KR100209245B1 - Manufacturing method of triazole derivatives - Google Patents

Abstract

The present invention reacts 1,2,4-triazole with 1- [2- (2,4-difluorophenyl) -2,3-epoxypropyl] -1H-1,2,4-triazole, The present invention relates to a method for producing a triazole derivative obtained by reacting a compound of the general formula (R ₁ ) ₃ R ₂ N ⁺ X ^- with trimethylsulfonoxium iodide to obtain fluconazole.

Description

Method for preparing triazole derivative

The present invention relates to a process for the preparation of triazole derivatives of the following compound (1) having antifungal action and useful for the treatment of fungal infections.

European Patent Application 0044605 (ICI), published January 27, 1982, discloses compounds of the general formula and salts or metal complexes, ethers or esters thereof.

Wherein R ₁ is an aryl group unsubstituted or substituted with halogen, and Y ₁ and Y ₂ are carbon or nitrogen atoms.

1,3-bis- (1,2,4-triazol-1-yl) -2- (2,4-dichloro of the following compound (2) in claims 7 and Example 1 of this patent application Phenyl) -propan-2-ol is disclosed.

However, no 2,4-difluorophenyl compounds are described in the ICI patent application.

The compound (1) is well known under the common name fluconazole, and has been patented as a method for producing the same (Europe Patent 009656, Canada Patent 1191076, Canada Patent 1182822, Canada Patent 1170263, UK Patent 2099818, US Patent 4404216, Spain Patent 9502961, Spain Patent 9002961, Spain Patent 549020, Spain Patent 949684, Spain Patent 549022, Spain Patent 549021, Spain Patent 83-303244) Typical of these are as follows.

First described in British Patent Application No. 2099818 (Pfizer), Canadian Patent Application Nos. 1182822 and 1180076, Grignard or 1-lithiation of 1-bromo-2,4-difluorobenzene as shown in Scheme 1 below. Converted to intermediate form and reacted with 1,3-dichloroacetone to obtain dihaloalcohol of compound (2a), and fluconazole of compound (1) was synthesized by reacting compound (2a) with 1,2,4-triazole; Or compound (1) by reacting with 1,3-ditriazole acetone of compound (2b).

However, n-butyllithium is very sensitive to moisture and air, highly flammable and highly corrosive in the above-described method, which corresponds to lithiation of 1-bromo-2,4-difluorobenzene. The solvent used in the lithiation reaction or the Grignard reaction is diethyl ether or tetrahydrofuran. These solvents are extremely flammable and explosive and dangerous.

Therefore, the above reagents and solvents are dangerous to handle a large amount, and thus are not suitable for mass production on a commercial scale.

The process described in British Patent Application No. 2099818 (Pfizer, Inc.) is the epoxide of compound (3) from 1,3-difluorobenzene, ie 1- [2- (2,4-difluoro, as shown in Scheme 2 below. Rophenyl) -2,3-epoxypropyl] -1H-1,2,4-triazole was prepared, using 1,2,4-triazole and dimethylformamide solvent in the presence of a base K ₂ CO _3. It is a method of synthesize | combining target compound (1) by reacting at 90 degreeC for 4.5 hours.

This method has the advantage that the synthesis of each step is relatively easy, but the reaction yield of the final step is 44%, which is very low.

In order to solve this disadvantage, Canadian Patent Application No. 2051281 reacts the halohydrin intermediate of Compound (4a) with 4-amino 1,2,4-triazole to give 77.8% of Compound (4b) as shown in Scheme 3 below. A method of obtaining in yield, which is treated with NaNO ₂ / HCl to deaminoate to obtain fluconazole of compound (1) in high yield (85.4%), is disclosed.

However, this method is also not very good as the total yield of the last stage reaction is 66.44%.

In addition, J Heterocyclic chem. Considering the preparation of fluconazole disclosed in Vol. 30, p. 1405, (1993), the intermediate (3), ie 2 ', 4'_difluoro-2- (1H-1, 2,4-triazol-1-yl) acetophenone and trimethyl sulfoxonium iodide were refluxed for 18 to 48 hours using t-butyl alcohol as a solvent in the presence of potassium hydroxide as a target compound, fluconazole It is a method of synthesizing (1).

However, this method is very long as the reaction time is 18 to 48 hours, and the yield of the target compound fluconazole (1) is 38%. Yield is low, and there is a problem that the manufacturing cost is high. In addition, various by-products are generated during the reaction, which makes it difficult to separate and purify.

The present inventors have made a lot of research and efforts to solve the above problems, and have developed an efficient method for preparing triazole derivatives from the intermediate compound (3).

It is an object of the present invention to provide a process for the preparation of triazole derivatives.

The present invention is described in detail as follows.

As shown in Scheme 5, in the reaction of 1,2,4-triazole with compound (3), a compound of the general formula (R ₁ ) ₃ R ₂ N ⁺ X ^- and trimethylsulfonsonium In the presence of iodide, acetonitrile, methyl alcohol, n-propyl alcohol, iso-propyl alcohol, t-butyl alcohol, n-butyl alcohol, iso-butyl alcohol or one or more of them in a mixed solvent of water to react It relates to a method for producing a triazole derivative to obtain 1).

(Wherein R ₁ is alkyl having 1-20 carbons, R ₂ is alkyl or aralkyl having 1-20 carbons, and X is F, Cl, Br, I, hydroxy or methoxy.)

The added amount of the compound is 2.0 to 3.5 equivalents, preferably 2.0 to 3.7 equivalents ^of-the formula _{(R 1) 3 R 2 N} + X.

Reaction temperature is 40-130 degreeC, Preferably it is 45-65 degreeC.

The reaction time is the reaction temperature and the tetraalkyl triammonium fluoride used, tetraalkyl triammonium chloride, tetraalkyl triammonium hydroxide, tetraalkyl triammonium methoxide, aralkyl triammonium fluoride, aralkyl Depending on the type and the amount of triammonium chloride, aralkyl triammonium hydroxide or aralkyl triammonium methoxide, it takes about 2 to 8 hours.

Compounds of the general formula (R ₁ ) ₃ R ₂ N ⁺ X ^- are benzyltrimethylammonium chloride, benzyltrimethylammonium hydroxide, benzyltrimethylammonium fluoride, benzyltriethylammonium chloride, tetrabutylammonium fluoride , Tetraethylammonium fluoride, tetramethylammonium fluoride, tetramethylammonium chloride, tetrabutylammonium chloride, tetrapropylammonium chloride, tetraethylammonium chloride, cetyltrimethylammonium chloride tetramethylammonium hydroxide And tetrabutyl ammonium hydroxide, tetrapropyl ammonium hydroxide, tetraethyl ammonium hydroxide and the like.

The mixed solvent used for the reaction is 1: 3-3: 1 of at least one of acetonitrile, methyl alcohol, n-propyl alcohol, iso-propyl alcohol, t-butyl alcohol, n-butyl alcohol and iso-butyl alcohol and water. It is preferable to mix and use.

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

Example 1

[Preparation of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) -propan-2-ol]

을 가하고, 테트라부틸암모니움플로라이드 3H₂O(3.54g, 11.188mM)을 가하고 83℃에서 6시간 반응시키면 반응이 완결된다.2 ', 4'-difluoro-2- (1H-1,2,4-triazol-1-yl) acetophenone (1.0 g, 4.481 mM), 1,2.4-triazole (0.65 g, 9.408 mM And t-butyl alcohol 15 in trimethylsulfonoxium iodide (1.232g, 5.598mM)

The reaction was completed by adding tetrabutylammonium fluoride 3H ₂ O (3.54 g, 11.188 mM) and reacting at 83 ° C. for 6 hours.

와 20% 식염수 20

를 가하여 5분간 교반한 후 층 분리하여 유기층을 취하고, 다시 20% 식염수 20

와 포화식염수 20

로 순차 세척한 유기층을 무수 MgSO₄로 탈수하여 여과하고, 여액에 활성탄 0.25g을 가한 후 실온에서 30분간 교반하고 여과한다.The reaction mixture was concentrated under reduced pressure to remove the solvent, and ethyl acetate 80 was added to the residue.

With 20% saline 20

After stirring for 5 minutes, the layers were separated, the organic layer was taken, and 20% brine 20 was added.

With saturated saline 20

The organic layer washed sequentially with water was filtered by dehydration with anhydrous MgSO ₄ , 0.25 g of activated carbon was added to the filtrate, and stirred at room temperature for 30 minutes and filtered.

를 가하여 용해시키고, 10

로 농축하여 0∼5℃에서 2시간동안 교반하면 결정이 생성된다.Concentrate the filtrate under reduced pressure to give isopropyl alcohol 50

Dissolve by adding 10

The mixture was concentrated to and stirred at 0-5 ° C. for 2 hours to form crystals.

The crystals were filtered off and dried to yield the title compound (0.85 g, 62%).

Example 2

[Preparation of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) -propan-2-ol]

용매중에서 50∼55℃의 온도를 유지하여 1시간 교반한 후 감압농축하여 용매를 제거한다. 잔유물에 2',4'-디플루오로-2-(IH-1,2,4-트리아졸-1-일)아세토페논(1.0g, 4.481mM)과 트리 메틸설프옥소니움아이오다이드(1.232g, 5.598mM) 그리고 1,2,4-트리아졸(0.65g, 9.408mM)을 가하고, t-부틸알콜 15

을 가한다음, 80℃에서 6시간 반응시키고 반응혼합액을 감압농축시켜 용매를 제거하고, 실시예 1에서의 방법에 준하여 처리하면 표제화합물(0 892g, 65%)이 얻어진다.Benzyltrimethylammonium chloride (2.10 g, 11.308 mM) and potassium fluoride 2H ₂ O (1.065 g, 11.314 mM) were dissolved in acetonitrile 20

The temperature is maintained at 50 to 55 ° C. in the solvent, stirred for 1 hour, and then concentrated under reduced pressure to remove the solvent. In the residue 2 ', 4'-difluoro-2- (IH-1,2,4-triazol-1-yl) acetophenone (1.0 g, 4.481 mM) and trimethylsulfonoxium iodide ( 1.232 g, 5.598 mM) and 1,2,4-triazole (0.65 g, 9.408 mM) were added and t-butyl alcohol 15

The reaction mixture was added at 80 DEG C for 6 hours, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the mixture was treated according to the method of Example 1 to obtain the title compound (0 892 g, 65%).

Melting Point (M.p) = 139,3 ℃

¹ H-NMR analysis results were the same as in Example 1.

Example 3

[Preparation of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) -propan-2-ol]

와 물 10

를 가하고 벤질트리메틸암모니움하이드록사이드 (40% 수용액, 8.845

, 22.40mM)을 가한다.2 ', 4'-difluoro-2- (1H-1,2,4-triazol-1-yl) acetophenone (2.0 g, 8.961 mM) and trimethylsulfonoxium iodide (2.465 g, 11.202 mM) and 1,2,4-triazole (1.299 g, 18.818 mM) were added followed by t-butyl alcohol 15

And water 10

Benzyltrimethylammonium hydroxide (40% aqueous solution, 8.845

, 22.40 mM).

The mixture was stirred for 1 hour while refluxing, the reaction mixture was filtered to remove insoluble matters, the filtrate was concentrated under reduced pressure to remove the solvent, and then separated by column chromatography on silica gel using chloroform-methanol (15: 1) as the eluent. Compound (1.921 g, 70%) is obtained.

Melting Point (M.p) = 139,7 ℃

¹ H-MM analysis results were the same as the results of Example 1.

Example 4

[Preparation of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) -propan-2-ol]

용매중에 가하고 벤질트리메틸암모니움메톡사이드(40% 메틸알콜용액, 10.153

, 22.403mM)을 가한다음 반응온도를 80∼83℃로 하여 6시간 반응시킨다.2 ', 4'_difluoro-2- (1H-1,2,4-triazol-1-yl) acetophenone (2.0 g, 8.961 mM) and trimethylsulfonoxium iodide (2.465 g, 11.202 mM) and 1,2,4-triazole (1.20 g, 17.374 mM) were added to tert-butyl alcohol 40

Benzyltrimethylammonium methoxide (40% methyl alcohol solution, 10.153)

, 22.403 mM) was added and the reaction temperature was 80-83 ° C. for 6 hours.

After completion of the reaction, the reaction mixture was filtered to remove insoluble matters, the filtrate was concentrated under reduced pressure to remove the solvent, and then treated in accordance with the method of Example 1 to obtain the title compound (1.729 g, 63%).

Melting Point (M.p) = 139,2 ℃

¹ H-NMR analysis results were the same as in Example 1.

Example 5

[Preparation of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) -propan-2-ol]

용매중에 가하고 벤질트리메틸암모니움하이드록사이드(40% 메틸알콜용액) (9,367

, 22.403mM)을 가한다.2 ', 4'-difluoro-2- (1H-1,2,4-triazol-1-yl) acetophenone (2.0 g, 8.961 mM) and trimethylsulfonoxium iodide (2.465 g, 11.202 mM) and 1,2,4-triazole (1.20 g, 17,374 mM) in n-butyl alcohol 20

Benzyltrimethylammonium hydroxide (40% methyl alcohol solution) (9,367)

, 22.403 mM).

The mixture was stirred for 1.5 hours while refluxing, the reaction mixture was concentrated under reduced pressure to remove the sulphate, and then treated according to the method of Example 1 to obtain the title compound (1.770 g, 64.5%).

Melting Point (M.p) = 139,0 ℃

¹ H-NMR analysis results were the same as in Example 1.

Example 6

[Preparation of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) -propan-2-ol]

용매중에 가하고 벤질트리메틸암모니움하이드록사이드 (40% 메틸알콜용액) (9,367

, 22.403mM)을 가한다.2 ', 4'-difluoro-2- (1H-1,2,4-triazol-1-yl) acetophenone (2.0 g, 8.961 mM) and trimethylsulfonoxium iodide (2.465 g, 11.202 mM) and 1,2,4-triazole (1.20 g, 17.374 mM) isobutyl alcohol 20

Benzyltrimethylammonium hydroxide (40% methyl alcohol solution) (9,367)

, 22.403 mM).

The mixture was stirred at reflux for 1.5 hours, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then treated in accordance with the method of Example 1 to obtain the title compound (1.825 g, 66.5%).

Melting Point (M.p) = 139,5 ℃

¹ H-NMR analysis results were the same as in Example 1.

Claims (4)

In reacting 1,2,4-triazole with compound (3), acetonitrile, methyl alcohol, in the presence of a compound of general formula (R ₁ ) ₃ R ₂ N ⁺ X ^- and trimethylsulfonoxium iodide, Triazole derivative characterized by reacting n-propyl alcohol, iso-propyl alcohol, t-butyl alcohol, n-butyl alcohol, iso-butyl alcohol or one or more of them in a mixed solvent of water to obtain compound (1) Manufacturing method.

(Wherein R ₁ is alkyl having 1 to 20 carbons, R ₂ is alkyl or aralkyl having 1 to 20 carbons, and X is F, Cl, hydroxy or methoxy.) The method for producing a triazole derivative according to claim 1, wherein 2.0 to 3.5 equivalents of a compound having the structure of General Formula (R ₁ ) ₃ R ₂ N ⁺ X ⁻ is used. The method for producing a triazole derivative according to claim 1, wherein 2.0 to 2.7 equivalents of a compound having the structure of General Formula (R ₁ ) ₃ R ₂ N ⁺ X ^- is used. The mixing ratio of at least one of acetonitrile, methyl alcohol, n-propyl alcohol, iso-propyl alcohol, t-butyl alcohol, n-butyl alcohol, and iso-butyl alcohol with water is 1: 3 to 3 A method for producing a triazole derivative, which is: 1.