阅读说明：本技术 一种二氧化碳参与的布替萘芬的制备方法 (Preparation method of carbon dioxide-participated butenafine ) 是由 李新锋 郭志强 魏学红 于 2021-09-06 设计创作，主要内容包括：本发明提供了一种二氧化碳参与的布替萘芬的制备方法,所述制备方法以4-叔丁基苄胺、1-萘甲醛以及二氧化碳(CO-(2))为起始原料,以硼氢化钠为还原剂,经过还原胺化和还原甲基化一锅两步法合成目标产物。本发明方法简便、易操作,原料来源广泛,成本较低,同时合成中不需要过渡金属及贵金属等催化剂的参与,避免了金属在药物中的残留,安全、环保,符合绿色化学要求。(The invention provides a preparation method of butenafine with carbon dioxide, which comprises the following steps of 4-tert-butylbenzylamine, 1-naphthaldehyde and carbon dioxide (CO) 2 ) Sodium borohydride is used as a reducing agent as an initial raw material, and a target product is synthesized by a one-pot two-step method of reductive amination and reductive methylation. The method is simple and convenient, easy to operate, wide in raw material source and low in cost, simultaneously, the participation of catalysts such as transition metal, noble metal and the like is not needed in the synthesis, the residue of metal in the medicine is avoided, and the method is safe and environment-friendly and meets the green chemical requirement.)

1. A preparation method of butenafine participated by carbon dioxide is characterized in that the reaction equation is as follows:

2. the method of claim 1, comprising the steps of: adding 4-tert-butylbenzylamine, 1-naphthaldehyde and sodium borohydride into a reaction kettle, vacuumizing for replacing carbon dioxide for 2-4 times, adding dioxane serving as a reaction solvent, and stirring at room temperature for 12-18 hours; then adding a proper amount of sodium borohydride under the carbon dioxide gas flow, pressurizing the reaction kettle to 1MPa, heating to 80-100 ℃, and continuously stirring for 12-24 hours; after the reaction is finished, adding water to quench the reaction, and extracting the reaction by ethyl acetate; and mixing the organic phases, drying the organic phases with anhydrous sodium sulfate, concentrating the organic phases, and separating the organic phases by column chromatography to obtain the target compound.

3. The process for preparing butenafine with participation of carbon dioxide according to claim 2, wherein the charge amount in the reaction step is in a molar ratio of 4-tert-butylbenzylamine: 1-naphthaldehyde: sodium borohydride is 1: 1: 3-4.

Technical Field

The invention relates to the field of antifungal drug synthesis, in particular to a preparation method of butenafine with carbon dioxide participation.

Background

The chemical name of butenafine is N-methyl-N- (naphthalene-1-ylmethyl) -1- (4-tert-butylphenyl) methylamine, the trade name of butenafine is Mentax Cream, the compound is developed by Penederm corporation in 1992, the compound is currently marketed in China, Japan and the United states, and belongs to allylamine antifungal drugs, and the action mechanism of the compound is that the compound selectively inhibits fungal squalene epoxidase, interferes with the biosynthesis of ergosterol of fungal cell walls, influences the lipid metabolism of fungi, damages or dies fungal cells and plays a role in sterilization and bacteriostasis. It is mainly used for treating dermatophytosis infection such as tinea corporis, tinea cruris, tinea pedis and tinea versicolor.

At present, the main synthetic methods of butenafine are as follows:

(1) reacting 1-chloromethyl naphthalene with monomethylamine to obtain N-methyl-1-naphthylmethylamine, and reacting the N-methyl-1-naphthylmethylamine with p-tert-butyl benzyl chloride to obtain butenafine. In the preparation process of N-methyl-1-naphthylmethylamine, the disadvantages of low reaction yield of 1-chloromethyl naphthalene and monomethylamine, more side reactions and the like exist.

(2) 4-tert-butylbenzoic acid is subjected to acyl chlorination, methylation and lithium aluminum hydride reduction in sequence, and then nucleophilic substitution is carried out on 1-naphthalene benzyl chloride to obtain a target product (US 5021458). The whole process is complicated to operate and is accompanied with the problems of generation of a large amount of inorganic salt by-products and the like.

(3) 1-naphthaldehyde and 4-tert-butylbenzylamine are used as raw materials, carbon dioxide is used as a C1 source, and a target product is obtained under the catalysis of ruthenium (Angew. chem. int. Ed.,2014,53, 11010-11014). The synthesis process requires very high pressure [ CO ]₂/H₂(20/60bar)]The operation is not easy to carry out. In addition, noble metal ruthenium is used for catalysis, and the ruthenium catalyst is expensive, so that the synthesis cost is high, metal can remain in the synthesized drug due to the participation of the metal catalyst, and the development requirement of environmental protection and green is not met.

(4) 4-tert-butylbenzylamine and 1-naphthoyl chloride are subjected to substitution reaction in an organic solvent under the catalysis of alkali to generate an amidation product, and then the amidation product and formic acid are subjected to N-methylation reaction in the organic solvent under the catalysis of a non-metal boron compound by taking an organosilane compound as a reducing agent, and an amido bond is reduced to obtain a target product (CN 105130823B). The problems of high cost, complex post-treatment and the like also exist.

In order to solve the problems in the prior art, the invention provides a novel preparation method of butenafine with carbon dioxide.

Disclosure of Invention

The invention aims to provide a method for preparing butenafine by carbon dioxide participation, which is simple and convenient, has wide raw material sources and lower cost and is environment-friendly. Meanwhile, catalysts such as transition metal, noble metal and the like are not needed in the synthesis, so that the metal residue in the medicine is avoided, and the method is safe and environment-friendly and meets the green chemical requirement.

The invention provides a preparation method of butenafine with participation of carbon dioxide, which comprises the following steps: adding 4-tert-butylbenzylamine, 1-naphthaldehyde and sodium borohydride into a reaction kettle, vacuumizing for replacing carbon dioxide for 2-4 times, adding dioxane serving as a reaction solvent, and stirring at room temperature for 12-18 hours. Then adding a proper amount of sodium borohydride under the carbon dioxide gas flow, pressurizing the reaction kettle to 1MPa, heating to 80-100 ℃, and continuing stirring for 12-24 hours. After the reaction was completed, water was added to quench the reaction and extraction was performed with ethyl acetate. And mixing the organic phases, drying the organic phases with anhydrous sodium sulfate, concentrating the organic phases, and separating the organic phases by column chromatography to obtain the target compound.

Wherein 4-tert-butylbenzylamine: 1-naphthaldehyde: the molar ratio of sodium borohydride is 1: 1: 3-4.

Compared with the prior art, the invention does not need transition metal and noble metal catalysts, avoids the residue of metal in the medicine, has simple and convenient operation, high yield, easy separation and purification of products, low cost and little environmental pollution, and meets the requirement of green chemistry.

Drawings

FIG. 1 preparation of butenafine from example 1¹H NMR chart

FIG. 2 preparation of butenafine from example 1¹³C NMR chart

Detailed Description

The following specific examples are given only for the purpose of illustrating the present invention in detail and are not intended to limit the scope of the present invention.

Example 1

In a dry 25mL reaction vessel, 4-tert-butylbenzylamine (1.0mmol), 1-naphthaldehyde (1.0mmol), sodium borohydride (1.0mmol) were added in this order, carbon dioxide was replaced 3 times by vacuum pumping using a vacuum pump, dioxane (2mL) was added as a reaction solvent, and the reaction was stirred at room temperature for 18 hours. Then sodium borohydride (3.0mmol) is added under the carbon dioxide gas flow, and the reaction kettle is pressurized to1MPa, raising the temperature to 100 ℃, and continuing stirring for 24 hours. After the reaction was completed, water was added to quench the reaction and extraction was performed 3 times with ethyl acetate (10 mL). And combining the organic phases, drying the organic phases by anhydrous sodium sulfate, concentrating the organic phases, and separating the organic phases by column chromatography to obtain the target compound (butenafine). Yield: 76 percent.¹H NMR(600MHz,CDCl₃)δ8.22(d,J＝7.9Hz,1H),7.82(d,J＝7.3Hz,1H),7.74(d,J＝8.2Hz,1H),7.51-7.43(m,3H),7.41-7.36(m,1H),7.33(d,J＝8.3Hz,2H),7.28(d,J＝8.2Hz,2H),3.92(s,2H),3.57(s,2H),2.20(s,3H),1.30(s,9H).¹³C NMR(151MHz,CDCl₃)δ149.97(s),136.43(s),135.21(s),134.03(s),132.67(s),128.92(s),128.48(s),128.00(s),127.51(s),125.72(d,J＝16.6Hz),125.20(s),125.03(s),77.37(s),77.16(s),76.95(s),62.18(s),60.57(s),42.52(s),34.59(s),31.56(s).GC-MS:317.

Example 2

In a dry 25mL reaction vessel, 4-tert-butylbenzylamine (1.0mmol), 1-naphthaldehyde (1.0mmol), sodium borohydride (1.0mmol) were added in this order, carbon dioxide was replaced 3 times by vacuum pumping using a vacuum pump, dioxane (2mL) was added as a reaction solvent, and the reaction was stirred at room temperature for 18 hours. Then, sodium borohydride (2.0mmol) is added under the carbon dioxide gas flow, the reaction kettle is pressurized to 1MPa, the temperature is raised to 100 ℃, and the stirring is continued for 24 hours. After the reaction was completed, water was added to quench the reaction and extraction was performed 3 times with ethyl acetate (10 mL). And combining the organic phases, drying the organic phases by anhydrous sodium sulfate, concentrating the organic phases, and separating the organic phases by column chromatography to obtain the target compound (butenafine). Yield: 71 percent.

Example 3

In a dry 25mL reaction vessel, 4-tert-butylbenzylamine (1.0mmol), 1-naphthaldehyde (1.0mmol), sodium borohydride (1.0mmol) were added in this order, carbon dioxide was replaced 3 times by vacuum pumping using a vacuum pump, dioxane (2mL) was added as a reaction solvent, and the reaction was stirred at room temperature for 12 hours. Then adding sodium borohydride (3.0mmol) under the carbon dioxide gas flow, pressurizing the reaction kettle to 1MPa, heating to 80 ℃, and continuing stirring for 24 hours. After the reaction was completed, water was added to quench the reaction and extraction was performed 3 times with ethyl acetate (10 mL). And combining the organic phases, drying the organic phases by anhydrous sodium sulfate, concentrating the organic phases, and separating the organic phases by column chromatography to obtain the target compound (butenafine). Yield: and 69 percent.