JP3467709B2 - Method for selective extraction and separation of optical isomers - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention provides a mixture of β-aminoalcohol or an optically active substance of β- (substituted amino) alcohol which is useful as a pharmaceutical or an intermediate of a pharmaceutical, boric acid and / or borate and 1 , 2-diol or β-
Method of selectively extracting and separating one optically active substance of a mixture into one liquid phase by extracting and separating between two liquid phases of an aqueous phase and an organic phase in the presence of an optically active substance of (substituted amino) alcohol and a pharmaceutical or A mixture of optically active 1,2-diols useful as an intermediate for pharmaceuticals is prepared from boric acid and / or borate and 1,2-diol, β-aminoalcohol or β- (substituted amino) alcohol. In the presence of the body 2
The present invention relates to a method of performing extraction and separation between liquid phases to selectively extract and separate one optically active substance of a mixture into one liquid phase.

[0002]

2. Prior Art and Problems to be Solved by the Invention
Examples of using tartaric acid diesters for the optical resolution of a mixture of optically active diol compounds, β-amino alcohols or β- (substituted amino) alcohols include mobile phase or stationary phase of liquid chromatography (for example, a). C. Pe
tterson and HW Sturmann, J. Chromaotogr. Sci.,
22 , 441 (1984) .b) Y. Dobashi and S. Hara, J. A
m. Chem. Soc., 107, 3406 (1985) .c) Y. Dobashi and
S. Hara, Tetrahed. Lett., 26 , 4217 (1985) .d) Y. Do
bashi and S. Hara, J.Org. Chem., 52., 2490 (198
7). C. Pettersson, E. Heldin and HW Stuurman,
J. Chromatogr. Sci., 28, 413 (1990) .f) E. Heldi
n, NH Huynh and C. Pettersson, J. Chromatogr. S
ci., 585, 35 (1991). ] And a stationary phase carrier for gas chromatography [eg, a) K. Nakam
ura, T. Saeki, M. Matsuo, S. Hara and Y. Dobashi,
Anal. Chem., 62 , 539 (1990) .b) Y. Dobashi, K. N aka
mura, T. Saeki, M. Matsuo, S. Hara and A. Dobashi,
J. Org. Chem., 56 , 3299 (1991). ]]

On the other hand, although it is well known that 1,2-diols and β-amino alcohols form a complex with boric acid, diols such as tartaric acid diester and boric acid and / or Or an example in which the optical isomers are resolved by using together with a salt thereof,
Of course, the extraction method is not chromatography.

[0004] In addition to the above-mentioned literatures, a stationary phase having tris (3,5-dimethylphenylcarbamate) -cellulose supported on silica was used as an example in which the optical isomers of aminoalcohol were separated by liquid chromatography. Example (Y. Okamoto, M. Kawashima, R. Aburatani, K.
Hatada, T. Nishiyama and M. Masuda, Chem. Lett.,
(1986), 1237.], using bovine serum albumin as a stationary phase [S. Allenmark, AM Krustlovic ed., "Chi .
ral Separation by HPLC ", Willey / Ellis Horwood, New
York, see P285 (1989)], alpha ₁ '- acid glycoprotein (α _1' -acid glycoprotein) stationary phase as the Example [G. The
Schill, I. Wainer and S. Barkan, J. Liq. Chromatog
r., 9, 621 (1986)], using ovomucoid as a stationary phase [J. Haginaka, J. Wakai, K. Takahashi, H. Ya.
suda and T. Katagi, Chromatographia, 29 , 587 (199
0).], An example using a stationary type of Pirkle type [WH Pirkle and JA Burke, J. Chromatogr.,
557, 173 (1991)], N, N'-3,5-dinitrobenzoyl- (1R, 2R) -diaminocyclohexane was immobilized on silica gel [B. Gallinella, F. La Tor.
re, R. Cirilli and C. Villani, J. Chromatogr., 639,
193 (see 1993)], but there is no known example in which they are allowed to coexist with boric acid and / or salts thereof for optical resolution.

[0005]

DISCLOSURE OF THE INVENTION The present inventors have made two liquids, an organic phase and an aqueous phase, in the presence of not only an optically active 1,2-diol but also boric acid and / or borate. Upon extraction and separation between the phases, Formula I:

[Chemical 5] [In the formula, X represents O, NH or NR ¹⁰¹ (R ¹⁰¹ represents an organic group); R ¹¹ represents an organic group; R ¹² , R ¹³ and R
¹⁴ are the same or different from each other and represent H or an organic group; and at least one of the carbon atoms to which R ¹² is bonded and the carbon atom to which R ¹³ is bonded is an asymmetric carbon atom. ] The distribution ratio of the mixture of the optically active substance of the compound represented by the formula to the organic phase between the two liquid phases of the organic phase and the aqueous phase is remarkably high, and the separation ratio is increased due to the difference in the distribution ratio of the optically active substances. Therefore, it was found that the efficiency of optical division becomes very high. Therefore, the present inventor has prepared a mixture of optically active isomers of the compound represented by the above formula I with boric acid and / or borate and 1,
Provided herein is a method for performing selective separation between two liquid phases in the presence of an optically active substance of 2-diol to selectively extract and separate one optically active substance of a compound represented by the formula I into one liquid phase. To do.

The present invention further provides a mixture of an optically active substance of a diol, a boric acid and / or a borate salt and an optically active substance of the compound represented by the above formula I in the presence of an organic phase and an aqueous phase. A method of selectively extracting and separating one optically active substance of a diol into one liquid phase by performing extraction and separation between liquid phases.

The present invention further comprises a mixture of an optically active substance of the compound represented by the above formula I, boric acid and / or borate, and a formula II:

[Chemical 6] (In the formula, R ²¹ represents an organic group; R ²² , R ²³ , R ²⁴ , R ²⁵
And R ²⁶ are the same or different from each other and represent H or an organic group; and at least one of the carbon atoms to which R ²¹ and R ²³ are bonded is an asymmetric carbon atom. 2) of the organic phase and the aqueous phase in the presence of the optically active compound represented by
Provided is a method for selectively extracting and separating one optically active substance of a compound represented by the formula I into one liquid phase by performing extraction separation between liquid phases.

The organic radicals in the definitions of the substituents of the above formulas I and II and the following formula III are hydrocarbon radicals which may contain one or more oxygen, sulfur or nitrogen atoms, eg straight-chain or Branched alkyl group of 1 to 30 carbon atoms, which may be interrupted by 1 to 10 oxygen, sulfur or nitrogen atoms. For example, it is an alkyl group having 1 to 30 carbon atoms such as a methyl group, an ethyl group or a propyl group; an alkoxyalkyl group such as a methoxyethyl group or an ethoxyethyl group. In particular, the organic group which is R ¹¹ or R ²¹ is, for example, an unsubstituted or substituted aromatic ring methyl group, an unsubstituted or substituted aromatic ring oxymethyl group, an unsubstituted or substituted aromatic ring thiomethyl group. Is.

The organic solvent used in the organic phase of the two phases is
An optically active 1,2 that is sparingly soluble in water and an optical resolving agent
A mixture of a diol and an optically active substance of a compound of formula I to be optically resolved; a mixture of an optically active substance of a compound of formula I which is an optical resolving agent and an optically active substance of a 1,2-diol to be optically resolved; Or an optically active form of the compound of formula II which is an optical resolving agent and an optically active form of the compound of formula I to be optically resolved. And the kind of the suitable organic solvent is a combination of the properties of both the optically active 1,2-diol used as a resolving agent and the mixture of the optically active substance of the compound of formula I to be optically resolved, and A combination of the properties of both the optically active substance of the compound of formula I used and the mixture of the optically active substance of the diol to be optically resolved, or optically resolved with the optically active substance of the compound of formula II which is an optical resolving agent. Depending on the combination of both properties of the mixture of optically active compounds of the formula I to be obtained, there is a tendency to differ. Therefore, the selection of a suitable organic solvent should be made by routine work considering the particular combination of mixture of optical resolving agent and optically active substance.

The organic solvent used in the two-liquid organic phase of the present invention may be one kind or a mixture of two or more kinds. It depends on the separation system used and the optically active substance to be optically resolved. On the other hand, it is chemically inactive, has low solubility in water, and has low viscosity at room temperature to the degree of free-flowing, and the separation line between the two liquids can be easily made clear when the two liquid phases are statically separated. The boiling point is 1 which is easy to handle and low in volatility at the extraction and separation operation temperature between the two phases, and easy to recover.
It is a liquid organic solvent at 50 ° C or lower.

Hydrocarbons such as n-hexane; aromatic solvents such as benzene, toluene, xylene, nitrobenzene and chlorobenzene; halogenated hydrocarbons such as methylene chloride, chloroform and tetrachloride. Carbon, 1,2-dichloroethane, 1,1,1-trichloroethane; alcohols such as n-butyl alcohol; ethers such as isopropyl ether, esters such as methyl acetate, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, methyl isobutyrate, etc. Is mentioned.

Routine selection of the organic solvent is carried out in the presence of the corresponding optical resolving agent, the resolving aid boric acid and / or its salt, water and a mixture of the optically active substance to be resolved. The organic solvent is tested to measure the distribution ratio of the optically active substance to be separated into the organic phase from the aqueous phase, and the preferable separation coefficient with high selectivity of the optically active substance from the organic solvent having an appropriate distribution ratio. It suffices to select an organic solvent that gives In that case, two or more kinds of organic solvents may be used to form the two-phase system, and the two-phase system may be prepared, for example, chloroform-methanol-water (100: 15: 100).

More specifically, L-didodecyl tartrate (L-DDT) is used as an optical resolving agent, and (±) -pindolol (0.5 mM relative to the total amount of water and an organic solvent) is used as a mixture to be optically resolved. As a splitting aid, 40 mM
Methylene chloride, chloroform and 1,2-dichloroethane are selected as suitable organic solvents when the aqueous boric acid phase is used according to the routine work described above.

The optically active 1,2-diol used as the optical resolving agent may be any one which is biasedly dissolved in one of the two liquid phases which are not mixed with each other. As an example, formula III:

[Chemical 7] (Wherein R ³¹ and R ³³ are the same or different from each other, and are R ³³¹ OC (O) —, R ³³² OH ₂ C— or an unsubstituted or 1 to 3 halogen atom such as fluorine. Represents a phenyl group substituted by an atom, a chlorine or bromine atom, an alkyl group having 1 to 5 carbon atoms or an alkoxy group, and R ³³¹ and R ³³² are the same or different from each other and represent an organic group; R ³² and R ³⁴ are the same or different from each other and represent H or an organic group, but at least one of the carbon atom to which R ³¹ is bonded and the carbon atom to which R ³³ is bonded is an asymmetric carbon atom. There are diols represented by the atom. As another example, D- or L-tartaric acid diester such as dialkyl ester, dihexyl ester, diaralkyl ester such as dibenzyl ester, or the above diester consisting of different ester moieties, such as alkyl ester-cyclohexyl ester diester, alkyl ester- Diesters of aralkyl esters, derivatives of optically active sugar alcohols such as threitol, optically active hydrobenzoins such as hydrobenzoin itself and benzene-substituted derivatives thereof,
Those which can be easily derived from optically active 1,2-diols, for example, diols which can be stereoselectively produced from tartaric acid diesters, epoxy compounds or olefins by using a catalyst or an enzyme, for example, 1-phenyl-1,2-propane. Diol, 1-acetoxy-3-phenyl-2,3
-Such as propanediol.

These optically active diols have such a distribution ratio that the optically active substance to be optically resolved can be distributed between the organic phase and the aqueous phase in an appropriate ratio in the two-liquid phase distribution system of the present invention. It is desirable to be selected so that it can be. The selection is done in a routine manner.

Examples of those which are biased to the organic phase to a desirable extent when chloroform is used as the organic solvent include D- or L-diesel tartrate such as D- or L.
-Di (C5-C20 alkyl) esters of tartaric acid, especially di- (C8-C12 alkyl) esters, dibenzyl esters, dicyclohexyl esters and the like. In this case, D-dibutyl tartrate is not preferable because it also dissolves in the aqueous phase.

These tartaric acid diesters are esterified by dehydrating the corresponding tartaric acid and alcohol by azeotropic distillation (the azeotropic solvent is benzene, for example) in the presence of p-toluenesulfonic acid using a Dean-Stark apparatus. It is produced by a method of post-treatment by a conventional method.

It is necessary that the concentration of the optically active 1,2-diol used is sufficiently higher than the molar concentration of the mixture of the optically active substances to be optically resolved, and the concentration based on the total amount of the organic solvent and water is. Preferably, the concentration in the range close to the total molar concentration of boric acid and / or its salt is, in other words, about 0.1 to 10 times, specifically about 1 to 150 mM, but it is not always specified within this range. Not something. The choice of such concentration depends on the optically active 1,2-diol being bound to the optically active form of the compound of formula I to be optically resolved via boric acid and / or borate. Presumed.

The pH of the aqueous solution containing boric acid and / or its salt is usually in the range of 5 to 12, but its preferable pH value varies depending on the type of the optical resolving agent and the optically active substance to be optically resolved. To do. For example, when chloroform is used as an organic solvent and L-didodecyl tartrate is used as an optical resolving agent, when (±) -pindolol is optically resolved, aqueous boric acid (pH 5.2) and (±) -propranolol are optically resolved. A mixed water of boric acid and sodium borate (pH 6.7) is preferable.

For adjusting the pH, a buffer solution other than boric acid may be used and boric acid may be added thereto. For example, when chloroform is used as an organic solvent and L-dodecyl tartrate is used as an optical resolving agent, and (±) -propranolol is resolved, 100 m in 50 mM phosphate buffer (pH 5.3) is used.
Aqueous phase in which boric acid is dissolved so that M becomes
Will be 5.2. ) Is preferred (the pH in this case is not always the same as when using an aqueous solution of a mixture of boric acid and sodium borate).

The types of borate used as a partitioning aid include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium salts, ammonium salts and the like. The borate can be obtained by adding the corresponding borate directly to water, or by adding a predetermined amount of an alkali metal or alkaline earth metal hydroxide to boric acid water to obtain a desired pH.
Use the one adjusted by neutralizing the value.

The concentration of boric acid and / or its salt, which is a resolving aid, in the aqueous solution at the time of starting the resolving by the two-liquid separation is sufficiently higher than the concentration of the mixture of the optically active substances to be optically resolved. Required, specifically 1 to 150
Although it is about mM, it is not always specified within this range. Selection of such a concentration is
It is presumed that the 2-diol is responsible for coupling via the boric acid and / or borate with the optically active form of the compound of formula I to be optically resolved.

The compound of formula I to be optically resolved is a compound capable of binding via a boric acid and / or a borate salt to the above-mentioned 1,2-diol which is an optical resolution agent. Examples of β-amino alcohols or mixtures of β- (substituted amino) alcohols which are to be optically resolved include optically active substances such as pindolol, propranolol, alprenolol, chlorprenaline, bunitrolol, arotinolol, atenolol and terbutaline. There is a mixture of activators.

The concentration of the mixture of the optically active substances to be optically resolved is such that the addition of the optically active 1,2-diol and boric acid and / or its salt causes selective distribution in the organic phase and the aqueous phase. Is preferred. If the concentration of the mixture of the optically active substances having low water solubility to be optically resolved is too high, the mixture before the optical resolution may be biased toward the organic phase side, and the optical resolution may be poor. Usually, the concentration is in the range of 0.05 to 20 mM, preferably 0.1 to 5 mM. However, the concentration is not necessarily limited to these ranges.

For example, chloroform is used as an organic solvent for the organic phase, and 100 mM (in chloroform) of a tartaric acid diester (for example, n-octyl, n-dodecyl, as a resolving agent).
Cyclohexyl or benzyl diester), when using 50 to 150 mM boric acid as a resolution aid, 2
It is preferred to use 0.1-5 mM (±) -pindolol, propranolol or alprenolol relative to the total amount of liquid phase. Further, in the case of (±) -propranolol, it is also preferable to perform separation under the same conditions as described above except that (boric acid + sodium borate) is used instead of boric acid.

The temperature of the extraction and separation operation between the two phases is usually-
10 ° C to a temperature lower than the lower boiling point of water or the organic solvent used and close to the lower boiling point, or 0 to 60 ° C,
The temperature is preferably outside air temperature, more preferably 0 to 25 ° C.

The case where the optical resolving agent is an optically active 1,2-diol has been described above. The optical resolving agent is an optically active substance of the compound represented by formula I, and the mixture of the optically active substances to be optically resolved is that of 1,2-diol; and the optical resolving agent is represented by formula II. The same relationship should be chosen for the organic solvent and the boric acid and / or borate, even when the compound is an optically active compound and the mixture of optically active compounds to be optically resolved is that of the compound of formula I. There is. The selection of the compound of formula I or formula II as an appropriate optical resolving agent from the optically active substance is preferably carried out by a routine selection operation.

The above-mentioned two liquid phases are simply the two liquid phases in a single separating tank.
Not only liquid phase, continuous countercurrent separation system, liquid-liquid chromatography, concentric rotation countercurrent-continuous separation system (e.g., H. Nishizawa, K. Tahara, A. Hayashida and Y.
Abe, Anal. Sci., 9, 611 (1993)].

[0029]

EXAMPLES The present invention will be described in more detail with reference to the following reference examples and examples. The present invention is not limited to these examples. Reference Example 1: Synthesis of tartaric acid diesters L-Didodecyl tartrate was prepared by synthesizing L-tartaric acid using a Dean-Stark apparatus. L-tartaric acid 15 g, dodecyl alcohol 41 g, p-toluenesulfonic acid 1 g
600 ml of benzene is added to and the water produced by reflux is removed. After cooling, benzene was distilled off, the residue was dissolved in dichloromethane and washed with a saturated aqueous sodium hydrogen carbonate solution and water to remove unreacted tartaric acid and sulfonic acid. After drying over anhydrous magnesium sulfate and filtering, the solvent is distilled off under reduced pressure to obtain a white solid. This is recrystallized from hexane to obtain 46.6 g (yield = 96%) of didodecyl tartrate. (Mp 64 ° C. [α] _D +2.9 (C = 10.
0, CHCl ₃ )) D-Dartartrate is similarly obtained from D-tartaric acid. Similarly, other alcohols can be used to obtain the corresponding tartaric acid diesters.

Example 1: Test showing the effect of the presence of boric acid CHCl ₃ as organic solvent, L-tartaric acid didodecyl ester as optical resolving agent (used at a concentration of 100 mM in CHCl ₃ ), optical activity to be optically resolved. Using 0.5 mM (±) -pindolol based on the total amount of the two liquid phases as a body mixture and 100 mM boric acid as a partitioning aid in the aqueous phase, shake well and perform an extraction experiment between the two liquid phases Did. The partition ratio was measured by the HPLC method described in Example 2.
As shown in Table 1, the distribution ratio was large, and a difference in the extraction rate between the optical isomers was recognized (in other words, the separation coefficient was larger than 2). Therefore, in order to confirm that the large distribution ratio and the difference in extraction ratio are specifically realized by the combination of the optically active 1,2-diol and boric acid used, the same concentration as above is confirmed. Then, the boric acid aqueous solution was replaced with 100 mM acetate buffer or 100 mM phosphate buffer, and the same experiment as described above was carried out. As a result, the extraction rate of each isomer of pindolol into the organic phase was extremely small and the separation coefficient was also relatively small. (See Table-1).

[0031]

[Table 1]

(Note) ^*

[Equation 1] However, the distribution ratio was calculated from the area of the chromatogram as follows. That is, the initial amount of pindroll (0.5 m
The area S _{0 of the} chromatogram obtained by injecting an amount corresponding to 1 ml in M) into the HPLC is determined. Next, 1 ml of the aqueous phase after extraction is evaporated and analyzed by HPLC to determine the area S _a of the obtained chromatogram. The area S ′ of the chromatogram corresponding to the amount of pindolol transferred to the organic phase after extraction is (volume of the two liquid phases at the time of extraction (V)
From the above S _a and S ₀ , S ′ = S ₀ −S _a is calculated. The distribution ratio D is obtained by experimentally _obtaining S ₀ and S _a .

[Equation 2] Was calculated as ^**

[Equation 3] ^*** These values of α are not very accurate because the distribution ratio itself is too small.

Example 2: (±) -pindolol with L-didodecyl tartrate and aqueous boric acid in chloroform,
Optical resolution of (±) -propranolol, (±) -alprenolol 4 ml of a chloroform solution of 100 mM L-didodecyl tartrate as an optical resolving agent and 1 mM of (±)
-100 mM boric acid solution in which pindolol is dissolved 4
ml was put in a container, tightly stoppered, and shaken well at room temperature. After separating the two liquid phases, concentrating the aqueous phase and examining the composition of the optical isomers of pindolol by HPLC (see note below) shows that one isomer was selectively extracted into the organic phase. (See FIG. 2 (a)). The concentration ratio of the optical isomers at this time was 60:40. As an example of β-alkylaminoalcohol, in addition to pindolol, the results of similar treatment of propranolol and alprenolol using the same two-phase system were combined, and the separation coefficient α was calculated from the HPLC data. It becomes the value described in. From these results, it is understood that the mixture of the optically active substance of β-alkylamino alcohol can be optically resolved by the method of the present invention. (Note) For analysis by HPLC, HPL manufactured by JASCO Corporation
The C880 series was used. Chiralcel OD-R (Daicel) was used for the pindolol and propranolol columns. The eluent used was 0.1 M KPF ₆ : acetonitrile = 60: 40. For the analysis of alprenolol,
Ultron Es-PhCD (Shinwa Kako) is used, the eluent is 20m
M phosphate buffer (pH 4.6): acetonitrile = 8
0:20 was used.

[0034]

[Table 2] (Note) ^*

[Equation 4]

Example 3: Effect of ester group distribution ratio and separation coefficient when optically active tartaric acid diesters are used as resolving agents CHCl ₃ as an organic phase and L-tartaric acid diesters as optical resolving agents (100 mM- CHCl ₃ solution) 4 ml,
4 ml of 100 mM aqueous boric acid solution as an optical resolution aid,
(±) -as a mixture of optical isomers to be optically resolved
Pindolol (0.5 mM relative to the total amount of the two liquid phases) is used, and these are shaken well at room temperature in a sealed container. After separating the two liquid phases, the aqueous phase was concentrated and the composition of the optical isomers of pindolol was examined in the same manner as in Example 2. The results are shown in Table-3.

[0036]

[Table 3] See Note to Table-1 for distribution ratio ^* and separation factor ^** .

When CHCl _{3 is} used as an organic phase, an aqueous boric acid solution is used as an optical resolution aid, (±) -pindolol is used as a mixture of optically active substances to be optically resolved, and L-tartaric acid diester is used as the optical resolution agent. , L-tartaric acid diester was dioctyl ester, didodecyl ester, dicyclohesyl ester and dibenzyl ester, the result of the separation factor was good. However, with di-n-butyl ester, the partition ratio was low and a good separation coefficient could not be obtained. It is considered that this is not suitable for separation by the extraction method because di-n-butyl ester also shows solubility in the aqueous phase. It is preferable to use an optical resolving agent that is soluble in only one phase.

Example 4: Effect of type of organic solvent in organic phase on distribution ratio and separation coefficient L-tartaric acid didodecyl ester (40 mM in organic solvent in organic phase) as an optical resolving agent, and boric acid ( 40 mM aqueous solution), (±) -pindolol (0.5 mM relative to the total amount of the two liquid phases) is used as a mixture of optically active substances to be optically resolved, and the organic solvent shown in Table 4 is used as the organic solvent. Then, the partition ratio and separation coefficient of the optical isomers described in Example 1 were tested. The results are shown in Table-4.

[0039]

[Table 4] See Note to Table-1 for distribution ratio ^* and separation factor ^** . Considering the distribution ratio and the separation coefficient in the table, halogenated hydrocarbons, particularly halogenomethanes and halogenoethanes, especially dichloromethane, chloroform and 1,2-dichloroethane are preferable as the solvent.

Example 5: Effect of Boric Acid Concentration on Partition Ratio and Separation Coefficient Chloroform was used as the organic solvent of the organic phase, and (±)
-Constant pindolol concentration (0.
5 mM) and the amount of boric acid with respect to the optical resolving agent L-tartaric acid didodecyl ester (100 mM in chloroform) was changed to examine changes in the partition ratio and the separation coefficient (α) described in Example 1. The results are shown in Fig. 1. If the amount of boric acid is sufficient for the mixture of the optically active substance to be optically resolved and the optical resolving agent, it will not significantly affect the distribution ratio and the separation coefficient. The distribution ratio tended to decrease with the increase. It was found that increasing the concentration of boric acid from 25 mM to 150 mM had a slight positive effect on the separation factor.

Example 6: Effect of repeating extraction several times The aqueous phase of (±) -pindolol extracted once under the same conditions as in Example 2 was further added 4 times with 100 mM didodecyl tartrate solution. The result of extraction and measurement by HPLC (see Example 2) is shown in FIG. 2 (b). The concentration ratio after a total of 5 extractions was 77:23.

Example 7: Extraction of (±) -pindolol with D-didodecyl tartrate 100 mM dissolved in 100 mM D-dodecyl tartrate in chloroform and 1 mM (±) -pindolol
The two-phase system of boric acid aqueous solution was thoroughly shaken at room temperature. After separation of the two liquid phases, the aqueous phase was concentrated and the composition of pindolol was examined by HPLC (see Example 2). As shown in FIG. 3, the isomerism completely opposite to that when L-didodecyl tartrate was used. It can be seen that the body was selectively extracted into the organic phase. The concentration ratio of the optical isomers at this time was 40:60.

Example 8: 100 m as an optical resolution aid
Effect of (±) -propranolol on partition ratio and separation coefficient when M- (borate-sodium borate) is used 100 mM of a solution of L-didodecyl tartrate in chloroform and 1 mM of (±) -propranolol were dissolved.
mM boric acid-sodium borate aqueous solution (pH 6.7)
The two-phase system is shaken well at room temperature. After separating the two liquid phases, the aqueous phase was concentrated and the composition of each optical isomer was examined by HPLC (see Example 1). The results are shown in FIG.
The concentration ratio of the optical isomers at this time was 62:38.
With propranolol, the distribution ratio is small as shown in Table 5 when sodium borate is not added, but when sodium borate is added and the pH of the aqueous phase is adjusted to 6.7, the distribution ratio increases with each isomer. Appropriately divided into two phases.

[0044]

[Table 5] See Note to Table-1 for distribution ratio ^* and separation factor ^** .

[0045]

As described above, when a specific optically active substance is used as an optical resolving agent and a mixture of the specific optically active substances is selectively extracted and separated between two liquid phases of an organic phase and an aqueous phase. In addition, when boric acid and / or sodium borate is allowed to coexist, the separation ratio of the optically active substance increases together with the distribution ratio, and the optical resolution efficiency thereof remarkably increases.

[Brief description of drawings]

FIG. 1 shows (±) − for changes in the concentration of boric acid.
The changes in the distribution ratio (D1, D2) and the separation coefficient (α) of each pindolol isomer are shown.

FIG. 2 (a) shows (±) -pindolol 10
The chromatogram of the aqueous phase after one extraction with a chloroform solution containing 0 mM of L-didodecyl tartrate is shown, and (b) shows the chromatogram of the aqueous phase after five extractions. The numbers below indicate the area ratio of the chromatogram.

FIG. 3 shows a chromatogram of the aqueous phase when (±) -pindolol was extracted once with a chloroform solution containing 100 mM D-didodecyl tartrate. The numbers below are
The area ratio of the chromatogram is shown.

FIG. 4 is a graph showing an aqueous solution of sodium borate-containing (±) -propranolol in boric acid (pH 6.7) at 100 m.
1 with a chloroform solution containing M L-didodecyl tartrate
The chromatogram of the water phase at the time of extracting twice is shown. The numbers below indicate the area ratio of the chromatogram.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI C07D 209/32 C07D 209/32 // C07M 7:00 C07M 7:00 (58) Fields investigated (Int.Cl. ⁷ , DB) Name) C07B 57/00 340 C07B 57/00 350 C07B 57/00 360 C07C 213/10 C07C 217/30 C07D 209/32

Claims (5)

(57) [Claims] 1. Formula I: [In the formula, X represents O, NH or NR ¹⁰¹ (R ¹⁰¹ represents an organic group); R ¹¹ represents an organic group; R ¹² , R ¹³ and R
¹⁴ are the same or different from each other and represent H or an organic group; and at least one of the carbon atoms to which R ¹² is bonded and the carbon atom to which R ¹³ is bonded is an asymmetric carbon atom. ] A mixture of optically active compounds of the compound represented by the following formula is extracted and separated between an organic phase and an aqueous phase in the presence of boric acid and / or borate and an optically active substance of 1,2-diol. A method of selectively extracting and separating one optically active substance of the compound represented by the formula I into one liquid phase. 2. A mixture of optically active diols, boric acid and / or borate and a compound of formula I: [In the formula, X represents O, NH or NR ¹⁰¹ (R ¹⁰¹ represents an organic group); R ¹¹ represents an organic group; R ¹² , R ¹³ and R
¹⁴ are the same or different from each other and represent H or an organic group; and at least one of the carbon atoms to which R ¹² is bonded and the carbon atom to which R ¹³ is bonded is an asymmetric carbon atom. ] A method of selectively extracting and separating one optically active substance of a diol into one liquid phase by performing extraction and separation between two liquid phases of an organic phase and an aqueous phase in the presence of an optically active substance of the compound represented by 3. Formula I: embedded image [In the formula, X represents O, NH or NR ¹⁰¹ (R ¹⁰¹ represents an organic group); R ¹¹ represents an organic group; R ¹² , R ¹³ and R
¹⁴ are the same or different from each other and represent H or an organic group; and at least one of the carbon atoms to which R ¹² is bonded and the carbon atom to which R ¹³ is bonded is an asymmetric carbon atom. ] A mixture of optically active compounds of the compound represented by the formula: boric acid and / or borate, and a compound of formula II: (In the formula, R ²¹ represents an organic group; R ²² , R ²³ , R ²⁴ , R ²⁵
And R ²⁶ are the same or different from each other and represent H or an organic group; and at least one of the carbon atom to which R ²¹ is bound and the carbon atom to which R ²³ is bound is an asymmetric carbon atom. ) In the presence of the optically active substance of the compound represented by the formula (1), extraction and separation are carried out between two liquid phases, an organic phase and an aqueous phase, and one optically active substance of the compound represented by the formula I is selectively extracted into one liquid phase. How to separate. 4. The method according to claim 1, wherein the 1,2-diol is tartaric acid diester and the compound represented by the formula I is β-amino alcohol or β- (substituted amino) alcohol. 5. The organic solvent of the organic phase is methylene chloride, chloroform or 1,2-dichloroethane, and the organic group bonded to the oxygen atom of the ester moiety of the tartaric acid diester is an alkyl group having 4 or more carbon atoms or a benzyl group. Or a tartaric acid diester which is a cyclohexyl group, wherein β-amino alcohol or β- (substituted amino) alcohol is pindolol, propranolol, alprenolol, chlorprenaline, bunitrolol, arotinolol, atenolol or terbutaline. Method.