A kind of preparation method of Halofantrine hydrochloride

A technology of hydrochloride and halide, applied in the field of medicinal chemistry, can solve the problems of low free radical reaction yield, difficult industrial production, low reaction safety, etc., and achieves easy realization of reaction conditions, high reactivity and selectivity, The effect of reaction selectivity and specificity

Active Publication Date: 2022-05-17
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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  • A kind of preparation method of Halofantrine hydrochloride
  • A kind of preparation method of Halofantrine hydrochloride
  • A kind of 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] To a 500 ml four-mouth flask equipped with a stirring, thermometer, reflux condensing tube and a tail gas absorption device with a 20% NaOH aqueous solution, 350 g of dichloromethane, 69.8 g (0.2 moles) 4-trifluoromethyl-2- (3,5-dichlorophenyl) phenylacetic acid (II.), 20-30 °C dropwise add 27.5 g (0.23 moles) sulfoxide chloride, drop addition time 1 hour, thereafter 35-40 °C stirring reaction for 4 hours, distillation recovery of solvent and excess sulfoxide chloride. To give 72.5 g of colorless transparent liquid 4-trifluoromethyl-2-(3,5-dichlorophenyl)phenylacetyl chloride (III.), gas-phase purity of 99.6%, yield of 98.2%.

Embodiment 2

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

[0078] To a 500 ml four-mouth flask connected to a stirring, the thermometer, reflux condensing tube and a 20% NaOH aqueous solution of the tail gas absorption apparatus, 150 g of dichloromethane, 20.0 g (0.15 moles) of anhydrous aluminum trichloride, cooled, 5-10 ° C dropwise added 36.7 g (0.1 mole) embodiment 1 to obtain 4-trifluoromethyl-2- (3,5-dichlorophenyl) phenylacetyl chloride (III.) and 50 g dichloromethane mixed solution, 1 hour dropwise added, thereafter, Stir the reaction at 35 to 40 °C for 3 h. Cooled to 0-5 ° C, the resulting liquid is slowly added to 0-5 ° C of 200 g of 3% hydrochloric acid, layered, the aqueous layer with dichloromethane extracted twice, each time 50 g of dichloromethane, the combined organic phase in turn with 50 g of saturated sodium bicarbonate aqueous solution washed once, pure water washed 2 times, 50 g each time, organic phase distillation to ...

Embodiment 3

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

[0080]To a stirring, the thermometer, reflux condensing tube of 500 ml four-mouth flask, add 200 g of methanol, 22.5 g (0.11 moles) 27% sodium methanol methanol solution, heated to 50 to 55 ° C, at this temperature added dropwise 33.1 g (0.1 moles) embodiment 2 to give 3-trifluoromethyl -6,8-dichloro-9-keto-10-hydrophenanthrene (IV.) and 21.5 g (0.1 moles) N, N- di-n-butyl - β - methyl propionate (V). 1 and a mixed solution of 50 grams of methanol, added dropwise in 1 hour, and then kept warm at this temperature for 2 hours; the material is distilled and distilled dry methanol under reduced pressure, adding 50 grams of water and 200 grams of dichloromethane, Neutralized pH with acetic acid of 5.0-6.0, the organic phase was separated, the aqueous layer was extracted with dichloromethane twice, 50 g each time, the organic phase was combined, the d...

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Abstract

The invention provides a preparation method of halofantrolene hydrochloride. The method utilizes 4‑trifluoromethyl‑2‑(3,5‑dichlorophenyl) phenylacetic acid to generate corresponding acid chlorides with acyl chloride reagents, and then carry out Friedel-Crafts cyclization, followed by N,N-di-n-butyl Base-β-aminopropionate condensation, and finally through reduction, aromatization, and salt formation to obtain halofantrine hydrochloride. The method of the invention has cheap and easy-to-obtain raw materials and low cost; the reaction conditions are easy to realize, the technological process and operation are safe and convenient, the amount of waste water is generated less, and the method is environmentally friendly; the intermediate has good stability, high reactivity and selectivity, and few side reactions. The preparation of halofantrolene hydrochloride has less impurity, high purity and high yield.

Description

Technical field [0001] The present invention relates to a method for preparing halobendotriline hydrochloride, belonging to the field of medicinal chemical technology. Background [0002] Halofantrine is also known as halofantrine, English name halofantrine, CAS number is 69756-53-2. The structure of halobendotriline hydrochloride is as follows: [0003] [0004] Malaria is an infectious disease that has seriously endangered human health in human history, and with the development of medicine, human beings have gradually mastered various treatment methods. But in the 21st century, there are still many people who suffer from it, with 212 million cases of malaria reported in 2016 alone, of which 429,000 died, and malaria is still the enemy of human health. Halobendotriline is an antimalarial drug listed by SMITHKLINEBEECHAM in 1984, which is a phenanthrene methanol derivative with schizosome killing activity and has obvious efficacy in the treatment of falciparum malaria. [0005...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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