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Method for synthesizing adapalene intermediate 6-bromo-2-naphthoate

A technology of adapalene and naphthoate, which is applied in the field of synthesis of adapalene intermediate 6-bromo-2-naphthoate, can solve the problems of low process yield and pollution discharge, and achieve reaction selection High solubility, less side effects, good solubility

Active Publication Date: 2019-03-08
THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, 6-bromo-2-naphthoic acid ester is obtained by esterification of 6-bromo-2-naphthoic acid, and 6-bromo-2-naphthoic acid is obtained by oxidation of 6-bromo-2-substituted naphthalene , strong oxidants such as potassium dichromate, concentrated sulfuric acid, concentrated nitric acid, and potassium permanganate need to be used in this process, which is prone to polluting emissions, and the overall process yield is not high

Method used

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  • Method for synthesizing adapalene intermediate 6-bromo-2-naphthoate
  • Method for synthesizing adapalene intermediate 6-bromo-2-naphthoate
  • Method for synthesizing adapalene intermediate 6-bromo-2-naphthoate

Examples

Experimental program
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Effect test

Embodiment 1

[0030] The synthetic method of 6-bromo-2-naphthoic acid methyl ester, comprises the following steps:

[0031] 1) Mix 2-naphthoic acid and methanol, add the catalyst, stir and pass in argon, control the pressure to 6 atmospheres, control the temperature to 150°C, and keep it for 60 minutes; start adding the mixture of sodium bromide and benzenesulfonic acid dropwise Aqueous solution, when the dripping volume reaches 8% of the solution volume, start to drop the sodium hypobromite aqueous solution; control the same dropping speed of the two solutions, and the total dropping time is 110min; after the dropping, the system is heated to 170°C , pressurized to 15 atmospheres to continue the reaction for 6h to end.

[0032] The catalyst is obtained by the following method: uniformly grinding nano-titanium dioxide and nano-silicon dioxide, soaking in hydrochloric acid with a mass concentration of 8% for 5 hours, filtering, washing with water, drying in the air, and drying at 300°C.

[...

Embodiment 2

[0036] The synthetic method of 6-bromo-2-naphthoic acid isopropyl ester comprises the following steps:

[0037] 1) Mix 2-naphthoic acid and isopropanol, add the catalyst, stir and pass nitrogen, control the pressure to 4 atmospheres, control the temperature to 130 ° C, and keep it for 50 minutes; start dropping potassium bromide and benzenesulfonic acid Mix the aqueous solution, and when the dropwise addition volume reaches 5% of the solution volume, start to drop the aqueous solution of potassium hypobromite; control the same dropping speed of the two solutions, and the total dropping time is 90min; The pressure was raised to 11 atmospheres and the reaction was continued for 5h to end.

[0038] The catalyst is obtained by the following method: uniformly grinding nano-titanium dioxide and nano-silicon dioxide, soaking in hydrochloric acid with a mass concentration of 5% for 3 hours, filtering, washing with water, drying in the air, and drying at 250°C.

[0039] The molar rati...

Embodiment 3

[0042] The synthetic method of 6-bromo-2-naphthoic acid ethyl ester, comprises the following steps:

[0043] 1) Mix 2-naphthoic acid and ethanol, add the catalyst, stir and pass in argon, control the pressure to 7 atmospheres, control the temperature to 155°C, and keep it for 70 minutes; start to add the mixture of sodium bromide and benzenesulfonic acid dropwise Aqueous solution, when the dropping volume reaches 10% of the volume of the solution, start to drop the sodium hypobromite aqueous solution; control the dropping speed of the two solutions to be the same, and the total dropping time is 150min; after the dropping, the system is heated to 180°C , the pressure was increased to 17 atmospheres and the reaction was continued for 7h to end.

[0044] The catalyst is obtained by the following method: uniformly grinding nano-titanium dioxide and nano-silicon dioxide, soaking in hydrochloric acid with a mass concentration of 10% for 6 hours, filtering, washing with water, drying...

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Abstract

The invention provides a method for synthesizing adapalene intermediate 6-bromo-2-naphthoate. The method comprises the following steps: 1), mixing 2-naphthalic acid and an organic solvent uniformly, adding a catalyst, performing stirring, introducing protective gas, controlling pressure at 4-7 atmospheres, controlling the temperature at 130-155 DEG C, maintaining the conditions for 50-70 minutes,then adding dropwise a mixed aqueous solution containing bromide salt and benzenesulfonic acid, adding dropwise an aqueous solution containing only hypobromite, controlling the total dropwise additiontime within 90-150 minutes, heating the system to 165-180 DEG C after dropwise addition, raising pressure to 11-17 atmospheres to continue the reaction for 5-7 hours and ending the reaction; 2) removing solid by filtering while the mixed solution is hot, adding the solid to ice water with weight 3-5 times that of the filtrate, and performing extraction, drying, evaporative concentration for removing a solvent to obtain a product. The method has high yield, and no harmful substances are discharged.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a method for synthesizing an adapalene intermediate 6-bromo-2-naphthoate. Background technique [0002] Adapalene (Compound 1), a naphthoic acid derivative, belongs to the third generation of retinoic acid drugs, and its chemical name is 6-[3-(1-adamantyl)-4-methoxybenzene Base]-2-naphthoic acid is an anti-acne drug developed by Galderma Pharmaceutical Company of France. Its chemical structure is shown in the figure below: [0003] [0004] Adapalene is a retinoid compound that binds to specific nuclear retinoic acid receptors like all-trans retinoic acid, but the difference is that it can selectively bind to vitamin A related to keratinocyte proliferation and differentiation Acid receptor gamma, which does not bind cytoplasmic retinoic acid-binding protein. Its mechanism of action is mainly to reduce the formation of microcomedone by regulating the differentiation of hai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/08C07C69/78
CPCC07C51/363C07C67/08C07C63/70C07C69/78
Inventor 谭回李维平黄贤键唐爱发刘文兰张猛
Owner THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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