KR100327818B1 - Process for the Preparation of Fluconazole - Google Patents

Abstract

The present invention relates to a method for preparing fluconazole, and more particularly, to a cyclization reaction using formamide to a compound of formula (II) to produce fluconazole of formula (I). In particular, the present invention relates to a method of producing fluconazole of formula (I) with high yield and high purity by fundamentally blocking the production of fluconazole isomers of formula (III), unlike the prior art.

Description

Process for the Preparation of Fluconazole

The present invention relates to a method for preparing fluconazole, and more particularly, to a cyclization reaction using formamide to a compound of formula (II) to produce fluconazole of formula (I). In particular, the present invention relates to a method of producing fluconazole of formula (I) with high yield and high purity by fundamentally blocking the production of fluconazole isomers of formula (III), unlike the prior art.

Fluconazole of formula (I) is an antifungal agent in Korean Patent No. 20,312 (1985), in which oxirane compound of formula (IV) and 1,2,4-triazole of formula (V) are present in the presence of a base, as shown in Scheme 1 below. A method for producing fluconazole of structural formula (I) by reacting is disclosed.

In Scheme 1, the yield was low at 44%.

The reason for this low yield is that theoretically, due to the structural characteristics of Structural Formula (V), isomers are produced by the competition reaction of nitrogen in the molecule during the nucleophilic reaction. Moreover, the isomers are characterized by the physical and chemical properties such as the solubility and the compound of Structural Formula (I). This is because they are so similar that it is not easy to selectively remove only isomers.

Bauer L. et al. Of Illinois State University of the United States reacted with the oxirane compound of formula (IV) and 1,2,4-triazole of formula (V) as shown in Scheme 2 below. It has been reported that fluconazole and fluconazole isomers of formula (III) are produced [J. Heterocyclic Chem. 30, 1405, 1993].

In the above Reaction Scheme 2, when the compound of Structural Formula (IV) and the compound of Structural Formula (V) react, N ₁ , N ₂ and N ₄ in the 1,2,4-triazole of Structural Formula (V) are all nucleophilic. This is because fluconazole of formula (I) is produced when N ₁ or N ₂ is nucleophilic, whereas fluconazole isomer of structure (III) is produced when N ₄ is nucleophilic.

In addition to the above Schemes 1 and 2, a method for preparing fluconazole of Structural Formula (I) using 1,2,4-triazole of Structural Formula (V) is disclosed in WO 95/07895 and U.S. Patent No. 5,508,423 (1996). 5,633,386 (1997), 5,710,280 (1998), and 5,750,719 (1998), although these methods also use 1,2,4-triazole, which is fundamental to the formation of isomers. It could not be prevented.

Keay JG and Scriven EFV generally produce 10-30% of isomers by N ₄ during the nucleophilic reaction of 1,2,4-triazole. 4-amino-1,2,4-triazole was used to block the formation of this isomer, in which case an additional step was required to remove the amino group of N ₄ (J. Organic Chem. 54, 731, 1989). ).

In Korean Patent Publication No. 94-21,536, the oxirane compound of formula (IV) is reacted with 4-amino-1,2,4-triazole of formula (VII) to react the compound of formula (VII) A method for preparing fluconazole of formula (I) is disclosed.

In Scheme 3, fluconazole was synthesized in a total yield of 60.5% without separating the compound of formula (VII).

In Canadian Patent No. 2,051,281 (1998), a compound of Formula (VII) is reacted with 4-amino-1,2,4-triazole of Structural Formula (VII) to form A method for preparing a compound and preparing fluconazole of formula (I) through deamine reaction is disclosed.

Where X is fluorine, chlorine, bromine or iodine.

In Scheme 4, the total yield of fluconazole was 66%.

As described above, in Scheme 3 or Scheme 4, 4-amino-1,2,4-triazole was used to block the formation of fluconazole isomers, but additional deprotection was required. It had the disadvantage of using highly corrosive high concentration of inorganic acid and sodium nitrite, and because the reaction had to be carried out at low temperature, there was a risk of explosion if the temperature control was wrong, which made it difficult to apply to industrial mass production.

In Spanish Patent No. 549,022 (1986), fluconazole is prepared by blocking the formation of fluconazole isomers by reacting with Structural Formula (XI) using Grignard Reagent of Formula (XIII) as shown in Scheme 5 below. A method is disclosed.

Wherein X is halogen.

Scheme 5 also blocks the formation of fluconazole isomers, but the Grignard reagent of formula (XII) is also unsuitable for mass production because it is highly explosive and very sensitive to water and air and must be reacted only under anhydrous conditions. .

International Patent Application Publication No. 97 / 44,330 discloses a compound of formula (II) by reacting an oxirane compound of formula (IV) with a hydrazine monohydrate of formula (XIII) to form a compound of formula (XIV). A method of producing fluconazole by reacting with 1,3,5-triazine is disclosed.

In Scheme 6, the overall yield of fluconazole was only 53%. (Applicant is the numerical value obtained by the actual experiment according to the embodiment of the patent (see Comparative Example))

Scheme 6 also blocks the production of fluconazole isomers, but 1,3,5-triazine is an expensive reagent and requires 0.67 equivalents in theory for the compound of formula II, but actually has to use an excess of 3.4 equivalents.

The method of producing 1,3,5-triazine by reacting formamidine acetate with triethylorthoformate (Synthesis, 690, 1979) is also a method that has no industrial utility, such as a sublimation process in the purification process. It has been recognized.

As such, the existing prior arts are difficult to separate and purify pure fluconazole due to the formation of fluconazole isomers, or difficult to apply to industrial production because they use expensive reagents or reagents that are harmful to the human body and difficult to handle, even though no fluconazole isomers are produced. There were problems.

Accordingly, the present inventors have conducted a long research to develop a method for easily producing fluconazole without generating fluconazole isomers.

As a result, when cyclization reaction was carried out using formamide to the compound of formula (II), it was confirmed that fluconazole was not produced in the high yield and fluconazole was produced in a high yield.

The present invention relates to a method for producing fluconazole, and more particularly, it is characterized by producing a fluconazole of the structural formula (I) by performing a cyclization reaction using formamide to the compound of the structural formula (II) as shown in Scheme 7 below. . In particular, the present invention relates to a method of producing fluconazole of formula (I) with high yield and high purity by fundamentally blocking the production of fluconazole isomers of formula (III), unlike the prior art.

Hereinafter, the present invention will be described in detail.

The formamide of the present invention not only acts as a cyclization reagent, but also itself as a reaction solvent. Thus, fluconazole of formula (I) can be prepared by simply adding a compound of formula (II) directly to formamide. At this time, it is preferable to use formamide per 1 equivalent of the compound of the formula (II) in a ratio of 33 to 68 equivalents.

In the present invention, formamide and formic acid may be used together as a cyclization reagent.

When both formamide and formic acid are used as cyclization reagents, the yield can be improved and the by-products of ammonia can be suppressed compared to using formamide alone. At this time, it is preferable to use 1-10 equivalents of formamide and 1.5-5 equivalents of formic acid per 1 equivalent of the compound of formula (II). If too much formic acid is used, a by-product is generated.

In addition, the present invention reacts by using a different reaction solvent instead of formamide which acts not only as a cyclization reagent but also as a reaction solvent, both in the case where formamide alone or formamide and formic acid are used as the cyclization reagent. You can. As such a reaction solvent, an inert organic solvent having a high boiling point is preferable, and a toluene solvent such as toluene or xylene is most preferable. In this case, it is preferable to use the reaction solvent added at a ratio of 5 to 10 ml per 1 g of the compound of formula (II).

As such, when an additional solvent such as toluene is used, the amount of formamide used as a solvent can be reduced, and additionally, water generated during the reaction can be easily removed. In other words, when a solvent such as toluene is additionally used, when formamide is used as a cyclization reagent, formamide is 2.5 to 5 equivalents to 1 equivalent of the compound of formula (II), and formamide and cyclization reagent are used. In the case of using formic acid together, it is possible to reduce the ratio of 1 to 5 equivalents of formamide and 1.5 to 5 equivalents with respect to 1 equivalent of the compound of formula (II).

The reaction temperature is 100 ° to 180 ° C, preferably 130 ° to 150 ° C, and the reaction time is 1 to 5 hours, preferably 1.5 to 3 hours.

Compounds of the formula (II), which are starting materials in the present invention, are compounds known from WO 96 / 04,256 and WO 97 / 44,330.

Example 1: Preparation of 2- (2,4-difluorophenyl) -1-hydrazino-3- (1H-1,2,4-triazol-1-yl) propan-2-ol

5.00 g (15.0 mmol) of 1- [2- (2,4-difluorophenyl) -2,3-epoxypropyl] -1H-1,2,4-triazole methanesulfonate 15 ml of isopropanol and toluene 7.5 ㎖ was added and 4.14 ml (83.6 mmol) of 98% hydrazine monohydrate was added thereto, followed by stirring under reflux for 3 hours. After the reaction was cooled to room temperature, the precipitate of methanesulfonic acid salt of hydrazine was filtered off, the filtrate was concentrated under reduced pressure, 10 ml of ethyl acetate was added and the mixture was stirred for 30 minutes, and the resulting solid was filtered to give 2.99 g of a titled substance (yield 74%). Got. The filtrate obtained by filtration was concentrated under reduced pressure again, 5 ml of ethyl acetate was added and stirred for 30 minutes, and the resulting solid was filtered to obtain 0.40 g (yield 10%) of the title substance.

Melting Point: 164 ° ~ 169 ℃

Example 2: Preparation of Fluconazole

Formamide in 2.69 g (10.0 mmol) of 2- (2,4-difluorophenyl) -1-hydrazino-3- (1H-1,2,4-triazol-1-yl) propan-2-ol 15.3 g (340 mmol) was added and stirred at 150 ° C. for 1.5 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in 10 ml of ethyl acetate. The organic layer was washed twice with 10 ml of water, and then extracted with 10 ml of 10% aqueous hydrochloric acid solution. After washing with ㎖, 0.50 g of activated carbon was added, stirred for 30 minutes, filtered, and the filtrate obtained by filtration was cooled to 5 ° C. and neutralized with an aqueous 10% caustic solution with stirring for 30 minutes to obtain a precipitate, which was filtered. Then washed several times with cold water and dried under reduced pressure to give 2.29 g (yield 75%) of the title compound as a white solid.

Melting Point: 138 ~ 139 ℃

Example 3: Preparation of Fluconazole

Formamide in 2.69 g (10.0 mmol) of 2- (2,4-difluorophenyl) -1-hydrazino-3- (1H-1,2,4-triazol-1-yl) propan-2-ol 1.80 g (40.0 mmol) and 13.5 ml of toluene were added and stirred at 150 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in 10 ml of ethyl acetate. The organic layer was washed twice with 10 ml of water, and then extracted with 10 ml of 10% aqueous hydrochloric acid solution. After washing with ㎖, 0.50 g of activated carbon was added, stirred for 30 minutes, filtered, and the filtrate obtained by filtration was cooled to 5 ° C. and neutralized with an aqueous 10% caustic solution with stirring for 30 minutes to obtain a precipitate, which was filtered. Then washed several times with cold water and dried under reduced pressure to give 2.20 g (72% yield) of the title compound as a white solid.

Melting Point: 137 ~ 139 ℃

Example 4: Preparation of Fluconazole

85% in 2.69 g (10.0 mmol) of 2- (2,4-difluorophenyl) -1-hydrazino-3- (1H-1,2,4-triazol-1-yl) propan-2-ol 1.08 g (20.0 mmol) of formic acid was added and stirred at 80 ° C. for 30 minutes, then 2.25 g (50.0 mmol) of formamide was added and stirred at 150 ° C. for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in 10 ml of ethyl acetate. The organic layer was washed twice with 10 ml of water, and then extracted with 10 ml of 10% aqueous hydrochloric acid solution. After washing with ㎖, 0.50 g of activated carbon was added, stirred for 30 minutes, filtered, and the filtrate obtained by filtration was cooled to 5 ° C. and neutralized with an aqueous 10% caustic solution with stirring for 30 minutes to obtain a precipitate, which was filtered. Then washed several times with cold water and dried under reduced pressure to give 2.33 g (76% yield) of the title compound as a white solid.

Melting Point: 138 ~ 140 ℃

Example 5: Preparation of Fluconazole

2- (2,4-difluorophenyl) -1-hydrazino-3- (1H-1,2,4-triazol-1-yl) propan-2-ol in 85% to 2.69 g (10.0 mmol) 1.08 g (20.0 mmol) of formic acid and 13.5 mL of toluene were added thereto, stirred at 80 ° C. for 30 minutes, and then 0.77 g (17.0 mmol) of formamide was added thereto, and stirred at 150 ° C. for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in 10 ml of ethyl acetate, the organic layer was washed twice with 10 ml of water, and then the components contained in 10 ml of 10% aqueous hydrochloric acid solution were extracted. 0.50 g of activated carbon was added thereto, stirred for 30 minutes, filtered, and the filtrate obtained by filtration was cooled to 5 ° C., neutralized with 10% aqueous sodium hydroxide solution for 30 minutes while stirring to obtain a precipitate, and the precipitate was filtered. After washing several times with cold water and drying under reduced pressure to give 2.42 g (79% yield) of the title compound as a white solid.

Melting Point: 138 ~ 139 ℃

Comparative example: Preparation of Fluconazole (According to the Example Method of WO-A-97 / 44,330)

12.5 ml of acetonitrile was added to 1.67 g (5.0 mmol) of 1- [2- (2,4-difluorophenyl) -2,3-epoxypropyl] -1H-1,2,4-triazole methanesulfonate. Then, 0.63 g (12.5 mmol) of hydrazine and monohydrate were added thereto, heated to reflux for 3 hours, cooled to 0 ° to 5 ° C., stirred for 10 minutes, and then the precipitate was filtered and washed with acetonitrile. Concentration under reduced pressure at temperature afforded 1.35 g of 2- (2,4-difluorophenyl) -1-hydrazino-3- (1H-1,2,4-triazol-1-yl) propan-2-ol. .

To 1.35 g (5.0 mmol) of 2- (2,4-difluorophenyl) -1-hydrazino-3- (1H-1,2,4-triazol-1-yl) propan-2-ol obtained above 1.42 g (17.0 mmol) of 1,3,5-triazine and 10 ml of acetic acid were added thereto, and the mixture was heated to reflux for 2.45 hours, concentrated under reduced pressure at 70 ° to 75 ° C. to remove acetic acid, and 3 g of sodium chloride was dissolved in 10 ml of water. Add 25 ml of methylene chloride, add 33% caustic soda solution, neutralize to pH 7, separate the two layers, wash the water layer with 10 ml of methylene chloride, collect all organic layers, dry with anhydrous sodium sulfate, and filter the filtrate at 40 ℃. Concentration under reduced pressure gave 1.40 g of fluconazole of the crude product.

11.2 ml of isopropanol was added to 1.40 g of fluconazole of the crude product obtained above, heated to 55 ° C., 0.28 g of activated carbon was added thereto, stirred at 55 ° to 65 ° C. for 20 minutes, filtered through activated diatomaceous earth, washed with isopropanol, and then filtrate. After distilling under reduced pressure, 2.8 ml of isopropanol was added thereto, cooled to 0 ° -5 ° C., stirred for 12 hours, filtered, and washed with isopropanol cooled to −11 ° C. to obtain 0.7 g of the title substance. In addition, the filtrate was quantified using high performance liquid chromatography. As a result, 0.12 g of the titled substance was found.

Therefore, the total production of fluconazole was 0.82g and the actual yield was 53%.

Comparing the fluconazole yields of the examples of the present invention and the comparative example it can be seen that the yield in the examples of the present invention is much higher than the yield in the comparative example as shown in Table 1 below.

The yield is the product of the yield of Example 1, which is the yield of the compound of formula II, and the yield of Examples 2-5.

Confirmation of the fluconazole isomer of Structural Formula (III) in the production method according to the present invention was dissolved in methanol after completion of the reaction in the embodiments of the present invention using high-performance liquid chromatography (HPLC) after analyzing the result of analysis It was confirmed that no fluconazole isomers were produced.

HPLC Conditions

Apparatus: Waters 510 High Performance Liquid Chromatograph

Detector: Waters 484 UV Absorbance Spectrometer

Measurement wavelength: 260nm

Column: μ -Bondapak C ₁₈ (3.9 × 300mm)

Mobile phase: Mixture of water-methanol (66: 34)

Flow rate: 1.0 ml / min

In the method for producing fluconazole according to the present invention, the formation of fluconazole isomers is carried out by performing a cyclization reaction for a short reaction time (1.5 to 3 hours) using formamide or formamide and formic acid which are inexpensive and easy to handle in industrial mass production. Fluconazole could be prepared in high yield and high purity by blocking essentially.

Claims (5)

A process for preparing fluconazole of formula (I) by reacting a compound of formula (II) with formamide and formic acid. A process according to claim 1, wherein the fluconazole of formula (I) is prepared using 1 to 10 equivalents of formamide and 1.5 to 5 equivalents of formic acid per equivalent of compound of formula (II). delete delete The process according to claim 1 or 2, wherein the fluconazole of formula (I) is prepared by reacting by adding a solvent such as toluene or xylene.