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Preparation method of 2-[(4R, 6S)-6-substitued methyl-2, 2-dimethyl-1, 3-dioxan]-acetate

A dioxane, dimethyl technology, applied in the direction of organic chemistry, etc., can solve the problems of complicated operation, difficult to obtain aldolase, harsh reaction conditions and so on.

Active Publication Date: 2013-11-13
江西博雅欣和制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield of this route is higher, but it is difficult to obtain aldol condensing enzyme
The above synthetic route has harsh reaction conditions, high requirements for equipment and labor protection, and complicated operation

Method used

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  • Preparation method of 2-[(4R, 6S)-6-substitued methyl-2, 2-dimethyl-1, 3-dioxan]-acetate
  • Preparation method of 2-[(4R, 6S)-6-substitued methyl-2, 2-dimethyl-1, 3-dioxan]-acetate
  • Preparation method of 2-[(4R, 6S)-6-substitued methyl-2, 2-dimethyl-1, 3-dioxan]-acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Step 1: (2 S ,4 R )-1-chloro-4-epoxy-2-pentanol ( )

[0036] ( S )-1-chloro-4-ene-2-pentanol ( ) 24 g (0.2 mol, 1.0 eq) and vanadyl acetylacetonate 1.06 g (4 mmol, 0.02 eq) were dissolved in 2 L of dichloromethane, 0 o C was added dropwise 28 mL (0.3 mol, 1.5 eq) of tert-butanol peroxide, reacted at room temperature for 36 hours, concentrated under reduced pressure, and purified by column chromatography to obtain a colorless oil (2 S ,4 R )-1-chloro-4-epoxy-2-pentanol ( ) (19.6 g, 0.14 mol), yield 72%. 11 H-NMR (400 MHz, CDCl 3 ) δ 1.60 (ddd, J = 6.8, 14.0, 21.6 Hz, 1H), 1.85 (m, 1H), 2.46 (dd, J = 2.8, 4.4 Hz, 1H), 2.71 (t, J = 4.4 Hz, 1H), 3.02 (m, 1H), 3.34 (br s, 1H), 3.40-3.57 (m, 2H), 3.93-3.95 (m, 1H); MS (EI): m / z = 136 (M).

[0037] Step 2: (3 S ,5 S )-6-chloro-3,5-dihydroxycapronitrile ( )

[0038] (2 S ,4 R )-1-chloro-4-epoxy-2-pentanol ( ) 19.6 g (0.14 mol, 1.0 eq) dissolved in 100 mL methanol and 20 mL water, 0 o C Add an aqueou...

Embodiment 2

[0044] Step 1: (2 S ,4 R )-1-chloro-4-epoxy-2-pentanol ( )

[0045] ( S )-1-chloro-4-ene-2-pentanol ( ) 24 g (0.2 mol, 1.0 eq) and vanadyl acetylacetonate 1.06 g (20 mmol, 0.1 eq) were dissolved in 2 L of ethyl acetate, 0 o C was added dropwise 28 mL (0.24 mol, 1.2 eq) of tert-butanol peroxide, reacted at room temperature for 36 hours, concentrated under reduced pressure, and purified by column chromatography to obtain a colorless oil (2 S ,4 R )-1-chloro-4-epoxy-2-pentanol ( ) (19.0 g, 0.14 mol), yield 70%. 11 H-NMR (400 MHz, CDCl 3 ) δ 1.60 (ddd, J = 6.8, 14.0, 21.6 Hz, 1H), 1.85 (m, 1H), 2.46 (dd, J = 2.8, 4.4 Hz, 1H), 2.71 (t, J = 4.4 Hz, 1H), 3.02 (m, 1H), 3.34 (br s, 1H), 3.40-3.57 (m, 2H), 3.93-3.95 (m, 1H); MS (EI): m / z = 136 (M).

[0046] Step 2: (3 S ,5 S )-6-chloro-3,5-dihydroxycapronitrile ( )

[0047] (2 S ,4 R )-1-chloro-4-epoxy-2-pentanol ( ) 19.6 g (0.14 mol, 1.0 eq) dissolved in 100 mL ethanol and 20 mL water, 0 o C Add an aqueous ...

Embodiment 3

[0053] Step 1: (2 S ,4 R )-1-bromo-4-epoxy-2-pentanol ( )

[0054] ( S )-1-bromo-4-ene-2-pentanol ( ) 32.8 g (0.2 mol, 1.0 eq) and vanadyl acetylacetonate 1.06 g (4 mmol, 0.02 eq) were dissolved in 2 L of acetonitrile, 0 o C was added dropwise 10 mL (0.3 mol, 1.5 eq) of hydrogen peroxide, reacted at room temperature for 12 hours, concentrated under reduced pressure, and purified by column chromatography to obtain a colorless oil (2 S ,4 R )-1-bromo-4-epoxy-2-pentanol ( ) (25.2 g, 0.14 mol), yield 70%. MS (EI): m / z = 180 (M).

[0055] Step 2: (3 S ,5 S )-6-chloro-3,5-dihydroxycapronitrile ( )

[0056] (2 S ,4 R )-1-bromo-4-epoxy-2-pentanol ( ) 25.2 g (0.14 mol, 1.0 eq) dissolved in 100 mL of acetonitrile and 20 mL of water, 0 o C Add 10 g (0.21 mol, 1.5 eq) of sodium cyanide solution dropwise, maintain the pH of the reaction solution at about 8, react at room temperature for 48 hours, extract with 300 mL × 3 ethyl acetate, anhydrous MgSO 4 Dry, filter off ...

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Abstract

The invention belongs to the technical field of organic chemistry, and specifically relates to a preparation method of 2-[(4R, 6S)-6-substituted methyl-2, 2-dimethyl-1, 3-dioxan]-acetate. The preparation method specifically comprises: performing asymmetric epoxidation on (S)-1-substituted-4-ene-2-pentanol (II) to prepare (2S, 4R)-1-substituted-4-epoxy-2-pentanol (III); performing sodium cyanide ring-opening addition to prepare (3S, 5S)-6-substituted-3, 5-dihydroxyacetonitrile; performing a Pinner reaction to prepare (3S, 5S)-6-substituted-3, 5-dihydroxyhexanoate; and then performing a protection reaction with 2, 2-dimethoxypropane to prepare 2-[(4R, 6S)-6-substitued methyl-2, 2-dimethyl-1, 3-dioxan]-acetate (I). The preparation method of the invention is mild in reaction conditions, simple in operation, cheap and easily-available in raw materials, high in yield of the obtained product and high in stereoselectivity, and is applicable to industrialized production.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, in particular to a 2-[(4 R ,6 S )-6-substituted methyl-2,2-dimethyl-1,3-dioxane]-acetate preparation method. Background technique [0002] Compound 2-[(4 R ,6 S )-6-substituted methyl-2,2-dimethyl-1,3-dioxane]-acetate has the following structural formula ( ) shown in the formula: [0003] [0004] where R is C 1 ~C 4 Alkyl, benzyl; A is halogen, such as: chlorine, bromine, iodine, preferably chlorine, benzyloxy. [0005] 2-[(4 R ,6 S )-6-substituted methyl-2,2-dimethyl-1,3-dioxane]-acetate ( ) is a key intermediate for the preparation of statins hypolipidemic drugs. Statins are hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, among which atorvastatin calcium has been occupying the top of the list of best-selling drugs in the world for many years. [0006] The world patent WO 20000811 synthesized an intermediate ( ). The biocatalytic step of this route...

Claims

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Application Information

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IPC IPC(8): C07D319/06
Inventor 陈芬儿陈晓飞熊方均李杰王新龙许灵君
Owner 江西博雅欣和制药有限公司
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