KR100203457B1 - Process for terbinafine - Google Patents

Abstract

The present invention relates to a novel method for preparing turbinapine represented by the following Chemical Formula 1 having excellent antifungal activity.

[Formula 1]

Description

Method for preparing turbina pin

The present invention relates to a novel method for preparing turbinapine represented by the following Chemical Formula 1 having excellent antifungal activity.

Represented by Formula 1 (E) - N - ( 6,6- dimethyl-2-hepten-4-ynyl) - N - (referred to as one people teoreu rain or pin) methyl-1-naphthalene methanamine hydrochloride is a known compound It is known to show excellent antifungal activity and little toxicity even when administered orally [ Angew. Chem. Int. Ed. Engl. 26 ( 1987 ), 320], ( E ) -1,3-ene, an arylamine derivative having a functional group. A-methyl-1-naphthalene methanamine is antifungal activity - while the cis-isomer of (Z) of teoreu rain or pin of the formula 1 - N - (6,6- dimethyl-2-hepten-4-ynyl) - N Known by-products not represented.

The manufacturing method for the turbina pin represented by the formula (1) has been a multi-faceted research since 1981, the typical manufacturing method is as follows.

In EP 24587, 3,3-dimethyl-1-butyne and butyllithium are used to react 1,2-addition of acrolein to an aqueous bromic acid solution to form a double bond geometry of trans ( E )-and cis ( A mixture of Z ) -ratio 3: 1 gave 1-bromo-6,6-dimethyl-2-hepten-4-yne, which was reacted with naphthalenemethanamine under basic conditions to give the trans ( E ) -isomer An isomer mixture was obtained in which the ratio of turbinafine and the cis ( Z ) -isomer as a byproduct thereof was mixed in a 3: 1 ratio. In the European patent, n -butyllithium is used, which is difficult to use for industrial mass production, and the final product is prepared as an isomer mixture of 3: 1. It is known that the separation yield of the turbinapine represented by the formula (1) is 43.5% from the mixture in which the trans ( E )-and cis ( Z )-are mixed in a 3: 1 ratio, so that the total manufacturing yield is only 27%.

As a production method different from the above, an excess (5 equivalents) of diisobutylaluminum after coupling with naphthalenemethaneamine in the presence of copper chloride using bromoacetylene or t -butylbutadiine as starting materials Hydride (DIBAL) was used to obtain turbinapine in 32% overall yield [ J. Med. Chem. 27 ( 1984 ), 1539-1543. 46% of trans-enein was produced and 19% of trans, cis-diene was produced as a by-product. In addition, in this method, copper complexes, aluminum complexes, and n -butyllithium are used, which is a problem of environmental pollution, and it is impossible to industrialize them, and since a large amount of by-products are generated, it is very difficult to separate only the trans ( E ) -isomer. it's difficult.

As another preparation method, 3-bromopropine is used as a starting material, n -butyllithium is used to introduce naphthalenemethanamine, and cyclopentylzirconium chloride and iodine are reacted to produce vinyl iodo compounds, followed by palladium. Turbinapine was prepared in a total yield of 58% using 3,3-dimethyl-1-butynyl tributyltin under a catalyst [ Tetrahedron Lett. 29 ( 1988 ), 1509-1512. In this manufacturing method, expensive cyclopentyl zirconium chloride is used, and palladium complexes, n -butyllithium and tin compounds are used, which is not only an economical synthesis method but also uses iodo compounds that are harmful to the human body. There are many restrictions on its use.

As another manufacturing method, turbinapine was prepared in a total yield of 29% by using a iodopropazyl alcohol as a starting material through a four-step manufacturing process [ Bull. Korean Chem. Soc. 16 ( 1995 ), 1002-1003]. This method also uses a palladium catalyst, copper iodide, sodium bis (2-methoxyethoxy) aluminum hydride (REDAL), etc., which is difficult to commercialize, and the production yield is very low.

As another preparation method, ( E ) -1,3-dichloropropene is used as a starting material for substitution reaction with naphthalenemethaneamine using potassium iodo and potassium carbonate, and then 3,3 using palladium complex and copper iodide. Turbinapine was synthesized in a relatively high yield of 75% overall yield by a two-step preparation process in which a dimethyl-1-butene was co-linked [ Tetrahedron Lett. 37 ( 1996 ), 57-58]. However, ( E ) -1,3-dichloropropene used as a starting material in this method is a very expensive compound, and also palladium complex and copper iodide are not easy to be used industrially.

The conventional manufacturing method as described above has a low production yield and uses a very expensive material as a starting material or heavy metal complexes such as n -butyllithium, copper complexes, aluminum complexes, tin complexes, and palladium complexes. Not only does it cause contamination problems, but it also consists of reactions that are difficult to apply to industrial production.

In the present invention, there is no industrial problem in the mass production of turbina pin, and the production of (Z) -isomer, which is a by-product, is minimized in the synthesis step of the final target turbina pin by using a raw material which is inexpensive and can be supplied in bulk. The present invention has been completed by long-term research on an economical method for producing turbinapine with high production yield.

Accordingly, an object of the present invention is to provide a method for preparing turbinafin, which is useful for industrial mass production.

The present invention provides a method for preparing turbinapine represented by the following Chemical Formula 1, the process of preparing a compound represented by the following Chemical Formula 4 by reacting a compound represented by the following Chemical Formula 2 and Chemical Formula 3; Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 with Chemical Formula 5; And it is made of a process for preparing a turbina pin represented by the following formula (1) by the reaction (elemination reaction) of the compound represented by the formula (6).

Formula 1

In the formulas above, Q represents a halogen atom, a methanesulfonyloxy group or a p -toluenesulfonyloxy group; L represents a hydroxy, methanesulfonyloxy group, p -toluenesulfonyloxy group or a halogen atom.

In addition, the compounds represented by the formula (4) and formula (6) made of the intermediate material in the present invention are each a novel compound.

Referring to the present invention in more detail as follows.

In the novel method for preparing turbinapine according to the present invention, an epoxy compound represented by Chemical Formula 2, which can be easily purchased in large quantities, is used as a starting material, and instead of n -butyllithium, which is difficult to be industrially used, potasium t -butoxide is used. It does not use any heavy metal compounds such as palladium complexes and copper complexes, and its production yield is high, which is useful for industrial mass production.

In addition, in the final manufacturing step of synthesizing the target compound, the overall yield was greatly improved by minimizing the formation of by-products, and the separation process can be easily carried out with a high yield.

The preparation method according to the present invention is shown in detail in each step as shown in Scheme 1 below.

In the above scheme, Q is a halogen atom, a methanesulfonyloxy group or a p -toluenesulfonyloxy group; Y represents a methanesulfonyl group or p -toluenesulfonyl group, and X represents a halogen atom.

First, the epoxy compound and the 3,3-dimethyl-1-butyne of the formula (3) represented by the above formula (2) potassium t - reacting to -38 ~ 0 ℃ temperature under base-butoxide in tetrahydrofuran solvent the general formula (4) 6,6-dimethyl-1,2-epoxy-4-heptin represented by is obtained in quantitative yield.

The compound represented by Chemical Formula 4 and the naphthalene methane amine hydrochloride represented by Chemical Formula 5 were reacted at 60 to 80 ° C. in a triethylamine base and toluene solvent at a temperature of 60 to 80 ° C. Get in yield.

The following is a process for preparing the turbina pin represented by the formula (1) for the purpose of the present invention from the compound represented by the formula (6), as shown in the scheme 1 to prepare the target by two routes.

A methanesulfonyl group (mesyl group; Ms) or p -toluenesulfonyl group (tosyl group; tosyl) is introduced as a hydroxyl group protecting group of the amine alcohol compound represented by the formula (6a) to obtain a compound represented by the formula (6b). A terbinapine represented by Chemical Formula 1 may be obtained by elimination reaction at a temperature of −20˜0 ° C. under a potassium t -butoxide base and a dimethylformaldehyde solvent.

Alternatively, the halogen compound represented by Chemical Formula 6c may be obtained by treating the hydroxy group of the amine alcohol compound represented by Chemical Formula 6a with triphenylphosphine, imidazole and halogen under a mixed solvent of acetonitrile and diethyl ether. The compound represented by the formula (6b) can be obtained by treating with sodium halide in an acetone solvent. A halogen compound represented by the formula 6c is potassium t - may be obtained teoreu rain pin represented by the general formula (1) for the purpose of the reaction was removed (elemination reaction) to -20 ~ 0 ℃ temperature under butoxide base and dimethyl formaldehyde solvent .

The protecting group introduction reaction into the compound represented by Chemical Formula 6a is caused by reaction with methanesulfonyl halide or p -toluenesulfonyl halide in the presence of triethylamine base at a temperature of 0 to 5 ° C., and the yield is quantitative. The reaction of preparing the compound represented by Chemical Formula 6c by substituting a halogen atom for the compound represented by Chemical Formulas 6a and 6b is performed at a high yield of 85 to 95%.

Further, in the reaction for preparing the turbinapine represented by the desired formula (1) by removing the compound represented by the formula (6b) or (6c) reaction reaction (triethylamine, diisopropylethylamine, pyridine, etc.) Trialkylamine of; Cyclic amines such as 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] unde-7-ene (DBU); Alkoxide inorganic salts such as sodium methoxide, sodium ethoxide, sodium t -butoxide, potassium methoxide, potassium ethoxide, and potassium t -butoxide; Amides such as sodium amide, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, and the like can be used. As the removal reaction solvent, any inert organic solvent which does not affect the reaction, such as benzene, toluene, tetrahydrofuran, dimethylformaldehyde, dimethyl sulfoxide, methanol, ethanol and butanol, may be used. Removal reaction temperature may vary depending on the type of solvent and base used, the temperature range is -78 ~ 100 ℃.

In the reaction product produced by the preparation method of the present invention, the molar ratio of the ( Z ) -isomer as turbinafine and by-products depends on the type of base and solvent, and the reaction temperature. For example, the compound represented by Chemical Formula 6b generates an isomer of ( E ) / ( Z ) in a 5/1 molar ratio when it is reacted at -20 ° C using a dimethylformaldehyde solvent and potassium t -butoxide.

As described above, in the method for preparing turbinapine according to the present invention, no heavy metal compound including copper and palladium is used, and the novel compound can be obtained in high yield by performing under mild reaction conditions.

When the present invention is described in more detail based on the following examples, the present invention is not limited thereto.

Example 1 Preparation of 6,6-Dimethyl-1,2-epoxy-4-heptin (Formula 4)

3,3-Dimethyl-1-butyne (4.1 mL, 33.3 mmol) was added to tetrahydrofuran (40 mL) and potassium t -butoxide (4.1 g, 36.6 mmol) was added at -20 ° C. After stirring for 30 min at the same temperature, glacidoltosylate (7.6 g, 33.3 mmol) was added. After stirring for 12 hours at 0 ° C., an aqueous ammonium chloride solution was added. Ethyl acetate (200 mL) was added to the reaction solution to separate the organic layer, and the organic layer was washed with water and brine in that order and dried over magnesium sulfate. The dried solution was concentrated under reduced pressure to obtain the target compound (5 g) as a liquid in quantitative yield.

R _f : 0.6 (10% ethyl acetate / hexane)

¹ H-NMR (300 MHz, CDCl ₃ ) ppm: δ 1.22 (s, 9H), 2.40 to 2.47 (m, 2H), 2.68 (dd, 1H), 2.79 (dd, 1H), 3.08 to 3.09 (m, 1H )

Example 2 Preparation of 6,6-Dimethyl-1,2-epoxy-4-heptin (Formula 4)

3,3-Dimethyl-1-butyne (0.41 mL, 3.33 mmol) was added to tetrahydrofuran (4 mL), and potassium t -butoxide (0.41 g, 3.66 mmol) was added at -20 ° C. After stirring for 30 min at the same temperature, epibromohydrin (0.43 mL, 3.36 mmol) was added. After stirring for 12 hours at 0 ° C., an aqueous ammonium chloride solution was added. Ethyl acetate was added to the reaction solution to separate the organic layer, and the organic layer was washed with water and brine sequentially and dried over magnesium sulfate. The dried solution was concentrated under reduced pressure to give the target compound (460 mg) in liquid form in quantitative yield.

Example 3 : Preparation of 6,6-dimethyl-1,2-epoxy-4-heptin (Formula 4)

3,3-Dimethyl-1-butyne (0.41 mL, 3.33 mmol) was added to tetrahydrofuran (4 mL), and potassium t -butoxide (0.41 g, 3.66 mmol) was added at -20 ° C. After stirring for 30 min at the same temperature, epichlorohydrin (0.26 mL, 3.33 mmol) was added. After stirring for 12 hours at 0 ° C., an aqueous ammonium chloride solution was added. Ethyl acetate was added to the reaction solution to separate the organic layer, and the organic layer was washed with water and brine sequentially and dried over magnesium sulfate. The dried solution was concentrated under reduced pressure to obtain a target compound (400 mg, yield 87%) in liquid form.

Example 4 Preparation of N- (6,6-dimethyl-2-hydroxy-4-heptinyl) -N -methyl-1-naphthalenemethanamine (Formula 6a)

6,6-dimethyl-1,2-epoxy-4-heptin (1.33 g, 9.63 mmol) and N -methyl-1-naphthalenemethaneamine hydrochloride (2 g, 9.63 mmol) were dissolved in toluene (20 mL), Triethylamine (2.68 mL, 19.26 mmol) was added. The reaction solution was stirred at 80 ° C. for 6 hours, cooled to room temperature, ethyl acetate (50 mL) was added to separate the organic layer, and the organic layer was washed sequentially with water and brine, and dried over magnesium sulfate. The dried solution was concentrated under reduced pressure to give a solid target compound (2.09 g, yield 72%).

R _f : 0.1 (10% ethyl acetate / hexane)

Melting Point: 48 ~ 50 ℃

¹ H-NMR (300 MHz, CDCl ₃ ) ppm: δ 1.20 (s, 9H), 2.32 (s, 3H), 2.40 (dd, 1H), 2.47 (dd, 1H), 3.78-3.83 (m, 1H), 3.93 (d, 1H), 4.10 (d, 1H), 7.41-7.43 (m, 2H), 7.49-7.55 (m, 2H), 7.79-7.89 (m, 2H), 8.23-8.24 (m, 1H)

Example 5 Preparation of N- (6,6-dimethyl-2-methanesulfonyloxy-4-heptinyl) -N -methyl-1-naphthalenemethanamine (Formula 6b)

N- (6,6-dimethyl-2-hydroxy-4-heptinyl) -N -methyl-1-naphthalenemethanamine (330 mg, 1.07 mmol) was dissolved in dichloromethane (5 mL), and then at 0 ° C. Triethylamine (0.22 mL, 1.61 mmol) and methanesulfonyl chloride (0.09 mL, 1.18 mmol) were added. After stirring at the same temperature for 10 minutes, dichloromethane (20 ml) was added to the reaction solution, and the organic layer was washed sequentially with aqueous sodium bicarbonate solution, water and brine, and dried over magnesium sulfate. The dried solution was concentrated under reduced pressure to give the target compound (415 mg) as a liquid in quantitative yield.

R _f : 0.7 (ethyl acetate / hexane = 1/2)

¹ H-NMR (300 MHz, CDCl ₃ ) ppm: δ 1.20 (s, 9H), 2.35 (s, 3H), 2.52-2.58 (m, 2H), 2.80 (dd, 1H), 2.88 (dd, 1H), 3.94 (d, 1H), 4.02 (d, 1H), 4.62-4.73 (m, 1H), 7.41-7.43 (m, 2H), 7.52-7.55 (m, 2H), 7.80-7.89 (m, 2H), 8.28 ~ 8.29 (m, 1H)

Example 6 Preparation of N- (6,6-dimethyl-2-iodo-4-heptinyl) -N -methyl-1-naphthalenemethanamine (Formula 6c)

N- (6,6-dimethyl-2-methanesulfonyloxy-4-heptinyl) -N -methyl-1-naphthalenemethanamine (400 mg, 1.03 mmol) was dissolved in acetone (3 mL), followed by iodolation. Sodium (155 mg, 1.03 mmol) was added. After heating for 1 hour, the reaction solution was cooled to room temperature, the insoluble substance was filtered, and then concentrated under reduced pressure to obtain a target compound (388 mg, 90% yield) as a liquid.

R _f : 0.7 (10% ethyl acetate / hexane)

¹ H-NMR (300 MHz, CDCl ₃ ) ppm: δ 1.24 (s, 9H), 2.23 (s, 3H), 2.79 (dd, 2H), 2.99 (dd, 2H), 3.90 (d, 1H), 4.09 ( d, 1H), 4.16 to 4.19 (m, 1H), 7.42 to 7.45 (m, 2H), 7.51 to 7.57 (m, 2H), 7.80 to 7.89 (m, 2H), 8.40 to 8.43 (m, 1H)

Example 7 Preparation of N- (6,6-dimethyl-2-iodo-4-heptinyl) -N -methyl-1-naphthalenemethanamine (Formula 6c)

N- (6,6-dimethyl-2-hydroxy-4-heptinyl) -N -methyl-1-naphthalenemethanamine (370 mg, 1.20 mmol) was dissolved in acetonitrile (3 mL) and diethyl ether (5 mL). ), Triphenylphosphine (422 mg, 1.61 mmol) and imidazole (112 mg, 1.64 mmol) were added at 0 ° C. After stirring for 5 minutes at the same temperature, iodine (437 mg, 1.72 mmol) was added slowly. After stirring at the same temperature for 45 minutes, diethyl ether (40 mL) was added to the reaction solution, and the organic layer was washed with an aqueous sodium thiosulfate solution, an aqueous copper sulfate solution, and water, and then dried over magnesium sulfate. The dried solution was concentrated under reduced pressure to obtain a target compound (433 mg, yield 88%) as a liquid.

Example 8 Preparation of N- (6,6-dimethyl-2-hepten-4-ynyl) -N -methyl-1-naphthalenemethanamine (Formula 1)

N- (6,6-dimethyl-2-methanesulfonyloxy-4-heptinyl) -N -methyl-1-naphthalenemethanamine (400 mg, 1.03 mmol) was dissolved in dimethylformamide (3 mL), Potassium t -butoxide (139 mg, 1.13 mmol) was added at -20 ° C. After stirring for 30 minutes, an aqueous ammonium chloride solution (1 mL) and ethyl acetate (10 mL) were added at 0 ° C. After separating the organic layer, the organic layer was washed sequentially with water and brine and dried over magnesium sulfate. The dried solution was filtered and concentrated under reduced pressure to give a target compound (285 mg, 95% yield) as a solid. The E / Z ratio of this target compound was measured by ¹ H-NMR and found to be 5/1 molar ratio.

R _f : 0.5 ( E -isomer, 10% ethyl acetate / hexane)

0.4 ( Z -isomer, 10% ethyl acetate / hexanes)

Integral area ratio of E / Z mixture by ¹ H-NMR: E / Z = 5/1

¹ H-NMR of E -isomer (300MHz, CDCl ₃ ) ppm: δ

1.28 (s, 9H), 2.25 (s, 3H), 3.40 (d, 2H), 3.92 (s, 2H), 5.70 (dt, 1H), 6.23 (dt, 1H), 7.41 to 7.54 (m, 4H) , 7.78 to 7.81 (m, 1H), 7.85 to 7.88 (m, 1H), 8.28 to 8.31 (m, 1H)

¹ H-NMR (300 MHz, CDCl ₃ ) ppm of Z -isomer: δ

1.28 (s, 9H), 2.28 (s, 3H), 3.50 (d, 2H), 3.95 (s, 2H), 5.70 (dt, 1H), 6.23 (dt, 1H), 7.41 to 7.54 (m, 4H) , 7.78 to 7.81 (m, 1H), 7.85 to 7.88 (m, 1H), 8.28 to 8.31 (m, 1H)

Example 9 Preparation of N- (6,6-dimethyl-2-hepten-4-ynyl) -N -methyl-1-naphthalenemethanamine (Formula 1)

N- (6,6-dimethyl-2-iodo-4-heptinyl) -N -methyl-1-naphthalenemethanamine (380 mg, 0.906 mmol) was dissolved in dimethylformamide (3 mL), and then -20. Potassium t -butoxide (111 mg) was added at ° C. After stirring at the same temperature for 1 hour, an aqueous ammonium chloride solution and ethyl acetate were added at 0 ° C. After separating the organic layer, the organic layer was washed sequentially with water and brine and dried over magnesium sulfate. The dried solution was filtered and concentrated under reduced pressure to give the target compound (237 mg, 90% yield) as a solid. The E / Z ratio of this target compound was measured by ¹ H-NMR and found to be 4/1 molar ratio.

Example 10 Preparation of N- (6,6-dimethyl-2-hepten-4-ynyl) -N -methyl-1-naphthalenemethanamine (Formula 1)

N- (6,6-dimethyl-2-methanesulfonyloxy-4-heptinyl) -N -methyl-1-naphthalenemethanamine (400 mg, 1.03 mmol) was dissolved in tetrahydrofuran (5 mL),- Sodium bis (trimethylsilyl) amide (208 mg, 1.13 mmol) was added at 78 ° C. After stirring for 30 minutes at the same temperature, stirring was continued for 30 minutes at -20 ° C. An aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution. After separating the organic layer, the organic layer was washed sequentially with water and brine and dried over magnesium sulfate. The dried solution was filtered and concentrated under reduced pressure to give the target compound (275 mg, yield 91.7%) as a solid. The E / Z ratio of this target compound was measured by ¹ H-NMR and found to be 4/1 molar ratio.

Example 11 Preparation of N- (6,6-dimethyl-2-hepten-4-ynyl) -N -methyl-1-naphthalenemethanamine hydrochloride (Formula 1)

N- (6,6-dimethyl-2-methanesulfonyloxy-4-heptinyl) -N -methyl-1-naphthalenemethanamine (1.68 g, 4.35 mmol) is dissolved in dimethylformaldehyde (10 ml),- Potassium t -butoxide (585 mg, 5.22 mmol) was added at 20 ° C. and stirred for 1 hour. An aqueous ammonium chloride solution (5 mL), ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution, and the organic layer was separated and dried over magnesium sulfate. The dried solution was filtered and concentrated under reduced pressure to give a mixture of N- (6,6-dimethyl-2-hepten-4-ynyl) -N -methyl-1-naphthalenemethanamine having an E / Z ratio of 5/1 (1.2 g, yield). 95%).

N- (6,6-dimethyl-2-hepten-4-ynyl) -N -methyl-1-naphthalenemethanamine mixture was dissolved in ethanol (10 mL), and then 3N hydrochloric acid aqueous solution (1.4 mL) was added and the solvent was dried under reduced pressure. Was removed. The resulting solid was recrystallized with isopropanol (10 mL) and diethyl ether (25 mL), filtered, and dried under reduced pressure at 25 to 30 ° C. for 2 hours to obtain the target compound (945 mg, yield 70%).

Melting Point: 194 ~ 196 ℃ (Literature Value: 195 ~ 198 ℃)

¹ H-NMR (300 MHz, CDCl ₃ ) ppm: δ 1.23 (s, 9H), 2.59 (s, 3H), 3.87 to 3.96 (m, 2H), 4.70 to 4.76 (m, 1H), 4.80 to 4.85 (m , 1H), 6.03 (bd, 1H), 6.17 to 6.25 (m, 1H), 7.57 to 7.67 (m, 3H), 7.91 (d, 1H), 8.01 to 8.07 (m, 2H), 8.33 (d, 1H) ), 10.81 (s, 1H)

In the production method according to the present invention, a compound which can be easily purchased in large quantities as a raw material, excludes the use of n -butyllithium, which is difficult to use industrially, and instead uses potassium t -butoxide, palladium complex and copper complex It is useful for the industrial mass production of turbinapine with high anti-fungal effect without using any heavy metal compound.

Claims (11)

In the manufacturing method of the turbina pin represented by the following formula (1), Preparing a compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 2 with Chemical Formula 3; Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 with Chemical Formula 5; And A method for producing turbinafine, characterized in that for removing the compound represented by the formula (elemination reaction). Formula 1

Formula 2

Formula 3

Formula 4

Formula 5

Formula 6

In the above formulas, Q represents a halogen atom, a methanesulfonyloxy group or a p -toluenesulfonyloxy group; L represents a hydroxy, methanesulfonyloxy group, p -toluenesulfonyloxy group or a halogen atom. According to claim 1, wherein the L substituent of the compound represented by the formula (6) is a hydroxy group to introduce a methanesulfonyloxy group or p -toluenesulfonyloxy group to the compound represented by the following formula (6b) to remove the reaction Method for producing turbinafin, characterized in that to perform the (elemination reaction).

In the formula, Y represents a methanesulfonyloxy group or a p -toluenesulfonyloxy group. According to claim 1, wherein the L substituent of the compound represented by the formula (6) is a hydroxy group, methanesulfonyloxy group or p -toluenesulfonyloxy group by halogenating the compound to convert the compound represented by the following formula (6c), A method for producing turbinafine, characterized in that to perform an elimination reaction.

In the above formula, X represents a halogen atom. According to any one of claims 1 to 3, wherein the elimination reaction (elemination reaction) is carried out in the presence of a base selected from trialkylamine, cyclic amine, alkoxide inorganic salt, amides Method for preparing vina pin. The method of claim 1, wherein the elemination reaction is performed under an inert solvent selected from benzene, toluene, tetrahydrofuran, dimethylformaldehyde, dimethylsulfoxide, methanol, ethanol, butanol. Method for producing turbinafine, characterized in that performed. The method of claim 1, wherein the elimination reaction is performed at a temperature range of −78 to 100 ° C. 5. The novel compound represented by the following formula (4). Formula 4

The novel compound represented by the following formula (6). Formula 6

In the above formula, L represents a hydroxy, methanesulfonyloxy group, p -toluenesulfonyloxy group or halogen atom. The compound according to claim 8, wherein the substituent L of the compound represented by Chemical Formula 6 is a hydroxy group. The compound according to claim 8, wherein the substituent L of the compound represented by Chemical Formula 6 is a methanesulfonyloxy group. The compound of claim 8, wherein the substituent L of the compound represented by Chemical Formula 6 is an iodo atom.