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Rosuvastatin calcium intermediate compound

A technology for rosuvastatin calcium and a compound, applied in the field of pharmaceutical synthesis, can solve the problems of low yield, high impurity content of rosuvastatin calcium Z-isomer, low reaction selectivity, etc. Good water solubility and high HPLC purity

Active Publication Date: 2020-09-29
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the selectivity of the wittig reaction between the mother nucleus and the side chain is not high, and a large number of Z-configuration by-products are produced, resulting in a low yield, and the Z-configuration by-products continue to participate in subsequent reactions, resulting in Z-type isomerization of rosuvastatin calcium. High body impurity content

Method used

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  • Rosuvastatin calcium intermediate compound
  • Rosuvastatin calcium intermediate compound
  • Rosuvastatin calcium intermediate compound

Examples

Experimental program
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Effect test

Embodiment 1

[0078] The preparation of embodiment 1 compound I

[0079] (1) Add 507.6g of compound III (X=OTs), 196.0g of 5-thiol-1-phenyltetrazolium, 155.1g of diisopropylethylamine and 2.5L of toluene into a three-necked flask, and control the temperature to 0 ~5°C, stir for 3~5 hours, TLC detection, after the reaction is complete, add 2.0L deionized water, stir, wash, and separate liquids. The organic phase was washed with 500 ml of saturated brine, separated, anhydrous sodium sulfate was added to the organic phase to dry, and the solution of compound II was obtained by filtration.

[0080] (2) Add 122.3 g of urea hydrogen peroxide complex to the solution of compound II, control the temperature at -5-5° C., stir for reaction, and detect by TLC. After the reaction is complete, add 2.0 L of deionized water, wash and separate. Anhydrous sodium sulfate was added to the organic phase, dried, filtered, and concentrated under reduced pressure to obtain 536.3 g of crude compound I.

[0081] (...

Embodiment 2

[0084] The preparation of embodiment 2 compound I

[0085] (1) Add 431.5g of compound III (X=OMs), 267.3g of 5-thiol-1-phenyltetrazolium, 192.3g of triethylamine and 3.4L of dichloromethane into a three-necked flask, and control the temperature at -5 ~0°C, stirred for 3~5h, detected by TLC, after the reaction was complete, added 2.5L deionized water, stirred, washed, and separated. The organic phase was washed with 500 ml of saturated brine, separated, anhydrous sodium sulfate was added to the organic phase to dry, and the solution of compound II was obtained by filtration.

[0086] (2) Add 91.3 g of peroxyacetic acid to the solution of compound II, control the temperature at -15 to -10° C., stir for reaction, and detect by TLC. After the reaction is complete, add 2.0 L of deionized water to wash and separate the liquid. Anhydrous sodium sulfate was added to the organic phase, dried, filtered, and concentrated under reduced pressure to obtain 532.7 g of crude compound I.

[...

Embodiment 3

[0090] The preparation of embodiment 3 compound I

[0091] (1) Add 371.9g of compound III (X=Cl), 187.1g of 5-thiol-1-phenyltetrazolium, 87.0g of pyridine and 3.4L of chloroform into a three-necked flask, control the temperature at 5-10°C, and stir React for 3 to 5 hours, TLC detection, after the reaction is complete, add 2.5L of deionized water, stir and wash, and separate liquids. The organic phase was washed with 500 ml of saturated brine, separated, anhydrous sodium sulfate was added to the organic phase to dry, and the solution of compound II was obtained by filtration.

[0092] (2) Add 64.6 g of hydrogen peroxide to the solution of compound II, control the temperature at -10 to -5° C., stir the reaction, and detect it by TLC. After the reaction is complete, add 2.0 L of deionized water to wash and separate the liquid. Anhydrous sodium sulfate was added to the organic phase, dried, filtered, and concentrated under reduced pressure to obtain 530.3 g of crude compound I. ...

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Abstract

The invention belongs to the field of organic chemistry, and discloses a rosuvastatin calcium intermediate compound, a synthesis method thereof and application thereof in preparation of rosuvastatin calcium. The preparation method of the rosuvastatin calcium intermediate compound comprises the following specific steps: (1) reacting a compound III with 5-mercapto-1-phenyltetrazole under the actionof an organic alkali to obtain a compound II; (2) reacting the compound II with an oxidant to obtain a compound I crude product. The prepared rosuvastatin calcium intermediate compound I is novel in structure, short in synthesis route, mild in reaction conditions, high in yield and convenient in after-treatment. The compound I reacts with a rosuvastatin side chain, the reaction conditions are mild, the yield and purity of the product are high, and the method has a good industrial prospect.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and relates to a rosuvastatin calcium intermediate compound, a synthesis method thereof and an application thereof in preparing rosuvastatin calcium. Background technique [0002] Rosuvastatin calcium is a selective HMG-CoA reductase inhibitor, which was first developed by Shionogi Pharmaceutical Co., Ltd. in Japan and later transferred to AstraZeneca. Rosuvastatin calcium has a remarkable lipid-lowering effect and is known as a "super statin". [0003] Rosuvastatin calcium chemical name: bis-[E-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5 -yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt (2:1), CAS: 147098-20-2. The structural formula is as follows: [0004] [0005] There are two main synthetic routes of rosuvastatin calcium: In 1992, US Patent No. 5,260,440 disclosed rosuvastatin calcium and its preparation method. This patent is the earli...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D239/42
CPCC07D403/12C07D239/42C07B2200/09Y02P20/55
Inventor 张贵民黄文波王学应
Owner LUNAN PHARMA GROUP CORPORATION
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