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Synthesis method of high-purity methyl 5-hydroxy-2-methyl benzoate

A technology of methyl toluate and a synthesis method, applied in the field of synthesis of methyl 5-hydroxy-2-methylbenzoate, can solve problems such as being difficult to enlarge, achieve easy operation, low production equipment requirements, and economical The effect of production costs

Inactive Publication Date: 2011-09-21
上海药明康德新药开发有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The purpose of the present invention is to provide a method for effectively preparing and purifying methyl 5-hydroxy-2-methylbenzoate, which mainly solves the technical problem that it is not easy to amplify in the existing synthesis and purification process and requires column purification

Method used

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  • Synthesis method of high-purity methyl 5-hydroxy-2-methyl benzoate

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0011] Methyl 5-hydroxy-2-methylbenzoate

[0012] Dissolve methyl 5-amino-2-methylbenzoate (100g, 0.6mol) in 800mL (~2.55M) sulfuric acid solution at 5~10°C, stir for about 10min, all the solids are dissolved, and the temperature of the solution drops to 0~ 5°C, slowly add 334mL of 11.5% sodium nitrite solution dropwise, control the temperature at 0-5°C during the dropping process, react at 0-5°C for 1 hour after the dropwise addition, add the reaction solution to the Hydrolyze in 722mL (~0.86M) sulfuric acid solution, pay attention to the dropping speed, control the temperature at 70-80°C during the dropping process, react at 70-90°C for 35min after dropping, cool to 0-5°C to crystallize, Stir at ~5°C for 3h and filter.

[0013] Purification of methyl 5-hydroxy-2-methylbenzoate

[0014] Dissolve the crude product in 200mL of dichloromethane, wash with 300mL of water three times, slowly drop 400mL of heptane into dichloromethane to precipitate a solid, stir at 5-15°C for 12h...

example 2

[0016] Methyl 5-hydroxy-2-methylbenzoate

[0017] Dissolve methyl 5-amino-2-methylbenzoate (100g, 0.6mol) in 800mL (~2.55M) sulfuric acid solution at 5~10°C, stir for about 10min, all the solids are dissolved, and the temperature of the solution drops to 0~ 5°C, slowly add 334mL of 11.5% sodium nitrite solution dropwise, control the temperature at 0-5°C during the dropping process, react at 0-5°C for 1 hour after the dropwise addition, and add the reaction solution to the Hydrolyze in 720mL (~0.86M) sulfuric acid solution, pay attention to the dropping speed, control the temperature at 80-90°C during the dropping process, react at 70-90°C for 45min after dropping, cool to 0-5°C to crystallize, Stir at ~5°C for 3h and filter.

[0018] Purification of methyl 5-hydroxy-2-methylbenzoate

[0019] Dissolve the crude product in 200mL of dichloromethane, wash with 300mL of water three times, slowly drop 400mL of heptane into dichloromethane to precipitate a solid, stir at 5-15°C for...

example 3

[0021] Methyl 5-hydroxy-2-methylbenzoate

[0022] Dissolve methyl 5-amino-2-methylbenzoate (100g, 0.6mol) in 800mL (~2.55M) sulfuric acid solution at 5~10°C, stir for about 10min, all the solids are dissolved, and the temperature of the solution drops to 0~ 5°C, slowly add 334mL of 11.5% sodium nitrite solution dropwise, control the temperature at 0-5°C during the dropping process, react at 0-5°C for 1 hour after the dropwise addition, and add the reaction solution to the Hydrolyze in 720mL (~0.86M) sulfuric acid solution, pay attention to the dropping speed, control the temperature at 70-90°C during the dropping process, react at 70-90°C for 60min after dropping, cool to 0-5°C to crystallize, Stir at ~5°C for 3h and filter.

[0023] Purification of methyl 5-hydroxy-2-methylbenzoate

[0024] Dissolve the crude product in 150 mL of dichloromethane, slowly drop 300 mL of heptane into dichloromethane to precipitate a solid, stir at 5-15°C for 14 h, filter, and then use dichloro...

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Abstract

The invention relates to a synthesis method of methyl 5-hydroxy-2-methyl benzoate. The invention mainly solves the technical problems of disordered reaction process and difficulty in purifying the reaction products in the existing synthesis method. The technical scheme is as follows: the synthesis method of methyl 5-hydroxy-2-methyl benzoate comprises the following steps: sequentially diazotizing and carrying out hydrolysis reaction on methyl 5-amino-2-methyl benzoate which is used as a raw material to obtain a crude product, dissolving the crude product in dichloromethane, washing with water to remove the byproduct 5-hydroxy-2-methylbenzoic acid generated in the reaction liquid so as to obtain a crude methyl 5-hydroxy-2-methyl benzoate product, and recrystallizing with a dichloromethane / n-heptane mixed solvent to obtain the light yellow powder methyl 5-hydroxy-2-methyl benzoate. The methyl 5-hydroxy-2-methyl benzoate obtained by using the method provided by the invention is an important and common medicine intermediate.

Description

Technical field: [0001] The present invention relates to the synthetic method of 5-hydroxyl-2-methylbenzoic acid methyl ester. Background technique: [0002] 5-Hydroxy-2-methylbenzoic acid methyl ester is a kind of comparatively important commonly used drug intermediate, for the preparation of 5-hydroxyl-2-methylbenzoic acid methyl ester, there are literature reports to use 5-amino-2-methyl Benzoic acid is used as a raw material, and the target product is obtained by diazotization, hydrolysis, and re-esterification, and finally the target compound (EP21033620) is obtained by column purification; Chemicalization, hydrolysis, and finally column purification (US6689922). The main drawback of these processes is the need for column purification, which is not suitable for large-scale production. Therefore, finding a suitable post-processing method so that the process can be applied to production on a large scale becomes a key problem to be solved in the present invention. Inve...

Claims

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Application Information

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IPC IPC(8): C07C69/84C07C67/31
Inventor 刘淼秀贾默黄平李忠波胡伟峰陈曦陈民章唐苏翰
Owner 上海药明康德新药开发有限公司
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