Method for preparing atovaquone

A technology of atovaquone and chlorophenyl, which is applied in the field of preparation of antimalarial drugs, can solve the problems of high industrial production cost, many side reactions, and many impurities, and achieve improved product quality, improved dissolution, and increased conversion rate Effect

Inactive Publication Date: 2012-10-03
WUHAN TITON BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the solubility of acetonitrile to 4-(4-chlorophenyl)-cyclohexyl-1-carboxylic acid, 2-chloro-1,4-naphthoquinone and silver nitrate is very different, and with the addition of ammonium persulfate solution , the phenomenon of phase separation is becoming more and more obvious, and there are many side reactions. The reaction of this route produces many impurities, and the yield is low. The actual yield is only 20%, and the cost of industrial production is high.

Method used

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  • Method for preparing atovaquone
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  • Method for preparing atovaquone

Examples

Experimental program
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Effect test

Embodiment 1

[0025] 4-(4-chlorophenyl)cyclohexyl-1-carboxylic acid (4.95g, 0.02mol) and 2-chloro-1,4-naphthoquinone (4g, 0.02mol), silver nitrate (2.1g, 0.012mol) Put it into a mixed solvent of acetonitrile (80ml) and dichloromethane (20ml), add dropwise 100ml aqueous solution of sodium persulfate (12.3g, 0.05mol) at 60°C, dropwise for 4.5 hours, and raise the temperature to 80°C after the addition Insulate the reaction for 3 hours, lower it to normal temperature, add 50ml of chloroform and stir for 10 minutes, let it stand for stratification, separate the water phase, concentrate the organic phase under reduced pressure, evaporate the solvent, add 80ml of acetonitrile to the residue to dissolve under reflux, and filter while it is hot. Crystallize at about 0°C, filter, and dry the filter cake to obtain 4 g of yellow powdery solid, which is (3S)-2-chloro-3-(4-(4-chlorophenyl)cyclohexyl)-1,4- Naphthalenedione was added to 60ml methanol and refluxed for 30 minutes, 15ml of 10% (weight) potas...

Embodiment 2

[0027] 4-(4-chlorophenyl)cyclohexyl-1-carboxylic acid (4.95g, 0.02mol) and 2-chloro-1,4-naphthoquinone (4g, 0.02mol), silver nitrate (2.1g, 0.012mol) Put it into a mixed solvent of acetonitrile (80ml) and dichloromethane (20ml), add dropwise 100ml aqueous solution of potassium persulfate (14g, 0.05mol) at 60°C, add dropwise for 4.5 hours, and heat up to 80°C after the dropwise addition Reacted for 3 hours, and other operations were the same as in Example 1 to obtain 2.5 g of atovaquone with a yield of 33.1% and a purity (HPLC): 99.1%.

Embodiment 3

[0029] 4-(4-chlorophenyl)cyclohexyl-1-carboxylic acid (4.95g, 0.02mol) and 2-chloro-1,4-naphthoquinone (4g, 0.02mol), silver nitrate (2.1g, 0.012mol) Put it into a mixed solvent of acetonitrile (80ml) and dichloromethane (20ml), add dropwise 100ml aqueous solution of sodium percarbonate (16.3g, 0.05mol) at 60°C, dropwise for 4.5 hours, and raise the temperature to 80°C after the addition The reaction was incubated for 3 hours, and the remaining operations were the same as in Example 1 to obtain 1.9 g of atovaquone with a yield of 24.8% and a purity (HPLC): 98.2%.

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Abstract

The invention discloses a method for preparing atovaquone, which comprises the following steps: taking 4-(4-chlorophenyl)-cyclohexyl-1-methanoic acid and 2-chlorine-1, 4-naphthoquinone as raw materials, generating (3S)-2-chlorine-3-(4-(4-chlorophenyl) cyclohexyl)-1, 4-naphthalenedione by oxidative decarboxylation through a peroxide in the action of a catalyst of silver nitrate, and then obtaining the atovaquone through hydrolysis with alkaline. The method is characterized in that the mixed solvent of acetonitrile and choromethane is used as the solvent for the oxidative decarboxylation and the peroxide is one of the four substances, i.e., sodium persulfate, potassium persulfate, sodium percarbonate and potassium peroxycarbonate. The improved preparation method considerably improves the dissolution of the raw materials in the solvent, raises the rate of conversion, increases the yield, reduces impurities, and significantly enhances the product quality. Therefore, the method is more suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of antimalarial medicine, in particular to a preparation method of atovaquone. Background technique [0002] Malaria is one of the outstanding problems of public health in the world today, and it is the most widespread and harmful parasitic disease in the world. At present, there are many varieties of antimalarial drugs such as artemisinin, lumefantrine, and atovaquone, among which the synergistic effect of atovaquone and proguanil greatly enhances the antimalarial effect, and the side effects are the lowest among similar drugs Therefore, atovaquone has become the drug of choice for the prevention and treatment of malaria. [0003] The chemical name of atovaquone is (3S)-2-hydroxy-3-[4-(4-chlorophenyl)cyclohexyl]-1,4-naphthalenedione [CAS: 95233-18-4], which The structure is as follows: [0004] [0005] In the known preparation method of atovaquone, M.P.Clark & ​​D.R.Williams used self-synthesized cy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C50/32C07C46/00A61P33/06
Inventor 桂厚瑛周秋名胡新明
Owner WUHAN TITON BIOTECH
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