JPH02237939A - Optical resolution of compound having carboxylic acid group - Google Patents

Abstract

PURPOSE:To enable to partially optically resolve various carboxylic acids to provide the optically active carboxylic acids in high selectivities by employing an optically active porphyrin derivative or a metal salt thereof as a transporting carrier in a liquid membrane method. CONSTITUTION:When a racemic compound having a carboxylic acid group such as an amino acid is subjected to an optical resolution process, the optical resolution is performed by a liquid membrane method employing an optically active porphyrin N-substituted product organic acid complex metal complex of formula I or II (R1-12 is H, <=20C monovalent hydrocarbon group or carboxylic acid derivative wherein R2 is <=10C monovalent hydrocarbon group; the groups of at least one pair selected from the pairs of R1 and R2, R3 and R12, R4 and R11, R3 and R10, R6 and R9, and R7 and R8 is different from each other; M is Zn, Mn, Fe, Co, etc.; X is halogen, etc.). The method permits to optically resolve various carboxylic acids partially and the modification of the substituent of the porphyrin provides the objective optically active carboxylic acid in a high asymmetric selectivity. The method is profitable.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for optical resolution of racemic compounds having a carboxyl group such as amino acids. [Prior Art] Generally, there are enzymatic methods, inoculation methods, acylase methods, diastereomer methods, chromatography methods, etc. for obtaining optically active forms of compounds having carboxylic acid groups such as amino acids. Among them, high-performance liquid chromatography and diastereomer methods are mainly used. Although high-performance liquid chromatography is effective on a laboratory scale, it is difficult to use on an industrial scale, and diastereomer methods are difficult to use on an industrial scale. There are disadvantages such as the need for additional reaction and decomposition steps before and after the process. In addition, for optical resolution by liquid film transport, D. J. CraIll et al. (J-Amen. CheI1
．． Soc. 101 4941 (1979)) and J.
M. Lehn. (J. CheIl. Soc.
, Comm 949 (1978)) is known. [Means for Solving the Problem] The present inventors have discovered that racemic compounds having carboxylic acid groups can be efficiently optically resolved by using an optically active polyphyllin derivative or its metal complex as a transport carrier in a liquid film method. They discovered this and completed the present invention. That is, the present invention provides: (1) Optically active general formula (1) (II) [wherein R + "R t is a monovalent group selected from hydrogen and a hydrocarbon group having 20 or less carbon atoms, or The group consisting of a carboxylic acid derivative, Ra, is a monovalent group selected from hydrocarbon groups having carbon atoms of 10 or less, and R, and R!R
s and RI! , R4 and RII, R, and R,. , R, and R
9 R't and R. At least one of the combinations is not equal. M is a metal selected from zinc, manganese, iron, cobalt, nickel, copper and aluminum, and X is a halogen or carboxylate. (If M is aluminum,
The number of X is 2)] or porphyrin N-
This is an optical resolution method for racemic compounds that uses a metal stirrup of a substitute to optically resolve racemic compounds containing carboxylic acid groups using a liquid film method. The N-substituted porphyrin or its metal complex used as a carrier for the liquid film method of the present invention is [Rl and R z R
x and R+tSRa and Rll, Rs and RI. ,R,
and R 9 R 'r and R1, the fewest combinations (
As is clear from the statement "both sets are not equal", N
It is a porphyrin derivative that is asymmetric about the Ra and NH groups. In general formula (1) or CI[], R and -R are hydrogen, a chain alkyl group such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-bentyl group, an iso-propyl group, etc. group, iso-butyl group, sea-butyl group, tar
A branched alkyl group such as a t-butyl group, an unsaturated hydrocarbon group such as a vinyl group or an allyl group, a phenyl group that may have a substituent, a benzyl group that may have a substituent, etc. 20 or less, preferably monovalent groups selected from hydrocarbon groups having 10 or less carbon atoms in terms of ease of synthesis and solubility, and carboxylic acid derivatives that are esters of acetate groups, propionate groups, butyrate groups, etc. Examples include groups. Ra is a chain alkyl group such as methyl group, ethyl group, n-probyl group, n-butyl group, n-bentyl group, iso-
proyl group, iso-butyl group, see-butyl group, t
a branched alkyl group such as an ert-butyl group, a vinyl group,
Unsaturated hydrocarbon groups such as allyl groups, hydroxyalkyl groups, carboxylic acid derivatives such as esters, phenyl groups that may have substituents, and! Examples include hydrocarbon groups having 10 or less carbon atoms, such as a benzyl group which may have an A group. Among the above-mentioned examples, N-methylethioborphyline I and N-methyl-2.7,12.17-tetrahexyl-3.8,13.18-tetramethylborphyline are particularly preferred. The optically active form represented by general formula (1) can be obtained by optically resolving the corresponding racemate. The method of optical separation is not particularly limited. Methods of dividing diastereomers or diastereomeric salts based on differences in physical properties such as solubility, methods of dividing diastereomers or diastereomeric salts by asymmetric crystallization (physical method), asymmetric resolution using enzymes or living organisms themselves (biological method) ) method and chromatography. Among these, the method using chromatography is the most preferred. Chromatography includes paper chromatography, gas chromatography, and high performance liquid chromatography. In particular, recent high-performance liquid chromatography technology, both hardware and software, has become extremely sophisticated, and direct optical resolution using high-performance liquid chromatography is a very simple method and is particularly preferred. Direct optical resolution by chromatography requires the introduction of an asymmetric environment into the phase system, and this method includes methods using eluents containing optically active additives and methods using optically active stationary phases. ．． The latter method is more advantageous when the purpose is preparative separation, as it does not require processing such as removing additives from the eluate. As the stationary phase, cellulose tris (3,5-dimethylphenylcarbamate) (manufactured by Daicel) or the like is used. General formula CI1
The metal complex represented by ) is obtained by reacting the optically active N-substituted voluphyrin obtained above with a metal halide or an organometallic compound, such as N-methylethioborfinate zinc acetate, N-methylethioborfinate zinc acetate, N-methylethioborfinate zinc acetate, -Methylethioborfinate zinc chloride, etc. To carry out the optical resolution method of the present invention, the optically active compound represented by the general formula (1) or (II) prepared above is dissolved in a solvent such as methylene chloride, and taken into a U-shaped tube. Add an aqueous electrolyte solution such as sodium hydroxide containing a racemic compound having a carboxylic acid group to one side of the U-shaped tube, and add an aqueous electrolyte solution such as hydrochloric acid or sodium chloride to the other side, and stir. By appropriately selecting the optically active form represented by the general formula (!) or (n) used as a carrier, it is possible to obtain an optically active form of a compound having carpon #R in excess of D-form or L-form. Compounds having a carboxyl group that can be used in the present invention include amino acids such as phenylalanine and phenylglycine, bebutides such as alanylalanine, and asymmetric carbon atoms such as mandelic acid and α-methoxybrobionic acid. Examples include carboxylic acids having a camphane skeleton such as camphanic acid, dicarboxylic acids such as tartaric acid, etc. Optical resolution of N-substituted vorufiline) Optical resolution of N-substituted vorufiline was performed using cellulose and tris(3,5-dimethylphenylcarbamate) as the chiral stationary phase.
was adsorbed onto silica gel and packed into a column, and was analyzed by high-performance liquid chromatography. Fractionation was performed using n-hexane-isobutyl alcohol-diethylamine as an eluent to obtain two components with different retention times. These two components were confirmed to be optical isomers from CD spectra. Reference Example 2 (Production of Metal Complex) Optically active N-monosubstituted vorufiline Q obtained in Reference Example 1
, 1 mmol in an eggplant-shaped flask, and then added 3.1 mmol of methylene chloride. j, zinc chloride 100■, acetonitrile 1
0- was added and allowed to react at room temperature for 3 hours. After the reaction was completed, methylene chloride and acetonitrile were removed under reduced pressure. After dissolving the obtained dried product in methylene chloride, water was added and shaken to remove unreacted zinc chloride. Methylene chloride was removed under reduced pressure to obtain N-1 substituted borfinate zinc chloride as a liquid membrane transport carrier. Examples 1 to 7 N-monosubstituted porphinate zinc chloride of the carrier obtained in Reference Example 2 0. A methylene chloride solution containing 0.3 m+gol was placed in a U-shaped tube with an inner diameter of 11 vm and a height of 100 mm. DL-amino acids 0.6 mm on one side of the U-tube
0 including 1. IN-Sodium hydroxide aqueous solution 6nd
and 0. to the other side. IN-hydrochloric acid aqueous solution 6- was added and stirred at 10°C using a magnetic cooler. 0 every predetermined time. The I N-hydrochloric acid aqueous solution phase was sampled and 0. IN-0.0 from the aqueous sodium hydroxide phase. IN - The amount of amino acids transported to the hydrochloric acid aqueous solution phase is expressed as U
Determined by V absorbance. Transport amino acid L/D or D
/L ratio was determined by high performance liquid chromatography using a column packed with octadecyl silica gel after reacting amino acids with 2,3,4,6-tetra-0-acetyl-β-D-glucopyranosyl isothiocyanate. Table 1 shows the L/D or D/L ratio of amino acids at the initial stage of transport. If the carrier synthesized from N-monosubstituted vorufiline, which has the smaller retention time in high-performance liquid chromatography obtained in Reference Example 1, is used, an amino acid with an excess of L-form is obtained, and when the other carrier is used, an excess of D-form is obtained. It was shown that the following amino acids could be obtained. Example Day 0.1N monohydrochloric acid aqueous solution was replaced with 0.1N aqueous hydrochloric acid solution. 1 mol/
Liquid membrane transport of 1N-penzyloxycarbonyl-DL-alanine was carried out in the same manner as in Examples 1 to 7 under the conditions listed in Table 1, except that the sodium chloride aqueous solution of Example 1 was used. The L/D ratio of N-penzyloxycarbonylalanine sent by M was determined by high performance liquid chromatography using the optical isomer separation column described in Reference Example 1. The results are shown in Table 1.

Example 9 DL-mandelic acid was transported through a liquid film in the same manner as in Example 8 under the conditions shown in Table 1. L of transported mandelic acid
/D ratio is 0. Determined by comparative luminosity in an aqueous solution of IN-hydrochloric acid. The results are shown in Table 1. *3 Carrier (1) C & HI3 CI{s
CHs carrier (2) - C H . −@
・T body (3) -C, H, carrier (4) 〃 CtH
s Example 10 18 Liquid membrane transport of DL-mandelic acid was carried out in the same manner as in Example 9, except that N-methylethioponolephylline hydrochloride was used instead of N-methylethioporphynate zinc chloride. Ta. When a carrier synthesized from optically active N-methylethioborphyriine I, which has a smaller retention time in high-performance liquid chromatography obtained in Reference Example 1, is used, mandelic acid with an excess of L-isomer can be obtained, and the transport rate is lower. is 9
%, the L/D ratio of mandelic acid was 1.04. [Effects of the Invention] The optical resolution method of the present invention allows various carboxylic acids to be separated by a liquid film axis method using an optically active organic or inorganic acid salt of a monosubstituted vorufirin N or a metal complex of a monosubstituted vorufirin N. can be partially optically resolved, and by changing the substituent group of voluphyrin, the desired optically active carboxylic acid can be obtained with higher chiral selectivity. Furthermore, the present invention is an industrially excellent optical resolution method that can resolve large amounts of racemic compounds by catalytically recycling the carrier. Trainee: Nippon Soda Co., Ltd.

Claims (1)

[Claims] (1) Optically active general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 to R_1_2 are selected from hydrogen and hydrocarbon groups having 20 or less carbon atoms. Ra is a monovalent group selected from hydrocarbon groups having 10 or less carbon atoms, and R_1, R_2, R_3
and R_1_2, R_4 and R_1_1, R_5 and R_1_
At least one of the combinations of 0, R_6 and R_9, and R_7 and R_8 is not equal. M is a metal selected from zinc, manganese, iron, cobalt, nickel, copper and aluminum, and X is a halogen or carboxylate. (When M is aluminum, the number of An optical resolution method for racemic compounds, which is characterized by optical resolution of racemic compounds by a liquid film method.