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Synthesis method of high-grade intermediate R-1 of rosuvastatin calcium

A technology for rosuvastatin calcium and a synthesis method, which is applied in the field of fine chemical synthesis, can solve the problems of Z-configuration compound residues, drug efficacy effects, etc., and achieves the effects of simple reaction route, reduced cost, and reduced drug burden on residents

Active Publication Date: 2020-12-04
NENTER & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] The above three routes are relatively better than AstraZeneca’s. The Wittig condensation reaction does not require cryogenic conditions. However, due to the ratio of cis and trans isomers in the Wittig reaction, even after recrystallization and other operations, in the E-configuration compound There are still Z-configured compounds remaining, so the inevitable follow-up reaction forms cis-rosuvastatin calcium impurities, and this impurity has an impact on the efficacy of the drug, etc.

Method used

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  • Synthesis method of high-grade intermediate R-1 of rosuvastatin calcium
  • Synthesis method of high-grade intermediate R-1 of rosuvastatin calcium
  • Synthesis method of high-grade intermediate R-1 of rosuvastatin calcium

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Effect test

Embodiment 1

[0048]

[0049] Add 70 grams of NMP, 35 grams of compound 1 and 23.8 grams of 2-mercapto-5-methyl-1,3,4-thiadiazole into a 500ml three-necked reaction flask, then add 3.5 grams of benzyltriethylammonium chloride and 21.2 grams of sodium carbonate, three times of nitrogen vacuum displacement, then the temperature was raised in an oil bath under nitrogen protection, the temperature was controlled at 115±5°C, and the reaction was completed in about 20 hours (HPLC analysis + spot plate analysis). After taking a sample to confirm that the reaction is complete, the reaction solution is cooled to room temperature. After cooling, 140 grams of water and 140 grams of ethyl acetate are added to the reaction solution to extract the product. After layering, 140 grams of ethyl acetate is added to the water phase to re-extract the water phase. Once, combine the organic phases and add 140 grams of water to wash once, concentrate at normal pressure to recover ethyl acetate, after the concent...

Embodiment 2

[0051] Add 700gDMSO, 350g compound 1 and 238g 2-mercapto-5-methyl-1,3,4-thiadiazole to a 5000ml three-neck reaction flask, then add 35g tetrabutylammonium bromide and 212g sodium carbonate , Nitrogen vacuum replacement three times, the temperature was raised in an oil bath under nitrogen protection, the temperature was controlled at 115±5°C, and the reaction was completed in about 20 hours (HPLC analysis + spot plate analysis). After taking a sample to confirm that the reaction is complete, the reaction solution is cooled to room temperature. After cooling, 1400 grams of water and 1400 grams of ethyl acetate are added to the reaction solution to extract the product. After layering, 1400 grams of ethyl acetate is added to the water phase to re-extract the water phase. Once, combine the organic phases and add 1400 grams of water to wash once, concentrate and recover ethyl acetate under normal pressure, weigh a total of 587 grams after the concentration is completed, the content i...

Embodiment 3

[0053]

[0054] Add 300 grams of acetonitrile to the concentrated solution of 61.2 grams of compound 2 to dissolve, transfer the solution to a 1000 ml three-necked flask after dissolving, add 10 grams of phosphomolybdic acid, and add 300 grams of 30% hydrogen peroxide dropwise to the reaction flask. During the process, the temperature is controlled at 30-40°C. After the drop is completed, it is stirred at room temperature until the reaction is complete (the raw materials + intermediates are all converted into products), and the HPLC analysis is completed in about 20 hours. After the reaction is completed, add 300 grams of 10% sodium bisulfite aqueous solution dropwise to the reaction liquid to quench the hydrogen peroxide. After the dropwise addition, stir and detect that there is no hydrogen peroxide, start to recover acetonitrile under normal pressure, concentrate until the internal temperature reaches 100°C, stop heating, and cool down to room temperature. Finally, add 60...

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Abstract

The invention relates to a synthesis method of a high-grade intermediate R-1 of rosuvastatin calcium. The synthesis method comprises the following steps: condensing a compound 1 serving as an initialraw material with 2-mercapto-5-methyl-1,3,4-thiadiazole to generate a compound 2, oxidizing the compound 2 with hydrogen peroxide to obtain a compound 3, and carrying out Julia-Kocienski Olefination condensation reaction on the compound 3 and a compound 4 to obtain the R-1, wherein the compound 1 is (4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester, and the compound4 is pyrimidine aldehyde. The synthesis method has the advantages of simple reaction route, mild reaction conditions, cheap raw materials, high reaction selectivity and almost no generation of cis-isomers; the method avoids the use of a phosphine salt in the route, so the generation of a large-polarity byproduct triphenylphosphine oxide in the product is avoided; the cost for synthesizing a rosuvastatin calcium bulk drug is greatly reduced; and no cis-rosuvastatin calcium impurity is formed in a subsequent reaction, so the influence of the impurity on the medicine effect of rosuvastatin calcium is avoided, and the method has great significance for reducing the medication burden of residents.

Description

technical field [0001] The present invention relates to the synthetic method of advanced intermediate R-1 of rosuvastatin calcium, and the chemical name of R-1 is 6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropyl Base-2-[methyl(methylsulfonyl)amino]-5-pyrimidine]vinyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, this method belongs to Fine chemical synthesis technology field. Background technique [0002] Rosuvastatin Calcium. [0003] Chemical name: (+)-(3R, 5S)-bis{7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonamido)pyrimidine -5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid} hemicalcium salt [0004] Product name: Crestor [0005] Developer: Shionogi Pharmaceutical Co., Ltd. of Japan developed and screened the product in the late 1980s. Afterwards, AstraZeneca of the United Kingdom re-developed it all over the world except Japan and other East Asian countries. Listing time: February 2003, listed in China in 2006. [0006] Listed countries and regions: mo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/08
CPCC07D405/08Y02P20/55
Inventor 乔建成左昌涛王文鹏
Owner NENTER & CO
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