Method of preparing adapalene

A compound and alkyl technology, applied in the field of pharmaceutical synthesis, can solve the problems of complicated operation, increased complexity and high cost, and achieve the effects of simplifying operation steps, increasing raw material consumption and improving yield

Inactive Publication Date: 2011-05-04
北京精华耀邦医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Research finds that the shortcoming of this method is: (1) after Grignard reagent is formed, carry out next step reaction with zinc chloride, zinc chloride is very easy to absorb water, causes the productive rate of generating organic zinc reagent to be very low, needs to consume excessive chlorine Zinc chloride increases the cost and affects the yield of subsequent steps; (2) obtains IV' with 6-bromo-2-naphthoic acid methyl ester coupling product, intermediate IV' is not easy to be completely hydrolyzed, and IV' is hydrolyzed with it The molecular polarity of the product, adapalene, is similar, resulting in the need for multiple recrystallization and purification of the final product, which increases the complexity of the operation in production
[0014] Although this method omits the reaction of esterification to protect the carboxyl group and the final hydrolysis step, its bigger disadvantages are: 1) the generation of VI requires high reaction conditions, requires argon protection, and is completed under acetone dry ice bath conditions. Industrialization The cost of reaching the required conditions in production is too high, and the operation is complicated; 2) one step of generating I has used an expensive transition metal palladium catalyst, which increases the production cost

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1 Synthesis of ethyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate

[0052] Add 6.6 grams of zinc powder, 200 milliliters of tetrahydrofuran and 2 grams of iodine in a 1000 milliliter round bottom flask, after initiating the reaction, slowly add 32 grams (0.1 moles) of 2-(1-adamantyl)-4-bromobenzyl ether, stirring to keep the reaction slightly boiling. Reflux for 3 hours, cool to room temperature, add 28 grams of 6-bromo-2-naphthoic acid ethyl ester, and 1.2gNiCl to the reaction mixture 2 / DPPE catalyst, stirred and reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into 250 ml of water, extracted with dichloromethane, and the organic phase was separated. The organic phase was washed with water until neutral, dried, and recrystallized with ethyl acetate. 41.60 g of white solid was obtained with a yield of 94.5%.

Embodiment 2

[0053] Example 2 Synthesis of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid (adapalene)

[0054] In a 1000 ml four-necked flask, 200 ml of tetrahydrofuran solution containing 11 grams of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid ethyl ester was added, and then mass Concentration is 200 milliliters of potassium hydroxide solution of 4%, reflux reaction for 3 hours, after the reaction is complete, tetrahydrofuran is distilled off. Add 250 ml of water to the residue, filter to obtain a solid, wash with water until neutral, add the solid to 300 ml of water, acidify to pH 1 with concentrated hydrochloric acid, stir for 2 hours, filter to obtain a crude product, and recrystallize the crude product from tetrahydrofuran to obtain the product 9.8 g, the yield is 95.1%.

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Abstract

This invention relates to a new synthesis route and method of adapalene, namely 6-[3-(1-adamanty)-4-methoxy phenyl]-2-naphthoic acid. In a ethers solvent or a non-polar solvent, an organic zincon is generated by reacting 2-(1-adamanty)-4-bromoanisole with a metal zinc. In the presence of a catalyst of niCl2 / DPPE, the organic zincon is reacted with 6-bromo-2-naphthoic acid methyl ether, then the adapalene is obtained after processes of alkaline saponification reaction, water washing, acidifying with hydrochloric acid and recrystallization or the like. The invention has advantages of mild reaction temperature, simple operation, low cost and high yield, so that the yield of each step is more than 90% and the total yield is more than 65%.

Description

Technical field: [0001] The invention belongs to the field of medicine synthesis. Specifically, it relates to a novel synthesis method of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, and this compound is adapalene, a drug for treating acne. Background technique [0002] Adapalene, whose Chinese name is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, has a structural formula such as formula I: [0003] [0004] Formula I [0005] Adapalene is a new naphthoic acid derivative. It belongs to the third generation of retinoic acid drugs, and its external preparation is 0.01% adapalene gel (Duffin), which has good anti-inflammation and improves the differentiation ability of epidermal keratinocytes (keratinocytes). It has a good curative effect on acne, and has better tolerance and lower side effects than other vitamin A acids. [0006] The key step of the currently disclosed synthetic route for preparing adapalene is to obtain the target product adapalene thr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C51/347C07C65/26
Inventor 卫永刚田兆桐张秋越
Owner 北京精华耀邦医药科技有限公司
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