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Synthetic method of terbinafine

A technology of terbinafine and a synthesis method, applied in the field of medicinal chemistry synthesis, can solve the problems of many side reactions, low reaction yield and the like, and achieve the effects of simple steps, high yield, and reduction of by-products.

Active Publication Date: 2018-05-11
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Said method is in the preparation process of N-methyl-1-naphthylmethylamine, and 1-chloromethylnaphthalene and monomethylamine reaction yield are lower, and side reaction is more

Method used

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  • Synthetic method of terbinafine
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1. Add 1000ml of purified water to a 2000ml four-necked reaction flask, slowly add 36g of monomethylamine to the water, then add 312g of potassium carbonate to the reaction flask, and add 1-chloromethylnaphthalene to two constant pressure funnels respectively 100g, 93.2g of 1-chloro-6,6-dimethyl-2-hepten-4-yne, temperature controlled at 10°C, slowly drop 1-chloromethylnaphthalene and 1-chloro-6,6-di Methyl-2-heptene-4-yne, control the rate of addition, so that 1-chloromethylnaphthalene and 1-chloro-6,6-dimethyl-2-heptene-4-yne are all added dropwise at the same time, Then, the temperature was controlled at 10°C and the reaction was incubated for 2 hours. Add 500ml of chloroform to the reaction solution to extract the reaction solution, control the temperature of the water bath at 60°C to concentrate the organic layer under reduced pressure to dryness, add 450ml of ethyl acetate to the residue, heat and reflux for 30 minutes, cool to below 10°C, and suction filte...

Embodiment 2

[0028] Example 2. Add 1000ml of purified water to a 2000ml four-necked reaction flask, slowly add 43.5g of monomethylamine to the water, then add 370.6g of potassium carbonate to the reaction flask, and add 1-chloroform to the two constant pressure funnels respectively Base naphthalene 117.7g, 1-chloro-6,6-dimethyl-2-hepten-4-yne 109.7g, temperature control 20 ℃, slowly drop 1-chloromethylnaphthalene and 1-chloro-6, 6-Dimethyl-2-heptene-4-yne, control the rate of addition, so that 1-chloromethylnaphthalene and 1-chloro-6,6-dimethyl-2-heptene-4-yne are dropped simultaneously After the addition was complete, the temperature was controlled at 20°C and the reaction was kept for 3 hours. Add 500ml of chloroform to the reaction solution to extract the reaction solution, control the temperature of the water bath at 60°C to concentrate the organic layer under reduced pressure to dryness, add 450ml of ethyl acetate to the residue, heat and reflux for 30 minutes, cool to below 10°C, and...

Embodiment 3

[0029] Example 3. Add 1000ml of purified water to a 2000ml four-necked reaction flask, slowly add 40.4g of monomethylamine to the water, then add 344g of potassium carbonate to the reaction flask, and add 1-chloromethyl to the two constant pressure funnels respectively Naphthalene 109g, 1-chloro-6,6-dimethyl-2-heptene-4-yne 101.8g, temperature control 15°C, slowly drop 1-chloromethylnaphthalene and 1-chloro-6,6- Dimethyl-2-hepten-4-yne, control the rate of addition, so that both 1-chloromethylnaphthalene and 1-chloro-6,6-dimethyl-2-hepten-4-yne are added dropwise at the same time , and then keep the temperature at 15°C for 2.5 hours. Add 500ml of chloroform to the reaction solution to extract the reaction solution, control the temperature of the water bath at 60°C to concentrate the organic layer under reduced pressure to dryness, add 450ml of ethyl acetate to the residue, heat and reflux for 30 minutes, cool to below 10°C, and suction filter to obtain The white solid was dri...

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Abstract

The invention provides a synthetic method of terbinafine. Monomethylamine, 1-chloromethyl naphthalene and 1-chloro-6,6-dimethyl-2-heptene-4-alkyne are subjected to a one-step reaction to generate theterbinafine. Particularly, the monomethylamine is slowly added into a solvent, and then an acid-binding agent is added; the 1-chloromethyl naphthalene and the 1-chloro-6,6-dimethyl-2-heptene-4-alkyneare simultaneously slowly dropwise added, and a dropwise adding speed is controlled so as to enable both the 1-chloromethyl naphthalene and the 1-chloro-6,6-dimethyl-2-heptene-4-alkyne to be simultaneously dropwise added up; a temperature control reaction is performed for 2 to 3 hours at a temperature of 10 to 20 DEG C; chloroform is added to extract reaction liquid, vacuum concentration is carried out on an organic layer to a dry state, and ethyl acetate is added into residues to carry out crystallization to obtain the terbinafine. The synthetic method is high in yield, simple in step and convenient to operate, generates few byproducts, and is beneficial to industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of terbinafine. Background technique [0002] Terbinafine is an allylamine antifungal drug, which inhibits squalene cyclooxygenase in the process of ergosterol synthesis in fungal cells, and makes squalene accumulate in cells to play a bactericidal effect. The sensitivity of human cells to this product is one ten thousandth of that of fungi. This product has a broad-spectrum antifungal effect, has a bactericidal effect on skin fungi, and has an antibacterial effect on Candida albicans. It is suitable for skin and nail infections caused by superficial fungi, such as tinea corporis, jock itch, athlete's foot, onychomycosis, and skin Candida albicans infections caused by Trichophyton, Microsporum canis, and Epidermophyton flocculus. [0003] Mainly used in the preparation process is the hydrochloride of terbinafine, the main synthetic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/08C07C211/30
CPCC07C209/08C07C211/30
Inventor 赵孝杰苏曼
Owner SHANDONG BOYUAN PHARM CO LTD
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