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A kind of preparation method of naftifine hydrochloride

A technology of naftifine hydrochloride and acid-binding agent, which is applied in the field of preparation of naftifine hydrochloride, can solve the problems of high cost, low yield and low purity of naftifine hydrochloride, achieve simple steps, shorten process production time, and save raw materials cheap effect

Active Publication Date: 2021-07-13
福建金山准点制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0021] Chinese patent CN1324790, through self-made raw material N-methyl-1-naphthylmethylamine, and cinnamyl chloride, 20-40% sodium hydroxide solution as an acid-binding agent, react in toluene, and get naphthalene hydrochloride after hydrochloric acidification tifen, the technique has been greatly improved, and the operation is simplified, but the yield and the purity of the finished product naftifine hydrochloride are all low
[0022] Chinese patent CN1011578 improves the above-mentioned process, takes N-methyl-1-naphthylmethylamine hydrochloride as raw material, and organic ethers as solvent, the product is purified by hydrochloric acid ethyl acetate solution, and then crystallized to obtain a higher quality product High finished product (HPLC purity ≥ 98.0%), but this process requires PEG-600 as a catalyst, and directly uses the raw material of splicing two fragments as the starting material, and the cost is higher

Method used

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  • A kind of preparation method of naftifine hydrochloride
  • A kind of preparation method of naftifine hydrochloride
  • A kind of preparation method of naftifine hydrochloride

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preparation example Construction

[0033] A preparation method of naftifine hydrochloride, comprising the following steps,

[0034] Step 1: Mix cinnamyl alcohol and dichloromethane to dissolve, control the temperature of the solution at 20-40°C, then add a chlorinated reagent and keep it warm for 2-6 hours, then add water to quench the reaction, then separate the organic phase, and use Wash the organic phase with saturated brine, let it stand, and then separate the organic phase and concentrate to obtain cinnamyl chloride;

[0035] Step 2: Mix the cinnamyl chloride in step 1 with the organic solvent as the reaction solvent, add dropwise to the methylamine solution, and keep it warm at 20-50°C for 1-5 hours, then concentrate to obtain a concentrate, and then add to the concentrate Dichloromethane was added to mix, filtered, and the filtrate was concentrated to obtain the crude product of trans-N-cinnamylmethylamine;

[0036] Step 3: Add toluene and acid-binding agent to the crude product of trans-N-cinnamylmeth...

Embodiment 1

[0057] A preparation method of naftifine hydrochloride, comprising the following steps:

[0058] Step 1: Dissolve cinnamyl alcohol (10g, 74.5mmol) in dichloromethane (50mL, 5V / w), stir evenly, control the temperature of the solution to 25°C, add thionyl chloride (13.3g, 111.8mmol) dropwise , dropwise, after 3 h of incubation at 25 ° C, add water (25 mL) to quench the reaction, separate the organic phase, and wash the organic phase with saturated brine (25 mL), let it stand, then separate the organic phase, and Concentrate under reduced pressure to obtain 11.2 g of brown liquid (cinnamyl chloride);

[0059] Step 2: Dissolve the brown liquid (cinnamyl chloride) in step 1 with absolute ethanol (11.2g) to obtain a feed solution. At 25°C, add the above feed solution dropwise to 45.6g of 30% methylamine ethanol solution ( Methylamine equivalent is about 6.0), dropwise, react for 2h, the reaction solution is concentrated under reduced pressure at 55°C until no liquid flows out, then...

Embodiment 2

[0066] A preparation method of naftifine hydrochloride, comprising the following steps:

[0067] Step 1: Dissolve cinnamyl alcohol (10g, 74.5mmol) in dichloromethane (50mL, 5V / W), stir evenly, control the temperature of the solution to 25°C, add thionyl chloride (16.0g, 89.1mmol) dropwise , dropwise, after 2h of heat preservation reaction at 25°C, add water (25mL) to quench the reaction, separate the organic phase, and then wash the organic phase with saturated brine (25mL), let it stand, separate the organic phase, and reduce Concentrate under reduced pressure to obtain 10.9 g of brown liquid (cinnamyl chloride).

[0068] Step 2: Dissolve the brown liquid (cinnamyl chloride) in step 1 with absolute ethanol (10.9g) to obtain a feed solution. At 25°C, add the above feed solution dropwise to 67.2g of 30% methylamine tetrahydrofuran solution ( Methylamine equivalent is about 8.0), dropwise, react for 2.5h, the reaction solution is concentrated under reduced pressure at 55°C unti...

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Abstract

The invention provides a preparation method of naftifine hydrochloride, which uses relatively cheap cinnamyl alcohol as a raw material, which is chlorinated by a chlorinated reagent, methylated, replaced by 1-chloromethylnaphthalene, and finally acidified to form a salt, crystallized and refined. to get the finished product. In the preparation method of the present invention, each intermediate in the first three steps of the reaction is reacted without purification, and the process continues without intermission, which simplifies the operation, improves the yield and production efficiency of the product, and ensures the purity of the product at the same time. It is industrialized and has the advantages of simple reaction conditions, low cost and environmental friendliness.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of naftifine hydrochloride. Background technique [0002] Naftifine hydrochloride is a substituted naphthylbenzylamine antifungal drug with the chemical name (E)-3-phenyl-2-propene-N-methyl-1-naphthylmethylamine hydrochloride. Molecular formula is C 21 h 22 NCl, molecular weight 323.9, structural formula: [0003] [0004] Naftifine hydrochloride has a strong affinity and inhibitory effect on squalene cyclooxygenase, so it is often used to treat skin and its accessories (hair, fingernails, toenails) caused by Trichophyton, Microsporum and epidermophyton Skin fungal infection caused by fungus, superficial pearl disease, onychomycosis, sugar rash. It has the characteristics of wide antibacterial spectrum and low toxicity, and was first listed in Malaysia and Singapore by the Swiss company Sandoz in 1984. [0005] There are many sy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C209/08C07C209/00C07C209/84C07C211/30
CPCC07C209/00C07C209/08C07C209/84C07C211/30C07C211/28
Inventor 王章跃沙其强柯庆勇
Owner 福建金山准点制药有限公司
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