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A kind of synthetic method of rosuvastatin calcium key chiral intermediate

A technology for rosuvastatin calcium and chiral intermediates, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of inability to realize the synthesis route, difficult removal of enantiomeric impurities, inability to guarantee the optical purity of diols, and the like. The effect of improving ee value, high ee value and saving production cost

Inactive Publication Date: 2018-08-21
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Starting from (E)-phenyl-3,5-dicarbonyl-6-heptenoic acid methyl ester, although the synthetic route is very short, the optical purity of the chiral reduced diol cannot be guaranteed at all, and its Enantiomeric impurities are almost difficult to remove, and in the industrialization process, this synthetic route cannot be realized at all

Method used

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  • A kind of synthetic method of rosuvastatin calcium key chiral intermediate
  • A kind of synthetic method of rosuvastatin calcium key chiral intermediate
  • A kind of synthetic method of rosuvastatin calcium key chiral intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038]

[0039] In a 2000mL reaction flask with mechanical stirring and a thermometer, add 50g (0.735mol) of furan and 1000mL of methanol, place it at -50°C, replace the air and protect it under nitrogen, slowly add 240g (1.5mol) of bromine dropwise, After the dropwise addition, react for 3 hours, raise the temperature to 0°C and continue the reaction for 2 hours. After the reaction is completed, rise to room temperature, adjust the pH of the reaction solution to 7-8 with 1000mL saturated sodium bicarbonate solution, distill off the remaining methanol under reduced pressure, and then use ethyl acetate The reaction solution was extracted three times with 1000 mL, the combined organic phase was washed with saturated sodium chloride solution, the organic phase was separated, and the ethyl acetate was distilled off to obtain 76 g of compound 1,1,4,4-tetramethoxy-2-butene.

Embodiment 2

[0041]

[0042] Add 70g of compound 1,1,4,4-tetramethoxy-2-butene and 500mL of dimethyl sulfide into a 1000mL reaction bottle with mechanical stirring and a thermometer, place it at -10°C, and replace it in the bottle Nitrogen was introduced after the air, and 30g of ozone was slowly injected into the closed reaction system, and the reaction temperature was controlled to maintain at -10°C. After 10 hours of reaction, the raw materials were completely reacted, raised to room temperature, and the solvent was distilled off to obtain the compound 1,1-dimethoxy Acetaldehyde 29g.

Embodiment 3

[0044]

[0045] In a 1000mL reaction flask with mechanical stirring and a thermometer, add 30g (0.3mol) of 1,1-dimethoxyacetaldehyde, 19g (0.3mol) of nitromethane and 3g (0.03mol) of anhydrous aluminum oxide into DMF In 500mL, under nitrogen protection, heat to 130°C. After the reaction, cool down to room temperature, and filter the reaction solution with suction. After the filtrate is concentrated, add 500mL of saturated sodium chloride solution, then extract the reaction solution twice with 600mL of dichloromethane, and combine The organic phase was distilled off to obtain 39 g of 1,1-dimethoxy-2-hydroxy-3-nitropropane.

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Abstract

The invention discloses a synthesis method of a rosuvastatin calcium key chiral intermediate and belongs to the technical field of synthesis of medical intermediates. According to the technical scheme, the method is characterized as the specification. With the adoption of the process route, use of an expensive medicine, namely, ethyl (R)-4-bromo-3-hydroxybutyrate, is avoided, the ee (enantiomeric excess) value of a product is effectively increased due to use of a chiral catalyst, raw materials of the synthesis method are simple and easy to obtain, the route is simple to operate, the repeatability is good, the yield is very high, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of a key chiral intermediate of rosuvastatin calcium. Background technique [0002] Rosuvastatin (ROSUVASTATIN), its chemical name is (+)-(3R,5S)-bis{7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl -N-methylsulfonamido)pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid} hemicalcium salt, trade name CRESTOR. The drug was first successfully developed by Shionogi Company in Japan, and later Shionogi transferred the drug technology to ZENECA Company in the UK, and was approved by the US FDA for marketing in August 2003. It is currently on the market in more than 60 countries. Clinical trials have been completed. Preclinical experiments and multiple clinical trials conducted around the world have shown that rosuvastatin has a stronger lipid-lowering effect and similar safety than existing statins. Like other statins, ro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D319/06
CPCC07B2200/07C07D319/06
Inventor 毛龙飞崔安琪张淑婷姜玉钦李伟徐桂清蒋涛侯茜茜董文佩
Owner HENAN NORMAL UNIV