane, under N 2Under protection, lower the temperature to -70°C to -80°C. Then, 4.2 g (13.5 mmol) of bis(trichloromethyl)carbonate was dissolved in 30 ml of dichloromethane, and this solution was added dropwise to the above reaction liquid at -70°C to -80°C. After the dropwise addition, the reaction solution was continuously stirred for 30 min to 60 min, and then the temperature of the reaction solution was slowly raised to room temperature, and then continued to stir for 1 h to 2 h. After the reaction of raw material 3-a was detected by TLC, after-treatment was carried out. Saturated ammonium chloride aqueous solution was added dropwise to the above reaction solution to terminate the reaction until no bubbles were generated. Then the reaction solution was qu...

Embodiment 2

[0055] Synthesis of Example 2 Compound 3 (R=tert-butyl, X=Br)

[0056]

[0057] In a 250ml three-neck round bottom flask, add DMF 50ml, compound 3-b 3.1g (10mmol), NaIO 4 2.1g (10mmol) and stirred to dissolve. The solution was heated to reflux (about 150°C) for 1h-2h. After the reaction of raw materials was monitored by TLC spot plate, post-processing was carried out. After the reaction solution was cooled to room temperature, 100 ml of water was added, and then 40 ml of ethyl acetate was used to extract 3 times. The ethyl acetate phases were combined, dried with anhydrous magnesium sulfate, filtered, and the ethyl acetate solvent was concentrated to obtain a light yellow solid. After recrystallization from petroleum ether / ethyl acetate, 2.1 g of compound 3 was obtained as a white solid, with a yield of 86.1%. 1 H NMR (400M, CDCl 3 )δ: 9.58(s, 1H), 4.50(m, 1H), 4.28(m, 1H), 2.68(m, 2H), 2.34(m, 2H), 1.45(s, 9H). MS (m / z): [M+H] + = 245.18.

Embodiment 3

[0058] Synthesis of Example 3 Compound 3-b (R=methyl, X=Cl)

[0059]

[0060] In a 100ml three-necked round bottom flask, 3.9g (20.0mmol) of compound 3-a, 10.0g (122.8mmol) of pyridine were dissolved in 23ml of dichloromethane, and the 2 Under protection, lower the temperature to -70°C to -80°C. Then, 3.7 g (12.0 mmol) of bis(trichloromethyl)carbonate was dissolved in 28 ml of dichloromethane, and this solution was added dropwise to the above reaction liquid at -70°C to -80°C. After the dropwise addition, the reaction solution was continuously stirred for 30 min to 60 min, and then the temperature of the reaction solution was slowly raised to room temperature, and then continued to stir for 1 h to 2 h. After the reaction of raw material 3-a was detected by TLC, after-treatment was carried out. Saturated ammonium chloride aqueous solution was added dropwise to the above reaction solution to terminate the reaction until no bubbles were generated. Then the reaction solution...

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Abstract

The invention relates to a rosuvastatin calcium preparation intermediate, and a method for preparing rosuvastatin calcium from the intermediate. The intermediate compound 1-a being able to realize easy control of the purity of optical isomers in the rosuvastatin calcium preparation process undergoes cyclic carbonate protection group removal under an alkaline condition to prepare the rosuvastatin calcium, the purity is 99.5% or above, and almost no optical isomer are generated, so the impurity control difficulty is greatly reduced, and the high quality level of the product rosuvastatin calcium is guaranteed. The method selecting a short route and mild reaction conditions to prepare rosuvastatin calcium reduces the difficulty of a technologic device and operation, so industrialization is easy to realize.

Description

technical field [0001] The invention relates to a method for preparing a novel blood lipid-lowering drug rosuvastatin calcium, and at the same time relates to an intermediate compound used for preparing rosuvastatin calcium and a preparation method thereof. Background technique [0002] Rosuvastatin calcium (trade name Crestor, CAS: 147098-20-2), chemical name: bis-[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2 -[Methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-hydroxyhept-6-enoic acid] calcium salt (2:1), the structural formula is shown in formula 1 below : [0003] [0004] Rosuvastatin calcium is a new type of blood lipid-lowering drug developed by AstraZeneca. As the third-generation HMG-COA reductase inhibitor developed by the company, the drug has a strong HMG-CoA reductase inhibitory activity, which has the ability to reduce LDL-C (high-density lipoprotein cholesterol) and increase HDL-C ( High-density lipoprotein cholesterol) is better than other statins on th...

Claims

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Application Information

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IPC IPC(8): C07D319/06C07D405/06C07D239/42
CPCY02P20/55
Inventor 姜桥张兴孙培轩王旭辉
Owner PKU HEALTHCARE CORP LTD
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