JP2659237B2 - New anionic cyclophane derivatives - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel cyclophane derivative which is extremely useful, for example, as a functional material for separating cationic compounds.

[Problems to be solved by conventional technology and invention]

Conventionally, a separating agent using a crown ether derivative, a cryptand derivative, or the like is known, and an ammonium salt such as an amino acid or an amine is well separated. However, there is a need for a separating agent that exhibits an excellent function as a separating agent between cationic compounds.

The present invention seeks to provide a novel anionic cyclophane derivative having a further enhanced ability to separate an organic cationic compound by positively incorporating an anionic moiety and a neutral moiety into a cyclophane skeleton. Things.

[Means for solving the problem]

That is, the present invention relates to the following general formula (I) Wherein X and Y are methylene chains having 1 to 10 carbon atoms.

X and Y in the above formula (I) may be the same or different.

The cyclophanes represented by the general formula (I) according to the present invention may be added to a mobile phase of liquid chromatography in a small amount, or may be retained on a carrier and used as a chromatographic packing material to form an organic cationic compound. It is expected to exhibit excellent functions for separating compounds.

The synthesis of the cyclophan derivative of the present invention represented by the above general formula (I) is carried out, for example, by using 4,4'-dimethoxy-3,5,3 ', 5'
Starting from tetramethoxycarbonyldiphenylketone, reduction of the ketone and cleavage of the methyl ether bond to give 3,5,3 ′, 5′-tetraalkoxycarbonyl-4,
After 4'-dihydroxyldiphenylmethane is obtained, it is obtained by reacting a spacer corresponding to X and Y to form a cyclophane skeleton and hydrolyzing an ester bond.

〔Example〕

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Synthesis Example 1 Synthesis of Cyclophane ( 1 ) The cyclophane represented by the above formula ( 1 ) was synthesized according to the following synthesis scheme.

Hereinafter, each step of the above synthesis will be described in detail.

Synthesis of 4,4'-dimethoxy-3,5,3 ', 5'-tetramethoxycarbonyldiphenylketone ( 2 ) Known method [literature; F. Seebach, Ber., 73, 1338 (194
0)].

THF (15 ml) of ketone ( 2 ) (4.7 g, 10 mmol) obtained in the synthesis of 4,4'-dimethoxy-3,5,3 ', 5'-tetramethoxycarbonyldiphenylmethane ( 3 )
Et ₃ SiH (5.0 ml, 31 mmol) is added to the solution, and the mixture is stirred at room temperature for 20 hours. The reaction solution was poured into cold water (200 ml), and the precipitated crystals were collected by filtration, dried and then recrystallized from acetone-hexane to obtain colorless needles of ( 3 ) (4.5 g, 97%). Its physical properties were as follows.

Mp; eighty-four to eighty-five ° C. IR spectrum ^{_{(CHCl 3, cm -1);}} 1730 1 H-NMR spectrum _{(CDCl 3, δ); 3.92} (18H, s), 4.02 (2H, s), 7.72 (4H, s) elemental analysis _{(C 23 H 24 O 10)} ; calculated; C59.99, H5.25 Found; C59.81, H5.21 3,5,3 ', 5'- tetra carboxymethyl 4-4' Ester ( 3 ) (2.30 g, 5 mmol) obtained in the synthesis of dihydroxyl diphenylmethane ( 4 ) in CH ₂ Cl ₂ (2
0 ml) was cooled to -78 ° C. to, BBr C of ₃ (1.0ml, _11mmol)
H ₂ Cl ₂ (6 ml) solution is added dropwise over 0.5 h. After stirring at −78 ° C. for 2 hours and at room temperature for 24 hours, H ₂ O (50 ml) is added. The precipitate is collected by filtration, dissolved in AcOEt and extracted with a 5% aqueous sodium carbonate solution. The aqueous layers are combined, made acidic with a 10% aqueous HCl solution, and the precipitated precipitate is collected by filtration. After drying this,
Recrystallization from acetone-hexane gives ( 4 ) (1.6 g, 85%) as colorless needles. Its physical properties are as follows.

Melting point: 298 ° C IR spectrum (KBr, cm ^-1 ); 3070,1711 ¹ H-NMR spectrum (DMSO-d ₆ , δ); 3.98 (2H, s), 7.89 (4H, s), 11.57 (6H, s) , Disappeared in D ₂ O) Elemental analysis value (C ₁₇ H ₁₂ O ₁₀ · H ₂ O); Calculated value; C51.82, H3.58 Actual value; C51.67, H3.26 3,5,3 ′, 5'-tetraethoxycarbonyl-4,4'-
Carboxylic acid ( 4 ) (5.0 g, 13.3 mmol) obtained in the synthesis of dihydroxydiphenylmethane ( 5 ), p-T
sOH.H ₂ O (4.0 g, 21 mmol) in EtOH (60 ml) -benzene (4
0 ml) After heating the solution under reflux for 8 hours, the solvent is distilled off. The residue is dissolved in AcOET (200 ml), washed with an 8% aqueous NaHCO ₃ solution, saturated saline, and dried over MgSO ₄ . AcOEt is distilled off, and the residue is subjected to column chromatography (silica gel, AcOt
Et) to give crude ( 5 ) (4.40 g, 68%). AcOEt−
Recrystallization from hexane gives colorless needles. Its physical properties are as follows.

Melting point: 84-85 ° C IR spectrum (CHCl ₃ , cm ⁻¹ ); 1720,1675 ¹ H-NMR spectrum (CDCl ₃ , δ); 1.36 (12H, t, J = 7 Hz), 3.85 (2H, s), 4.32 (8H, q, J = 7H
z), 7.68 (4H, s ), 11.78 (2H, s) Mass spectrum ^{m / z; 488 (M +} ) Elemental analysis _{(C 25 H 28 O 10)} ; Calculated; C61.47, H5.78 Found Value; C61.22, H5.62 4,4'-di (4-bromobutoxy) -3,5,3 ', 5'-
Synthesis of 1,4-dibromobutane tetraethoxy carbonyl diphenylmethane (6) (10.8g, 50mmol) and K ₂ CO ₃ (6.
9g, 50mmol) was added to DMF (250ml) and kept at 60 ° C under stirring, and the ester ( 5 ) (2.44g, 5.0mmol) obtained therefrom was added.
Is added dropwise over 3 hours. further
After stirring at 60 ° C. for 1 hour, the mixture is left overnight at room temperature. The reaction solution was filtered through celite, and the filtrate was partitioned between Et ₂ O (200 ml) and saturated saline (1). The Et ₂ O layer was separated, dried over MgSO ₄ and concentrated, and the obtained residue was purified by column chromatography silica gel, Et ₂ O-hexane) to give ( 6 ) as a colorless oil (2.84 g, 75% Get) The characteristics are as follows.

IR spectrum (Film, cm ⁻¹ ); 1720 ¹ H-NMR spectrum (CDCl ₃ , δ); 1,39 (12H, t, J = 7.3 Hz), 1.8 to 2.3 (8H, m), 3.52 (4H,
t, J = 6.3Hz), 3.98 (4H, t, J = 6.3Hz), 4.10 (2H, s), 4.
37 (8H, q, J = 7.3 Hz), 7.68 (4H, s) Mass spectrum m / z; 758 (M ⁺ ) Elemental analysis (C ₃₃ H ₄₂ O ₁₀ Br ₂ ); Calculated value; C 52.24, H5.58 Actual value; C51.98, H5.41 Synthesis of cyclophan octaethyl ester ( 7 ) The dibromo form ( 6 ) (758 mg, 1 mmol) and the tetraester form ( 5 ) (488 mg, 1 mmol) obtained above were obtained. DMF (60 ml) of K ₂ CO ₃ (690 mg, 5 mmol) kept at 60 ° C. in DMF (40 ml) solution
It is added dropwise to the suspension over 1.5 hours with stirring. After further stirring at 60 ° C. for 9 hours, the mixture is left overnight at room temperature. The reaction solution was filtered through celite, and AcOEt (200 ml) was added to the filtrate, which was washed with saturated saline (1). The organic layer was separated and MgSO
After drying in ₄ , concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, AcOEt-hexane).
( 7 ) (240 mg, 22%) as a colorless solid is obtained. Recrystallization from AcOEt-hexane gives colorless needles. Its physical properties are as follows.

Melting point: 156 to 157 ° C IR spectrum (Nujol, cm ^-1 ); 1725 ¹ H-NMR spectrum (CDCl ₃ , δ); 1,35 (24H, t, J = 7 Hz), 1.9 (8H, m), 3.87 (4H, s),
~3.9 (8H, m), 4.31 (16H, q, J = 7Hz), 7.66 (8H, s) Mass spectrum ^{m / z; 1085 (M +} ) Elemental analysis _{(C 58 H 68 O 20 ·} H 2 O Calculated value; C63.15, H6.40 Actual value; C63.24, H6.21 Synthesis of cyclophan octacarboxylic acid ( 8 ) Octaethyl ester ( 7 ) (70 mg, 0.0
65 mmol) in 5N KOH methanol solution (2.0 ml) and H ₂ O (1.
0 ml) and this is heated under reflux for 2 hours. After cooling 1
The pH was adjusted to about 1 by adding 0% aqueous HCl, and the precipitated crystals were collected by filtration and dried to obtain colorless needles of ( 8 ) (25.4 mg, 46%). Its physical properties are as follows.

Mp; 300 ° C. IR spectrum ^{(KBr, cm -1); 1718} 1 H-NMR spectrum _{(DMSO-d 6 + D 2} O, δ); 1.85 (8H, m), 3.99 (12H, m), 7.70 (8H, s) elemental analysis _{(C 42 H 30 O 20 ·} 2H 2 O); calculated; C56.25, H4.50 Found; C56.20, H4.79 synthesis a of cyclophane octa potassium salt (1)) Octacarboxylic acid ( 8 ) obtained above in a solution of KOH (1.0 g, 17.9 mmol) in MeOH (40 ml) (185 mg, 0.21 mmol)
And heat under reflux for 2 hours. After evaporating MeOH (about 30 ml), the mixture was allowed to cool, and the precipitated precipitate was collected by filtration and washed with MeOH and Et ₂ O to obtain a colorless powder ( 1 ) (154 mg, 63%). Its physical properties are as follows.

Melting point; 300 ° C. or higher ¹ H-NMR spectrum (D ₂ O, δ); 1.55 (8H, m), 3.80 (12 H, m), 7.24 (8H, s) b) 5N KOH in methanol (1.0 ml) and MeOH (2.0
octaethyl ester ( 8 ) (273 mg, 0.25 mmol) obtained above is added to the mixture of the above, and the mixture is heated under reflux for 4 hours. After allowing to cool, the precipitate that precipitates is collected by filtration, cold MeOH and
Washing with Et ₂ O gives ( 1 ) as a colorless powder (246 mg, 92%). This product is identical to that obtained in a) above.

Application example (separating agent) The difference in the incorporation ability of an anionic cyclophane according to the present invention into an organic cationic compound in D ₂ O was determined by ¹ H-NM.
It was investigated by calculating the stability constant Ks of the complex from the change in the chemical shift of R [Ref: Kenji Koga, Pharmacia,
22 , 21 (1986); Michio Hiraoka, Hiroaki Yanagida, Masaaki Ohara, Kenji Koga, Host Guest Chemistry, Kodansha Scientific, 1984].

Next, differences in the complex stability constants (Ks) for various cationic compounds are shown below.

* Minus is incorporated and indicates that the chemical shift shifts to higher fields.

〔The invention's effect〕

The novel ionic cyclophane derivative of the present invention has a molecular inclusion function of incorporating an organic compound in a specific form. In particular, a cationic organic compound such as a quaternary ammonium salt or a sulfonium salt having an aromatic ring is included in an aqueous solution, and is useful as a separating agent therefor.

Claims (1)

(57) [Claims] (1) The following general formula (I) (Wherein X and Y are methylene chains having 1 to 10 carbon atoms) A novel anionic cyclophane derivative represented by the formula: