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Method for synthesizing substituted benzo (1,4) dioxane derivative

A technology for the synthesis of dioxane and its synthesis method, which is applied in the technical field of synthesis of pharmaceutical intermediates, and can solve the problems of unfavorable synthesis and application of dioxane derivatives, reduced reaction yield, difficulty in improving purity, etc.

Inactive Publication Date: 2009-02-25
北京金源化学集团有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This not only greatly reduces the reaction yield, but also because the properties of the epoxy hexacyclic structure products with opposite hydroxyl positions are very close, it is difficult to separate and the purity is difficult to improve, so the overall synthetic reaction yield is very low, generally lower than 30%
This is very unfavorable for the synthesis and application of substituted benzo(1,4)dioxane derivatives, and urgently needs to be solved

Method used

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  • Method for synthesizing substituted benzo (1,4) dioxane derivative
  • Method for synthesizing substituted benzo (1,4) dioxane derivative
  • Method for synthesizing substituted benzo (1,4) dioxane derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Synthesis of 5-fluoro-1,4-benzodioxane-2-carboxamide

[0026]

[0027] Dissolve 52g of 2,6-difluorophenol (400mmol) and 115g of 2,3-dibromopropionamide (500mmol, 1.25eq.) in 400mL of absolute ethanol, and slowly add 17.6g (440mmol, 1.1eq. ) sodium hydroxide. After the addition, the temperature was slowly raised to 60°C for 3 hours. The reaction mixture was evaporated to dryness, washed with water, and recrystallized from acetone to obtain 86 g of a nearly colorless light yellow solid with a yield of 85%.

[0028]Dissolve 53g (200mmol) of the above product in 500mL of anhydrous tetrahydrofuran, cool to 0°C and slowly add 200mL (25g, 220mmol, 1.1eq.) potassium tert-butoxide solution dropwise, the color of the solution turns brown. After the dropwise addition was complete, the temperature was slowly raised to room temperature, the solvent was evaporated, and 200 mL of dichloromethane was added, ammonium chloride aqueous solution and pure water were washed and dried. ...

Embodiment 2

[0031] Synthesis of 2-Hydroxymethyl-7,8-dichloro-1,4-benzodioxane

[0032]

[0033] Dissolve 18g (100mmol) of 2-fluoro-5,6-dichlorophenol in 200mL of absolute ethanol, add 15g (120mmol) of benzyl chloride, heat up, slowly add 11mL (115mmol) of 40% sodium hydroxide solution dropwise, and heat Reflux reaction for 3h. Evaporate the solvent, dissolve in 100mL of dichloromethane, wash with acid, wash with water, dry, and evaporate the solvent. The residue was recrystallized from hexane to obtain 23 g of 2-fluoro-5,6-dichlorophenylbenzyl ether, with a yield of 85%.

[0034] Take 27 g (100 mmol) of 2-fluoro-5,6-dichlorophenyl benzyl ether and 22 g (200 mmol) of anhydrous 2-chloro-1,3-propanediol and dissolve in anhydrous THF, nitrogen protection, and cool to 4.8g (200mmol) sodium hydride was slowly added at 0°C, and the color of the solution turned brown. After the addition, the temperature was slowly raised to 70° C., and the reaction was kept for 2 hours, and 10 mL (115 mmol)...

Embodiment 3

[0038] Synthesis of 7-methyl-1,4-benzodioxan-2-one

[0039]

[0040] Dissolve 63g of 2-fluoro-p-cresol (500mmol) and 60g of methyl chloroacetate (600mmol, 1.2eq.) in 400mL of absolute ethanol, under nitrogen protection, slowly add 90mL of 40% (1000mmol, 2eq.) sodium hydroxide dropwise solution. After the addition, the temperature was slowly raised to 60°C for 3 hours. The reaction mixture was evaporated to dryness and recrystallized from water / acetone to obtain 100 g of a nearly colorless solid, which remained 90 g after vacuum drying for 24 hours, with a yield of 88%.

[0041] Suspend 52g (250mmol) of the above product in 500mL of anhydrous DMF, cool to 0°C and slowly add 250mL (34g, 300mmol, 1.2eq.) potassium tert-butoxide solution dropwise, the color of the solution turns brown. After the dropwise addition was complete, the temperature was slowly raised to room temperature, the solvent was evaporated, and 200 mL of dichloromethane was added, ammonium chloride aqueous s...

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Abstract

The invention belongs to the synthesis technical field of pharmaceutical intermediates, and discloses a synthetic method of the pharmaceutical intermediate which is substituted benzo (1, 4) dioxane ramification. The method takes 2-fluorophenol as raw material which is processed by reactions such as etherification to cause phenolic hydroxyl to be functionalized and lead fluorine to be functionalized as the phenolic hydroxyl or substituted benzene oxygen ether under the action of alkali metal compound; finally, the target product substituted benzo (1, 4) dioxane ramification is obtained by circle combining reaction. The method uses the phenolic hydroxyl for locating to obtain the target product quantificationally in a highly selective way, so that the problems of low yield as well as difficult analysis and purification caused by isomer, and the like, are avoided, and the target product with high purity can be obtained without needing complicated process of separation and purification. The method has cheap raw materials which are easy to obtain, easily realized reaction steps, mild reaction conditions as well as higher productive rate and product purity, and is very suitable for commercial process.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and relates to a synthesis method for substituted benzo(1,4)dioxane derivatives of pharmaceutical intermediates. The method uses substituted 2-fluorophenol as a raw material and undergoes etherification In the reaction, the phenolic hydroxyl group is functionalized and the fluorine is functionalized into a phenolic hydroxyl group or a substituted phenoxyether under the action of an alkali metal compound, etc., and finally the target product is obtained through a ring closure reaction to obtain a substituted benzo(1,4)dioxane derivative things. Background technique [0002] Substituted benzo(1,4)dioxane derivatives are widely used in many fields and can be used as pharmaceutical intermediates, as shown in the right picture [0003] [0004] Significant curative effect. [0005] From the reported synthetic literature (US4224333, EP0004494, J.Heterocycl.Chem.19...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D319/20
Inventor 姚加陈朝晖邱明建张雅丽
Owner 北京金源化学集团有限公司