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Preparation method of statin compounds and intermediates thereof

A compound and statin technology, applied in the field of preparation of statin compounds and their intermediates, can solve the problems of complex synthesis routes, difficult quality control and purification of oily substances, and difficulty in obtaining product purity, etc.

Inactive Publication Date: 2020-08-11
SHANDONG POLYTECHNIC COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The above line adopts the method of oxidizing the synthesized side chain from olefin to aldehyde, the yield is not high, and the use of an oxidation system tends to result in low product purity
[0014] 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 statin compounds and intermediates thereof
  • Preparation method of statin compounds and intermediates thereof
  • Preparation method of statin compounds and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Preparation of compound 2

[0086] 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.

[0087] 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.

[0088] LC-Ms: [M+H] = 365.20.

[0089] Preparation of compound 3

[0090] 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.

[0091] After adding 60 mL of dichloromethane for extraction and separation, the hydrogen peroxide was quenched with saturated sodium bisulfite, the li...

Embodiment 2

[0107] Preparation of Compound 2

[0108] 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.

[0109] 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.

[0110] Preparation of compound 3

[0111] 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.

[0112] After adding 150 mL 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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Abstract

The invention provides a preparation method of statin compounds and intermediates thereof. A novel compound with an Evans prosthetic group structure is introduced into a synthesis route as a key intermediate; JULIA is adopted for alkene formation, so the selectivity of E / Z is improved; conditions for removing the prosthetic group are mild, isomerization can be avoided, and impurities can be eliminated; synthesis route is simple; key intermediates (a compound as shown in a formula 5 and a compound as shown in a formula 6) are solids, so product purification and scientific material feeding reaction are facilitated, and thus, high-purity products are obtained.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of statin compounds and intermediates 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)amino]-pyrimidi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42C07D403/12C07D405/14C07D403/06
CPCC07D239/42C07D403/06C07D403/12C07D405/14
Inventor 杨桂芝陈雨傅丽陈丽姣
Owner SHANDONG POLYTECHNIC COLLEGE
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