KR100343948B1 - Piperazinyltriazole compound and preparation thereof - Google Patents

Abstract

The present invention relates to an isoxazole piperazine-based compound having formula (1), or an acceptable salt thereof, and a method for preparing the compound, wherein the compound has formula (1) below, and the preparation method is a compound of formula (2) It consists of carrying out 1, 3-dipole cyclization addition reaction of the compound of 3.

The present invention also relates to a library prepared by applying the above production method to solution phase combinatorial synthesis.

[Formula 1]

[Formula 2]

[Formula 3]

In Formula 1, 2 and 3 R ₁ is replaced by an alkoxy of C ₆ -C ₁₀ aromatic hydrocarbons, C ₁ -C ₆ a C ₆ -C ₁₀ aromatic hydrocarbons, C ₁ -C ₄ alkyl group substituted by a a C ₆ -C ₁₀ aromatic hydrocarbon, a halogen-substituted C ₆ -C ₁₀ aromatic hydrocarbon and the alkyl or aryl of C ₇ -C _10; R ₂ -R ₅ are independently of each other hydrogen, halogen, methyl or ethyl; R ₆ -R ₇ are independently of each other hydrogen, phenoxy substituted by halogen, -OC (O) R ₈ , -NR ₉ R ₁₀ , , or Wherein Y is O or S, R ₈ is an alkyl group of C ₁ -C ₆ , R ₉ and R ₁₀ are independently of each other an alkyl group of C ₁ -C ₆ , and R ₁₁ is hydrogen, C _1- C ₆ is an alkyl group or phenyl, R ₁₂ is independently of each other hydrogen or an alkyl group of C ₁ -C ₆ , n is an integer of 1-2, k is 5 if n = 1, 6 if n = 1, m Is 4 if n = 1 and 5 if n = 2.

Description

Piperazinylethyl triazole compound and its preparation method {PIPERAZINYLTRIAZOLE COMPOUND AND PREPARATION THEREOF}

The present invention relates to a piperazinylethyl triazole compound and a preparation method thereof. The present invention also relates to a library prepared by the solution phase combination synthesis applying the above production method.

By "library" is meant a mixture of individual organic compounds characterized by structurally common components. In other words, it means a group or a group of compounds of most organic compounds having a common component. The common component means that the compound has a skeleton structure in common, and the specific position of the skeleton structure can be variously changed.

The past method of eliciting lead compounds for the discovery of new drugs is to synthesize the target compound and then test its effects. This classical synthesis method cannot solve the problem of time and many compounds. Inefficient progress has been made by the manufacturing process. Currently, a method for synthesizing a large amount of the leading compounds has been devised, including solid-phase combinatorial synthesis and solution-phase combinatorial synthesis. Solid phase combination synthesis refers to a technique for synthesizing a large number of compounds at the same time by immobilizing or separating a reactant to a solid phase (solid support) using a plurality of linkers to construct a solid phase library. This method is approaching the synthesis of organics, peptides, non-peptides and a lot of research is being conducted. However, solid phase combinatorial synthesis, despite their many advantages, is limited by the requirements and scale of the solid phase support, and requires a special device to track the progress of the reaction at each stage in multiple stages of synthesis. However, there is a disadvantage that the reaction in each step must proceed with high efficiency, and a large investment is required for the purification of the compound separated from the solid phase and the optimization conditions for all reaction steps. However, solution phase combinatorial synthesis, which allows for the construction of structurally diverse libraries using solution phase organic synthesis, proceeds in solution phase and is relatively unrestricted in reaction volume and can yield soluble intermediates or final products directly. In addition, the identification process of the product is easy, can be obtained in high yield and purity, and has the advantage of not requiring a process of adhesion / separation on the solid support.

It is therefore an object of the present invention to provide a process for the application of novel piperazinylethyl triazole-based compounds and solution phase combination synthesis.

It is still another object of the present invention to provide a library composed of piperazinylethyl triazole-based compounds or salts thereof by solution-phase combination synthesis applying the above production method.

The piperazinylethyl triazole compound of the present invention has the following formula (1).

In Formula 1, R ₁ is C ₆ -C ₁₀ aromatic hydrocarbon, C ₁ -C ₆ aromatic hydrocarbon substituted by C ₆ -C ₁₀ aromatic hydrocarbon, C ₁ -C ₄ alkoxy substituted by C _6- C ₁₀ aromatic hydrocarbon, C ₆ -C ₁₀ aromatic hydrocarbon substituted by halogen or C ₇ -C ₁₀ arylalkyl; R ₂ -R ₅ are independently of each other hydrogen, halogen, methyl or ethyl; R ₆ -R ₇ are independently of each other hydrogen, phenoxy substituted by halogen, -OC (O) R ₈ , -NR ₉ R ₁₀ , , or Wherein Y is O or S, R ₈ is an alkyl group of C ₁ -C ₆ , R ₉ and R ₁₀ are independently of each other an alkyl group of C ₁ -C ₆ , and R ₁₁ is hydrogen, C _1- C ₆ is an alkyl group or phenyl, R ₁₂ is independently of each other hydrogen or an alkyl group of C ₁ -C ₆ , n is an integer of 1-2, k is 5 if n = 1, 6 if n = 2, m Is 4 if n = 1 and 5 if n = 2.

Examples of C ₆ -C ₁₄ aromatic hydrocarbons include C ₆ H _5- , C ₁₀ H ₇ -or C ₁₄ H ₉ -and the like.

Examples of C ₁ -C ₆ alkyl groups include methyl, ethyl, propyl, isopropyl, n-butane, isobutane, t-butane, pentane, isopentane, cyclopentane, hexane and cyclohexane.

Examples of C ₁ -C ₄ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy and butoxy groups.

Examples of arylalkyl of C ₇ -C ₁₀ are C ₆ H ₅ CH _3- , C ₆ H ₅ CH ₂ CH _3- , C ₆ H ₅ CH ₂ CH ₂ CH _3- , C ₆ H ₅ CH ₂ CH ₂ CH ₂ CH ₃ -and the like.

Halogen atom means fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

Acceptable salts of compounds of formula 1 include nontoxic inorganic acids, nontoxic salts formed from organic acids, or quaternary ammonium salts. Examples of inorganic acids include hydrogen chloride, hydrogen bromide, sulfonic acid, sulfamic acid, phosphoric acid, nitric acid, and examples of organic acids include propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, methanesulfuric acid. Phonic acid and the like.

Acceptable salts of the present invention are the steps used for the purpose of purification in the development of the manufacturing process, and are synthesized from the compound of formula 1 containing a base by a chemical method. In general, the salts can be produced in organic solvents such as methanol, chloroform, methylene chloride, ether and mixed solvents thereof, and are produced by reaction with free amines using an excess or equivalent amount of acid.

Manufacturing method

The method for preparing a compound having Formula 1, which is the subject of the present invention, comprises the reaction of the compound of Formula 2 and the compound of Formula 3 with 1,3-dipole cycloaddition reaction, and the reaction is the same as that of Scheme 1. However, as shown in Scheme 1 below, when the substituents R ₆ and R ₇ of the dipole itself having Formula 3 are different from each other, positional isomers may be generated.

In Formulas 2, 3 and Scheme 1, the definition of R ₁ -R ₇ is as described above.

In the above production method, the material that can be used as the reaction solvent is not particularly limited, and a protic solvent such as ethanol may be used in addition to an aprotic solvent such as toluene. Preferably toluene is used. If the dipole itself can act as a reaction solvent, no other solvent can be used.

The reaction temperature is preferably in the range of 80-130 ° C., most preferably 120 ° C.

The reaction time depends on the reactivity of Dipolarphiles formula 3, but usually takes about 10-40 hours.

The progress of the reaction was confirmed using thin layer chromatography.

After the progress of the reaction, the separation and purification of the desired product uses organic or inorganic acids as described above, with hydrogen chloride being most economical.

Representative examples of the material having the formula (1) synthesized by the above production method are shown in Table 1.

In Table 1, the definition of R ₁ and the dipole itself is as follows.

The azide compound of formula 2, which is a starting material used in the preparation method, can be synthesized from commercially available substituted phenylpiperazine, and the reaction is shown in Scheme 2.

In Scheme 2, the definition of R ₁ -R ₅ is as described above. As a typical example, phenylpiperazine, 2-methoxy 1-phenylpiperazine, (4-fluorophenyl) piperazine, benzylpiperazine, and the like are reacted with 1-bromo-2-chloroethane to give a chloroethylphenylpiperazine derivative. After the synthesis, these derivatives were iodinated and azide to synthesize starting azide compound 2.

In the dipole itself of Formula 3, R ₆ -R ₇ is Phosphorus compounds and phenoxy substituted by halogen were synthesized using the methods represented by Schemes 3 and 4.

In Schemes 3 and 4, the definitions of R ₁₁ and n are as described above and X refers to a halogen atom, ie fluorine, chlorine, bromine or iodine.

In the same manner as in Scheme 3, the compound in which the ring is substituted with an alkyl group of C ₁ -C ₆ and R ₆ -R ₇ is -NR ₉ R ₁₀ , or Phosphorus compounds were synthesized.

The resulting compound of Formula 1 was separated and purified in the form of a salt by concentrating hydrogen chloride gas (HCl) in diethyl ether. All reactions did not require other additives and the reaction proceeded well without other impurities. After the reaction, the solvent used in the reaction was simply removed using a rotary evaporator without the work-up process of the extraction step using the organic solvent, and then dissolved in 1 mL of ether, and then dissolved in an organic solvent. About 1-10 equivalents of hydrogen chloride present were added to obtain a salt. As the organic solvent that can be used to prepare the hydrogen chloride solution, chloroform, methylene chloride, ether, methanol, ethyl acetate or a mixed solvent thereof can be used, preferably ether is useful. The resulting white salt product was obtained by centrifugation or filtration, washed with ether over 2-3 times and then dried well to obtain the desired compound 1 of the present invention in the form of a salt.

Another method of producing a library by solution-phase combinatorial synthesis using the above-described production method of the present invention is as follows. That is, after adding one of the starting material 2 and the starting material 3 differently to each room in a container having five or more rooms, the reaction of the formula (1) having a different chemical structure in each room by reacting by the method described above Libraries consisting of ferrazinyl triazole-based compounds can be prepared.

For example, a rectangular parallelepiped (width x height x height: 5 cm x 5 cm x 3 cm) container with 25 compartments, each with a side opening x height x height 1 cm x 1 cm x 3 cm. In each room forming one horizontal axis is different from each other, but the same compound of formula 2 is put in the same way, and each room forming one longitudinal axis is different, but the same compound of the formula (3) By reacting in the same manner as in the above-described preparation method, a library consisting of piperazinyl triazole-based compounds of Formula 1 having 25 chemical structures having different chemical structures can be prepared.

Example

The following examples will explain in more detail the preparation of the compounds of the present invention. Of the following examples, Examples 1-19 illustrate the preparation of compounds having Formula 1 of the present invention, and Examples 20-25 illustrate the preparation of the starting materials of Formulas 2 and 3. However, these embodiments are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Example 1

Synthesis of 1- [2- (4-phenylpiperazinyl) ethyl] -1,2,3-triazole hydrochloride

About 2 mL of 1- (3-aza-3-diazoprop-3-enyl) -4-phenylpiperazine (15.0 mg, 0.06 mmol, 1 equiv) as a solvent of vinyl acetate was used. The reaction was carried out in a pressure bottle at about 120 ° C. for 24 hours. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 16.9 mg (88.8%) of product was obtained.

Example 2

Synthesis of Methyl 4- (methoxycarbonyl) -1- [2- (4-phenylpiperazinyl) ethyl] -1,2,3-triazole-carboxylate hydrochloride

1- (3-aza-3-diazoprop-3-enyl) -4-phenylpiperazine (16.0 mg, 0.07 mmol, 1 equiv) and dimethyl acetylenedicarboxylate (10.8 μl, 0.07 mmol, 1.1 equiv) After dissolving in 2 mL of toluene, and reacted for 12 hours in a pressure bottle (Pressure bottle) of about 120 ℃. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 25.6 mg (100.0%) were obtained.

Example 3

Methyl 1- [2- (4-phenylpiperazinyl) ethyl] -1,2,3-triazole-5-carboxylate hydrochloride and methyl 1- [2- (4-phenylpiperazinyl) ethyl] -1 Synthesis of 2,3-triazole-4-carboxylate hydrochloride

Toluene 1- (3-aza-3-diazoprop-3-enyl) -4-phenylpiperazine (15.0 mg, 0.06 mmol, 1 equiv) and methyl propiolate (6.35 μl, 0.07 mmol, 1.1 equiv) After dissolving in 2 mL, it was reacted for 14 hours in a pressure bottle (Pressure bottle) of about 120 ℃. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 20.0 mg (97.8%) of product was obtained.

Positional isomers were generated at a ratio of about 2.6: 1.

Example 4

Ethyl 1- [2- (4-phenylpiperazinyl) ethyl] -1,2,3-triazole-5-carboxylate hydrochloride and ethyl 1- [2- (4-phenylpiperazinyl) ethyl] -1 Synthesis of 2,3-triazole-4-carboxylate hydrochloride

Toluene 1- (3-aza-3-diazoprop-3-enyl) -4-phenylpiperazine (15.5 mg, 0.067 mmol, 1 equiv) and ethyl propiorate (13.6 μl, 0.13 mmol, 2.0 equiv) After dissolving in 2 mL, it was reacted for 16 hours in a pressure bottle (Pressure bottle) of about 120 ℃. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 21.4 mg (97.0%) of the product were obtained.

Positional isomers were generated in a ratio of 2.4: 1.

Example 5

4-phenylpiperazinyl 1- [2- (4-phenylpiperazinyl) ethyl] (1,2,3-triazol-4-yl) ketone hydrochloride and 4-phenylpiperazinyl 1- [2- ( 4-phenylpiperazinyl) ethyl] (1,2,3-triazol-5-yl) ketone hydrochloride

1- (3-Aza-3-diazoprop-3-enyl) -4-phenylpiperazin (19.5 mg, 0.09 mmol, 1 equiv) and 1- (4-phenylpiperazinyl) prop-2-yne -1 temperature (21.0 mg, 0.09 mmol, 1.0 equiv) was dissolved in 2 mL of toluene and reacted for 24 hours in a pressure bottle at about 120 ° C. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. The product was purified using column chromatography. 29.2 mg (72.0%) were obtained.

Positional isomers were generated at a ratio of about 1: 1.5.

Example 6

Methyl-[(3-chlorophenoxy) methyl] -1- [2- (4-phenylpiperazinyl) ethyl] -1,2,3-triazole-5-carboxylate hydrochloride and methyl 5-[(3 -Chlorophenoxy) methyl] -1- [2- (4-phenylpiperazinyl) ethyl] -1,2,3-triazole-4-carboxylate hydrochloride

1- (3-Aza-3-diazoprop-3-enyl) -4-phenylpiperazine (13.5 mg, 0.06 mmol, 1 equiv) and methyl 4- (3-chlorophenoxy) but-2-inoate (17.0 mg, 0.07 mmol, 1.3 equiv) was dissolved in 2 mL of toluene, and then reacted in a pressure bottle at about 120 ° C. for 16 hours. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 12.7 mg (75.2%) of product were obtained.

Positional isomers were generated at a ratio of about 1: 1.5.

Example 7

3-chloro-1-({1- [2- (4-phenylpiperazinyl) ethyl] (1,2,3-triazol-5-yl)} methoxy) benzene hydrochloride and 3-chloro-1- Synthesis of ({1- [2- (4-phenylpiperazinyl) ethyl] (1,2,3-triazol-4-yl)} methoxy) benzene hydrochloride

1- (3-Aza-3-diazoprop-3-enyl) -4-phenylpiperazine (13.7 mg, 0.06 mmol, 1 equiv) and 3-chloro-1-prop-2-ynyloxybenzene (12.8 mg, 0.08 mmol, 1.3 equiv) was dissolved in 2 mL of toluene, and then reacted in a pressure bottle at about 120 ° C. for 40 hours. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 13.7 mg (58.1%) were obtained.

Positional isomers were generated at a ratio of about 1: 1.5.

Example 8

Synthesis of 2-methoxy-1- [4- (2- (1,2,3-triazolyl) ethyl) piperazinyl] benzene hydrochloride

1- [4- (3-aza-3-diazoprop-3-enyl) piperazinyl] -2-methoxybenzene (14.1 mg, 0.05 mmol, 1 equiv) and vinyl acetate in about 2 mL of solvent use. The reaction was reacted for 24 hours in a pressure bottle at about 120 ℃. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 15.4 mg (99.0%) of product were obtained.

Example 9

Synthesis of Methyl 4- (methoxycarbonyl) -1- {2- [4- (2-methoxyphenyl) piperazinyl] ethyl} -1,2,3-triazole-5-carboxylate hydrochloride

1- [4- (3-aza-3-diazoprop-3-enyl) piperazinyl] -2-methoxybenzene (9.0 mg, 0.034 mmol, 1 equiv) and dimethyl acetylenedicarboxylate (5.4 μl, 0.037 mmol, 1.1 equivalents) was dissolved in 2 mL of toluene, and then reacted in a pressure bottle at about 120 ° C. for 20 hours. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 13.8 mg (100.0%) of product were obtained.

Example 10

Methyl 1- {2- [4- (2-methoxyphenyl) piperazinyl] ethyl} -1,2,3-triazole-5-carboxylate hydrochloride and methyl 1- {2- [4- (2- Synthesis of Methoxyphenyl) piperazinyl] ethyl} -1,2,3-triazole-4-carboxylate hydrochloride

1- [4- (3-Aza-3-diazoprop-3-enyl) piperazinyl] -2-methoxybenzene (8.3 mg, 0.03 mmol, 1 equiv) and methyl propiolate (4.2 μl, 0.05 mmol, 1.5 equivalents) was dissolved in 2 mL of toluene, and then reacted in a pressure bottle at about 120 ° C. for 19 hours. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 11.0 mg (100.0%) of product were obtained.

Positional isomers were generated at a ratio of about 3.8: 1.

Example 11

Ethyl 1- {2- [4- (2-methoxyphenyl) piperazinyl] ethyl} -1,2,3-triazole-5-carboxylate hydrochloride and 1- {2- [4- (2-meth Synthesis of oxyphenyl) piperazinyl] ethyl} -1,2,3-triazole-4-carboxylate hydrochloride

1- [4- (3-Aza-3-diazoprop-3-enyl) piperazinyl] -2-methoxybenzene (10.8 mg, 0.04 mmol, 1 equiv) and ethyl propiolate (6.3 μl, 0.06 mmol, 1.5 equiv) was dissolved in 2 mL of toluene, and then reacted in a pressure bottle at about 120 ° C. for 24 hours. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 14.7 mg (99.0%) of the product were obtained.

Positional isomers were generated at a ratio of about 2: 1.

Example 12

Synthesis of 1- {2- [4- (4-fluorophenyl) piperazinyl] ethyl} -1,2,3-triazole hydrochloride

1- (3-aza-3-diazoprop-3-enyl) -4- (4-fluorophenyl) piperazinyl (12.0 mg, 0.05 mmol, 1 equiv) and vinyl acetate in about 2 mL of solvent use. The reaction was reacted for 48 hours in a pressure bottle at about 120 ℃. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 13.9 mg (99.0%) of product were obtained.

Example 13

Synthesis of Methyl 1- {2- [4- (4-fluorophenyl) piperazinyl] ethyl} -4- (methoxycarbonyl) -1,2,3-triazole-5-carboxylate hydrochloride

1- (3-aza-3-diazoprop-3-enyl) -4- (4-fluorophenyl) piperazinyl (12.9 mg, 0.05 mmol, 1 equiv) and dimethyl acetylenedicarboxylate (7.8 μl, 0.05 mmol, 1.0 equivalent) was dissolved in 2 mL of toluene, and then reacted in a pressure bottle at about 120 ° C. for 12 hours. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 22.5 mg (93.2%) of product was obtained.

Example 14

Methyl 1- {2- [4- (4-fluorophenyl) piperazinyl] ethyl} -1,2,3-triazole-5-carboxylate hydrochloride and methyl 1- {2- [4- (4- Synthesis of fluorophenyl) piperazinyl] ethyl} -1,2,3-triazole-4-carboxylate hydrochloride

1- (3-Aza-3-diazoprop-3-enyl) -4- (4-fluorophenyl) piperazine (9.7 mg, 0.04 mmol, 1 equiv) and methyl propiolate (4.0 μl, 0.045 mmol , 1.1 equivalents) was dissolved in 2 mL of toluene, and then reacted in a pressure bottle at about 120 ° C. for 13 hours. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 11.0 mg (80.0%) of product was obtained.

Positional isomers were generated at a ratio of about 3.0: 1.

Example 15

Ethyl 1- {2- [4- (4-fluorophenyl) piperazinyl] ethyl} -1,2,3-triazole-5-carboxylate hydrochloride and ethyl 1- {2- [4- (4- Synthesis of fluorophenyl) piperazinyl] ethyl} -1,2,3-triazole-5-carboxylate hydrochloride

1- (3-Aza-3-diazoprop-3-enyl) -4- (4-fluorophenyl) piperazine (12.0 mg, 0.05 mmol, 1 equiv) and ethyl propiolate (7.75 μl, 0.075 mmol) , 1.5 equivalents) was dissolved in 2 mL of toluene, and then reacted in a pressure bottle at about 120 ° C. for 20 hours. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 16.2 mg (91.4%) of product were obtained.

Positional isomers were produced at a ratio of about 2.5: 1.

Example 16

Synthesis of 1- {2- [4-benzylpiperazinyl] ethyl} -1,2,3-triazole hydrochloride

Dissolve 1- (3-aza-3-diazoprop-3-enyl) -4-benzylpiperazine (17.5 mg, 0.07 mmol, 1 equiv) and vinyl acetate in about 2 mL of a solvent and then The reaction was carried out for 48 hours in a pressure bottle. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 19.3 mg (99.0%) of product were obtained.

Example 17

Synthesis of Methyl 4- (methoxycarbonyl) -1- {2- [4-benzylpiperazinyl] ethyl} -1,2,3-triazole-5-carboxylate hydrochloride

1- (3-aza-3-diazoprop-3-enyl) -4-benzylpiperazine (9.5 mg, 0.04 mmol, 1 equiv) and dimethyl acetylenedicarboxylate (5.6 μl, 0.04 mmol, 1.0 equiv) After dissolving in 2 mL of toluene, it was reacted for 22 hours in a pressure bottle (Pressure bottle) of about 120 ℃. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 14.5 mg (96.7%) were obtained.

Example 18

Methyl 1- {2- [4-benzylpiperazinyl] ethyl} -1,2,3-triazole-5-carboxylate hydrochloride and methyl 1- {2- [4-benzylpiperazinyl] ethyl} -1 Synthesis of 2,3-triazole-4-carboxylate hydrochloride

Toluene 1- (3-aza-3-diazoprop-3-enyl) -4-benzylpiperazine (12.1 mg, 0.05 mmol, 1 equiv) and methyl propiolate (6.6 μl, 0.07 mmol, 1.5 equiv) After dissolving in 2 mL, the reaction was carried out in a pressure bottle of about 120 ℃ for 23 hours. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 15.2 mg (93.6%) were obtained.

Positional isomers were generated at a ratio of about 3.0: 1.

Example 19

Ethyl 1- {2- [4-benzylpiperazinyl] ethyl} -1,2,3-triazole-5-carboxylate hydrochloride and ethyl 1- {2- [4-benzylpiperazinyl] ethyl} -1 Synthesis of 2,3-triazole-4-carboxylate hydrochloride

Toluene 1- (3-aza-3-diazoprop-3-enyl) -4-benzylpiperazine (17.5 mg, 0.07 mmol, 1 equiv) and ethyl propiolate (10.7 μl, 0.10 mmol, 1.5 equiv) After dissolving in 2 mL, the reaction was carried out in a pressure bottle of about 120 ℃ for 23 hours. After the reaction proceeded, the reaction was transferred to a 10 mL round bottom flask and the solvent was removed. After dissolving in 1 mL diethyl ether, hydrogen chloride was concentrated in diethyl ether and added dropwise. The resulting solid was washed twice with 2 mL of diethyl ether. 24.4 mg (99.6%) of product were obtained.

Positional isomers were generated in a ratio of 3: 1.

Example 20

Synthesis of 1- (4-phenylpiperazinyl) prop-2-yn-1-one (D5)

Propiolic acid (0.48 mL, 7.85 mmol, 1 equiv) was added to a 25 mL round bottom flask under nitrogen atmosphere with 10 mL of methylene chloride and PCl ₅ (1.63 g, 7.85 mmol, 1.2 equiv) and reacted at about 40 ° C. for 1 hour. I was. After the reaction was cooled down to room temperature, phenylpiperazine (1.06 g, 6.54 mmol, 1 equiv) was dissolved in methylene chloride and added dropwise. After 2 minutes, triethylamine (2.19 mL, 15.7 mmol, 2.4 equiv) was dissolved in 0.5 mL of methylene chloride and added dropwise. The reaction was performed at room temperature for about 1 hour. After the reaction proceeded, the mixture was extracted using methylene chloride. The organic layer was dried over magnesium sulfate, the solvent was removed under reduced pressure, and the product was purified by column chromatography to obtain 0.72 g (51.4%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.14-3.23 (overlap m, 5H), 3.79 (t, 2H, J = 5.13 Hz), 3.92 (t, 2H, J = 5.01 Hz), 6.92 (m, 3H ), 7.29 (m, 2 H)

Example 21

Synthesis of 1-chloro-3-prop-2-ynyloxybenzene (D6)

3-chlorophenol (1.5 g, 11.67 mmol, 1 equiv) was dissolved in dimethylformamide, K ₂ CO ₃ (2.0 g, 15.2 mmol, 1.3 equiv), propazyl bromide (1.56 mL, 17.5 mmol, 1.5 equiv) Was added and reacted at about 50 ° C. for about 24 hours. The reaction was terminated and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and then the solvent was removed and the product was purified by column chromatography to give 1.41 g (73.2%) of product.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.25 (t, 1H), 4.68 (d, 2H), 6.88 (d, 1H, J = 4.17 Hz), 7.00 (overlap, 2H) 7.23 (t, 1H, J = 8.22 Hz)

Example 22

Synthesis of Methyl 4- (3-chlorophenoxy) but-2-inoate (D7)

Tetrahydrofuran is added under 1-chloro-3-prop-2-ynyloxybenzene (0.22 g, 1.4 mmol, 1 equiv) nitrogen atmosphere, 1.0 M BuLi (1.5 mL, 1.55 mmol, 1.1 qe.) Is added The reaction was carried out at -70 ° C for about 30 minutes. Methylchloroformate (0.32 mL, 4.09 mmol, 3 equiv) was added at about −30 ° C. After raising the temperature to room temperature, the organic layer was extracted with ethyl acetate. Dry over magnesium sulfate and purify using column chromatography. 97.5 mg (31.9%) of product was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.78 (s, 3H), 4.79 (s, 2H), 6.85 (dd, 1H, J = 2..46 Hz, 2.46 Hz), 6.95 (t, 1H, J = 2.43 Hz), 6.97 (dd 1H), 7.23 (t, 1H, J = 8.25 Hz)

Example 23

Synthesis of 1- (2-chloroethyl) -4-phenylpiperazine

Phenyl-piperazine (1.0g, 6.55 mmol, 1 equivalent) of a tetrahydrofuran: dimethylformamide = 3: 1, and then dissolved in 20 ml of _{solvent, (n-Bu) 4 N} + HSO 4 - (0.22 mg, 0.65 mmol , 10 mol%) and triethylamine (0.91 mL, 6.54 mmol, 1 equiv) were added followed by 1-chloro-2-bromo-ethane (0.6 mL, 7.2 mmol, 1.1 equiv). The reaction was carried out at 65 ° C. for about 5 hours. The organic layer was extracted with ethyl acetate, then dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification using chromatography gave 0.61 g (30.5%) of product.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.70 (t, 4H, J = 4.89 Hz), 2.81 (t, 4H, J = 7.05 Hz), 3.23 (t, 4H, J = 4.6 Hz), 3.64 (t , 4H, J = 7.14 Hz), 6.92 (dt, 3H, J = 8.46 Hz, J = 7.41 Hz), 7.27 (t, 2H, J = 7.71 Hz)

Example 24

Synthesis of 1- (2-iodineethyl) -4-phenylpiperazine

Dissolve 1- (2-chloroethyl) -4-phenylpiperazine (0.31 g, 1.38 mmol 1 equiv) in dimethyformamide, add Nal (0.62 g, 4.15 mmol, 3 equiv) and react at about 50 ° C I was. After about 5 hours, the organic layer was extracted with ethyl acetate, dried over magnesium sulfate, and purified using column chromatography. 0.3 g (68.6%) of product was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.69 (t, 4H, J = 5.22 Hz), 2.81 (t, 2H, J = 6.87 Hz), 3.23 (t, 4H, J = 4.89 Hz), 3.64 (t , 2H, J = 6.87 Hz), 6.90 (dt, 1H, J = 7.08 Hz, J = 7.08 Hz), 6.93 (d, 2H, J = 8.31 Hz) 7.28 (t, 2H, J = 8.01 Hz)

Example 25

Synthesis of 1- (3-aza-3-diazoprop-3-enyl) -4-phenylpiperazine

Dissolve 1- (2-iodoethyl) -4-phenylpiperazine (0.35 g, 1.10 mmol 1 equiv) in dimethicamide, add NaN ₃ (0.21 g, 3.30 mmol, 3 equiv) and ca. 50 ° C. Reaction at After about 5 hours, the organic layer was extracted with ethyl acetate and dried over magnesium sulfate. Purification using column chromatography gave 0.2 g (78.4%) of product.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.68 (m, 6H), 3.24 (m, 4H), 3.40 (t, 2H, J = 6.03 Hz), 6.88 (t, 1H, J = 7.2 Hz), 6.95 (d, 2H, J = 8.04 Hz), 7.28 (t, 2H, J = 8.07 Hz)

The solution having the physiological / physical activity desired to be obtained by the solution phase combinatorial synthesis method of the present invention can be obtained quickly, and the library using the method can ensure the efficiency in performing optimization of the leading material. It became.

Claims (4)

Piperazinylethyl triazole compounds having Formula 1 below and their acceptable salts: [Formula 1] In Formula 1, R ₁ is C ₆ -C ₁₀ aromatic hydrocarbon, C ₁ -C ₆ aromatic hydrocarbon substituted by C ₆ -C ₁₀ aromatic hydrocarbon, C ₁ -C ₄ alkoxy substituted by C _6- C ₁₀ aromatic hydrocarbon, C ₆ -C ₁₀ aromatic hydrocarbon substituted by halogen or C ₇ -C ₁₀ arylalkyl; R ₂ -R ₅ are independently of each other hydrogen, halogen, methyl or ethyl; R ₆ -R ₇ are independently of each other hydrogen, phenoxy substituted by halogen, -OC (O) R ₈ , -NR ₉ R ₁₀ , , or Wherein Y is O or S, R ₈ is an alkyl group of C ₁ -C ₆ , R ₉ and R ₁₀ are independently of each other an alkyl group of C ₁ -C ₆ , and R ₁₁ is hydrogen, C _1- C ₆ is an alkyl group or phenyl, R ₁₂ is independently of each other hydrogen or an alkyl group of C ₁ -C ₆ , n is an integer of 1-2, k is 5 if n = 1, 6 if n = 1, m Is 4 if n = 1 and 5 if n = 2. A method for preparing a piperazinylethyl triazole compound having the formula (1) according to claim 1 consisting of 1,3-dipole cycloaddition reaction of a compound of formula (2) and a compound of formula (3) below. [Formula 2] [Formula 3] In Formulas 2 and 3, the definition of R ₁ -R ₇ is as described above. The method according to claim 2, wherein the compound of formula 1 is separated and purified using hydrogen chloride concentrated in diethyl ether. delete