JPH0275952A - Packing material for liquid chromatography - Google Patents

Abstract

PURPOSE:To obtain the packing material which is useful for sepn. of various compds. and particularly the optical resolution of isomers and further racemic modifications by using the optically active compd. expressed by the specific general formula as a stationary phase. CONSTITUTION:The modified optically active 1, 1'-binaphtyl-2, 2'-dicarboxylic acid having the axial asymmetrical part expressed by the general formula (where the 1, 1'-binaphtyl-2, 2'-dicarbonyl group part is the optical activator having the configuration of either aR or aS; R1, R2 denote any of a hydrogen atom, chain alkyl group and (S)-or (R)-1-(1-naphtyl)ethyl group) is used as the optically active stationary phase. The application of the packing material over a wide range to the optical resolution of the racemic compds. such as modified d1-alcohol and axial asymmetrical biaryl racemic modifications which are heretofore difficult to be separated is possible in this way.

Description

[Detailed description of the invention] [Industrial application field] The invention relates to the separation of various compounds, especially isomers.

Furthermore, it is a packing material for liquid chromatography useful for optical resolution of racemates, which have been difficult to resolve in the past.

[Prior Art] Stationary phases using various optically active amides have been known. As a packing material for liquid chromatography, J.

Liq, Chromatogr, 9,241 (198
6), J,Liq,Chromatogr,,9,44
3 (1986), J. Chromatogr., 40.
3,275 (1986) and Tosoh Research Report, 32
．． 51 (1988) and others. Optically active substances used in stationary phases that have been known so far include (L)-amino acids, optically active amines, optically active amides, and optically active carboxylic acids. For example (L)-
These include valine, (L)-leucine, (L)-phenylglycine derivatives, (S)-(-)-1-(1-naphthyl)ethylamine derivatives, and citric acid.

The optically active stationary phase is synthesized by forming an ionic or covalent bond between the amino group of the aminoalkyl group grafted onto the silica gel surface and the carboxyl group of the optically active derivative described above. Racemic identification of these optically active stationary phases is generally achieved through hydrogen bond interactions between amide bonds and racemic amide bonds, ester bonds, or hydroxyl groups, π-π
Separation occurs due to minute differences in interaction and steric environment, and hexane-based eluents are mainly used as the eluent.
[Problems to be Solved by the Invention] The basic concept of optical resolution using a stationary phase, which has been known as a hydrogen-bonded optically active stationary phase, is that, as mentioned above, the straight line between the stationary phase and the racemate is The diastereomeric environment formed by these interactions creates a difference in retention force, and optical resolution is achieved.

For this reason, a major objective is to synthesize an optically active stationary phase that can produce a more effective difference, and to achieve a wider range of racemic resolution. however,
In the various optically active stationary phases obtained so far,
The applicability of one stationary phase to the optical resolution of racemates was limited.

That is, the scope is mainly di-amine derivatives.

Although it has become possible to resolve many racemates of di-carboxylic acid derivatives and dl-amino acid derivatives, other racemates, such as dl-alcohol derivatives (especially aliphatic alcohol derivatives), di-epoxy compounds, and even axial Widespread application to the resolution of racemates such as biaryl compounds with chirality has not been possible.

[Means and effects for solving the problems] As a result of intensive studies to expand the range of racemic samples that can be divided as described above, the present invention has been developed based on the general formula [IF] Optical activity 1.1'-binaphthyl-2,2
By using a dicarboxylic acid modified product as an optically active stationary phase, it can be applied to a wide range of optical resolutions of racemic compounds that are difficult to separate, such as dl-alcohol modified products and axially asymmetric biaryl racemates. The present inventors have discovered that a packing material for liquid chromatography can be obtained, and have completed the present invention.

That is, the present invention provides the following formula: is a hydrogen atom, a chain alkyl group, and (S)- or (R)-1-
(1-naphthyl) Represents any ethyl group. ] It provides a packing material for liquid chromatography using an optically active compound represented by the following as a stationary phase.

The present invention will be further explained in detail below.

The optically active 1,1'--binaphthyl-2,2'-dicarboxylic acid moiety represented by general formula [I] can be prepared by a known method, that is, (d I) -1,1--binaphthyl-2,2'-dicarboxylic acid moiety It can be obtained by optically resolving an acid with an alkaloid such as purusin, but it can be efficiently obtained by the methods shown by the formulas [I] and [2] that we have developed.

(aS,S), (aR,S) mixture or (aS,R), (aR,R) mixture [wherein R1 in the amine compound is a phenyl group, l-naphthyl group, and represents an aromatic group such as a 2-naphthyl group. * represents an asymmetric carbon, and the amine compound is an optically active substance with S coordination or R coordination. ] [Formula 2] (Each diastereomer integrated) (aR) or (a S) form [Formula 3 (aR) or (a S) form [Formula [2], [3], Ri is a phenyl group, 1- Represents an aromatic group such as a naphthyl group or a 2-naphthyl group. Binaphthyl monoamide is obtained by recrystallizing the diastereomer mixture obtained in the previous formula [I],
It is an optically active substance, and racemization does not occur during each reaction. ] As shown in the above formula, after reacting di-1,1-binaphthyl-2,2'-dicarboxylic acid with dicyclohexylcarbodiimide, an optically active amine, e.g. (S)-(-)- or (
R)-(+)-1-phenylethylamine, (S)-(
-)- or (R)-(+)-1-(1-naphthyl)ethylamine, the corresponding (aR,S), (a
S.

S) diastereomeric mixture, or (aR,R), (a
A mixture of S, R) diastereomers is obtained.

By recrystallizing them and recrystallizing the mother liquor, the corresponding (aR,S) and (aS,S) or (aR,R) and (
aS, R) diastereomer optically active form can be obtained.

By treating these optically active substances with thionyl chloride, the corresponding optically active 2'-cyano-1.1'-binaphthyl-2-carboxylic acids are obtained. Subsequently, these were hydrolyzed with NaOH or the like to obtain optically active 1.1'-binaphthyl-2'2'-dicarboxylic acid, and it was also confirmed that no reaction racemization occurred.

Another feature of the present invention is that the optically active binaphthyl monoamide carboxylic acid compound obtained by formula [I] can be used as it is as an optically active stationary phase.

Next, the obtained optically active dicarboxylic acid is treated with dicyclohexylcarpodoimide, and then various amine compounds, such as aliphatic primary or secondary amines, or optically active amines (Zenchu optical The optically active compound of the present invention can be synthesized by reacting with a compound (including a chemically synthesized amine).

When using the optically active compound of the present invention as a stationary phase filler, the base material is silica gel.

Porous carriers such as glass beads and diatomaceous earth are used,
It may be spherical or crushed, but spherical is preferable. Particle size is 0.1-1000μm and pore size is 10-100OA
preferably with a particle size of 1 to 100 μm and a pore size of 50 μm.
~500A is good.

Examples of methods for immobilizing the optically active compound on the base carrier include a method in which it is absorbed into the base carrier, a method in which it is immobilized by an ionic bond, a method in which it is immobilized by an amide bond, and the like. Considering the conditions for liquid chromatography, it is preferable to immobilize by amide bond or ionic bond.

In order to form an amide bond or an ionic bond, an amino group-containing organo-3 silane treatment agent is reacted on the surface of the base carrier in a solvent to introduce amino groups onto the surface of the base carrier. The amount of amino groups introduced is 2.0% on a dry carrier basis. On+e
Up to q/g is preferred. The amino group-containing carrier thus obtained is added to a condensing agent used in peptide synthesis, such as dicyclohexylcarbodiimide, N-ethoxycarbonyl-2-ethoxy-1,3-dihydroquinoline, 1-ethyl-3-( In the presence of 3-dimethylaminopropyl)-carbodiimide or the like, the above-mentioned optically active binaphthyl monoamide carboxylic acid is reacted and immobilized. Alternatively, immobilization can be performed by ionic bonding without adding a condensing agent. Of course, it is also possible for both bonds to exist.

The packing material of the present invention can be packed into a column by a known conventional method.

[Effects of the Invention] As explained above, the present invention can be said to be widely effective for optical resolution of dl-alcohol modified products and axially asymmetric racemic products.

[Examples] The present invention will be further explained below with reference to Examples, but the present invention is not limited thereto.

Example 1 l-1 (Preparation of aminoalkyl grafted silica gel) 50 g of silica gel (dried at 150°C and lXl0-'torr for about 6 hours) anhydrous-toluene 300 ml
38.5 g (115 mmol) of 11-aminoundecyltriethoxysilane was added to the suspension, and the mixture was gently heated under reflux for 16 hours under a nitrogen atmosphere. After cooling the reaction suspension, it was filtered through a G4 glass filter and filtered with toluene and THF.
, MeOH, acetone, and ether, and then dried to obtain an aminoundecyl group-grafted silica gel.

Yield: 54.2g Elemental analysis: C%, 9.64; H%, 2.04
;N%, 0.18 Amount of amino group introduced: 0.58 meq/g (from elemental analysis value) 1-2 ((di)-1,1-binaphthyl-2゜2'
-Optical resolution of dicarboxylic acid) 1-2-1 ((d 1)-1,1-binaphthyl-
Condensation of 2,2'-dicarboxylic acid and (L)-1-phenylethylamine) (d I) -15.0 g (43.8 mmol) of -1,1''-binaphthyl-2,2''-dicarboxylic acid -
9.04 g of synchhexylcarbodiimide (hereinafter abbreviated as DCC) in a THF (150 ml) solution under nitrogen atmosphere
100 ml of THF solution of (43,8 mmo 1)
After the dropwise addition over a period of time, the mixture was stirred at room temperature for 2 hours and then heated under reflux for 4 hours. Next, 5 ml of triethylamine and 6.37 g (52.6 mmol) of (L)-(-)-1-phenylethylamine are added to the reaction mixture, and after heating under reflux for an additional 3 hours, the reaction mixture is cooled to room temperature. The precipitated cyclohexylurea was dissolved in chloroform by distilling off the filtrate under reduced pressure, and after sequentially washing with concentrated HCI and H2O, activated carbon and anhydrous MgSO4 were added to the organic phase, and after drying, the solvent was distilled off under reduced pressure. 21.55 g of a reaction mixture (diastereomer mixture) was obtained.

1-2-2 (Separation of diastereomers) $112″-f(S)-1-phenylethyl thus obtained)
Aminocarbonyl-(aR)-1,1°-binaphthyl-
After heating and dissolving 21.55 g of a mixture of 2-carboxylic acid and 2′-+(S)-1-phenylethyl)aminocarbonyl-(aS)-1,1-binaphthyl-2-carboxylic acid in 1°00 ml of acetonitrile, 700 ml of the solvent was distilled off at normal pressure and left to stand at 4°C for 15 hours to form crystals of aS, S) 9°1.
4g (acetonitrile 1 molecule clathrate, 18.8mmq
1, yield of 85.8% [(aS)-1,1-1binaphthyl-2,2-carboxylic acid group L$]) was obtained.

The residue obtained by concentrating the filtrate under reduced pressure was diluted with ethanol 260
After heating and dissolving 150 ml of solvent, 150 ml of solvent was distilled off at 4°C, 15 ml.
After standing for a while, 9.12 g of crude crystals were obtained. Crude crystals 9.12g
Further, after heating and dissolving in 250 ml of ethanol, 150 ml of the solvent was distilled off and the aR,S was left to stand at 4°C for 15 hours.
) body crystal 8.68g (1 molecule of ethanol O-contact, 1
7.7 mmol, yield 80.8% [(aR)-1,1
--binaphthyl-2,2'-carboxylic acid standard]) was obtained.

(aS, S) Body mp: 190.5-192°C [α] 20D--123,3° (cl, 38°CH
C13) Optical purity: 10096d, e, (analyzed by HPLC as methyl ester) I R cITl-': 3260 (NH stretching), 2
930-3060 (aromatic and aliphatic CH stretching),
1595 (7mid C-O stretching) NMR (DMSO-d
6) δ; 6.3~8゜5 (18H, m, aromatic H
, amide H).

4.6 (IH, m, methine H), 2.05 (3H, s
, acetonitrile H), 0.99 (3H, d, methyl H) Elemental analysis (CHNo -CH8CN): Calculated value, C;
78.99%, H; 5.39%, N, 5.76%: Actual value, C, 79° 27%, H, 5.67%, N, 5.29
%(aR,S) body mp: 260-261°C [α] ”OD-+ 183.2° (cl, 01°CH
CL3) Optical purity: 10026d, e, (analyzed by HPLC as methyl ester) NMR (DMSO-d6) δ: 8.30 (IH, d,
amide H), 6.6-8.2 (17H, m, aromatic H), 4.6 (LH, m.

Methine H), 3.4 (2H,q, ethanolmethylene H), 1.00 (3H,t, ethanolmethyl H),
0.79 (3H, d.

Methyl H) Elemental analysis (CHNo -CHOH): Calculated value, C, 7
8,19%, H, 5,95%, N, 2.85%: Actual value, C, 78°25%, H, 6,09%, N, 2.91%
1-2-3 (optical activity 1.1'-binaphthyl-2゜2
’-dicarboxylic acid) 9.14 g (18.8 mm
ol) with SOC1100m1. Add DMF-drops and heat to reflux for 3 hours. Subsequently, SOC1 is distilled off under reduced pressure, and the resulting reaction mixture is dried under reduced pressure to remove purified 1-phenylethyl chloride to obtain a crude nitrile. Use in the next reaction without purification. It was methyl esterified and identified by IR and NMR, and confirmed to be 100% e, e by HPLC.

(aS)-2--cyano-1,1-1binaphthyl-2-
Carboxylic acid methyl ester TRL1cm-1:3050
(Aromatic CH stretching), 2200 (CN stretching, 171
5 (C-0 stretch)), NMR (CDC1a) δ; 6
．． 9-8.3. (12H, m, naphthyl ring), 3.5
6 (3H,s, methyl).

After heating and dissolving the crude nitrile in 130 ml of ethanol, a solution of 10 g of KOH in 30 ml of HO was added, and the mixture was heated under reflux for 5 hours. Subsequently, the reaction solution was distilled off, and the residue contained 12
．． Add 400 ml of 5% NaOH aqueous solution and heat under reflux for 40 hours. After cooling the reaction solution, it was diluted with HO, non-acidic components were extracted with Et20, and the aqueous layer was diluted with aH.
Acidify with Cl and extract with ethyl acetate. After drying the organic layer over activated carbon and anhydrous Mg5O, the solvent was distilled off under reduced pressure, and the resulting product was recrystallized from toluene to give (aS)-1,1--
Binaphthyl-2,2'-dicarboxylic acid, yield 5°84g
(yield 91%).

(a S) Unity: [α] −-125” (
c1.00. O, IN-NaOH), literature value (J.

Chem, Soc, 1955. 124
2) [(2]54G --125,2' (c
1.023,0. 1N-NaOH), optical purity 100%
d, e, (converted to dimethyl ester and confirmed by HPLC) (aR) -1,1-binaphthyl-2,2-dicarboxylic acid was converted using the same method using the obtained (aR,S) form. It can be done in a way.

1-3-1 ((aS) -1,1-binaphthyl-2
, 2''-dicarboxylic acid monoamidation with ethylamine) (aS)-1,1-binaphthyl-2,2-dicarboxylic acid 6.06 g (17.7 mmol).

DCC3.66g (17.7mmol),
2 ml of tri-ethylamine, 1 ml of ethylamine
, 74 ml (26.

6 mmol) by the method of Example (1-2-1) to obtain 7.2 g of a crude product.

The crude product was methyl esterified and purified using a silica gel column (ethyl acetate:hexane, 1:1) to give methyl 2'-2'-dithylaminocarbonyl-(aS)-1,1'-binaphthyl-2-carboxylate. 3.3 g of ester are obtained. Next, the methyl ester was hydrolyzed to obtain 2.68 g (yield: 41%) of 2'-ethylaminocarbonyl-(aS)-1,1-binaphthyl-2-carboxylic acid.

2'-ethylaminocarbonyl-(a 5)-1゜1'
-Binaphthyl-2-carboxylic acid mp: 201.5-202.5°[ffl--152.9° (cl, 02° acetone) Optical purity 100% e, e, (confirmed with optical resolution column) IRνcm- ': 2600~3750,3275°3
045.2950, 2920, 1607°1589.1
55O NMR (CDC13) δ: 6.4-8.0° (13
H, m, naphthyl, amide), 2゜82 (2H, m,
methylene), 0.32 (3H, t, methyl) Elemental analysis (C24H19NO3): Calculated value, C; 78,
03. H,,5,18,N;3. 79゜fruit 71
p+ value, C, 78, 28, H, 5, 03°N, 3.89
゜1-4 (11-aminolandercyl group-bonded silica gel and 2'-ethylaminocarbonyl-(aS)-1,1-
-Concentration of binaphthyl-2-carboxylic acid...Synthesis of optically active stationary phase (1)) 2'-ditylaminocarbonyl-(
aS)-1゜1-1-binaphthyl-2-carboxylic acid 2.0
g (5,41 mmol) and N-ethoxycarbonyl-
2-ethoxy-1,3-dihydroquinoline (hereinafter referred to as EE
3.3 g of the aminoundecyl group-bonded silica synthesized in 1-1 is suspended in 2.5 g (10.1 mmol) of anhydrous DMF solution (abbreviated as DQ), and irradiated with ultrasonic waves for 8 hours. (At this time, the reaction temperature will be 70 to 80°.) Next, the reaction suspension is filtered to remove silica using a 64-glass filter, and the silica is washed sequentially with THF, methanol, acetone, and ether, and then dried under reduced pressure. did.

Yield: 3.58g.

Elemental analysis value 2 0% H% 8%15.96
．． 2.147.1.28 Conversion rate 47% (calculated from 6%) Example 2 2-1 (2--diethylaminocarbonyl-(aS)-
Synthesis of 1,1-binaphthyl-2-carboxylic acid) 2.08 g (8,18 mmo 1) of (aS)-1,1-binaphthyl-2,2-dicarboxylic acid.

DCCl, 69 g (8,18 mmol 1), diethylamine 1.27 ml (12,27 mmol),
Example (1-2-
A crude product was obtained by synthesis according to method 1). This was recrystallized from ethanol and 2'-diethylaminocarbonyl-(
aS)-1,1-binaphthyl-2-carboxylic acid 2.2
7 g (yield 70%) was obtained.

mp:238. 5-239. 5°, [
α Co 20D--150,2" (c 1.01
2. acetone).

IR cm-1: 2500-3700. 30
40. 2950. 2920. 2865. 171
5. 1565, NMR (CDC13) δ; 6.9
~8.1° (12H, m, naphthyl), 2.
6-3. 8 (4H, m, 2-methylene), 1.12
(3H, t.

Methyl), 0.36 (3H, t, methyl) 1-element analysis (C24H19N03); Calculated value, C, 7g, 57, H
, 5,83, N, 3.52, actual value, C; 78.48.
H,5,91,N,3.842-2 (Condensation of 11-aminolandercyl group-bonded silica gel and 2'-diethylaminocarbonyl-1゜1--(aS)-binaphthyl-2-carboxylic acid... Synthesis of optically active stationary phase (n)) 11
-3°3 g of aminolandercil group-bonded silica, 2--
Diethylaminocarbonyl-(a5)-1,1-binaphthyl-2-carboxylic acid 2.0g (5,03mmo
1), using 2.5 g (10°1 mmol) of EEDQ in the same manner as in Example (1-4). It was.

Yield 3.46g Elemental analysis value 2 0% H% 8% 14.11,
2.31, 1.21 Conversion rate 2 30% (calculated from 0%) Example 3 3-1 (2'-+(S)-1-(1-naphthyl)ethyl)aminocarbonyl-(aR)-1 , 1''-binaphthyl-2-carboxylic acid) (aR)-1,1''-binaphthyl-2,2-dicarboxylic acid 3.0 g (8,76
mmo 1), DCCl, 8-1 g (8,76 mmo
l), (S)-1-(1-naphthyl)ethylamine 2
．． Synthesis is performed by the method of Example (1-2-1) using 15 ml (13,14 mmol) and 2 ml of triethylamine to obtain a crude product. This was recrystallized from ethanol/acetone system to yield 3.06 g of 2--((S)-1-(1-naphthyl)ethyl)aminocarbonyl-(aR)-1,1-binaphthyl-2-carboxylic acid. rate 7096
) was obtained.

m, p, :279. 5～280℃
, [α ko 20−+273.1°(cl,
040, THF), optical purity 100% d, e, (HP
(analyzed by LC).

IRνcm-': 2500~3700,3240,3
040, 2950. 1699. 1585. 15
41, NMR (CMSO-d6) δ; 8.6 (IH
.

d, amide), 6.6-8.2 (19H, d,
Methyl), single element analysis (C34H24NO3); calculated value.

0%;82. 57. H%, 4. 89.
H%: 2°83, actual A-1 value, C%: 82.14.
H%; 4.99, H%; 3.09 3-2 (11-aminolandercyl group-bonded silica gel and 2--((S)-1-(1-naphthyl)ethyl)aminocarbonyl-(aR) -1,1″-binaphthyl-2
- Condensation of carboxylic acid...Fixed optical activity) Synthesis of 11(m)) 11-Aminolandercyl group-bonded silica 3°3g, 2
-- f(S)-1-(1-naphthyl)ethyl)aminocarbonyl-(aR) -1,1--binaphthyl-2-
Carboxylic acid 2.0g (4.04mmo I), EED
Q2.5g (10.1mm.

1) in the same manner as in Example (1-4).

Yield 3.5g Elemental analysis value = 0% H% 8%14, 93
．． 2. 40. 1. 12 Conversion rate: 27% (calculated from 0%) Application example 1 The optically active liquid chromatography packing material obtained in Examples 1 to 3 was packed into a column by the slurry method, and a racemic sample was prepared under the following ΔP1 constant conditions. The retention coefficient (
Kl and separation coefficient (α) were determined.

The results are shown in Tables 1-■.

Further, using the optically active stationary phase (m), a Val-3,5-DNB-Bu derivative as a (di)-amino acid modified product, a 1-phenethylamine derivative and a Val-3,5-DNB-Bu derivative as a (di)-amine-3,5-DNB, 2,2′ as an axial inerasemate
-bis(butylaminocarbonyl)-(di) -1,
Chromatograms obtained when 1-dinaphthyl is separated are shown in Figures 1 to 3.

Condition 2 column 4, 611! l I, D,
X 25 am L stainless steel column detector UV-8010 (manufactured by Tosoh) Pump CCPD ('') Temperature 25°C Flow rate 1.0 ml/min Dissolving solution Hexane/alcohol system (ratios are shown in Table 6).

) [Effects of the Invention] As explained above, by using the optically active binaphthyl dicarbonyl moiety as the stationary phase, the filler using the optically active compound of the present invention as the stationary phase can be used to separate racemates that have conventionally been resolved, e.g. It can be applied to the resolution of dl-amino acid derivatives, noic acid derivatives, dl-amine derivatives, di-carboxylic acid: A monomer, axially asymmetric bialichelate racemates, etc., and its synthesis is easy, making it an extremely excellent filler. It is.

[Brief explanation of the drawing]

1 to 3 are chromatograms showing examples of optical resolution using the filler for optical resolution of the present invention. Ala-3,5-DNB-Bu 10
1. 04 5. 601-phenethylamine
20 1.03 6.511-(
1-naphthyl>20 1.1
0 8.09NPC DNB-dinitrobenzoyl, Bu-butyl ester. DNPC-dinitrophenyl carbamate H Ala-3,5-DNB-Bu 10
1. 03 5. 69NPC DNB-nonitrobenzoyl, Bu-butyl ester:
DNPC-dinitrophenyl carbamate table■ Ala-3,5-DNB-Bu 30
1.03 5. 69Val-3,5-DNB-B
u 30 1.03 5. 69Le
u-3,5-DNB-Bu 30 1
．． 07 6. 601-Phenethylamine
30 (ethanol) 1. 03 6. 511-
(1-Naftinori 30 (ethanol)
1. 10 8. 09 Ethylamine DNPC 1-phenethyl alcohol 20
1. 59 6. 021-Phenylpropertool
20 1.67 5. 741-Phenylbutanol 20 1.69
5. 33 Special 1: 'Applicant Tosoh Co., Ltd. Procedure?113-Author (formality) January 5, 1986

Claims (1)

[Claims] General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc. It is an optically active substance with any steric configuration, and R_1 and R_2 are hydrogen atoms, chain alkyl groups, and (S)- or (R)-1-(1
-naphthyl) ethyl group. A packing material for liquid chromatography, characterized in that an optically active compound represented by the following formula is used as a stationary phase.