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Preparation method of halofantrine hydrochloride

A hydrochloride and halogen flooding technology, applied in the field of medicinal chemistry, can solve the problems of large amount of wastewater, high cost, and many impurities

Active Publication Date: 2020-08-04
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] It can be seen from the synthetic route 3 that the existing method for preparing the phenanthrene ring uses ferrous sulfate to reduce the nitro group, and simultaneously uses copper to catalyze the cyclic formation. In this route, a large amount of waste water containing iron ions will inevitably be produced, and even more Wastewater containing heavy metal copper ions makes it difficult to treat wastewater; in addition, the last step reaction is a free radical reaction, which will produce a large number of polymerization by-products, resulting in low yield and high cost, causing difficulties for industrial production
[0016] In summary, the existing synthetic methods of halofantrine have a large amount of waste water, high cost of raw materials, low reaction safety, and low yield. During the process of constructing the phenanthrene ring, waste water containing iron ions and copper ions, and free radical reactions Problems such as low yield and many impurities

Method used

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  • Preparation method of halofantrine hydrochloride
  • Preparation method of halofantrine hydrochloride
  • Preparation method of halofantrine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1: Preparation of 4-trifluoromethyl-2-(3,5-dichlorophenyl)phenylacetyl chloride (Ⅲ)

[0076] Into a 500 ml four-necked flask equipped with a stirring, thermometer, reflux condenser and exhaust gas absorption device of 20% NaOH aqueous solution, 350 g of dichloromethane and 69.8 g (0.2 mole) of 4-trifluoromethyl-2-( 3,5-Dichlorophenyl)phenylacetic acid (II), 27.5g (0.23mol) of thionyl chloride was added dropwise at 20-30℃ for 1 hour, and then stirred and reacted at 35-40℃ for 4 hours, then distilled Recover solvent and excess thionyl chloride. 72.5 g of colorless transparent liquid 4-trifluoromethyl-2-(3,5-dichlorophenyl)phenylacetyl chloride (III) was obtained, with a gas phase purity of 99.6% and a yield of 98.2%.

Embodiment 2

[0077] Example 2: Preparation of 3-trifluoromethyl-6,8-dichloro-9-one-10-hydrophenanthrene (IV)

[0078] Into a 500 ml four-necked flask connected with a stirring, thermometer, reflux condenser and exhaust gas absorption device of 20% NaOH aqueous solution, add 150 g of dichloromethane, 20.0 g (0.15 mole) of anhydrous aluminum trichloride, cool, and At 5-10°C, add dropwise a mixed solution of 36.7 g (0.1 mole) of 4-trifluoromethyl-2-(3,5-dichlorophenyl)phenylacetyl chloride (Ⅲ) obtained in Example 1 and 50 g of dichloromethane , The dripping was completed in 1 hour, after that, the reaction was stirred at 35 to 40°C for 3 hours. Cool to 0-5°C, slowly add the obtained liquid to 200 g of 3% hydrochloric acid at 0-5°C, separate the layers, and extract the aqueous layer twice with dichloromethane, each time with 50 g of dichloromethane. The organic phase was washed with 50 grams of saturated sodium bicarbonate aqueous solution and twice with pure water, 50 grams each time, the organ...

Embodiment 3

[0079] Example 3: 3-Trifluoromethyl-6,8-dichloro-9-one-10-[3-(di-n-butylamino)ethyl-1-keto]-10-hydrophenanthrene (VI ) Preparation

[0080] Into a 500 ml four-necked flask connected with a stirring, thermometer, and reflux condenser, add 200 g of methanol, 22.5 g (0.11 mol) of 27% sodium methoxide methanol solution, heat to 50 to 55°C, and add 33.1 dropwise at this temperature G (0.1 mole) of 3-trifluoromethyl-6,8-dichloro-9-one-10-hydrophenanthrene (IV) obtained in Example 2 and 21.5 g (0.1 mole) of N,N-di-n-butyl- Methyl β-alanine (V 1 ) And a mixed solution of 50 grams of methanol, the dripping is completed in 1 hour, and then kept at this temperature for 2 hours; the material is distilled under reduced pressure to evaporate the methanol, 50 grams of water and 200 grams of dichloromethane are added, and the pH value is neutralized with acetic acid For 5.0-6.0, separate the organic phase, extract the water layer twice with dichloromethane, 50 grams each time, combine the organ...

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Abstract

The invention provides a preparation method of halofantrine hydrochloride. The method comprises the following steps: generating corresponding acyl chloride from 4-trifluoromethyl-2-(3, 5-dichlorophenyl) phenylacetic acid and an acylating chlorination reagent, carrying out Friedel-Crafts reaction cyclization, performing condensation with N, N-di-n-butyl-beta-aminopropionate, and finally, carrying out reduction, aromatization and salification to obtain the halofantralin hydrochloride. The method has the advantages of cheap and accessible raw materials and low cost; reaction conditions are easy to realize, the technological process and operation are safe, simple and convenient, less wastewater is generated, and environmental friendliness is achieved; and the intermediate is good in stability,the reaction activity and selectivity are high, there are fewer side reactions, and the prepared halofantrine hydrochloride is few in impurity, high in purity and high in yield.

Description

Technical field [0001] The invention relates to a preparation method of halofantrine hydrochloride, belonging to the technical field of medicinal chemistry. Background technique [0002] Halofantrine is also known as halofantrine, its English name is halofantrine, and its CAS number is 69756-53-2. The structural formula of halofantrine hydrochloride is as follows: [0003] [0004] Malaria is an infectious disease that has seriously endangered human health in human history. With the development of medicine, humans have gradually mastered various treatment methods. However, in the 21st century, many people are still suffering. In 2016 alone, 212 million cases of malaria were reported, of which 429,000 people died. Malaria is still the enemy of human health. Halovatraline is an antimalarial drug marketed by SMITHKLINEBEECHAM in 1984. It is a phenanthroline derivative with schizont killing activity and has obvious curative effect on the treatment of falciparum malaria. [0005] In th...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C215/38
CPCC07C213/00C07C221/00C07C45/46C07C51/60C07C2603/26C07C215/38C07C225/18C07C49/697C07C57/74
Inventor 江枭南戚聿新腾玉奇
Owner XINFA PHARMA
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