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A kind of statin drug intermediate and its preparation method and application

A technology for intermediates and drugs, applied in the field of organic chemical synthesis, can solve problems such as low reaction yield, and achieve the effect of cheap and easy-to-obtain raw materials

Active Publication Date: 2017-06-20
ABIOCHEM BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method also has the problem of low reaction yield, and it is difficult to form R due to steric hindrance and other reasons. 1 Esters with more than 3 carbon atoms in the position

Method used

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  • A kind of statin drug intermediate and its preparation method and application
  • A kind of statin drug intermediate and its preparation method and application
  • A kind of statin drug intermediate and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]

[0038] Dissolve 1,4-cyclohexanedione (10.0g) in 100mL of toluene, add trimethyl orthoformate (19.8g) and p-toluenesulfonic acid (0.46g) under stirring at room temperature, stir for 1 hour, add 6-chloro Methyl-4-hydroxy-tetrahydropyran-2-one (30.0 g), continued stirring for 1 hour. The reaction solution was poured into aqueous sodium bicarbonate solution, extracted twice with toluene, the combined organic phases were washed once with saturated brine, dried over sodium sulfate, concentrated to dry column chromatography to obtain 33.5 g of the target product with a molar yield of 80%.

[0039] The structure of the product was confirmed by H NMR spectroscopy and electrospray ionization mass spectrometry.

[0040] 1 H NMR (300MHz, CDCl 3 ): δ4.53-4.62(1H,m),4.31-4.40(1H,m),3.95-4.15(2H,m),3.68(3H,s),3.66(3H,s),3,44-3.56 (4H, m), 2.35-2.65 (4H, m), 1.22-2.08 (12H, m).

[0041] MS (ESI) m / z: (M+H) = 469.1.

Embodiment 2

[0043]

[0044] Dissolve 1,4-cyclohexanedione (12.0g) in 120mL of dichloromethane, add trimethyl orthoformate (23.8g) and p-toluenesulfonic acid (0.46g) under stirring at room temperature, stir for 1 hour, add 6 - Azidomethyl-4-hydroxy-tetrahydropyran-2-one (40.2 g), continue stirring for 1 hour. The reaction solution was poured into aqueous sodium bicarbonate solution, extracted twice with toluene, the combined organic phases were washed once with saturated brine, dried over sodium sulfate, concentrated to dry column chromatography to obtain 40.2 g of the target product with a molar yield of 78%.

[0045] The structure of the product was confirmed by H NMR spectroscopy and electrospray ionization mass spectrometry.

[0046] 1 H NMR (300MHz, CDCl 3 ):δ4.48-4.57(1H,m),4.30-4.43(1H,m),3.91-4.12(2H,m),3.64(3H,s),3.61(3H,s),2.32-2.64(4H ,m), 1.19-2.04(16H,m).

[0047] MS (ESI) m / z: (M+H) = 483.2.

Embodiment 3

[0049]

[0050] Dissolve 1,4-cyclohexanedione (15.0g) in 150mL tetrahydrofuran, add triethyl orthoformate (42.3g) and p-toluenesulfonic acid (0.67g) under stirring at room temperature, stir for 1 hour, add 6-cyano methyl-4-hydroxy-tetrahydropyran-2-one (44.3 g), and the stirring reaction was continued for 1 hour. The reaction solution was poured into aqueous sodium bicarbonate solution, extracted twice with toluene, the combined organic phases were washed once with saturated brine, dried over sodium sulfate, concentrated to dry column chromatography to obtain 50.9 g of the target product with a molar yield of 82%.

[0051] The structure of the product was confirmed by H NMR spectroscopy and electrospray ionization mass spectrometry.

[0052] 1 H NMR (300MHz, CDCl 3 ):δ; 4.56-4.68(1H,m),4.31-4.40(1H,m),4.13(2H,q),3.44-3.56(4H,m),2.35-2.65(8H,m),1.21-2.06 (18H,m).

[0053] MS (ESI) m / z: (M+H) = 479.2.

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PUM

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Abstract

The invention discloses a compound which can be used as a statin medicine intermediate and has a structure shown in a general formula I, and a preparation method and application of the compound. According to the compound disclosed by the invention, by introducing cyclohexanedione, a bimolecular intermediate can be produced by virtue of one-step reaction, the purpose that the statin medicine intermediate with high yield and environment-friendly performance is prepared by using cheap and easily-available raw materials can be achieved, and the compound is more suitable for the implementation of industrial production.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and in particular relates to a statin drug intermediate and its preparation method and application, in particular to a compound represented by general formula I and its preparation method and application. Background technique [0002] Statins are hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that block intracellular hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase by competitively inhibiting endogenous cholesterol synthesis rate-limiting enzyme (HMG-CoA) reductase The acid metabolism pathway reduces intracellular cholesterol synthesis, thereby feedback stimulating the number and activity of low-density lipoprotein receptors on the surface of cell membranes (mainly liver cells), increasing serum cholesterol clearance and reducing levels. Statins can also inhibit the synthesis of apolipoprotein B-100 in the liver, thereby reducing the synthesis and secretion of trigly...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/10C07D239/42
CPCC07D239/42C07D493/10
Inventor 罗煜丁时澄瞿旭东孙传明
Owner ABIOCHEM BIOTECH CO LTD