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High purity 2,5-dimethyl-3,4-dihydroxy methylbenzoate synthesis method

A technology of methyl dihydroxybenzoate and methyl methylbenzoate, applied in the field of high-purity 2, can solve the problems of difficult preparation of starting materials, unsuitable for large-scale production, hidden dangers of production safety, etc., and meets the requirements of production equipment The effect of not high, short reaction steps and short production time

Active Publication Date: 2015-12-09
上海睿腾医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] 2,5-dimethyl-3,4-dihydroxybenzoic acid methyl ester is a kind of comparatively important drug intermediate, for the preparation of 2,5-dimethyl-3,4-dihydroxybenzoic acid methyl ester, no literature report
Its main defect is that the starting material is difficult to prepare and unstable, it needs to use a large amount of butyllithium and low temperature, it has high requirements on equipment, and it brings certain hidden dangers to production safety
The purity of the precursor prepared by this method is not high, and the product obtained by esterification with methanol needs to be purified by column chromatography, so it is not suitable for large-scale production

Method used

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  • High purity 2,5-dimethyl-3,4-dihydroxy methylbenzoate synthesis method

Examples

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Effect test

Embodiment 1

[0019] In the embodiment of the present invention, 3,4-dihydroxy-2-methyl-5-morpholine methyl benzoate: 2L of isopropanol and 478g of morpholine were added to a 10L three-necked bottle, and 37% formaldehyde was added under mechanical stirring Solution 478g, then reflux reaction 20min. The temperature was lowered to 50° C., and 5 L of isopropanol and 1000 g of methyl 3,4-dihydroxy-2-methylbenzoate solution were quickly added. Then heated to reflux for 2.5h, the raw material disappeared. Cool down to 10°C and filter, and wash the filter cake with 500ml of isopropanol. It was sucked dry and dried at 50°C to obtain 1253 g of off-white solid with a yield of 81%.

[0020] Synthesis of 2,5-dimethyl-3,4-dihydroxybenzoic acid methyl ester: 5L autoclave, add 3.5L acetic acid, 3,4-dihydroxy-2-methyl-5-morpholine methylbenzoic acid Methyl ester 700g, palladium carbon 5%, hydrogen replacement 3 times, 80MPa pressure, 100°C reaction for 24h, hydrogen needs to be added during the reaction...

Embodiment 2

[0022] In the embodiment of the present invention, 3,4-dihydroxy-2-methyl-5-morpholine methyl benzoate: 2L of isopropanol and 478g of morpholine were added to a 10L three-necked bottle, and 37% formaldehyde was added under mechanical stirring Solution 478g, then reflux reaction 20min. Cool down to 20°C, quickly add 5L of isopropanol and 1000g of 3,4-dihydroxy-2-methylbenzoic acid methyl ester solution. Then heated to reflux for 2.5h, the raw material disappeared. Cool down to 20°C and filter, and wash the filter cake with 500ml of isopropanol. Drained and dried at 50°C to obtain 1235 g of off-white solid with a yield of 80%.

[0023] Synthesis of 2,5-dimethyl-3,4-dihydroxybenzoic acid methyl ester: 5L autoclave, add 3.5L acetic acid, 3,4-dihydroxy-2-methyl-5-morpholine methylbenzoic acid Methyl ester 700g, palladium hydroxide 5%, hydrogen replacement 3 times, 30MPa pressure, 100°C reaction for 24h, hydrogen needs to be added during the reaction. There is little raw materia...

Embodiment 3

[0025] In the embodiment of the present invention, 3,4-dihydroxy-2-methyl-5-morpholine methyl benzoate: 2L of isopropanol and 478g of morpholine were added to a 10L three-necked bottle, and 37% formaldehyde was added under mechanical stirring Solution 478g, then reflux reaction 20min. The temperature was lowered to 50° C., and 5 L of isopropanol and 1000 g of methyl 3,4-dihydroxy-2-methylbenzoate solution were quickly added. Then heated to reflux for 2.5h, the raw material disappeared. Cool down to -5°C and filter, and wash the filter cake with 500ml of isopropanol. It was sucked dry and dried at 50°C to obtain 1275 g of off-white solid with a yield of 82.5%.

[0026] Synthesis of 2,5-dimethyl-3,4-dihydroxybenzoic acid methyl ester: 5L autoclave, add 3.5L acetic acid, 3,4-dihydroxy-2-methyl-5-morpholine methylbenzoic acid Methyl ester 700g, palladium carbon 5%, hydrogen replacement 3 times, 30MPa pressure, 150°C reaction for 24h, hydrogen needs to be added during the reacti...

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Abstract

The present invention discloses a high purity 2,5-dimethyl-3,4-dihydroxy methylbenzoate synthesis method, which comprises: adopting 3,4-dihydroxy-2-methyl methylbenzoate as a raw material, carrying out a Mannich reaction to obtain a first-step product, dissolving the first-step product in an acetic acid solution, adding a catalyst, carrying out morpholine removing at a temperature of 70-150 DEG C under a hydrogen pressure of 20-80 MPa to obtain a crude product, and carrying out recrystallization on the obtained crude product with an acetic acid aqueous solution to obtain the high purity product. According to the present invention, the raw materials are stable and easy to synthesize; the reaction steps are short, the operation is simple, and the requirement on the production equipment is not high; the required production time is short, and the production cost is saved; and the method is suitable for large-scale industrial production and small batch preparation in the laboratory.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing high-purity methyl 2,5-dimethyl-3,4-dihydroxybenzoate. Background technique [0002] 2,5-dimethyl-3,4-dihydroxybenzoic acid methyl ester is a kind of comparatively important drug intermediate, for the preparation of 2,5-dimethyl-3,4-dihydroxybenzoic acid methyl ester, There is no literature report. But its precursor corresponding carboxylic acid 2,5-dimethyl-3,4-dihydroxybenzoic acid uses 3,6-dimethylcatechol as raw material, reacts with butyllithium at -78°C, Then react with dry ice to obtain the target compound. Its main disadvantage is that the starting materials are difficult to prepare and unstable, and a large amount of butyllithium and low temperature are required, which has high requirements for equipment and brings certain hidden dangers to production safety. The purity of the precursor prepared by this method is not high, and the product o...

Claims

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Application Information

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IPC IPC(8): C07C67/317C07C69/84
CPCC07C67/317C07D295/155C07C69/84
Inventor 王西徐代旺
Owner 上海睿腾医药科技有限公司
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