KR20120128097A - Precursor of f-labeled pet radiopharmaceuticlas and preparation method thereof - Google Patents

Abstract

PURPOSE: A precursor comprising is provided to simplify existing complex production steps for manufacturing radiopharmaceuticals to one single step, to reduce production cost because a large amount of phase change catalyst is not necessary, to facilitate separation of compounds after a reaction and to have quick reaction rate. CONSTITUTION: A precursor comprises an organic salt leaving group represented by chemical formula 1. In chemical formula 1, R1 is a C1-1000 hydrocarbon group which is 18F-labeled radioactive tracer except a part of -X-CH2-18F. Carbon of the backbone of the C1-100 hydrocarbon group can be substituted or unsubstituted by oxygen, nitrogen, sulfur, phosphorous or combinations thereof, halogen of the backbone can be substituted or unsubstituted by halogen, X is oxygen, sulfur or -C(O)-, and the leaving group is a substituted or unsubstituted C2-50 tetravalent ammonium salt. [Reference numerals] (AA) Leaving group

Description

Precursor of 1F-labeled PET radiopharmaceuticals and preparation method therefor {PRECURSOR OF 1F-LABELED PET RADIOPHARMACEUTICLAS AND PREPARATION METHOD THEREOF}

The present invention is a ¹⁸ F in a single step by positron emission tomography (PET) relates to a precursor, a method of manufacturing and application of the radiopharmaceutical, and more particularly 4 precursor having an organic salt of departure, a method of manufacturing and using this The present invention relates to a method for producing a desired ¹⁸ F-labeled PET radiopharmaceutical with high radiochemical yield within a short manufacturing time.

Positron emission tomography (PET), a nuclear medicine molecular imaging technique for real-time imaging of the human body, is an effective human imaging technique that can detect biochemical and physiological changes in the human body that occur early in the disease. The market is showing steep growth. In the initial PET drug research on new diseases, ¹¹ C, a positron emitting radioisotope, is used because it is relatively easy to label and has the advantage of being the basic skeleton of organic matter. ¹¹ C, however, has a short half-life of 20 minutes, making it unsuitable for commercial use.

On the other hand, ¹⁸ F, another radioisotope, has several excellent properties, such as being easily mass-produced from cyclotron, and has recently attracted attention as a commercially available nuclide due to its relatively long half-life of 110 minutes. Since usefulness of ¹⁸ F, the ¹¹ C-labeled compounds developed to replace existing or newly developed disease with ¹⁸ F- labeled compounds - introducing profile functional as a way to introduce ¹⁸ F in the target compound as a ^[18 F] fluoro How to do is generalized. However, radiopharmaceuticals incorporating [ ¹⁸ F] fluoropropyl functional groups have a tendency to decrease the binding force to the target material, increase in lipophilic intake in some tissues, increased selectivity due to increased non-specific binding There is a problem that the image is bad. This problem can be solved by introducing a [ ¹⁸ F] fluoromethyl group structurally similar to the [ ¹¹ C] methyl group instead of the [ ¹⁸ F] fluoropropyl functional group.

An existing method for introducing [ ¹⁸ F] fluoromethyl groups is to use [ ¹⁸ F] fluoromethylation reagents. Such reagents can generally be obtained by labeling ¹⁸ F with methane compounds having two or more leaving groups. The nucleophilic substitution reaction with the precursor may produce a radiopharmaceutical into which a desired [ ¹⁸ F] fluoromethyl group is introduced. However, this method requires a two-step synthesis process for the ¹⁸ F label, and thus has a disadvantage in that the process is complicated and the manufacturing time is long. Complex manufacturing processes make it difficult to implement automated synthesis systems that are essential to commercialization.

It is an object of the present invention to provide tetravalent organic salt precursors for the preparation of ¹⁸ F-labeled PET radiopharmaceuticals.

Another object of the present invention is to provide a method for preparing a tetravalent organic salt precursor for preparing an ¹⁸ F-labeled PET radiopharmaceutical.

Another object of the present invention is to provide a nucleophilic fluorination reaction using a tetravalent organic salt precursor.

It is still another object of the present invention to provide an ¹⁸ F-labeled PET radiopharmaceutical prepared by nucleophilic fluorination of a tetravalent organic salt precursor.

In order to achieve the above object, the present invention provides a precursor comprising a tetravalent organic salt leaving group represented by the following formula (1).

In Formula 1,

R ₁ is -X-CH ₂ at the ¹⁸ F radiotracer the cover - as a portion other than the portions ¹⁸ F, C ₁ -C ₁₀₀₀ and a hydrocarbon group, the group is a C ₁ carbon of the main chain hydrocarbon -C oxygen _1000, May be substituted or unsubstituted with nitrogen, sulfur, phosphorus or a combination thereof, hydrogen in the main chain may be substituted or unsubstituted with halogen,

X is oxygen, sulfur, or -C (O)-,

The leaving group is a substituted or unsubstituted tetravalent ammonium salt of C ₂ -C ₅₀ .

Preferably, in Formula 1,

R ₁ is a C ₁ -C ₂₀₀ hydrocarbon group, the C ₁ -C ₂₀₀ hydrocarbon group may be unsubstituted or substituted with oxygen, nitrogen, sulfur, phosphorus or a combination of carbon in the main chain, hydrogen of the main chain May be substituted or unsubstituted with halogen,

X is oxygen, sulfur, or -C (O)-,

이고, 상기 이탈기에서, Breakaway

And in the leaving group,

A, B, C, D and E are independently of each other nitrogen, oxygen, sulfur or carbon,

(i) hydrogen of each carbon may be substituted or unsubstituted with R ₂ or R ₃ ,

(ii) for each nitrogen, R ₂ or May be substituted or unsubstituted with R ₃ ,

R ₂ and R ₃ are independently of each other a C ₁ -C ₂₀ hydrocarbon group in which carbon in the main chain may be substituted or unsubstituted with oxygen, nitrogen, sulfur, or a combination thereof, and hydrogen in the main chain may be substituted or unsubstituted. Can be exchanged,

Y is a halogen anion, a sulfonate anion, BF ₄ ^- is selected from the group consisting ^{_{of, -, PF 6 -, SbF}} 6 -, N (SO 2 CF 3) 2 - and N (CN) ₂

n is 0 or 1;

Preferably, in Formula 1,

R ₁ is a C ₁ -C ₁₀₀ hydrocarbon group, the C ₁ -C ₁₀₀ hydrocarbon group may be unsubstituted or substituted with oxygen, nitrogen, sulfur, phosphorus or a combination of carbon of the main chain, hydrogen of the main chain May be substituted or unsubstituted with halogen,

X is oxygen, sulfur, or -C (O)-,

Breakaway

또는

중에서 선택되는 4가 양이온; 및 (ii) Y인 음이온으로 구성되는 염이고, (i)

or

Tetravalent cation selected from; And (ii) a salt consisting of Y anion,

One nitrogen in the ring of the tetravalent cation is substituted with R ₃ and each carbon can be independently substituted or unsubstituted with R ₂ ,

R ₂ and R ₃ are C ₁ -C ₂₀ hydrocarbon groups, carbon of the main chain may be substituted or unsubstituted with oxygen, nitrogen, sulfur or a combination thereof, hydrogen of the main chain may be substituted or unsubstituted with halogen, ,

Y is independently selected from the group consisting of trifluoromethanesulfonate (CF ₃ SO ₃ ⁻ ), paratoluenesulfonate, methanesulfonate and paranitrobenzenesulfonate.

Preferably, in Formula 1,

,

,

,

,

,

,

,

,

,

,

및

로 이루어지는 군으로부터 선택되고,R ₁ is

,

,

,

,

,

,

,

,

,

,

And

Is selected from the group consisting of

X is oxygen, sulfur, or -C (O)-,

Breakaway

또는

중에서 선택되는 4가 양이온; 및 (ii) Y인 음이온으로 구성되는 염이고, (i)

or

Tetravalent cation selected from; And (ii) a salt consisting of Y anion,

,

, 및

로 이루어지는 군으로부터 선택되고, 4 is a nitrogen in a ring of the cation substituted with R ₃ each carbon may be unsubstituted or substituted by R ₂ independently from each other, R ₂ and R ₃ are independently C _{1 -4} straight or branched chain alkyl groups each For example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl and the like, phenyl,

,

, And

Is selected from the group consisting of

Y is independently selected from the group consisting of trifluoromethanesulfonate (CF ₃ SO ₃ ⁻ ), paratoluenesulfonate, methanesulfonate and paranitrobenzenesulfonate.

Preferably, the precursor represented by the formula (1),

4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;

4-methoxycarbonyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;

4- [3,5-di (trifluoromethyl) phenyl] -3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;

4- (4-methoxyphenyl) -3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;

3-methyl-4-phenyl-1- (2-phenylethane-2-one-1-yl) -1,2,3-triazolium trifluoromethanesulfonate;

4-tert-butyl-3-methyl-1-[(phenylthio) methyl] -1,2,3-triazolium trifluoromethanesulfonate;

3-methyl-1-((2-naphthoxy) methyl) -4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

3-methyl-1- [3- (2-naphthoxy) -n -propyl] oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

1- [1-methylsulfonyloxy-3- (2-naphthyl) -2-oxypropyl] oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

3-methyl- (2-naphthyl) methyloxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

3-methyl-1-((2-naphthoxy) methyl) -4-phenylimidazolium trifluoromethanesulfonate;

(S) -1- (4- (2-BOC-amino-2- (t-butoxycarbonyl) ethyl) phenyloxymethyl) -4-phenyl-1,2,3-triazolium trifluoromethanesulfo Nate;

1- (4-biphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

1- (4-bromo-2-methylphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

1- (3,4-dimethoxyphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

3-methyl-1- (4-nitrophenyl) oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

1- (4-acetylaminophenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

1- (3- O -estronyl) methyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate; And

It may be selected from the group consisting of 3-acetonaphthyl-1-methylimidazolium.

In addition, the present invention is a method for producing a precursor containing a tetravalent organic salt leaving group represented by the formula (1) may be provided by various methods according to the sub-concept of the formula (1), specifically to be provided by the following methods 1 to 4 Can be.

Method 1:

Specifically, as represented by Scheme 1 below,

Synthesizing an azido compound of formula 3 from the compound represented by formula 2 (step 1);

Synthesizing the compound of formula 5 through a [3 + 2] cycloaddition reaction between the azido compound of formula 3 obtained in step 1 and the alkyne compound represented by formula 4 (step 2);

It provides a compound of Formula 1-a comprising the step (step 3) of synthesizing the organic salt of Formula 1-a using the compound of Formula 5 obtained in step 2 using the alkylation reagent represented by Formula 6.

[Reaction Scheme 1]

In Scheme 1, R ₁ , R ₂ , R ₃ and Y are as defined above and Z is chlorine, bromine, iodine, R ₄ SO ₃ ⁻ . Wherein R ₄ is a C ₁ -C ₂₀ hydrocarbon group where carbon in the main chain may be substituted or unsubstituted with oxygen, nitrogen, sulfur or a combination thereof, and hydrogen in the main chain may be substituted or unsubstituted with halogen.

In the method for preparing a precursor including a tetravalent organic salt leaving group of the present invention, Step 1 of Scheme 1 is a step of synthesizing the azido compound of Formula 3 from the compound represented by Formula 2, and reacts with the reagent used herein The solvent may use an organic chemical reaction that is commonly applied. Step 2 of Scheme 1 is a copper (I) -catalyzed alkyne / azide [3 + 2] cycloaddition reaction between the azido compound of Formula 3 obtained in Step 1 and the alkyne compound represented by Formula 4 (Copper (I ) -catalyzed Alkyne / Azide [3 + 2] Cycloaddition (CuAAC) to synthesize compounds of formula 5 under mild conditions, wherein the compounds of formulas 2 and 3 are commercially available or can be synthesized by conventional methods. It is a possible compound, and the reaction solvent used may be a solvent conventionally used in the alkyne / azide [3 + 2] cycloaddition reaction under the copper (I) -catalyst between the azido compound and the alkyne compound. Step 3 of Scheme 1 is a step of synthesizing an organic salt of Formula 1-a using an alkylating reagent represented by Formula 1 to 1,2,3-triazole compound of Formula 5 obtained in Step 2, wherein Formula 6 The compound represented by is a compound which is commercially available or can be synthesized by a conventional method, the reaction solvent used may be a solvent commonly used in organic salt production reaction.

Recipe 2 :

Specifically, as represented by Scheme 2 below,

Synthesizing the compound of Formula 5 through a nucleophilic substitution reaction between the compound represented by Formula 7 and the compound represented by Formula 8 (step 1); And

Provided is a method for preparing a compound of Formula 1-b, comprising the step (step 2) of synthesizing an organic salt of Formula 1-b using an alkylation reagent represented by Formula 6 with the compound of Formula 5 obtained in Step 1.

Scheme 2

In Scheme 2, R ₁ , R ₂ , R ₃ , A, B, C, D, E, X, Y and n are as defined above, Z is as defined in Preparation Method 1 above.

In the method for preparing a precursor compound of Formula 1 comprising a tetravalent organic salt leaving group of the present invention, Step 1 of Scheme 2 is carried out through a nucleophilic substitution reaction between the compound represented by Formula 7 and the compound represented by Formula 8 Synthesis of the compound of Formula 5, wherein the compounds represented by Formulas 7 and 8 are commercially available or can be synthesized by conventional methods, the reaction solvent used is a solvent commonly used in nucleophilic substitution reaction Can be used. Step 2 of Scheme 2 is a step of synthesizing an organic salt of Formula 1-b using an alkylation reagent represented by Formula 6 to the compound of Formula 5 obtained in Step 1, wherein the compound represented by Formula 6 is commercially purchased Is a compound which can be synthesized by a conventional method or available, and the reaction solvent used may be a solvent commonly used in organic salt preparation reaction.

Recipe 3:

Specifically, as represented by Scheme 3 below,

It provides a method for preparing a compound of Formula 1-b comprising the step (step 1) of synthesizing the compound of Formula 1-b through a nucleophilic substitution reaction between the compound represented by Formula 7 and the compound represented by Formula 9.

Scheme 3

In Scheme 3, R ₁ , R ₂ , R ₃ , A, B, C, D, E, X, Y and n are as defined above, and Z is as defined in Preparation Method 1 above.

In the method for preparing a precursor compound of Formula 1 comprising a tetravalent organic salt leaving group of the present invention, Step 1 of Scheme 3 is carried out through a nucleophilic substitution reaction between the compound represented by Formula 7 and the compound represented by Formula 9 Comprising the step of synthesizing the compound of Formula 1, wherein the compound represented by the formula (7) is commercially available or can be synthesized by a conventional method, the compound represented by the formula (9) is a compound represented by the formula (8) Can be synthesized by reacting with an alkylation reagent represented by the formula (6). The reaction solvent used in step 1 may be a solvent commonly used in organic salt preparation reaction.

Recipe 4 :

Specifically, as represented by Scheme 4 below,

It provides a method for preparing a compound of Formula 1-b comprising the step (step 1) of synthesizing the compound of Formula 1-b through a nucleophilic substitution reaction between the compound represented by Formula 10 and the compound represented by Formula 11.

Scheme 4

In Scheme 4, R ₁ , R ₂ , R ₃ , A, B, C, D, E, X, Y and n are as defined above.

In the method for preparing a precursor compound of Formula 1 comprising a tetravalent organic salt leaving group of the present invention, Step 1 of Scheme 4 is carried out through a nucleophilic substitution reaction between the compound represented by Formula 10 and the compound represented by Formula 11 In the step of synthesizing the organic salt of 1-b, wherein the compounds represented by formulas (10) and (11) are commercially available or can be synthesized in a conventional manner, the reaction solvent used is usually in the organic salt production reaction The solvent used can be used.

In addition, the present invention is a method for producing a ¹⁸ F-labeled compound characterized in that the compound containing a tetravalent organic salt leaving group represented by the formula (1) and the fluorine salt represented by the formula MF as shown in Scheme 5 Nuclear fluorination reaction) and an ¹⁸ F-labeled compound represented by Formula 12.

Scheme 5

In Scheme 5, R ₁ , X and leaving groups are as defined in Formula 1, M is a metal cation selected from the group consisting of Li, Na, K, Rb and Cs; Tetravalent ammonium cation; Or a tetravalent phosphonium cation, F is ¹⁸ F.

Compounds containing tetravalent organic salt leaving groups of Formula 1 according to the present invention can be used as precursors in nucleophilic fluorination reactions with fluoride anions in the form of various metal salts or organic salts, as shown in FIG. In Figure 1, the intermediate compound is formed by the reaction of a tetravalent organic salt precursor with a fluoride anion in the form of a metal salt or an organic salt, resulting in anion exchange, which is a product of the formula F- Converted to a labeled compound. The nucleophilic fluorination reaction (F is ¹⁸ F) can be carried out under reaction conditions that are commonly used.

Furthermore, the present invention provides ¹⁸ F-labeled compound which is the product of Scheme 5.

Precursors of the present invention can introduce ¹⁸ F-fluoromethyl groups into radiopharmaceuticals in a simple one step tablet. In addition, by introducing a tetravalent organic salt to the precursor leaving the activated leaving group to produce ¹⁸ F-fluoromethyl group in one step, there is an effect of simplifying the existing multi-step complex synthesis. In addition, since the tetravalent organic salt contained in the leaving group of the precursor acts as a phase transfer catalyst, an additional excess phase transfer catalyst required for a general nucleophilic [ ¹⁸ F] fluorination reaction is not required, thereby reducing production costs. There is an advantage of easy separation. The phase transfer catalysis by tetravalent organic salts in such precursors induces intramolecular nucleophilic fluorination reaction and has a much faster reaction rate than general intermolecular nucleophilic fluorination reaction. This feature is well suited for mass production of [ ¹⁸ F] radiopharmaceuticals by automated synthesis systems.

1 is a scheme for preparing an ¹⁸ F-labeled compound in a single step using a precursor having a tetravalent organic salt leaving group of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Production Examples and Examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited thereto.

Preparation Example 1 Preparation of 2- (azidomethoxy) naphthalene ( 3a )

Step 1:

Dissolve 2-naphthol ( 7a , 1.15 g, 8.0 mmol) in hexamethylphosphoramide (hexamethylphosphoramide, HMPA, 40 mL), add sodium hydride (NaH, 352 mg, 8.8 mmol), and wait for 30 minutes at room temperature. Stir at and add chloromethyl-methyl sulfide (0.737 mL, 8.8 mmol) and then stir at rt for 16 h. Water was added to terminate the reaction, and then the organic compound was extracted with ethyl acetate. The extracted ethyl acetate solution was treated with anhydrous sodium sulfate and then subjected to column chromatography (20% ethyl acetate / n -hexane) to obtain a sulfide intermediate ( 13 , 410 mg, 25%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.26 (s, 3H), 5.22 (s, 2H), 7.20-7.16 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.73 (m, 3H).

Step 2:

The sulfide compound ( 13 , 410 mg, 2.0 mmol) obtained in step 1 was dissolved in dichloromethane and then sulfuryl chloride (1.0 M SO ₂ Cl ₂ / CH ₂ Cl _2). 2.4 mL, 2.4 mmol) was slowly added to the solution, stirred for 30 minutes, and then the solvent and the reaction residue were removed under reduced pressure. The remaining organics were dissolved in dimethylformamide (DMF) solvent and then sodium azide (NaN ₃ , 650 mg, 10 mmol) was added thereto and stirred for 12 hours. Water was added to terminate the reaction, and the organic compound was extracted with ethyl acetate. The extracted ethyl acetate solution was treated with anhydrous sodium sulfate, and then subjected to column chromatography (10% ethyl acetate / n -hexane) to give a target compound, 2- (azidomethoxy) naphthalene ( 3a , 279 mg, 70%). Got.

¹ H NMR (500 MHz, CDCl ₃ ) δ 5.27 (s, 2H), 7.21 (dd, J = 9.0 Hz, J = 2.5 Hz, 2H), 7.30 (d, J = 2.5 Hz, 1H), 7.40-7.37 (m, 1H), 7.48-7.45 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 9.0 Hz, 2H).

Preparation Example 2 Preparation of 2 -azidoacetophenone ( 3b )

2-bromoacetophenone ( 10a , 1.97 g, 10.0 mmol) was dissolved in acetonitrile (40 mL), and sodium azide (NaN ₃ , 650 mg, 11.0 mmol) was added thereto, followed by stirring for 12 hours. Water was added to terminate the reaction, and the organic compound was extracted with dichloromethane. The extracted dichloromethane solution was treated with anhydrous sodium sulfate and subjected to column chromatography (10% ethyl acetate / n -hexane) to obtain 2- azidoacetophenone ( 3b , 2.11 g, 100%) as a target compound.

¹ H NMR (500 MHz, CDCl ₃ ) δ 4.56 (s, 2H), 7.49 (t, J = 6.2 Hz, 2H), 7.62 (t, J = 6.0 Hz, 1H), 7.90 (d, J = 7.6 Hz , 2H).

Preparation Example 3 Preparation of Azidomethyl Phenyl Sulfide ( 3c )

Bromomethyl phenyl sulfide ( 10b , 1.58 g, 10.0 mmol) was dissolved in dimethylformamide (40 mL), and sodium azide (NaN ₃ , 1.3 g, 20.0 mmol) was added thereto, followed by stirring for 12 hours. Water was added to terminate the reaction, and the organic compound was extracted with ethyl acetate. The extracted ethyl acetate solution was treated with anhydrous sodium sulfate and subjected to column chromatography (1% ethyl acetate / n -hexane) to obtain azidomethyl phenyl sulfide ( 3c , 1.62g, 98%) as a target compound.

¹ H NMR (500 MHz, CDCl ₃ ) δ 4.54 (s, 2H), 7.37-7.25 (m, 3H), 7.45 (d, J = 8.0 Hz, 2H).

Example  1: 4- tert -Butyl-3- methyl -1-((2- Naphthoxy ) methyl ) -1,2,3- Triazolium Trifluoromethanesulfonate  Preparation of (1a)

Step 1:

Compound 2- (azidomethoxy) naphthalene ( 3a , 390 mg, 2.0 mmol) and 3,3-dimethyl-1-butyne ( 4a , 246 mg, 3.0 mmol) obtained in step 2 of Preparation Example 1 were treated with aceto. After dissolving in nitrile (8 mL), copper iodide (77 mg, 0.4 mmol) and triethylamine (0.056 mL, 0.4 mmol) were added, stirred at room temperature for 2 hours, concentrated under reduced pressure, and then column chromatography (1% methanol). / Dichloromethane) was carried out to give the title compound 4-tert-butyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5a , 477 mg, 85%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.35 (s, 9H), 6.30 (s, 2H), 7.19 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.40-7.38 (m, 1H) , 7.46-7.44 (m, 2H), 7.51 (s, 1H), 7.76 (t, J = 8.0 Hz, 3H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 158.8, 154.3, 134.3, 130.14, 130.05, 127.8, 127.5, 126.9, 124.9, 118.7, 118.6, 109.9, 76.2, 31.0, 30.4.

Step 2:

4-tert-butyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5a , 477 mg, 1.69 mmol) obtained in step 1 was dissolved in acetonitrile (7.0 mL) and methyl tri Fluoromethanesulfonate ( 6a , MeOTf, 0.278 mL, 2.5 mmol) was added, stirred at 0 ° C. for 30 minutes, and the solvent was removed under reduced pressure to afford the desired compound 4-tert-butyl-3-methyl-1- ( (2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a , 580 mg, 77%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.46 (s, 9H), 4.35 (s, 3H), 6.60 (s, 2H), 7.22 (dd, J = 9.0, 2.5 Hz, 1H), 7.42-7.39 ( m, 1H), 7.49-7.45 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 8.5 Hz, 2H), 8.60 (s, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) d 153.1, 152.3, 134.1, 130.6, 130.4, 128.4, 127.8, 127.6, 127.2, 125.4, 120.8 (q, J = 319 Hz), 118.0, 110.2, 79.2, 40.9, 31.6 , 28.4.

Example  2: 4- Methoxycarbonyl -3- methyl -1-((2- Naphthoxy ) methyl ) -1,2,3- Triazolium  Preparation of Trifluoromethanesulfonate (1b)

Step 1:

Proceed in the same manner except using methylpropiorate ( 4b , 252 mg, 3.0 mmol) instead of 3,3-dimethyl-1-butyne ( 4a ) used in step 1 of Example 1 Methoxycarbonyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5b , 346 mg, 61%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.94 (s, 3H), 6.41 (s, 2H), 7.17 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.36 (d, J = 2.5 Hz , 1 H), 7.42-7.39 (m, 1H), 7.49-7.45 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.79-7.77 (m, 2H), 8.34 (s, 1H) ;

¹³ C NMR (125 MHz, CDCl ₃ ) δ 161.0, 153.6, 141.0, 134.1, 130.5, 130.3, 127.9, 127.6, 127.4, 127.1, 125.2, 118.3, 110.2, 76.7, 52.5.

Step 2:

Instead of 4-tert-butyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5a ) used in step 2 of Example 1, 4-methoxycarbonyl-1-(( Proceed in the same manner except using 2-naphthoxy) methyl) -1,2,3-triazole ( 5b , 346 mg, 1.22 mmol) 4-methoxycarbonyl-3-methyl-1- ((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1b , 513 mg, 94%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.96 (s, 3H), 4.35 (s, 3H), 6.70 (s, 2H), 7.22 (dd, J = 9.0 Hz, 2.5 Hz, 1H), 7.41 (td , J = 7.8, 1.2 Hz, 1H), 7.47 (td, J = 7.3, 1.3 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 9.0 Hz, 2H), 9.26 (s, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 155.4, 152.9, 134.1, 133.8, 133.3, 130.8, 130.7, 127.8, 127.7, 127.3, 125.6, 120.7 (t, J = 318 Hz), 118.0, 110.9, 80.3, 54.3 , 41.5.

Example  3: 4- [3,5-di ( Trifluoromethyl ) Phenyl ] -3- methyl -1-((2- Naphthoxy ) methyl ) -1,2,3- Triazolium Trifluoromethanesulfonate  Preparation of (1c)

Step 1:

1-ethynyl-3,5-bis (trifluoromethyl) benzene ( 4c , 530 μl, 3.0 mmol) was used in place of the 3,3-dimethyl-1-butyne ( 4a ) used in Step 1 of Example 1 In the same manner, except that 4- [3,5-di (trifluoromethyl) phenyl] -1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5c , 700 mg, 80%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 6.45 (s, 2H), 7.20 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.41-7.38 (m, 1H), 7.43 (d, J = 2.5 Hz, 1 H), 7.49-7.45 (m, 1 H), 7.80-7.75 (m, 3 H), 7.83 (s, 1 H), 8.19 (s, 1 H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 134.2, 132.6, 132.4, 132.3, 130.4, 130.2, 127.9, 127.4, 127.1, 125.9, 125.2, 124.4, 122.2, 122.1, 120.7, 118.4, 109.9, 76.5.

Step 2:

4- [3,5-di (trifluor) instead of 4-tert-butyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5a ) used in step 2 of Example 1 Proceed in the same manner, except that methyl) phenyl] -1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5c , 700 mg, 1.60 mmol) is used. , 5-di (trifluoromethyl) phenyl] -3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1c , 860 mg, 89%) was obtained.

¹ H NMR (500 MHz, MeOD) δ 4.36 (s, 3H), 6.81 (s, 2H), 7.35 (dd J = 9.0 Hz, 2.5 Hz, 1H), 7.43 (td, J = 7.0 Hz, 1.0 Hz, 1H), 7.50 (td, J = 7.0 Hz, 1.0 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.85 (t, J = 7.0 Hz, 2H), 7.73 (d, J = 9.0 Hz , 1H), 8.33 (s, 1 H), 8.36 (s, 2 H);

¹³ C NMR (125 MHz, MeOD) δ 153.2, 141.2, 134.2, 132.7 (q, J = 34 Hz), 130.6, 130.4 (d, J = 3 Hz), 130.2, 127.4, 127.1, 126.7, 125.4 (q, J = 4 Hz), 125.0, 124.9, 123.9, 121.8, 120.4 (q, J = 317 Hz), 117.8, 110.7, 79.8, 38.4.

Example  4: 4- (4- Methoxyphenyl ) -3- methyl -1-((2- Naphthoxy ) methyl ) -1,2,3- Triazolium  Preparation of Trifluoromethanesulfonate (1d)

Step 1:

Proceed in the same manner except using 4-ethynylanisole ( 4d , 252 mg, 3.0 mmol) instead of 3,3-dimethyl-1-butyne ( 4a ) used in step 1 of Example 1 4- (4-methoxyphenyl) -1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5d , 391 mg, 59%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.83 (s, 3H), 6.39 (s, 2H), 7.00-6.93 (m, 2H), 7.20 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H) , 7.27 (d, J = 9.0 Hz, 1H), 7.40-7.37 (m, 1H), 7.47-7.44 (m, 2H), 7.78-7.72 (m, 5H), 7.93 (s, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 134.3, 133.9, 130.3, 130.2, 129.9, 127.8, 127.5, 127.4, 127.3, 127.0, 125.0, 123.0, 118.7, 118.6, 114.5, 110.1, 76.5, 55.5.

Step 2:

4- (4-methoxyphenyl) -1 instead of 4-tert-butyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5a ) used in step 2 of Example 1 Proceed in the same manner except using ((2-naphthoxy) methyl) -1,2,3-triazole ( 5d , 391 mg, 1.18 mmol) 4- (4-methoxyphenyl)- 3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1d , 521 mg, 89%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.82 (s, 3H), 4.25 (s, 3H), 6.65 (s, 2H), 7.03-7.00 (m, 2H), 7.25 (dd, J = 9.0, 2.5 Hz, 1H), 7.42 (td, J = 7.5, 1.0 Hz, 1H), 7.53-7.47 (m, 4H), 7.79 (d, J = 8.5 Hz, 1H), 7.83 (t, J = 9.0 Hz, 2H ), 8.76 (s, 1 H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 162.7, 153.1, 144.1, 134.2, 131.3, 130.8, 130.6, 128.5, 127.8, 127.7, 118.0, 115.5, 113.5, 110.5, 79.6, 55.7, 38.9.

Example  5: 3- methyl -4- Phenyl -1- (2- Phenylethane -2-one-1-yl) -1,2,3- Triazolium Trifluoromethanesulfonate  Preparation of (1e)

Step 1:

2-Azidoacetophenone ( 3b , 322 mg, 2.0 mmol) and phenylacetylene ( 4e , 225 mg, 2.2 mmol) were dissolved in acetonitrile (8 mL), followed by copper iodide (77 mg, 0.4 mmol) and triethylamine (0.056 mL, 0.4 mmol) was added thereto, stirred at room temperature for 2 hours, concentrated under reduced pressure, and subjected to column chromatography (1% methanol / dichloromethane) to give the title compound 4-phenyl-1- (2-phenylethane- 2-on-1-yl) -1,2,3-triazole ( 5e , 520 mg, 83%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 5.90 (s, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 7.55 (t, J = 7.8 Hz , 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.95 (s, 1H), 8.03 (t, J = 8.4 Hz, 2H).

Step 2:

4-phenyl-1- (2-phenylethane-2-one-1-yl) -1,2,3-triazole ( 5e , 520 mg, 1.67 mmol) obtained in step 1 was added to acetonitrile (7.0 mL). After dissolving, methyl trifluoromethanesulfonate ( 6a , MeOTf, 0.278 mL, 2.5 mmol) was added thereto, stirred at 0 ° C. for 30 minutes, and the solvent was distilled off under reduced pressure to yield the title compound 3-methyl-4-phenyl-1- (2 -Phenylethane-2-one-1-yl) -1,2,3-triazolium trifluoromethanesulfonate ( 1e , 694 mg, 87%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 4.31 (s, 3H), 6.43 (s, 2H), 7.55-7.72 (m, 8H), 8.04 (d, J = 6.0 Hz, 2H), 8.76 (s, 1H).

Example  6: 4- tert -Butyl-3- methyl -One-[( Phenylthio ) methyl ] -1,2,3- Triazolium Trifluoromethanesulfonate  (1f) Preparation

Step 1:

Compound azidomethyl phenyl sulfide ( 3c , 330 mg, 2.0 mmol) and 3,3-dimethyl-1-butyne ( 4a , 246 mg, 3.0 mmol) obtained in Preparation Example 3 were dissolved in acetonitrile (8 mL). Then copper iodide (77 mg, 0.4 mmol) and triethylamine (0.056 mL, 0.4 mmol) were added thereto, stirred at room temperature for 2 hours, concentrated under reduced pressure, and then subjected to column chromatography (1% methanol / dichloromethane). Target compound 4-tert-butyl-1-[(phenylthio) methyl] -1,2,3-triazole ( 5f , 411 mg, 83%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.23 (s, 9H), 5.90 (s, 2H), 7.45-7.34 (m, 5H), 7.76 (s, 1H).

Step 2:

4-tert-butyl-1-[(phenylthio) methyl] -1,2,3-triazole ( 5f , 411 mg, 1.66 mmol) obtained in step 1 was dissolved in acetonitrile (7.0 mL) and methyl trifluor After adding romethanesulfonate ( 6a , MeOTf, 0.278 mL, 2.5 mmol), stirring at 0 ° C. for 30 minutes, and then decompressing the solvent to give the desired compound 4-tert-butyl-3-methyl-1-[(phenylthio). 5) methyl] -1,2,3-triazolium trifluoromethanesulfonate ( 1f , 615 mg, 90%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.46 (s, 9H), 4.28 (s, 3H), 5.93 (s, 2H), 7.43-7.38 (m, 5H), 8.17 (s, 1H).

Example  7: 3- methyl -1-((2- Naphthoxy ) methyl )-4- Phenyl -1,2,3- Triazolium Trifluoromethanesulfonate  (1g) Preparation

Step 1:

2-naphthol ( 7a , 720 mg, 5.0 mmol) and potassium carbonate (2.07 g, 15 mmol) were dissolved in acetonitrile (20 mL), and then 1- (chloromethyl) -4-phenyl-1,2,3- Triazole ( 8a , 1.45 g, 7.5 mmol) was added and stirred at 80 ° C. for 5 hours. Water was added to terminate the reaction, and then the organic compound was extracted with ethyl acetate. The extracted ethyl acetate solution was treated with anhydrous sodium sulfate, and then subjected to column chromatography (30% ethyl acetate / n -hexane) to 4-phenyl-1-((2-naphthoxy) methyl) -1,2,3 -Triazole ( 5 g , 1.13 g, 75%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 6.40 (s, 2H), 7.20 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.26 (d, J = 9.5 Hz, 1H), 7.47-7.31 (m, 6H), 7.79-7.76 (m, 3H), 7.83-7.81 (m, 2H), 8.01 (s, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 134.2, 133.9, 130.3, 130.2, 129.9, 129.0, 128.6, 127.8, 127.5, 127.0, 126.03, 125.94, 125.0, 119.6, 118.5, 110.1, 76.5.

Step 2:

4-phenyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5 g , 1.13 g, 3.75 mmol) obtained in step 1 was dissolved in acetonitrile (15.0 mL) and methyl trifluoro Methanesulfonate ( 6a , MeOTf, 0.618 mL, 5.63 mmol) was added, stirred at 0 ° C. for 30 minutes, and the solvent was removed under reduced pressure to afford the desired compound 4-phenyl-3-methyl-1-((2-naph). Methoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1 g , 1.68 g, 96%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) d 3.81 (s, 3H), 6.35 (s, 2H), 7.22 (dd, J = 9. 0 Hz, 2. 0 Hz, 1H), 7.40-7.35 (m, 3H), 7.54-7.43 (m, 6H), 7.75 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.85 (t, J = 8.5 Hz, 1H), 9.63 ( s, 1 H);

¹³ C NMR (125 MHz, CDCl ₃ ) d 152.8, 138.3, 136.6, 134.3, 131.1, 130.6, 130.4, 129.64, 129.60, 127.7, 127.2, 125.3, 124.5, 120.9 (d, J = 319 Hz), 118.4, 118.1 , 110.3, 76.0, 35.1.

Example  8: 3- methyl -1- [3- (2- Naphthoxy ) - n -profile] Oxymethyl -4- Phenyl -1,2,3- Triazolium Trifluoromethanesulfonate  (1h) Preparation

Step 1:

3- (2-naphthoxy) propanol ( 7b , 1.01 g, 5.0 mmol) and potassium tert -butoxide (1.69 g, 15 mmol) were dissolved in tetrahydrofuran (20 mL), followed by 1- (chloromethyl) 4-phenyl-1,2,3-triazole ( 8a , 1.16 g, 6.0 mmol) was added and stirred at room temperature for 3 hours. Water was added to terminate the reaction, and then the organic compound was extracted with dichloromethane. The extracted dichloromethane solution was treated with anhydrous sodium sulfate and then subjected to column chromatography (30% ethyl acetate / n -hexane) to give 1- [3- (2-naphthoxy) -n -propyl] oxymethyl-4- Phenyl-1,2,3-triazole ( 5h , 1.25 g, 70%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.10 (q, J = 6.0 Hz, 2H), 3.79 (t, J = 6.3 Hz, 2H), 4.12 (t, J = 6.3 Hz, 2H), 5.74 (s , 2H), 7.05 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H), 7.38-7.31 (m, 4H), 7.44-7.41 (m, 1H) , 7.65 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.76-7.73 (m, 3H), 7.87 (s, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 156.9, 148.9, 134.7, 130.4, 129.6, 129.2, 129.0, 128.5, 127.8, 126.9, 126.5, 126.0, 123.8, 119.3, 118.9, 106.8, 79.3, 66.5, 64.2, 29.3 .

Step 2:

1- [3- (2-naphthoxy) -n -propyl] oxymethyl-4-phenyl-1,2,3-triazole ( 5h , 1.25 mg, 3.5 mmol) obtained in step 1 was purified by acetonitrile (14.0 mL ), Methyl trifluoromethanesulfonate ( 6a , MeOTf, 0.57 mL, 5.25 mmol) was added, stirred at 0 ° C. for 30 minutes, the solvent was removed under reduced pressure, and the desired compound 3-methyl-1- [3 -(2-naphthoxy) -n -propyl] oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1h , 1.4 g, 76%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) d 2.11 (q, J = 5.8 Hz, 2H), 4.01-3.99 (m, 5H), 4.08 (t, J = 5.5 Hz, 2H), 5.95 (s, 2H) , 7.01 (dd, J = 9.0, 2.5 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 7.44-7.26 (m, 7H), 7.51-7.48 (m, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 8.68 (s, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) d 156.7, 143.8, 134.7, 132.0, 129.71, 129.66, 129.5, 129.1, 128.3, 127.8, 126.9, 126.8, 12.0, 121.7, 120.8 (d, J = 318 Hz), 118.6 , 106.8, 83.6, 68.2, 63.7, 38.7, 29.1

Example  9: 1- [1- Methylsulfonyloxy -3- (2- Naphthyl )-2- Oxypropyl ] Oxymethyl -3- methyl -4- Phenyl -1,2,3- Triazolium Trifluoromethanesulfonate  Preparation of (1i)

Use of 2-hydroxy-3- (2-naphthalenyloxy) propyl methanesulfonate ( 7c , 889 mg, 3.0 mmol) instead of the 3- (2-naphthoxy) propanol ( 7b ) used in Example 8 Proceed in the same manner except 1- [1-methylsulfonyloxy-3- (2-naphthyl) -2-oxypropyl] oxymethyl-3-methyl-4-phenyl-1,2,3-tria Zolium trifluoromethanesulfonate ( 1i , 1.39 g, 75%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.99 (s, 3H), 4.15 (s, 3H), 4.31-4.22 (m, 2H), 4.43 (d, J = 5.5 Hz, 2H), 4.69-4.67 ( m, 1H), 6.22 (q, J = 9.3 Hz, 2H), 7.07 (dd, J = 8.8, 2.8 Hz, 1H), 7.13 (d, J = 2.5 Hz, 1H), 7.43 (td, J = 7.5 Hz, 1.0 Hz, 1H), 7.52-7.48 (m, 4H), 7.57-7.54 (m, 1H), 7.69 (d, J = 9.0 Hz, 2H), 7.23 (t, J = 8.0 Hz, 2H), 8.91 (s, 1 H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 155.9, 143.9, 134.5, 132.1, 129.9, 129.8, 129.6, 129.5, 128.8, 127.8, 127.2, 126.9, 124.4, 122.0, 120.9 (d, J = 319 Hz), 118.3 , 107.5, 82.8, 78.5, 69.7, 67.2, 38.8, 37.4.

Example  10: 3- methyl -(2- Naphthyl ) Methyloxymethyl -4- Phenyl -1,2,3- Triazolium Trifluoromethanesulfonate  Preparation of (1j)

Proceed in the same manner except using naphthalenemethanol ( 7d , 475 mg, 3.0 mmol) instead of 3- (2-naphthoxy) propanol ( 7b ) used in Example 8 and proceeding with 3-methyl- (2-naph Tyl) methyloxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1j , 1.09 g, 76%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.96 (s, 3H), 4.88 (s, 2H), 5.94 (s, 2H), 7.24 (d, J = 7.5 Hz, 2H), 7.45-7.32 (m, 6H), 7.68 (d, J = 8.5 Hz, 1H), 7.76-7.71 (m, 3H), 8.48 (s, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 143.39, 143.38, 133.1, 132.9, 131.8, 129.5, 129.3, 128.3, 128.2, 128.1, 127.69, 127.67, 126.61, 126.55, 125.9, 124.6, 121.59, 121.58, 120.8 (q , J = 319 Hz), 82.7, 73.9, 38.5.

Example  11: (S) -1- (4- (2- BOC -Amino-2- (t- Butoxycarbonyl )ethyl) Phenyloxymethyl ) -4-phenyl-1,2,3- Triazolium Trifluoromethanesulfonate  (1k) Preparation

Step 1:

N-BOC-L-tyrosine tert-butyl ester ( 7e, 0.79 g, 2.35 mmol) was dissolved in acetone (23 mL), followed by cesium carbonate (2.00 g, 5.87 mmol), 1- (chloromethyl) -4-phenyl -1,2,3-triazole ( 8a , 0.46 g, 2.59 mmol) was added sequentially and stirred at 50 ° C. for 6 hours. The reaction was distilled under reduced pressure, diluted with ethyl acetate and filtered. The filtrate is washed with 1.0 normal aqueous hydrochloric acid solution, water and saturated aqueous sodium chloride solution in that order. The washed organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (SiO _{2 ,} 20% ethyl acetate / hexane) to give a white solid compound (S) -1- (4- (2-BOC-amino-2- (t-butoxycarbonyl) ethyl) phenyloxymethyl) -4-phenyl-1,2,3-triazole ( 5k , 1.07 g, 2.16 mmol, 92%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.38 (s, 18H), 2.99 (s, 2H), 4.39 (d, J = 6.4 Hz, 1H), 5.03 (d, J = 8 Hz, 1H), 6.23 (s, 3H), 7.09 (d, J = 8 Hz, 2H), 7.33 (d, J = 6.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.82 (d, J = 7.6 Hz , 2H), 7.97 (s, 1H),

Step 2:

(S) -1- (4- (2-BOC-amino-2- (t-butoxycarbonyl) ethyl) phenyloxymethyl) -4-phenyl-1,2,3-triazole obtained in step 1 above. ( 5k , 0.47 g, 0.96 mmol) is dissolved in acetonitrile (2.5 mL), and methyl trifluoromethanesulfonate ( 6a , 53 μl, 0.48 mmol) is added and stirred at room temperature for 90 minutes. The reaction mixture was concentrated and subjected to column chromatography (SiO _2, 5% methanol / dichloromethane) to give the target compound (S) -1- (4- (2-BOC-amino-2- (t-butoxycarbonyl). ) Ethyl) phenyloxymethyl) -3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1k , 0.22 g, 0.34 mmol, 70%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.40 (s, 18H), 3.04-2.98 (m, 2H), 4.30 (s, 3H) 4.37 (d, J = 6.0 Hz, 1H), 5.00 (d, J = 8.0 Hz, 1H), 6.54 (s, 2H), 7.03 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.61-7.54 (m, 5H), 8.70 (s , 1H).

Example  12: 3- methyl -1-((2- Naphthoxy ) methyl )-4- Phenylimidazolium Trifluoromethanesulfonate  (1l) Preparation

Step 1:

2-naphthol ( 7a , 720 mg, 5.0 mmol) and potassium carbonate (2.07 g, 15 mmol) were dissolved in acetonitrile (20 mL) and then 1- (chloromethyl) -4-phenyl-imidazole ( 8b, 1.44 g, 7.5 mmol) was added, followed by stirring for 5 hours at 80 ° C. heating conditions. Water was added to terminate the reaction, and then the organic compound was extracted with ethyl acetate. The extracted ethyl acetate solution was treated with anhydrous sodium sulfate and subjected to column chromatography (20% ethyl acetate / n -hexane) to 4-phenyl-1-((2-naphthoxy) methyl) imidazole ( 5l , 931 mg, 62%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 5.94 (s, 2H), 7.13 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 7.28-7.24 (m, 2H), 7.43-7.36 (m, 4H), 7.48 (td, J = 7.4 Hz, J = 1.2 Hz, 1H), 7.71 (d, J = 1.2 HZ, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.81-7.77 (m, 4H).

Step 2:

4-phenyl-1-((2-naphthoxy) methyl) imidazole ( 5l , 931 mg, 3.10 mmol) obtained in step 1 was dissolved in acetonitrile (15.0 mL) and methyl trifluoromethanesulfonate ( 6a , MeOTf , 0.51 mL, 4.65 mmol) was added, followed by stirring at 0 ° C. for 30 minutes, and then the solvent was removed under reduced pressure to yield the desired compound 4-phenyl-3-methyl-1-((2-naphthoxy) methyl) imidazolium Trifluoromethanesulfonate ( 1L , 734 mg, 51%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) d 3.78 (s, 3H), 6.33 (s, 2H), 7.21 (dd, J = 8.8, 2.3 Hz, 1H), 7.78-7.34 (m, 3H), 7.52- 7.41 (m, 6H), 7.73 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 9.57 (s, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) d 152.9, 138.1, 136.5, 134.3, 131.0, 130.6, 130.3, 129.6, 129.5, 127.72, 127.69, 127.1, 125.2, 124.5, 120.9 (q, J = 319 Hz), 118.5 , 118.2, 110.3, 76.0, 35.1.

Example  13: 3- methyl -1-((2- Naphthoxy ) methyl )-4- Phenyl -1,2,3- Triazolium Trifluoromethanesulfonate  (1g) Preparation

2-naphthol ( 7a , 288 mg, 2.0 mmol) and potassium carbonate (829 mg, 6.0 mmol) were dissolved in acetonitrile (8 mL), and then 1- (chloromethyl) -4-phenyl-3-methyl-1, 2,3-triazolium trifluoromethanesulfonate ( 9a , 858 mg, 2.4 mmol) was added, followed by stirring at 80 ° C. for 5 hours. Water was added to terminate the reaction, and then the organic compound was extracted with dichloromethane. The extracted dichloromethane solution was treated with anhydrous sodium sulfate, and then subjected to column chromatography (5% methanol / dichloromethane) to give the same target compound 4-phenyl-3-methyl-1-((2-naph) as in Example 7. Oxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1g , 577 mg, 62%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) d 3.81 (s, 3H), 6.35 (s, 2H), 7.22 (dd, J = 9. 0 Hz, 2. 0 Hz, 1H), 7.40-7.35 (m, 3H), 7.54-7.43 (m, 6H), 7.75 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.85 (t, J = 8.5 Hz, 1H), 9.63 ( s, 1 H);

¹³ C NMR (125 MHz, CDCl ₃ ) d 152.8, 138.3, 136.6, 134.3, 131.1, 130.6, 130.4, 129.64, 129.60, 127.7, 127.2, 125.3, 124.5, 120.9 (d, J = 319), 118.4, 118.1, 110.3, 76.0, 35.1.

Example  14: 1- (4- Biphenyl ) Oxymethyl -3- methyl -4- Phenyl -1,2,3- Triazolium Trifluoromethanesulfonate  (1 m)

Proceed in the same manner except using 4-phenylphenol ( 7f , 510 mg, 3.0 mmol) instead of 2-naphthol ( 7a ) used in Example 12 and proceeding with 1- (4-biphenyl) oxymethyl-3 -Methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1m , 1.28 g, 87%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 4.26 (s, 3H), 6.56 (s, 2H), 7.19 (q, J = 5.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.32 (td, J = 7.5, 1.3 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.61-7.50 (m, 9H), 7.80 (t, J = 8.5 Hz, 2H), 8.79 (s, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 154.8, 144.0, 140.0, 137.4, 132.3, 129.9, 129.7, 129.0, 128.9, 128.8, 127., 121.7, 120.8 (q, J = 319 Hz), 116.6, 79.7, 39.1.

Example  15: 1- (4- Bromo -2- Methylphenyl ) Oxymethyl -3- methyl -4- Phenyl -1,2,3- Triazolium Trifluoromethanesulfonate  Preparation of (1n)

Proceed in the same manner except using 4-bromo-2-methylphenol ( 7g , 561 mg, 3.0 mmol) instead of 2-naphthol ( 7a ) used in Example 12 and proceeding with 1- (4-biphenyl ) Oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1n , 1.14 g, 75%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.20 (s, 3H), 4.28 (s, 3H), 7.04 (d, J = 9.5 Hz, 2H), 7.31-7.27 (m, 2H), 7.61-7.53 ( m, 5H), 8.83 (s, 1 H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 152.8, 144.0, 134.5, 132.3, 130.5, 130.4, 129.9, 129.7, 128.9, 121.7, 120.7 (q, J = 319 Hz), 116.6, 115.3, 79.6, 39.1, 16.1 .

Example  16: 1- (3,4- Dimethoxyphenyl ) Oxymethyl -3- methyl -4- Phenyl -1,2,3- Triazolium  Preparation of Trifluoromethanesulfonate (1o)

Proceed in the same manner except using 3,4-dimethoxyphenol ( 7h , 462 mg, 3.0 mmol) instead of 2-naphthol ( 7a ) used in Example 12 and proceeding with 1- (3,4-dimethoxy Phenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1o , 927 mg, 65%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.79 (s, 3H), 3.82 (s, 3H), 4.24 (s, 3H), 6.43 (s, 2H), 6.62 (dd, J = 8.5, 2.8 Hz, 1H), 6.68 (s, 1H), 6.76 (d, J = 8.5 Hz, 1H), 7.58-7.48 (m, 5H), 8.72 (s, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 105.2, 149.4, 146.0, 143.8, 132.2, 129.8, 129.5, 128.6, 121.7, 120.7 (q, J = 319 Hz), 111.7, 106.8, 102.4, 80.6, 56.3, 56.2 , 39.0.

Example  17: 3- methyl -1- (4- Nitrophenyl ) Oxymethyl -4- Phenyl -1,2,3- Triazolium Trifluoromethanesulfonate  (1p)

Proceed in the same manner except 4-nitrophenol ( 7i , 417 mg, 3.0 mmol) instead of 2-naphthol ( 7a ) used in Example 12, proceeding in the same manner as 3-methyl-1- (4-nitrophenyl) Oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1p , 898 mg, 65%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 4.36 (s, 3H), 6.79 (s, 2H), 7.41 (d, J = 9.5 Hz, 2H), 7.72-7.64 (m, 5H), 8.30 (d, J = 9.5 Hz, 2H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 160.1, 144.2, 143.8, 131.8, 129.4, 129.2, 125.7, 122.1, 120.4 (d, J = 317 Hz, only two peaks of quartet of CF ₃ -C were shown), 116.3, 78.5, 38.3.

Example  18: 1- (4- Acetylaminophenyl ) Oxymethyl -3- methyl -4- Phenyl -1,2,3- Triazolium Trifluoromethanesulfonate  Preparation of (1q)

Proceed in the same manner except using 3-acetaminophenol ( 7j , 453 mg, 3.0 mmol) instead of 2-naphthol ( 7a ) used in Example 12 and proceeding with 1- (4-acetylaminophenyl) oxymethyl 3-Methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1q , 1.08 g, 76%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.09 (s, 3H), 6.41 (s, 2H) 4.26 (s, 3H), 6.72 (dd, J = 8.3, 2.3 Hz, 1H), 7.20-7.15 (m , 2H), 7.63-7.49 (m, 5H), 7.66 (d, J = 8.0 Hz, 1H), 8.70 (s, 1H), 8.93 (s, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 170.0, 155.4, 144.1, 140.9, 132.5, 130.8, 130.0, 129.7, 128.3, 121.7, 120.7 (q, J = 318 Hz), 116.0, 112.5, 106.6, 80.1, 39.2 , 24.5.

Example  19: 1- (3- O - Estroneil ) methyl -3- methyl -4- Phenyl -1,2,3- Triazolium Trifluoromethanesulfonate  Preparation of (1r)

Proceed in the same manner except using estrone ( 7k , 811 mg, 3.0 mmol) instead of 2-naphthol ( 7a ) used in Example 12 and proceeding with 1- (3- O -estronyl) methyl-3- Methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1r , 1.26 g, 71%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 0.89 (s, 3H), 1.64-1.39 (m, 6H), 1.95-1.93 (m, 1H), 2.16-1.98 (m, 4H), 2.24-2.20 (m , 1H), 2.37-2.35 (m, 1H), 2.49 (dd, J = 19.0, 8.5 Hz, 2H), 2.92-2.90 (m, 2H), 4.27 (s, 3H), 6.50 (s, 2H), 6.88-6.87 (m, 2H), 7.24 (d, J = 9.5 Hz, 1H), 7.62-7.55 (m, 5H), 8.70 (s, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 220.7, 153.5, 144.0, 139.3, 136.1, 132.3, 129.9, 129.7, 128.7, 127.2, 121.8, 120.8 (q, J = 319 Hz), 116.3, 113.5, 80.0, 50.6 , 48.1, 44.2, 39.0, 38.3, 36.0, 31.7, 29.6, 26.5, 26.0, 21.7, 14.0.

Example  20: 3- Acetnaphthyl -One- Methylimidazolium  Manufacture of 1s

2-bromo-2-acetonaphtone ( 10a , 2.49 g, 10 mmol) was dissolved in acetonitrile (50 mL), followed by addition of methylimidazole ( 11a , 0.836 mL, 10.5 mmol) and heating at 80 degrees. Stirred under conditions for 12 hours. After the reaction was completed, the reaction solvent was removed under reduced pressure, and then column chromatography (10% methanol / dichloromethane) was carried out to obtain the desired compound 3-acetnaphthyl-1-methylimidazolium ( 1s , 3.08 g, 93%). Got it.

¹ H NMR (500 MHz, CDCl ₃ ) δ 4.02 (s, 3H), 6.15 (s, 2H), 7.68 (m, 4H), 7.99 (m, 4H), 8.74 (s, 1H), 9.01 (s, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 191.3, 139.5, 137.7, 134.0, 132.5, 130.9, 130.5, 130.0, 129.4, 129.0, 128.7, 125.4, 124.6, 124.3, 56.3, 36.8.

Example  21: Nucleophilicity  Fluorination reaction

4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a , 0.5 mmol) and tetra obtained in Example 1 above Butyl ammonium fluoride (TBAF, 0.75 mmol) was added to the reaction vessel, acetonitrile (2.0 mL) was added thereto, dissolved, and the mixture was stirred at 80 ° C. for 1 hour. Water was added to terminate the reaction, and then the organic compound was extracted with dichloromethane. The extracted dichloromethane solution was treated with anhydrous sodium sulfate and column chromatography (2% ethyl acetate / hexane) was carried out to obtain ( 12a , 78 mg, 89%) of the target compound 2-fluoromethoxynaphthalene.

¹ H NMR (500 MHz, CDCl ₃ ) δ 5.85 (d, J = 55.0 Hz, 2H), 7.29 (dd, J = 9.0, 2.5 Hz, 1H), 7.44 (t, J = 7.3 Hz, 1H), 7.52 -7.49 (m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 9.0 Hz, 2H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 154.9, 134.5, 130.5, 130.1, 128.0, 127.6, 126.9, 125.1, 118.8, 111.4, 101.1 (d, J = 218 Hz).

Example  22: Fluorination Reaction Under Various Organic Solvent Conditions

4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a , 0.5 mmol) and tetra obtained in Example 1 above The same as Example 20 above using butylammonium fluoride (TBAF, 196 mg, 0.75 mmol) and various organic solvents (2.0 mL) such as tert-butanol, tetrahydrofuran, dimethylformamide instead of acetonitrile solvent The fluorination reaction was advanced by the method. The reaction time was confirmed for each reaction and the amount of 2-fluoromethoxynaphthalene which was a product for the fluorination reaction was measured. The measured results are shown in Table 1 below.

menstruum Time (min) Yield (%) MeCN 60 89 t-BuOH 60 81 THF 40 85 DMF 20 79

Example  22: various Fluorination  Reaction with reagent

4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a , 0.5 mmol) obtained in Example 1 was used. The fluorination reaction was carried out in the same manner as in Example 21 using cesium fluoride instead of tetrabutylammonium fluoride as the fluorination reagent. The reaction time was confirmed for each reaction and the amount of 2-fluoromethoxynaphthalene which was a product for the fluorination reaction was measured. The measured results are shown in Table 2 below.

MF (equivalent) time Yield (%) CsF (3.0) 24 hours 38 TBAF (1.5) 60 minutes 89

Example  24: 2- (3- Fluoromethoxy - n - Propoxy Preparation of Naphthalene (12b)

3-methyl- instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 Using 1- [3- (2-naphthoxy) -n -propyl] oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1h , 262 mg, 0.5 mmol) The procedure was followed in the same manner except to obtain 2- (3-fluoromethoxy- n -propoxy) naphthalene ( 12b , 90 mg, 77%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.19 (q, J = 6.1 Hz, 2H), 3.98 (td, J = 6.3, 2.0 Hz, 2H), 4.21 (t, J = 6.0 Hz, 2H), 5.30 (d, J = 56.0 Hz, 2H), 7.16-7.14 (m, 2H), 7.34 (td, J = 7.5, 1.2 Hz, 1H), 7.45 (td, J = 7.5, 2.0 Hz, 1H), 7.78- 7.72 (m, 3 H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 154.9, 134.5, 130.5, 130.1, 128.0, 127.6, 126.9, 125.1, 118.8, 111.4, 101.1 (d, J = 218 Hz).

Example  25: 2- (2- Fluoromethoxy -3- Methanesulfonyloxy - n - Propoxy Preparation of Naphthalene (12c)

1- [1 instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 -Methylsulfonyloxy-3- (2-naphthyl) -2-oxypropyl] oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1i , 310 mg , (0.5 mmol) was used in the same manner to obtain 2- (2-fluoromethoxy-3-methanesulfonyloxy- n -propoxy) naphthalene ( 12c , 110 mg, 67%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.06 (s, 3H), 4.37-4.23 (m, 3H), 4.58-4.49 (m, 2H), 5.46 (ddd, J = 55.8, 17.5, 3.0 Hz, 2H ), 7.16-7.14 (m, 2H), 7.37 (td, J = 8.0, 1.0 Hz, 1H), 7.47 (td, J = 8.3, 1.3 Hz, 1H), 7.76 (q, J = 9.00 Hz, 3H) ;

¹³ C NMR (125 MHz, CDCl ₃ ) δ 156.1, 134.6, 130.0, 129.5, 127.9, 127.1, 126.9, 124.4, 118.7, 107.2, 103.8 (d, J = 216 Hz), 69.1, 67.0, 37.8.

Example  26: (2- Fluoromethoxy ) -2-methylnaphthalene (12d) Preparation

3-methyl- instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 Proceed in the same manner except using (2-naphthyl) methyloxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1j , 240 mg, 0.5 mmol) ( 2-fluoromethoxy) -2-methylnaphthalene ( 12d , 75 mg, 79%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 4.95 (s, 2H), 5.40 (d, J = 56.4 Hz, 2H), 7.75 Hz, 2H), 7.51-7.47 (m, 3H), 7.87-7.83 (m , 4H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 134.0, 133.4, 133.3, 128.6, 128.1, 127.9, 127.2, 126.5, 126.4, 125.9, 102.9 (d, J = 213 Hz), 72.0.

Example  27: O- Fluoromethyl -N- BOC L-tyrosine tert Preparation of -Butyl Ester 12e

(S)-instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 1- (4- (2-BOC-amino-2- (t-butoxycarbonyl) ethyl) phenyloxy methyl) -3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfo Proceed in the same manner except using Nate ( 1k , 0.22g, 0.36 mmol) to give O-fluoromethyl-N-BOC-L-tyrosine-tert-butyl ester ( 12e , 75 mg, 60%). Got it.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.42 (d, J = 4.0 Hz, 18H), 3.01-3.04 (m, 2H), 4.42 (d, J = 6.8 Hz, 1H), 4.98 (d, J = 6.8 Hz, 1H), 5.62 (s, 1H), 5.76 (s, 1H), 7.00 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H).

Example  28: 4- Fluoromethoxybiphenyl  Preparation of 12e

1- (4 instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 -Biphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1m , 246 mg, 0.5 mmol) 4- Fluoromethoxybiphenyl ( 12f , 74 mg, 73%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 5.78 (d, J = 55.0 Hz, 2H), 7.21 (d, J = 9.0 Hz, 2H), 7.39 (td, J = 7.5, 1.0 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 7.61 (d, J = 8.5 Hz, 4H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 156.59, 156.57, 140.7, 136.9, 129.1, 128.7, 127.4, 127.2, 117.23, 117.22, 101.0 (d, J = 218 Hz).

Example  29: 5- Bromo -2- Fluoromethoxytoluene  (12g) Preparation

1- (4 instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 -Bromo-2-methylphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1n , 254 mg, 0.5 mmol) same Proceed to the method 5-bromo-2-fluoromethoxytoluene ( 12g , 91 mg, 83%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.24 (s, 3H), 5.70 (d, J = 54.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 1H) 7.31 (m, 2H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 154.4, 133.9, 130.5, 130.0, 116.6, 116.0, 101.0 (d, J = 218 Hz), 16.2.

Example  30: 4- Fluoromethoxy -1,2- Dimethoxybenzene  Preparation of 12h

4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate (1a1- (3,4-dimethoxyphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate (1o, 238 mg, 0.5 mmol) was used in the same manner to yield 4-fluoromethoxy-1,2-dimethoxybenzene (12h, 70 mg, 75%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.84 (s, 3H), 3.85 (s, 3H), 5.64 (d, J = 55.0 Hz, 2H), 6.65-6.61 (m, 2H), 6.78 (d, J = 8.5 Hz, 1H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 151.3, 149.8, 145.5, 111.6, 107.6, 102.6, 101.8 (d, J = 217 Hz), 56.4, 56.0.

Example  31: 4- Fluoromethoxy Preparation of -1-nitrobenzene (12i)

3-methyl- instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 Proceed in the same manner except using 1- (4-nitrophenyl) oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1p , 230 mg, 0.5 mmol) 4-Fluoromethoxy-1-nitrobenzene ( 12i , 62 mg, 72%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 5.79 (d, J = 53.0 Hz, 2H), 7.18-7.17 (m, 2H), 8.26-8.24 (m, 2H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 161.3, 143.7, 126.1, 116.6, 99.8 (d, J = 221 Hz).

Example  32: N - (3- Fluoromethoxyphenyl ) Acetamide  Preparation of 12j

1- (4 instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 -Acetylaminophenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1q , 236 mg, 0.5 mmol) proceeds in the same manner To give N- (3-fluoromethoxyphenyl) acetamide ( 12j , 70 mg, 76%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.20 (s, 3H), 5.72 (d, J = 54.5 Hz, 2H), 6.85 (d, J = 7.0 Hz, 1H), 7.20 (d, J = 7.5 Hz , 1H), 7.29-7.26 (m, 1H), 7.41 (s, 1H), 7.46 (bs, 1 H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 168.7, 157.4, 139.5, 130.2, 115.0, 112.5, 108.7, 100.9 (d, J = 218 Hz), 24.9.

Example  33: 3 -O- Fluoromethyl Estrone  Preparation of 12j

1- (3 instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 In the same manner except using O -estronyl) methyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1r , 296 mg, 0.5 mmol) Proceeded to 3 -O- fluoromethyl estrone ( 12k , 125 mg, 83%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 0.89 (s, 3H), 1.66-1.39 (m, 7H), 2.16-1.93 (m, 5H), 2.25-2.20 (m, 1H), 2.40-2.36 (m , 1H), 2.48 (dd, J = 19.0, 8.5 Hz, 1H), 2.89 (t, J = 4.3 Hz, 2H), 5.66 (d, J = 55.0 Hz, 2H), 6.81 (d, J = 2.5 Hz , 1H), 6.86 (dd, J = 8.5, 2.5 Hz, 1H), 7.22 (d, J = 8.5 Hz, 4H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 220.9, 155.1, 138.4, 135.2, 126.8, 117.0, 114.3, 101.1 (d, J = 217 Hz), 50.6, 48.2, 44.2, 38.4, 36.1, 31.8, 29.8, 26.7, 21.8, 14.1.

Example  34: 3 -O- [ ¹⁸ F]- Fluoromethyl Estrone  ([ ¹⁸ F] 12k) production

Distilled water (2.0 mL) and 0.2 M aqueous sodium methanesulfonate solution (2.0 mL) were sequentially added to Chromafix® and washed again with distilled water (2.0 mL). [ ¹⁸ F] fluoride [ ¹⁸ O] H ₂ O solution (1-10 mCi) produced in cyclotron was slowly flown and washed with distilled water (2.0 mL). Methanol (2.0 mL) was poured into the cartridge containing [ ¹⁸ F] fluoride to remove water, and 0.1 M tetrabutylammonium methanesulfonate solution (0.5 mL) was poured out to elute the [ ¹⁸ F] fluoride ion. The solvent was removed by heating to 100 ^o C and blowing nitrogen to remove 1- (3- O -estronyl) methyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1r , 5 mg) was dissolved in acetonitrile or t-amyl alcohol, and then potassium carbonate (3 mg) was added thereto, followed by stirring for 20 minutes at 120 ° C heating conditions. Radio-TLC was used to measure the yield of each reaction, which is shown in Table 3 below.

Acetonitrile t-amyl alcohol Radio-TLC (%) 100 82

Claims (11)

A precursor comprising a tetravalent organic salt leaving group represented by the following formula (1).
[Formula 1]

In Chemical Formula 1,
R ₁ is -X-CH ₂ at the ¹⁸ F radiotracer the cover - as a portion other than the portions ¹⁸ F, C ₁ -C ₁₀₀₀ and a hydrocarbon group, the group is a C ₁ carbon of the main chain hydrocarbon -C oxygen _1000, May be substituted or unsubstituted with nitrogen, sulfur, phosphorus or a combination thereof, hydrogen in the main chain may be substituted or unsubstituted with halogen,
X is oxygen, sulfur, or -C (O)-,
The leaving group is a substituted or unsubstituted tetravalent ammonium salt of C ₂ -C ₅₀ .
The method of claim 1,
In Chemical Formula 1,
R ₁ is a C ₁ -C ₂₀₀ hydrocarbon group, the C ₁ -C ₂₀₀ hydrocarbon group may be unsubstituted or substituted with oxygen, nitrogen, sulfur, phosphorus or a combination of carbon in the main chain, hydrogen of the main chain May be substituted or unsubstituted with halogen,
X is oxygen, sulfur, or -C (O)-,
Breakaway

And in the leaving group,
A, B, C, D and E are independently of each other nitrogen, oxygen, sulfur or carbon,
(i) hydrogen of each carbon may be substituted or unsubstituted with R ₂ or R ₃ ,
(ii) for each nitrogen, R ₂ or May be substituted or unsubstituted with R ₃ ,
R ₂ and R ₃ are independently of each other a C ₁ -C ₂₀ hydrocarbon group in which carbon in the main chain may be substituted or unsubstituted with oxygen, nitrogen, sulfur, or a combination thereof, and hydrogen in the main chain may be substituted or unsubstituted. Can be exchanged,
Y is a halogen anion, a sulfonate anion, BF ₄ ^- is selected from the group consisting ^{_{of, -, PF 6 -, SbF}} 6 -, N (SO 2 CF 3) 2 - and N (CN) ₂
n is a precursor comprising a tetravalent organic salt leaving group, characterized in that 0 or 1.
The method of claim 1,
In Chemical Formula 1,
R ₁ is a C ₁ -C ₁₀₀ hydrocarbon group, the C ₁ -C ₁₀₀ hydrocarbon group may be unsubstituted or substituted with oxygen, nitrogen, sulfur, phosphorus or a combination of carbon of the main chain, hydrogen of the main chain May be substituted or unsubstituted with halogen,
X is oxygen, sulfur, or -C (O)-,
Breakaway
(i)

or

Tetravalent cation selected from; And
(ii) a salt consisting of an anion that is Y,
One nitrogen in the tetravalent cation ring is substituted with R ₃ and each carbon may be independently substituted or unsubstituted with R ₂ ,
R ₂ and R ₃ are C ₁ -C ₂₀ hydrocarbon groups, carbon of the main chain may be substituted or unsubstituted with oxygen, nitrogen, sulfur or a combination thereof, hydrogen of the main chain may be substituted or unsubstituted with halogen, ,
Y is a carbonate sulfonium trifluoromethane independently of each other (CF ₃ SO ₃ ^-), p-toluene sulfonate, methane sulfonate, and para-nitrobenzene The sulfonate 4, characterized in that selected from the group consisting of containing an organic salt release Precursor.
The method of claim 1,
In Chemical Formula 1,
R ₁ is

,

,

,

,

,

,

,

,

,

,

And

Is selected from the group consisting of
X is oxygen, sulfur, or -C (O)-,
Breakaway
(i)

or

Tetravalent cation selected from; And
(ii) a salt consisting of an anion that is Y,
The tetravalent and nitrogen within a ring of the cation substituted with R ₃ may be unsubstituted or substituted on each carbon is independently R ₂ together, R ₂ and R ₃ are independently C _{1 -4} straight or branched chain with each other Alkyl groups, phenyl,

,

, And

Selected from the group consisting of
Y is a carbonate sulfonium trifluoromethane independently of each other (CF ₃ SO ₃ ^-), p-toluene sulfonate, methane sulfonate, and para-nitrobenzene The sulfonate 4, characterized in that selected from the group consisting of containing an organic salt release Precursor.
The method of claim 1,
A precursor represented by the formula (1),
4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;
4-methoxycarbonyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;
4- [3,5-di (trifluoromethyl) phenyl] -3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;
4- (4-methoxyphenyl) -3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;
3-methyl-4-phenyl-1- (2-phenylethane-2-one-1-yl) -1,2,3-triazolium trifluoromethanesulfonate;
4-tert-butyl-3-methyl-1-[(phenylthio) methyl] -1,2,3-triazolium trifluoromethanesulfonate;
3-methyl-1-((2-naphthoxy) methyl) -4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
3-methyl-1- [3- (2-naphthoxy) -n -propyl] oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
1- [1-methylsulfonyloxy-3- (2-naphthyl) -2-oxypropyl] oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
3-methyl- (2-naphthyl) methyloxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
3-methyl-1-((2-naphthoxy) methyl) -4-phenylimidazolium trifluoromethanesulfonate;
(S) -1- (4- (2-BOC-amino-2- (t-butoxycarbonyl) ethyl) phenyloxymethyl) -4-phenyl-1,2,3-triazolium trifluoromethanesulfo Nate;
1- (4-biphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
1- (4-bromo-2-methylphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
1- (3,4-dimethoxyphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
3-methyl-1- (4-nitrophenyl) oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
1- (4-acetylaminophenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
1- (3- O -estronyl) methyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate; And
A precursor comprising a tetravalent organic salt leaving group, characterized in that it is selected from the group consisting of 3-acetonaphthyl-1-methylimidazolium.
As represented by Scheme 1 below,
Synthesizing an azido compound of formula 3 from the compound represented by formula 2 (step 1);
Synthesizing the compound of formula 5 through a [3 + 2] cycloaddition reaction between the azido compound of formula 3 obtained in step 1 and the alkyne compound represented by formula 4 (step 2);
Method of preparing a compound of formula 1-a comprising the step (step 3) of synthesizing the organic salt of formula 1-a using the alkylation reagent represented by formula 6 to the compound of formula 5 obtained in step 2.
[Reaction Scheme 1]

In Scheme 1, R ₁ , R ₂ , R ₃ and Y are as defined in claim 2, and Z is R ₄ SO ₃ ⁻ . Wherein R ₄ is a C ₁ -C ₂₀ hydrocarbon group where carbon in the main chain may be substituted or unsubstituted with oxygen, nitrogen, sulfur or a combination thereof, and hydrogen in the main chain may be substituted or unsubstituted with halogen.
As represented by Scheme 2 below,
Synthesizing the compound of Formula 5 through a nucleophilic substitution reaction between the compound represented by Formula 7 and the compound represented by Formula 8 (step 1); And
Method for preparing a compound of formula 1-b comprising the step (step 2) of synthesizing the organic salt of formula 1-b by using the alkylation reagent represented by formula 6 to the compound of formula 5 obtained in step 1.

[Reaction Scheme 2]

In Scheme 2, R ₁ , R ₂ , R ₃ , A, B, C, D, E, X, Y and n are as defined in claim 2, Z is as defined in claim 6.
As represented by Scheme 3 below,
A method for preparing a compound of Formula 1-b, comprising the step (step 1) of synthesizing a compound of Formula 1-b through a nucleophilic substitution reaction between a compound represented by Formula 7 and a compound represented by Formula 9.

[Reaction Scheme 3]

In Scheme 3, R ₁ , R ₂ , R ₃ , A, B, C, D, E, X, Y and n are as defined in claim 2, Z is as defined in claim 6.
As represented by Scheme 4 below,
A method for preparing a compound of Formula 1-b comprising the step of synthesizing the compound of Formula 1-b through a nucleophilic substitution reaction between the compound represented by Formula 10 and the compound represented by Formula 11.

[Reaction Scheme 4]

In Scheme 4, R ₁ , R ₂ , R ₃ , A, B, C, D, E, X, Y and n are as defined in claim 2.
As shown in Scheme 5,
A method for producing an ¹⁸ F-labeled compound comprising reacting a compound comprising a tetravalent organic salt leaving group represented by Formula 1 with a fluorine salt represented by Formula MF.
Scheme 5

In Scheme 5, R ₁ , X and leaving groups are as defined in claim 1,
M is a metal cation selected from the group consisting of Li, Na, K, Rb and Cs; Tetravalent ammonium cation; Or a tetravalent phosphonium cation,
F is ¹⁸ F.
¹⁸ F-labeled compound synthesized from a precursor comprising a tetravalent organic salt leaving group represented by the formula (1).

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