JP2003128727A - Optically active polymethacrylate derivative having urethane bond on side chain, separating agent and method for separation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new optically active polymer having excellent optical properties, a separating agent comprising the optically active polymer and a method for separation using the separating agent. SOLUTION: The optically active polymer is a new optically active polymethacrylate derivative having a urethane bond on a side chain expressed by general formula (1) (wherein, R1 is methyl, phenyl, benzyl, isopropyl or isobutyl; R2 is phenyl, naphthyl or benzyl; n is a number in the range of 2-5,000; and the mark * indicates an optically active carbon). The separating agent for an optically active substance comprises the optically active polymethacrylate derivative, and the method for separating optically active substances uses the separating agent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an optically active polymethacrylate derivative having a urethane bond in a side chain, a separating agent comprising the derivative, and a method for separating an optically active compound using the separating agent.

[0002]

2. Description of the Related Art Many optically active synthetic polymer substances used as functional materials such as separating agents for optical resolution, liquid crystals and nonlinear optical materials have been known. For example,
Optically active triphenylmethyl methacrylate polymer (JP-A-56-106907, JP-A-56-142216), optically active acrylic acid amide polymer (JP-A-56-167708), diphenyl methacrylate -2-Pyridylmethyl (JP-A-57-209908), a poly (meth) acrylamide compound having an optically active substituent on the side chain chemically bonded to the surface of silica gel (JP-A-63-001446), and an optically active compound. Liquid crystal composition using various synthetic polymer compounds (Japanese Patent Application Laid-Open No. 01-07923)
No. 0), an optically active methacrylic acid ester polymer (JP 08-208749 A, JP 11-124365 A, JP 20 A).
Nos. 01-114828 and 2001-114832) are known.

[0003]

However, although each of these optically active polymers has unique properties, its application range is naturally narrow. For example, when the above-mentioned optically active polymer is used as a separating agent for an optically active substance, the separable racemic compound and usable solvent are limited. Therefore, in order to expand such application range, it is necessary to increase the kinds of novel optically active polymers.

The present invention has been made in view of the above circumstances, and is a novel optically active polymer which is expected to have excellent optical properties, a separating agent comprising the optically active polymer, and an optical activity using the separating agent. It is intended to provide a method for separating substances.

[0005]

[Means for Solving the Problems] In order to achieve the above-mentioned object, the present inventor has conducted extensive studies, and as a result, found a novel optically active methacrylate derivative, which has an excellent performance as an optical resolving agent. The inventors have found that they are expressed and completed the present invention.

That is, the optically active polymethacrylate derivative of the present invention is a novel optically active polymethacrylate derivative having a urethane bond in the side chain represented by the following general formula (1), and the separating agent of the present invention is A separating agent for an optically active substance consisting of an optically active polymethacrylate derivative,
The separation method of the present invention is a method of separating an optically active substance using the separating agent.

[0007]

[Chemical 2]

(In the formula, R ₁ represents a methyl group, a phenyl group, a benzyl group, an isopropyl group, or an isobutyl group, and R ₂
Represents a phenyl group, a naphthyl group, or a benzyl group, and n
Is a number in the range of 2 to 5000, and * indicates optically active carbon. )

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The optically active polymethacrylate derivative having a urethane bond in the side chain of the present invention is a novel compound represented by the above general formula (1), and its production method particularly limits the present invention. Although not limited, for example, it can be prepared by radical polymerization of an optically active methacrylate derivative represented by the following general formula (2) in the presence of a radical initiator (reaction initiator).

[0010]

[Chemical 3]

(Wherein R ₁ represents a methyl group, a phenyl group, a benzyl group, an isopropyl group, or an isobutyl group, and R ₂
Represents a phenyl group, a naphthyl group, or a benzyl group, *
The mark represents optically active carbon. ) Examples of the optically active methacrylate derivative represented by the above general formula (2), which is a raw material, include (S)-(2-benzoylamino-3-phenyl) propyl-N- (2-methacryloyloxyethyl) carbamate, (S)-(2-naphthoylamino-3-phenyl) propyl-N- (2-methacryloyloxyethyl) carbamate and the like.

The radical initiator is not particularly limited, but for example, azobisisobutyronitrile,
Examples include azo compounds such as 2,2′-azobisisobutyrate and 4,4′-azobis (4-cyanovaleric acid), and peroxides such as benzoyl peroxide and di-t-butyl peroxide. The amount used is preferably in the range of 0.01 to 10 mol% with respect to the optically active methacrylate derivative as a raw material to be used in the reaction.

As the solvent used for the polymerization, any solvent can be used as long as it is an inert solvent for the reaction. Usually, a solvent that can sufficiently dissolve the raw materials and the reaction initiator used for the reaction is used. . Specific examples thereof include tetrahydrofuran (hereinafter abbreviated as THF), N, N-dimethylformamide (hereinafter abbreviated as DMF), dichloromethane, chloroform, benzene, toluene, xylene, and the like. It is preferable to use 1 to 100 times by weight of the raw material methacrylate derivative.

The reaction temperature varies depending on the type of the methacrylate derivative or the reaction initiator used as the raw material to be subjected to the reaction and is not particularly limited, but is usually in the range of 50 to 150 ° C.

The reaction time varies depending on the kinds of the raw material methacrylate derivative and the reaction initiator and is not particularly limited, but usually the reaction is completed within the range of 1 hour to 240 hours.

After completion of the reaction, the reaction solution is dropped and crystallized in a solvent having a low solubility of the product such as hexane, heptane, methanol and ethanol to give the optically active polymethacrylate derivative having a urethane bond in the side chain of the present invention. It can be obtained as a powder. THF and D to improve purity
It is also possible to dissolve in a solvent such as MF and re-inject into a solvent such as methanol for recrystallization.

The optically active polymethacrylate derivative having a urethane bond in the side chain of the present invention can be used as a separating agent for an optically active compound.

The method of separating the optically active substance by using the optically active polymethacrylate derivative having a urethane bond in the side chain of the present invention is not particularly limited,
For example, the optically active methacrylate derivative represented by the above general formula (2), which is a raw material, is polymerized in the presence of a porous carrier having a vinyl group on the surface to give an optically active compound having a urethane bond in its side chain. An optically active substance can be easily separated by high performance liquid chromatography using a column packed with a separating agent prepared by chemically bonding a polymethacrylate derivative to a porous carrier.

The carrier for carrying the optically active polymethacrylate derivative having a urethane bond in the side chain of the present invention is not particularly limited, and examples thereof include silica gel, alumina, crosslinked styrene, polysiloxane and the like. The carrier particles are 1 μm to 200 μm, and the average pore size is 1
Those of 0Å to 300Å are preferable as the separating agent in high performance liquid chromatography.

The method for preparing the porous carrier having a vinyl group on the surface is not particularly limited. For example, silica gel is surface-treated with 3-aminopropyltriethoxysilane, and then 2-methacryloyloxyethylisocyanate. One that has been reacted with nato.

The supporting method is not particularly limited, but as described above, the optically active polymethacrylate derivative having a urethane bond in the side chain of the present invention may be chemically bonded to a porous carrier. Then, the optically active polymethacrylate derivative having a urethane bond in the side chain of the present invention may be brought into contact with a porous carrier to be physically supported.

The supported amount of the optically active polymethacrylate derivative having a urethane bond in the side chain of the present invention with respect to the carrier varies depending on the kind and the physical properties of the carrier to be used and is not particularly limited, but usually it depends on the weight of the filler. To 1
It can be supported in the range of up to 50% by weight.

The separating agent of the present invention in which an optically active polymethacrylate derivative having a urethane bond in the side chain is supported on a porous carrier is applied to separation of an optically active substance capable of hydrogen bonding, π-π interaction and the like. It is possible. For example, when it is used as a packing material for a column for high performance liquid chromatography, it can be widely applied to both a normal phase system using hexane-isopropanol or the like as an eluent and a reverse phase system using alcohol-water or the like.

According to the embodiment described in detail above,
The present invention provides a novel optically active polymer which can be expected to have excellent optical properties, a separating agent comprising the optically active polymer, and a method for separating an optically active substance using the separating agent. 1) Easy to manufacture because it can be prepared by radical polymerization, (2) Both carrier and chemical bond or physical bond are possible, and (3) In case of chemical bond type separating agent, there is no limitation in eluent. In addition, it can be used in both normal phase and reverse phase systems.

[0025]

EXAMPLES The present invention will be specifically described below with reference to examples, but it goes without saying that the present invention is not limited to these examples.

In the following examples, the average molecular weight was determined by gel permeation chromatography (SPD-10 manufactured by Shimadzu Corporation).
Calculated in terms of polystyrene according to A), and the specific rotation is JASCO
The DIP-140 manufactured by Shimadzu and the infrared spectroscopic spectrum were measured by FT IR-8100A manufactured by Shimadzu. Incidentally, the measurement of the separation ability of the prepared optically active polymethacrylate derivative, liquid chromatography LC-10AT manufactured by Shimadzu, UV-visible detector SPD-10A,
Chromatopack C-R8A was used.

Example 1 (S)-(2-benzoylamino-3-phenyl) was added to a polymerization tube.
Propyl-N- (2-methacryloyloxyethyl) carbamate (hereinafter abbreviated as BPMOC) 500 mg, azobisisobutyronitrile (hereinafter abbreviated as AIBN) 10 mg and THF 2 mL
Was charged, and polymerization was carried out for 24 hours while shaking at 60 ° C. in a nitrogen atmosphere.

After completion of the polymerization, the reaction solution was poured into 100 mL of methanol / water (50/50 _volume ), the precipitate was collected by filtration, and dried at room temperature under reduced pressure. After drying, the precipitate is DMF
Dissolve in 2 mL and again 100 mL of methanol / water (50
/ 50 _volume ) and recrystallized. Further, recrystallization was performed again by the same method and then dried at room temperature under reduced pressure to obtain 325 mg of the target poly (BPMOC) (yield 65%).

Specific rotation [α] ₄₃₅ ²⁵ = -33.8 ° (C =
1.0 g / dL, DMF) Molecular weight Mn = 26500 Polydispersity Mw / Mn =
1.43 Example 2 Using the same apparatus as in Example 1, (S)-(2-naphthoylamino-3-phenyl) propyl-N- (2-methacryloyloxyethyl) carbamate (hereinafter abbreviated as NPMOC) 500 m
g, AIBN 10 mg and THF 2 mL were charged, polymerization was carried out for 24 hours while shaking at 60 ° C., and after the same post-treatment operation as in Example 1, 395 mg of the target poly (NPMOC) was obtained (yield 79
%).

Specific rotation [α] ₄₃₅ ²⁵ = -21.9 ° (C =
1.0 g / dL, DMF) Molecular weight Mn = 25300 Polydispersity Mw / Mn =
3.09 Reference Example 1 Preparation of silica gel having vinyl group on the surface Silica gel (TSK-GEL SI100 manufactured by Tosoh Corp., average particle size 5 μ) was placed in a 100 mL eggplant flask equipped with a reflux condenser.
m, average pore size 100 Å) 10 g, 3-aminopropyltriethoxysilane 14 mL and toluene 80 mL were charged and refluxed for 24 hours. The reaction product was cooled, filtered, washed with toluene, acetone, and methanol in this order, and dried to obtain 3-aminopropyltriethoxysilane-treated silica gel.

Then, in a 100 mL eggplant-shaped flask, 8 g of silica gel treated with 3-aminopropyltriethoxysilane, 2 g
-Methacryloyloxyethyl isocyanate 16mL and dichloromethane 80mL were prepared and reacted at 35 ° C for 36 hours. After completion of the reaction, the silica gel having a vinyl group on the surface was obtained by filtering, then washing with dichloromethane, acetone, and methanol in this order and drying.

Example 3 Preparation of silica gel chemically bound to poly (BPMOC) and preparation of packed column thereof 1 g of silica gel having a vinyl group on the surface prepared in Reference Example 1 and 0.5 g of BPMOC in a 50 mL Schlenk tube. , AIBN 10
Charge mg and THF 10mL, 48 at 60 ℃ under nitrogen atmosphere.
The reaction was carried out with shaking for a time. After completion of the reaction, the reaction product was filtered, washed with THF, acetone, and methanol in this order and dried. In this way, the target poly (BPMO
Silica gel chemically bound to C) was obtained.

Poly (BPMO chemically bonded to silica gel
The weight of C) was calculated by the following operation.

The poly (BPMOC) prepared in Example 1 and the silica gel having vinyl groups on the surface prepared in Reference Example 1 were mixed in an appropriate weight ratio, and infrared spectroscopic measurement was carried out.
A calibration curve was prepared from the absorption intensity ratio of the absorption due to the phenyl group in poly (BPMOC) at 700 cm ^-1 and the absorption due to silica gel at 800 cm ^-1 , and then poly (BPMOC) was chemically bound. It was confirmed by infrared spectroscopy of silica gel that poly (BPMOC) was chemically bonded to silica gel at 28 wt%.

After dispersing the prepared silica gel chemically bound to poly (BPMOC) in methanol, a stainless steel 2 mm (ID) × 150 mm (L) column was used with a high-pressure pump to obtain a maximum pressure of 200 kg / cm 2. Filled with ² . The theoretical plate number of the obtained column was 1180.

The number of theoretical plates was measured by using methanol as an eluent and eluting with toluene. The theoretical plate number was calculated by the following formula.

Theoretical plate number (N) = 5.54 × [Tr / (W _1/2 )] ² Tr = holding time (sec) W _1/2 = half-width (mm) Example 4 Poly (NPMOC) was chemically Of silica gel and its packed column that were bound to each other in the same manner as in Example 3 1 g of silica gel having a vinyl group on the surface prepared in Reference Example 1, 0.5 g of NPMOC, AIBN 10
From mg and THF (10 mL), silica gel chemically bound with poly (NPMOC) was obtained.

As in Example 3, the amount of poly (NPMOC) chemically bonded to silica gel was measured and found to be 21 wt%.
Met.

As in Example 3, 2 mm made of Tenres
A column of (ID) × 150 mm (L) was packed with silica gel in which poly (NPMOC) was chemically bound, and the theoretical plate number was measured and found to be 3050 plates.

Examples 5 to 10 Using the columns prepared in Examples 3 and 4, various racemates were separated under the conditions shown in Table 1. The results are also shown in Table 1.

[0041]

[Table 1]

Remarks 1 Racemate (1): Histidine racemate (2): 2-Phenyl-N- (phenylsulfonyl) -4-pyridone racemate (3): Mandelic acid racemate (4): N-benzyl- ( 1-methyl-2-methoxycarbonyl) ethylamine racemate (5): ketoprofen racemate (6): 2-epoxycarbonylpyran-4-one Remark 2 Mobile phase 5/5: methanol / water (vol / vo)
l) Mobile phase 7/3: methanol / water (vol / vol) Mobile phase 9/1: n-hexane / 2-propanol (vol)
/ Vol) Note that as an example of the actually measured chromatogram, Example 10
The chromatogram obtained in 1. is shown in FIG. FIG. 1 shows that the optically active polymethacrylate derivative having a urethane bond in the side chain of the present invention has a high asymmetric recognition ability.

[0043]

The present invention provides a novel optically active polymer having excellent optical properties, a separating agent comprising the optically active polymer, and a method for separating an optically active substance using the separating agent. In addition, it can be prepared by radical polymerization, so it is easy to manufacture. Both carrier and chemical bond or physical bond are possible. When used as a chemical bond type separating agent, there is no limitation on the eluent, and normal phase system, reverse phase system It has the effect that it can be used together with the system.

[Brief description of drawings]

FIG. 1 Separation of 2-epoxycarbonylpyran-4-one using a separating agent in which an optically active polymethacrylate derivative having a urethane bond in a side chain of the present invention is chemically bonded to silica gel having a vinyl group on the surface. It is a figure which shows the example of the performed chromatogram.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Coat (Reference) G01N 30/88 G01N 30/88 W // G01N 30/26 30/26 A 30/56 30/56 AF Terms (reference) 4D017 AA03 BA03 CA13 CB01 DA03 4G066 AC12A AC12B AD11A AD11B AE20B CA56 DA07 EA01 4J100 AL08P BA34P BA38P BC43P BC49P CA01 JA15 JA17

Claims (6)

[Claims] 1. An optically active polymethacrylate derivative having a urethane bond in the side chain represented by the following general formula (1). [Chemical 1] (In the formula, R ₁ represents a methyl group, a phenyl group, a benzyl group, an isopropyl group, or an isobutyl group, R ₂ represents a phenyl group, a naphthyl group, or a benzyl group, and n is 2 to 5000.
The number in the range of, the * mark represents optically active carbon. ) 2. A separating agent comprising the optically active polymethacrylate derivative having a urethane bond in the side chain according to claim 1. 3. A separating agent comprising the carrier carrying the optically active polymethacrylate derivative having a urethane bond in the side chain according to claim 1. 4. A method for separating an optically active substance using the separating agent according to claim 2 or 3. 5. A high performance liquid chromatography column packed with the separating agent according to claim 2 or 3. 6. A method for separating an optically active substance by high performance liquid chromatography using the high performance liquid chromatography column according to claim 5.