KR100372559B1 - Novel chromogenic calix[4]arene azacrown ether derivatives selectively adsorbing potassium ions - Google Patents

Abstract

The present invention relates to a chromogenic calix [4] arena azacrown ether derivative that selectively adsorbs potassium ions, a method for preparing the same, and a use thereof. Specifically, the present invention relates to a chromogenic calyx [4] arene azacrown ether ( Since calix [4] arene azacrown ether derivatives adsorb potassium ions more selectively than other azacrown ether compounds, it can be used to measure potassium ion concentration in serum and to be used as a fundamental chemical treatment of hyperkalemia. In addition, the compound of the present invention, in which the chromophoric compound represented by Formula 2 is introduced, can visually confirm the complexation with a specific metal ion and thus can easily recognize the degree of complexation of the metal ion.

Wherein R, R 'and n are as described in the specification.

Wherein R 'and X are as described in the specification.

Description

Novel chromogenic calix [4] arene azacrown ether derivatives selectively adsorbing potassium ions}

The present invention relates to a chromogenic [4] arene azacrown ether derivative represented by the following formula (1), specifically, the present invention can be separated by selectively adsorbing potassium ions in serum Chromogenic calix [4] arene azacrown ether derivatives, methods for their preparation and their use as potassium ion selective extractants.

Formula 1

In Chemical Formula 1,

R is a linear alkyl group having 10 or less carbons,

R 'is an ester group of a nitro group, a cyano group or a C ₁ ~C _3,

n is a natural number of 3 or less.

Formula 2

In Chemical Formula 2,

R 'is an ester group of a nitro group, a cyano group or a C ₁ ~C _3,

X is a halogen element.

Potassium concentration is one of the clinically important indicators. Low concentrations of potassium in serum and severe differences in intracellular and extracellular concentrations in the human body are known to have a tremendous effect on human metabolism.Clinical Chemistry, Medical and cultural history. First Edition, 193,1988). Pathological example, 1 kg of tissues such as muscle or erythrocytes contains about 3.3 g of potassium.In case of muscle damage, hemolysis or internal bleeding, when these cells are damaged, they release potassium into the plasma to cause hyperkalemia ( hyperkalemia) (Wilson, JD et al:Harrison's Principles of Internal medicine, 12th edition, McGraw-Hill, 285,1991). Increased or decreased serum potassium levels can cause serious side effects such as weakness and paralysis in the nervous-muscular system, and even death due to severe arrhythmia in the myocardium. Accurately measuring or removing concentrations is of great clinical importance.

Current methods commonly used to measure potassium levels in clinical laboratories include emission photometry and ion-specific potentiometric electrodes. In the case of measuring the potassium concentration, the use of liquid ion-exchange membrane electrode using the antibiotic valinomycin as the potassium binder as the potassium selection electrode is a potentiometric selectivity ratio. , K ^Pot _{K / Na} ) 2.5 × 10 ⁻⁴ , most known for potassium ions (Henry, JB: Clinical Diagnosis & Management By Laboratory Methods, 18th edition, WB Saunders, 131, 1991, Wilson, JD et al. Harrison's Principles of Internal medicine , 12th edition, McGraw-Hill, 288, 1991 ).

In general, however, membrane separation or metal ion extraction experiments have many difficulties because the anion is insoluble in the organic phase. This is due to the co-movement of hard anions such as chloride, nitrate, and sulfate when complexes are formed on the membrane, which is likely to precipitate the complex in the organic phase, and in practice in medical or industrial settings. Since the chloride or nitrate ions are mainly used as anions for the target metals, the membrane electrode method is limited in its use as a potassium ion binder in actual clinical practice.

A method for preventing co-movement of such anions is to introduce functional groups capable of having anions in the organic ligand itself. In order to facilitate the introduction of functional groups, azacrown ethers substituted with nitrogen instead of oxygen were synthesized in the molecules of crown ethers, and studies on molecular recognition as well as complex formation of azacrown ethers with various metals were actively conducted. (Czech, A .; Czech, BP; Bartsch, RA J. Org. Chem. 5, 53 , 1988 )

Since ionophores, which are present in most of nature, are known to be antibiotics and selectively transfer cations through biofilms, separation of metal ions using ion recognition materials has been of great interest. The substance is known to form a quasi-cavity structure by the end group and selectivity for the cation and to enclose the cation by electrostatic attraction with donor-atom when complexed with the cation (Lutz, WK; Fruh, PV). Simon, W. Helv. Chim. Acta. 2762, 54, 1971 ).

A liquid membrane system using a carrier as a carrier in the separation of metal ions was introduced by Rob et al. (Ward, W. J; Robb, WL Science 1481, 156, 1967 ). Ion separation techniques are being introduced in many fields, including metal separation, recovery, separation of toxic waste, selective sensitizers, and concentration of chemicals.

As such, as the research on the separation of metal ions using ion recognition materials has become a class of organic chemistry, studies on the synthesis of calyx arene and adsorption with metals have been actively conducted. Calix [4] arene represented by the following general formula (3) is generally a cone, a partial cone, a 1,2-alternate (1,2-alternate), and 1, It has four stereoisomers of three alternating (1,3-alternate). In recent years, a great deal of research has been conducted on the selectivity of metals in Kalix [4] arene (Vogtle, F .; Weber, E. In Host Guest Complex Chemistry Macrocycles , Springer-Verlag, 378, 1985 ).

In addition, the azacrown ether compound represented by the following formula (4) as an ion recognition material is known to form complexes with transition metal ions or heavy metal ions. And the nature and effects of complex bonding due to the presence of impurities are being studied. (Tsukube, H .; Yamashita, K .; Twachido, T .; Zenki, M.J. Org. Chem.268, 56, 1991, Kim, S. J.J. Kor. Chem. Soc.645,35,1991)

Furthermore, by developing a macrocyclic ligand such as a compound introduced with Kalix [4] arene and crown ether represented by the following formula (5), it is possible to develop various ion selective electrodes using the amount of unknown metal present in the liquid phase or the relative ratio thereof. A lot of progress has been made. Examples of practical studies include sodium (Diamond, D .; Svehla, G .; Seward, EM; McKervy, MA Anal. Chim. Acta 223-227, 204, 1988 , Careri, M .; Casnati, A .; Guarinoni, A. ; Mangia, A .; Mori, G .; Pochini, A .; Ungaro, R. Anal.Chem . , 3156-3160, 65, 1993 ), Potassium (Cadogan, A .; Diamond, D .; Cremin, S. McKervy, MA; Harris, SJ Anal.Proc . 13-14, 28, 1991 ) and cesium (Kim, JS; Ohki, A. Talanta 705, 48, 1999 , Bocchi, C .; Careri, M .; Casnati, A .; Mori, G. Anal. Chem. 4234-4238, 67, 1995 ). In particular, the cesium ion selective electrode has been developed an electrode having high selectivity by using the calix arene derivative and its structural specificity.

In 1995, Reinhoudt and his co-workers conducted a study on the synthesis of calix [4] arene-crown-6 represented by the following formula (6) and alkali metal ion adsorption of its ligands [4]. Four stereoisomers of arene-crown-6 were isolated and found that 1,3-shifted calyx [4] arene-crown-6 had a significantly higher adsorption selectivity for cesium ions. The reason is that when the organic ligand is adsorbed with cesium ions, it is not only complexed by oxygen, the electron donor of the crown ether ring, but also capable of Cs ⁺ -π adsorption by two benzene rings at 1,3-cross positions. It can be seen from the X-ray results. (Reinhoudt, DN; Casnati, A .; Pochini, A .; Ungaro, R .; Ugozzoli, F .; Arnaud, F .; Fanni, S .; Schwing, M .; Egberink, RJM; Jong, F. J. Am. Chem. Soc. 2767, 117, 1995 )

In addition, the Kalix [4] arene dibenzo crown ether represented by the formula (7) in which two benzene rings are introduced to increase the planarity and firmness in the ether ring of the Kalix [4] arene crown of Formula 6 is known as a radioactive material Excellent selectivity for cesium ions. (Kim, JS; Yu, IY; Pang, JH; Kim, JK; Lee, YI; Lee, KW; Oh, WZ Microchem. J. 225-235, 58, 1998 ) (Kim, JS; Pang, JH Suh, IH; Kim, DW; Kim, DW, Synthetic Commun. 677, 28, 1998 ) (Kim, JS; Suh, IH; Cho, MH; Kim, JK J. Chem. Soc.Perkin Trans. 1, 2307, 1998. (Kim, JS; Pang, JH; Yu, IY; Lee, WK; Kim, JK; Suh, IH; Cho, MH; Kim, ET J. Chem. Soc.Perkin Trans. 2, 837-846, 1999 ) .

On the other hand, as mentioned above, the azacrown ether compound not only prevents co-movement of hard anions because proton-ionizable functional groups are introduced, but also protonation of ionizable functional groups. Since the denatured and deprotonated states show different patterns in the ultraviolet or fluorescence spectrum, it is easy to know the degree of complexation of metal ions. In this regard, professors Izatt and Bradshaw of the United States have studied and published the synthesis of new azacrown ethers, their physical properties and the thermodynamic parameters of complexing with specific metals (Bordunov). , AV; Hellier, PC; Bradshaw, JS; Dalley, Kent N .; Kou, X .; Zhang XX; Izatt, RM J. Org. Chem. 6097, 60, 1995 ), Professor Nakamura of Japan Azacrown ether compounds containing chromogenic nitrophenol groups were synthesized for the first time as compounds capable of ionizing azacrown ether skeletons, which are represented by 8 and 9, and subjected to selective experiments on metalpicrate and various metal ions. As a result, it was selective for lithium and potassium but was not so large. (Nakamura, H. et al., Chem. Lett. 1305, 1981 ; Nishida, H. et al., Chem. Lett. 1853, 1982 )

Accordingly, the present inventors have made efforts to develop an organic ligand that selectively adsorbs potassium ions. As a result, the present inventors synthesized a Kalix [4] arena azacrown ether derivative represented by Formula 1 and the compounds selectively adsorb potassium ions. Including the chromophore, the encapculation of capturing metal ions in three dimensions can be easily and accurately predicted using a UV-Vis spectrophotometer.

It is an object of the present invention to provide a chromogenic calix [4] arene azacrown ether compound capable of selectively extracting potassium ions, a method for preparing the same, and a use thereof.

In order to achieve the above object,

The present invention provides a calix [4] aren azacrown ether compound of formula 1, a method for preparing the same, and a selective extracting agent of potassium ion, which have a colorimetric compound having a proton-ionizable functional group represented by formula (2) It is to provide a use as.

Formula 1

In Chemical Formula 1,

R is a linear alkyl group having up to 10 carbons,

R 'is an ester group of a nitro group, a cyano group or a C ₁ ~C _3,

n is a natural number of 3 or less.

Preferably, in the formula

R is a propyl group, R 'is a nitro group and n is 1.

Formula 2

In Chemical Formula 2,

R 'is an ester group of a nitro group, a cyano group or a C ₁ ~C _3,

X is a halogen element.

In the present invention, in order to synthesize an organic ligand having excellent selectivity to potassium ions, a functional group capable of being ionized by combining a carboxylics [4] arene having structural robustness and a chromogenic azacrown ether is substituted with a side chain. Synthesize azacrown ethers.

Of the four benzene rings of Calix [4] Aren, 1,3- alternating CalixAren with two benzenes facing each other facing downwards, the π-orbital and potassium ions of the two benzene rings facing downwards Since the adsorption is expected, the steric sized alkyl group is introduced in R (Reinhoudt, DN; Casnati, A .; Pochini, A .; Ungaro, R .; Ugozzoli, F .; Arnaud, F .; Fanni, S .; Schwing, M .; Egberink, RJM; Jong, F., J. Am. Chem. Soc. 2767, 117, 1995 ). However, increasing the chain length of R to propyl, butyl or octyl groups in Formula 1 increases the hydrophobicity of the Kalix [4] arene azacrown ether compound when it is complexed with the metal ion, solubility in the organic layer. Since potassium desorption to the larger, hydrophilic receiving phase is reduced, the shorter alkyl groups in propyl, butyl and octyl groups show the highest efficiency and selectivity for potassium ions. Therefore, it is most preferable to introduce a propyl group out of many alkyl groups of calyx [4] arene to be introduced in R of formula (1).

The chromogenic calix [4] arene azacrown ether of the present invention was obtained by introducing a compound of formula (2) into the calyx [4] arene azacrown ether, and was easily stabilized using an ultraviolet spectrometer which is a great advantage of the organic ligand having color development. It is possible to obtain a constant, and in the case of an organic ligand having a high color development degree, it is possible to directly check the color change when complexed with a specific metal ion.

As a chromophoric compound, a compound having a multiple bond including a double bond or a triple bond in structure, particularly an aromatic compound, has a -OH group, and when the electron withdrawing group coexists, the color can be visually seen. Can introduce electron attraction groups other than the above-mentioned functional groups.

The preparation method of the Calix [4] arene azacrown ether compound of the present invention is as shown in Scheme 1 below.

Scheme 1

(Wherein R, R ', X and n are as described above.)

The preparation method of the compound of the present invention

1) Tetraalkylated kal of Structural Formula (III) in the presence of cesium carbonate (Cs ₂ CO ₃ ) by reacting a Calix [4] arene compound represented by Structural Formula (I) with tosylate represented by Structural Formula (II) Preparing a Rix [4] arene compound (step 1);

2) cyclizing the tetraalkylated calyx [4] arene compound of formula (III) to prepare N -tosylated calyx [4] arene azacrown ether compound of formula (IV) (step 2);

3) Deprotecting the N -Tosylated Calix [4] Arene Azacrown Ether Compound of Formula (IV) to Prepare Calix [4] Aren Azacrown Ether Compound of Formula (V) (Step 3) ; And

4) preparing a chromogenic Kalix [4] Arene azacrown ether derivative of Chemical Formula 1 by reacting the Calix [4] Arene Azacrown Ether Compound of Formula (V) with a chromogenic compound of Formula 2 in a suitable solvent in the presence of a base. It consists of a step (step 4).

The compound of formula (I) to be used as a starting material in the preparation method of the present invention can be easily synthesized by a known method. (Kim, JS; Pang, JH; Yu, IY; Lee, WK; Kim, JK; Suh, IH; Cho, MH; Kim, ET J. Chem. Soc.Perkin Trans. 2, 837-846, 1999)

In step 1, a tolylate compound (0.5 to 10 equivalents) and cesium carbonate (1 to 100 equivalents) of the structural formula (II) are reacted with a calix [4] arene compound of the structural formula (I) as a starting material. Reaction is performed at 0-200 degreeC. The reaction is carried out in an inert gas nitrogen or argon gas atmosphere for about 5 minutes to 30 days to obtain a tetraalkylated calix [4] arene compound of formula (III). Solvents usable here include methylene chloride, tetrahydrofuran, chloroform, benzene, acetonitrile, 1,4-dioxane or diethyl ether.

Step 2 reacts the tetraalkylated calix [4] arene compound of formula (III) with para-toluenesulfonamide in a cyclization reaction. The reaction solvent was refluxed using DMF ( N, N- Dimethyl formamide) for 10 to 48 hours at a high temperature where the reaction solvent boiled to obtain N -tosylated calyx [4] arene azacrown ether (IV). No side reaction product was observed on thin membrane chromatography at this time.

The deprotection reaction in step 3 includes a method using LiAlH ₄ , a method using 30% HBr / acetic acid, etc., but most preferably, the Kalix [4] arene azacrown ether compound of formula (IV) is sodium-mercury. It is reacted with amalgam (sodium-mercury amalgam).

Suitable solvents in step 4 are preferably selected from the group consisting of methylene chloride, tetrahydrofuran, chloroform, benzene, acetonitrile, dioxane and diethyl ether. As the base, tertiary organic amines having low basicity can be used, for example trimethylamine, triethylamine, diisopropylethylamine, 2,6-lutidine, picoline, N, N -dimethylaniline, pyridine And 4-dimethylaminopyridine. The base is preferably used in an amount of 0.5 to 20 equivalents based on 1 equivalent of Calix [4] arene azacrown ether compound (V).

Preferred chromogenic compounds with hydrogen which can be ionized are 2-bromomethyl-4-nitrophenol, 2-bromomethyl-4-cyanophenol, 2-bromomethyl-4-carboxyethylphenol, in particular 2 -Bromomethyl-4-nitrophenol is more preferred because it can have stronger color development since the benzene ring has the most electron attracting nitro group. In this case, it is preferable to add 1 to 10 equivalents of the chromogenic compound to 1 equivalent of Calix [4] arene azacrown (V).

The compound of formula 1 having a structure in which the azacrown ether ring was grafted to calix arene confirmed the selectivity to metal ions by liquid membrane separation.

The liquid membrane separation method has been widely used to separate metals present in wastewater, and in particular, the bulk liquid membrane method has been widely used in recent years. This method puts an organic solvent between the source phase and the receiving phase, and the ligand dissolved in the organic solvent transfers metal ions in the water phase to the aqueous phase of the water phase. To remove the metal ions in water. At this time, the pH is preferably fixed to 12. This is because when the pH is 13 or 14, it shows little selectivity for all metal atom ions and the amount of migration is too small under neutral or acidic conditions.

As a result of the experiment, it was found that the potassium ion selectivity of the compound of the present invention is excellent compared to the compounds of the formulas (8) and (9).

The reason for the relatively high selectivity of potassium in the Kalix [4] arene azacrown ether of Formula 1 is that first, the electrostatic attraction of the azacrown ring and the potassium ion is present, and secondly, the diameter of the pupil and the size of the potassium cation Nearly identical and third, when potassium ions are adsorbed into the pupil, adsorption between potassium ions and π-electrons is facilitated by two benzene rings pointing downward among the four benzenes of four calix arenes in a 1,3-shift Fourth, the hydroxy group of the nitrophenol group attached to nitrogen appears to be involved in the three-dimensional complex behavior at high pH.

Since the Kalix [4] arene azacrown ether compound represented by the general formula (1) of the present invention can selectively extract potassium ions, the composition having these as an active ingredient can be usefully used as a potassium ion selective extracting agent. In addition, the selective extracting agent for potassium ions may be used for the treatment of hyperkalemia.

Hereinafter, the present invention will be described in more detail with reference to Examples.

However, the following examples are merely to illustrate the content of the present invention is not limited to the scope of the present invention.

Example 1 Synthesis of Chromolytic Kalix [4] Aren Azacrown Ether

(Step 1) Synthesis of 25,27-bis (5-chloro-3-oxapentyloxy) -26,28-bis (1-propyloxy) calix [4] arene (III).

To 50 mL of purified acetonitrile under nitrogen at 25,27-bis (1-propyloxy) calix [4] arene (0.92 g, 1.81 mmol) (I), 1.84 g (3.62 mmol) of 2- (2-chloroethoxy) ethanol tosylate (ⅡCesium Carbonate (Cs)₂CO₃, 1.2 g, 3.62 mmol) was added and refluxed for 24 hours. After confirming that the reaction was completed by TLC, the acetonitrile was distilled under reduced pressure, 50 mL of 10% hydrochloric acid solution and 50 mL of methylene chloride were added, shaken well, and the organic layer was separated. The organic layer was washed with 10% hydrochloric acid solution (2 × 50 mL) and the organic layer was dried over anhydrous magnesium sulfate. After filtering anhydrous magnesium sulfate, the organic solvent was distilled off under reduced pressure. The brown oil remaining after distillation under reduced pressure was purified by column chromatography using ethyl acetate: hexane (1: 8) as a developing solvent to obtain 60% (0.78 g) of the title compound as a solid. _f = 0.5).

mp: 149-151 ° C. IR (plate potassium bromide, cm ⁻¹ ): 2926, 1451, 1251, 1189, 1127, 1050, 764 ¹ H NMR (CDCl ₃ ): δ7.07-6.99 (m, 8H), 6.79-6.67 (m , 4H), 3.77-3.52 (m, 28H), 1.65-1.53 (m, 4H), 0.91 (t, 6H). ¹³ C NMR (CDCl ₃ ): ppm 157.2, 156.4, 134.32, 134.33, 130.5, 130.4, 122.6, 122.3, 74.3, 72.0, 71.1, 70.8, 43.5, 36.9, 24.1, 11.1. FAB MS m / z (M ⁺ ) calcd 721.77, found 722.60. Anal. Calcd for C ₄₂ H ₅₀ Cl ₂ O ₆ : C, 69.83; H, 6.93. Found: C, 69.71; H, 6.96.

(Step 2) Synthesis of 25,27-bis (1-propyloxy) calix [4] arene azacrown ether tosylate (IV).

Potassium carbonate (0.96 g, 6.95 mmol) and 30 mL of purified DMF under nitrogen were placed in a three-necked round flask and refluxed for 30 minutes, followed by compound (10 mL) of purified DMF.Ⅲ) (1.00 g, 1.38 mmol) and para-toluenesulfonamide (0.23 g, 1.38 mmol) were slowly added dropwise at the same time for about 2 hours using different dropping funnels. When the dropping was completed, refluxed for 24 hours and confirmed that the reaction was completed by TLC, and then DMF was removed by simple distillation to obtain a brown oil. An aqueous sodium hydrogen carbonate solution (100 mL) and methylene chloride (100 mL) were added thereto, and the organic layer was separated. The organic layer was washed with water (2 × 50 mL), dried over anhydrous magnesium sulfate, filtered over anhydrous magnesium sulfate, and the organic solvent was distilled off under reduced pressure. The yellow oil remaining after distillation under reduced pressure was purified by column chromatography using ethyl acetate: hexane (1: 8) as a developing solvent (R). _f = 0.3) to give 72% (0.9 g).

mp: 168-171 ° C. IR (plate potassium bromide, cm ⁻¹ ): 2919, 1458, 1397, 1340,1248, 1210, 1160, 1092, 1056, 1009, 965, 762. ¹ H NMR (CDCl ₃ ): δ7.76-6.60 (m , 16 H, ArC H ₂ Ar), 6.79-6.67 (m, 4H), 3.80 (dd, J = 15.8 Hz, Δ = 9.5 Hz, 8H), 3.53-3.24 (m, 20H), 2.46 ( s, 3H), 1.30-1.22 (m, 4H), 0.72 (t, 6H). ¹³ C NMR (CDCl ₃ ): ppm 157.9, 157.4, 143.9, 137.3, 134.7, 134.2, 130.6, 130.3, 127.8, 122.8, 122.6, 72.6, 71.7, 71.3, 70.8, 49.3, 38.7, 23.2, 10.7. FAB MS m / z (M ⁺ ) calcd 819.2, found 820.3. Anal. Calcd for C ₄₉ H ₅₇ NO ₈ S: C, 71.79; H, 6.96. Found: C, 71.52; H, 6.94.

(Step 3) Synthesis of Calix [4] Arene Azacrown Ether (V).

Under nitrogen, 1.0 g (1.22 mmol) of 25,27-bis (1-propyloxy) calix [4] arene azacrown ether tosylate ( IV ) in a mixed solvent of 10 mL of 1,4-dioxane and 2 mL of methanol ( IV ) Sodium dihydrogen phosphate (Na ₂ HPO ₄ , 0.37 g, 2.56 mmol) was added thereto, stirred well, and then 6% sodium (mercury) amalgam (6 g) was carefully added thereto and refluxed at 80 ° C. for about two days. After cooling to room temperature the precipitate is filtered off and the solvent is distilled off under reduced pressure. 50 mL of methylene chloride and 50 mL of water were added to the residue, and the organic layer was separated. The organic layer was washed with 10% aqueous sodium hydrogen phosphate solution (3 × 50 mL), dried over anhydrous magnesium sulfate, filtered over anhydrous magnesium sulfate, and the organic solvent was removed by distillation under reduced pressure. The colorless oil remaining after distillation under reduced pressure was recrystallized with diethyl ether to obtain the title compound (52%).

IR (platelet potassium bromide, cm ⁻¹ ); 2926, 1456, 1359, 1176, 1094, 928, 767, 664. ¹ H NMR (CDCl ₃ ): δ7.13-6.70 (m, 12H, Ar- H ), 3.72 (s, 8H, Ar CH ₂ Ar ), 3.52-3.45 (m, 16H, -CH _2- ), 2.79 (s, 4H, -OCH ₂ C H ₂ N-), 1.54-1.43 (m, 4H, -CH ₂ CH ₂ CH ₃ ), 0.84-0.80 (t, 6H, -CH ₃ ). ¹³ C NMR (CDCl ₃ ): ppm 157.6, 157.1, 134.7, 131.2, 122.6, 122.5, 78.0, 77.7, 77.3, 73.1, 71.6, 70.9, 70.7, 49.1, 38.5, 23.4, 10.7

(Step 4) N Synthesis of -chromic 1,3-dipropyloxy callix [4] arene azacrown ether

Under nitrogen, 1.0 g (1.51 mmol) of Calix [4] aren azacrown ether ( V ), 100 mL of THF and triethylamine (0.24 mL, 3.31 mmol) were added to a 250 mL three necked round flask and stirred at 0 ° C. Under an ice bath, 2-bromomethyl-4-nitrophenol (0.384 g, 1.6 mmol) dissolved in 20 mL of THF was slowly added dropwise using an addition funnel for about 30 minutes. After the addition was completed, the mixture was stirred for 12 hours in an ice bath at 0 ° C., and then stirred at 65 ° C. for 8 hours. When it was confirmed that the reaction was completed, stirring and reflux were stopped, cooled to room temperature, and THF was removed by distillation under reduced pressure. Add 100 mL of methylene chloride and 100 mL of water, shake well, separate the organic layer, wash with 50 mL of water (2 × 100 mL), dry with anhydrous magnesium sulfate, filter the anhydrous magnesium sulfate, and then remove the organic solvent. Was removed by distillation under reduced pressure. After distillation under reduced pressure, the remaining yellow solid (78%) was obtained by column chromatography using a developing solvent of (ethanol / ethyl acetate = 1/1).

IR (plate potassium bromide, cm ⁻¹ ): 3058, 2926, 1590, 1458, 1336, 1212, 1088, 1011, 919, 764 ¹ H NMR (CDCl ₃ ): δ 7.13-6.70 (m, 15 H, Ar- H ), 3.72 (s, 8H, Ar CH ₂ Ar), 3.52-3.45 (m, 16H, -CH _2- ), 2.79 (s, 4H, -OCH ₂ C H ₂ N-), 1.54 -1.43 (m, 4H, -CH ₂ CH ₂ CH ₃ ), 0.84-0.80 (t, 6H, -CH ₃ ). ¹³ C NMR (CDCl ₃ ): ppm 165.5, 157.1, 156.9, 134.1, 133.5, 129.7, 129.5, 125.3, 124.8, 122.2, 121.9, 116.6, 77.6, 77.0, 76.3, 71.8, 70.9, 69.7, 68.7, 58.7, 52.8 , 38.2, 22.1, 9.8. FAB MS m / z (M ⁺ ) calcd. 816.0, found 816.0

<Examples 2 to 6>

The compound of Examples 2 to 6 was prepared by the same reaction as in Example 1, and the compound of Formula 1 is shown in Table 1 .

Compound of Formula 1 Substituent Examples R R ' n Example 2 Butyl Nitro One Example 3 Octyl Nitro One 4 to implementation profile Nitro 2 Example 5 profile Cyano One Example 6 profile Ethyl ester One

Comparative Example 1 Synthesis of N- (2-hydroxy-5-nitrobenzyl) -aza-15-crown-5

In order to compare potassium selectivity with the Kalix [4] arene azacrown ether compound of the present invention, the title compound represented by Formula 8 was prepared according to a known preparation method (Nakamura, H. et al., Chem. Lett. 1305 , 1981 ; Nishida, H. et al., Chem. Lett. 1853, 1982 ).

Comparative Example 2 Synthesis of N- (2-hydroxy-5-nitrobenzyl) -aza-18-crown-6

In order to compare potassium selectivity with Kalix [4] arene azacrown ether compounds of the present invention, the title compound represented by Formula 9 was prepared according to a known preparation method (Nakamura, H. et al., Chem. Lett. 1305 , 1981 ; Nishida, H. et al., Chem. Lett. 1853, 1982 ).

Experimental Example 1 Selective Separation of Potassium Ion Using Bulk Liquid Membrane

The well-known bulk liquid membrane method (Cho, Moon-Hwan et. Al. , Bull. Korean. Chem. Soc. , 16, 33,) for investigating the selectivity for potassium of the Calix [4] arene azacrown ethers of the present invention 1995 ) was used to test the selective resolution of potassium ions.

Separation experiments of metal ions using the bulk liquid membranes of the compounds of Comparative Examples 1 and 2 and Examples 1 to 6 were carried out at 25 ^° C., and the target ions were alkali metals. 3 mL each of 1.0 mM solutions prepared by dissolving the compounds of Comparative Examples 1 and 2 and Examples 1 to 6 in 1,2-dichloroethane were respectively filled at the lower end of the cylinder, and the organic phase was a source phase. The upper inner part is filled with 0.10 M lithium nitrate (LiNO ₃ ), sodium nitrate (NaNO ₃ ), potassium nitrate (KNO ₃ ), rubidium nitrate (RbNO ₃ ), cesium nitrate (CsNO ₃ ) and 0.8 mL each. It was. 0.1 M nitric acid was added to the outer portion of the upper layer in a receiving phase, followed by stirring with a magnetic stirrer coated with a 13 mm Teflon membrane. Atomic absorption spectra were used to determine the amount of metal in the outer water phase. Experimental results were averaged after three or more repetitions. In order to compare the mobility of ions as a control, a blank test was performed using an organic layer to which an organic ligand of Chemical Formula 1 was not added. The amount of the transferred metal was expressed in terms of the shift amount Flux as shown in Equation 1 below. Flux is defined as the number of moles moved per unit time and per unit area.

Table 2 shows the metal mobility according to the compounds of Formulas 8 and 9 and Examples 1 to 6. In the case of N- (2-hydroxy-5-nitrobenzyl) -aza-15-crown-5 represented by the formula (8), the selectivity of potassium is small compared to sodium because of the small cavity that can form a complex with metal. All. As the concentration of hydrogen ions in the outer water decreases, that is, as the pH increases, the hydrogen of the hydroxy group dissociates well in the nitrophenol group substituted as a side chain to nitrogen, thereby increasing the amount of migration.

In the case of N- (2-hydroxy-5-nitrobenzyl) -aza-18-crown-6 represented by the formula (9), the effect of the pH change of the side branches attached to nitrogen is also remarkable. In the case of, the selectivity for potassium ions is shown to increase ring size for lithium ions, but small selectivity (K ⁺ / Na ⁺ = 1.64).

The chromogenic calyx arene azacrown ether of Example 1 exhibited greater selectivity (K ⁺ / Na ⁺ = 34.07) for potassium although the amount of movement per unit time and unit area was less than that of the compound of formula (9).

Flux value of alkali metal ions using bulk liquid membrane. compound Flux value (unit: 10 ^-8 mole s ^-1 m ^-2 ) Li ⁺ Na ⁺ K ⁺ Rb ⁺ Cs ⁺ Example 1 1.28 0.64 21.81 8.57 4.75 Comparative Example 1 0.84 4.44 1.20 0.32 0.31 Comparative Example 2 22.07 22.43 36.87 17.29 25.04

As described in detail above, the chromogenic calix [4] arene azacrown ether selectively adsorbs potassium ions more than known azacrown ethers, thereby developing a new clinical test method by applying to the measurement of potassium in serum. It is of great value as a chemotherapeutic agent for hyperkalemia. Furthermore, the compound of the present invention is a new compound that has not been studied in Korea as well as abroad, and can be applied to all parts related to potassium as well as the field of new organic chemistry. In particular, extensive research has been made on the possibility of the formation of metal ions and π-complexes between two benzenes of chromogenic calix arene azacrown ethers. Application is possible.

Claims (4)

Chromic calyx [4] arene azacrown ether derivative represented by the following formula (1) capable of selectively removing potassium. Formula 1 In the above formula, R is a linear alkyl group having up to 10 carbons, R 'is an ester group of a nitro group, a cyano group or a C ₁ ~C _3, n is a natural number of 3 or less. The chromogenic calyx [4] arene azacrown ether derivative according to claim 1, wherein R is a propyl group, R 'is a nitro group, and n is 1. 1) Tetraalkylated kal of Structural Formula (III) in the presence of cesium carbonate (Cs ₂ CO ₃ ) by reacting a Calix [4] arene compound represented by Structural Formula (I) with tosylate represented by Structural Formula (II) Preparing a Rix [4] arene compound (step 1); 2) cyclizing the tetraalkylated calyx [4] arene compound of formula (III) to prepare N -tosylated calyx [4] arene azacrown ether compound of formula (IV) (step 2); 3) Deprotecting the N -Tosylated Calix [4] Arene Azacrown Ether Compound of Formula (IV) to Prepare Calix [4] Aren Azacrown Ether Compound of Formula (V) (Step 3) ; And 4) preparing a chromogenic Kalix [4] arena azacrown ether derivative of formula (I) by reacting with a chromogenic compound to the Kalix [4] arena azacrown ether compound of formula (V) in a suitable solvent in the presence of a base (step A method for producing the chromogenic calix [4] arena azacrown derivative according to claim 1, comprising 4). Scheme 1 (Wherein R, R 'and n are as defined in claim 1, and X is a halogen element.) A selective extracting agent for potassium ions, comprising the chromogenic calix [4] arene azacrown ether compound of claim 1.