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Preparation method of HMG-CoA reductase inhibitor and intermediate thereof

A reductase inhibitor and solvent technology, applied in the field of preparation of HMG-CoA reductase inhibitors and their intermediates, can solve the problems of low product purity, E/Z selectivity to be improved, and difficulty in obtaining product purity, etc.

Active Publication Date: 2020-07-28
SHANDONG POLYTECHNIC COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] For example: both EP0521471A1 and WO0049014A1 have reported their synthetic methods, but the multi-step synthetic intermediates in the disclosed synthetic routes are oily substances, and most of the synthetic processes adopt WITIG reaction, which has poor control over Z / E selectivity
[0007] The side chains synthesized by the synthesis method disclosed in CN201910190264 are oxidized from olefins to aldehydes, the yield is not high, and the use of an oxidation system tends to result in low product purity
[0008] In general, the technical problems of the current synthetic route are: the synthetic route is complex, the intermediate is oily, it is difficult to control and purify the quality, and the E / Z selectivity needs to be improved, so it is difficult to obtain higher product purity

Method used

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  • Preparation method of HMG-CoA reductase inhibitor and intermediate thereof
  • Preparation method of HMG-CoA reductase inhibitor and intermediate thereof
  • Preparation method of HMG-CoA reductase inhibitor and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Preparation of Compound 2

[0080] At room temperature, PMTA (3.2g, 18.0mmol) was dissolved in DMF (20mL), and Na 2 CO 3 (2.2g, 21.6mmol) and compound 1 (4g, 18mmol), heated to 90°C, reacted for 24h, detected by LC-Ms.

[0081] After adding 10 mL of water, adjust the pH=5-6 with 10% HCl, extract with dichloromethane (40 mL×2), combine the organic phases with water (10 mL×2), dry, and concentrate in vacuo at 40° C. to obtain an oil, which is washed with in the next step.

[0082] LC-Ms: [M+H] = 365.20.

[0083] Preparation of compound 3

[0084] At room temperature, add iPrOH (20mL) to the oil in the previous step, then add ammonium heptamolybdate (1.1g) and H 2 o 2 (20 mL), after the addition was completed, the stirring reaction was continued at 25° C. for 18 h, and the reaction was complete as detected by Lc-Ms.

[0085] After adding 60 mL of dichloromethane for extraction and separation, the hydrogen peroxide was quenched with saturated sodium bisulfite, the l...

Embodiment 2

[0101] Preparation of Compound 2

[0102] At room temperature, PMTA (12.0g, 67.5mmol) was dissolved in DMF (50mL), and Na 2 CO 3 (7.1g, 67.5mmol) and compound 1 (10g, 45.0mmol), heated to 90°C, and reacted for 24h to complete the reaction.

[0103] After adding 25 mL of water, adjust the pH=5-6 with 10% HCl, extract with dichloromethane (100 mL×2), combine the organic phases with water (25 mL×2), dry, and concentrate in vacuo at 40° C. to obtain an oil, which is washed with in the next step.

[0104] Preparation of compound 3

[0105] At room temperature, add iPrOH (50mL) to the oil in the previous step, then add ammonium heptamolybdate (2.7g) and H 2 o 2 (50mL), after the addition was completed, the reaction was continued to stir at 25°C for 18h and the reaction was complete.

[0106] After adding 150mL of dichloromethane for extraction and separation, the hydrogen peroxide was quenched with saturated sodium bisulfite, the liquid was separated, and the organic phase wa...

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PUM

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Abstract

The invention provides a preparation method of an HMG-CoA reductase inhibitor and an intermediate of the HMG-CoA reductase inhibitor. A new compound with an Evans auxiliary group structure as a key intermediate is introduced into a synthesis route, JULIA is adopted for alkene formation, so that the selectivity of E / Z is improved, the conditions for removing auxiliary groups are mild, isomerizationcan be avoided, impurities can be eliminated, the synthesis route is simple, key intermediates (a compound shown in a formula 5 and a compound shown in a formula 6) are solids, product purification and scientific material feeding reaction are facilitated, and a high-purity product is obtained.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of an HMG-CoA reductase inhibitor and an intermediate thereof. Background technique [0002] Rosuvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), which can be used for the treatment of hypercholesterolemia and mixed dyslipidemia. High LDL cholesterol, total cholesterol, triglycerides, and apoprotein B concentrations, with elevated HDL cholesterol; can be used in primary hypercholesterolemia and mixed lipodystrophy and homozygous familial forms The comprehensive treatment of hypercholesterolemia is called super statin. [0003] In treatment, rosuvastatin is administered as its calcium salt, and it is a single enantiomer, which has been marketed in the United States, Japan, Europe, China and other countries and regions, and its chemical name is bis-[E-7 -[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42C07D403/06C07D405/14C07D403/12
CPCC07D239/42C07D403/06C07D403/12C07D405/14
Inventor 陈雨
Owner SHANDONG POLYTECHNIC COLLEGE
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