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Synthesis process method of rosuvastatin

A technology for rosuvastatin and synthesis process, applied in the direction of organic chemistry, etc., can solve the problems of unfriendly process conditions, unsatisfactory E/Z selectivity and yield, and unsuitable for scale-up production.

Pending Publication Date: 2022-01-28
绍兴市上虞区武汉理工大学高等研究院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis process of rosuvastatin calcium reported in the literature basically adopts the Wittig reaction on the link between the core and the side chain, and the E / Z selectivity and yield are not ideal, and the process conditions are not friendly and are not suitable for for scale-up

Method used

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  • Synthesis process method of rosuvastatin
  • Synthesis process method of rosuvastatin

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Experimental program
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Effect test

Embodiment 1

[0009] Embodiment 1: the synthesis of intermediate 2

[0010]

[0011] Under nitrogen protection, add 92 g of zinc powder into 800 mL of tetrahydrofuran, stir for 20 min, then add 69 g of a, slowly add 112.4 g of b at room temperature, raise the temperature to reflux for 3 h, slowly add 2 mol / L hydrochloric acid dropwise, and adjust the pH to 5-6, add 400 mL ethyl acetate and 400 mL water, separate the organic phase, extract the aqueous layer three times with 200 mL ethyl acetate, combine the organic phases, wash the organic phase with 200 mL saturated brine, and dry over anhydrous sodium sulfate , and then the solvent was removed by distillation under reduced pressure to obtain 101.2 g of oil c.

[0012] Dissolve 93.8 g of compound c in 1.3 L of dry tetrahydrofuran and 400 mL of ethanol, cool to -65°C under nitrogen protection, add 595 mL of sodium borohydride solution in tetrahydrofuran (1 mol / L), stir for 20 min, and then add boron Sodium hydride 22.6 g, react at this t...

Embodiment 2

[0015] Embodiment 2: the synthesis of intermediate 3

[0016] Add 6.78 g 1 (0.01mol), 3.02 g 2 (0.01mol), 30 mL dimethyl sulfoxide to the reaction flask, dissolve and stir, heat up to 70-80︒C, add 3.52 g sodium carbonate, stir overnight, TLC Monitor the response. After the reaction is completed, stop heating and cool to room temperature, slowly add 80 mL of water and 100 mL of toluene, stir and separate the phases, add toluene to the water phase for extraction (50 ml×2), combine the organic phases, add 60 mL of saturated saline to wash, 45︒C The solvent was removed under reduced pressure to obtain 5.2 g of a light yellow crude product, which was recrystallized from anhydrous methanol to obtain 5 g of product 3 as a white solid. The yield is 85%. The melting point is 145°C. m.p145°C. ESI-MS m / z: 590.3 [M+H] + . 1 HNMR (300MHz, DMSO- d 6 ), δ: 1.23~1.21 (d, J =6.66Hz, 6H), 1.58~1.79(m, 8H), 1.81~2.29(m, 2H), 2.42~2.51(d, J =13.44, 4.74 Hz, 2H), 3.28~3.39 (m, 1H), 2.95 ...

Embodiment 3

[0017] Embodiment 3: the synthesis of intermediate 4

[0018] Add 2.886 g (5 mmol) of intermediate 3 and 25 mL of acetonitrile into the reaction flask, dissolve and stir, then add 8 mL of 1 mol / L hydrochloric acid solution dropwise at 30-35 °C, keep warm and monitor the reaction by TLC. After the reaction, cool to room temperature, add 8 mL of 1 mol / L hydrochloric acid solution dropwise, and keep the reaction at 30-35°C; TLC monitors the reaction. After the reaction is complete, cool down to room temperature, add 3 mL of 1mol / L sodium hydroxide dropwise to maintain the pH at 9~10, then distill off acetonitrile at 45°C under reduced pressure, add 30 mL of water, and extract with ethyl acetate (10 mL×2) , combined the organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to dryness under reduced pressure to obtain 2.68 g of crude white solid. The crude product was purified with 20 mL of isopr...

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Abstract

The invention discloses a synthesis process of rosuvastatin and a preparation method of an intermediate of rosuvastatin. The preparation method comprises the steps of by taking [4-[4-fluorophenyl-6-(1-methyl ethyl)-2-[N-methyl-(N-methylsulfonyl) amino]]-5-pyrimidinyl] methyl triphenylphosphine bromide as a starting material, performing wittig condensation, deprotection, hydrolysis and calcium salt formation to obtain a final product. The structures of a key intermediate and a target compound are confirmed by 1H-NMR, 13C-NMR and MS spectrums, the total yield is 32.2%, and the HPLC purity is 99.9%. The process route is simple, the operation is simple and convenient, each intermediate is easy to separate and purify, and the yield is relatively high.

Description

technical field [0001] The present invention relates to organic chemistry and medicinal chemistry, in particular to a synthetic process of rosuvastatin. 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. It is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor developed by AstraZeneca. It is mainly used clinically for the treatment of adult hyperlipidemia and mixed dyslipidemia. The drug was approved for marketing in the European Union for the first time in March 2003. It has strong HMG-CoA reductase inhibitory activity, and its effect of lowering LDL-C and raising HDL-C is superior to other statins on the market. Good tolerance and safety, known as "super statin". Because this product has the advantages of high efficiency, low toxicity, and less adverse react...

Claims

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Application Information

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IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 秦华利冯康范晓庆
Owner 绍兴市上虞区武汉理工大学高等研究院
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