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Preparation method of atovaquone

A technology of atovaquone and naphthoquinone, which is applied in the field of drug synthesis, can solve the problems of high production cost, high cost, and high price, and achieve the effects of reducing production cost, reducing adverse effects, and reducing production cost

Inactive Publication Date: 2014-02-12
SHANDONG LUKANG SHELILE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But this method also uses silver nitrate and ammonium persulfate, the production cost is high, and the impact on the environment is not good
[0011] In the above two methods, expensive silver nitrate is used, not only the cost is high but the yield is very low, and at the same time, the post-treatment process will cause great damage to the environment

Method used

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  • Preparation method of atovaquone
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  • Preparation method of atovaquone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] The preparation of A, 2-(4-(4-chlorophenyl) cyclohexyl)-1-naphthol (formula V)

[0062]Under the protection of nitrogen, 2.9g of 4-(4-chlorophenyl)cyclohexanol, 2g of α-naphthol, and 2.63g of p-toluenesulfonic acid were added to 30ml of toluene, and the reaction was refluxed at 140°C for 3h, and the progress of the reaction was monitored by TLC. After the reaction was complete, the organic phase was washed with water, separated to remove water, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and crystallized to obtain 2-(4-(4-chlorophenyl)cyclohexyl)-1-naphthol.

[0063] Preparation of B, 2,3-dibromo-2-(4-(4-chlorophenyl)cyclohexyl)-1,4-naphthoquinone (formula III)

[0064] (a), the preparation of 2-(4-(4-chlorophenyl) cyclohexyl)-1,4-naphthoquinone (formula IV)

[0065] Add 2-(4-(4-chlorophenyl)cyclohexyl)-1-naphthol 2.98g to 15ml of acetonitrile, then add dropwise 4ml of concentrated hydrochloric acid (38%, v / v), 16ml o...

Embodiment 2

[0073] The preparation of A, 2-(4-(4-chlorophenyl) cyclohexyl)-1-naphthol (formula V)

[0074] Add 30ml of chlorobenzene, 2g of α-naphthol, 4.65g of 4-(4-chlorophenyl) cyclohexanol and 0.8g of p-toluenesulfonic acid in a 100ml three-necked flask, and reflux reaction for 3h. TLC monitors the reaction, and the reaction is complete. Concentrate under reduced pressure, add chloroform for extraction, wash with water, separate the organic layer, and evaporate the solvent to obtain the product 2-(4-(4-chlorophenyl)cyclohexyl)-1-naphthol.

[0075] Preparation of B, 2,3-dibromo-2-(4-(4-chlorophenyl)cyclohexyl)-1,4-naphthoquinone (formula III)

[0076] In 30ml carbon tetrachloride, add 2-(4-(4-chlorophenyl) cyclohexyl)-1-naphthol 3.36g, Br 2 1.6g, 1.2ml of 30% hydrogen peroxide solution, 0.6ml of 98% concentrated sulfuric acid, the reaction solution was refluxed for 20min, concentrated and cooled to 0°C, the solid was retained after suction filtration, an appropriate amount of water wa...

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Abstract

The invention discloses a preparation method of atovaquone, and belongs to the drug synthesis field. The method comprises the following steps: condensing alpha-naphthol and 4-(4-chlorophenyl)cyclohexanol under acid catalysis to obtain 2-(4-(4-chlorophenyl)cyclohexyl)-1-naphthol (formula V), oxidizing the compound represented by formula V to obtain 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-naphthoquinone (formula IV), enabling the compound represented by the formula IV to react with bromine in additive reaction to obtain 2,3-dibromo-2-(4-(4-chlorophenyl)cyclohexyl)-1,4-naphthoquinone (formula III), releasing a molecule of hydrogen bromide to obtain 3-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-1,4-naphthoquinone (formula II), hydrolyzing to obtain the atovaquone (formula I). Compared with the prior art, the method disclosed by the invention is simple in process, the expensive silver nitrate is prevented from using in the preparation process; and meanwhile, the yield is improved, the pollution to the environment is reduced, and the method has good popularization and application value.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of atovaquone. Background technique [0002] Atovaquone (Atovaquone) is a homologue of coenzyme Q, which is suitable for oral treatment of AIDS patients with mild to moderate pneumonia who cannot tolerate SMZ-TMP, and also exhibits certain antimalarial activity , whose chemical name is 2-(trans-4-(4-chlorophenyl)cyclohexyl)-3-hydroxyl-1,4-naphthalenedione, and its chemical structure is shown in formula Ⅰ [0003] [0004] In the prior art, the following methods are mainly used to synthesize atovaquone: [0005] ⑴ [0006] [0007] The main references of this method are US 5053432 and EP 0362996. The above-mentioned process is the main synthesis process of atovaquone at present, which consists of 2-chloro-1,4-naphthoquinone (chlorinated naphthoquinone) and 4-(4-chloro-naphthoquinone) Phenyl)-cyclohexyl-1-carboxylic acid condensation generation. The reac...

Claims

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Application Information

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IPC IPC(8): C07C50/32C07C46/00C07C39/42C07C37/62
CPCC07C46/00C07C37/16C07C46/06C07C50/32C07C50/24C07C39/42
Inventor 董咪咪颜丙春郭强董坤彭欣武茂成
Owner SHANDONG LUKANG SHELILE PHARMA
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