JPH0788313B2 - Separation agent - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel separating agent, and more particularly to a packing material for chromatography for optically resolving a racemate.

[Conventional technology]

Conventionally, as a separating agent which holds an optically active group on an inorganic carrier or an organic polymer, artificially obtained amino acids such as phenylglycine and tertiary leucine, bases or acidic compounds derived from natural amino acids, tartaric acid Alternatively, natural amino acids are directly used as optically active compounds as raw materials except for the case where optically resolved arylethylamines are used. For example, VA Davankov et al., Journal of Chromatography, Vol. 82, p. 359 (1973). Journal of Chromatography, Vol. 204, page 185 (1981), C. Cubilon et al., Chromatographer, Vol. 13, page 677 (1980) by VA Davankov, et al. Graphography and Chromatography Communication Vol. 2 pp. 145 (1 979) etc. are known. As an example using a base compound derived from an artificially obtained amino acid such as phenylglycine or tertiary leucine or a natural amino acid, W. Parkle et al., Journal of Chromatography Vol.
Page (1980), VA Davankov et al. Chromatography Vol. 13, page 339 (1980).

[Problems to be solved by the invention]

The present inventors have arrived at the present invention as a result of various studies in order to further improve the performance of these known separating fillers. That is, the separating agent having an optically active group has been used as a packing material for separation, particularly for optically resolving a racemate, but it has been used as a starting material for an optically active compound or a natural amino acid. Applicable to compounds that could not be separated until now because of the chemically synthesized amino acids, bases or acidic compounds derived from them, tartaric acid, or optically resolved arylethylamines, the optically resolvable target is limited. A packing material for separation using a novel optically active substance that can be obtained has been desired.

[Means for solving problems]

As a result of diligent studies on the conventional problems, the present inventors have found a separating filler having a novel optically active group applicable to a compound that cannot be separated by a conventional separating filler, It was the completion of the invention.

That is, the present invention relates to a separating agent in which any one of optically active groups represented by the following general formulas (1-1) to (1-4) is held on a carrier.

(However, Ph represents a phenyl group, R represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, or 6 to 10 carbon atoms.
Is an aryl group. X represents an -O- group or an -S- group, and Z represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms or a metal atom. ) Next, the configuration of the present invention will be described.

(Optically Active Group) In the present invention, the optically active group is represented by the following general formula (1-1) to
It is shown by (1-4).

(However, Ph represents a phenyl group, R represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, or 6 to 10 carbon atoms.
Is an aryl group. X represents an -O- group or an -S- group, and Z represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms or a metal atom. ) More specific contents of this optically active group are as follows.

That is, in the general formulas (1-1) to (1-4), R is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms. X represents an -O- group or an -S- group, and Z represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms or a metal atom. More specifically, R is a hydrogen atom,
Examples thereof include a methyl group, an ethyl group, a phenyl group, a tolyl group, and a naphthyl group. Examples of Z include a methyl group, an ethyl group and the like as an alkyl group having 1 to 10 carbon atoms, and a metal atom such as copper, zinc, nickel, iron, cobalt, magnesium, calcium, sodium and potassium.

(Carrier) The carrier used in the present invention includes an organic substance or an inorganic substance. As the organic substance, there are filling base materials made of high molecular substances such as polystyrene, polyamide, polyacrylate, polymethacrylate, and as the inorganic substances, there are inorganic filling base materials such as silica gel, alumina, glass beads, etc. May be a mixture or composite, or may be a reaction product with another elemental compound. These carriers are preferably in the form of particles and have a particle size of 0.1 μm to 1000 μm.
m, preferably 1 to 100 μm. Further, these carriers are preferably microporous ones having a large surface area, and their pore diameters are 10Å-10000Å. However, the ratio of pore diameter / particle diameter is 1/10 or less.

(Synthesis Method) In the present invention, the separation agent is specifically synthesized by causing the carrier to chemically or physically retain the optically active compound with or without a spacer. The amount retained is 0.1 to 100% by weight, preferably 1 to 10% by weight of the carrier.
% By weight. A more specific synthetic method is shown below.

<Synthesis Method of Optically Active Group> The optically active group forming the characteristic part of the present invention is an optically active pair of erythro-2-amino-1,2-diphenylethanol represented by the following general formula, that is, (1S, 2R). Form (2) or (1R, 2S) form (3), or threo-2 represented by the following general formula obtained by chemically converting these
The (1R, 2R) -form (4) or (1S, 2S) -form (5) of -amino-1,2-diphenylethanol can be obtained as a starting material.

(However, Ph represents a phenyl group.) That is, after alkylation with each optically active substance, a carbomethylating agent such as ethyl bromoacetate, and a substituted carbomethylating agent such as methyl chloropropionate, The ester portion can be converted to a metal salt with sodium hydroxide, sodium hydrosulfide, or the like, and then converted to an acid or converted to another metal salt. Alternatively, the reaction may be performed using a racemate and then optically resolved. But,
Not limited to this method, it can also be synthesized by a ring-opening reaction of an optically active trans-stilbene oxide with an esterified product of glycine or an esterified product of alanine. Further, a reaction product of trans or cis racemic stilbene oxide and glycine, alanine or a derivative thereof may be optically resolved.

These optically active substances preferably have high optical purity,
It does not have to be pure.

Further, as described below, when chemically retained on a carrier, the synthetic route can be changed in various ways, and therefore the above method is not always necessary.

(Spacer) In the present invention, the spacer has a role of binding the carrier and the optically active group, and for example, when an inorganic filling base material such as silica gel, alumina or glass beads is used as the support, various silane cups are used. A ring agent is used.
In addition, the following can be used. That is, a relatively strong interaction with a bifunctional or higher functional substance having a group capable of reacting without impairing the optical activity of the optically active group represented by the general formulas (1-1) to (1-4), or a carrier. A monofunctional substance that can satisfy the above conditions can be given. For example, when the optically active group represented by the general formulas (1-1) to (1-4) is a residue forming an amide with a carboxylic acid and its derivative such as an acid anhydride, an acid halide or an ester,
When it is a residue that has reacted with halides, epoxides, etc., when it is a residue that has been reduced after reacting with aldehydes and imines, and with long-chain aliphatic monocarboxylic acids or their derivatives, long-chain monohalides, mono-chains. The case where it is a residue reacted with an epoxide or the like is exemplified.

<Chemical holding method> As a method for chemically bonding the carrier and the optically active group represented by the general formulas (1-1) to (1-4), silica gel treated with a silane coupling agent, or A method of directly reacting with an organic polymer having a functional group, for example, when the carrier has an epoxy group, ring-opening addition can be performed with an amino group. Further, it can be chemically bonded by amidation with an amino group and a carboxylic acid or a derivative thereof, alkylation by substitution of an amino group with a halide or tosyl group, or urea bond with isocyanic acid. However, a silane coupling agent to which an optically active group represented by any of the general formulas (1-1) to (1-4) is previously bound may be reacted with the inorganic-filled base material. In addition, the general formula (1-
1) to (1-4), a polymerizable compound having an optically active group previously bound thereto may be homopolymerized or copolymerized with another polymerizable compound to be used as a filler, for example, p-chloromethylstyrene, Glycidyl acrylate, glycidyl methacrylate, acrylic acid and its derivatives, methacrylic acid and its derivatives are represented by the general formulas (1-1) to (1-
An example is a compound to which an optically active group represented by 4) is previously bound.

When the optically active group is held on an inorganic carrier or an organic polymer, first, an optically active form of erythro-2-amino-1,2-diphenylethanol, that is, a (1S, 2R) form or a (1R, 2S) form. ) Form, or the amino group of the (1R, 2R) form or (1S, 2S) form of threo-2-amino-1,2-diphenylethanol, is reacted with a spacer or carrier or a polymerizable compound, and then, for example, bromoacetic acid. Alkylation is performed using a carbonyl methylating agent such as ethyl, a substituted carbonyl methylating agent such as methyl chloropropionate,
Thereafter, the same treatment may be performed to obtain a metal salt. For example, as shown in the following formula (6), after alkylating (1S, 2R) -2-amino-1,2-diphenylethanol with ethyl bromoacetate, the ester moiety is sodium hydroxide with sodium hydroxide. After being made into a salt, as a spacer, 3-glycidoxypropyltrimethoxysilane is supported by reacting it with the glycidyl group of the reacted silica gel,
It can then be converted to a metal salt such as a copper salt.

(However, Ph represents a phenyl group, Y represents silica gel, and m and n are integers whose sum is 3.) As shown in the following formula (7), (1S, 2R) After reacting 2-amino-1,2-diphenylethanol with 3-glycidoxypropyltrimethoxysilane used as a spacer, alkylation was performed using ethyl bromoacetate, and the ester moiety was further treated with sodium hydroxide. The sodium salt may be supported by reacting it with silica gel and then converted into a metal salt such as a copper salt.

(However, Ph represents a phenyl group, Y represents silica gel, and m and n are integers in which the sum thereof is 3.) <Physically retaining method> Examples of the physical method include: General formula (1-1)
To (1-4), a hydrophobic group such as a long-chain alkyl group is introduced into the optically active group, and this is adsorbed onto silica gel or activated carbon having hydrophobicity or an organic polymer having a hydrophobic group. Can be held.

(Optical Resolution Method) As means for obtaining an optically active substance by using the separating agent of the present invention, there are a chromatography method such as a gas chromatography method, a liquid chromatography method and a thin layer chromatography method.

The developing solvent for liquid chromatography or thin layer chromatography is not particularly limited, except for a liquid that dissolves or reacts with the separating agent. When the separating agent is bound to the carrier by a chemical method or is insolubilized by crosslinking, there is no limitation except the reactive liquid. Needless to say, the separation characteristics of the compound or the optical isomer change depending on the developing solvent, so it is desirable to study various developing solvents.

〔Example〕

Hereinafter, examples and application examples of the separating agent of the present invention will be shown together with comparative examples, but the present invention is not limited to these examples.

In addition, capacity ratio (K '), separation coefficient (α), separation degree (Rs)
Are respectively calculated by the following equations.

Reference Example 1 (1R, 2S) -2-Ethoxycarbonylmethylamino-1,2
-Synthesis of diphenylethanol.

(1R, 2S) -2-Amino-1,2-diphenylethanol 2.
10 g are dissolved in 30 ml methylene chloride and stirred at room temperature.
A solution prepared by dissolving 2.00 g of ethyl bromoacetate in 15 ml of methylene chloride was added thereto, and stirring was continued at room temperature for 7 days. Then, 1.5 ml of triethylamine is added and stirred at room temperature for 1 day. After confirming the consumption of the raw materials by TLC, the methylene chloride is distilled off. 100 ml of benzene is added to the residue, and the mixture is washed once with water to remove triethylamine / hydrogen bromide, washed with saturated saline, and the organic layer is dried with sodium sulfate.

When benzene was distilled off, crude (1R, 2S) -2-ethoxycarbonylmethylamino-1,2-diphenylethanol 2.6
0 g (88%) was obtained, and silica gel TLC (developing medium CH ₂ Cl ₂ /
It was almost 1 spot at MeOH = 19/1). This crude product can be used in the subsequent steps. Yield 2.20 g (75%).

The physical properties of this compound are as follows.

Melting point; 123-125 ° C Specific rotation; [α] ¹⁸ _D + 2.4 ° (c 1.00, EtOH) Infrared absorption spectrum (IR) value (KBr); 3180,1745,765,70
5 cm ^-1 proton nuclear magnetic resonance spectrum ( ¹ H-NMR) value (CDC
l ₃ ); δ 1.17 (t, 3H, J = 7Hz), 2.35 (bs, 2H), 3.16 (p
seudo s, 2H), 3.98 (q, 2H, J = 7Hz), 4.15 (d, 1H, J = 6H
z), 4.76 (d, 1H, J = 6Hz), 7.20 (s, 10H) ppm Elemental analysis value; Calculated value (C ₁₈ H ₂₁ NO ₃ ) C 72.22, H 7.07, N 4.68% Measured value C 72.43, H 7.11, N 4.47% Reference Example 2 Synthesis of (1R, 2S) -2-carboxymethylamino-1,2-diphenylethanol monosodium salt.

(1R, 2S) -2-Ethoxycarbonylmethylamino-1,2
-Suspension of 2.60 g of diphenylethanol in 20 ml of methanol, and 8.6 ml of 1N aqueous sodium hydroxide solution.
And stir for 3 days at room temperature. During this time, the suspension becomes a homogeneous transparent solution. Then, methanol and water are distilled off,
When vacuum dried (about 2 mmHg) at 70 ℃ for 12 hours, (1R, 2S)-
2.47 g (97%) of 2-carboxymethylamino-1,2-diphenylethanol monosodium salt are obtained. This crude product is a TLC of silica gel (developing medium CH ₂ Cl ₂ / MeOH = 19
/ 1) has only one spot at the origin, which can be used in the subsequent process.

The physical properties of this compound are as follows.

Melting point: 231-235 ° C (decomposition) Specific rotation: [α] ¹⁷ _D + 3.8 ° (c 0.83, H ₂ O) IR value (KBr); 3280, 1600, 1415, 760, 700 cm-1 Example 1 Reference Reaction of (1R, 2S) -2-carboxymethylamino-1,2-diphenylethanol monosodium salt obtained in Example 2 with glycidoxypropylsilane treated silica gel.

The monosodium salt is dissolved in 20 ml of methanol (99.5%), 7.0 g of glycidoxypropylsilane-treated silica gel [Lichrosorb Si100, 10 μm (E.Merck)] is added, and the mixture is allowed to stand at room temperature for 7 days. Filter the silica gel,
After washing with methanol, it is transferred to an aqueous solution of copper sulfate to form a copper salt. The structural formula of the obtained substance is presumed to be as follows.

(However, Ph represents a phenyl group, Y represents silica gel, and m and n are integers with a total of 3.) Reference Example 3 (1S, 2S) -2-Ethoxycarbonylmethylamino-1 , 2
-Synthesis of diphenylethanol.

(1S, 2S) -2-Amino-1,2-diphenylethanol 2.
1 g is dissolved in 30 ml methylene chloride and stirred at room temperature. 2.0 g of ethyl bromoacetate was dissolved in 15 ml of methylene chloride, and the mixture was stirred at room temperature for 7 days. Next, triethylamine
Add 1.5 ml and continue stirring (room temperature, 1 day). TLC
After confirming the completion of the reaction with, methylene chloride is distilled off and replaced with benzene. After removing triethylamine / hydrogen bromide by washing with water, the organic layer is washed with saturated saline and dried with sodium sulfate. The crude product obtained by distilling off benzene is 3.0 g.

The crude product was separated by silica gel column chromatography using CH ₂ Cl ₂ / MeOH (19/1) as a developing solvent to give purified (1S, 2S) -2-ethoxycarbonylmethylamino-1,2-diphenylethanol. Was obtained as an oily substance. The physical properties of this compound are as follows.

Specific rotation; [α] ¹⁷ _D -33.8 ° (c 1.03, MeOH) IR value ^{(neat); 3350,1740,1205,765,705cm -1 1 H} -NMR value _{(CDCl 3); δ 1.20 (} t, 3H , J = 7Hz), 3.02 (b
s, 2H), 3.66 (d, 1H, J = 8Hz), 4.07 (q, 2H, J = 7Hz), 4.5
9 (d, 1H, J = 8Hz), 7.05 (s, 10H) ppm Elemental analysis value; Calculated value (C ₁₈ H ₂₁ NO ₃ ) C 72.22, H 7.07, N 4.68% Measured value C 72.48, H 7.21, N 4.42% Reference Example 4 Synthesis of (1S, 2S) -2-carboxymethylamino-1,2-diphenylethanol monosodium salt.

3.0 g of the ethyl ester obtained in Reference Example 3 was added to methanol 20
It was dissolved in 1 ml of water, and 8.6 ml of a 1N aqueous sodium hydroxide solution was added, followed by hydrolysis at room temperature.

After the solvent was distilled off, the solid was obtained by vacuum drying.

The physical properties of this compound are as follows.

Melting point; 222 to 225 ° C. (decomposition) Specific optical rotation; [α] ¹⁸ _D −43.3 ° (c 1.06, MeOH) IR value (KBr); 3305,1590,1415,770,700 cm ⁻¹ Example 2 In Reference Example 4 Reaction of the obtained (1S, 2S) -2-carboxymethylamino-1,2-diphenylethanol monosodium salt with glycidoxypropylsilane-treated silica gel.

The monosodium salt is dissolved in 20 ml of methanol (99.5%), 7.0 g of glycidoxypropylsilane-treated silica gel [Lichrosorb Si100, 10 μm (E. Merck)] is added, and the mixture is allowed to stand at room temperature for 7 days. The silica gel is filtered, washed with methanol, and then transferred into an aqueous solution of copper sulfate to form a copper salt.
The structural formula of the obtained substance is presumed to be as follows.

(However, Ph represents a phenyl group, Y represents silica gel, and m and n are integers in which the sum thereof becomes 3.) Example 3 As a raw material, (1S, 2R) -2-amino-1 Using 1,2-diphenylethanol under the same reaction conditions as in Reference Example 1 (1
S, 2R) -2-Ethoxycarbonylmethylamino-1,2-
Diphenylethanol was synthesized.

The physical properties of this compound are as follows.

Melting point; 126.5 to 127 ° C Specific rotation; [α] ²² _D −2.5 ° (c 1.01, EtOH) IR, ¹ H-NMR spectrum and Rf value are (1R, 2S) -2-amino-1,2-diphenyl This is completely the same as the product obtained when ethanol is used as the starting material (Reference Example 1).

From this (1S, 2R) -2-ethoxycarbonylmethylamino-1,2-diphenylethanol, under the same reaction conditions as in Reference Example 2, (1S, 2R) -2-carboxymethylamino-1,2-diphenylethanol mono. The sodium salt was synthesized.

The physical properties of this compound are as follows.

Melting point: 229-234 ℃ (decomposition) Specific rotation: [α] ¹⁶ _D −3.7 ° (c 0.76, H ₂ O) IR value (KBr); 3280,1600,1415,760,700cm ^-1 This (1S, 2R ) -2-Carboxymethylamino-1,2-diphenylethanol monosodium salt was obtained under the same reaction conditions as in Example 1 to obtain a separating agent estimated to have the following structural formula.

(However, Ph represents a phenyl group, Y represents silica gel, and m and n are integers in which the sum thereof becomes 3.) Example 4 As a raw material, (1R, 2R) -2-amino-1 Using 2,2-diphenylethanol, a separating agent presumed to have the following structural formula could be obtained under the same reaction conditions as in Reference Examples 3 to 4 and Example 2.

(However, Ph represents a phenyl group, Y represents silica gel, and m and n are integers in which the sum thereof is 3.) Application Example 1 Using the separating agent obtained in Example 1, various Optical resolution of racemate was performed. That is, the above separating agent was packed in a stainless steel column for high performance liquid chromatography (25 cm × 0.46 cmφ), and a 0.25 mM copper sulfate aqueous solution was used as a solvent at a flow rate of 1.0 m / min.
Optical resolution of various racemates was performed at l (30 ℃), and
Good results such as

Application Example 2 Using the separating agent obtained in Example 2, various racemates were optically resolved. That is, the above separating agent was packed in a stainless steel column for high performance liquid chromatography (25 cm × 0.46 cmφ), and a 0.25 mM copper sulfate aqueous solution was used as a solvent at a flow rate of 1.0 m / min.
Optical resolution of various racemates was performed at l (30 ° C), and Table-2
Good results such as

Claims (1)

[Claims] 1. A separating agent in which any one of optically active groups represented by the following general formulas (1-1) to (1-4) is held on a carrier. (However, Ph represents a phenyl group, R represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, or 6 to 10 carbon atoms.
Is an aryl group. X represents an -O- group or an -S- group, and Z represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms or a metal atom. )