Preparation method of rosuvastatin intermediate and intermediate compound

A technology of rosuvastatin and compounds, applied in the field of drug synthesis, can solve the problems of high toxicity, etc., and achieve the effect of avoiding pollution, reducing the difficulty of reaction, and fewer steps

Inactive Publication Date: 2014-09-24
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

WO2004054986A2 reported a method for preparing the core of rosuvastatin with guanidine hydrochloride. This method reduces many complex reaction steps and can obtain the target product relatively easily, but the reagents used are relatively toxic

Method used

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  • Preparation method of rosuvastatin intermediate and intermediate compound
  • Preparation method of rosuvastatin intermediate and intermediate compound
  • Preparation method of rosuvastatin intermediate and intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] (1): Preparation of isobutyrylacetonitrile

[0063]

[0064] 60% NaH (mass percentage concentration, 8.93g, 0.22mol) was added to THF (150mL), heated to 60°C, and a mixture of ethyl isobutyrate (21.6g, 0.186mol) and acetonitrile (9.14g, 0.22mol) was added dropwise , dripped within 1h, continued to react for 6h, GC showed that the reaction of raw materials was almost complete, stopped, evaporated to dryness under reduced pressure, the residue was dissolved in water (300mL), CH 2 Cl 2 Wash (50mL×2), adjust pH3 Wash with solution (50 mL), wash with water (50 mL), and evaporate to dryness under reduced pressure to obtain isobutyrylecetonitrile (19.17 g, yield 88.4%) as a red oil, with a GC purity of 95.2%.

[0065] 1 HNMR (500MHz, CDCl 3 ): 1.18-1.19 (d, 6H); 2.79-2.84 (m, 1H); 3.55 (s, 2H). Such as figure 1 shown.

[0066] (2): Preparation of 4-(4-fluorophenyl)-6-isopropyl-2-thio-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (compound 2)

[0067]

[0068] Mix is...

Embodiment 2

[0084] (1): Preparation of isobutyrylacetonitrile

[0085] Calcium hydride (15.62g, 0.37mol) plus THF (150mL), heated to 60 ° C, dropwise added ethyl isobutyrate (21.6g, 0.186mol) and acetonitrile (11.44g, 0.28mol) mixture, dropwise completed within 1h , continued to react for 6h, GC showed that the reaction of raw materials was almost complete, stopped, evaporated to dryness under reduced pressure, the residue was dissolved in water (300mL), CH 2 Cl 2 Wash (50mL×2), adjust pH3 Wash with solution (50 mL), wash with water (50 mL), and evaporate to dryness under reduced pressure to obtain isobutyrylecetonitrile (19.61 g, yield 89.3%) as a red oil, with a GC purity of 94.0%.

[0086] (2): Preparation of 4-(4-fluorophenyl)-6-isopropyl-2-thio-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (compound 2)

[0087]Mix isobutyrylacetonitrile (1.00g, 9.00mmol), p-fluorobenzaldehyde (1.23g, 9.90mmol), thiourea (1.37g, 18.00mmol), add EtOH (10mL), CuBr (0.01g, 0.09mmol) , Sodium bisulfate (...

Embodiment 3

[0096] (1): Preparation of isobutyrylacetonitrile

[0097] Add THF (150mL) to 27% sodium methoxide methanol solution (mass percentage, 55.80g, 0.28mol), heat to 60°C, add ethyl isobutyrate (21.6g, 0.186mol) and acetonitrile (11.44g, 0.28mol) dropwise ) mixture, dripped within 1h, continued to react for 6h, GC showed that the reaction of raw materials was almost complete, stopped, evaporated to dryness under reduced pressure, the residue was dissolved in water (300mL), CH 2 Cl 2 Wash (50mL×2), adjust pH3 Wash with solution (50 mL), wash with water (50 mL), and evaporate to dryness under reduced pressure to obtain isobutyrylecetonitrile (19.14 g, yield 86.6%) as a red oil, with a GC purity of 93.4%.

[0098] (2): Preparation of 4-(4-fluorophenyl)-6-isopropyl-2-thio-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (compound 2)

[0099] Mix isobutyrylacetonitrile (1.00g, 9.00mmol), p-fluorobenzaldehyde (1.45g, 11.70mmol), thiourea (1.03g, 13.50mmol), add EtOH (10mL), ferrous chloride...

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Abstract

The invention discloses a preparation method of a rosuvastatin intermediate: 4-(4-fluorobenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-formonitrile. The method comprises the following steps: carrying out a reaction on ethyl isobutyrate and acetonitrile to generate isobutyryl acetonitrile; and then carrying out cyclization, methylation, reduction, oxidization and substitution on isobutyryl acetonitrile and p-fluoro benzaldehyde as well as thiourea to prepare the intermediate. The 4-(4-fluorobenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-formonitrile prepared by the method is low in cost, simple to react, high in yield and easy to realize industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to an intermediate 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanol) of rosuvastatin The preparation method of sulfonylamino) pyrimidine-5-carbonitrile. Background technique [0002] Rosuvastatin, the chemical name is (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methylN-methylsulfonylamino )pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoic acid, its structure is shown in the following formula, it is found through research that rosuvastatin calcium, as a kind of HMG-CoA inhibitor, can be used For the treatment of cardiovascular diseases, it has the characteristics of strong potency, high safety, few side effects and good tolerance, and plays an important role in reducing the risk of cardiovascular diseases. [0003] [0004] The basic structure of rosuvastatin skeleton is 4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-sub...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42C07D239/22C07D239/38
CPCC07D239/22C07D239/38C07D239/42
Inventor 张玲玲戴立言王晓钟陈英奇
Owner ZHEJIANG UNIV
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