CN113493388A - Synthesis method of butenafine hydrochloride - Google Patents

Synthesis method of butenafine hydrochloride Download PDF

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CN113493388A
CN113493388A CN202010268275.9A CN202010268275A CN113493388A CN 113493388 A CN113493388 A CN 113493388A CN 202010268275 A CN202010268275 A CN 202010268275A CN 113493388 A CN113493388 A CN 113493388A
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butenafine hydrochloride
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methyl
butenafine
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CN113493388B (en
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于成彬
张乃华
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Lunan Pharmaceutical Group Corp
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    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of butenafine hydrochloride; n-methyl-1-naphthylmethylamine and p-tert-butyl benzyl alcohol are used as raw materials, and butenafine is synthesized under the action of a catalyst. Salifying with HCl/organic solvent, filtering, and drying the filter cake under reduced pressure to obtain butenafine hydrochloride; the product obtained by the invention has higher purity and yield.

Description

Synthesis method of butenafine hydrochloride
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of butenafine hydrochloride.
Background
Butenafine hydrochloride (butenafine hydrochloride), which is chemically known as N- (4-tert-butylphenyl) -N-methyl-1-naphthylmethylamine hydrochloride, is an allylamine antifungal drug developed by japan scientific research corporation and is first marketed in japan in 1992 under the trade name of Mentax. The product can inhibit squalene epoxidase activity of fungi with high selectivity, and inhibit biosynthesis of squalene and ergosterol in fungi, thereby destroying cell membrane formation of fungi and leading to death of fungi. Has the characteristics of wide antibacterial spectrum, high antibacterial activity, low recurrence rate, small side effect and the like, and is widely applied to clinic. The chemical structure is as follows:
Figure BDA0002442176940000011
the currently reported synthesis processes of butenafine mainly comprise the following processes:
the mainstream technology adopts the methods reported in the patents EP221781, CN1597660A, CN1727325A, CN101077858A and the document Yakugaku Zashi, 1991,111(2) 126-. The technology adopts naphthalene (or its downstream intermediate) as raw material, and adopts chloromethylation to synthesize 1-chloromethylnaphthalene, then makes it react with methylamine to produce N-methylnaphthalene methylamine, then makes it react with p-tert-butyl benzyl halide to make substitution and salification so as to obtain butenafine hydrochloride. The route is as follows:
Figure BDA0002442176940000012
the route has the advantages of easily obtained raw materials, simple operation and the like. However, the reaction is mostly carried out in dry DMF by using anhydrous sodium carbonate or anhydrous potassium carbonate as an acid-binding agent. DMF has a high boiling point and is inconvenient to recover; the p-tert-butylbenzyl bromide is usually obtained by brominating p-methyl tert-butylbenzene, has many byproducts during preparation, is relatively polluted and relatively high in cost, and is not suitable for industrial workshop production because severe operations such as reduced pressure distillation and the like are usually involved in refining the p-tert-butylbenzyl bromide. Meanwhile, due to the fact that side chain halohydrocarbon used in the N-alkylation reaction is excessive and the reaction temperature is high, disubstituted impurities are easy to generate, quaternary ammonium salt structural intermediates are further generated, quaternary ammonium salt impurities are easy to generate in the synthesis of finished products, the product purity is low, and the total yield is low after further refining (related structures of the impurities are shown as follows).
Figure BDA0002442176940000021
German applied chemistry angelw.chem.int.ed., 2014,53(41),11010-11014 reports that 1-naphthaldehyde and 4-tert-butylbenzylamine are used as raw materials, carbon dioxide is used as a carbon source, and a target product is prepared under the catalysis of ruthenium. The route is as follows:
Figure BDA0002442176940000022
however, the whole process in this method is complicated to operate and is accompanied by the formation of a large amount of inorganic salt as a by-product. Moreover, the conversion of the above end products requires very high pressures [ CO ]2/H2(20/60bar)]The method is carried out in the next step, and the operation requirement on equipment is high. In addition, because noble metal ruthenium is used for catalysis, the ruthenium catalyst is expensive, so that the production cost is high.
J.org.chem.,2018,83, 11886-type 11895 is reduced by 4-fluorobenzenethiol under the catalysis of cadmium selenide/cadmium sulfide and visible light, and then diisopropyl azodicarboxylate (DIAD) and triphenylphosphine are added. In the presence of the catalyst, the catalyst reacts with methyl iodide to prepare a target product. The route is as follows:
Figure BDA0002442176940000023
however, the process uses a heavy metal cadmium compound with high toxicity to synthesize a key intermediate, and the limit requirement is extremely low; when the target product is prepared, methyl is introduced by taking iodomethane with high toxicity and low boiling point as a carbon source, N-multi-alkylated quaternary ammonium salt impurities are also introduced, and the yield of the triphenylphosphine oxide generated after the reaction is low after repeated refining due to poor solubility.
In addition, in recent years, the research on genotoxic (or genotoxic) impurities has been increasingly emphasized for the quality control of raw material medicines. When the concentration of the genotoxic impurities is very low, the genetic materials of the human body can be damaged, so that gene mutation is caused, and tumors can be promoted. Therefore, the method has important practical significance in strictly controlling the content of related genotoxic impurities in the production process. In the process, reaction materials of monohaloalkane and naphthaldehyde have genotoxicity warning structures, and need to be subjected to risk assessment and strict limit requirements.
Patent US5021458 uses 1-naphthoic acid as raw material, chloridizes with thionyl chloride to obtain 1-naphthoyl chloride, condenses with 1- (4-tert-butylbenzyl) -N-methyl methylamine to obtain N- (4-tert-butylbenzyl) -N-methyl-1-naphthamide, and finally reduces with lithium aluminum hydride to form salt, thus obtaining butenafine hydrochloride. The route is as follows:
Figure BDA0002442176940000031
in addition, the patent also reports a method for preparing butenafine hydrochloride by using p-tert-butylbenzoic acid as a raw material, chlorinating the p-tert-butylbenzoic acid by thionyl chloride to obtain p-tert-butylbenzoyl chloride, condensing the p-tert-butylbenzoyl chloride with N-methylnaphthalene methylamine to obtain 4-tert-butyl-N-methyl-N- (methylnaphthalene) benzamide, and then reducing the N-tert-butylbenzoyl chloride by lithium aluminum hydride to form salt. The route is as follows:
Figure BDA0002442176940000032
however, both methods need to use acyl chloride with high toxicity and irritation, have high requirements on equipment and need to be carried out in a special reaction room; meanwhile, lithium aluminum hydride with stronger activity is needed in the reduction reaction, so that the operation risk is stronger, the production cost is higher, and the preparation method is not suitable for large-scale preparation.
Patent CN105130823B discloses a method for obtaining butenafine by taking 4-tert-butylbenzylamine as a raw material, 1-naphthoyl chloride and formic acid in an organic solvent, taking organosilane compounds [ diphenylsilane, diethylsilane, poly (methylhydrosiloxane), phenylsilane ] as reducing agents, and carrying out N-methylation reaction under the condition that non-metal boron compounds [ triethylboron, tris (pentafluorophenyl boron) ] are used as catalysts, and reducing amide bonds. The route is as follows:
Figure BDA0002442176940000033
the literature Angew. chem. int.Ed.,2015,54,9042-9046 uses 1-naphthoic acid as a raw material, and uses formic acid as a carbon source to prepare butenafine after being catalyzed by phenylboronic acid and reduced by an organic silane compound and a non-metallic boron compound. The route is as follows:
Figure BDA0002442176940000034
however, the reduction reaction of the method is applied to the organosilane compound and the nonmetal boron compound with higher price, so that the production cost is higher, and meanwhile, the reaction temperature of the organosilane compound and the nonmetal boron compound is higher, the reaction time is longer, and the method is not suitable for industrial production.
In summary, the reported technical methods for preparing butenafine mainly have the following problems:
(1) halogenated alkanes are used for N-alkylation reaction, so that N-over-alkylated impurities are easily generated and need to be further refined;
(2) in the reduction ammoniation process, expensive ruthenium is required to be used as a catalyst, so that the production cost is high;
(3) n-alkylation reaction material monohalogenated alkane and naphthaldehyde have genotoxicity warning structures and need to be subjected to risk assessment and strict limit requirements;
(4) an N-alkyl side chain is introduced by amide reduction, but the N-alkyl side chain needs to be applied to lithium aluminum hydride or an organosilane compound/non-metallic boron compound as a reducing agent, so that not only are the reaction conditions harsh, but also the production cost is high;
(5) heavy metal cadmium compounds with high toxicity are required to be applied in the reduction ammoniation process, so that the detection limit of finished products is extremely low.
In view of more problems in the prior art, the research and search for a preparation method which has mild reaction conditions, simple and convenient operation process, high product yield, high purity and low production cost and is suitable for industrial production of butenafine still needs to solve the problems at present.
Disclosure of Invention
Aiming at the problems of the prior art for preparing butenafine, the invention provides a method for synthesizing butenafine hydrochloride. The method can effectively avoid N-over-alkylation impurities and related genotoxicity warning structure impurities, and the prepared target product has higher purity and yield.
The specific technical scheme of the invention is as follows:
a synthesis method of butenafine hydrochloride comprises the following steps of reacting N-methyl-1-naphthylmethylamine with p-tert-butyl benzyl alcohol to obtain butenafine hydrochloride:
Figure BDA0002442176940000041
a synthetic method of butenafine hydrochloride specifically comprises the following steps:
under the protection of inert gas, adding a catalyst, N-methyl-1-naphthylmethylamine, p-tert-butyl benzyl alcohol and a reaction solvent into a sealing device, sealing and controlling the temperature until the reaction is finished, extracting by an extracting agent, concentrating the extract under reduced pressure, forming hydrochloride by HCl/an organic solvent, filtering, and drying the filter cake under reduced pressure to obtain the butenafine hydrochloride.
The catalyst is as follows: a Cp x Ir complex catalyst in combination with a base system; wherein the Cp IrI complex is preferably [ Cp IrI2]2、[Cp*IrCl2]2One of (1); among them, [ Cp IrCl ] is particularly preferable2]2Combined with a base.
Preferably, the base is NaHCO3，Na2CO3，K2CO3AcONa, TEA or a combination thereof, wherein NaHCO is particularly preferred3. The alkali can be prepared into an alkali aqueous solution, or can be directly added into the reaction.
In another preferred embodiment the catalyst is a Rh-based complex catalyst; preferably RhCl (PPh)3)3，RhH(PPh3)4One of (1);
preferably, the molar ratio of the N-methyl-1-naphthylmethylamine to the p-tert-butyl benzyl alcohol is 1: 1.0 to 1.1.
Preferably, the molar ratio of the N-methyl-1-naphthylmethylamine to the Cp Ir complex catalyst to the base is 1: 0.5% -5%: 1 to 10 percent. Among them, 1: 2%: 5 percent.
Preferably, the feeding molar ratio of the N-methyl-1-naphthalene methylamine to the Rh complex catalyst is 1: 0.5% to 5%, wherein 1: 2 percent.
Preferably, the reaction solvent is one or a combination of deionized water, benzene, toluene, xylene, 1, 4-dioxane, acetonitrile, and the like, wherein deionized water is particularly preferred.
Preferably, the temperature control reaction can place the sealing device in heating equipment with the temperature of 100-150 ℃. The heating device can be selected from heating equipment such as oil bath heating, electric heating sleeves, steam heating, electric furnaces and the like. The sealing equipment can be selected from a sealing glass tube, a stainless steel reaction kettle with good sealing performance, a sealing Schlenk device and the like. The invention is preferably validated with a Schlenk apparatus.
Preferably, the temperature-controlled reaction time is 5-10 hours; detection determinations may also be made.
Preferably, the extraction solvent is one or a combination of dichloromethane, chloroform and ethyl acetate.
Preferably, the HCl/organic solvent is one of HCl/methanol, HCl/ethanol, HCl/isopropanol, HCl/1, 4-dioxane, HCl/ethyl acetate or a combination thereof, wherein HCl/methanol is particularly preferred;
preferably, the concentration of the hydrochloric acid in the HCl/organic solvent is 0.5-4 mol/L, and particularly preferably 2 mol/L.
In the present invention, the inert gas is generally selected from nitrogen and argon, and argon is particularly preferred.
Compared with the prior art, the invention has the following technical effects:
(1) the catalyst is used for carrying out the N-alkylation mono-substitution reaction of the p-tert-butyl benzyl alcohol and the N-methyl-1-naphthylmethylamine, so that N-over-alkylation impurities are effectively avoided, the catalyst is less in use amount, the production cost is greatly reduced, and the yield and the purity of the obtained product are improved.
(2) The target product is obtained while the crude product is refined through one-step salification, the reaction steps are few, the post-treatment is simple, and the method is more suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
Materials used in the experiment: the compound N-methyl-1-naphthylmethylamine can be purchased and can also be prepared by referring to the prior published technology; the compound p-tert-butyl benzyl alcohol can be purchased or prepared according to the prior published technology; all materials used in other experiments, which have not been indicated for their origin and specification, are commercially available, analytically pure or chemically pure.
The invention adopts HPLC to measure the purity of butenafine, and the chromatographic conditions are as follows:
a chromatographic column: welch Ultimate XB-C18(4.6mm×150mm,3.0μm)；
Mobile phase: acetate buffer (taking 18.0g of sodium acetate, 9.8mL of glacial acetic acid, diluting to 1000mL with water) -methanol-isopropanol (17:70: 13);
column temperature: 30 ℃;
detection wavelength: 282 nm;
flow rate: 1.0 mL/min;
sample introduction amount: 10 μ L.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1
Under the protection of argon, [ Cp IrCl ] is added2]2Adding (1.59g, 0.002mol), sodium bicarbonate (0.42g, 0.005mol), N-methyl-1-naphthylmethylamine (17.12g, 0.10mol), p-tert-butyl benzyl alcohol (16.42g, 0.10mol) and deionized water (150mL) into a Schlenk device, hermetically placing the Schlenk device in a temperature-controlled 110 ℃ oil bath for reacting for 8 hours, cooling the reaction liquid to room temperature after the reaction is finished, adding dichloromethane (50mL multiplied by 3) for extraction, combining the extract liquid and concentrating the extract liquid under reduced pressure to dryness, adding HCl/methanol (150mL,2mol/L) for salifying, continuing stirring for crystallizing for 2-3 hours, and filtering, wherein the filter cake is butenafine hydrochloride after drying under reduced pressure, the yield is 96.3%, and HPLC: 99.89 percent.
Example 2
Under the protection of nitrogen, [ Cp IrCl ] is added2]2Adding (1.59g, 0.002mol), sodium bicarbonate (0.42g, 0.005mol), N-methyl-1-naphthylmethylamine (17.12g, 0.10mol), p-tert-butyl benzyl alcohol (18.07g, 0.11mol) and deionized water (150mL) into a Schlenk device, hermetically placing in a temperature-controlled 110 ℃ oil bath for reacting for 8 hours, cooling the reaction liquid to room temperature after the reaction is finished, adding dichloromethane (50mL multiplied by 3) for extraction, combining the extract liquid and concentrating under reduced pressure to dryness, adding HCl/methanol (300mL,0.5mol/L) for salifying, continuously stirring for crystallizing for 2-3 hours, filtering, and drying the filter cake under reduced pressure to obtain butenafine hydrochloride, wherein the yield is 96.8%, and HPLC: 99.80 percent.
Example 3
Argon shieldThen, [ Cp IrCl2]2(1.59g, 0.002mol), sodium bicarbonate (0.42g, 0.005mol), N-methyl-1-naphthylmethylamine (17.12g, 0.10mol), p-tert-butyl benzyl alcohol (18.89g, 0.115mol) and deionized water (150mL) are added into a Schlenk device, the Schlenk device is hermetically placed in a temperature-controlled 110 ℃ oil bath for reaction for 8 hours, after the reaction is finished, the reaction liquid is cooled to room temperature, dichloromethane (50mL multiplied by 3) is added for extraction, the extract liquid is combined and concentrated to be dry under reduced pressure, HCl/1, 4-dioxane (150mL,2mol/L) is added for salt formation, the mixture is continuously stirred for crystallization for 2-3 hours and then filtered, and the filter cake is dried under reduced pressure to obtain butenafine hydrochloride, the yield is 95.8%, HPLC: 99.76 percent.
Example 4
Under the protection of argon, [ Cp IrCl ] is added2]2Adding (0.40g, 0.0005mol), potassium carbonate (0.69g, 0.005mol), N-methyl-1-naphthylmethylamine (17.12g, 0.10mol), p-tert-butyl benzyl alcohol (16.42g, 0.10mol) and toluene (150mL) into a Schlenk device, hermetically placing in a temperature-controlled 130 ℃ oil bath for reaction for 10 hours, cooling the reaction liquid to room temperature after the reaction is finished, adding dichloromethane (50mL multiplied by 3) for extraction, combining the extract liquid and concentrating under reduced pressure to dryness, adding HCl/methanol (150mL,2mol/L) for salification, continuing stirring for crystallization for 2-3 hours, and filtering, wherein the filter cake is butenafine hydrochloride after drying under reduced pressure, the yield is 90.9%, and HPLC: 99.75 percent.
Example 5
Under the protection of argon, [ Cp IrCl ] is added2]2(3.98g, 0.005mol), sodium bicarbonate (0.42g, 0.005mol), N-methyl-1-naphthylmethylamine (17.12g, 0.10mol), p-tert-butyl benzyl alcohol (16.42g, 0.10mol) and deionized water (150mL) are added into a Schlenk device, the Schlenk device is hermetically placed in an oil bath with the temperature controlled at 110 ℃ for reaction for 5 hours, after the reaction is finished, the reaction liquid is cooled to room temperature, dichloromethane (50mL multiplied by 3) is added for extraction, the extraction liquid is combined and concentrated to be dry under reduced pressure, HCl/isopropanol (150mL,2mol/L) is added for salification, the mixture is continuously stirred for crystallization for 2-3 hours and then filtered, and the filter cake is butenafine hydrochloride after being dried under reduced pressure, the yield is 92.6%, and HPLC: 99.73 percent.
Example 6
Under the protection of argon, [ Cp ] IrI2]2(2.32g, 0.002mol), triethylamine (0.51g, 0.005mol), N-methyl-1-naphthylmethylamine (17.12g, 0).10mol), p-tert-butyl benzyl alcohol (16.42g, 0.10mol) and deionized water (150mL) are added into a Schlenk device, the Schlenk device is sealed and placed in an oil bath with the temperature controlled at 110 ℃ for reaction for 7 hours, after the reaction is finished, the reaction liquid is cooled to room temperature, dichloromethane (50mL multiplied by 3) is added for extraction, the combined extract liquid is decompressed and concentrated to be dry, HCl/ethanol (150mL,2mol/L) is added for salification, the mixture is continuously stirred for crystallization for 2 to 3 hours and then filtered, the filter cake is decompressed and dried to be butenafine hydrochloride, the yield is 95.8%, and HPLC: 99.84 percent.
Example 7
Under the protection of argon, [ Cp IrCl ] is added2]2(1.59g, 0.002mol), sodium bicarbonate (0.084g, 0.001mol), N-methyl-1-naphthylmethylamine (17.12g, 0.10mol), p-tert-butyl benzyl alcohol (16.42g, 0.10mol) and deionized water (150mL) are added into a Schlenk device, the Schlenk device is hermetically placed in an oil bath with the temperature controlled at 110 ℃ for reaction for 9 hours, after the reaction is finished, the reaction liquid is cooled to room temperature, ethyl acetate (50mL multiplied by 4) is added for extraction, the combined extract liquid is concentrated to be dry under reduced pressure, HCl/ethyl acetate (150mL,2mol/L) is added for salification, the mixture is continuously stirred for crystallization for 2-3 hours and then filtered, and the filter cake is dried under reduced pressure to obtain butenafine hydrochloride, the yield is 90.1%, and HPLC: 99.75 percent.
Example 8
Under the protection of argon, [ Cp IrCl ] is added2]2(1.59g, 0.002mol), sodium bicarbonate (0.84g, 0.01mol), N-methyl-1-naphthylmethylamine (17.12g, 0.10mol), p-tert-butyl benzyl alcohol (16.42g, 0.10mol) and deionized water (150mL) are added into a Schlenk device, the Schlenk device is hermetically placed in a temperature-controlled 110 ℃ oil bath for reaction for 6 hours, after the reaction is finished, the reaction liquid is cooled to room temperature, chloroform (50mL multiplied by 3) is added for extraction, the extraction liquid is combined and concentrated to be dry under reduced pressure, HCl/methanol (150mL,2mol/L) is added for salification, the mixture is continuously stirred for crystallization for 2-3 hours and then filtered, and the filter cake is butenafine hydrochloride after being dried under reduced pressure, the yield is 89.2%, HPLC: 99.72 percent.
Example 9
Under the protection of argon, RhCl (PPh)3)3(1.85g, 0.002mol), N-methyl-1-naphthylmethylamine (17.12g, 0.10mol), p-tert-butyl benzyl alcohol (16.42g, 0.10mol) and 1, 4-dioxane (150mL) are added into a stainless steel reaction kettle, the stainless steel reaction kettle is hermetically placed in an oil bath with the temperature controlled at 150 ℃ for reaction for 5 hours, and after the reaction is finished, the stainless steel reaction kettle is sealed and placed in an oil bath with the temperature controlled at 150 DEG for reactionCooling the reaction solution to room temperature, adding dichloromethane (50mL multiplied by 3) for extraction, combining extract solutions, concentrating the extract solutions under reduced pressure to dryness, adding HCl/methanol (150mL,2mol/L) for salification, continuing stirring for crystallization for 2-3 h, filtering, drying a filter cake under reduced pressure to obtain butenafine hydrochloride, wherein the yield is 94.5%, and performing HPLC: 99.85 percent.
Example 10
Under the protection of argon, adding RhH (PPh)3)4(2.31g, 0.002mol), N-methyl-1-naphthylmethylamine (17.12g, 0.10mol), p-tert-butyl benzyl alcohol (16.42g, 0.10mol) and acetonitrile (150mL) are added into a Schlenk device, the Schlenk device is hermetically placed in a temperature-controlled 120 ℃ oil bath for reaction for 6 hours, after the reaction is finished, the reaction liquid is cooled to room temperature, dichloromethane (50mL multiplied by 3) is added for extraction, the combined extract liquid is decompressed and concentrated to dryness, HCl/methanol (150mL,2mol/L) is added for salification, the mixture is continuously stirred for crystallization for 2 to 3 hours and then filtered, the filter cake is decompressed and dried to obtain butenafine hydrochloride, the yield is 96.1%, and HPLC: 99.81 percent.
Example 11
Under the protection of argon, [ Cp IrCl ] is added2]2(1.59g, 0.002mol), sodium bicarbonate (0.42g, 0.005mol), N-methyl-1-naphthylmethylamine (17.12g, 0.10mol), p-tert-butyl benzyl alcohol (16.42g, 0.10mol) and benzene (150mL) are added into a Schlenk device, the Schlenk device is hermetically placed in a temperature-controlled 110 ℃ oil bath for reaction for 8 hours, after the reaction is finished, the reaction liquid is cooled to room temperature, dichloromethane (50mL multiplied by 3) is added for extraction, the extract liquid is combined and concentrated to dryness under reduced pressure, HCl/methanol (150mL,2mol/L) is added for salt formation, the mixture is continuously stirred and crystallized for 2-3 hours, and then filtered, the filter cake is dried under reduced pressure to obtain butenafine hydrochloride, the yield is 94.2%, and HPLC: 99.87 percent.
Example 12
Under the protection of argon, [ Cp IrCl ] is added2]2Adding (1.59g, 0.002mol), sodium bicarbonate (0.42g, 0.005mol), N-methyl-1-naphthylmethylamine (17.12g, 0.10mol), p-tert-butyl benzyl alcohol (16.42g, 0.10mol) and xylene (150mL) into a glass tube, sealing the glass tube, placing the glass tube in an electric furnace with the temperature of 140 ℃ for reaction for 5 hours, cooling the reaction liquid to room temperature after the reaction is finished, adding dichloromethane (50mL multiplied by 3) for extraction, combining the extract liquid, concentrating the extract liquid under reduced pressure to dryness, adding HCl/methanol (150mL,2mol/L) for salification, continuing stirring for crystallization for 2-3 hours, filtering, reducing the filter cake weight, and obtaining the productDrying under pressure to obtain butenafine hydrochloride with the yield of 95.4 percent, HPLC: 99.85 percent.

Claims (10)

1. The synthesis method of butenafine hydrochloride is characterized in that the butenafine hydrochloride is obtained by reacting N-methyl-1-naphthylmethylamine with p-tert-butyl benzyl alcohol, and the reaction formula is as follows:
Figure FDA0002442176930000011
2. the method for synthesizing butenafine hydrochloride according to claim 1, which comprises the following steps: under the protection of inert gas, adding a catalyst, N-methyl-1-naphthylmethylamine, p-tert-butyl benzyl alcohol and a reaction solvent into a sealing device, sealing and controlling the temperature until the reaction is finished, extracting by an extracting agent, concentrating the extract under reduced pressure, forming hydrochloride by HCl/an organic solvent, filtering, and drying the filter cake under reduced pressure to obtain the butenafine hydrochloride.
3. The method of synthesizing butenafine hydrochloride according to claim 1 or 2, wherein the catalyst is: a Cp x Ir complex catalyst in combination with a base system; Cp-Ir complex catalyst is [ Cp-IrI2]2Or [ Cp IrCl ]2]2One kind of (1).
4. The method for the synthesis of butenafine hydrochloride according to claim 1 or 2, wherein the catalyst is an Rh-based complex catalyst, preferably RhCl (PPh)3)3，RhH(PPh3)4One kind of (1).
5. The method of synthesizing butenafine hydrochloride of claim 3 wherein said base is NaHCO3、Na2CO3、K2CO3AcONa, TEA or a combination thereof, wherein NaHCO is particularly preferred3。
6. The method for synthesizing butenafine hydrochloride according to claim 1 or 2, wherein the molar ratio of N-methyl-1-naphthylmethylamine to p-tert-butylbenzyl alcohol is 1: 1.0 to 1.1.
7. The method of synthesizing butenafine hydrochloride according to claim 3, wherein the molar ratio of N-methyl-1-naphtalenemethylamine, Cp Ir complex catalyst and base is 1: 0.5% -5%: 1 to 10 percent.
8. The method for synthesizing butenafine hydrochloride according to claim 4, wherein the molar ratio of the N-methyl-1-naphthylmethylamine to the Rh complex catalyst is 1: 0.5 to 5 percent.
9. The synthesis method of butenafine hydrochloride according to claim 2, wherein the reaction solvent is one or a combination of deionized water, benzene, toluene, xylene, 1, 4-dioxane and acetonitrile, and particularly preferably deionized water; the temperature control reaction can place the sealing device in heating equipment with the temperature of 100-150 ℃.
10. The synthesis method of butenafine hydrochloride according to claim 2, wherein the extraction solvent is one or a combination of dichloromethane, chloroform and ethyl acetate; the HCl/organic solvent is one or the combination of HCl/methanol, HCl/ethanol, HCl/isopropanol, HCl/1, 4-dioxane and HCl/ethyl acetate.
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CN1727325A (en) * 2005-06-24 2006-02-01 焦家良 Compound of butenafine hydrochloride, preparation method, and application as medication for restraining and killing fungus
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