JP2655907B2 - Separating agent - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a separating agent using a cationic cyclophane derivative which is effective for separating organic compounds having polar functional groups and organic anionic compounds. It is.

[Problems to be solved by the prior art and the 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, organic compounds having a functional group that can be dissociated to generate an anion have not been separated so far.

The present invention seeks to provide a separating agent having an enhanced ability to separate organic anionic and neutral organic compounds by positively incorporating an organic cationic moiety and a neutral moiety into the cyclophane skeleton. .

[Means for solving the problem]

That is, the present invention relates to the following general formula (I) (In the formula, R and R ₁ represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, which may be the same or different, and R ₂ is a hydrocarbon group having 1 to 7 carbon atoms. X, Y has a skeleton of a hydrocarbon group having 1 to 10 carbon atoms and may have a functional group containing a double bond, an aromatic group or a hetero atom.) It relates to a separating agent as a component.

Examples of the hydrocarbon group represented by R and R ₁ in the above formula (I) include an aliphatic hydrocarbon group such as —CH ₃ , —C ₂ H ₅ , and —CH (CH ₃ ) ₂ ; And other aromatic hydrocarbon groups. It is preferably a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms. R ₂ is −
CH ₃ , −C ₂ H ₅ , And the like. On the other hand, X, Y is equivalent to a spacer connecting the two diphenylmethane moiety, as a specific structure _{- (CH 2) n - (} n: 1~10 integer), And substituted or unsubstituted chain alkylene groups and aromatic derivatives. Furthermore, even if X and Y are the same,
They can be different.

The synthesis of the cyclophane compound represented by the general formula (I) according to the present invention can be performed, for example, by using bis (4-aminophenyl)
After synthesizing a cyclophane skeleton by condensing and reducing a methane derivative with a hydrocarbon dihalide corresponding to a spacer, all four amino groups are protected, and only one is selectively deprotected, and then further protected , Deprotection, and quaternization of the amino group with a monohalogenated hydrocarbon, the desired cationic cyclophane can be synthesized.

To apply the cyclophane compound as a separating agent,
For example, there is a method in which the carrier is physically and chemically retained on a carrier for liquid chromatography.

As a physical method, the cyclophane compound is dissolved in a soluble solvent, mixed well with the carrier, and under reduced pressure or heating,
A method of distilling off the solvent by an air current, or dissolving the cyclophane compound in a soluble solvent, mixing well with the carrier, stirring and dispersing in a liquid incompatible with the solvent,
There is also a method of diffusing the solvent.

As a chemical method, the surface of the carrier is treated with cyclophane 2
There is a method of treating with a treating agent having a functional group capable of reacting with a secondary amino group (for example, a compound having a C1 or -COOH group at a terminal) and then reacting with the cyclophane to carry the compound.

The size of the carrier varies depending on the size of the column used, but is generally 1 μm to 10 mm, preferably 1 μm to 30 mm.
0 μm. The carrier is preferably porous and has an average pore size of 10 to 100 μm, preferably 50 to 50,000.
0Å.

Examples of the carrier include a porous organic carrier and a porous inorganic carrier, and examples of the porous organic carrier include polymers made of agarose, polyacrylamide, polystyrene, and the like. Also suitable as a porous inorganic carrier are silica,
Examples include alumina, magnesia, titanium oxide, and glass.

〔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 A cationic cyclophane derivative 5 of the present invention was synthesized according to a synthesis scheme shown below, and reacted with an agarose gel having a carboxylic acid group at a terminal to obtain a separating agent 6 .

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

Known methods synthetic cyclophane 1 of cyclophane 1 [K.Odashima, A.Itai, Y.
Iitaka and K. Koga, J. Org. Chem., 50 , 4478 (1985)].

Synthesis of Cyclophane 2 Compound 1 (4.0 g, 8 mmol) and Et ₃ N (4.0 g, 40 mmol) in CH ₂
(CF ₃ CO) ₂ O (8.4 g, 40 mmol) is added to a Cl ₂ (350 ml) solution, and the mixture is stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, EtOH (100 ml) was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from CH ₂ Cl ₂ -EtOH to give colorless prismatic cyclophane 2 (6.28 g, 88% Get) Its physical properties were as follows.

Melting point: 296-297.5 ° C IR spectrum (KBr, cm ^-1 ); 1690 mass spectrum m / z; 888 (M ⁺ ) ¹ H-NMR spectrum (CDCl ₃ , δ); 1.6 (8H, m), 3.8 ( 8H, m), 4.06 (4H, s), 7.09 (8H, d, J
= 8Hz), 7.29 (8H, d, J = 7Hz) Elemental analysis _{(C 42 H 36 O 4 N} 4 F 12); Calculated; C 56.76, H 4.08, N 6.30 Found; C 57.02, H 4.33, N 6.02 Synthesis of Cyclophane 3 KOH was added to a solution of compound 2 (3.01 g, 3.4 mmol) in THF (420 ml).
(111 mg, 1.7 mmol) in MeOH-THF (1: 1) (84 ml) was added, and the mixture was stirred at room temperature for 48 hours. After evaporation of the solvent, the residue
Dissolved in CH ₂ Cl ₂ (400 ml), NaHCO ₃ saturated aqueous solution, H ₂ O, Na
Wash with saturated aqueous Cl and dry with K ₂ CO ₃ . CH ₂ Cl ₂ was distilled off, CH ₂ Cl ₂ (15 ml) was added to the residue, and (Boc) ₂ O (0.49 g,
2.3 mmol) in CH ₂ Cl ₂ (2 ml) is added and heated under reflux for 66 hours. The reaction solution is concentrated under reduced pressure, benzene (170 ml) is added to the residue, and the mixture is stirred well, and then insolubles are filtered off. The filtrate is concentrated under reduced pressure, and the residue is chromatographed [silica gel. _{CH 2 Cl 2 -Et 2 O (} 40: 1) to give] to give the cyclophane 3 colorless powder (847mg, 28%). CH ₂ Cl ₂ −
Reprecipitation from hexane gives a colorless powder with a dp of 210.5-211.5 ° C. Its physical properties were as follows.

IR spectrum (KBr, cm ^-1 ); 1690 ¹ H-NMR spectrum (CDCl ₃ , δ); 1.43 (9H, s), 1.53 (8H, m), 3.69 (8H, m), 3.95 (2H,
s), 4.01 (2H, s ), 7.10 (16H, m) Mass spectrum FAB-MS m / z; 893 (M + +1) Elemental analysis _{(C 45 H 45 O 5 N} 4 F 9); Calculated; C 60.54, H 5.08, N 6.27 Found; C 60.77, H 5.10, N 6.56 Synthesis of Cyclophane 4 KOH was added to a solution of compound 3 (331 mg, 0.37 mmol) in THF (14 ml).
(295 mg, 4.5 mmol) in MeOH (14 ml) was added and stirred at room temperature for 18 hours. After evaporation of the solvent, CH ₂ Cl ₂ (100m
l) is added, washed with a saturated aqueous solution of H ₂ O and NaCl, and dried with K ₂ CO ₃ . CH ₂ Cl ₂ is distilled off to obtain a crude cyclophane 4 as a colorless powder (210 mg, 94%). When reprecipitated from CH ₂ Cl ₂ -hexane, a colorless powder having a dp of 168 to 168.5 ° C. is obtained. Its physical properties were as follows.

IR spectrum (KBr, cm^-1); 3380,1690¹ H-NMR spectrum (CDCl_Three+ D_TwoO, δ); 1.40 (9H, s), 1.5 to 1.7 (8H, m), 3.0 to 3.6 (8H, m), 3.7
0 (2H, s), 3.80 (2H, s), 6.4 to 7.2 (16H, m) Mass spectrum m / z; 604 (M⁺) Elemental analysis value (C₃₉H₄₈O_TwoN_FourCalculated value; C 77.45, H 8.00, N 9.26 Actual value; C 77.16, H 7.97, N 9.42 Cyclophane5Synthesis of compounds4(620 mg, 1.0 mmol) in DMF (10 ml)
Bu_ThreeN (29 ml, 122 mmol) and CH_ThreeI (7.4 ml, 119 mmol) and MeO
H (5 ml) is added and stirred at room temperature. n-Bu_ThreeN (29ml, 1
22 mmol) and CH_ThreeI (7.4 ml, 119 mmol) after 1 day and 2 days
After 4 days and 5 days, it was added to prevent crystal precipitation.
5 ml after 1 day, 5 ml after 2 days and 30 ml after 4 days.
I can. After 7 days, the reaction mixture was evaporated to dryness under reduced pressure,_TwoO (1
Dissolved in CH)_TwoCl_Two(500ml) 4 times after washing
Allow to dry. The residue was subjected to gel chromatography (TOYOPEARL,
HW-40, MeOH) to give a yellow powder. This is an ion
Exchange column [Dewex-1 (ClO_Four Type), MeOH-H_TwoO (1:
1)], and the distillate is evaporated to dryness under reduced pressure._TwoRecrystallize from O
And colorless needles of cyclophane5(229mg, 23%)
You. dp 177.5-180.5 ° C. Its physical properties were as follows.

IR spectrum (KBr, cm ^-1 ); 3420,1680 ¹ H-NMR spectrum (acetone-d ₆ , δ); 1.36 (9H, s), 1.5 (8H, m), 3.69 (6H, s), 3.76 ( 6H,
s), 3.82 (6H, s) 4.0 (8H, m), 4.05 (2H, s), 4.19 (2H,
s), 7.0~7.9 (16H, m ) Elemental analysis _{(C 46 H 63 N 4 O} 14 Cl 3 · 1.5H 2 O) Calcd; C 53.13, H 6.54, N 5.51, Cl 10.45 Found; C 53.16 , H 6.43, N 5.53, Cl 10.47 Synthesis of separating agent 6 Compound 5 (58.5 mg, 58 μmol) in H ₂ O-MeOH (1: 1) (5 m
l) 1N aqueous HCl (2.5 ml) was added to the solution, and the mixture was stirred for 5 minutes, and then the solvent was distilled off to obtain a white solid. This is dissolved in acetone (2 ml), H ₂ O (10 ml) is added, and the pH is adjusted to pH 4.4 (BCG test paper) with 1N aqueous NaOH. This solution was added to ECH Sepharose 4B (3m
l, in addition to H ₂ O (15 ml) suspension of swollen state), further 1-
A solution of ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.72 g, 3.75 mmol) in water (15 ml) is added, the pH is again adjusted to 4.4 and gently stirred. After 1 hour, adjust the pH to 4.4 again and stir for 11 hours. The gel in the reaction solution was collected by filtration on a glass filter, H ₂ O (150 ml), a commercially available buffer (pH 10.02) (6 ml) three times, and a commercially available buffer (pH 4.01)
(6 ml) three times with H ₂ O (150 ml) to give a separating agent 6 for liquid chromatography.

Take a portion of the above and add 1M aqueous NaCl (20 ml), H ₂ O, MeOH
(12 ml), washed with Et ₂ O (12 ml), dried under reduced pressure for 5 hours, air-dried until the weight became constant, and subjected to elemental analysis.
1.94% results were obtained. Calculated from the elemental analysis value of only the gel treated in the same manner, 12.5 ml of carboxyl groups in 1 ml of gel
It was estimated that μmol was present, of which 66% was amide with cyclophane.

Application Example (Separating Agent) Separating agent 6 was packed in a glass column (10 mmφ × 68 mml), and the separation ability for various polar compounds was examined at a flow rate of 0.62 ml / min.

Separation example 1 Separation example 2 Separation example 3 Separation example 4 Separation example 5 [Effect of the Invention] The separating agent using the cationic cyclophane derivative of the present invention has molecular recognition ability and is useful for separating organic compounds having a similar structure. In particular, it has an excellent effect on the separation of various aromatic compounds having a functional group that dissociates in water to generate an anion.

Claims (1)

(57) [Claims] (1) The following general formula (I) (In the formula, R and R ₁ represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, which may be the same or different, and R ₂ is a hydrocarbon group having 1 to 7 carbon atoms. X, Y has a skeleton of a hydrocarbon group having 1 to 10 carbon atoms and may have a functional group containing a double bond, an aromatic group or a hetero atom.) Separating agent as a component.