JPS59216841A - Agent for optical resolution - Google Patents

Abstract

PURPOSE:To provide a novel optical resolution agent consisting of an optically active diacetylenediol derivative and suitable for the separation of antipodes of racemic lactones, lactams, sulfoxides, esters, ketones, etc. CONSTITUTION:The objective agent consists of optically active 1,6-di(halophenyl)- 1,6-diphenyl-2,4-hexadiyn-1,6-diol of formula I (X is halogen) which is synthesized easily by the coupling reaction of the optically active 1-o-halophenylpropargyl alcohol of formula II in an organic solvent such as acetone in the presence of cuprous chloride, pyridine and oxygen. It is effective especially for the optical resolution of the lactones of formula III (Y is O or N; R' is 1-4C alkyl, NH2, OH, etc.), lactams, and cyclic ketones of formula IV (R'' is R'). The molar ratio of the charged resolution agent to the lactone, etc. is preferably 1:4-1:8.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to optical resolving agents, and more particularly to lactones,
The present invention relates to an optical resolution agent that separates racemic enantiomers such as lactams, sulfoxides, esters, and ketones.

(1) It is well known that many active substances have physiological activities such as insect pheromones, fragrances, and antibiotics, and have many uses such as pharmaceuticals, fragrances, and agricultural chemicals.

Conventionally, the synthesis of optically active forms of lactones and lactams has mostly relied on ring-closing reactions of optically active oxyacids and optically active amino acids, and there is no practical method. for example,
Racemic bodies of lactones and lactams are ring-opened to form esters or salts with optically active resolving reagents to form diastereomers, which are subjected to fractional crystallization using the difference in solubility, and then fractionated. An example of this method is to obtain an optically active oxyacid or amino acid through a neutralization or hydrolysis reaction, and then ring-close it again to synthesize optically active lactones or lactams. However, this method requires complicated operations, and has the serious drawback that lactones and lactams in which the brochiral carbon atom is adjacent to a nitrogen or oxygen atom are partially racemized during the ring-closing reaction. Furthermore, I am glad to say that there is no method for optical resolution of ketones.

(2) Purpose and structure of the invention In view of the above-mentioned circumstances, the present inventors have conducted intensive research to develop an optical resolution agent that can optically resolve lactones, lactams, ketones, and other compounds. , 1゜6-'; (halophenyl) represented by the following general formula (r)
-1,6-diphenyl-2,4-hexadiyne-1,6
- It has been discovered that diols (hereinafter referred to as diacetylene diol derivatives) are useful as practical optical resolution agents for lactones, lactams, ketones, etc., and the present invention has been carried out. , especially chlorine, fluorine, and bromine.) The optically active diacetylene diol derivative represented by the general formula (1) is an optically active diacetylene diol derivative having the following structure.
Coupling reaction of o-halophenyl-1-phenylzo(3) lovargyl alcohol (hereinafter referred to as monoacetylene alcohol derivative) in an organic solvent (e.g. acetone) in the coexistence of cuprous chloride, pyridine and oxygen. can be easily synthesized by

Next, a synthesis example in the case of X=C1 will be shown.

So, 48g of optically active monoacetylene monoalcohol derivative CX=CI is 100mj! of acetone and 10 m
When the mixture of β and pyridine is dissolved, 862 μl of cuprous chloride is added, and the reaction is carried out at room temperature for 16 hours while oxygen is passed through the reaction solution at a flow rate of 200 mβ/hour, to precipitate pale blue crystals. The reaction solution was removed, the crystals were dissolved in benzene, washed with an equal volume of 12% hydrochloric acid, and after further washing with water, the benzene layer was dried with sodium sulfate to remove benzene.
43 g of white crystals of optically active diacetylene diol <x=ci> (4) are obtained. The melting point of the product is 175℃
, [α Ri is -106° (1% C1130+1)
There is.

The optically active monoacetylene monoalcohol derivative which is the starting material for the above synthesis is disclosed in Japanese Patent Application No. 57-33011 and Japanese Patent Application No. 57-164 filed earlier by the present inventors.
It can be obtained by the method described in No. 969.

Next, a method for optically resolving lactams and lactones using this optically active diacetylene diol as a novel resolving agent will be described in detail.

First, lactones and lactams that can be separated are of the general formula (II
β-lactones, δ-lactams, γ-lactones, γ-lactams, δ-lactones, δ-lactams, ε-lactones, ε-lactams with n=1 to 4 represented by I) Particularly effective are those in which the prochiral carbon atom is adjacent to the oxygen atom of the lactone ring or the nitrogen atom of the lactam ring. Further, as the ketones, cyclic ketones with n=2 to 5 represented by the general formula (rV) are particularly effective.

(5) 1 0 (m = 2 to 5) (wherein, Y is O or N, R' and Rrr have 1 to 4 carbon atoms
represents a lower alkyl group, amino group, hydroxyl group or carboxyl group. ) At the time of separation, it is appropriate to set the molar ratio of optically active diacetylene diol to lactones, lactams, ketones, etc. to 1:4 to 1:10. Considering crystallization rate and optical purity of separated lactones, lactams, ketones, etc., preferably 1:4 to 1.
:8 is good.

The solvent used in the separation is preferably one that dissolves the optically active diacetylene diol and the lactones, lactams, ketones, etc. to be separated, and that has a small amount of dissolved carbon for the formed clathrate compound.

(6) Examples of such solvents include henzene, toluene, carbon tetrachloride, chloroporum, methylene chloride, ethyl acetate, methyl acetate, petroleum ether, tetrahydrofuran, ethyl ether, etc.; Considering the optical purity of the lactones, lactams, ketones, etc., the most suitable solvent is tetrahydrofuran and an ether-petroleum ether mixed solvent (arbitrary volume ratio).

The amount of solvent used is optically active diacetylene diol 1
It is preferable to use 2 to 10 mA per g, and to use 2 to 3 ml in consideration of the crystallization rate of the clathrate compound and the optical purity of the separated lactones, lactams, and ketones.

The temperature during division is room temperature, and the time required for crystallization varies depending on the lactones, lactams, ketones, etc. to be divided, but it is preferably 5 to 80 hours.

The crystallized optically active diacetylene diol and clathrate compounds such as lactones, lactams, and quinones are collected by filtration, separated by column chromatography (7), or heated under reduced pressure. In some cases, the desired optically active lactones, lactams, and ketones can be separated from optically active diacetylene diol. At that time, the developing solvent of the column chromatography, the temperature and degree of vacuum during separation by distillation, and the guest compound lactones,
It may be selected appropriately depending on the physical properties of lactams, ketones, etc.

The recovered optically active diacetylene diol derivative can be used again as a resolving agent without losing its optical purity even after the above-mentioned operations.

Furthermore, if optically active diacetylene diol derivatives are used as a resolving agent, only one enantiomer of lactones, lactams, and ketones can be included and crystallized, but it is possible to obtain the other enantiomer. In some cases, optically active diacetylene diol derivatives with opposite polarities of optical rotation may be used as the resolving agent, and the resolving operation is no different from the procedure described above.

EXAMPLES The present invention will now be described in more detail with reference to Examples (8), but it goes without saying that the scope of the present invention is not limited to these Examples.

II 1 Optically active (-)-diacetylene diol (X=C, 1
)CtX]'; Knee-122° (1% Ct130Il
), 30 g was dissolved in 75 mA of tetrahydrofuran. When the racemic form of 26H T-valerolactone was dissolved in this solution and left at room temperature for 40 hours, 33 g of needle-shaped white crystals were crystallized. When this crystal was subjected to X-ray diffraction and thermal analysis, it was found to be an inclusion compound in which two molecules of γ-halerolactone were included per one molecule of optically active (-)-diacetylene diol CX=C4>. Ta. The crystals were collected by filtration and petroleum ether-methyl alcohol (volume ratio 11
) After washing with a mixed solvent of 2 to 3 wlHg at room temperature.
It was dried for 16 hours.

The crystals were placed in a distillation pot and heated to a size of 10 mm and 11 g under reduced pressure.
Heated to 0°C and added optically active γ-valerolactone (7,6
g) was obtained. [α] - + 10.7° (neat)
The optically active (+)-γ-valero (9) lactone thus obtained was further divided in the same manner three times to obtain (α)′, 7−+ 16.2° (n
eat) optically active (+)-γ-valerolactone 2
．． I got 4g.

On the other hand, optically active (-) obtained as residue during distillation
-Diacetylene diol<x=c7! > was washed with acetone and then dried at 60° C. for 16 hours under reduced pressure from 2 to 311 figs. As a result, the optically active (-)-diacetylene diol <x=ce> recovered was 29.
4 g, [αC--122° (1%Cl130
H). Therefore, it was recovered with a recovery rate of 98% while maintaining 100% optical purity.

Kai 1 Optically active (-)-diacetylene diol (30 g of - Diacetylene diol (X-C7 and γ-ethyl-γ-butyrolactone (10)) A junction compound was crystallized. After collecting the crystals by filtration, they were added to tetrahydrofuran again and recrystallized. Recrystallization operation After repeating 5 times, the precipitated clathrate crystals were collected by filtration again, washed with a mixed solvent of petroleum ether and methyl alcohol (volume ratio 3:1), and washed at room temperature for 2 to 3 mn.
It was dried under reduced pressure of Ilg for 20 hours. The crystals of the clathrate compound thus obtained (l1g) were placed in a distillation pot, and the crystals were heated to 2mmtl
When heated to 63°C under reduced pressure of
)-γ-ethyl-T-butyrolactone (1.99 g) was obtained.

[α) Knee +18.8° (neat).

30 g of optically active (-)-diacetylene diol was dissolved in 75 m 12 of tetrahydrofuran, and 32.1 g of a racemic form of γ-propyl-γ-butyrolactone was dissolved. Thereafter, the same operation as in Example 2 was carried out to obtain 10.3 g of (-)-diacetylene diol (X=CI) and γ-propyl-γ-butyrolactone clathrate crystals. 8 under reduced pressure of 2*vs Ilg
When heated at 2°C, 2.2 g of optically active (-)-r-propyl-γ-butyrolactone was obtained. [α] Revised--
0.27° (1% CI + 3011) Example 4 5 g of optically active (-)-diacetylene diol (X-07) was dissolved in 8 mp of tetrahydrofuran, and 8.9 g of β-butyrolactone was further dissolved in this solution. Room temperature So 4
When the mixture was left to stand for 8 hours, crystals of an clathrate compound of (-)-diacetylene diol (X=Cρ) and β-butyrolactone precipitated. After washing with a mixed solvent of petroleum ether and methyl alcohol (volume ratio 3:1), 2 to 3 m
Dry for 16 hours at room temperature under reduced pressure of 11 g, 4.97 g
White crystals were obtained.

The crystals were placed in a distillation pot and heated under a reduced pressure of 101 mHH at 75 mH.
When heated to ~85°C, 1.28 g of optically active (-)-β-butyrolactone was obtained. [α]g--1.89
° (neat) Example 5 Optically active (→-)-diacetylene diol (X-Cβ
) Cα-122° (1%C1130+1) was used, but the optical resolution of T-valerolactone was carried out in exactly the same manner as in Example 1, and optically active (-)-γ was obtained in one splitting operation. - 5.1 g of valerolactone was obtained. [α] = -7,0o (1%C113011) When this optically active (-)-T-valerolactone was divided three times in the same manner, [α] = -17,3° ( 1%
1.3 g of optically active (-)-γ-valerolactone (CI+3011) was obtained.

Anal optically active (+)-diacetylene diol (X-cx)
(α] ma = ~122° (1% (j13011),
Add 30 g to the tetra 1025 fufu 5 and add 33 g of α-amino-ε-caprolactam to this solution.
was dissolved. When left at room temperature for 48 hours (-)-
Diacetylene diol (X=CI) and α-amino-ε~
A clathrate of caprolactam was crystallized.

The crystals were collected by filtration and petroleum ether-methyl alcohol (
After washing with a mixed solvent at a volume ratio of 3:1), it was dried with salt for 16 hours under a reduced pressure of 2 to (13) 3 mmRg.

The crystals were dissolved in ethyl acetate and Wakogel C-200
The sample was subjected to column chromatography using .

Using ethyl acetate as a developing solvent, the fraction containing α-amino-ε-caprolactam was collected and the solvent was removed.
Optically active α-amino-ε-caprolactam was obtained.

Othotropically active (-)-diacetylene diol (X-c7ri (at α = -122° (CI + 5011 1%) 19
．． 2g and 17.8g of 3-methylcyclohexanone in ether-petroleum ether (volume ratio 1:I)? J% combined solvent 1
0 0ml! When dissolved in and left at room temperature for 6 hours,
(−)-Diacetylene diol (X = Cβ) and 3-
A methylcyclohexanone clathrate was crystallized.

After collecting the crystals by filtration, they were recrystallized again using a mixed solvent of ether and petroleum ether (volume ratio 1:1). After repeating this recrystallization operation twice, the precipitated crystals were collected by filtration. 11.6 g of crystals of the clathrate compound (14) thus obtained were placed in a distillation pot and distilled at normal pressure to obtain 3.3 g of optically active (+)-3-methylcyclohexanone. Its [α]t is +9.5° (CII
Cl, 31%).

Optically active (-)-diacetylene diol (X-ce>
IGg and 9.4 g of 2-methylcyclohexanone were dissolved in 50 ml of ether-petroleum ether (volume ratio 1:9) mixed solvent.
When dissolved in j+ and left at room temperature for 6 hours, (-)-
14.0 g of a clathrate compound of diacetylene diol (X=07) and 2-methylcyclohexanone was crystallized.

When the crystals were placed in a distillation pot and distilled at normal pressure, 4.1 g of optically active (+)-2-methylcyclohexanone was obtained. (αfo-+0.3' (Cll+Oil 1
% ) Kail Optically active (=)-diacetylene diol (X-CIl
) (αgu--122° (C1160111%)1
A mixed solution of 5.4 g and 12.6 g of 3-methylcyclopentanone in nitrogen petroleum ether (volume ratio 1:1)]
00mff. The following operation is carried out in exactly the same manner as in Example 7.
8.4 g of a methylcyclopentanone clathrate compound was obtained.

When this crystal was put into a distillation pot and distilled at normal pressure, (-
2.2 g of )-3-methylcyclopentanone were obtained.

Its αC was −43.6° (C11301%).

patent applicant Ube Industries Co., Ltd. patent application agent Patent attorney Akira Aoki Patent attorney Kazuyuki Nishidate Patent Attorney Ishi 1) Takashi Patent attorney Akira Yamaguchi

Claims (1)

[Claims] 1. Optically active 1°6-di(
herophenyl)-1,6-diphenyl-2,4-hexadiyne-1,6-diol (wherein, X represents a halogen atom).