JPS63264536A - Separation agent - Google Patents

Abstract

PURPOSE:To obtain a packing agent for chromatography for the optical resolution of a racemic compound, by supporting an optically active group of (1R,2 S)-2-ethoxycarbonylmethylamino-1-phenyl-1-propanol, etc, on a carrier. CONSTITUTION:Either one optically active group of formula I-IV (Ph is phenyl; R<1> is 1-4C alkyl; R<2> is H, 1-10C alkyl or 6-10C aryl; X is O or S; Z is H, 1-10C alkyl or metal) is supported on a carrier (e.g. polystyrene or silica gel) to obtain the objective separation agent. The separation agent can be used in the separation of compound contained in natural or synthetic amino acid, tartaric acid, etc., which are used as raw optically active compounds and hitherto unable to be separated by optical resolution. The separation agent is produced by chemically or physically bonding an optically active compound with a carrier directly or via a spacer (e.g. silane coupling agent). The amount of supported compound is preferably 1-10wt.%.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel separating agent 1, particularly a packing material for chromatography for optically resolving racemic compounds.

[Prior Art] Conventionally, in the case of separation agents in which optically active groups are supported on inorganic carriers or organic polymers, there are examples in which natural amino acids are used as raw material optically active compounds. A,
Davankov et al., Journal of Chromatography, Vol. 82, p. 359 (1973).

Journal of Chromatography Vol. 204, p. 185 (1981) by C. Cupilon et al., ν, A.
Chromatography by Davankov et al., Volume 13, 677
Page (1980), Journal of High Resolution Chromatography and Chromatography Communication, Vol. 2, p. 145 (1979) by G. Gubitz et al., and others are known.

Furthermore, as an example of using basic compounds derived from artificially obtained amino acids and natural amino acids such as phenylglycine and tert-leucine, W. Burkle et al., Journal of Chromatography, Vol. 192, 143
Page (1980), Chromatography by V. A. Davankov et al., Vol. 13, p. 339 (1980) are known.

[Problem to be solved by the invention] The present inventors
The present invention was achieved 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 racemic compounds, but conventionally, separating agents with optically active groups have been used as fillers for chromatography for optical resolution of racemic compounds. For artificially synthesized amino acids, bases or acidic compounds derived from them, tartaric acid, or optically resolved arylethylamines, the targets that can be optically resolved are limited, and so far, it has not been possible to separate them. There has been a desire for a separating packing material using a new optically active substance that can be applied to compounds for which conventional methods have not been used.

[Means for Solving the Problems] As a result of intensive study on these conventional problems, the present inventors have developed a new optically active group that can be applied to compounds that cannot be separated using conventional separation packing materials. We have discovered a separation filler consisting of □, and have completed the present invention. That is, the present invention provides the following general formulas (1-1) to (1-4)
The present invention relates to a separating agent in which any one of the optically active groups represented by is supported on a carrier.

HH MaPh＞(-(IHOPh...C-OHOI
II I 11R1) C-N-
Cll-(XZ R1...(nee N-CH-C
XZi II Mu IIHR2)
(R2 l H MaPh>(-OHOPh...C-0HQI I
I II IIH1・+)-N-
C) l-CXZ R1>C-N-CH-CXZ
i II i II+(R2HR
2 (However, Ph represents a phenyl group, R1 represents an optionally branched alkyl group having 1 to 4 carbon atoms, and R2 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, or Indicates 6 to 10 aryl groups.

Further, X represents a 10-group or a -5-group, and I and Z represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a metal. ) Next, the present invention will be explained in detail.

(Optically active group) In the present invention, the optically active group is the following general formula % HH MaPh5-C-OHQ Ph...C-01
101,11111 R'>(-N-CH-CXZ R"...('
Knee N-C)! -(':XZ: 11
M 11 HR2) I RQ HH MaPh＞(-OHOPh...C-OHOI I
I I IIR1・C, -N-
C) l-CXZ R1>c-N-CH-CXZ
: l'l il+ HR2HR2 (However, ph represents a phenyl group, R1 represents an alkyl group having 1 to 4 carbon atoms which may be branched, and R2 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. group or an aryl group having 6 to 10 carbon atoms.

Further, X represents a 10- group or an -S- group, and Z represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a metal. ) More specific details of this optically active group are as follows.

That is, in the general formulas (1-1) to (1-4), R2 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms. Furthermore, X represents a 10-group or a -5-group, and Z represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a metal. More specifically, R1 is a methyl group, ethyl group, isopropyl group, 5ec-butyl group, t
An example is the ert-butyl group. Examples of R2 include a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a tolyl group, and a naphthyl group.

Examples of the alkyl group having 1 to 10 carbon atoms for Z include methyl group and ethyl group, and examples of metal salts include copper, zinc,
Nickel, iron, cobalt, magnesium, calcium,
Examples include sodium and potassium.

(Carrier) The carrier used in the present invention may be an organic substance or an inorganic substance. Organic materials include polystyrene, polyamide, and polyacrylate! There are filling base materials made of polymeric substances such as ・Inorganic materials include inorganic filling base materials such as silica gel, alumina, and glass beads, but these may be mixtures or composites, and other elemental compounds may also be used. It may also be a reaction product with. These carriers are preferably in the form of particles, with a particle size of 0.1 μm to 1000 μm, preferably 1 μm.
~100 μm. Further, these carriers are preferably microporous ones with a large surface area, and the pore diameter is from 10 to 100 mm. 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 supporting a carrier and an optically active compound with or without a spacer. The amount retained is 0.1 to 100% by weight, preferably 1% by weight based on the carrier.
~10% by weight.

A more specific synthesis method is as follows.

Synthesis method of optically active group> Specifically, the optically active group that is a characteristic part of the present invention is an optically active form of erythro-2-amino-1-phenyl-1-propatol (norephedrine), that is, (IS ,
2R) form (2) or 1R12S) form (3), or (IR,2R) form (IR,2R) of threo-2-amino-1-phenyl-1-propatool (norpsoidephedrine).
4) or (Is, 2S) form (5) can be obtained as a starting material.

HH map h＞C-θHPh...C-0RC)13returnt''
-, -Nl2 C'H3...CN)1
2m old
HHH MaPh)C-CIHPh...t”-(l)1(]H
3...CNl2
C) 13Thc-Nl2muIt
H(4)'
(5) (However, ph indicates a phenyl group.) That is, alkylation was performed using each optically active substance and a carbomethylating agent such as ethyl bromoacetate or a substituted carbomethylating agent such as methyl chloropropionate. After that, the ester moiety is converted into a metal salt with sodium hydroxide or sodium hydrosulfide, and then converted into an acid or converted into another metal salt. Alternatively, the racemate may be used for reaction and then optically resolved. These optically active substances preferably have high optical purity, but do not necessarily need to be pure.

Furthermore, as will be described below, in the case of 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 binding 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 silica A coupling agent is used.

Other items that can be used include: That is, the general formula (1
-1) to (1-4), the above conditions can have a relatively strong interaction with a trifunctional or higher functional substance or carrier having a reactive group without impairing the optical activity of the optically active group. Examples include monofunctional substances that satisfy this requirement. For example, the general formula (1-
When the optically active groups of 1) to (1-4) are residues that have formed amides with carboxylic acids and their derivatives such as acid anhydrides, acid halides, and esters, residues that have reacted with halides, epoxides, etc. , residues reacted with alkyl acids, imines, and then reduced, and residues reacted with long-chain aliphatic monocarboxylic acids or their derivatives, long-chain monohalides, monoepoxides, etc. An example is a group.

1) Method of chemically retaining> As a method of chemically bonding the optically active groups of general formulas (1-1) to (1-4), silica gel treated with a silane coupling agent, 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 with an amino group is possible.Also, an amide reaction with an amino group and a carboxylic acid or its derivative can be performed. Chemical bonding can also be achieved by alkylation by substituting an amino group with a halide or supersyl group, or by urea bonding with isocyanic acid.However,
A silane coupling agent to which optically active groups of general formulas (1-1) to (1-4) have been bonded in advance may be reacted with the inorganic filling base material. In addition, a polymerizable compound to which an optically active group of the general formula (1) has been bonded in advance may be used as a filler by homopolymerization or copolymerization with a polymerizable compound such as °, p-chloromethylstyrene, chrycidyl, etc. Examples include methacrylate, acrylic acid and its derivatives, and compounds in which optically active groups of general formulas (1-1) to (1-4) are bonded in advance to methacrylic acid and its derivatives.

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-1-phenyl-1-propatol (norephedrine), that is, (Is, 2R ) form or (IR,2S) form, or (IR,2R) form or (IS) form of trio-2-amino-1-phenyl-1-propatur (norpseudoephedrine).

The amino group of the 2S) body is reacted with a spacer or carrier or a polymerizable compound, and then alkylated using a carbonyl methylating agent such as ethyl furomoacetate or a substituted carbonyl methylating agent such as methyl chloropropionate. , and thereafter may be treated in the same manner to form a metal salt.

For example, as shown in the following equation (6), (IR,2S)-2
-Amino-1-phenyl-1-propatol ((IR,
After alkylating 2S)-norephedrine) using ethyl bromoacetate, the ester moiety was hydroxylated with thorium to form a sodium salt, and then 3 was added as a spacer.
- It can be supported by reacting glycidyl groups of silica gel with glycidoxypropyltrimethoxysilane, and then converted into metal salts such as copper salts.

phs--NiOHNa0H l + BrCH2CQOC2H5-
-Ej [3-C-N)12 Ph>C-OH ■ CH3b-1: -N)l-CH2-COONaPh)
C-01(/ \ l + Ym(C)130)nSi(C)12
)a-0-CH2Cl(-C)12(H3>C-NH-
CH2COONa uSO4 QI C)12Cθ2CLJ1/2! I Ym(CH30)nSi-C)12cH2cH2-0-
CH2()ICH2-N -CH4CH3HO-1'r
4Ph (However, Ph represents a phenyl group, Y represents silica gel, and m and 11 are integers whose total sum is 3.) Furthermore, as shown in the following formula (7), (IR, 2S)-2-
Amino-1-phenyl-1-propatol ((IR,2
S)-norephedrine) as a spacer 3
- After reacting with glycidoxybrobyltrimethoxysilane, alkylation is performed using ethyl bromoacetate, and the ester moiety is further converted into a sodium salt with sodium hydroxide and supported by reacting it with silica gel,
It can then be converted into metal salts such as copper salts.

Ph>C-OH/\ 1 + Ym(CHaO)nSi(C)1z)3-
0-CI(2cI(CH2Cl13ThC-NH2OHH(Ct(30)3S i -C)+2cH2cH2-0
-CH2C)1012-NH-(-g CH3)10-
C-Ph BrCf12COOC2H5 0)I CH2CO2C2H5 (C)+30)351-C)12c82c)12-0-
CH3COCH3-N -(14CH3穣HO-C-4Ph NaO)l O)I CH2Cf:12Na (ChO)3Si-CH2CH2CH2-0-CH2C
) IC) Iz-N-Cf14CH3t+o-c4ph Silica kale (2LISO4 0)I CH2C02Cutz2 I Ym(CH30)nS i -CH2CH2CH2-0
-CH3COCH3-N -CH4C)+3LidHO-C4Ph (However, Plq represents a phenyl group, Y represents silica gel, and m and n are integers whose total is 3.) Physically Holding method〉 Examples of physical methods include general formulas (1-1) to (
A hydrophobic group such as a long-chain alkyl group is introduced into the optically active group of 1-4), and this is adsorbed onto silica gel or activated carbon that has been given hydrophobicity, or an organic polymer having a hydrophobic group. can hold.

(Optical resolution method) As means for obtaining the optically active substance of the present invention using the above-mentioned separating agent, there are chromatography methods such as gas chromatography, liquid chromatography, and thin 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 compounds or optical isomers change depending on the developing solvent, so it is desirable to consider various developing solvents.

[Example 7] 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.

The capacity ratio (1('), separation coefficient (α), and degree of separation (Rs) are determined by the following formulas, respectively.

[(retention time of enantiomer) - (taed time), separation coefficient of the volume ratio of the more strongly adsorbed enantiomer (α): □ Distance separation (Rs) between both peaks of the enantiomer and the more weakly adsorbed enantiomer = 2X □ Sum of the bandwidths of both peaks Example 1. Synthesis of (IR,2S)-2-ethoxycarbonylmethylamino-1-phenyl-1-propatol.

(IR,2S)-2-amino-1-phenyl-1-propatol ((IR,2S)-norephedrine) 1.
21 g are dissolved in 10 ml of methylene chloride and stirred at room temperature. To this was added 1.50 g of ethyl bromoacetate dissolved in 10 ml of methylene chloride and stirred for 3 hours, then 1.2 ml of triethylamine was added and stirring was continued. (Room temperature, 2 and a half hours) After confirming the completion of the reaction by TLC, methylene chloride was distilled off and replaced with benzene. After removing triethylamine/hydrogen bromide 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 1.55 g (82″0
), and TLC on silica gel (methylene chloride:methanol-11=9:1) gave one spot. When this was purified by a silica gel column using a solvent of hexane-ethyl acetate 1:1, 1.48 g (78 $) of (IR, 2S) -2-ethoxycarbonylmethylamino-1-phenyl-1-propatol was obtained. Ta. The physical properties of this compound are as follows.

Specific optical rotation; [αko22-40 +2.4' (C0,
414, EtOH) infrared absorption spectrum (IR) value (K
Br): 3470, 1?47.1455.1241,
1148.703 cm-1 Proton nuclear magnetic resonance spectrum (II (-NMR) value (CDC13): δ0.78
(d, 3H, j near H2).

1.22 (t,, 3) t, j near) 12), 2.
74 (m, 3H) 3.30 (S, 2H), 4
．． 08 ((1, 2H, j=71(z).

4.57 (d, IH, J=4)1z), 7.23
(s, 5t()ppm Example 2. (IR, 2S
)-2-Carboxymethylaminonyphenyl-I-propatur monosodium salt synthesis.

1.45 g of the ethyl ester obtained in Example 1 was dissolved in 15 m of ethanol, and 3.2 m of a 1N aqueous sodium hydroxide solution was added. was added and hydrolyzed at room temperature.

After the solvent was distilled off, the residue was dried under vacuum to obtain a solid (1.17 g). The physical properties of this compound are as follows.

Infrared absorption spectrum (IR) value (KBr): 3400,
1600.1415.1000.760.700cm1
Example 3. (lR,2s) −2 obtained in Example 2
- Reaction of carboxymethylamino l-phenyl-1-propanol monosodium salt with glycidoxypropylsilaned silica gel.

1.17 g of monosodium salt was dissolved in methanol (99,5'
E) Silica gel [Developosil 100] dissolved in 20ml and treated with glycidoxyprobylsilane
-5.5 μm (Nomura Chemical)] 7. Add Og and leave at room temperature for 6 days. After filtering the silica gel and washing with methanol, it is prepared as a copper salt in an aqueous copper solution.

It is presumed that the structural formula of the obtained substance is something similar.

OR' OHC) 12cO2cut/2
Silica case-110-5i-C) 12c82c) 12-0
-C)12C)I(H2-N CH4CH31,1
R' No-C4Ph (however, in the formula R
', R'' indicates that either one or both of them is a methyl group, or that both or one of them are the same silica gel. Also, Pb indicates a phenyl group.) Application Example 1 Optical resolution of various racemic compounds was carried out using the packing material obtained in Example 3. That is, the above packing material was used in a stainless steel column for high performance liquid chromatography (25 cm x
0.46 cmφ) and 0.25 mM ERiM steel water solution) at a flow rate of 0.5 ml/min (35°C)
Optical resolution of various racemic compounds was carried out, and good results were obtained as shown in Table 1.

Table-1 Racemic compound Volume ratio Separation factor 'Lk for resolution
'o α Rs O Shiichivaline 7.50 8,28 1.10
1.10DL-isoleucine 8,94 9.90
1.11 1.15OL-tert-leucine6.
58 7.65 1.16 1. OQ [ratio - Proline 9,73 8.74 1.11 0.87
[) L-7/l, Guinin 9.05 9.75 1.0
8 0.55HCI salt DL-asparagine 4.39 3.75 1.17
1.380 - Asparagine 5.22 6.05
1.16 1.06 Acid Phenyl 10.2 11.6 1.14
1.15 Alanine OL-Tyrosine 8.28 10.1 1.22
1.51D Shiichisujin HCI salt? , 43 7.1
5 1.04 ----D Serine 4.4
0 4.72 1.0? 0.56DL-Threonine 4,61 5.04 1.09 0.83Table-1Continued Racemic compound Volume ratio Separation factor Separation degree 'L
k'o α Rs DL-trypto 16.2 18.7 1,15
0.83 Fan 0L-N- to 2 BZ-F 9,92 9
,10 1.09--Nylalanine 0L-N-CBZ-3,563,341,07--Alanine 0L-N-CBZ-4,744,361,09--Valine DL-N-C8Z-3,503, 1? 1.10
0.95 Asparaquine

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,
There are chemical formulas, tables, etc.▼(1-4) (However, Ph represents a phenyl group, R^1 represents an alkyl group having 1 to 4 carbon atoms which may have branching, and R^2
represents 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 an -O- group or a -S- group, and Z represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a metal. )