KR0161803B1 - Terbinafine for fungicide - Google Patents

Abstract

The present invention relates to a method for preparing terbinapine and its hydrochloride for an antifungal agent, wherein the three-step reaction of palladium coupling reaction, reduction reaction and coupling reaction of sulfonate and amine is performed to stereo-specifically the E-stereochemistry of the olefin. The present invention relates to a method for preparing terbinaic hydrochloride in high yields, which can be synthesized in a conventional manner, and that there is no need to separate stereospecific mixtures of the final material.

Description

[Name of invention]

Method for preparing terbinafine and its hydrochloride for antifungal agents

Detailed description of the invention

[Purpose of invention]

The present invention provides (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethamine (also called terbinafine) and its hydrochloride for antifungal agents. It relates to a process for the preparation of, in more detail can be synthesized stereospecifically the olefin E- stereochemistry of the olefin by a three-step reaction of the palladium coupling reaction, the reduction reaction and the coupling reaction of sulfonates and amines, The present invention relates to a process for preparing terbinafine and its hydrochloride, which can be obtained in high yield without difficult separation process.

[Use of invention]

Fungi-related diseases include Onychomycosis, athlete's foot, tinea, tinea corporis, pityriasis versicolor, tinea cruris, tinea capitis, oral candidosis. And vaginal candidosis (vaginal candidosis) and the like, the causative agents of these are various, such as dermatophytes, yeast, mold.

The development of conventional antifungal agents has been less successful than antibacterial agents, and various antifungal agents have recently been developed. In addition, the draft of the fungus is mainly a skin disease, which is often caused by complex infections, and thus the development of a wide range of antifungal agents is required.

In recent years, since naftifine has been found to have an antifungal effect by a general screening method, intensive studies on naphtipine derivatives have shown that terbinafine, an object of the present invention, exhibits very strong antifungal action. Terbinafin of the present invention is widely used in the above-mentioned diseases because it has an excellent effect with less toxicity as a broad antifungal agent.

[Private Technology]

The naphtipine antifungal agent has allylamine as an essential component, and terbinafine, the object of the present invention having the best antifungal effect among the naphtipine series, is an (E) -1,3-ene substituent (E- Allylamine derivatives containing 1,3-enyne substituent) are characterized in that arylamine and t-butylacetylene are coupled by trans.

In other words, when the double bond of arylamine and the triple bond of t-butylacetylene are connected, only the trans-linked one exhibits an antifungal effect. Thus, the method of preparing terbinafine has been improved in the direction of producing only E-body. have.

The first process for the synthesis of terbinapine was carried out by condensation reaction of allyl bromide with secondary amine, followed by reduction with diisobuty1 aluminum hydride (DIBAH) to 6.6-dimethyl-2E-hepten-4-ynyl t-. After obtaining an amine, it was reacted with naphthalene methyl halide to obtain terbinafine. However, according to the above reaction, since the target terbinafin is obtained as a mixture of Form E and Form Z, only the Form E is separated again (J. Med. Chem. 1984, 27, 1539-1543, Tetrahedron Vol. 41, No. 23, pp 5685-5696, 1985).

As also another manufacturing method is made after the naphthalene methylamine-butyl lithium as a recreational utility then propargyl bromide was added to it dihydro create a propargyl amine zirconate was Nation after E- vinyl child added iodine iodide Bu ₃ There is a method of making terbinafin by adding tin compounds such as Sn-C≡C-C (CH ₃ ) ₃ (Tetrahedron Letters; 1988, 29, 13, 1509-1512).

This method has the advantage that it is possible to fix only E-type in the case of turbina pin alone, but has the disadvantage of using a tin compound, which is limited in use due to its own toxicity as an intermediate.

In addition, according to Spanish Patent No. 550015, a method of producing terbinafin by condensation reaction of naphthalene methyl halide and secondary amine is described, but this patent describes only a process of condensing secondary amine reaction such as naphthalene methyl halide. There is no mention of a method for preparing a secondary amine.

Therefore, the inventors have invented a new method of manufacturing turbinafin as a result of research to solve the above problems.

The present invention is a novel process for preparing terbinafine and its hydrochloride. According to the method of the present invention, terbinafine and its hydrochloride of type E are prepared in stereospecific high yield without the need to separate the mixture of final materials. can do.

[Configuration of Invention]

Hereinafter, the present invention will be described in detail.

(1) 6,6-dimethyl-2,4 represented by the following structural formula (V) by coupling a iodine propargyl alcohol represented by the following structural formula (III) with t-butylacetylene represented by the following structural formula (IV) under a palladium catalyst: -Diheptinyl alcohol is obtained, and (2) reduction of 6,6-dimethyl-2,4-diheptinyl alcohol represented by Structural Formula V with an aluminum-based reducing agent in a tetrahydrofuran (hereinafter referred to as THF) solvent is performed. After obtaining 6,6-dimethyl-2E-heptene-4-ynyl alcohol represented by VI, (3) 6,6-dimethyl-2E-heptene-4-ynyl alcohol represented by Structural VI was converted to methanesulfonyl chloride. Reaction was carried out to obtain a sulfonate intermediate, and coupling reaction with N-methyl-1-naphthalenemethylamine represented by the following structural formula Ⅶ under potassium carbonate base to obtain terbinapine represented by the following structural formula (I), followed by hydrochloric acid in a methanol solvent. By processing Turbina It relates to an antifungal terbinafin and a method for producing the hydrochloride, characterized in that the production of the pin hydrochloride.

Hereinafter, the present invention will be described in more detail.

In the present invention, iodine propargyl alcohol represented by formula III is prepared by a conventional method from propargyl alcohol represented by formula II (Bull, Chem. Soc. Jpn, 1972, 45, 2611), and the compound of formula III The t-butylacetylene of Structural Formula IV was coupled to a palladium catalyst, tetrakis (triphenylphosphine) palladium (Ph (PPh ₃ ) ₄ ), copper iodide (CuI), and diisopropylamine, yielding 38% yield. 6,6-dimethyl-2E-diheptinyl alcohol represented by the above is obtained.

The compound of formula V was then added to sodium bis (2-methoxyethoxy) aluminum hydride and lithium aluminum hydride (LiAlH ₄ ) in THF solvent to obtain E-aryl alcohol. Reduction reaction to the one selected from to obtain 6,6-dimethyl-2E-heptene-4-ynyl alcohol represented by the formula (VI).

This aryl alcohol was rapidly reacted with 2 equivalents of methanesulfonyl chloride to obtain a sulfonate compound, and then reacted with a secondary amine represented by structural formula (I) under potassium carbonate base treatment to obtain terbinapine represented by structural formula (I). Treatment with hydrochloric acid in methanol solvent yields terbinafine hydrochloride and recrystallization in ethyl acetate solvent.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to Examples.

Physical properties of each compound in the Example was measured by the following method.

(1) Column chromatography was measured with a silica gel 60 from Merck based on the flask method.

(2) Melting point (m.p) was measured by Thomas-Hover Melting Point gauge.

(3) The nuclear magnetic resonance spectrum (NMR) was obtained with a Bruker ARX300 spectrometer, where (CH ₃ ) ₄ Si peaks for ¹ H and ¹³ C NMR were measured.

(4) the coupling constant J is expressed in Hz,

(5) Infrared spectrum (IR) was measured with a Nicolet 710 FT-IR spectrometer.

(6) GC-mass spectrometry (MS) was performed with the Hewlett-Pepard MSD5890 series equipped with a capillary column.

Example 1

Synthesis of 6,6-dimethyl-2,4-diheptinyl alcohol (6,6'-dimethyl-2,4-diheptynyl alcohol)

10 mmol (1.82 g) of 3-hydroxy-1-iodine propine (Formula III), 12 mmol (1.5 ml) of t-butylacetylene (Formula IV), Pd (PPh ₃ ) ₄ 350 mg, CuI 60 mg 3.0 ml of diisopropylamine was added to 40 ml of THF under nitrogen stream, and the mixture was stirred at room temperature for 3 hours, and then the mixture was diluted with 100 ml of ether solvent, washed with saturated ammonium chloride solution and distilled water, and the organic solvent layer was dried over magnesium sulfate. I was. The distilled mixture was concentrated and separated by silica gel chromatography (hexane: methyl acetate = 5: 1) to give 517 mg of 6,6-dimethyl-2,4-diheptinyl alcohol (formula V) in 38% yield.

At this time, the physical properties of 6,6-dimethyl-2,4-diheptinyl alcohol were as follows.

¹ H NMR (CDC _l3 ) d 4.32 (s, 2H), 1.85 (br, 1H), 1.24 (s, 9H): ¹³ C NMR (CDCl ₃ ) d 89.3, 75.0, 70.4, 63.0, 51.2, 30.2, 27.8 : MS (M ⁺ + H) 137.0: IR 2970, 2252, 1022 cm ^-1

Example 2

Synthesis of 6,6-dimethyl-2E-heptene-4-ynyl alcohol

2.57 mmol (350 mg) of 6,6-dimethyl-2,4-diheptinyl alcohol (formula V) was dissolved in 1.5 ml THF solution, followed by 4.1 mmol (1.27 g) of 60% sodium bis (2-methoxy). Oxy) aluminum hydride was added slowly at 0 ° C.

The mixture was raised to room temperature and then stirred at room temperature for 1 hour. 1.0N sulfuric acid solution (1.5 ml) was added to the reaction to stop the reaction, and the resulting white solid was filtered off. After diluting with ether (30 ml), the organic solvent layer was washed twice with distilled water and once with saturated brine, and the organic solvent was dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, 6,6-dimethyl-2E-heptene-4-ynyl alcohol (formula III) was obtained quantitatively.

The physical properties of the synthesized 6,6-dimethyl-2E-heptene-4-ynyl alcohol are as follows.

¹ H NMR (CDCl ₃ ) d 6.2 (dt, 1H), 5.3 (dt, 1H), 4.2 (dd, 2H), 1.6 (s, 2H), 1.3 (s, 9H): ¹³ C NMR (CDC _l3 ) d 140.0, 112.0, 99.0, 63.0, 60.5, 31.0, 28.0: MS (M ⁺ + H) 139.0: IR 2960, 2287, 1265 cm ^-1

Example 3

Synthesis of Terbinafine HCl Salt

2.17 mmol (300 mg) of 6,6-dimethyl-2E-hepten-4-ynyl alcohol, triethylamine ((CH ₃ CH ₂ ) ₃ N), and a catalytic amount of dimethylaminopyridine (DMAP) in dichloromethane solvent After dissolving, methane sulfonyl chloride (3.0 ml) was added at 0 ° C. After stirring at 0 ° C. for 5 minutes, distilled water was added and stirred at 0 ° C. for 1 hour. Diluted with dichloromethane solvent, the organic solvent was washed with distilled water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oily sulfonate intermediate.

Then 1.5 ml of 2.0 mmol (342.4 mg) of N-methy-1-naphthalene methylamine (formula VII) and 10.8 mmol (1.5 g) of potassium carbonate (K ₂ CO ₃ ) The sulfonate compound was added to a solution dissolved in dimethylformamide (DMF).

The reaction mixture was stirred at room temperature for 6 hours and then distilled water was added to terminate the reaction. The reaction solution was diluted with ethyl acetate (EtOAc, 20 ml), washed with distilled water, and the organic solvent was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oily compound. The compound was treated with hydrochloric acid in a methanol solvent, methanol was distilled to obtain crystals, and recrystallized from ethyl acetate to obtain 1.54 mol (448 mg) of a white solid having a yield of 77% and a melting point of 188 to 192 캜.

[Effects of the Invention]

The present invention is a novel method completely different from the conventional method, the raw materials and intermediates are also different and the reaction conditions are different. According to the method of the present invention, the pharmacologically active substance E is fixed and prepared, thereby separating the mixture of the final substances. There is no need for steps, and unlike conventional methods, it is a safe method because it does not use harmful substances, and it is also possible to obtain terbinafine in high yield.

Claims (4)

(1) Coupling reaction of iodine propargyl alcohol represented by the following structural formula (III) with t-butylacetylene represented by the structural formula (IV) under a palladium catalyst to give 6,6-dimethyl-2,4-diheptinyl alcohol , (2) 6,6-dimethyl-2E- represented by Structural Formula (VI) by reducing the 6,6-dimethyl-2,4-diheptinyl alcohol represented by the following Structural Formula (V) with an aluminum reducing agent in a solvent. After heptene-4-ynyl alcohol was obtained, (3) 6,6-dimethyl-2E-heptene-4-ynyl alcohol represented by Structural Formula (VI) was reacted with methanesulfonyl chloride to obtain a sulfonate intermediate. EN- (6,6-dimethyl-2-hepten-4-ynyl)-represented by the following structural formula (I) by coupling-reacting with N-methyl-1-naphthalenemethylamine represented by the following structural formula (i) under a base. N-methyl-1-naphthalenemethanamine (terbinafine) is obtained, and (4) hydrochloric acid is then treated on a methanol solvent. A method for producing terbinafine and its hydrochloride for antibacterial agents. The method of claim 1, wherein the palladium catalyst is tetrakis (triphenylphosphine) palladium is used for the production of antifungal turbinapine and its hydrochloride. The antifungal agent terbinafine and hydrochloride thereof according to claim 1, wherein the aluminum-based reducing agent is selected from sodium bis (2-methoxyethoxy) aluminum hydride and lithium aluminum hydride (LiAlH ₄ ). Manufacturing method. The method of claim 1, wherein tetrahydrofuran is used as the solvent.