KR101214942B1

KR101214942B1 - Sulfonate precursors having 1,2,3-triazole groups, preparation and application thereof

Info

Publication number: KR101214942B1
Application number: KR1020100050565A
Authority: KR
Inventors: 지대윤; 이병세; 권혜림; 추소영
Original assignee: 서강대학교산학협력단
Priority date: 2010-05-28
Filing date: 2010-05-28
Publication date: 2012-12-26
Also published as: KR20110130977A

Abstract

The present invention relates to a sulfonate precursor having a 1,2,3-triazole group, a method for producing the same, and an application thereof, which induces an intramolecular nucleophilic substitution reaction and thus speeds up the reaction. , 2,3-triazole can be easily introduced by the alkoxy / azide [3 + 2] ring reaction under the representative click chemistry, copper-catalyst, and is the most important for Positron Emission Tomography [ ¹⁸ F] can be applied as an effective sulfonate precursor for the manufacture of radiopharmaceuticals.

Description

Sulfonate precursor having 1,2,3-triazole group, preparation method thereof and application thereof {Sulfonate precursors having 1,2,3-triazole groups, preparation and application}

The present invention relates to sulfonate precursors having 1,2,3-triazole groups, methods for their preparation and applications thereof.

Nucleophilic substitution reaction is one of the most widely used organic chemistry reactions in organic chemistry, and is an important reaction for introducing various functional groups and constructing an organic compound skeleton (AR Katritzky, Chem . Soc . Rev. , 19, 83-105, 1990; SR Hartshorn, Cambridge University Press: Cambridge, 1973). Among these, heterogeneous nucleophilic substitution reaction using a solid nucleophile requires a catalyst that induces phase transition between the solid-liquid phase to increase not only the solubility of the nucleophile but also the reactivity (CM Starks, J. Am . Chem . Soc, 93 (1), 195-199, 1971;. M. Makosza, Pure Appl . Chem . , 72 (7), 1399-1403, 2000; AW Herriott, J. Am . Chem . Soc . , 97 (9), 2345-2349, 1975). Typical phase transfer catalysts used are neutral multidentates consisting of polyethers, crown ethers, aminopolyethers, cryptands and kryptofixes [2.2.2] (kryptofix [2.2.2]). And ionic compounds of tetraalkylammonium salts and tetraalkylphosphonium salts. Recently, it has been reported that new types of ionic liquids present as liquids at room temperature act as phase transfer catalysts (DW Kim, J. Am . Chem . Soc . 124, 10278-10279, 2002; YR Jorapur, Bull. Korean Chem . Soc . 27 (3), 345-353, 2006).

Most nucleophilic substitution reactions, including nucleophilic halogenation reactions, are commercially available or can be used to obtain sufficiently desired results using the phase transfer catalysts studied. However, nucleophilic fluorination reactions require high temperatures and long reaction times due to the low reactivity of the fluoride ions. In addition, due to the basicity of the fluoride olefin compound due to the E2 removal reaction in the nucleophilic fluorination reaction is obtained as the main by-product, in the case of a compound having a steric hindrance is characterized in that the production of the olefin compound is increased. In particular, the most widely studied and applied [ ¹⁸ F] radioactive tracers in nuclear medicine molecular imaging technology, Positron Emission Tomography, have been developed through nucleophilic aliphatic [ ¹⁸ F] fluorination reactions. (PW Miller, Angew. Chem. Int. Ed ., 47, 8998-9033, 2008; SM Ametamey, Chem. Rev. , 108, 1501-1516, 2008; D. Le Bars, J. Fluorine Chem , 127, 1488-1493, 2006; ME Phelps, Proc. Natl. Acad. Sci . USA , 97, 9226-9233, 2000). The positron emitting isotope ¹⁸ F used above has a half-life of 110 minutes and is very expensive to produce, so it should be synthesized in high yield as soon as possible.

In general, the nucleophilic fluorination reaction was carried out in a polar anhydrous aprotic solvent, in which an amount of the olefin byproduct is formed. On the contrary, the nucleophilic fluorination reaction in primary protic solvents such as methanol and ethanol is significantly reduced in reactivity due to strong hydrogen bonds between protons and fluoride ions in the alcohol solvent, so that the fluorination reaction does not proceed well. However, in tertiary alcohol solvents having a large steric hindrance and relatively nonpolar tertiary alcohols, the hydrogen bond between the fluoride ion and the proton of the solvent is weak, so that the nucleophilicity of the fluoride ion is maintained, and the basicity is greatly reduced (DW Kim, J.). .. Am Chem Soc 126, 16394 , 2006;.. WO 2006/065038 A1). Thus, the tertiary alcohol solvent has the advantage of increasing the reaction selectivity of the nucleophilic fluorination reaction but has a disadvantage that the reaction rate is slower than the fluorination reaction in the conventional polar aprotic solvent. Hybrid molecules have been studied to compensate for this drawback, and as a result ionic liquids having imidazolium-based tertiary alcohol functional groups have been reported (SS Shinde, Tetrahedron Lett . 50, 6654-6657, 2009; SS Shinde, Org . Lett ., 10, 733-735, 2008). The imidazolium-based ionic liquid showed much faster reactivity than the reaction in heterogeneous nucleophilic fluorination reaction using cesium fluoride (CsF). The synergistic effect was greater than the sum of the reactivity in the ionic liquid or tertiary alcohol solvent. In addition, the nucleophilic fluorination reaction of the imidazolium-based ionic liquid effectively inhibited the formation of olefins in acetonitrile solvent, which is a polar aprotic solvent.

Another subject of the nucleophilic [ ¹⁸ F] fluorination reaction is the fast and high purity separation of the product after the reaction. Typically, radioactive isotopes, F-18, are used in trace amounts and sulfonate precursors to label F-18 are used in relatively high amounts. In addition, the nucleophilic [ ¹⁸ F] fluorination reaction is characterized in that the reaction is required to add an excess of base, unlike the general nucleophilic substitution reaction using F-19. Due to the use of such excess sulfonate precursors and bases, many by-products are made that contain excess sulfonate precursor that remains unreacted in addition to the desired F-18 labeled product after the reaction. In general, the F-18 label product is separated by HPLC, and the byproducts make the separation of the F-18 label product difficult and take a long time.

In order to effectively remove the byproducts and the remaining precursors after the reaction, several methods have been developed that modify the leaving groups of the precursor sulfonate precursors to facilitate separation after the reaction.

First, studies have been reported to synthesize perfluoroalkane sulfonate precursors supported on a polymer using a non-insoluble polymer having a sulfonyl chloride functional group, and easily remove it by filtration after the reaction (WO 2005/012319 A1; L, J. Brown, Angew . Chem . Int . Ed . 46, 941-944, 2007). However, the insoluble polymer having the perfluoroalkane sulfonyl chloride functional group is very complicated to manufacture, and the analytical data of each step of the polymer is insignificant, making it difficult to reproduce. After the reaction, most of the compounds fall into the solution phase due to side reactions. Contrary to purpose, there is little effect on compound separation.

In addition, the synthesis and nucleophilic [ ¹⁸ F] fluorination reactions of sulfonate precursors having perfluoroalkyl groups attached to leaving groups using the large lipophilic properties of perfluoroalkyl groups have been reported (R. Bejot, Angew . Chem . Int . Ed . 48, 586-589, 2009). However, the reaction must be followed by a very complex multi-phase solid phase extraction to remove the perfluoro compounds, including precursors, after the reaction, which in turn leads to lower radiochemical yields and more production time. Lengthen.

Thus, the present inventors have been studying how to increase the nucleophilic [ ¹⁸ F] fluorination reactivity and effectively remove the by-products and the remaining precursors after the reaction, alkyne / azide under copper-catalyst, one of the click chemistry [ 3 + 2] ring reaction to prepare a new sulfonate compound having 1,2,3-triazole group, the sulfonate compound exhibits a high nucleophilic [ ¹⁸ F] fluorinated reactivity in the molecule, There is no need to use an additional phase transfer catalyst, and there is an advantage of easy separation of the product after the reaction, confirming that when used as a precursor for F-18 labeling, it is possible to provide a high yield of product in a short time and complete the present invention. It was.

An object of the present invention is to provide a sulfonate precursor having a 1,2,3-triazole group.

Another object of the present invention to provide a method for producing a sulfonate precursor having the 1,2,3-triazole group.

Another object of the present invention is to provide a nucleophilic fluorination reaction using the sulfonate precursor having the 1,2,3-triazole group.

Still another object of the present invention is to provide a method for labeling radioisotopes using the sulfonate compound precursor having the 1,2,3-triazole group.

In order to achieve the above object, the present invention provides a sulfonate compound having a 1,2,3-triazole group represented by the following formula (1).

[Formula 1]

(Wherein R ¹ , R ² and n are as defined herein).

The present invention also provides a method for producing a sulfonate compound having the 1,2,3-triazole group.

Furthermore, the present invention provides a nucleophilic fluorination reaction using the sulfonate compound having the 1,2,3-triazole group.

Furthermore, the present invention provides a method for labeling a radioisotope using the sulfonate compound precursor having the 1,2,3-triazole group.

1,2,3-triazole group included in the sulfonate precursor according to the present invention is located in the leaving group of the compound to form an intermediate that interacts with the metal salt to effect the reaction faster to induce nucleophilic substitution reaction in the molecule The cost of the expensive phase transfer catalyst is reduced because there is no need to use an additional phase transfer catalyst during the reaction, and there is no need to use a phase transfer catalyst that is difficult to separate after the reaction. When used as a precursor for ¹⁸ F label can provide a high yield of product in a short time can be useful for the production of radiopharmaceutical [ ¹⁸ F].

1 is a diagram showing an intramolecular nucleophilic substitution reaction using a compound of the present invention as a precursor.
Figure 2 is an HPLC analysis graph showing the reactivity according to the acetonitrile solvent of the compound according to the embodiment of the present invention.
Figure 3 is an HPLC analysis graph showing the reactivity according to the t- butanol solvent of the compound according to the embodiment of the present invention.
4 is an HPLC analysis graph showing the reactivity according to the presence or absence of an ionic liquid of a compound according to an embodiment of the present invention.
5 is an HPLC analysis graph showing the reactivity of various metal fluoride salts of a compound according to an embodiment of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention provides a sulfonate compound having a 1,2,3-triazole group represented by the following formula (1).

In Formula 1,

R ¹ is hydrogen; C ₁ -C ₁₀ straight or branched chain alkyl unsubstituted or substituted with hydroxy; C ₅ -C ₁₀ aryl C ₁ -C ₁₀ alkyl; Or C ₁ -C ₁₀ alkoxy,

R ² is a compound having a structure or a protecting group other than ¹⁸ F in the [ ¹⁸ F] radiopharmaceutical structure used for positron emission tomography,

n is an integer of 1 to 5;

Preferably,

R ¹ is hydrogen; Hydroxymethyl; t -butyl; 2-hydroxy-isopropyl; Phenyl or benzyloxymethyl,

R ² is

,

And

Is selected from the group consisting of

n is an integer of 1 to 3;

In more detail, the sulfonate compound having the 1,2,3-triazole group of Chemical Formula 1 according to the present invention is as follows.

(1) 3- (2-naphthoxy) propyl 3- (4- (hydroxymethyl) -1 H -1,2,3-triazol-1-yl) propane sulfonate;

(2) 3- (2-naphthoxy) propyl 3- (4- (benzyloxymethyl) -1 H -1,2,3-triazol-1-yl) propane sulfonate;

(3) 3- (2-naphthoxy) propyl 3- (4- (trimethylsilyl) -1 H -1,2,3-triazol-1-yl) propane sulfonate;

(4) 3- (2-naphthoxy) propyl 3- ( 1H -1,2,3-triazol-1-yl) propane sulfonate;

(5) 3- (2-naphthoxy) propyl 3- (4- (1-hydroxy-1-methyl) ethyl-1 H -1,2,3-triazol-1-yl) propane sulfonate;

(6) 3- (2-naphthoxy) propyl 3- (4-phenyl-1 H -1,2,3-triazol-1-yl) propane sulfonate;

(7) tris N, N, N- (1- (3- (3- (2-naphthoxy) propoxy) sulfonyl) propyl-1,2,3-triazol-4-yl) methylamine;

(8) E- (2- (2- (2- (4- (4- ( tert -butoxycarbonyl (methyl) amino) styryl) phenoxy) ethoxy) ethoxy) ethoxy) ethyl 3- (4-phenyl-1 H -1,2,3-triazol-1-yl) propane sulfonate;

(9) tert -butyl 3-((2R, 4R, 5R) -4- (3- (4-benzyloxymethyl) -1 H -1,2,3-triazol-1yl) propylsulfonyloxy) 5- (trityl oxy methyl) tetrahydrofuran-2-yl) -5-methyl-2,6-dioxo-2,3-dihydro-pyrimidin--1 (6 H) - carboxylate; And

(10) (2,2,7,7-tetramethyltetrahydro-3a H -bis [1,3] dioxolo [4,5-b: 4 ', 5'-d] pyran-5yl) methyl 3 -(4- (benzyloxymethyl) -1 H -1,2,3-triazol-1 yl) propane sulfonate.

The structural formulas of the above compounds are summarized in Table 1 below.

compound
constitutional formula compound
constitutional formula
One

6

2

7

3

8
4

9

5

10

The present invention also provides a method for producing a sulfonate compound having a 1,2,3-triazole group.

Specifically, the method for preparing a sulfonate compound having a 1,2,3-triazole group according to the present invention is an aliphatic alcohol represented by azido alkanesulfonyl chloride represented by the formula (3) and the formula (4), as shown in Scheme 1 below. Reacting the compound having a functional group under an organic solvent and a base to obtain an azidoalkane sulfonate compound represented by Chemical Formula 5 (step 1); And

1,2,3-triazole sulfonate of Chemical Formula 1 by reacting azido alkane sulfonate represented by Chemical Formula 5 prepared in step 1 with a compound having a terminal alkyn functional group represented by Chemical Formula 6 under an organic solvent and a copper catalyst Obtaining (step 2).

[Reaction Scheme 1]

(R ¹ , R ² in the scheme And n is as defined in Formula 1.

In the method for preparing a sulfonate compound having a 1,2,3-triazole group of the present invention, the step 1 is azido alkanesulfonyl chloride represented by the formula (3) and the primary, secondary or 3 represented by the formula (4) A sulfonylation reaction of a compound having a primary aliphatic alcohol functional group under an organic solvent and a base is carried out to obtain an azido alkane sulfonate compound represented by the formula (5). At this time, the organic solvent is tetrahydrofuran (THF), 1,4-dioxane (1,4-dioxane), dichloromethane (CH ₂ Cl ₂ ), chloroform (CHCl ₃ ), carbon tetrachloride (CCl ₄ ), 1,2 Dichloroethane (1,2-dichloroethane), benzene, toluene, acetonitrile, dimethylformamide (N, N-dimethylformamide, DMF), dimethyl sulfoxide (dimethylSO) can be used, preferably May use dichloromethane, chloroform or 1,2-dichloroethane. The base may be an alkali metal salt of bicarbonate ions or carbonate ions or an amine base of triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, preferably triethylamine or diisopropylethylamine Can be used.

Specifically, in step 1, the compounds of Formulas 3 and 4 are dissolved in dichloromethane, the reaction mixture is cooled to 0, triethylamine is slowly added, and then reacted at 0 for 30 minutes to obtain azidoalkane sulfonate compound of Formula 5 You can get it.

In the method for preparing a sulfonate compound having a 1,2,3-triazole group of the present invention, the step 2 is azido alkanes sulfonate represented by the formula (5) prepared in step 1 and the terminal alkyne represented by the formula (6) A compound having a functional group is reacted under an organic solvent and a copper catalyst to obtain 1,2,3-triazole sulfonate of Chemical Formula 1. At this time, the organic solvent is tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, Organic solvents such as isopropanol and t -butanol, water or a mixed solution of the organic solvent and water can be used, and preferably a mixed solvent of acetonitrile or dimethylformamide / water can be used.

The copper catalyst is a copper catalyst having an oxidation number of 1 consisting of copper iodide (CuI), copper bromide (CuBr), and copper chloride (CuCl), or copper sulfate (CuSO ₄ ), copper acetate (Cu (OAc) ₂ ), and copper nitrate ( A copper catalyst having an oxidation number of 2 consisting of Cu (NO 3) ₂ ), copper trifluoretasulfonate (Cu (OTf) ₂ ) and copper oxide (CuO) can be used. When using a copper catalyst having an oxidation number of 2, a reducing agent consisting of Na-ascorbate, sodium sulfite (Na ₂ SO ₃ ), dithiothreitol may be further used. Preferred copper catalysts may be copper iodide or copper sulfate / Na-ascorbate.

When using a copper catalyst having 1 oxidation number, the base is also added, and bicarbonate ions, alkali metal salts of carbonate ions or amine base triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, etc. may be used. Preferably triethylamine or diisopropylethylamine can be used.

Specifically, in step 2, each of the azide and alkyne compounds represented by Chemical Formulas 5 and 6 is dissolved in an acetonitrile solvent, iodine copper and triethylamine are added at room temperature, and then stirred at room temperature. A triazole sulfonate compound can be obtained.

Furthermore, the present invention provides a nucleophilic reaction using the sulfonate compound precursor having the 1,2,3-triazole group.

The 1,2,3-triazole sulfonate compounds of formula 1 according to the present invention can be used to prepare compounds of formula 7 by substitution reaction with nucleophiles in the form of various metal salts or organic salts as shown in FIG. 1. In Figure 1, the intermediate compound represented by Formula 2 represents a form in which 1,2,3-triazole interacts with a solid metal salt to form a cation, and the intramolecular nucleophilic substitution reaction is carried out through the structure of the intermediate. Try to get up quickly.

In this case, the metal cations corresponding to M of FIG. 1 include metal cations such as Li, Na, K, Rb, and Cs; Tetraalkylammonium cations each substituted with the same or different C ₁ -C ₈ alkyl group; Tetraalkylphosphonium cations each substituted with the same or different C ₁ -C ₈ alkyl group; 1,3-dialkylimidazolium each substituted with the same or different C ₁ -C ₈ alkyl group; N-alkyl pyridinium and the like each substituted with the same or different C ₁ to C ₈ alkyl group,

Nucleophiles corresponding to Nu include F, Cl, Br, I, hydroxide, alkoxide, acetate (OAc), nitrate (NO ₃ ), azide (N ₃ ), cyanide (CN), thiocyanate ( when the SCN), isothiocyanate (NCS) and the like, wherein Nu is F, wherein F can be a ¹⁸ F or ¹⁹ F.

Therefore, it is possible to take advantage of a nucleophilic substitution reaction with the sulfonate compound having a 1,2,3-triazol asleep according to the invention also to cover a radioisotope, such as ¹⁸ F.

Specifically, when a sulfonate compound having a 1,2,3-triazole group according to the present invention is used in a nucleophilic fluorination reaction, as shown in Scheme 2 below, a sulfo having a 1,2,3-triazole group of Formula 1 The F-labeled compound can be prepared by nucleophilic substitution reaction of the nate compound with fluoride in an organic solvent.

Scheme 2

(In Scheme 2, R ¹ , R ² , n are as defined in the specification, F is ¹⁸ F or ¹⁹ F)

In this case, the organic solvent may be selected from the group consisting of acetonitrile, t -butanol and t -amyl alcohol.

The ¹⁸ F labeling method using a sulfonate compound having 1,2,3-triazole groups can be carried out using a polymer cartridge, for example a [ ¹⁸ F] fluoride cartridge in a Chromafix ^® (PS-HCO ₃ ) cartridge. [ ¹⁸ F] fluoride is eluted to the reaction vessel using a TBAOMs methanol solution. The eluted solution is blown with nitrogen and heated to 100-120 to remove the solvent and water. Next, the precursor of Chemical Formula 1 and t -amyl alcohol are added to the reaction vessel, and the reaction mixture is stirred at 120 ° C. for 10 minutes and cooled to room temperature to obtain a compound labeled ¹⁸ F.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are not limited to the contents of the present invention by the following examples.

< Manufacturing example 1 > 2- (3- Hydroxypropoxy Production of Naphthalene 4a

2-naphthol (1.00 g, 6.94 mmol) was dissolved in dimethylformamide (15.0 mL), and then 3-bromo-1-propanol (0.690 mL, 7.63 mmol) was added to the reaction mixture at 80 ° C. for 15 hours. After stirring, water was added, and then the organic compound was extracted with ethyl acetate. The extracted ethyl acetate solution was treated with sodium sulfate and then subjected to column chromatography (40% ethyl acetate / n -hexane) to give the desired compound 2- (3-hydroxypropoxy) naphthalene ( 4a , 1.08 g, 77%) Got.

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.74 (br s, 1H), 2.12 (m, 2H), 3.92 (t, J = 6.0 Hz, 2H), 4.25 (t, J = 6.0 Hz, 2H), 6.16-7.13 (m, 2H), 7.34 (t, J = 7.0 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.72-7.76 (m, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 32.2, 60.8, 65.9, 106.9, 119.0, 123.9, 126.6, 126.9, 127.8, 129.2, 129.6, 134.7, 156.9.

< Manufacturing example 2> Benzyl Propazyl Preparation of Ether 6b

Anhydrous dimethylformamide (20.0 mL) was added to a reaction vessel containing 60% sodium hydride (702 mg, 17.7 mmol) under nitrogen, and propazyl alcohol ( 6a , 492 mg, 8.76 mmol) was added at 0 ° C. for 30 minutes. Stirred at ℃. Anhydrous dimethylformamide (10.0 mL) solution in which benzyl bromide (1.00 g, 5.84 mmol) was dissolved was slowly added to the reaction solution, stirred at room temperature from 0 ° C. for 3 hours, and 2N hydrochloric acid was added to terminate the reaction. The organic compound was extracted with ethyl acetate, and the extracted ethyl acetate solution was treated with sodium sulfate and subjected to column chromatography (3% ethyl acetate / n -hexane) to give the target compound benzyl propazyl ether ( 6b , 958 mg, 75). %) Was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.46 (t, J = 2.5 Hz, 1H), 4.17 (d, J = 2.5 Hz, 2H), 4.61 (s, 2H), 7.29-7.37 (m, 5H) ; ¹³ C NMR (125 MHz, CDCl ₃ ) δ 57.2, 71.7, 74.8, 79.8, 128.1, 128.3, 128.6, 137.4.

< Comparative example 1 > 2- (3- Methanesulfonoxypropoxy Production of naphthalene (7)

2- (3-hydroxypropoxy) naphthalene ( 4a , 700 mg, 3.46 mmol) obtained in Preparation Example 1 was dissolved in dichloromethane (10.0 mL), and then methanesulfonyl chloride (321 mL, 4.15 mmol) and tree Ethylamine (723 mL, 5.19 mmol) was added sequentially, followed by stirring at 0 ° C. for 1 hour. Water was added to terminate the reaction, and the organic compound was extracted with dichloromethane. The extracted dichloromethane solution was treated with sodium sulfate and then subjected to column chromatography (40% ethyl acetate / n -hexane) to give the desired compound 2- (3-methanesulfonoxypropoxy) naphthalene ( 7 , 873 mg, 90% )

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.30 (quintet, J = 6.0 Hz, 2H), 3.00 (s, 3H), 4.22 (t, J = 5.8 Hz, 2H), 4.50 (t, J = 6.0 Hz , 2H), 7.13-7.15 (m, 2H), 7.34-7.37 (m, 1H), 7.44-7.48 (m, 1H), 7.73-7.79 (m, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 29.2, 37.4, 63.3, 67.0, 106.8, 118.8, 124.0, 126.7, 126.9, 127.8, 129.2, 129.7, 134.6, 156.6.

< Comparative example 2> 2- (3- Propanesulfoneoxypropoxy Production of naphthalene (8)

Comparative Example 1, except that 2- (3-methanesulfonoxypropoxy) naphthalene ( 4a , 500 mg, 2.47 mmol) and propanesulfonyl chloride (303 mL, 2.72 mmol) obtained in Preparation Example 1 were used. In the same manner as in the title compound 2- (3-propanesulfonoxypropoxy) naphthalene ( 8 , 714 mg, 94%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.00 (t, J = 7.4 Hz, 3H), 1.82-1.91 (m, 2H), 2.28 (quintet, J = 6.0 Hz, 2H), 3.04-3.08 (m, 2H), 4.21 (t, J = 6.0 Hz, 2H), 4.47 (t, J = 6.2 Hz, 2H), 7.12-7.14 (m, 2H), 7.32-7.34 (m, 1H), 7.42-7.46 (m , 1H), 7.71-7.77 (m, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 13.0, 17.4, 29.4, 52.1, 63.4, 66.5, 106.9, 118.8, 124.0, 126.6, 126.9, 127.8, 129.2, 129.7, 134.6, 156.6.

< Example 1>

Step 1: 2- [3- (3- Azapropane sulfonoxy ) Propoxy ] Manufacture of Naphthalene (5a)

Except for using the compound 2- (3-methanesulfonoxypropoxy) naphthalene ( 4a , 200 mg, 0.99 mmol) and 3-azidosulfonyl chloride (200 mg, 1.09 mmol) obtained in Preparation Example 1 above. The same method as in Comparative Example 1 was carried out to obtain the title compound 2- [3- (3-azidopropanesulfonoxy) propoxy] naphthalene ( 5a , 342 mg, 98%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.07 (quintet, J = 6.8 Hz, 2H), 2.31 (quintet, J = 5.9 Hz, 2H), 3.19 (t, J = 7.3 Hz, 2H), 3.41 (t , J = 6.3 Hz, 2H), 4.22 (t, J = 5.8 Hz, 2H), 4.51 (t, J = 6.0 Hz, 2H), 7.15-7.16 (m, 2H), 7.37 (t, J = 7.5 Hz , 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.74-7.80 (m, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 23.6, 29.3, 47.4, 49.3, 63.3, 67.0, 106.8, 118.8, 124.0, 126.7, 126.9, 127.8, 129.2, 129.7, 134.6, 156.5.

Step 2: 3- (2- Naphthoxy ) Propyl [3-[(4- Hydroxymethyl ) -1,2,3- Triazole -1-yl] propane] Sulfonate Preparation of (1a)

Propazyl alcohol ( 6a , 17.7 mg, 0.315 mmol) and compound 2- [3- (3-azidopropanesulfonoxy) propoxy] naphthalene ( 5a , 100 mg, 0.286 mmol) obtained in step 1 of Example 1 above To dimenylformamide (2.00 mL) was added, the solution was then added 0.2 M copper sulfate (0.29 mL, 0.057 mmol) and 0.2 M sodium-ascorbate (0.57 mL, 0.114 mmol). After the reaction mixture was stirred at room temperature for 2 hours, water was added and the organic compound was extracted with ethyl acetate. The extracted ethyl acetate solution was washed with an aqueous ammonium chloride solution, treated with sodium sulfate, and subjected to column chromatography (50% ethyl acetate / n -hexane) to give the title compound 3- (2-naphthoxy) propyl [3-[( 4-hydroxymethyl) -1,2,3-triazol-1-yl] propane] sulfonate ( 1a , 59 mg, 51%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.28 (quintet, J = 6.0 Hz, 2H), 2.42 (quintet, J = 6.9 Hz, 2H), 2.65 (br s, 1H), 3.11 (t, J = 7.3 Hz, 2H), 4.20 (t, J = 5.8 Hz, 2H), 4.42 (t, J = 6.8 Hz, 2H), 4.49 (t, J = 6.0 Hz, 2H), 4.72 (s, 2H), 7.11- 7.13 (m, 2H), 7.35 (td, J = 8.0 Hz, 1.0 Hz, 1H), 7.41 (s, 1H), 7.45 (td, J = 8.3 Hz, 1.3 Hz, 1H), 7.72-7.77 (m, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 24.6, 29.2, 46.9, 47.9, 56.5, 63.3, 67.3, 106.9, 118.8, 122.4, 124.1, 126.7, 126.9, 127.8, 129.2, 129.8, 134.6, 148.1, 156.5.

< Example 2 > 3- (2- Naphthoxy ) Propyl [3-[(4- Benzyloxymethyl ) -1,2,3- Triazole -1-yl] propane] Sulfonate Preparation of (1b)

Benzyl propazyl ether ( 6b , 150 mg, 1.02 mmol) which is a compound obtained in Preparation Example 2, and compound 2- [3- (3-azidopropanesulfonoxy) propoxy] naphthalene obtained in step 1 of Example 1 5a , 325 mg, 0.93 mmol) was subjected to the same method as Step 2 of Example 1, except that Compound 3 (2-naphthoxy) propyl [3-[(4-benzyloxymethyl) was obtained. -1,2,3-triazol-1-yl] propane] sulfonate ( 1b , 408 mg, 89%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.27 (quintet, J = 5.9 Hz, 2H), 2.42 (quintet, J = 6.9 Hz, 2H), 3.11 (t, J = 7.0 Hz, 2H), 4.19 (t , J = 6.0 Hz, 2H), 4.42 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.3 Hz, 2H), 4.59 (s, 2H), 4.63 (s, 2H), 7.10-7.13 (m, 2H), 7.28-7.31 (m, 1H), 7.32-7.35 (m, 4H), 7.44 (td, J = 8.3 Hz, 1.3 Hz, 1H), 7.46 (s, 1H), 7.71-7.76 ( m, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 0.17, 24.6, 29.2, 47.0, 47.8, 63.3, 63.7, 67.3, 72.8, 104.9, 106.8, 118.8, 123.2, 124.0, 126.7, 126.9, 127.8, 128.0, 128.1, 128.6 , 129.2, 129.8, 134.6, 137.9, 145.7, 156.5.

< Example 3 > 3- (2- Naphthoxy ) Propyl [3-[(4- Trimethylsilyl ) -1,2,3- Triazole -1-yl] propane] Of sulfonate (1c) Produce

Trimethylsilyl acetylene (124 mg, 1.26 mmol) and compound 2- [3- (3-azidopropanesulfonoxy) propoxy] naphthalene ( 5a , 400 mg, 1.14 mmol) obtained in Step 1 of Example 1 were used. The target compound 3- (2-naphthoxy) propyl [3-[(4-trimethylsilyl) -1,2,3-triazole-1 was carried out in the same manner as in Step 2 of Example 1, except that -Yl] propane] sulfonate ( 1c , 47%, 240 mg) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 0.31 (s, 9H), 2.29 (quintet, J = 5.9 Hz, 2H), 2.44 (quintet, J = 6.9 Hz, 2H), 3.14 (t, J = 7.0 Hz , 2H), 4.16 (t, J = 6.0 Hz, 2H), 4.45-4.51 (m, 4H), 7.11-7.14 (m, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.43-7.47 ( m, 2H), 7.72-7.77 (m, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) d -0.97, 24.8, 29.3, 47.1, 47.3, 63.3, 67.3, 106.9, 118.8, 124.0, 126.7, 126.9, 127.8, 129.2, 129.6, 129.8, 134.6, 147.1, 156.5.

< Example 4> 3- (2- Naphthoxy ) Propyl 3-[(1,2,3- Triazole -1-yl) propane] Sulfonate Preparation of (1d)

Methanol (3.00 mL) in which the compound [3-[(4-trimethylsilyl) -1,2,3-triazol-1-yl] propane] sulfonate ( 1c , 230 mg, 0.514 mmol) prepared in Example 3 was dissolved. Potassium fluoride (45 mg, 0.77 mmol) was added to the solution, followed by stirring at 50 ° C. for 4 hours. After completion of the reaction by addition of water, the organic compound was extracted with ethyl acetate, and the extracted ethyl acetate solution was treated with sodium sulfate and subjected to column chromatography (80% ethyl acetate / n -hexane) to give the title compound 3- (2-naphthoxy) propyl 3-[(1,2,3-triazol-1-yl) propane] sulfonate ( 1d , 23%, 86 mg) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.28 (quintet, J = 6.0 Hz, 2H), 2.44 (quintet, J = 6.9 Hz, 2H), 3.10 (t, J = 7.3 Hz, 2H), 4.20 (t , J = 5.8 Hz, 2H), 4.47-4.50 (m, 4H), 7.11-7.13 (m, 2H), 7.33-7.37 (m, 1H), 7.43-7.45 (m, 2H), 7.65 (s, 1H ), 7.72-7.78 (m, 3 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 24.7, 29.2, 46.9, 47.7, 63.3, 67.3, 106.8, 118.8, 124.1, 124.1, 126.7, 126.9, 127.8, 129.2, 129.8, 134.2, 134.6, 156.5.

< Example 5 > 3- (2- Naphthoxy ) Propyl [3-[[4- (1-hydroxy-1- methyl ) Ethyl] -1,2,3- Triazole -1-yl] propane] Of sulfonate (1e) Produce

2-methyl-3-butyn-2-ol (26.4 mg, 0.315 mmol) and the compound 2- [3- (3-azidopropanesulfonoxy) propoxy] naphthalene ( 5a , obtained in Step 1 of Example 1 above) 100 mg, 0.286 mmol) was subjected to the same method as in Step 2 of Example 1, except that Compound 3 (2-naphthoxy) propyl [3-[[4- (1-hydroxy-) 1-methyl) ethyl] -1,2,3-triazol-1-yl] propane] sulfonate ( 1e , 75%, 192 mg) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.61 (s, 6H), 2.29 (quintet, J = 5.9 Hz, 2H), 2.43 (quintet, J = 7.0 Hz, 2H), 3.14 (t, J = 7.0 Hz , 2H), 4.21 (t, J = 6.0 Hz, 2H), 4.41 (t, J = 6.8 Hz, 2H), 4.50 (t, J = 6.3 Hz, 2H), 7.11-7.14 (m, 2H), 7.35 (t, J = 7.8 Hz, 1H), 7.38 (s, 1H), 7.45 (t, J = 7.3 Hz, 1H), 7.72-7.78 (m, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 24.6, 29.2, 30.6, 47.1, 47.8, 63.3, 67.3, 68.7, 106.9, 118.8, 119.8, 124.1, 126.7, 126.9, 127.8, 129.2, 129.8, 134.6, 156.0, 156.5 .

< Example 6> 3- (2- Naphthoxy ) Propyl [3- (4- Phenyl -1,2,3- Triazole -1-yl) propane] Of sulfonate (1f) Produce

Using phenylacetylene (34.5 mg, 0.315 mmol) and compound 2- [3- (3-azidopropanesulfonoxy) propoxy] naphthalene ( 5a , 100 mg, 0.286 mmol) obtained in step 1 of Example 1 above Except for the same method as Step 2 of Example 1, except that the target compound 3- (2-naphthoxy) propyl [3- (4-phenyl-1,2,3-triazol-1-yl) propane ] Sulfonate ( 1f , 89%, 408 mg).

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.29 (quintet, J = 6.0 Hz, 2H), 2.49 (quintet, J = 6.9 Hz, 2H), 3.16 (t, J = 7.0 Hz, 2H), 4.20 (t , J = 5.8 Hz, 2H), 4.49-4.51 (m, 4H), 7.10-7.13 (m, 2H), 7.32-7.36 (m, 2H), 7.41-7.45 (m, 3H), 7.68 (s, 1H) ), 7.70-7.75 (m, 2 H), 7.76-7.79 (m, 2 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 24.6, 29.2, 46.9, 47.9, 63.3, 67.4, 106.8, 118.8, 120.3, 124.0, 125.9, 126.7, 126.9, 127.8, 128.5, 129.1, 129.2, 129.8, 130.4, 134.6 , 148.2, 156.5.

< Example 7> Tris N, N, N-[[1- [3- [3- (2- Naphthoxy ) Propoxy ] Sulfonylpropyl ] -1,2,3- Triazole -4 days] methyl ] Preparation of Amine (1 g)

Tripropazylamine (161 mL, 1.12 mmol) and compound 2- [3- (3-azidopropanesulfonoxy) propoxy] naphthalene ( 5a , 1.30 g, 3.72 mmol) obtained in Step 1 of Example 1 were prepared. The target compound Tris N, N, N-[[1- [3- [3- (2-naphthoxy) propoxy] sulfonylpropyl was carried out in the same manner as in Step 2 of Example 1, except that it was used. ] -1,2,3-triazol-4yl] methyl] amine ( 1 g , 55%, 720 mg) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.25-2.29 (m, 6H), 2.39-2.43 (m, 6H), 3.12 (t, J = 7.0 Hz, 6H), 3.71 (s, 6H), 4.19 ( t, J = 5.8 Hz, 6H), 4.40-4.44 (m, 6H), 4.49 (t, J = 6.0 Hz, 6H), 7.12-7.14 (m, 6H), 7.35 (t, J = 7.5 Hz, 3H ), 7.44 (t, J = 7.5 Hz, 3H), 7.65 (s, 3H), 7.72-7.77 (m, 9H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 24.9, 2.5, 47.3, 37.7, 48.1, 63.6, 67.7, 107.1, 119.0, 124.3, 124.5, 127.0, 127.2, 128.1, 129.5, 130.0, 134.8, 144.7, 156.8

< Example 8>

Step 1: E- (2- (2- (2- (4- (4- ( tert - Butoxycarbonyl (methyl) amino ) Styryl ) Phenoxy ) Ethoxy ) Ethoxy ) Ethoxy Ethyl 3- Azaidopropane -One- Of sulfonate (5b) Produce

Compound (E) -tert -butyl-4- (4- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) styryl) phenyl (methyl) carbamate ( 4b , 150 mg, 0.379 mmol) and 3-azidopropanesulfonylchloride ( 3a, 76.6 mg, 0.415 mmol) were prepared in the same manner as in Comparative Example 2 to obtain the target compound E- (2- (2- (2- ( 4- (4- ( tert -butoxycarbonyl (methyl) amino) styryl) phenoxy) ethoxy) ethoxy) ethoxy) ethyl 3-azidopropanesulfonate ( 5b , 89%, 177 mg) Got it.

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.46 (s, 9H), 2.10 (quintet, J = 6.88 Hz, 2H), 3.24-3.27 (m, 5H), 3.47 (t, J = 6.5 Hz, 2H) , 3.69-3.74 (m, 4H), 3.74-3.76 (m, 2H), 3.86 (t, J = 4.8 Hz, 2H), 4.15 (t, J = 9.0 Hz, 2H), 4.37-4.39 (m, 2H) ), 6.91 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 16.5 Hz, 1H), 7.01 (d, J = 16.5 Hz, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 7.5 Hz, 4H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 23.7, 28.5, 37.4, 47.7, 49.5, 67.7, 69.2, 69.4, 70.0, 70.8, 70.9, 71.0, 80.5, 115.0, 125.7, 126.3, 126.5, 127.9, 128.1, 130.6 , 134.8, 143.0, 154.9, 158.6.

Step 2: Preparation of Compound 1h

Except for using the compound benzyl propazyl alcohol ( 6b , 79.7mg, 0.546mmol) obtained in Preparation Example 2 and the compound 5b (300mg, 0.496mmol) obtained in step 1 was carried out in the same manner as in step 2 The target compound 1h (82%, 307 mg) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.46 (s, 9H), 2.47 (quintet, J = 6.9 Hz, 2H), 3.20 (t, J = 7.25 Hz, 2H), 3.27 (s, 3H), 3.66 -3.71 (m, 4H), 3.73-3.75 (m, 2H), 3.82 (t, J = 4.5 Hz, 2H), 4.12 (t, J = 4.5 Hz, 2H), 4.36-4.38 (m, H), 4.50 (t, J = 6.8 Hz, 2H), 4.60 (s, 2H), 4.67 (s, 2H), 6.88 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 16.5 Hz, 1H), 7.00 (d, J = 16.0 Hz, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.28-7.30 (m, 1H), 7.32-7.36 (m, 4H), 7.41-7.44 (m, 4H) , 7.58 (s, 1 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 24.7, 28.5, 37.4, 47.3, 47.9, 63.8, 67.7, 69.1, 69.8, 69.9, 70.8, 70.9, 72.8, 80.5, 115.0, 123.3, 125.7, 126.3, 126.5, 127.9 , 128.0, 128.0, 128.1, 128.6, 130.6, 134.8, 138.0, 143.0, 145.6, 154.9, 158.5.

< Example 9>

Step 1: Preparation of Compound 5d

Step 1-A: Preparation of Compound 5c

Compound 4c (300 mg, 0.584 mmol) and 3-azidosulfonylchloride ( 3a , 118 mg, 0.643 mmol) were dissolved in pyridine (6.00 mL) and silver (I) trifluoromethane sulfonate (0.159 mL, 0.0.584 mmol) ) Was added and stirred overnight from 0 ° C to room temperature. After completion of the reaction by adding water, the organic compound was extracted with ethyl acetate, washed with 2N hydrochloric acid, treated with sodium sulfate, and subjected to column chromatography (40% ethyl acetate / n -hexane) to give the title compound 5c (365). mg, 99%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.71-1.92 (m, 5H), 2.43-2.53 (m, 1H), 2.73-3.10 (m, 3H), 3.28-3.39 (m, 3H), 3.60-3.68 (m, 1H), 4.18-4.26 (m, 1H), 5.28 (t, J = 3.8 Hz, 1H), 6.25-6.30 (m, 1H), 7.24-7.38 (m, 10H), 7.40-7.46 (m , 6H), 9.19 (s, 1 H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 12.5, 23.1, 39.6, 48.6, 48.9, 61.3, 78.6, 81.2, 83.8, 87.5, 111.2, 127.5, 128.0, 128.6, 135.1, 143.2, 150.5, 163.7.

Step 1-B: Preparation of Compound 5d

Compound 5c (218 mg, 0.345 mmol) prepared in step 1 was dissolved in tetrahydrofuran (3.00 mL), and N, N-dimethylaminopyridine (54.9 mg, 0.449 mmol) and di- t -butyldicarbonate (90.3 mg, 0.414 mmol) was added at 0 ° C and then stirred for 1 hour. After completion of the reaction by adding water, the organic compound was extracted with ethyl acetate, treated with sodium sulfate, and subjected to column chromatography (40% ethyl acetate / n -hexane) to obtain the title compound 5d (250 mg, 99%).

¹ H NMR (200 MHz, CDCl ₃ ) d 1.60 (s, 9H), 1.68-1.90 (m, 5H), 2.43-2.53 (m, 1H), 2.71-3.06 (m, 3H), 3.28-3.39 (m , 3H), 3.59-3.67 (m, 1H), 4.20-4.27 (m, 1H), 5.28-5.42 (m, 1H), 6.23 (dd, J = 7.7 Hz, 2.9 Hz, 1H), 7.20-7.37 ( m, 10H), 7.42-7.45 (m, 6H); ¹³ C NMR (50 MHz, CDCl ₃ ) d 12.5, 23.1, 27.4, 39.6, 48.5, 48.9, 61.4, 78.6, 81.4, 84.2, 86.9, 87.5, 110.8, 127.5, 128.0, 128.6, 134.5, 143.2, 147.8, 148.5 , 161.1.

Step 2: Preparation of Compound 1i

Step 2 of Example 1, except that compound 5d (252 mg, 0.343 mmol) prepared in Step 1 and the benzyl propazyl ether ( 6b , 55.1 mg, 0.377 mmol) obtained in Preparation Example 2 were used. In the same manner as the target compound 1i (235 mg, 78%) was obtained.

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.60 (s, 9H), 1.76 (s, 3H), 2.23 (quintet, J = 6.3 Hz, 2H), 2.47 (dd, J = 15.5 Hz, 2.0 Hz, 1H ), 2.73-2.79 (m, 1H), 2.85-2.97 m, 2H), 3.36 (dd, J = 10.0 Hz, 1.0 Hz, 1H), 3.62 (dd, J = 10.0 Hz, 1.0 Hz, 1H), 4.18 -4.21 (m, 1H), 4.34 (t, J = 6.5 Hz, 2H), 4.61 (s, 2H), 4.66 (s, 2H), 5.24 (t, J = 2.5 Hz, 1H), 6.20 (dd, J = 7.8 Hz, 3.3 Hz, 1H), 7.25-7.36 (m, 15H), 7.35-7.41 (m, 6H), 7.48 (s, 1H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 12.7, 24 2.427.6, 39.8, 47.6, 48.3, 60.6, 61.5, 65 Hz, 72.9z, 77.9, 81.5, 84.4, 87.1, 87.8 Hz, 10, 123.3, 127.7 , 128.0, 128.1, 128.2, 128.7, 128.8, 134.6, 137.9, 143.3, 145.8, 148.0, 148.7, 161.3.

< Example 10>

Step 1: Preparation of Compound 5e

1,2,3,4, -di- o -isopropyridine-aD-lactopyranose ( 4d , 1.00 g, 3.84 mmol) and 3-azidosulfonylchloride ( 3a , 641 mg, 3.49 mmol) were used A target compound 5e (1.549 g, 99%) was obtained in the same manner as in Comparative Example 1 except for doing the same.

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.33 (d, J = 1.5 Hz, 6H), 1.45 (s, 3H), 1.54 (s, 3H), 2.11-2.18 (m, 2H), 3.23-3.35 ( m, 2H), 3.45-3.54 (m, 2H), 4.09-4.11 (m, 1H), 4.23 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 4.34-4.42 (m, 4H), 4.64 (dd , J = 7.75 Hz, 2.3 Hz, 1H), 5.53 (d, 4.5 Hz, 1H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 23.7, 24.5, 25.0, 26.1, 26.1, 47.9, 49.6, 66.6, 69.6, 70.5, 70.8, 96.4, 109.2, 110.1.

Step 2: Preparation of Compound 1j

Except for dissolving compound 5e (500 mg, 1.19 mmol) obtained in step 1 and compound benzyl propazyl alcohol ( 6b , 191 mg, 1.30 mmol) obtained in Preparation Example 2 in dimenylformamide (5.00 mL). The target compound 1j (629 mg, 96%) was obtained in the same manner as in Step 2 of Example 1.

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.31 (d, J = 9.0 Hz, 6H), 1.44 (s, 3H), 1.49 (s, 3H), 2.48-2.54 (m, 2H), 3.15-3.21 ( m, 1H), 3.24-3.30 (m, 1H), 4.08-4.10 (m, 1H), 4.21 (dd, J = 7.5 Hz, 1.5 Hz, 1H), 4.32-4.33 (m, 1H), 4.35-4.44 (m, 2H), 4.55 (t, J = 6.8 Hz, 2H), 4.61-4.63 (m, 3H), 4.69 (s, 1H), 5.51 (d, J = 5.0 Hz, 1H), 7.28-7.31 ( m, 1H), 7.33-7.36 (m, 4H), 7.65 (s, 1H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 24.5, 24.8, 25.0, 26.1, 26.1, 47.5, 48.1, 63.9, 66.7, 69.9, 70.4, 70.8, 72.8, 96.3, 109.3, 110.2, 123.2, 128.0, 128.1, 128.6 , 137.9, 145.6.

< Experimental Example 1> 1,2,3- Triazole Akylsulfonates Fluorination of Compounds

Comparative experiments of the nucleophilic fluorination reaction of the sulfonate compounds prepared in Comparative Examples 1 and 2, Example 1 Step 1, Example 1 Step 2, Examples 2, 4, 5, 6 and 7 were performed. . All reactions used 0.1 mmol of sulfonate precursor and 3.0 equivalents of cesium fluoride in 1.00 mL of solvent at 80 ° C. However, the compound 1h obtained in Example 10 used 0.03 mmol. Acetonitrile and t - butanol were used as solvents. The compound was analyzed by HPLC after reaction at 80 ° C. for 12 hours using acetonitrile as a solvent, and the results are shown in Table 2 and FIG. 2. The compound was reacted at 80 ° C. for 3 hours using t -butanol as a solvent. After HPLC analysis, the results are shown in Table 3 and FIG. 3. The results in Tables 2-3 and 2-3 were obtained by calculating the HPLC integral values after the reaction.

division
Reactant HPLC (%) Compound number R Reactant A B C unknown One 7 -CH ₃ 83 15 2 0 0 2 8 -CH ₂ CH ₂ CH ₃ 87 12 One 0 0 3 5a -CH ₂ CH ₂ CH ₂ N ₃ 71 52 4 0 0 4 1a -CH ₂ OH 7 91 One One 0 5 1b -CH ₂ OCH ₂ Ph 56 41 2 One 0 6 1d -H 51 46 3 0 0 7 1e -C (CH ₃ ) ₂ OH 12 86 One One 0 8 1f -Ph 82 15 One One 1.0 9 1 g 8 83 4 5 0

As shown in Table 2, Compound 7, 8, which is a sulfonate compound having no 1,2,3-triazole group, showed the progress of reaction of 15% and 12% under the same reaction conditions at the same time, while 1,2,3-tria The sulfonate compound having a sol group showed a high reaction progress of 41-91%. In particular, compound 1a showed a good reactivity 6-7 times higher than the general methanesulfonate compound (7) and propanesulfonate compound (8).

division
Reactant HPLC (%) Compound number R Reactant A B C unknown One 7 -CH ₃ 37 55 0 One 7 2 8 -CH ₂ CH ₂ CH ₃ 29 70 0 One 0 3 5a -CH ₂ CH ₂ CH ₂ N ₃ 13 86 0 One 0 4 1a -CH ₂ OH 24 72 0 0 4 5 1b -CH ₂ OCH ₂ Ph 9 90 0 One 0 6 1d -H 8 87 0 0 5 7 1e -C (CH ₃ ) ₂ OH 6 87 One One 5 8 1f -Ph 66 31 0 One 2 9 1 g 14 51 0 One 34

Table 3 shows the results of t -butanol and fluoride as shown in WO 2006/065038 A1 (DW Kim, J. Am . Chem . Soc . 126, 16394, 2006) as a test result using t -butanol as a reaction solvent . Due to the high solubility of cesium fluoride by hydrogen bonding, the reaction proceeded faster than the reaction in the acetonitrile solvent of Table 1 as a whole, and the effect of 1,2,3-triazole group was not significantly noticeable, but 1,2,3- Compound 1b having a triazole group showed 1.3-1.6 times better reactivity than compounds 7 and 8.

< Experimental Example 2> 1,2,3- with or without ionic liquid Triazole Akylsulfonates Fluorination of Compounds

Compounds 7 and 1a prepared in Comparative Examples 1 and 1 were subjected to a nucleophilic fluorination reaction using an ionic liquid as a phase transfer catalyst. All reactions used 0.1 mmol of sulfonate precursor and 3.0 equivalents of cesium fluoride in 1.00 mL of solvent at 80 ° C., and acetonitrile and t -butanol were used as solvents. The ionic liquids used were imidazolium-based [bmim] [OTf] and [bmim] [OMs], respectively, and the reaction solvents were acetonitrile and t -butanol. The compound was analyzed by HPLC after 1 hour of reaction at 80 ° C., and the results are shown in Table 4 and FIG. 4, and the results of Table 4 and FIG. 4 were obtained by calculating HPLC integral values after the reaction.

division compound Ionic Liquid menstruum HPCL (%) Reactant A B C unknown One 7 [bmim] [OTf]
Aceto
Nitrile
94 6 0 0 0 2 1a 56 44 0 0 0 3 7 [bmim] [OMs] 54 41 4 One 0 4 1a 32 67 One 0 0 5 7 [bmim] [OTf]
t-butanol

40 60 0 0 0 6 1a 8 90 0 One One 7 7 [bmim] [OMs] 23 78 0 0 One 8 1a 3 95 0 0 2

As shown in Table 4 and FIG. 4, the experimental results indicate that the fluorination reactivity according to the ionic liquid type is 41% and 67% when the fluorination reaction of the compound (1a) of the present invention uses acetonitrile solvent, respectively. It was confirmed that the reactivity is better than (6%, 41%, respectively), when using a t- butanol solvent Compound 7 represented 60%, 78%, respectively, Compound 1a of the present invention represented 90% and 95%, respectively As a result, it was confirmed that excellent fluorination reactivity was shown.

Therefore, the sulfonate compound having a 1,2,3-triazole group according to the present invention is excellent in fluorination reactivity, and thus can be usefully used for preparing a [ ¹⁸ F] fluoro compound for a contrast agent.

< Experimental Example 3> various metals Fluoride Used Triazole compound Fluorination Experiment

Fluorination experiments were carried out using various metal fluoride salts with compounds 7 and 1a prepared in Comparative Examples 1 and 1 above. All reactions were carried out using 0.1 mmol of precursor and 3.0 equivalents of fluoride in 1.00 mL of acetonitrile. Potassium fluoride (KF), rubidium fluoride (RbF), cesium fluoride (CsF) was used as the metal fluoride salt, and the reaction was performed at 80 ° C. The experimental results were determined by HPLC integral values, and the results of Table 5 and FIG. 5 were obtained by calculating HPLC integral values after the reaction.

Configuration
Reactant
MF
Time (h)
HPLC (%) Reactant A B C unknowm One
7
KF 24 100 0 0 0 0 2 RbF 24 96 4 0 0 0 3 CsF 24 64 32 4 0 0 4
1a
KF 24 82 17 One 0 0 5 RbF 24 21 74 One One 0 6 CsF 11 10 88 One One 0

As shown in Table 5 and FIG. 5, the experimental results showed that the reactivity of the compound (1a) of the present invention was higher than that of the compound 7 in the fluorination reactivity with various metal fluoride salts for the sulfonate compound. In addition, reactivity was found to be high even when high molecular weight rubidium fluoride (RbF) and cesium fluoride (CsF) were added.

Therefore, the compounds of the present invention have high fluorination reactivity, and thus can be usefully used for [ ¹⁸ F] fluoride labels.

< Experimental Example 4> Methanesulfonate 7's Nucleophilicity [ ¹⁸ F] fluorination reaction

[ ¹⁸ F] fluoride (3.21 mCi) was taken on a Chromafix ^® (PS-HCO ₃ ) cartridge and eluted with 0.1 M TBAOMs methanol solution (0.5 mL) to elute [ ¹⁸ F] fluoride into the reaction vessel. The amount of [ ¹⁸ F] fluoride remaining in the cartridge was 0.12 mCi. The eluted solution was heated to 120 ℃ blowing nitrogen to remove the solvent and water. Methanesulfonate precursor 7 (3 mg, 10.7 mmol) and t -amyl alcohol (0.5 mL) were added to the reaction vessel, and the reaction mixture was stirred at 120 ° C. for 10 minutes and then cooled to room temperature. To determine the reaction progress, ¹⁸ F label yield was checked using Radio Thin Film Chromatography (Radio-TLC) at 2, 5, and 10 minutes.

Experimental results were 39.2, 53.8 and 82.6% for radio thin film chromatography at 2, 5 and 10 minutes, respectively.

< Experimental Example 5> 1,2,3- Triazoleacyl Sulfonate (1b) Nucleophilicity [ ¹⁸ F] fluorination reaction

[ ¹⁸ F] fluoride (3.68 mCi) was taken on a Chromafix ^® (PS-HCO ₃ ) cartridge and then eluted with 0.1 M TBAOMs methanol solution (0.5 mL) to elute [ ¹⁸ F] fluoride into the reaction vessel. The amount of [ ¹⁸ F] fluoride remaining in the cartridge was 0.27 mCi. The eluted solution was heated to 120 ℃ blowing nitrogen to remove the solvent and water. Precursor 1b (3 mg, 10.7 mmol) and t -amyl alcohol (0.5 mL) prepared in Example 10 were added to the reaction vessel, and the reaction mixture was stirred at 120 ° C. for 10 minutes and then cooled to room temperature. At this time, ¹⁸ F label yield was checked by radio thin layer chromatography (Radio-TLC) at 2, 5 and 10 minutes to determine the progress of the reaction.

Experimental results were 47.7%, 60.7% and 83.1%, respectively.

Claims

A sulfonate compound having a 1,2,3-triazole group represented by Formula 1 below:
[Formula 1]

(In Formula 1,
R ¹ is C ₁ -C ₁₀ straight or branched chain alkyl substituted with hydroxy,
R ² is

,

or

Is selected from the group consisting of
n is an integer from 1 to 5).

delete

According to claim 1, wherein the sulfonate compound having a 1,2,3-triazole group
(1) 3- (2-naphthoxy) propyl 3- (4- (hydroxymethyl) -1 H -1,2,3-triazol-1-yl) propane sulfonate; And
(5) 3- (2-naphthoxy) propyl 3- (4- (1-hydroxy-1-methyl) ethyl-1 H -1,2,3-triazol-1-yl) propane sulfonate A sulfonate compound having a 1,2,3-triazole group, selected from the group.

As shown in Scheme 1 below,
Reacting azidoalkanesulfonyl chloride represented by Formula 3 with a compound having an aliphatic alcohol functional group represented by Formula 4 under an organic solvent and a base to obtain an azidoalkanesulfonate compound represented by Formula 5 (step 1); And
The 1,2,3-triazole sulfonate compound of Chemical Formula 1 is reacted by reacting the azido alkane sulfonate of Chemical Formula 5 prepared in step 1 with a compound having a terminal alkyne functional group represented by Chemical Formula 6 under an organic solvent and a copper catalyst. Method for preparing a sulfonate compound having a 1,2,3-triazole group of claim 1 comprising the step (step 2) of obtaining:
[Reaction Scheme 1]

(Wherein R ¹ , R ² and n are as defined in Formula 1 of claim 1).

The method of claim 4, wherein the aliphatic alcohol of step 1 is a primary to tertiary aliphatic alcohol.

The method of claim 4, wherein the base of step 1 is selected from the group consisting of bicarbonate ions, carbonate ions, alkali metal salts, triethylamine, diisopropylethylamine, pyridine, lutidine, and collidine.

The method of claim 4, wherein the solvent of step 1 is tetrahydrofuran (THF), 1,4-dioxane (1,4-dioxane), dichloromethane (CH ₂ Cl ₂ ), chloroform (CHCl ₃ ), carbon tetrachloride ( CCl ₄ ), 1,2-dichloroethane, acetonitrile, dimethylformamide (N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), benzene and Method for producing a compound, characterized in that any one selected from the group consisting of toluene.

The copper catalyst of claim 4, wherein the copper catalyst of step 2 is any one monovalent copper compound selected from the group consisting of copper iodide (CuI), copper bromide (CuBr), and copper chloride (CuCl), or copper sulfate (CuSO). ₄ ) a divalent copper compound selected from the group consisting of copper acetate (Cu (OAc) ₂ ), copper nitrate (Cu (NO ₃ ) ₂ and copper trifluoromethasulfonate (Cu (OTf) ₂ ) Method for producing a compound characterized by.

The method according to claim 8, wherein when a monovalent copper catalyst of oxidation number is used as the copper catalyst, it is selected from the group consisting of bicarbonate ions, alkali metal salts of carbonate ions, triethylamine, diisopropylethylamine, pyridine, rutidine and collidine. Method for producing a compound, characterized in that the base is added together.

9. A divalent copper catalyst according to claim 8, wherein when a divalent copper catalyst is used as the copper catalyst, a reducing agent selected from the group consisting of sodium ascorbate, sodium sulfide and dithiothreitol (DTT) is further added. Method for producing a compound.

The method of claim 4, wherein the solvent of step 2 is tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, acetonitrile, dimethylformamide, Method for producing a compound, characterized in that the organic solvent, water or a mixed solution of the organic solvent and water selected from the group consisting of dimethyl sulfoxide, methanol, ethanol, isopropanol and t -butanol.

As shown in Scheme 2, a method for preparing a ¹⁸ F or ¹⁹ F labeled compound comprising the step of nucleophilic fluorination reaction using the sulfonate compound having the 1,2,3-triazole group of claim 1 .
[Reaction Scheme 2]

(R ¹ above , R ² And n is as defined in Formula 1 of claim 1, wherein F is ¹⁸ F or ¹⁹ F.)

The method of claim 12, wherein the labeled reaction is acetonitrile, t - butanol, and t - is ¹⁸ F or ¹⁹ F, characterized in that takes place under any one solvent selected from amyl group consisting of an alcohol for producing a labeled compound Way.

A method for producing a diagnostic [ ¹⁸ F] radioactive medicine comprising the step of nucleophilic fluorination reaction using a sulfonate compound having a 1,2,3-triazole group of claim 1.