KR100204096B1 - Preparation method for bis-triazole derivatives - Google Patents

Abstract

The present invention utilizes an oxirane compound and silyl triazole in the form of 2- (2,4-difluorophenyl) -1,3-bis (1,2,4-triazole) using catalytic amounts of tetraalkylammonium halides or metal halides. 1-yl) -2- (trimethylsilyloxy) propane is prepared and desilylated under acidic conditions to easily produce fluconazole in high yield.

Description

Method for preparing bis-triazole derivative

The present invention relates to a novel method for preparing a bis-triazole derivative of formula (1) having an antifungal action.

The chemical of formula (1) is well known under the common name fluconazole, and according to British Patent No. 2,099,818, the process for preparing 1- [2- (2,4-difluorophenyl) -2,3-epoxy as shown in Scheme 1 below. Propyl] -1h-1, 2, 4-triazole (2) [hereinafter referred to as oxirane compound (2)] and bis-triazole derivative (1) by reaction of 1h-1, 2, 4-triazole (1) A method of making is described. However, it is pointed out that the compound of the formula (2) has a low reactivity with 1, 2, 4-triazole, so that the yield of obtaining the bistriazole derivative (1) is only 45%.

And in Israel Patent Application No. 105,200, it can be obtained by the reaction of the oxirane compound (2) and 4-amino-1; 2, 4-triazole as shown in Scheme 2 below, but this method under acid conditions It is pointed out that the reaction is carried out and the protection group removal reaction is required.

In British Patent No. 2,099,818 described above, the reaction proceeds under equivalents of potassium carbonate, while in Israel Patent Application 105,200, the reaction proceeds under equivalents of sodium nitrite. It is an object to provide a process for obtaining fluconazole in a high yield with the reaction under.

The present invention uses the oxirane compound (2) and silyl triazole in the form of 2- (2,4-difluorophenyl) -1,3-bis (1,2,4) using catalytic amounts of tetraalkylammonium halides or metal halides. (Trimethylsilyloxy) propane (4) is prepared and desilylated under acidic conditions to easily produce fluconazole (1) in high yield.

In the scheme 3, the (a) process is 2- (2,4-difluorophenyl) -1,3-bis (1,2,4-triazol-1-yl) -2- (trimethylsilyloxy) propane (4) Processes known in the art are those which are reacted under acidic or basic conditions, while this process is a milder reaction condition using a catalytic amount of tetraalkylammonium fluoride. The catalysts are tetraalkylammonium fluoride and silyltriazole. Increasing the reactivity of the oxirane to yield high yields of 2- (2,4-difluorophenyl) -1,3-bis (1,2,4-triazol-1-yl) -2- (trimethylsilyloxy) It can be seen that propane 4 is produced. The tetraalkylammonium halides used here include tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium iodide, and the metal halides include sodium fluoride, potassium fluoride and sodium iodide. Equivalents are used.

The silyltriazole uses 1.1 to 1.3 equivalents of the oxirane compound (2), and the reaction temperature is preferably 60 to 100 ° C. Examples of the solvent used at this time include dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and the like.

Compound (4) thus obtained was confirmed by various analytical methods such as nuclear magnetic resonance, infrared spectrum, mass spectrometry and elemental analysis.

(B) Process is 2- (2,4-difluorophenyl) -1,3-bis (1,2,4-triazol-1-yl) -2- (trimethylsilyloxy) propane (4 Fluconazole (1) is readily prepared by desilylating under acidic conditions. At this time, the solvent used is dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methylene chloride, water and the like, and a mixed solvent is used if necessary.

In addition, since N, N-dimethylformamide and dimethyl sulfoxide used as reaction solvents are high boiling point solvents, distilled water is best used to remove them. However, in British Patent No. 2.099,818, when distilled water is used to remove N, N-dimethylformamide, the target compound (1) is dissolved in and dissolved in the water layer, thereby reducing the yield. In the present invention, 2- (2,4-difluorophenyl) -1,3-bis (1,2,4-triazol-1-yl) -2- (trimethylsilyloxy) propane (4) Even when washed with water to remove N, N- dimethylformamide, dimethyl sulfoxide, the solubility of the compound (4) in water is very low, there is an advantage that the solvent can be removed without reducing the yield.

The method for producing a bistriazole derivative of the present invention can react under milder conditions than before, and provides a method for obtaining fluconazole with a higher yield.

The following examples are intended to illustrate the invention in more detail and are not intended to limit the scope of the invention.

Example 1: 2- (2, 4-difluorophenyl) -1, 3-bis (1, 2, 4-triazol-1-yl) -2- (trimethylsilyloxy) propane (4)

Dissolve 1- [2- (2,4-difluorophenyl) -2,3-epoxypropyl] -1H-1,2,4-triazole (5.93, 25 mmol) in 10 ml of dimethylformamide and heat to 90 ° C. Then, 0.25 ml (1 N, THF) of tetrabutylammonium fluoride was added dropwise, and silyltriazole (4.59 g, 1.3 equivalents) dissolved in 5 ml of dimethylformamide was slowly added dropwise for 30 minutes, and stirred at 90 ° C. for 2.5 hours. After the reaction was cooled to room temperature, 40 ml of methylene chloride and 30 ml of distilled water were added thereto. The organic layer was washed twice with 30 ml of water to remove digotylformamide, concentrated under reduced pressure, and then stirred with 40 ml of water to form a precipitate. Filtration gave the desired compound (8.36 g, 88.5%).

Melting Point: 69 ~ 71 ℃

¹ H NMR (CDC1 ₃ ): δ 0.13 (s. 9H) 4.74 (s .4H) 6.75 to 6.70 (m, 1H) 7.25 to 7.40 (m, 1H) 7.89 (s, 2H) 8.07 (s, 2H)

Example 2: 2- (2, 4-difluorophenyl) -1, 3-bis (1, 2, 4-triazol-1-yl) -2- (trimethylsilyloxy) propane (4) (8.36 g) was added 3.3 ml of concentrated hydrochloric acid and 30 ml of water and stirred at room temperature for 1 hour. The reactions were gradually neutralized (pH 5-6) with 4N aqueous sodium hydroxide solution, extracted twice with 40 ml of methylene chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue. 15 ml of ethyl acetate was added to the residue, and the mixture was refluxed for 20 minutes and cooled slowly to room temperature to obtain a crude product (6.03 g). This crude product (6.03 g) was added 3.3 ml of concentrated hydrochloric acid and 30 ml of water, stirred at room temperature, washed with 10 ml of ethyl acetate, and slowly added dropwise (pH 5-6) with 4N aqueous sodium hydroxide solution to obtain a precipitate. Formed, filtered and dried to afford the title compound (5.16 g, 76.3%).

Melting point: 137 ~ 139 ℃

1R (KBr): 3100, 1620cm ^-1

¹ H NMR (CDC1 ₃ ): δ 4.40 to 4.80 (dd, 4H) 5.50 (s, 1H) 6.70 to 6.50 (m, 2H) 7.35 to 7.50 (m, 1H) 7.85 (s, 2H) 8.05 (s, 2H)

Example 3: 2- (2, 4-difluorophenyl) -1, 3-bis (1H 1, 2, 4-triazol-1-yl) -2-propane (1)

Dissolve 1- [2- (2,4-difluorophenyl) -2,3-epoxypropyl] -1H-1,2,4-triazole (5.93 g, 25 mmol) in 10 ml of dimethylformamide and proceed to 90 ° C. After heating, 0.25 ml (1N, THF) of tetrabutylammonium fluoride was added dropwise, and silyltriazole (4.59 g, 1.3 equivalents) dissolved in 5 ml of dimethylformamide was slowly added dropwise for 30 minutes, followed by stirring at 90 ° C for 3 hours. After the reaction was cooled to room temperature, 40 ml of methylene chloride and 30 ml of water were added thereto. The organic layer was washed twice with 30 ml of water to remove dimethylformamide and concentrated under reduced pressure to give crude product. 4.4 ml of concentrated hydrochloric acid are added to 30 ml of water, and the crude product obtained above is added and stirred at room temperature for 1 hour. The reaction was gradually neutralized with 4N aqueous sodium hydroxide solution, extracted twice with 50 ml of methylene chloride, washed with 20 ml of water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a residue. 15 ml of ethyl acetate was added to the residue, and the mixture was refluxed for 20 minutes, and cooled slowly to room temperature. An impure target compound (6.0 g) was obtained. 3.3 ml of concentrated hydrochloric acid was added to 30 ml of water for purification, and the product was completely dissolved. Stirring gradually with neutralizing aqueous solution of OdA gives a precipitate (pH 5-6), and filtration and drying gives the title compound (5,33 g, 69.6%).

Melting point: 137 ~ 139 ℃

1R (KBr): 3100, 1620cm ^-1

¹ H NMR (CDC1 ₃ ): δ 4.40 to 4.80 (dd, 4H) 5.50 (s. 1H) 6.70 to 6.50 (m, 2H) 7.35 to 7.50 (m, 1H) 7.85 (s, 2H) 8.05 (s, 2H)

Example 4: 2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propane (1)

Dissolve 1- [2- (2,4-difluorophenyl) -2,3-epoxypropyl] -1H-1,2,4-triazole (5.93 g, 25 mmol) in 10 ml of dimethylformamide and proceed to 90 ° C. After heating, 0.18 g (0.05 eq) of sodium fluoride was added dropwise, and 4.59 g (1.3 equivalents) of silyltriazole dissolved in 5 ml of dimethylformamide was slowly added dropwise for 30 minutes and stirred at 90 ° C. for 3 hours. After the reaction was cooled to room temperature, 40 ml of methylene chloride and 30 ml of water were added thereto. The organic layer was washed twice with 30 ml of water to remove dimethylformamide and concentrated under reduced pressure to give a residue. 10 ml of water and 4.4 ml of concentrated hydrochloric acid are added to the residue, followed by stirring at room temperature for 1 hour. The reaction was slowly neutralized with 4N aqueous sodium hydroxide solution, extracted twice with 50 ml of methylene chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue. To the residue was added 10 ml of ethyl acetate, refluxed for 20 minutes, and cooled slowly to room temperature to give a compound (4.44 g). 30 ml of water and 3.3 ml of concentrated hydrochloric acid were added to the compound, and the compound was completely dissolved. After stirring, the mixture was gradually neutralized with 4N aqueous sodium hydroxide solution and stirred to obtain a precipitate (pH 5-6). 67.5%) is obtained.

Melting point: 137 ~ 139 ℃

1R (KBr): 3100, 1620cm ^-1

¹ H NMR (CDC1 ₃ ): δ 4.40 to 4.80 (dd, 4H) 5.50 (s, 1H) 6.70 to 6.50 (m, 2H) 7.35 to 7.50 (m, 1H) 7.85 (s, 2H) 8.05 (s, 2H)

Example 5: 2- (2, 4-difluorophenyl) -1, 3-bis (1H 1, 2, 4-triazol-1-yl) -2-propane (1)

Dissolve 1- [2- (2,4-difluorophenyl) -2,3-epoxypropyl] -1H-1,2,4-triazole (5.93 g, 25 mmol) in 10 ml of dimethylformamide and proceed to 90 ° C. After heating, 0.25 ml (1N, THF) of tetrabutylammonium fluoride was added dropwise, and silyltriazole (4.59 g, 1.3 equivalents) dissolved in 5 ml of dimethylformamide was slowly added dropwise for 30 minutes, followed by stirring at 90 ° C for 3 hours. After the reaction was cooled to room temperature, 40 ml of methylene chloride and 30 ml of water were added thereto. The organic layer was washed twice with 30 ml of water to remove dimethylformamide and concentrated under reduced pressure to give a residue. 30 ml of water and 4.4 ml of concentrated hydrochloric acid are added to the residue, followed by stirring at room temperature for 1 hour. The reaction is slowly neutralized with 4N aqueous sodium hydroxide solution to form a precipitate, which is filtered to give a residue. To this residue was added 30 ml of water and 3.3 ml of concentrated hydrochloric acid, completely dissolved, and slowly neutralized with 4N aqueous sodium hydroxide solution. The precipitate was obtained by stirring (pH 5-6), and the title compound was obtained by filtration and drying. To this target compound was added 10 ml of isopropyl alcohol, refluxed for 20 minutes and cooled slowly to room temperature to give the title compound (4.97 g, 64.9%).

Melting point: 137 ~ 139 ℃

1R (KBr): 3100, 1620cm ^-1

¹ H NMR (CDC1 ₃ ): δ 4.40 to 4.80 (dd, 4H) 5.50 (s, 1H) 6.70 to 6.50 (m, 2H) 7.35 to 7.50 (m, 1H) 7.85 (s, 2H) 8.05 (s, 2H)

Claims (3)

In the presence of a tetra alkylammonium halide or an alkali metal halide catalyst, a compound of formula (2) is reacted with silyltriazole (3) to prepare a compound of formula (4), which is then tasylyzed under acidic conditions to give a compound of formula (1) To prepare a compound.

The method of claim 1 wherein the tetraalkylammonium halide is selected from tetrabutylammonium iodide. The method of claim 1 wherein the alkali metal halide is selected from sodium fluoride, potassium fluoride, sodium iodide, potassium iodide.