JPS62228030A - Separating agent - Google Patents

Abstract

NEW MATERIAL:A substance obtained by supporting any one of optically active groups shown by formulas I-IV (Ph is phenyl; R is H, 1-10C alkyl or 6-10C aryl; X is O or S; Z is H, 1-10C alkyl or metallic atom) on a carrier such as high polymer substance, silica gel, alumina, glass beads, etc. USE:A filler for chromatography for optically resolving racemic modification. PREPARATION:For example, (1S,2R)-2-amino-1,2-diphenylethanol shown by formula V is alkylated with ethyl bromoacetate, an ester part is treated with NaOH into a Na salt and the resulting substance is reacted with glycidyl group of silica gel reacted with 3-glycidoxypropyltrimethoxysilane, thus supported and then converted into a metallic salt such as copper salt, etc., to give a compound shown by formula VI (estimation).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel separating agent, and particularly to a packing material for chroma I-graphy for optically resolving racemates.

[Conventional technology]

Conventionally, separation agents in which optically active groups are held on inorganic carriers or organic polymers include artificially obtained amino acids such as phenylglycine and tert-leucine, bases or acidic compounds derived from natural amino acids, tartaric acid, etc. Or, except for examples using optically resolved arylethylamines, natural amino acids are used directly as raw material optically active compounds, for example, V.

Δ, Journal of Chromatography 82, p. 359 (1973) by Davankov et al., Journal of Chromatography 204 by C, Cupilon et al.
Vol. 185 (1981), ■, Yaheda Pankov et al., Chromatographia Vol. 13, p. 677 (1980), G.

Journal of High Resolution Chromatography and Chromatography Comics 93F, Volume 2, Page 145 (1979) by Gubit et al.
etc. are known. In addition, as an example using basic compounds derived from artificially obtained amino acids and natural amino acids such as phenylglycine and tert-leucine,
Journal of Chromatography, Vol. 192, p. 143 (1980) by Juparkle et al., Chromatography, p.
It is known.

[Problem that the invention seeks to solve]

The present inventors have arrived at the present invention as a result of various studies to further improve the performance of these known separation fillers. In other words, separating agents containing optically active groups have been used as chromatographic fillers for separation, especially for optical resolution of racemates, but natural amino acids or artificial amino acids that have traditionally been used as raw material optically active compounds The targets that can be optically resolved are limited for synthetically synthesized amino acids, bases or acidic compounds derived from them, tartaric acid, or optically resolved arylethylamines, and this method is applicable to compounds that have not been able to be separated so far. There has been a desire for a separating packing material that uses a novel optically active substance that can be used.

[Failure to solve the problem]

As a result of intensive studies on these conventional problems, the present inventors have discovered a separation packing material containing a novel optically active group that can be applied to compounds that could not be separated using conventional separation packing materials. The invention has now been completed.

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

(However, ph represents a phenyl group, R represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms. Also, X represents a 10-group or a -3 - group, and Z represents a hydrogen atom, an alkyl group having 1 to 1 o carbon atoms, or a metal atom.) Next, the present invention will be explained in detail.

(Optically active group) In the present invention, an optically active group is defined by the following general formula % (where ph represents a phenyl group, and R represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, or a C 6 to 10 alkyl group). Indicates that it is an aryl group. Also, X indicates a 10- group or -S- group, and 2 indicates a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a metal atom.) More specific details 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.

Further, X represents a 10-group or a -3-group, and Z represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a metal atom.

More specifically, examples of R include a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a tolyl group, and a naphthyl group. Examples of Z include a methyl group and an ethyl group as alkyl groups having 1 to 10 carbon atoms, and examples of metal atoms include copper, zinc, nickel, iron, cobalt, magnesium, calcium, sodium, potassium, and the like.

(Carrier) The carrier used in the present invention may be an organic substance or an inorganic substance. Examples of organic substances include filling base materials made of polymeric substances such as polystyrene, polyamide, polyacrylate, and polymethacrylate, and examples of inorganic substances include inorganic filling base materials such as silica gel, alumina, and glass beads. may be a mixture or composite, or may be a reaction product with other elemental compounds.

These carriers are preferably in the form of particles, and the particle size is 0.
1 to 101,000II, preferably 1 to 100ρ. Further, these carriers are preferably microporous ones with a large surface area, and the pore diameter is from 10 to 10,000 pores. However, the ratio of pore size/particle size is 1710 or less.

(Synthesis method) In the present invention, the separation agent is specifically synthesized by chemically or physically holding an optically active compound on a carrier with or without a spacer. The amount retained is 0.1 to 100% by weight, preferably 1 to 10% by weight, based on the carrier. A more specific synthesis method is shown below.

<Method of Synthesizing Optically Active Group> The optically active group that is a characteristic part of the present invention is erythro-2-amino-I represented by the following general formula.

Optically active form of 2-diphenylethanol, namely (IS).

2R) form (2) or (IR,2S) form (3), or the (IR,2S) form (IR, 2R) Body (4) Also (1s, 2S
) can be obtained as starting material.

(21+3+ (4+ +5+(
However, ph represents a phenyl group. ) That is, after alkylating each optically active substance using a carbomethylating agent such as ethyl bromoacetate or a substituted carbomethylating agent such as methyl chloropropionate, the ester moiety is treated with sodium hydroxide or sodium hydrogen sulfide. After making it into a metal salt, it can be converted into an acid or further converted into another metal salt. Alternatively, the racemate may be used for reaction and then optically resolved. but,
Not limited to this method, it can also be synthesized by a ring-opening reaction between optically active trans-stilbene oxide and an esterified product of glycine or esterified alanine. Further, a reaction product of trans or cis racemic mystilbenoxide and glycine, alanine or a derivative thereof may be optically resolved.

These optically active substances preferably have high optical purity, but
It doesn't necessarily have to be pure.

Furthermore, as described below, when chemically retaining on a carrier, the synthesis route can be changed in various ways, so it is not necessarily necessary to use the above method.

(Spacer) In the present invention, a spacer has the role of bonding a carrier and an optically active group. For example, when an inorganic filling base material such as silica gel, alumina, or glass beads is used as a carrier, various silane cups are used. A ring agent is used.

In addition, the following can be used: That is, a trifunctional or higher functional substance having a group that can react without impairing the optical activity of the optically active group represented by the general formulas (1-1) to (1-4), or a carrier that has a relatively strong interaction. Examples include monofunctional substances that do not meet the above conditions. For example, when the optically active group represented by the general formulas (1-1) to (1-4) is a residue formed with an amide with a carboxylic acid and a derivative thereof such as an acid anhydride, an acid halide, or an ester,
In the case of residues reacted with halides, epoxides, etc., in the case of residues reduced after reacting with aldehydes or imines, in the case of long-chain aliphatic monocarboxylic acids or their derivatives, long-chain monohalides, monocarboxylic acids, etc. An example is a residue that has reacted with an epoxide or the like.

<Chemical retention method> As a method for chemically bonding the carrier and the optically active groups 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 using an amino group. Chemical bonding can also be achieved by amidation of an amino group with a carboxylic acid or a derivative thereof, alkylation by substitution of an amino group with a halide or tosyl group, or a urea bond with an isocyanic acid. However, a silane coupling agent to which optically active groups represented by general formulas (1-1) to (1-4) are bonded in advance may be reacted with the inorganic filling base material. Also, the general formula (]-
Polymerizable compounds to which optically active groups shown in 1) to (1-4) have been bonded in advance may be used as fillers by homopolymerization or copolymerization with other polymerizable compounds, such as p-chloromethylstyrene, General formulas (1,-1) to (1,
-4) A compound to which an optically active group is bonded in advance is exemplified.

In addition, when holding the optically active group on an inorganic carrier or an organic polymer, first the optically active form of erythro-2-amino-L2-diphenylethanol, that is, the (Is, 2R) form or the (iR, 2S) form, is used. , or by reacting the amino group of the (IR, 2R) or (Is, 2S) form of threo-2-amino-1,2-diphenylethanol with a spacer or carrier or a polymerizable compound, and then reacting it with a carbonyl compound such as ethyl bromoacetate. 2. Perform alkylation using a methylating agent, a substituted carbonyl methylating agent such as methyl chloropropionate. It may be treated as a metal salt in the same manner as above. For example, as shown in the following equation (6), (I
s, 2R) -2-Amino-1,2-diphenylethanol was alkylated using ethyl bromoacetate,
After converting the ester moiety into a sodium salt with sodium hydroxide, it is supported by reacting the glycidyl group of silica gel with 3-glycidoxypropyltrimethoxysilane as a spacer, and then converted into a metal salt such as a copper salt. can be converted.

■! Ph C-NlIC1lzCOONa (However, ph represents a phenyl group, Y represents silica gel, and m and n are integers whose total is 3.) Also, as shown in the following formula (7), (Is, 2R)-2
-Amino-L2-diphenylethanol is reacted with 3-glycidoxyprobyltrimethoxysilane used as a spacer, then alkylated using ethyl bromoacetate, and the ester moiety is converted into a sodium salt with sodium hydroxide. It is also possible to support this by reacting it with silica gel and then convert it into a metal salt such as a copper salt.

Ph-11C-NH2 OHIt 1 Ma → (C1130) 3si-CHzCllzCHz-
0-CIIzCHC1l□-NH-C1・-・ph+1
OC-...ph HO-C...1ph (where ph represents a phenyl group, Y represents silica gel, and m and n are integers whose total sum is 3.) Physical holding method> As a physical method, for example, the above general formula (1-1)
A hydrophobic group such as a long-chain alkyl group is introduced into the optically active group represented by ~(1-4), and this is adsorbed onto silica gel or activated carbon that has been imparted with hydrophobicity, or an organic polymer having a hydrophobic group. and can be retained.

(Optical resolution method) As a means for obtaining an optically active substance using the separating agent of the present invention, there are chromatography methods such as gas chromatography, liquid chromatography, and jV surface layer chromatography.

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

〔Example〕

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

In addition, the capacity ratio (K”), separation coefficient (α), separation degree (Rs
) are determined by the following formulas.

Dead Time Example 1 2.10 g of (IR,2S)-2-amino-1,2-diphenylethanol is dissolved in 30 ml of methylene chloride and stirred at room temperature. Add to this 2. ethyl bromoacetate. QOg
A solution prepared by dissolving . followed by 1.5 m of triethylamine
1 and stirred at room temperature for 1 day. After confirming consumption of the raw material by TLC, methylene chloride is distilled off. Add 100 ml of benzene to the residue, wash once with water to remove triethylamine/hydrogen bromide, wash with saturated brine, and dry the organic layer with Glauber's salt.

When benzene was distilled off, 2.60 g (88χ) of crude (IR, 2s)-2-ethoxycarbonylmethylamino, 2-diphenylethanol was obtained, and the T of silica gel was
I, C (developing medium CHZC1□/MeOH=19/]) was approximately 1 subsoton. This crude product can be used in subsequent steps. Yield 2.20 g (75%).

The physical properties of this compound are as follows.

Melting point: 123-125°C Specific optical rotation: [α) ”D +2.4° (c 1.0
0. EtOII) Infrared absorption spectrum CI+? )value(
KThr) ;3180.1745,765,705
cm-'Proton nuclear magnetic resonance spectrum ('II-NM
R) value (CDCII); δ 1.1.7 (t, 3
H, J=7Hz), 2.35(bs, 2H),
3.16 (pseudo s, 2H) + 3°98 (q
, 2H1J=7Hz), 4.15(d, II, J=6t
lz), 4.76 (d, 1.H, J=6Hz), 7.2
0(s.

Loft) ppm Elemental analysis value; Calculated value (CI!21NO3) C72,22,H7,
07,N 4.68% Actual value C72,43
, If 7.11. N 4.47% Example 2 (IR,2S)-2-ethoxycarbonylmethylamino-1,2-diphenylethanol 2.60g in 20ml
of methanol, 8.6 ml of 1N aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at room temperature for 3 days. During this time, the suspension becomes a homogeneous clear solution.

Thereafter, methanol and water were distilled off and vacuum dried at 70'C for 12 hours (approximately 2 mm/1 g), resulting in (ill, 2
S) -2-carboxymethylamino-1,2-diphenylethanol monosodium salt 2.47 g (9
7χ) is obtained. This crude product was analyzed by TLC on silica gel.
(With the developing medium C112CIz/MeO1 (=19/1), there is 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 (decomposed) Specific rotation: [α) 17n +3.8° (c O,
83,1Izo) TR value (KBr); 3280.1
600.1415.760.700cm-]Example 3 Monosodium salt in 20ml of methanol (99.5χ)
Silica gel [Lichrosorb 5ilOO+1
0ttm (E, Merck) core, Og is added and left at room temperature for 7 days. The silica gel is filtered, washed with methanol, and then transferred to an aqueous solution of copper sulfate to form a copper salt. The structural formula of the obtained substance is estimated to be as follows.

Y, (CH30) l, 5i-cthcttzcn□
-0-CtlzCHCHz-N G 4Ph[0-C
-mPh (However, ph represents a phenyl group, Y represents silica gel, and m and n are integers whose total sum is 3.) Example 4 (is, 2s)-2-amino-1, 2.1 g of 2-diphenylethanol is dissolved in 30 ml of methylene chloride and stirred at room temperature. To this was added 2.0 g of ethyl bromoacetate dissolved in 15 ml of methylene chloride, and the mixture was stirred at room temperature for 7 days. Next, 1.5 ml of triethylamine was added and stirring was continued (room temperature, 1 day). After confirming the completion of the reaction at T1, C, methylene chloride is distilled off and replaced with benzene.

After removing triethylamine and hydrogen bromide salt by washing with water,
Wash with saturated saline and dry the organic layer with sodium sulfate. The crude product from which benzene was distilled off was 3.0 g.

Using this crude product as a developing solvent, Cll2CI z/Me
Separation by silica gel column chromatography using OH (19/1) gives the purified (Is, 2S) -
2-Ethoxycarbonylmethylamino-1,2-diphenylethanol was obtained as an oil. The physical properties of this compound are as follows.

Specific optical rotation; [α] weight', -33,8° (c 1.
03. MeOH) TR value (neat); 3350,
1740. '1205,765.705 cm-''I
I-NMR value (CDCIs); δ1.20 (t, 3H, J=71Lz), 3.02 (b
s, 2tl), 3.66 (d, IH, J=8Hz), 4
．． 07 (q, 2H, J=7Hz), 4.59 (d.

ill, J=8tlz), 7.05(s,
1oll) ppm elemental analysis value; Calculated value (CI8H21NO3) C72,22,11
7,07,N 4.68% actual value C72,
48,II 7.2L N 4.42%Example 5 (Is, 2S)-2-carboxymethylamino-1,
Synthesis of 2-diphenylethanol monosodium salt.

3.0 g of the ethyl ester obtained in Example 4 was dissolved in 20 ml of methanol, 8.6 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was hydrolyzed at room temperature.

After distilling off the solvent, the residue was vacuum dried to obtain a solid.

The physical properties of this compound are as follows.

Melting point: 222-225°C (decomposed) Specific rotation: [α) IBn 43.3' (c
1.061MeOII) TR value (KBr); 330
5.1590.1415.770.700cm-'Example 6 Monosodium salt in methanol (99,5χ) 20ml
Silica gel [Lichrosorb 5ilOO+ 10
g++([!.

Merck)) 7. Add Og and leave at room temperature for 7 days.

The silica gel is filtered, washed with methanol, and then transferred to an aqueous solution of copper sulfate to form a copper salt. The structural formula of the obtained substance is estimated to be as follows.

Y-(CthO)□5i-C11zC)1zcH□-0
-CH2CIICII□-IJ-C-Ph+10- C
■...Ph Mu (however, ph represents a phenyl group, Y represents silica gel, and m and n are integers whose total sum is 3.) Example 7 As a raw material, (IS, 2R) (Is, 2R) -2-ethoxycarbonylmethylamino-1,2-diphenylethanol was synthesized using -2-amino-1,2-diphenylethanol under the same reaction conditions as in Example 1.

The physical properties of this compound are as follows.

Melting point; L26.5-127°C Specific rotation; [α) zz[l-2,5° (c 1.
01. IEtOll) IR,,'H-NMR spectrum and Rf value are (111,2S)-2-amino-1,2
-Completely identical to the product obtained using diphenylethanol as the starting material (Example 1).

From this (Is, 2+i')-2-ethoxycarbonylmethylamino-1,2-diphenylethanol, under the same reaction conditions as in Example 2, (IS, 2R)-2-carboxymethylamino-1,2-diphenylethanol.
The monosodium salt was synthesized.

The physical properties of this compound are as follows.

Melting point: 229-234°C (decomposed) Specific rotation: [α) ”n -3,7' (c O,7
6, HzO) TR value (KBr); 32B0.160
0.1415.760.700cm-'this(IS,
A separating agent presumed to have the following structural formula could be obtained from 2'R)-2-carboxymethylamino-1,2-diphenylethanol monosodium salt under the same reaction conditions as in Example 3.

Example 8 As a raw material, (Il+, 2R)-2-amino- 1,2-
Using diphenylethanol, a separating agent presumed to have the following structural formula could be obtained under the same reaction conditions as in Examples 4 to 6.

(However, ph represents a phenyl group, Y represents silica gel, and m and n are integers whose total sum is 3.) Application Example 1 Using the separating agent obtained in Example 3, various Optical resolution of the racemate was performed. That is, the above separation agent was added to a stainless steel column for high performance liquid chromatography (25 cm x O, 4
6 cmφ), and optical resolution of various racemates was performed using a 0.25 mM copper sulfate aqueous solution as a solvent at a flow rate of 1.0 ml per minute (30° C.), and good results as shown in Table 1 were obtained.

Table-1 ((1)*Two flow rates: 1.5 m1 per minute (50°C) Hayashi: Flow rate: 8 m1 per minute (4Q°C) Application example 2 Using the separating agent obtained in Example 6, various racemic Optical resolution was performed.That is, the above separation agent was used in a stainless steel column for high performance liquid chromatography (25 cm x 0.4
6 cmφ), and optical resolution of various racemates was performed using a 0.25 mM copper sulfate aqueous solution as a solvent at a flow rate of 1.0 ml per minute (30°C), and good results as shown in Table 2 were obtained.

Table-2

Claims (1)

[Scope of Claims] A separating agent comprising any one of optically active groups represented by the following general formulas (1-1) to (1-4) supported on a carrier. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1-1)▲Mathematical formulas,
There are chemical formulas, tables, etc. ▼ (1-2) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (1-3) ▲ Mathematical formulas,
Chemical formulas, tables, etc. are available▼(1-4) (However, Ph represents a phenyl group, and R represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms. .Also, X is -O
- group or -S- group, and Z represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a metal atom. )