KR20080112306A - Synthesis of 4-[1-(4-cyano phenyl)-1-(1,2,4-triazol-1-yl)methyl] benzonitrile and 4-[1-(1h-1,2,4-triazol-1-yl)methylene benzonitrile intermediate - Google Patents

Abstract

The present invention relates to a process for the preparation of 4-[1-(4-cyano phenyl)-1-(1,2,4-triazol-1-yl) methyl] benzonitrile (letrozole), substantially free from its isomeric impurity. The preparation involves reaction of 4-[1-(1 H-1,2,4-triazol-1-yl)methylene benzonitrile with 4-fluorobenzonitrile in the presence of an organic solvent and a silicon amine. The present invention also relates to a process for the preparation of 4-[1-(1 H-1,2,4-triazol-1-yl)methylene benzonitrile which involves: (a) the reaction of a 4-halomethyl benzonitrile with 1,2,4-triazole in the presence of cesium carbonate and an organic solvent to obtain a reaction mass comprising 4-[1-(1,2,4-triazole-1-yl)methyl] benzonitrile of formula II; and (b) precipitation of 4-[1-(1,2,4-triazole-1-yl)methyl]benzonitrile (II) from the reaction mass using a suitable organic solvent. ® KIPO & WIPO 2009

Description

4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile and 4- [1- (1H-1,2,4-triazole Synthesis of -1-yl) methylene benzonitrile intermediate {SYNTHESIS OF 4- [1- (4-CYANO PHENYL) -1- (1,2,4-TRIAZOL-1-YL) METHYL] BENZONITRILE AND 4- [1- (1H-1,2,4-TRIAZOL-1-YL) METHYLENE BENZONITRILE INTERMEDIATE}

The present invention relates to 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl], which is a compound of formula I, substantially free of isomeric impurity. It relates to a process for producing benzonitrile.

The present invention also relates to compound 4 of formula II, which is a useful intermediate for the preparation of 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile. A method for producing-[1- (1H-1,2,4-triazol-1-yl) methylene benzonitrile.

4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile, or letrozole, is a potent aromatase inhibitor of estrogen biosynthesis ( As an aromatase inhibitor, it is useful for treating hormone-dependent breast cancer in postmenopausal women. Estrogen deprivation is most specifically achieved using inhibitors that block the final stage of the biosynthetic pathway, namely the conversion of androgens to estrogens by aromatase enzymes.

Experimental studies have demonstrated that letrozole substantially inhibits aromatase activity in malignant and non-malignant breast tissues and also significantly inhibits endogenous estrogens in breast cancer.

The final step of letrozole synthesis is the reaction of 4- [1- (1H-1,2,4-triazol-1-yl) methylene benzonitrile with 4-fluoro benzonitrile. For this reaction, various conditions and reagents are disclosed in the prior art, including the use of potassium tert-butoxide. All prior art methods produce letrozole in very low yields. In addition, the resulting letrozole product requires further purification to remove impurities involved in the reaction in order to obtain letrozole with 99% or more HPLC purity.

U.S. Patent 4,978,672 discloses 1,2,4 with 4- [alpha- (4-cyanophenyl) -1- (1,2,4-triazole) -methyl] benzonitrile and 4-bromomethyl benzonitrile A process for producing the same, which comprises reacting triazole to obtain 4- [1- (1,2,4-trizol-1-yl) methyl] benzonitrile. 4- [1- (1,2,4-trizol-1-yl) methyl] benzonitrile is further reacted with 4-fluorobenzonitrile to give 4- [1- (4-cyanophenyl) -1- ( 1,2,4-triazol-1-yl) methyl] benzonitrile (retrozole) is obtained.

In the preparation method disclosed in the '672 patent, 4-bromomethyl benzonitrile and 1,2,4-triazole are reacted under reflux in an acetone solvent in the presence of potassium carbonate and potassium iodide (according to Example 24), to 2% Together with other impurities of 87 wt% of 4- [1- (1,2,4-triazolyl) methyl] benzonitrile of Formula II and 11wt% of 4- [4- (1,2, 4-triazol-4-yl) methyl] benzonitrile. 4-Bromomethyl benzonitrile and 1,2,4-triazole were reacted in a mixture of chloroform and acetonitrile (Example 9), together with 20 wt% of other impurities to give a 30 wt% content of 4- [ 1- (1,2,4-triazolyl) methyl] benzonitrile and 40 wt% content of 4- [4- (1,2,4-triazol-4-yl) methyl] benzonitrile of formula III are obtained. The ratio of the desired product to impurities in the method of this document is determined by experiment.

Treatment of the reaction mixture of the above preparation step with 4-fluorobenzonitrile yields 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) ) -Methyl] benzonitrile and isomers thereof, which are compounds of Formula IV, are prepared. Therefore, impurities of formula III must be separated before treatment with 4-fluorobenzonitrile, which not only lengthens the process but also involves additional column purification steps which are very disadvantageous for large scale production.

WO 2004/076409 discloses 4-[(4-amino-4H-1,2,4-triazol-1-yl) by reacting 4-halomethyl benzonitrile with 4-amino-1,2,4-triazole. Methyl] benzonitrile halide was removed, and 4-[(4-amino-4H-1,2,4-triazolium-1-yl) methyl] benzonitrile halide was deamined to give 4- [1- ( 1H-1,2,4-triazol-1-yl) methylene benzonitrile is prepared, followed by 4- [1- (1H-1,2,4-triazol-1-yl) methylene benzonitrile and 4- Location specificity of 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile including reacting fluorobenzonitrile to obtain letrozole Regiospecific methods of preparation are disclosed. The application includes a further purification step of 4-[(4-amino-1,2,4-triazolium-1-yl) methyl] benzonitrile bromide, thus making the preparation process very redundant. The process for preparing letrozole is disclosed. The yield of letrozole from 4-bromomethyl benzonitrile is 35%, yielding very low and uneconomical results. The yield of 4-[(4-amino-4H-1,2,4-triazolium-1-yl) methyl] benzonitrile halide is 98 to 99%, but 1 to 2% of unwanted isomeric impurities (Compound III) It contains.

US 2005/0209294 discloses a process for the preparation of 4- (1H- (1,2,4-triazol-1-yl) methyl) benzonitrile, an intermediate used in the preparation of letrozole. This application discloses a process for using sodium and potassium salts of 1,2,4-triazole for the preparation of compounds of formula II. According to the production method disclosed in the above patent application, 4- (1H- (1,2,4-triazol-1-yl) methyl) benzonitrile is obtained in a yield of about 60%, and isomer impurities of 2 to 5% (2-5% of the compound of formula III).

Therefore, the main object of the present invention is 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl of formula I, wherein the content of isomeric impurities is substantially reduced. ) Methyl] benzonitrile. Another object of the present invention is 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] of formula I, which provides compound I in high yield. It is to provide a simple and economic method for preparing benzonitrile.

Summary of the Invention

According to a first aspect of the present invention, there is provided a process for preparing 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile of Formula II,

(a) 4-halomethyl benzonitrile and 1,2,4-triazole are reacted in the presence of cesium carbonate and an organic solvent to give 4- [1- (1,2,4-triazole-1- I) methyl] obtaining a reaction mixture comprising benzonitrile; And (b) precipitating 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile (II) from the reaction mixture using a suitable organic solvent. Is provided.

The presence of cesium carbonate makes it less likely to form unwanted impurities (compounds of Formula III).

In one embodiment, the organic solvent used in step (a) is selected from the group consisting of alcohols, ketones, nitriles, and other solvents such as dimethylsulfoxide, dimethylformamide, dimethyl acetamide and dichlorobenzene. Preferably the ketone is acetone.

The 4-halomethyl benzonitrile may be selected from the group consisting of 4-chloromethyl benzonitrile, 4-iodomethyl benzonitrile, and 4-bromomethyl benzonitrile.

In one embodiment, the organic solvent used in step (b) is a mixture of two or more organic solvents. Suitably the organic solvents are nonpolar organic solvents. Preferably, the organic solvents used in step (b) are nonpolar organic solvents selected from hexane, n-heptane, toluene, xylene, methylene chloride, chlorobenzene, diethyl ether, and diisopropyl ether. Most preferably, the solvent mixture is a mixture of diisopropyl ether and n-heptane.

The reaction can be carried out in the presence of a catalyst which helps to increase the reaction rate as needed. Preferably, the catalyst is potassium iodide.

4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile prepared according to the above aspect of the present invention is prepared according to a known method or described in the second aspect below. Depending on the method, it can be used to prepare 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile.

According to a second aspect of the present invention, 4- [1- (1H-1,2,4-triazol-1-yl) methyl] benzonitrile and 4-fluorobenzonitrile of the formula (II), an organic solvent and a silicone amine In the presence of a compound, there is provided a process for preparing 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile of the formula (I) comprising the step of reacting do.

The silicone amine may be an alkali metal disilazane or an alkali metal monosilazane. The alkali metal may be selected from lithium, sodium or potassium. Preferably the silicone amine is an alkali metal disilazane. In one embodiment, the silicone amine is a compound of Formula V.

Wherein R 1 is the same or different and is selected from hydrogen, optionally substituted C _1-6 alkyl and optionally substituted C _2-6 alkenyl; Z is selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, and silyl; M is selected from Li, K, and Na. In one embodiment, the silyl group is (R 2) ₃ Si −, where R 2 is as defined in R 1. Preferably, R 1 is unsubstituted C _1-6 alkyl. Preferably, R 2 is unsubstituted C _1-6 alkyl. Most preferably, the silicone amine is lithium 1,1,1,3,3,3-hexamethyldisilazane, also referred to as Li HMDS.

The use of such silicone amines allows the production of isomeric impurities (compound IV) to be minimized. In particular, the process of the present invention reduces isomeric impurities (Compound IV) to less than 0.1%. Another advantage of the silicone amine is that it is an organic amine and therefore can be dissolved in the organic reaction mixture. The reactants of the prior art (eg potassium tert-butoxide) are not organic and remain as a suspension in the organic reaction mixture, slowing the reaction.

In one embodiment, the organic solvent is selected from 1,4-dioxane, toluene, dichloromethane, dichloroethane and tetrahydrofuran.

The process of the second aspect of the present invention facilitates simple separation of the product from the reaction mixture by simple quenching and filtration. Thus, the redundant extraction and recrystallization processes used in the prior art can be avoided.

The reaction of 4- [1- (1H-1,2,4-triazol-1-yl) methylene benzonitrile with 4-fluobenzonitrile can be carried out at low temperatures, which is also an unwanted byproduct To avoid the formation of. For example, the reaction mixture may be cooled to about -30 to -10 ° C, preferably about -20 ° C. Typically, a solution of 4- [1- (1H-1,2,4-triazol-1-yl) methyl] benzonitrile in an organic solvent is added to the reaction mixture while maintaining the temperature below -15 ° C. The reaction mixture may then be slowly warmed to about −10 ° C. and stirred for about 30 minutes.

The 4- [1- (1H-1,2,4-triazol-1-yl) methyl] benzonitrile starting material is prepared by a known method or according to the production method of the present invention described in the first aspect. It may also be prepared.

According to a third aspect of the present invention, there is provided a process for preparing 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile of the formula (I) a) 4-halomethyl benzonitrile and 1,2,4-triazole are reacted in the presence of cesium carbonate and an organic solvent to give 4- [1- (1,2,4-triazol-1-yl) ) Methyl] benzonitrile to obtain a reaction mixture; (b) precipitating 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile (II) from the reaction mixture using a suitable organic solvent; And (c) the 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile and 4-fluorobenzonitrile in dimethylformamide in the presence of potassium tert-butoxide, There is provided a preparation method comprising the step of reacting.

According to a fourth aspect of the invention, there is provided a process for the preparation of 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile of formula (I) a) 4-halomethyl benzonitrile and 1,2,4-triazole are reacted in the presence of cesium carbonate and an organic solvent to give 4- [1- (1,2,4-triazol-1-yl) ) Methyl] benzonitrile to obtain a reaction mixture; (b) precipitating 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile (II) from the reaction mixture using a suitable organic solvent; And (c) reacting 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile and 4-fluorobenzonitrile in the presence of an organic solvent and a silicone amine. A manufacturing method is provided.

Detailed description of the invention

In one aspect, the present invention provides an improved process for preparing 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile, which is a compound of Formula II. The process produces a product containing less than 1.0% isomeric impurities (ie, compounds of formula III). The preparation method involves the reaction of 4-halomethyl benzonitrile with 1,2,4-triazole in the presence of cesium carbonate.

According to one embodiment, the process of step (a) is carried out by warming 4-halomethyl benzonitrile and 1,2,4-triazole in an organic solvent in the presence of cesium carbonate. The organic solvent may be an alkyl alcohol (eg, C _1-6 alkyl alcohol), an aryl alcohol (eg, C _6-12 aryl alcohol), an alkylaryl alcohol (eg, C _7-15 alkylaryl alcohol) Alcohol selected from. Suitable alcohols include ethanol, methanol, n-propanol, isopropanol, n-butanol, isobutanol, benzyl alcohol and the like. The organic solvent may be a ketone selected from alkyl ketones such as C _1-6 alkyl ketones, aryl ketones such as C _6-12 ketones, or alkylaryl ketones such as C _7-15 ketones. Suitable ketones include acetone, methyl isobutyl ketone, and methylethyl ketone. The organic solvent may be nitrile such as acetonitrile and benzonitrile. Optionally, the organic solvent can be another solvent selected from dimethylsulfoxide, dimethylformamide, dimethyl acetamide and dichlorobenzene.

The 4-halomethyl benzonitrile may be selected from the group consisting of 4-chloromethyl benzonitrile, 4-iodomethyl benzonitrile, and 4-bromomethyl benzonitrile, preferably 4-bromomethyl benzonitrile Can be.

Preferably, step (a) is carried out in a ketone solvent, more preferably in acetone.

Suitably, step (a) is carried out at a temperature in the range of about 20 to 150 ° C, typically about 40 to 100 ° C. Preferably, step (a) is carried out at a temperature in the range from 40 to 60 ° C, more preferably from 50 to 55 ° C.

The reaction of step (a) was carried out for 1 to 5 hours, preferably 2 to 4 hours, more preferably 3 hours.

The reaction of step (a) can be carried out in the presence of a catalyst, preferably potassium iodide, if necessary.

In the process of step (b), the organic layer comprising compound II can be washed with an acidified saturated sodium chloride solution, the insolubles are filtered off, and the solution is concentrated in vacuo to give a residue. The residue can be precipitated by adding two or more solvent mixtures. Preferably, the organic solvents are nonpolar organic solvents. The organic solvents include halo-substituted or unsubstituted alkyl hydrocarbons; And halo-substituted, unsubstituted, or alkyl-substituted aryl hydrocarbons. Suitably the organic solvents can be ethers such as hexane, n-heptane, toluene, xylene, methylene chloride, chlorobenzene, diethyl ether and diisopropyl ether. Preferably a mixture of diisopropyl ether and n-heptane is used. The solution containing the solids is 1.0% by cooling below 25 ° C., preferably to 10 ° C., stirring, filtering, washing with an aprotic solvent selected from aliphatic hydrocarbons, aromatic hydrocarbons and the like, most preferably n-heptane Compound II with less than isomeric impurities (compound III) can be obtained.

In one embodiment, the process further comprises reacting 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile of Formula II with 4-fluobenzonitrile of Formula I Preparing 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile. This additional step may be carried out by treating the compound of formula II with 4-flurobenzonitrile in an organic solvent such as dimethylformamide, in the presence of a base such as potassium tert-butoxide. The reaction can be carried out at a temperature in the range of 5 to 10 ℃. 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile of Formula (I) is composed of Compound III (isomer impurity from the previous step) It contains virtually no isomeric impurities (compound IV) resulting from side reactions with 4-fluobenzonitrile.

The reaction mixture is 4- [1- (4), a compound of formula I, containing less than 0.1% of isomeric impurities by extraction, concentration with an organic solvent, and work-up by purification as necessary. -Cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile can be obtained. Compound I can be recrystallized using a solvent selected from polar and nonpolar solvents such as alcohols, ketones, and esters, preferably methanol.

 4- [1- (1) of Formula II to obtain 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile of Formula I This additional reaction step of, 2,4-triazol-1-yl) methyl] benzonitrile with 4-fluorobenzonitrile can be carried out in the presence of an organic solvent and a silicone amine. This is the same step as described below in the second aspect of the invention. 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile of Formula II from the first step is dried or not dried before reacting with 4-fluorobenzonitrile. Can be separated without.

4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile I, prepared by these embodiments, is less than 0.1% of isomeric impurities It has a purity of 99.0% or more, containing (Compound IV).

According to a second aspect of the invention, 4- [1- (1H-1,2,4-triazol-1-yl) methylene benzonitrile of Formula II is present with 4-fluorobenzonitrile, an organic solvent and a silicone amine Provided is a process for preparing 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile of Formula I, comprising the step of reacting under do.

The silicone amine may be an alkali metal disilazane or an alkali metal monosilazane. The alkali metal may be selected from lithium, sodium or potassium. Preferably the silicone amine is an alkali metal disilazane. In one embodiment, the silicone amine is a compound of Formula V.

Wherein R 1 is the same or different and is selected from hydrogen, optionally substituted C _1-6 alkyl and optionally substituted C _2-6 alkenyl; Z is selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, and silyl; M is selected from Li, K, and Na. In one embodiment, the silyl group is (R 2) ₃ Si −, where R 2 is as defined in R 1. Preferably, R 1 is unsubstituted C _1-6 alkyl. Preferably, R 2 is unsubstituted C _1-6 alkyl.

The production method of the present invention uses very mild conditions and also avoids the formation of impurities. Li-HMDS is a preferred silicone amine. Tetrahydrofuran is a preferred organic solvent. The reaction mixture is cooled to about -30 to -10 ° C. Suitably, the reaction mixture is cooled to a temperature in the range of -30 to -15 ° C, preferably about -20 ° C. Further, 4- [1- (1H-1,2,4-triazole-1) in an organic solvent selected from 1,4-dioxane, toluene, dichloromethane, dichloroethane and tetrahydrofuran, preferably tetrahydrofuran -Yl) methyl] benzonitrile solution is added to the reaction mixture while maintaining the temperature below -15 ° C. The reaction mixture is slowly warmed to about −10 ° C. and stirred for 30 minutes. After completion of the reaction, the reaction mixture is quenched in water at 10 占 폚 or lower. The reaction mixture is stirred for 2-3 hours between 10-20 ° C. and the resulting solid is filtered and vacuum dried to give letrozole in high purity.

Preferred embodiments are shown in schemes as follows.

The process of the present invention solves the problems of the prior art and also provides technical advantages as well as economic advantages through cost reduction and the elimination of additional purification steps involving complex column chromatography.

The details of the invention are given in the following examples, which are provided to illustrate the invention and should not be construed as limiting the scope of the invention.

Example 1

Preparation of 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile (compound of formula II)

Acetone (1500 ml), 1,2,4-triazole (200 gm; 2.895 mol.eq), cesium carbonate (142 gm; 0.436 mol.eq) and potassium iodide (9 gm) were heated to reflux for 4 hours (55 ℃). The reaction mixture was cooled to room temperature. To this was added a solution of 4-bromomethyl benzonitrile (100 gm; 0.510 mol.eq) in dichloromethane (450 ml) over 2 hours. The reaction mixture was refluxed for 3 hours. After the reaction was completed, the reaction mixture was cooled to 25 ° C. and insolubles were filtered off. The filtrate was concentrated in vacuo to the residue. The residue was dissolved in dichloromethane (500 ml), washed with saturated aqueous sodium chloride solution, acidified to pH 1.0 with concentrated hydrochloric acid and concentrated in vacuo. To the residue was added a mixture of diisopropyl ether (160 ml) and n-heptane (160 ml), stirred at 10 ° C. for 30 minutes, filtered, washed with n-heptane and vacuum at 40-45 ° C. Drying afforded 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile (76 gm, 81% yield, 99.0% HPLC purity).

Example 2

Preparation of 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile (compound of formula I)

A solution of 4- [1- (1,2,4-triazolyl) methyl] benzonitrile (100 gm; 0.543 mol.eq) in dimethylformamide (480 ml) at a temperature of -5 to 0 ° C under nitrogen atmosphere To a solution of potassium tert-butoxide (192 gm; 1.711 mol. Eq) in dimethylformamide (800 ml) was added over 90 minutes and stirred for an additional 30 minutes.

To this solution, a solution of 4-fluorobenzonitrile (92 gm; 0.760 mol. Eq) in dimethylformamide (480 ml) was added at a temperature of 0-5 ° C and stirred at 5-10 ° C for 15 minutes. After the reaction was completed, water was added at 5-10 ° C., and the product was extracted with ethyl acetate. The organic layer was washed with water and concentrated in vacuo at 40 ° C. or lower to give a syrupy liquid, to which n-heptane (160 ml) was added, stirred at 25-30 ° C. for 15 minutes, filtered and n Washing with heptane yielded the crude product.

The crude product was dissolved in methanol (15 volumes) at reflux, treated with activated charcoal (20 gm), filtered hot and the filtrate was concentrated to a minimum volume. The contents were cooled to 0-5 ° C for 30 minutes, filtered and washed with methanol. The product obtained by filtration was slurried in a methanol-acetone mixture at 40-45 ° C. for 30 minutes, cooled to 20-25 ° C., filtered, washed with methanol and vacuum dried at 40-45 ° C. 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile was obtained (113-120 gm, 73-77.5% yield,> 99.7% HPLC purity).

Example 3

Preparation of 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile (compound of formula I)

Li-HMDS solution (0.79 lit, 1.41 mol) in tetrahydrofuran was taken in a clean, dried flask. It was cooled to -20 ° C and a solution of 4-fluorobenzonitrile (60 gm, 0.495 mol) in tetrahydrofuran (100 ml) was added below -20 ° C. The reaction mixture is stirred for 5 minutes and a solution of 4- [1- (1,2,4-triazolyl) methyl] benzonitrile (100 gm, 0.5434 mol.) In 300 ml tetrahydrofuran is charged at -15 ° C. It was added slowly below. The reaction mixture was stirred at the same temperature for 30 minutes and quenched with water (5 lit.) up to 10 ° C. The reaction mixture was stirred for 2-3 hours between 10-20 ° C., the solids were filtered and washed with water (1 lit.) to 130 gms 4- [1- (4-cyano) with HPLC purity 99.5%. Phenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile was obtained.

Example 4

Preparation of 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile (compound of formula I)

4- [1- (1,2,4-triazolyl) methyl] benzonitrile (50 gm., 0.2717 mol) and 4-fluorobenzonitrile (30 gm, 0.2479 mol) were added to the tetrahydrofuran in a reactor under a dry atmosphere. (0.5 lit). The reaction mixture was cooled to -20 ° C and a tetrahydrofuran solution (0.38 lit, 0.6826 mol) of Li-HMDS was added to the reaction mixture at a temperature of -15 ° C or less for 1 hour. The reaction mixture was stirred for 1 hour at −10 ° C. to −5 ° C. and quenched with saturated sodium chloride solution (3 lit.) at a temperature below 10 ° C. The reaction mixture was stirred for an additional 2-3 hours at a temperature between 10-20 ° C. The obtained solid was filtered and washed with water to obtain 50 gms of 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile.

Example 5

Preparation of 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile (compound of formula I)

4- [1- (1,2,4-triazolyl) methyl] benzonitrile (150 gm, 0.81 mol) was dissolved in tetrahydrofuran (750 ml) at room temperature under inert atmosphere. The mixture was cooled to -30 ° C and Li-HMDS solution (1.14 lit, 2.0 mol) in tetrahydrofuran was added dropwise over 30 minutes at a temperature below -25 ° C. The reaction mixture is stirred at −25 ° C. for 10 minutes and a solution of 4-fluorobenzonitrile (90 gm, 0.7438 mol) in tetrahydrofuran (0.25 lit) is maintained at about 30 ° C. while maintaining the temperature below −20 ° C. Slowly added over minutes. The reaction mixture was stirred at −20 ° C. to −15 ° C. for 45 minutes and quenched with water (7.5 lit.) at a temperature below 10 ° C. The quenched reaction mixture was extracted four times with ethyl acetate (2.5 lit.). The combined organic layers were washed twice with brine (1 lit). The ethyl acetate layer was dried over sodium sulphate and concentrated to give the product. The resulting product was refluxed with isopropanol (900 ml) at 80 ° C. for 1 hour, slowly cooled to 25-30 ° C. and filtered to 150 gm of 4- [1- (4-cyanophenyl) -1- (1, 2,4-triazol-1-yl) methyl] benzonitrile was obtained.

Example 6

Preparation of 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile (compound of formula I)

a) warmed reflux of acetone (2000 ml), 1,2,4-triazole (260 gm; 3.826 mol.eq), cesium carbonate (188 gm; 0.577 mol.eq) and potassium iodide (12 gm) for 4 hours (55 ° C). The reaction mixture was cooled to room temperature. To this was added a solution of 4-bromomethyl benzonitrile (132 gm; 0.673 mol.eq) in dichloromethane (600 ml) over 2 hours. The reaction mixture was refluxed for 3 hours. After the reaction was completed, the reaction mixture was cooled to 25 ° C. and insolubles were filtered off. The filtrate was concentrated in vacuo to the residue. The residue was dissolved in dichloromethane (750 ml), washed with saturated aqueous sodium chloride solution, acidified to pH 1.0 with concentrated hydrochloric acid and concentrated in vacuo. To the residue, a mixture of diisopropyl ether (210 ml) and n-heptane (210 ml) is added, stirred at 10 ° C. for 30 minutes, the solid obtained is filtered and washed with n-heptane, the next step Taken for

b) Li-HMDS solution (0.79 lit, 1.41 mol) in tetrahydrofuran was taken in a clean, dried flask. It was cooled to -20 ° C and a solution of 4-fluorobenzonitrile (60 gm, 0.495 mol) in tetrahydrofuran (100 ml) was added below -20 ° C. The reaction mixture was stirred for 5 minutes and 4- [1- (1,2,4-triazolyl) methyl] benzonitrile (100 gm, 0.5434 mol.) Obtained in step (a) in 300 ml tetrahydrofuran. The solution of was slowly added below -15 ° C. The reaction mixture was stirred at the same temperature for 30 minutes and quenched with water (5 lit.) up to 10 ° C. The reaction mixture was stirred for 2-3 hours between 10-20 ° C., the solids were filtered and washed with water (1 lit.) to 130 gms 4- [1- (4-cyano) with HPLC purity 99.5%. Phenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile was obtained.

It is to be understood that the invention may be modified within the scope of the appended claims.

Claims (26)

A process for preparing 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile of Formula II,

(a) 4-halomethyl benzonitrile and 1,2,4-triazole are reacted in the presence of cesium carbonate and an organic solvent to give 4- [1- (1,2,4-triazole-1- I) methyl] obtaining a reaction mixture comprising benzonitrile; And (b) precipitating 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile (II) from the reaction mixture using a suitable organic solvent. The method of claim 1 wherein the organic solvent used in step (a) is selected from the group consisting of alcohols, ketones, nitriles, and other solvents such as dimethylsulfoxide, dimethylformamide, dimethyl acetamide and dichlorobenzene. The manufacturing method to make. The method according to claim 2, wherein the ketone is acetone. The method of claim 1, wherein the 4-halomethyl benzonitrile is selected from the group consisting of 4-chloromethyl benzonitrile, 4-iodomethyl benzonitrile, and 4-bromomethyl benzonitrile. Manufacturing method characterized in that. The method according to any one of claims 1 to 4, wherein the organic solvent used in step (b) is a mixture of two or more organic solvents. The method of claim 5, wherein the organic solvents are nonpolar organic solvents. 7. The organic solvent according to claim 6, wherein the organic solvents used in step (b) are nonpolar organic solvents selected from hexane, n-heptane, toluene, xylene, methylene chloride, chlorobenzene, diethyl ether, and diisopropyl ether. Manufacturing method. 8. A process according to claim 7, wherein said solvent mixture is a mixture of diisopropyl ether and n-heptane. 9. The process according to claim 1, wherein step (a) is carried out in the presence of a catalyst. 10. The process according to claim 9, wherein said catalyst is potassium iodide. The reaction according to any one of claims 1 to 10, wherein the 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile of the formula (II) is reacted with 4-fluorobenzonitrile. To prepare 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile of formula (I).

12. The method of claim 11, wherein 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile and 4-fluorobenzonitrile of the formula (II) are potassium tert-butoxide in dimethylformamide. Reaction in the presence of a side to prepare 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile of formula (I) Way. Reacting 4- [1- (1H-1,2,4-triazol-1-yl) methylene benzonitrile with 4-fluorobenzonitrile in the presence of an organic solvent and silicone amine, A process for preparing 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile of Formula (I).

14. A process according to claim 13, wherein said silicone amine is lithium, sodium or potassium disilazane, or lithium, sodium or potassium monosilazane. The process of claim 13 wherein the silicone amine is a compound of Formula V:

Wherein R 1 is the same or different and is selected from hydrogen, optionally substituted C _1-6 alkyl and optionally substituted C _2-6 alkenyl; Z is selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, and silyl; M is selected from Li, K, and Na. The method according to claim 15, wherein the silyl group is (R2) ₃ Si-, wherein R2 is the same as defined in R1. The method of claim 16, wherein the production process, characterized in that R2 is an unsubstituted C _{1 -6} alkyl. 14. A process according to claim 13, wherein said silicon amine is lithium 1,1,1,3,3,3-hexamethyldisilazane. 19. The process according to claim 15, wherein R 1 is unsubstituted C _1-6 alkyl. 20. The process according to any one of claims 13 to 19, wherein the organic solvent is selected from 1,4-dioxane, toluene, dichloromethane, dichloroethane and tetrahydrofuran. The process according to any one of claims 1 to 10, wherein said 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile of formula (II) is selected from claims 13 to 20. A process according to one of the preceding claims, characterized in that it is converted to 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile of formula (I). . 21. The compound of any of claims 13-20, wherein said 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile of Formula (II) is selected from claims 1-10. Manufacturing method according to any one of the preceding. A process for preparing 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile of Formula I, (a) 4-halomethyl benzonitrile and 1,2,4-triazole are reacted in the presence of cesium carbonate and an organic solvent to give 4- [1- (1,2,4-triazole-1- I) methyl] obtaining a reaction mixture comprising benzonitrile; (b) precipitating 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile (II) from the reaction mixture using a suitable organic solvent; And (c) the 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile and 4-fluorobenzonitrile in the presence of potassium tert-butoxide in dimethylformamide, Reacting method comprising the step of reacting. A process for preparing 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile of Formula I, (a) 4-halomethyl benzonitrile and 1,2,4-triazole are reacted in the presence of cesium carbonate and an organic solvent to give 4- [1- (1,2,4-triazole-1- I) methyl] obtaining a reaction mixture comprising benzonitrile; (b) precipitating 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile (II) from the reaction mixture using a suitable organic solvent; And (c) reacting 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile and 4-fluorobenzonitrile in the presence of an organic solvent and a silicone amine. Manufacturing method. A process for preparing 4- [1- (1,2,4-triazol-1-yl) methyl] benzonitrile of Formula (II) substantially disclosed herein with reference to Example 1. A process for preparing 4- [1- (4-cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile substantially disclosed with reference to Examples 2-6.