JPH02101050A - Separation of optical isomer - Google Patents

Abstract

PURPOSE:To advantageously obtain an optical isomer by optically resolving an amine by using a separating agent prepared by supporting a specific optically active crown ether on a carrier. CONSTITUTION:A compound shown by formula II (m is 0 or 1; R1-R3 are H or substituent group) or formula III (R4 is H or substituent group; A is cyclic atomic group having 3-6 members of ring and no C2 symmetry axis) is optically resolved by using a separating agent prepared by supporting an optically active crown ether shown by formula I (Ar is optically active bifunctional aromatic group; R is H or 1-30C alkyl; n is 4-8) on a carrier. 2-Aminobutane, etc., may be cited as the amine shown by formula II and 3-amino-epsilon-caprolactam, etc., as the amine shown by formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for optical resolution of amines having one or more asymmetric structures and primary amino groups in the molecule.

[Prior art and problems to be solved by the invention] Hitherto, diastereomer methods, crystallization methods, enzyme methods, separation membrane methods, column methods, etc. have been known as methods for separating optical isomers of amines. ing. Among these, the column method has the advantage that it is possible to completely separate optical isomers, and continuous operation is also possible if the SOAPEX method is used.

However, there are only a few columns that can optically resolve amines, and most of them use the ligand exchange method as the separation principle. Optical isomers must have one or more functional groups capable of position bonding, and the eluent must contain metal ions such as copper ions, and in some cases other optically active compounds. The drawback was that it was unsuitable for preparative separation.

On the other hand, as a column method that does not rely on the ligand exchange type, a method using a packing material made of polystyrene or silica gel chemically bonded (covalently bonded) with an optically active or low-carbon compound (J
, Am, Chem, Soc,, 97°1259
(I975) and the same magazine 101.3035 (I979)
)It has been known. However, this method is difficult to use for water-soluble samples such as amines because the number of theoretical plates in the column is low, the synthesis of the packing material is complicated and expensive, and an organic solvent must be used as the eluent. had the disadvantage of being difficult to apply.

Means for Solving Problems c] The present invention provides a method for solving amine The present invention has been achieved by overcoming the above-mentioned drawbacks in optical resolution of similar types.

In the general formula (I), Ar is an optically active divalent aromatic group, such as one represented by the following general formula (II).

(wherein A and B are a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, or an isopropyl group, or an aryl group having 6 to 10 carbon atoms, such as a phenyl group, or Represents an aralkyl group having 7 to 9 carbon atoms, such as a benzyl group. A and B may be different groups, but are preferably the same.) In addition, R' and R'' are hydrogen atoms, carbon A straight or branched alkyl group having 1 to 30 carbon atoms, preferably 6 to 20 carbon atoms, an aryl group having 6 to 18 carbon atoms, or an aralkyl group having 7 to 30 carbon atoms. However, R' and R'' other than hydrogen are A of the condensed ring.
, B may be substituted anywhere other than the substitution position, and one digit each may be used, but up to five digits each may be substituted. Also, R', R
” may be different.) In the general formula (I), R is a hydrogen atom or a carbon number of 1
-30 straight or branched alkyl group, preferably an alkyl group having 6 to 20 carbon atoms, R may be bonded to any carbon of the cyclic oxyethyl group, and the number is 1 to 1
2, preferably 1-3. n represents an integer of 4 to 8, preferably 5 or 6.

In the general formula (II), A or B is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include a methyl group, an ethyl group, an isopropyl group, and a 6-carbon alkyl group. -10 aryl groups, such as phenyl, or aralkyl groups containing 7 to 9 carbon atoms, such as benzyl.

In the general formula (II), R' and R''' are preferably hydrogen atoms or alkyl groups having 4 to 30 carbon atoms, such as long-chain alkyl groups such as C8, -2+ CI6+ cue. Ru.

Further, examples of the aryl group and aralkyl group include the same ones as those exemplified in A or B.

R' and R'' other than hydrogen are preferably substituted at the 6 and 6° positions, but may be substituted at 2 to 5 positions.

The amines to be separated by the separation method of the present invention are represented by the following general formula (III-a) or (■-b).

(In the formula, m is O or 1, and R,, R2, and R3 are each different and represent a hydrogen atom or a substituent, but R,, R2゜R
There are no particular restrictions on 3, and examples include hydrogen atoms, alkyl groups such as methyl, ethyl, propyl, and butyl groups, and the alkyl chain may contain an unsaturated moiety. In addition, there are substituted alkyl groups, such as hydroxymethyl and benzyl groups. Other examples include alkoxy groups such as methoxy groups, aromatic groups such as phenyl groups, substituted aromatic groups such as chlorophenyl groups, hydroxyl groups, hydroxycarbonyl groups, and alkoxycarbonyl groups (eg methoxycarbonyl groups). However, when m is 0, two of R,, R2, R, are hydrogen atoms or carboxyl groups, and R,, R2, R
, excludes combinations of hydrogen atoms, methyl groups, and phenyl groups. ) Specific examples of the amines represented by the general formula (nl-a) include the following.

2-amitubukun, 2-amino-3-methylbutane, 2
-amino-1-propatur, l-amino-2-propaturpe 2-amino-l-pentanol, 2-amino-1-hexanol, 2-amino-2-phenylethanol, 2-amino-1-phenylethanol, Efthro-2-amino-1,2-diphenylethanol, 4-amino-3-(p-chlorophenyl)butyric acid, 3-amino-
2-methylpropionic acid, 3-amino-1-phenylbutane, 2-amino-1 phenylpropane.

(In the formula, R4 is a hydrogen atom or a substituent, but there is no particular restriction, such as a hydrogen atom, an alkyl group such as a methyl group,
Examples include ethyl group and propyl group, and the alkyl chain may contain an unsaturated moiety. In addition, there are substituted alkyl groups such as hydroxymethyl and benzyl groups. Alkoxy groups, such as methoxy groups, aromatic groups, such as phenyl groups, substituted aromatic groups, such as chlorophenyl groups,
Further examples include a hydroxyl group, a hydroxycarbonyl group, an alkoxycarbonyl group (eg, a methoxycarbonyl group), and the like. A represents a cyclic atomic group having 3 to 9 ring members and having no C2 axis of symmetry, and may include a divalent aromatic group as a part of the ring structure. Note that in addition to carbon, nitrogen, oxygen, sulfur, etc. may be included in the ring structure. The ring may further have a side chain such as an alkyl group or a carbonyl group. Alternatively, the ring structure may be a combination of a plurality of rings. However, when R4 is an amino group, A has an asymmetric center. ) As for the amines represented by the general formula (I-b),
Specifically, 3-amino-ε-caprolactam, 1.2.
Examples include 3.4-tetrahydro-1-aminonafuculene and 3-aminoquinuclidine.

The crown compound represented by the general formula (I) used in the present invention is, for example, the following general formula (IV) (wherein, Ar has the same meaning as above, and M is an alkali metal, such as sodium or potassium. etc.) is added to the optically active aromatic derivative represented by the general formula (wherein,
(X is chlorine, iodine or tosyloxy group, R and n have the same meanings as above) A dihalide or cytosylated product of penta or hexaethylene glycol, or an alkyl substituted product thereof, under an inert gas atmosphere, For example, it can be produced by reacting in approximately equimolar amounts in an organic solvent such as tetrahydrofuran, dioxane, N,N'' dimethylformamide, or the like.

The optically active raun compound used in the present invention is R form, 8
Any optical isomer of the body may be used.

In the present invention, the carrier on which the optically active or brown compound is adsorbed and supported has a hydrophobic surface (reverse phase adsorbent). In order to obtain such a surface-hydrophobic carrier, the surface of the carrier may be modified with a hydrophobic compound according to a conventionally known method.

In this case, examples of the carrier include various conventionally known carriers, such as silica, alumina, magnesia, and silica-alumina. On the other hand, hydrophobic compounds include hydrocarbons, such as lower alkyl groups such as methyl, propyl, and butyl, higher alkyl groups such as octyl, dodecyl, and octadecyl, and aryl groups such as phenyl and alkylphenyl. Examples include compounds having a haloalkyl group containing fluorine, chlorine, etc. Furthermore, methods for modifying the surface of the carrier using a hydrophobic compound include conventionally known methods such as physical adsorption methods and chemical bonding methods, and are not particularly limited. In the present invention, conventionally commercially available inorganic and organic surface hydrophobic carriers can be used as they are.

The filler for separating optical isomers used in the present invention is produced by physically adsorbing and supporting an optically active fat-soluble crown compound on the carrier having a hydrophobic surface. In this case, there is no particular restriction on the amount of crown compound to be adsorbed, but in order to obtain good separation results, it is necessary to
It is preferable to adjust the amount to 10-6 mol or more and 0.1 mol or less, preferably 10-5 mol or more and 10-3 mol or less per c.

This adsorption and loading is preferably carried out by filling a column with the surface-treated carrier, and passing the optically active fat-soluble crown compound into a mixed solvent of an organic solvent and water of a certain composition in the packed column. The solution is circulated using a pump.

In this case, the concentration of the crown compound in the circulating solution decreases with time due to the adsorption of the crown compound onto the carrier, so water is added to the solution for a certain period of time to reduce the solubility of the crown compound in the circulating solution and then re-incubate. Circulate through the column. By sequentially repeating such operations, a packing material adsorbing a crown compound at a predetermined concentration can be produced directly in the column. The organic solvent may include one that is compatible with water and dissolves the crown compound;
For example, in addition to alcohols such as methanol, ethanol, and propatool, acetonitrile, tetrahydrofuran, and the like are used.

In addition to the methods described above, this adsorption and loading can also be carried out by dissolving the crown ether in a soluble solvent, mixing well with the carrier, and distilling off the solvent with an air stream under reduced pressure or pressurization, or is dissolved in a soluble solvent,
This can also be carried out by mixing well with a carrier and then stirring and dispersing the solvent in a liquid that is incompatible with the solvent.

The eluent used in the present invention is pure water, a dilute aqueous salt or acid solution, or a mixture of the eluent and an organic solvent compatible with water, such as methanol or acetonitrile.

The temperature during separation may be any temperature as long as the eluent does not condense or boil, but is preferably between -10°C and
It is carried out at a temperature of 50°C.

〔Example〕

Next, the present invention will be explained in more detail with reference to Examples, but it goes without saying that the present invention is not limited to the following Examples.

The equipment used in this example is as follows.

Liquid pump: Nippon Bunko TRI ROTARV Shimadzu LC-6A UV detector: Nihon Bunko UVIDl EC-100-r
V Fluorescence detector: FP-110 manufactured by JASCO Corporation Data processor: CD386 manufactured by Nippon Chromato CR- manufactured by Shimadzu Corporation
3A In Table 1, 1'', 2°1α are defined as follows.

Capacity ratio (k,', 2°) (retention time of enantiomer) - (dead time)
time separation coefficient (α) Capacity ratio of enantiomers adsorbed more strongly than enantiomers adsorbed weakly Example-1 A: Preparation of optical isomer separation column General formula (I) In, Ar: 3.3°-diphenyl-1,1°-binaphthyl-2,2'-diyl, R; H
50 mg of eight optically active Raun compounds represented by the following structural formula (VT) having Sn; 5 were dissolved in an approximately 80% methanol aqueous solution.

= 15 This solution is circulated for 3 hours in a backed column filled with a 4φ x 100L (mm) stainless steel column filled with diphenylsilane-treated silica gel (particle size 7 μ) manufactured by Chemco, which is a carrier surface-treated with diphenyldichlorosilane. . Next, in this operation, water is added to the circulating fluid sequentially to reduce the methanol content in the circulating fluid (the methanol content of the final circulating fluid is approximately 30%), thereby almost completely removing the crown compound from the column. was adsorbed onto a surface-treated carrier.

B: Separation of optical isomers The above optical isomer separation column was connected to a high-performance liquid chromatography device (JASCO BIP = 1 type pump, Soma Optics 13101A type UV detector, Rheodyne sample injector installed) to separate various amines. Table 1 shows examples of separation of racemic forms of the following types.

Zero 1 Book 2 Eluent A + pH 2 perchloric acid aqueous solution B: pH 1 perchloric acid aqueous solution C: pH 2 perchloric acid aqueous solution + 15 Vo 1% methanol D
: pH 1,5 perchloric acid aqueous solution detection method A; UV 200 nm or 210 nm B: OPA color method Excitation wavelength 345 nm Detection wavelength 460 nm Color reagent

Claims (1)

[Claims] 1 The following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (However, in the formula, Ar is an optically active divalent aromatic group.R
is a hydrogen atom or a linear or branched alkyl group having 1 to 30 carbon atoms, and R may be bonded to any carbon on the cyclic oxyethyl group, and the number thereof is 1 to 12. n is 4
Indicates an integer of ~8. ) Compounds represented by the following general formula (III-a) or (III-b) can be obtained by using a separation agent in which an optically active crown ether supported on a carrier ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III-a) (In the formula, m is 0 or 1, and R_1, R_2, and R_3 are each different and represent a hydrogen atom or a substituent. However, if m is 0, two of R_1, R_2, and R_3 are hydrogen atoms, those that are carboxyl groups, and R_1, R_2,
Excludes those in which R_3 is a combination of a hydrogen atom, a methyl group, and a phenyl group. ) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III-b) (In the formula, R_4 represents a hydrogen atom or a substituent. A represents a cyclic atomic group with 3 to 9 ring members and no C_2 axis of symmetry. , may contain a divalent aromatic group as part of the ring structure.However, if R_4 is an amino group, it has an asymmetric center in A.) Optical isomers characterized by optical resolution of separation method. 2 R_1, R_2, R_3 are hydrogen atoms, alkyl groups,
2. The optical method according to claim 1, wherein the group is a substituted alkyl group, an alkoxy group, an aromatic group, a substituted aromatic group, a hydroxyl group, a hydroxycarbonyl group, or an alkoxycarbonyl group. 3. The method for separating optical isomers according to claim 1 or 2, wherein Ar is a group represented by the following general formula (II). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the formula, A and B are hydrogen atoms, straight chain or branched alkyl groups with 1 to 6 carbon atoms, aryl groups with 6 to 10 carbon atoms, or 7 carbon atoms. ~9 represents an aralkyl group. A and B may be different. Also, R' and R'' are a hydrogen atom, and an aralkyl group having 1 to 9 carbon atoms.
30 linear or branched alkyl groups, aryl groups having 6 to 18 carbon atoms, or aralkyl groups having 7 to 30 carbon atoms. However, R' and R'' other than hydrogen may be substituted anywhere other than the A and B substitution positions in the condensed ring, and up to 5 of each may be substituted.Also, R' and R'' may be different. . )