Synthetic method of adapalene

A synthesis method and a molar weight technology are applied in a synthesis field of adapalene, a medicine for treating acne, and can solve the problems of high price, high pollution, difficult handling and the like of methyl 6-bromo-2-naphthoate, and achieve production The effect of cost reduction, less three wastes, and simple process operation

Inactive Publication Date: 2014-08-27
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] But, the main defect of this synthetic method is that the price of 6-bromo-2-naphthoic acid methyl ester is expensive, and needs strict anhydrous anaerobic operation owing to use organozinc reagent during coupling reaction; After the reaction, the stoichiometric zinc Salt is highly polluting to the environment and difficult to handle
However, there is no report that diaryl boronic acid is used for the synthesis of adapalene in the current published literature

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] A synthetic method for adapalene, comprising the following steps:

[0030] (1) Under nitrogen atmosphere, add 356g (1.0 mole) 2-methoxycarbonyl-6-naphthol p-toluenesulfonate, 332g (0.65 mole) bis(4-methoxy yl-3-adamantylphenyl)boronic acid, 533g (2 mol) potassium phosphate trihydrate, 6.5g (0.01 mol) bistriphenylphosphine nickel chloride and 2.2g (0.01 mol) N-methyl-N' - Butylimidazolium ammonium bromide salt and 1.0L toluene solvent, react at 120°C under stirring until complete, and cool the reaction solution to room temperature.

[0031] (2) The reaction solution obtained in step (1) was washed with saturated brine, the organic phase was separated, and after drying, the solvent was recovered by atmospheric distillation, and the obtained solid was recrystallized with toluene, and the solid was precipitated after cooling, filtered to obtain 6-[3- Methyl (1-adamantyl)-4-methoxyphenyl]-2-naphthoate.

[0032] (3) Dissolve 160g (4 moles) of sodium hydroxide in 0.5L of met...

Embodiment 2

[0036] A synthetic method for adapalene, comprising the following steps:

[0037](1) Under nitrogen atmosphere, add 309g (1.0 mol) 2-methoxycarbonyl-6-naphthol dimethylaminosulfonamide, 332g (0.65 mol) bis(4-methyl) to the reactor with reflux device Oxy-3-adamantylphenyl)boronic acid, 533g (2 mol) potassium phosphate trihydrate, 6.5g (0.01 mol) bistriphenylphosphine nickel chloride and 2.2g (0.01 mol) N-methyl-N '-Butylimidazolium bromide ammonium salt and 1.0L toluene solvent, the reaction was completed at 120°C under stirring, and the reaction liquid was cooled to room temperature.

[0038] (2) (same as embodiment 1).

[0039] (3) (same as embodiment 1).

[0040] (4) The organic solvent was distilled off under normal pressure, the pH was adjusted to 1, and 355 g of adapalene was obtained by suction filtration, with a yield of 86%.

[0041] The identification of the adapalene prepared in Example 2 is the same as in Example 1.

Embodiment 3

[0043] A synthetic method for adapalene, comprising the following steps:

[0044] (1) Under nitrogen atmosphere, add 356g (1.0 mole) 2-methoxycarbonyl-6-naphthol p-toluenesulfonate, 332g (0.65 mole) bis(4-methoxy Base-3-adamantylphenyl)boronic acid, 533g (2 moles) potassium phosphate trihydrate, 25g (0.03 moles) bistris(4-methoxyphenyl)phosphine nickel chloride and 7.8g (0.03 moles) N , N'-bis-butylimidazolium bromide salt and 1.0L methyl tetrahydrofuran solvent, the reaction was completed at 70°C under stirring, and the reaction liquid was cooled to room temperature.

[0045] (2) (same as embodiment 1).

[0046] (3) (same as embodiment 1).

[0047] (4) The organic solvent was distilled off under normal pressure, the pH was adjusted to 1, and 371 g of adapalene was obtained by suction filtration, with a yield of 90%.

[0048] The identification of the adapalene prepared in Example 3 is the same as in Example 1.

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Abstract

The invention relates to the technical field of fine chemical engineering, and provides a synthetic method of adapalene. The synthetic method comprises: performing a coupling reaction of 2-methoxycarbonyl-6-naphthyl p-toluenesulfonate or 2-methoxycarbonyl-6-naphthyl dimethylamino sulfamide with bis(4-methoxyl-3-adamantyl phenyl)boric acid under the catalysis of nickel to obtain 6-[3-(1-adamantyl)-4-methoxyl phenyl]-2-methyl naphthoate, and then performing hydrolysis to obtain the adapalene product. The method of the invention substitutes bis(4-methoxyl-3-adamantyl phenyl)boric acid with a mild preparation condition and low price for 4-methoxyl-3-adamantyl phenylboronic acid with high price, and reaches the purpose of reducing raw material cost without using air-sensitive metal organic reagents; the method also partially substitutes cheap N,N'-bisalkyl N-heterocyclic carbene precursor quaternary ammonium halogen salt for organic phosphine ligands, is simple in preparation operation, and has a significantly increased product yield of 58-90%; the production cost is decreased obviously; the generation of 'three wastes' is less; and the method is suitable for industrial scale production.

Description

technical field [0001] The invention belongs to the technical field of fine chemicals, and in particular relates to a method for synthesizing adapalene, a drug for treating acne. Background technique [0002] Adapalene, whose chemical name is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, belongs to the third generation retinoic acid drugs and has good anti-inflammatory properties. Inflammatory effect, good curative effect on the treatment of acne. However, at present, the production cost of adapalene is high, and the amount of medicine used to treat acne is large, so how to efficiently and economically produce adapalene has become a problem. [0003] U.S. Patent US4717720 discloses a kind of synthetic method of adapalene, it is at first to prepare 2-(1-adamantyl)-4-bromoanisole, then it is prepared into Grignard reagent, and then with anhydrous ZnCl 2 Reaction made organozinc reagent. The obtained organozinc reagent and 6-bromo-2-naphthoic acid methyl ester are su...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C27/02C07C65/26C07C67/343C07C69/94
CPCC07C51/09C07C67/343C07C65/26C07C69/94
Inventor 邹刚可海华段高坤施炜佳翟娟娟
Owner EAST CHINA UNIV OF SCI & TECH
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