A compound useful as an intermediate in the preparation of butenafine

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a butenafine intermediate compound and a preparation method thereof. The butenafine intermediate compound I is prepared by taking N-(4-tert-butylbenzyl)-naphthalenemethylamine as a starting material, and reacting the starting material with an acylation reagent under the action of an acid binding agent. The hydrochloric acid butenafine is prepared by performing a one-step reduction reaction on the compound I. Compared with the prior art, the preparation method can effectively avoid the use of genotoxic reagents, such as methyl iodide and formaldehyde. The target product is obtained by performing a one-step salification on a crude product, so that the reaction steps are less, the post-treatment is simple, the yield and purity are relatively high, and the method is more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a butenafine intermediate compound and its preparation method. Background Technology

[0002] Butenafine hydrochloride, chemically named N-(4-tert-butylphenyl)-N-methyl-1-naphthylamine hydrochloride, is an allylamine antifungal drug developed by Nippon Research Corporation and first marketed in Japan in 1992 under the brand name Mentax. This drug selectively inhibits the activity of fungal squalene epoxidase and the biosynthesis of squalene and ergosterol within the fungus, thereby disrupting fungal cell membrane formation and leading to fungal death. It features a broad antibacterial spectrum, high antibacterial activity, low recurrence rate, and few side effects, and is widely used clinically. Its chemical structure is shown below:

[0003]

[0004] The main synthetic processes for butenafine reported so far are as follows:

[0005] The mainstream process adopts the methods reported in patents EP221781, CN1597660A, CN1727325A, CN101077858A and literature such as Yakugaku Zasshi, 1991, 111(2):126-137, and China Pharmaceutical Industry Magazine, 1999, (3):102-103. This process uses naphthalene (or its downstream intermediate) as raw material to first synthesize 1-chloromethylnaphthalene through chloromethylation, then reacts with methylamine to generate N-methylnaphthylmethylamine, and then condenses with p-tert-butylbenzyl halide to form a salt to obtain butenafine hydrochloride. The chemical reaction formula is as follows:

[0006]

[0007] While this route offers advantages such as readily available raw materials and simple operation, the reactions often occur in dry DMF using anhydrous sodium carbonate or anhydrous potassium carbonate as acid-binding agents. DMF has a high boiling point, making recovery difficult. Furthermore, p-tert-butylbenzyl bromide is typically obtained by brominating p-methyl-tert-butylbenzene, resulting in numerous byproducts, significant pollution, and high costs, making it unsuitable for industrial production. Additionally, the excessive use of side-chain halogenated hydrocarbons and the high reaction temperature during N-alkylation reactions readily generate disubstituted impurities, leading to quaternary ammonium salt intermediates. Quaternary ammonium salt impurities are also easily generated during the synthesis of the final product, resulting in low product purity and, even after further purification, a low overall yield (the impurity-related structures are shown below).

[0008]

[0009] Patent US5021458 uses 1-naphthoic acid as a raw material, chlorinates it with thionyl chloride to obtain 1-naphthoyl chloride, then condenses it with 1-(4-tert-butylbenzene)-N-methylmethylamine to obtain N-(4-tert-butylbenzyl)-N-methyl-1-naphthoamide, and finally reduces it with lithium aluminum hydride to form a salt, thus obtaining butenafine hydrochloride.

[0010]

[0011] In addition, the patent also reports a method for preparing butenafine hydrochloride by chlorinating p-tert-butylbenzoic acid with thionyl chloride to obtain p-tert-butylbenzoyl chloride, condensing it with N-methylnaphthylamine to obtain 4-tert-butyl-N-methyl-N-(methylnaphthyl)benzamide, and then reducing it with lithium aluminum hydride to form a salt.

[0012]

[0013] However, both of these methods require the use of acyl chlorides, which are highly toxic and irritating. They also require sophisticated equipment, need to be carried out in special reaction rooms, and are therefore highly dangerous and unsuitable for large-scale preparation.

[0014] Patent CN105130823B discloses a method for obtaining butenafine by reacting 4-tert-butylbenzylamine with 1-naphthoyl chloride and formic acid in an organic solvent, using organosilane compounds [diphenylsilane, diethylsilane, poly(methylhydrosiloxane), phenylsilane] as reducing agents, and non-metallic boron compounds [triethylboron, tris(pentafluorophenylboron)] as catalysts to undergo an N-methylation reaction, while the amide bond is reduced. This process also uses acyl chlorides to prepare related intermediates, which is inconvenient to operate and increases the cost of industrial production.

[0015]

[0016] The literature Angew. Chem. Int. Ed., 2015, 54, 9042-9046 describes the preparation of butenafine using 1-naphthoic acid as a raw material, which is catalyzed by phenylboronic acid and then reduced by organosilanes and non-metallic boron compounds, with formic acid as the carbon source.

[0017]

[0018] However, this type of method uses expensive organosilane compounds and non-metallic boron compounds for reduction reactions, resulting in high production costs. In addition, the latter have high reaction temperatures and long reaction times, making them unsuitable for industrial production.

[0019] Angewandte Chemie Int. Ed., 2014, 53(41), 11010-11014 reported the preparation of the target product using 1-naphthoaldehyde and 4-tert-butylbenzylamine as raw materials and carbon dioxide as a carbon source under ruthenium catalysis.

[0020]

[0021] However, this method is complex to operate and generates a large amount of inorganic salt byproducts; moreover, the conversion process of the above-mentioned final products needs to be carried out under high pressure [CO2 / H2(20 / 60bar)], which places high demands on the operation of the equipment; in addition, the use of expensive metal ruthenium for catalysis makes the production cost high.

[0022] J.Org.Chem., 2018, 83, 11886-11895 describes the preparation of the target product by reduction with 4-fluorobenzenethiol under cadmium selenide / cadmium sulfide and visible light catalysis, followed by reaction with iodomethane in the presence of diisopropyl azodicarbonate (DIAD) and triphenylphosphine.

[0023]

[0024] This process uses a key intermediate in the synthesis of a highly toxic heavy metal cadmium compound, and the limit requirements for its use are extremely low. When preparing the target product, iodomethane, which is highly toxic and has a low boiling point, is used as a carbon source to introduce methyl groups, which will also introduce N-polyalkylated quaternary ammonium salt impurities. In addition, the triphenylphosphine oxide generated after the reaction is highly polar and has good solubility, making it difficult to separate, which leads to a decrease in the yield of the final product after repeated purification.

[0025] In summary, given the numerous problems with existing technologies for preparing butenafine, finding a suitable method for the industrial production of butenafine that features mild reaction conditions, simple operation, and high product yield and purity remains a problem that needs to be solved. Summary of the Invention

[0026] To address the problems existing in current butenafine preparation techniques, this invention provides a butenafine intermediate compound and its preparation method. The synthetic process for further preparing butenafine hydrochloride from this intermediate is simple, effectively avoids the use of genotoxic methylating agents, and yields a target product with high purity and high yield.

[0027] The specific technical solution of the present invention is as follows:

[0028] A butenafine intermediate compound, as shown in Formula I, has the following structural formula:

[0029]

[0030] A method for preparing butenafine intermediate compound I, using N-(4-tert-butylbenzyl)-naphthylmethylamine (SM-1) as the starting material, reacts with an acylation reagent in the presence of an acid-binding agent to obtain compound I. The synthetic route is as follows:

[0031]

[0032] Preferably, the preparation method of the butenafine intermediate compound I is as follows: temperature control T 1A SM-1 was added to a mixed solution of acylation reagent, acid-binding agent, and reaction solvent A, and the temperature was controlled at T. 1B Compound I was obtained after the reaction was completed.

[0033] Preferably, the acylation reagent is selected from one or a combination of CbzCl, BocCl, Boc anhydride, and FmocCl, with BocCl being the most preferred.

[0034] Preferably, the acid-binding agent is selected from one or a combination of K2CO3, Na2CO3, triethylamine, N,N-diisopropylethylamine, and pyridine, with triethylamine being the most preferred.

[0035] Preferably, the reaction solvent A is selected from one or a combination of dichloromethane and chloroform, with dichloromethane being the most preferred.

[0036] Preferably, the molar ratio of SM-1 to the acylation reagent and the acid-binding agent is 1:1.05 to 1.3:1.4 to 2.2, and more preferably 1:1.1:1.5.

[0037] Preferably, the reaction temperature T 1A The temperature range is -10 to 10°C, preferably 0 to 5°C; T 1B The temperature range is 15–50℃, with 25–30℃ being preferred.

[0038] In a preferred embodiment, a post-processing operation is required after the reaction is completed. The specific steps are as follows: filter the reaction solution, wash the filtrate with saturated sodium bicarbonate solution, wash with saturated saline solution, and concentrate under reduced pressure to dryness to obtain compound I.

[0039] On the other hand, the present invention provides a method for preparing butenafine hydrochloride from the butenafine intermediate compound shown in Formula I. Compound I reacts with LiAlH4, and after the reaction is completed, butenafine hydrochloride is obtained through post-treatment. The reaction formula is as follows:

[0040]

[0041] Preferably, the method for preparing butenafine hydrochloride from the intermediate compound shown in Formula I is as follows: LiAlH4 is suspended in reaction solvent B, and the temperature is controlled at T. 2A Add compound I, and control the temperature T. 2BThe reaction was continued until it was completed, and after post-processing, butenafine hydrochloride was obtained.

[0042] Preferably, the reaction solvent B is one or a combination of tetrahydrofuran, diethyl ether, and preferably tetrahydrofuran.

[0043] Preferably, the molar ratio of compound I to LiAlH4 is 1:4.0 to 8.0, more preferably 1:6.0.

[0044] Preferably, the reaction temperature T 2A The temperature range is -10 to 10°C, preferably 0 to 5°C; T 2B The reflux temperature of reaction solvent B is .

[0045] In a preferred embodiment, the post-processing operation specifically includes the following steps: cooling the reaction solution to room temperature, quenching the reaction, filtering, extracting the filtrate with organic solvent C, combining the organic phases, washing with purified water, washing with saturated brine, concentrating the organic phase, drying, and then salting the obtained butenafine with HCl / organic solvent D, filtering, drying the filter cake, and obtaining butenafine hydrochloride.

[0046] Preferably, the quenching reaction method is a quenching method commonly used in the reduction reaction of lithium aluminum hydride, such as quenching with 5% ammonium chloride, quenching with water and 10% NaOH, etc.

[0047] Preferably, the organic solvent C is one of dichloromethane, chloroform, and ethyl acetate, with dichloromethane being the most preferred.

[0048] Preferably, the HCl / organic solvent D is one or a combination of HCl / methanol, HCl / ethanol, HCl / isopropanol, HCl / 1,4-dioxane, and HCl / ethyl acetate, with HCl / methanol being the most preferred.

[0049] The beneficial effects of this invention are:

[0050] This invention provides a novel intermediate compound I for butenafine hydrochloride and a novel method for preparing butenafine hydrochloride using compound I. The invention uses N-(4-tert-butylbenzyl)-naphthylmethylamine as the starting material, reacts it with an acylation reagent, and then reduces it with LiAlH4 to obtain butenafine hydrochloride. Using acylation reagents such as CBzCl, BocCl, Boc anhydride, and FmocCl as carbon sources effectively avoids the use of genotoxic reagents iodomethane and formaldehyde. Through a one-step salt formation, the crude product is purified to obtain the target product simultaneously. The reaction steps are few, the post-processing is simple, and the yield and purity are improved, making this invention more suitable for industrial production. Detailed Implementation

[0051] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0052] Materials used in the experiment: Compound N-(4-tert-butylbenzyl)-naphthylmethylamine (SM-1) can be purchased or prepared by referring to existing publicly available techniques; other materials used in the experiment whose source and specifications are not specified are commercially available analytical grade or chemically pure.

[0053] Confirmation of the structure of the compound obtained in this invention:

[0054]

[0055] 1 H-NMR (600MHz, DMSO-d6) δ7.96 (td, J=7.68, 0.96Hz, 1H), 7.91 (dd, J=8.36, 1.13 Hz,1H),7.78(td,J=7.50,1.22Hz,1H),7.56(dt,J=7.76,1.37Hz,1H),7.44(t,J= 7.46Hz, 1H), 7.39~7.29 (m, 3H), 7.18~7.11 (m, 2H), 7.06 (dd, J=7.35, 1.15Hz, 1H ),5.36(s,1H),5.19(s,1H),4.44(s,1H),4.38(s,1H),1.55(s,9H),1.38(s,9H); 13 C NMR (151MHz, DMSO-d6) δ153.42,149.56,136.43,133.69,132.28,131.07,128.77,128.75,127. 45,127.24,126.47,126.01,125.88,125.06,124.55,80.86,47.90,47.36,34.40,31.45,28.46.

[0056]

[0057] 1H-NMR(600MHz,DMSO-d6)δ7.91(td,J=7.52、1.08Hz,1H),7.84(dd,J=7.55、1.26Hz,1H),7.75(td,J=7.68、1.35Hz,1H),7.51(dt,J=7.50、1.44Hz,1H),7.44(t,J=7.43Hz,1H),7.36~7.23(m,8H),7.16~7.10(m,2H),7.08(dd,J=7.50、1.44Hz,1H),5.32(s,1H),5.17(s,1H),5.13(s,2H),4.50(s,1H),4.36(s,1H),1.37(s,9H); 13 C NMR(151MHz,DMSO-d6)δ154.28,150.64,137.62,137.09,133.69,132.28,131.07,128.77,128.76,128.32,128.18,128.16,127.50,127.24,126.47,126.02,125.86,125.09,124.56,67.04,48.90,47.45,34.31,31.43。

[0058]

[0059] 1 H-NMR(600MHz,DMSO-d6)δ7.88(td,J=7.50、1.36Hz,1H),7.76(dd,J=7.32、1.25Hz,2H),7.71(td,J=7.46、1.17Hz,1H),7.61(dd,J=7.48、1.32Hz,1H),7.51~7.46(m,3H),7.39(t,J=7.50Hz,1H),7.34(dt,J=7.40、1.34Hz,2H),7.31~7.23(m,5H),7.09~7.04(m,2H),6.98(dd,J=7.50、1.38Hz,1H),5.10(s,1H),5.07(s,1H),4.70(d,J=1.95Hz,2H),4.46(t,J=1.95Hz,1H),4.40(s,1H),4.28(s,1H),1.36(s,9H); 13C-NMR(151MHz,DMSO-d6)δ156.42,150.54,144.73,139.41,137.62,133.70,132.26,131.07,128.77,128.75,128.64,127 .48,127.42,127.22,126.45,126.02,125.84,125.07,124.56,124.21,122.79,67.10,48.90,48.03,47.47,34.30,31.42.

[0060]

[0061] ESI-HRMS (m / z): 318.2249 [M+H] + . 1 H-NMR(600MHz,MeOD)δ7.76(d,J=8.28Hz,

[0062] 1H), 7.97 (td, J=8.04, 0.68Hz, 1H), 7.74 (dd, J=7.02, 0.96Hz, 1H), 7.66 (dd, J=8.30, 0.42Hz, 1H), 7.56~7.61 (m, 4H) ,7.51~7.55(m,3H),5.01(d,J=13.56Hz,1H),4.61(d,J=13.56Hz,1H),4.43~4.53(m,2H),2.83(s,3H),1.37(s,9H); 13 C-NMR(151MHz,MeOD)δ155.04,135.52,133.14,132.49,132.37,132.35,130.32,128.6 3,127.93,127.65,127.50,126.79,126.47,123.66,61.36,56.60,40.77,35.74,31.63.

[0063] This invention uses HPLC to determine the purity of butenafine, and the chromatographic conditions are as follows:

[0064] Column: Welch Ultimate XB-C 18 (4.6mm×150mm, 3.0μm);

[0065] Mobile phase: Acetate buffer (18.0 g sodium acetate, 9.8 ml glacial acetic acid, diluted with water to 1000 ml) - methanol - isopropanol (17:70:13);

[0066] Column temperature: 30℃;

[0067] Detection wavelength: 282nm;

[0068] Flow rate: 1.0 ml / min;

[0069] Injection volume: 10 μl.

[0070] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0071] Synthesis of Compound I

[0072] Example 1

[0073] At room temperature, BocCl (15.02 g, 0.11 mol) and triethylamine (15.18 g, 0.15 mol) were added to 200 ml of dry dichloromethane. The mixture of N-(4-tert-butylbenzyl)-naphthylamine (30.34 g, 0.10 mol) and 100 ml of dry dichloromethane was added while maintaining the temperature at 0–5 °C. The reaction was continued at 25–30 °C. After the reaction was confirmed to be complete, the mixture was filtered. The filtrate was washed with 100 ml × 2 saturated sodium bicarbonate solution and 100 ml saturated brine. The organic phase was concentrated under reduced pressure to dryness to obtain 38.79 g of compound I-1, with a yield of 95.2% and a purity of 99.14%.

[0074] Example 2

[0075] At room temperature, BocCl (14.34 g, 0.105 mol) and K2CO3 (20.73 g, 0.15 mol) were added to 200 ml of dry dichloromethane. The mixture was then heated to 5–10 °C and a solution of N-(4-tert-butylbenzyl)-naphthylamine (30.34 g, 0.10 mol) in 100 ml of dry dichloromethane was added. The reaction was continued at 30–35 °C. After the reaction was confirmed to be complete, the mixture was filtered. The filtrate was washed with 100 ml × 2 saturated sodium bicarbonate solution and 100 ml saturated brine. The organic phase was concentrated under reduced pressure to dryness to obtain 37.42 g of compound I-1, with a yield of 91.8% and a purity of 98.95%.

[0076] Example 3

[0077] At room temperature, BocCl (13.66 g, 0.10 mol) and Na2CO3 (15.90 g, 0.15 mol) were added to 200 ml of dry dichloromethane. The mixture was then heated to 5–10 °C and a solution of N-(4-tert-butylbenzyl)-naphthylamine (30.34 g, 0.10 mol) in 100 ml of dry dichloromethane was added. The reaction was continued at 40–45 °C. After the reaction was confirmed to be complete, the mixture was filtered. The filtrate was washed with 100 ml × 2 saturated sodium bicarbonate solution and 100 ml saturated brine. The organic phase was concentrated under reduced pressure to dryness to obtain 34.44 g of compound I-1, with a yield of 85.4% and a purity of 98.13%.

[0078] Example 4

[0079] At room temperature, BocCl (17.75 g, 0.13 mol) and N,N-diisopropylethylamine (19.39 g, 0.15 mol) were added to 200 ml of dry dichloromethane. The mixture was then heated to -5–0 °C and a solution of N-(4-tert-butylbenzyl)-naphthylamine (30.34 g, 0.10 mol) in 100 ml of dry dichloromethane was added. The reaction was continued at 20–25 °C. After the reaction was confirmed to be complete, the mixture was filtered. The filtrate was washed with 150 ml × 3 saturated sodium bicarbonate solution and 100 ml saturated brine. The organic phase was concentrated under reduced pressure to dryness to obtain 37.91 g of compound I-1, with a yield of 93.0% and a purity of 99.01%.

[0080] Example 5

[0081] At room temperature, BocCl (19.12 g, 0.14 mol) and pyridine (11.87 g, 0.15 mol) were added to dry dichloromethane (200 ml). The mixture was then heated to -10 to -5 °C and a solution of N-(4-tert-butylbenzyl)-naphthylamine (30.34 g, 0.10 mol) in dry dichloromethane (100 ml) was added. The reaction was continued at 15–20 °C. After the reaction was confirmed to be complete, the mixture was filtered. The filtrate was washed with saturated sodium bicarbonate solution (150 ml × 3) and saturated brine (100 ml). The organic phase was concentrated under reduced pressure to dryness to obtain 34.56 g of compound I-1, with a yield of 85.7% and a purity of 98.46%.

[0082] Example 6

[0083] At room temperature, Cb2Cl (18.77 g, 0.11 mol) and triethylamine (14.17 g, 0.14 mol) were added to 200 ml of dry dichloromethane. The mixture was then heated to -5–0 °C and a solution of N-(4-tert-butylbenzyl)-naphthylamine (30.34 g, 0.10 mol) in 100 ml of dry dichloromethane was added. The reaction was continued at 30–35 °C. After the reaction was confirmed to be complete, the mixture was filtered. The filtrate was washed with 100 ml × 2 saturated sodium bicarbonate solution and 100 ml saturated brine. The organic phase was concentrated under reduced pressure to dryness to obtain 40.71 g of compound I-2, with a yield of 92.1% and a purity of 98.99%.

[0084] Example 7

[0085] At room temperature, Boc anhydride (24 g, 0.11 mol) and triethylamine (13.15 g, 0.13 mol) were added to dry dichloromethane (200 ml). The mixture was then heated to -10 to -5 °C and a solution of N-(4-tert-butylbenzyl)-naphthylamine (30.34 g, 0.10 mol) in dry dichloromethane (100 ml) was added. The reaction was continued at 35–40 °C. After the reaction was confirmed to be complete, the mixture was filtered. The filtrate was washed with saturated sodium bicarbonate solution (100 ml × 2) and then with saturated brine (100 ml). The organic phase was concentrated under reduced pressure to dryness to obtain 35.28 g of compound I-1, with a yield of 87.5% and a purity of 98.28%.

[0086] Example 8

[0087] At room temperature, FmocCl (28.46 g, 0.11 mol) and triethylamine (22.26 g, 0.22 mol) were added to 200 ml of dry dichloromethane. The mixture was then heated to 5–10 °C with a 100 ml solution of N-(4-tert-butylbenzyl)-naphthylamine (30.34 g, 0.10 mol) in dry dichloromethane. The reaction was continued at 25–30 °C. After the reaction was confirmed to be complete, the mixture was filtered. The filtrate was washed with 100 ml × 2 saturated sodium bicarbonate solution and 100 ml saturated brine. The organic phase was concentrated under reduced pressure to dryness to obtain 49.58 g of compound I-3, with a yield of 93.4% and a purity of 99.07%.

[0088] Example 9

[0089] At room temperature, Boc anhydride (24 g, 0.11 mol) and triethylamine (23.27 g, 0.23 mol) were added to dry dichloromethane (200 ml). The mixture was then heated to 5–10 °C and a solution of N-(4-tert-butylbenzyl)-naphthylmethylamine (30.34 g, 0.10 mol) in dry dichloromethane (100 ml) was added. The reaction was continued at 20–25 °C. After the reaction was confirmed to be complete, the mixture was filtered. The filtrate was washed with saturated sodium bicarbonate solution (100 ml × 2) and then with saturated brine (100 ml). The organic phase was concentrated under reduced pressure to dryness to obtain 36.01 g of compound I-1, with a yield of 89.3% and a purity of 98.65%.

[0090] Synthesis of butenafine hydrochloride

[0091] Example 10

[0092] Lithium aluminum hydride (11.39 g, 0.30 mol) was suspended in dry tetrahydrofuran (200 ml). A tetrahydrofuran solution of intermediate I-1 (20.18 g, 0.05 mol) was added at 0–5 °C. The reaction was continued under controlled reflux. After the reaction was confirmed to be complete, the reaction solution was cooled to room temperature and quenched with a 5% ammonium chloride aqueous solution. The solution was filtered, and the filtrate was extracted with dichloromethane (75 ml × 3). The combined organic phases were washed with purified water (50 ml × 2) and saturated brine (50 ml). The organic phase was concentrated and dried. The obtained butenafine was salted with HCl / methanol, filtered, and the filter cake was dried to obtain 16.71 g of butenafine hydrochloride, with a yield of 93.6% and a purity of 99.75%.

[0093] Example 11

[0094] Lithium aluminum hydride (7.59 g, 0.20 mol) was suspended in dry tetrahydrofuran (150 ml). A tetrahydrofuran solution of intermediate I-2 (21.88 g, 0.05 mol) was added at 5–10 °C. The reaction was continued under controlled reflux. After the reaction was confirmed to be complete, the reaction solution was cooled to room temperature and quenched with 5% ammonium chloride aqueous solution. The solution was filtered, and the filtrate was extracted with chloroform (75 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), and then washed with saturated brine (50 ml). The organic phase was concentrated and dried. The obtained butenafine was salted with HCl / ethanol, filtered, and the filter cake was dried to obtain 16.34 g of butenafine hydrochloride, with a yield of 91.5% and a purity of 99.40%.

[0095] Example 12

[0096] Lithium aluminum hydride (6.64 g, 0.175 mol) was suspended in dry tetrahydrofuran (120 ml). A tetrahydrofuran solution of intermediate I-1 (20.18 g, 0.05 mol) was added at 5–10 °C. The reaction was continued under reflux. After the reaction was confirmed to be complete, the reaction solution was cooled to room temperature. The reaction was quenched by adding water and 10% NaOH solution sequentially. The mixture was filtered, and the filtrate was extracted with ethyl acetate (75 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), and then washed with saturated brine (50 ml). The organic phase was concentrated and dried. The obtained butenafine was salted with HCl / isopropanol, filtered, and the filter cake was dried to obtain 15.56 g of butenafine hydrochloride, with a yield of 87.1% and a purity of 98.69%.

[0097] Example 13

[0098] Lithium aluminum hydride (15.18 g, 0.40 mol) was suspended in dry tetrahydrofuran (300 ml). A tetrahydrofuran solution of intermediate I-3 (26.28 g, 0.05 mol) was added at -5 to 0 °C. The reaction was continued under controlled reflux. After the reaction was confirmed to be complete, the reaction solution was cooled to room temperature and quenched with a 5% ammonium chloride aqueous solution. The mixture was filtered, and the filtrate was extracted with dichloromethane (75 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), and then washed with saturated brine (50 ml). The organic phases were concentrated and dried. The obtained butenafine was salted with HCl / 1,4-dioxane, filtered, and the filter cake was dried to obtain 16.55 g of butenafine hydrochloride, with a yield of 92.7% and a purity of 99.38%.

[0099] Example 14

[0100] Lithium aluminum hydride (16.13 g, 0.425 mol) was suspended in dry diethyl ether (320 ml). A dry diethyl ether solution of intermediate I-1 (20.18 g, 0.05 mol) was added at -10 to -5 °C. The reaction was continued under controlled reflux. After the reaction was confirmed to be complete, the reaction solution was cooled to room temperature and quenched with 5% ammonium chloride aqueous solution. The mixture was filtered, and the filtrate was extracted with dichloromethane (75 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), and then washed with saturated brine (50 ml). The organic phases were concentrated and dried. The obtained butenafine was salted with HCl / ethyl acetate, filtered, and the filter cake was dried to obtain 15.77 g of butenafine hydrochloride, with a yield of 88.3% and a purity of 98.55%.

Claims

1. A butenafine intermediate compound, as shown in Formula I, with the following structural formula: 。 2. A method for preparing the compound according to claim 1, characterized in that, Starting with N-(4-tert-butylbenzyl)-naphthylmethylamine (SM-1), compound I was prepared by reacting it with an acylation reagent in the presence of an acid-binding agent. The synthetic route is as follows: ； The acylation reagent is selected from one or a combination of CbzCl, BocCl, Boc anhydride, and FmocCl; the acid binding agent is selected from one or a combination of K2CO3, Na2CO3, triethylamine, N,N-diisopropylethylamine, and pyridine.

3. The preparation method according to claim 2, characterized in that, Specifically, the steps include: controlling the temperature T1A, adding SM-1 to a mixed solution of acylation reagent, acid-binding agent and reaction solvent A, and controlling the temperature T1B until the reaction is completed to obtain compound I, wherein the reaction temperature T1A is -10 to 10℃ and the reaction temperature T1B is 15 to 50℃.

4. The preparation method according to any one of claims 2 or 3, characterized in that, The molar ratio of SM-1 to the acylation reagent and the acid-binding agent is 1:1.05-1.3:1.4-2.

2.

5. A method for preparing butenafine hydrochloride from compound I according to claim 1, characterized in that, LiAlH4 was suspended in reaction solvent B, and compound I was added at temperature T2A. The reaction was continued at temperature T2B until completion. After post-treatment, butenafine hydrochloride was obtained. The synthetic route is as follows: ； Wherein, the reaction temperature T2A is -10 to 10℃, and T2B is the reflux temperature of the reaction solvent B.

6. The method according to claim 5, characterized in that, The molar ratio of compound I to LiAlH4 is 1:4.0 to 8.0.

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