CN113773206B - Preparation method of carbon dioxide-participated butenafine - Google Patents

Preparation method of carbon dioxide-participated butenafine Download PDF

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CN113773206B
CN113773206B CN202111035688.3A CN202111035688A CN113773206B CN 113773206 B CN113773206 B CN 113773206B CN 202111035688 A CN202111035688 A CN 202111035688A CN 113773206 B CN113773206 B CN 113773206B
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butenafine
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sodium borohydride
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CN113773206A (en
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李新锋
郭志强
魏学红
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Shanghai Tianlong Pharmaceutical Co ltd
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Abstract

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.

Description

Preparation method of carbon dioxide-participated butenafine
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, which was developed by Penederm corporation in 1992, and the butenafine is currently marketed in China, Japan and the United states, and belongs to allylamine antifungal agents. It is mainly used for treating dermatophytosis infection such as tinea corporis, tinea cruris, tinea pedis and tinea versicolor.
At present, the main synthesis 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, wide in raw material source, lower in cost and 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 method 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 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 that order, carbon dioxide was displaced 3 times by vacuum pumping with a vacuum pump, dioxane (2mL) was added as the reaction solvent, and the reaction was stirred at room temperature for 18 hours. Then adding sodium borohydride (3.0mmol) under the carbon dioxide gas flow, pressurizing the reaction kettle to 1MPa, heating 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, the reaction was quenched by addition of water and extracted 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.

Claims (3)

1. A preparation method of butenafine participated by carbon dioxide is characterized in that the reaction equation is as follows:
Figure FDA0003246986220000011
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.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101077858A (en) * 2006-05-24 2007-11-28 凌沛学 Method for preparing butenafine hydrochloride
CN103664631A (en) * 2013-12-20 2014-03-26 西北师范大学 Preparation method of naftifine hydrochloride
CN105130823A (en) * 2015-04-16 2015-12-09 中国科学技术大学 Butenafine synthesis method
CN108047057A (en) * 2017-12-28 2018-05-18 山东铂源药业有限公司 A kind of synthetic method of Butenafine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101077858A (en) * 2006-05-24 2007-11-28 凌沛学 Method for preparing butenafine hydrochloride
CN103664631A (en) * 2013-12-20 2014-03-26 西北师范大学 Preparation method of naftifine hydrochloride
CN105130823A (en) * 2015-04-16 2015-12-09 中国科学技术大学 Butenafine synthesis method
CN108047057A (en) * 2017-12-28 2018-05-18 山东铂源药业有限公司 A kind of synthetic method of Butenafine

Non-Patent Citations (4)

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Title
Ruthenium-Catalyzed Reductive Methylation of Imines Using Carbon Dioxide and Molecular Hydrogen;Beydoun, Kassem et al.;《Angewandte Chemie, International Edition》;20141231;第53卷(第41期);11010-11014 *
抗真菌药布替萘芬的合成;凌云 等;《中国医药工业杂志》;19991231(第3期);102-103 *
新型抗真菌药布替萘芬类似物的合成;王大威 等;《山 东 大 学 学 报 （理 学 版）》;20041031;第39卷(第5期);99-101 *
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