KR100283991B1 - Method for preparing bis-triazole derivative - Google Patents

Abstract

The present invention is a reaction of 2-acetoxy-2 ', 4'-difluoroacetophenone with trimethylsulfonium iodide to give 2-acetoxymethyl-2- (2,4-difluorophenyl-1- 1) preparing an oxirane and removing the acetyl group therefrom under a base to produce 2-hydroxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane, which is alkyl or substituted or unsubstituted Reacted with arylsulfonyl chloride to prepare 2-sulfonyloxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane derivative, which was then reacted with 1,2,4-triazole sodium salt. It relates to a method for preparing a bis-triazole derivative of formula (1) in a high yield without side reactions by reacting in an equivalent ratio of 1: 2.

[Formula 1]

Description

Method for preparing bis-triazole derivative

[Industrial use]

The present invention relates to a novel process for the preparation of bis-triazole derivatives of formula (1) having antifungal action, more particularly 2-sulfonyloxymethyl-2- (2,4-difluorophenyl-) of formula (8). It relates to a method for preparing a bis-triazole derivative of formula (I) by reacting a 1-yl) oxirane derivative with the sodium salt of 1,2,4-triazole.

[Formula 1]

[Formula 8]

Wherein R represents an alkyl or substituted or unsubstituted aryl group.

[Private Technology]

Bis-triazole derivative of Formula 1 is a compound having an antifungal action, it is well known as the common name fluconazole. Various methods are known as the production method so far, and representative examples thereof are as follows.

First, Korean Patent Publication No. 85-1132 discloses 1- (2- (2,4-difluorophenyl) -2,3-epoxy of Formula 2 having an oxirane structure, as shown in Scheme 1 below. Propyl] -1H-1,2,4-triazole is reacted with 1,2,4-triazole to prepare a bis-triazole derivative of formula (1).

Scheme 1

Meanwhile, the compound of Formula 2 may be prepared as in Scheme 2 below.

Scheme 2

However, the method is extremely low in reactivity between the compound of formula 2 and 1,2,4-triazole, so that the yield of bis-triazole derivatives of formula 1 is only 45% (see Korean Patent Publication No. 85-1132). Example 2 (D)), as shown in Scheme 2 above, the compound of Formula 2 is prepared from a commercially available 1,3-difluorobenzene through three stages of reaction, the second and third stages of The yield is very low (40% and 22%, respectively), and finally there is a problem that the total yield of the compound of formula 1 from 1,3-difluorobenzene is only 9.7%.

Second Korean Patent Publication No. 85-1132 discloses a bis-tria compound represented by Chemical Formula 1 by reacting a compound of Formula 3 with two equivalents of 1,2,4-triazole as shown in Scheme 3 as another manufacturing method. A process for preparing sol derivatives is disclosed (see Spanish Patent No. 549020).

Scheme 3

As shown in Reaction Scheme 3, the preparation method looks simpler than Reaction Scheme 1, but the intermediate step of each step is to be separated and purified by column chromatography, etc., the reaction process is complicated, the Green is used during the reaction (Grignard) Reagents or lithium salts are prepared under anhydrous conditions at -78 ° C and are extremely unstable compounds, which is not suitable for mass production systems.

Third, US Pat. No. 5,508,423 discloses a bis-triazole derivative of Formula 1 by reacting two equivalents of 1,2,4-triazole with a trihalo derivative in a manner similar to Scheme 3 below. Disclosed is a method of manufacturing.

Scheme 4

However, the method also has a very low yield and a complicated process for preparing a trihalo derivative as a starting material, and also a very low yield of 23% for preparing a bis-triazole derivative of Formula 1 from a trihalo derivative. Has a problem.

In addition, the above-mentioned methods can commonly be incorporated into isomers in which one of the 1,2,4-triazole rings is attached to the methylene adjacent to the 4-position, so that unnecessary isomers should be removed by silica gel chromatography or recrystallization. There is this.

Fourth, as a technology related to the present invention. International Publication No. WO 93/09114 discloses a process for preparing an oxirane compound having optical activity of the formula (4), as shown in Scheme 5 below.

Scheme 5

However, in the above method, since the compound of Formula 4 has optical activity as an intermediate in the process of preparing tetrahydrofuran derivative having an antifungal effect, the compound of Formula 1 requires a racemic compound having no optical activity. There is a problem that the manufacturing method can not be directly adapted.

Accordingly, the present inventors conducted intensive studies to solve the problems of the prior art as described above in preparing the bis-triazole derivatives of the formula (1). A novel production method that can be produced was devised to complete the present invention.

The present invention is to solve the above problems of the prior art, the 2-sulfonyloxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane derivative of the formula (8) 1,2,4 It is to provide a method for producing a large amount of bis-triazole derivative of formula (1) in high yield without side reactions by reacting with the sodium salt of -triazole.

The present invention provides a 2-sulfonyloxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane derivative of formula 8 in an equivalent ratio of 1,2,4-triazole sodium salt and 1: 2. It provides a method for preparing a bis-triazole derivative of formula (I) comprising the step of reacting.

[Formula 1]

[Formula 8]

In which R is the same as defined above.

2-sulfonyloxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane derivative of formula (8) is a derivative of 2-acetoxy-2 ', 4'-difluoroacetophenone of formula (5) Reaction with trimethylsulfonium iodide ((CH ₃ ) ₃ SOI) to prepare 2-acetoxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane of formula 6, To remove the acetyl group from 2-acetoxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane of formula (6) Prepare difluorophenyl-1-yl) oxirane, and alkyl or substituted or unsubstituted 2-hydroxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane of the formula Preferably prepared by a process comprising the step of reacting with arylsulfonyl chloride.

[Formula 5]

[Formula 6]

[Formula 7]

In addition, the 1,2,4-triazole sodium salt is preferably prepared by reacting 1,2,4-triazole with sodium hydride (NaH) in an equivalent ratio of 1.2: 2.

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

Representative method for preparing a bis-triazole derivative of formula 1 according to the present invention is shown in Scheme 6 below.

Scheme 6

In Scheme 6, 2-acetoxy-2 ′, 4′-difluoroacetophenone of Formula 5, which is a starting material, may be prepared by a known method, for example, as shown in Scheme 7 below. It may be prepared from an, 3-difluorobenzene via an acylation reaction and a substitution reaction.

Scheme 7

2-acetoxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane of formula 6 is the corresponding ketone compound 2-acetoxy-2 ', 4'-difluoro of formula 5 Acetophenone is prepared by reacting dimethyloxosulfonium methylide prepared from trimethylsulfonium iodide and sodium hydride (step 1). This reaction is usually carried out in a dimethyl sulfoxide solvent at a temperature of 0-50 ° C. under anhydrous conditions. Dimethyloxosulfonium methylide is preferably used in an amount more than stoichiometric amount with respect to the compound of the formula (5), and particularly preferably in an amount of 1.5 to 2.0 equivalents per 1 equivalent of the compound of the formula (5). Thereafter, 2-acetoxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane of formula (6) was removed under a base to remove a protecting group, ie, an acetyl group, to form 2-hydroxymethyl-2- of formula (7). (2,4-difluorophenyl-1-yl) oxirane is prepared, and a reaction solvent of water and one selected from alcohol compounds such as methanol, ethanol, isopropanol or n-butanol may be used as the reaction solvent. The base may be one or more selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and lithium hydroxide (step 2). The 2-hydroxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane of Formula 7 thus obtained was added with a catalytic amount of dimethylamino pyridine under organic base conditions and then alkyl or substituted or unsubstituted. By reacting with arylsulfonyl chloride, a 2-sulfonyloxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane derivative of formula 8 in which the hydroxy group is protected with sulfonate can be prepared ( Step 3). In this case, the catalyst amount may be used in an amount of 0.005 to 0.01 equivalents based on the compound of Formula 7. As the reaction solvent, one or more selected from carbon chloride compounds such as dichloromethane, chloroform and 1,2-chloroethane may be used, and as alkyl or substituted or unsubstituted arylsulfonyl chloride, methanesulfonyl chloride, tri One selected from fluoromethanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, and the like may be used. Preferably, methanesulfonyl chloride or p-toluenesulfonyl chloride may be used. Pyridine or triethylamine can be used.

Subsequently, the 2-sulfonyloxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane derivative 1,2,4-triazole sodium salt of Formula 8 is reacted at an equivalent ratio of 1: 2. (Step 4). Particularly, at this stage, bis-triazole derivatives were prepared by adding and warming 1,2,4-triazole under basic conditions. That is, in a polar solvent such as acetone, acetonitrile, dioxane, C ₁ -C ₂ alcohol or water or a mixed solvent thereof under basic conditions of potassium carbonate or sodium carbonate for 6 to 7 hours at room temperature to 120 ° C, especially 90 to 100 ° C. It was carried out by reaction. However, as described above, isomers in which the 4-position of 1,2,4-triazole is substituted are mixed and separated and purified by column chromatography and recrystallization, and the yield of the reaction is also reduced. In contrast, in the present invention, the 1,2,4-triazole sodium salt obtained by reacting 1,2,4-triazole with sodium hydride under anhydrous conditions is reacted with a compound of Formula 8 to form bis-tria of Formula 1. By preparing a sol derivative, the production of isomers in which the 4-position is substituted can be suppressed. In this case, one kind selected from amide compounds such as dimethylacetamide and dimethylformamide may be used as the reaction solvent, and the reaction temperature is from room temperature to 100 ° C, preferably 60 to 70 ° C. It can lower the temperature, complete the reaction within 2 hours, and improve the reaction yield. The 1,2,4-triazole sodium salt contains 1.2% of 60% sodium hydride and 1,2,4-triazole. In an equivalent ratio of 2: 2, it is particularly preferable to produce 2.4 equivalents and 4 equivalents, respectively, and to use 2.4 to 4 equivalents based on the compound of the formula (8).

EXAMPLE

Hereinafter, the present invention will be described in more detail with reference to the following examples, which are only intended to aid the understanding of the present invention and are not intended to limit the scope of the present invention.

[Example 1] Preparation of 2-acetoxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane

Slowly add 3.74 g (93.4 mM) of 60% sodium hydride (oil dispersion) and 20.6 g (93.4 mM) of trimethylsulfonium iodide to 250 ml of anhydrous dimethylsulfoxide solution, until room temperature is obtained. Stir for 30 minutes. After the reaction solution was cooled to 0 ° C., 10 g (46.7 mM) of 2-acetoxy-2 ′, 4′-difluoroacetophenone was slowly added, followed by stirring at room temperature for 2 hours. The reaction solution was dispersed in 500 ml of ice water and extracted twice with 200 ml of ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, then dehydrated with anhydrous magnesium sulfate and distilled under reduced pressure to yield 8.97 g of the title compound as an oil (yield = 75%). The ¹ H NMR analysis results are as follows.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.5 to 7.47 (m, 1H), 7.0 to 6.8 (m, 2H), 4.68 (d, 1H, J = 12.2 Hz), 4.18 (d, 1H, J = 12.2 Hz), 3.17 (d, 1H, J = 5.08 Hz), 2.88 (d, 1H J = 5.08 Hz) 2.04 (s, 3H).

[Example 2] Preparation of 2-hydroxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane

8.97 g (35 mM) of 2-acetoxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane prepared in Example 1 was dissolved in 50 ml of methanol, and 100 ml of water was added thereto, followed by carbonic acid. 4.84 g (35 mM) of potassium was added and stirred at room temperature for 1 hour. The reaction solution was filtered through a pad of celite, washed with 50 ml of n-hexane, and extracted twice with 100 ml of dichloromethane. The organic layer was dehydrated with anhydrous magnesium sulfate and the solvent was distilled under reduced pressure to yield 6.12 g of the title compound as an oil (yield = 94%). The ¹ H NMR analysis results are as follows.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.43 to 7.35 (m, 1H), 6.92 to 6.68 (m, 2H), 4.05 to 3.87 (m, 2H), 3.30 (d, 1H, J = 5.1 Hz), 2.84 (d, 1H, J = 5.1 Hz), 1.91 (m, 1H).

[Example 3] Preparation of 2-p-toluenesulfonyloxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane

14 g (75.3 mM) of 2-hydroxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane prepared in Example 2 was dissolved in 200 ml of dichloromethane, followed by 31.5 ml of triethylamine ( 3 equivalents) and 140 mg of dimethylaminopyridine were added and cooled to 0 ° C. 21.5 g (1.5 equivalents) of p-toluenesulfonyl chloride was slowly added dropwise, followed by stirring at room temperature for 2 hours. After the reaction was completed, the mixture was washed with 100 ml of water and then with 50 ml of aqueous sodium chloride solution. The organic layer was dehydrated with anhydrous magnesium sulfate and the solvent was distilled under reduced pressure to give 23.8 g of the title compound as an oil (yield = 93%). The ¹ H NMR analysis results are as follows.

¹ H NMR (300 MHz, CDCl ₃₎ δ (ppm): 7.67 (d, 2H), 7.34-7.26 (m, 3H), 6.86-6.63 (m, 1H), 7.75-6.67 (m, 1H), 4.54 ( d, 1H, J = 11.3 Hz, 4.12 (d, 1H, J = 11.3 Hz), 3.09 (d, 1H, J = 4.9 Hz), 2.82 (d, 1H, J = 4.9 Hz), 2.45 (s, 3H).

[Example 4] Preparation of 2- (2,4-difluorophenyl) -1,3-bis- (1H-1.2,4-triazol-1-yl) -2-propanol]

After adding 6.7 g (169.4 mM) of 60% sodium hydride to 250 ml of dimethylformamide, 19.5 g (282.4 mM) of 1,2,4-triazole was slowly added dropwise. The reaction solution was stirred for 30 minutes at room temperature until a clear solution. In a reaction solution, 24 g (70.6 mM) of 2-p-toluenesulfonyloxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane prepared in Example 3 was dissolved in 50 ml of dimethylformamide. The solution was added dropwise at room temperature. The reaction solution was heated to 60-70 ° C., stirred for 2 hours, cooled to room temperature and dispersed in 500 ml of water. Extracted twice with 250 ml of ethyl acetate and the organic layer was washed with 100 ml of saturated aqueous sodium chloride solution. The organic layer was dehydrated with anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure to disperse the crude product of the crystal in diethyl ether, followed by filtration to obtain 18 g of the target compound as a white crystal (yield = 83.4%). The result of analyzing the obtained compound is shown below.

Melting Point: 137.5 ~ 139 ℃

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

Mass: m / z: 306.8 (MH +)

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.06 (s, 2H), 7.86 (s, 2H), 7.47 ~ 7.39 (m, 1H), 6.84 ~ 6.75 (m, 2H), 5.50 (s, 1H), 4.75 (d, 2H, J = 14.3 Hz), 4.46 (d, 2H, J = 14.3 Hz).

By using the method for preparing a bis-triazole derivative of Formula 1 according to the present invention, a large amount of bis-triazole derivative can be prepared in high yield without side reaction.

Claims (3)

Reacting the 2-sulfonyloxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane derivative of formula 8 with 1,2,4-triazole sodium salt in an equivalent ratio of 1: 2 Method for producing a bis-triazole derivative of Formula 1 comprising a. [Formula 1] [Formula 8] Wherein R represents an alkyl or substituted or unsubstituted aryl group. According to claim 1, wherein the 2-sulfonyloxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane derivative of the formula 8 is 2-acetoxy-2 ', 4' -Difluoroacetophenone is reacted with trimethylsulfoxonium iodide to prepare 2-acetoxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane of formula 6, By removing the acetyl group from 2-acetoxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane of Chemical Formula 6, 2-hydroxymethyl-2- (2,4-di Fluorophenyl-1-yl) oxirane is prepared, and 2-hydroxymethyl-2- (2,4-difluorophenyl-1-yl) oxirane of formula 7 is alkyl or substituted or unsubstituted A method for preparing a bis-triazole derivative of formula 1, which is prepared by a process comprising the step of reacting with arylsulfonyl chloride. [Formula 5] [Formula 6] [Formula 7] The bis-triazole of Formula 1 according to claim 1, wherein the 1,2,4-triazole sodium salt is prepared by reacting 1,2,4-triazole with sodium hydride in an equivalent ratio of 1.2: 2. Process for the preparation of derivatives.