CN105001090A - Preparation method of 4-acetoxy-3-(3,4-dimethoxy-benzyl)-2-(4-hydroxy-3-methoxy-benzyl)-butyl-2-methyl methacrylate - Google Patents

Abstract

The present invention provides a novel preparation method of 4-acetoxy-3-(3,4-dimethoxy-benzyl)-2-(4-hydroxy-3-methoxy-benzyl)-butyl-2-methyl methacrylate. The intermediate is used for the synthesis of Arctigenin, and has the advantages of economical efficiency, environmental protection, efficiency and high yield.

Description

A kind of 4-acetoxy-3-(3,4-Dimethoxy-benzyl)-2-(4-hydroxy-3-methoxy-benzyl) preparation method of-but-2-ene acid methyl esters

Technical field

The present invention relates to intermediate 4-acetoxy-3-(3,4-dimethoxy-benzyl)-2-(4-hydroxy-3-methoxy-benzyl used by synthesis antigout drug l-arctigenin)-but-2-ene acid methyl esters and preparation method thereof.

Background technology

At present, clinical just by (3R, 4R)-4-(3,4-the dimethoxy-benzyl)-3-(4-hydroxyl-3-methoxybenzy described in CN20108001429)-dihydrofuran compound studies as anti-pancreatic cancer cell.Clinical trial needs actual this active medicine of large-scale synthesis, and for the preparation of the intermediate of this active medicine.Therefore, need to find preparation (3R, 4R)-4-(3,4-dimethoxy-benzyl)-3-(4-hydroxyl-3-methoxybenzy) novel synthesis of-dihydrofuran.

Summary of the invention

Accordingly, the present invention relates to l-arctigenin intermediate 4-acetoxy-3-(3,4-dimethoxy-benzyl)-2-(4-hydroxy-3-methoxy-benzyl)-but-2-ene acid methyl esters.

The present invention relates to and prepare l-arctigenin intermediate 4-acetoxy-3-(3,4-dimethoxy-benzyl)-2-(4-hydroxy-3-methoxy-benzyl)-but-2-ene acid methyl esters novel method.

In 1-3 case study on implementation, the invention provides a kind of preparation method of formula 2 compound; Comprise:

In a heated condition, in organotin catalyzed and solvent coexisted environment, under initiator causes, formula 1 compound changes formula 2 compound into;

Wherein:

Organotin catalysts is selected from dibutyltin dilaurate, stannous octoate, two (dodecyl sulphur) dibutyl tin, dibutyltin diacetate, dioctyl tin, dialkyl tin dimaleate, two mercaptan tin alkyls, mercaptan dioctyl tin, tributyl tin, perfluoro butyl sulfonic acid tin, fluoridize in tributyltin or three (2-perfluoro hexyl) ethyl stannic hydride one or more;

Solvent is selected from one or more in ethyl acetate, toluene, benzene, methylene dichloride, DMF, DMSO, perfluoromethyl cyclohexane or acetonitrile;

Initiator is selected from organo-peroxide class: benzoyl peroxide, lauroyl peroxide, isopropyl benzene hydroperoxide, tertbutyl peroxide, di-t-butyl peroxide, dicumyl peroxide, peroxidized t-butyl perbenzoate, peroxidation trimethylacetic acid tertiary butyl ester, methylethyl ketone peroxide, cyclohexanone peroxide, di-isopropyl peroxydicarbonate, di-cyclohexylperoxy dicarbonate; Azo: one or more in Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile) or azo-bis-iso-dimethyl;

Temperature of reaction is selected from one or more in 50-60 DEG C.

Embodiment 1:4-acetoxy-3-(3,4-dimethoxy-benzyl)-2-(4-hydroxy-3-methoxy-benzyl)-but-2-ene acid methyl esters preparation

Take (6.1 g, 10 mmol) 3-acetoxyl group-4-(3, 4-dimethoxy-phenyl)-2-(4-hydroxy-3-methoxy-benzyl)-2-nitro-3-thiophenyl-methyl-butyrate, (0.29 g, 10% mmol) tri-butyl tin hydride, (8.2 mg, 0.5% mmol) Diisopropyl azodicarboxylate adds in 250 mL there-necked flasks, with 50 mL toluene, bottleneck material is washed in bottle, stirring reaction at 50 DEG C, LC follows the tracks of reaction, react 24 h, there is the raw material of 10% unconverted, reaction solution is down to room temperature, 20 mL purified water are added in reaction solution, stir 10 min, leave standstill, separatory, which floor anhydrous sodium sulfate drying is had to be spin-dried for, through column chromatography purification enriched material, obtain yellow oil 1.5 g, yield 35%.

Embodiment 2:4-acetoxy-3-(3,4-dimethoxy-benzyl)-2-(4-hydroxy-3-methoxy-benzyl)-but-2-ene acid methyl esters preparation

Take (6.1 g, 10 mmol) 3-acetoxyl group-4-(3, 4-dimethoxy-phenyl)-2-(4-hydroxy-3-methoxy-benzyl)-2-nitro-3-thiophenyl-methyl-butyrate, (0.29 g, 10% mmol) tri-butyl tin hydride, add in 250 mL there-necked flasks, with 40 mL toluene, bottleneck material is washed in bottle, with 10 mL toluene by (16.4 mg, 1% mmol) Diisopropyl azodicarboxylate dissolving, in instillation reaction solution, slowly be warming up to 50 DEG C, LC follows the tracks of reaction, react 4 h, raw material is unconverted, reaction solution is down to room temperature, 20 mL purified water are added in reaction solution, stir 10 min, leave standstill, separatory, which floor anhydrous sodium sulfate drying is had to be spin-dried for, through column chromatography purification enriched material, obtain yellow oil 3.9g, yield 90%.

Embodiment 3:4-acetoxy-3-(3,4-dimethoxy-benzyl)-2-(4-hydroxy-3-methoxy-benzyl)-but-2-ene acid methyl esters preparation

Take (30.2 g, 50 mmol) 3-acetoxyl group-4-(3, 4-dimethoxy-phenyl)-2-(4-hydroxy-3-methoxy-benzyl)-2-nitro-3-thiophenyl-methyl-butyrate, (1.45 g, 10% mmol) tri-butyl tin hydride, add in 1000 mL there-necked flasks, with 200 mL toluene, bottleneck material is washed in bottle, with 50 mL toluene by (41.2mg, 0.5% mmol) Diisopropyl azodicarboxylate dissolving, in instillation reaction solution, slowly be warming up to 50 DEG C, LC follows the tracks of reaction, react 3 h, raw material is unconverted, reaction solution is down to room temperature, 100 mL purified water are added in reaction solution, stir 10 min, leave standstill, separatory, which floor anhydrous sodium sulfate drying is had to be spin-dried for, through column chromatography purification enriched material, obtain yellow oil 19.5 g, yield 88%.

Claims (4)

1. a l-arctigenin intermediate, is characterized in that: described l-arctigenin intermediate is the compound that general formula I represents,

In formula I:

R represents H, COR ¹or R ¹, wherein R ¹represent C _1-18alkane;

R ²represent halogen, SR ¹or OR ¹, wherein R ¹represent C _1-18alkane;

R ³representative, H, COR ¹or R ¹, wherein R ¹represent C _1-18alkane.

2. l-arctigenin intermediate according to claim 1, is characterized in that: in formula I, R is H, R ²for OR ¹, R ³for COR ¹, R ¹for CH _3,, structural formula as shown in Equation 3:

。

3. the preparation method of formula 2 compound; Comprise:

In a heated condition, in organotin catalyzed and solvent coexisted environment, under initiator causes, formula 1 compound changes formula 2 compound into;

。

4. method according to claim 3, wherein:

Organotin catalysts is selected from dibutyltin dilaurate, stannous octoate, two (dodecyl sulphur) dibutyl tin, dibutyltin diacetate, dioctyl tin, dialkyl tin dimaleate, two mercaptan tin alkyls, mercaptan dioctyl tin, tributyl tin, perfluoro butyl sulfonic acid tin, fluoridize in tributyltin or three (2-perfluoro hexyl) ethyl stannic hydride one or more;

Solvent is selected from one or more in ethyl acetate, toluene, benzene, methylene dichloride, DMF, DMSO, perfluoromethyl cyclohexane or acetonitrile;

Initiator is selected from organo-peroxide class: benzoyl peroxide, lauroyl peroxide, isopropyl benzene hydroperoxide, tertbutyl peroxide, di-t-butyl peroxide, dicumyl peroxide, peroxidized t-butyl perbenzoate, peroxidation trimethylacetic acid tertiary butyl ester, methylethyl ketone peroxide, cyclohexanone peroxide, di-isopropyl peroxydicarbonate, di-cyclohexylperoxy dicarbonate; Azo: one or more in Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile) or azo-bis-iso-dimethyl;

Temperature of reaction is selected from one or more in 50-60 DEG C.