JPH0774169B2 - Optical division method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention provides an optically active trans-2,2-dimethyl-α,
The present invention relates to an optical resolution method using α, α ′, α′-tetraphenyl-1,3-dioxolane-4,5-dimethanol (hereinafter sometimes abbreviated as a dioxolane derivative).

[Problems to be Solved by Prior Art and Present Invention]

Trans-2,2-Dimethyl-α, α, α ', α'-tetraphenyl-1,3-dioxolane-4,5-dimethanol is trans-α, α- (2,2-dimethyl-1,3 -Dioxolane-4,5-diyl) bis- (diphenylmethanol) is a known compound, but its use is hardly known, and it is used as a test sample for optically active substance separation liquid chromatogram. (Anal.Chem., 1
985, 57, p. 237).

As a method for optically resolving a racemate, a diastereomer method using an optically active resolving reagent is generally used industrially. However, depending on the type of resolving reagent, the racemate that forms a diastereomer is limited, and therefore development of various resolving reagents having optical activity is desired.

We have found that the optically active 1,6-di (halophenyl)-
A method using 1,6-diphenyl-2,4-hexadiyne-1,6-diol (hereinafter abbreviated as diacetylene derivative) is as follows.
We have previously found that it is an excellent optical resolution method for various racemates (Japanese Patent Application No. 58-90077).

However, the diacetylene derivative uses a naturally occurring resolving agent to obtain its optically active substance (US Pat.
102, Japanese Patent Application No. 57-164969), which is a considerably expensive compound when industrially implemented. Therefore, an excellent method for optically resolving an organic compound using a compound that can be inexpensively produced in large quantities has been desired.

[Means for solving problems]

The inventors of the present invention have completed the present invention as a result of intensive studies in view of such circumstances.

That is, the present invention relates to an optically active trans-2,2-dimethyl-α, α, α ', α'-tetraphenyl-1,3-dioxolane-4,5-dimethanol and a racemate of an organic compound. Is contacted in an organic solvent, and the trans-2,2-dimethyl-containing one enantiomer of the organic compound is included.
An optical method characterized in that an inclusion complex of α, α, α ', α'-tetraphenyl-1,3-dioxolane-4,5-dimethanol is formed, separated and then decomposed. It relates to the division method.

The optically active trans-2,2-dimethyl-α of the present invention,
α, α ′, α′-tetraphenyl-1,3-dioxolane-4,5-dimethanol (hereinafter sometimes abbreviated as a dioxolane derivative) is trans-α, α- (2,2-dimethyl- 1,3-dioxolane-4,5-diyl) bis- (diphenylmethanol) is a known compound,
The synthesis method is shown in the following formula. Moreover, a commercial item is also available.

Tartaric acid, which is the starting material for the dixolane derivative, is one of the cheapest compounds as an optically active organic compound, and is not only available in large quantities and at low cost,
Both (+) and (-) enantiomers are also available.

The dioxolane derivative of the present invention does not require any complicated optical resolution step in its production process, and any enantiomer can be industrially produced in large quantities and at low cost. In the present invention, since either (+) or (-) dioxolane derivative can be used, either (+) or (-) dioxolane derivative is appropriately selected depending on the enantiomer of the desired optically active organic compound. Can be used.

The organic compound of the present invention is a compound having an asymmetric center and may be of any type as long as it forms an inclusion complex with the dioxolane derivative. However, according to the finding obtained by the present inventors, a ketone group, Cyano group, ester group containing lactone,
A compound having a functional group such as a hydroxyl group, an ether group containing epoxy, an amide group containing lactam, an amino group, and a sulfoxide group is particularly preferably used. These compounds are
It may be chain-shaped, cyclic, aliphatic or aromatic, but an alicyclic compound is particularly preferably used.

In the present invention, the racemate of the organic compound is usually used in an amount of 1 to 10 mol with respect to 1 mol of the dioxolane derivative, but the crystallization rate of the inclusion complex and the optical purity of the divided target organic compound are taken into consideration. In this case, it is preferable to use 2 to 8 mol per mol of the dioxolane derivative.

The organic solvent used is preferably one that dissolves the optically active dioxolane derivative and the racemate of the organic compound to be optically resolved, and that the formed inclusion complex has low solubility. Specific examples of such an organic solvent include pentane, hexane, heptane, cyclohexane,
Hydrocarbon solvents such as petroleum ether, ligroin, benzene, toluene, xylene, ether solvents such as ether, dioxane, tetrahydrofuran, methanol,
Alcohol solvents such as ethanol, butanol, propanol, isopropanol, ester solvents such as ethyl acetate and butyl acetate, methylene chloride, chloroform,
Examples include chlorine-based solvents such as carbon tetrachloride, ketone-based solvents such as acetone and methyl ethyl ketone, and mixed solvents of these solvents.

The amount of the organic solvent used is preferably such that the concentration of the optically active dioxolane derivative is 1 to 50% by weight.

The racemic body of the above-mentioned organic compound and the optically active dioxolane derivative are brought into contact with each other in an organic solvent to obtain an inclusion complex, which is then separated.

In the present invention, to perform optical resolution of the racemate of the organic compound, for example, an optically active dioxolane derivative is added to a solution of the racemate of the organic compound in an organic solvent to form an inclusion complex. Preferably, it is allowed to stand at room temperature for several hours or overnight. At this time, in order to dissolve the raw materials or to accelerate the precipitation of crystals of the inclusion complex, heating or cooling can be performed as necessary.
The molar ratio of the racemate of the organic compound to be reacted and the dioxolane derivative is 1: 1 to 10: 1, preferably 2: 1 to 4: 1.

The contact between the racemate of the organic compound and the optically active dioxolane derivative is usually carried out at a temperature of 10 to 150 ° C. for 1 to 50 hours. By this contact, one enantiomer of the racemate of the organic compound is included in the optically active dioxolane derivative, and the inclusion complex is crystallized. The dioxolane derivative is combined with an organic compound to form an inclusion complex with a molar ratio of 1: 1 to 1: 2.

The crystallized crystal of the inclusion complex of the crystallized optically active dioxolane derivative and the organic compound can be separated by a method such as filtration under reduced pressure or centrifugation. Further, the inclusion crystals having extremely high optical purity can be obtained by recrystallizing the separated crystals in an organic solvent similar to the above reaction solvent.

The obtained inclusion compound is dissolved in a solvent and decomposed into a dioxolane derivative and an optically active organic compound by a column chromatogram of silica gel, alumina gel or the like. In some cases, the organic compound having a low boiling point can be separated from the dioxolane derivative by a distillation treatment. It can also be decomposed by treatment with alkali, acid or the like.

The developing solvent of the column chromatograph and the temperature at the time of separation by distillation can be appropriately selected according to the physical properties of the organic compound.

The recovered optically active dioxolane derivative can be used again for optical resolution without impairing its optical purity even if the above-mentioned operation treatment is carried out.

In order to obtain the other antipode of the organic compound, an optically active dioxolane derivative having the opposite polarities of optical rotation may be used for the optical resolution, and the resolution method is the same as that described above. No change.

[Production Example] Production of optically active dioxolane derivative (+)-(R, R) -Diethyl tartrate (105 g) and dimethoxymethane (100 g) were dissolved in benzene (400 ml), and p-toluenesulfonic acid (0.5 g) was added and subjected to atmospheric distillation. After distilling off about 300 ml of benzene-methanol azeotropic mixture, potassium carbonate (2 g) was added to the residue to neutralize it, and after washing with water and drying, benzene was distilled off.
Diethyl (R, R) -2,3-diisopropylidene tartrate (11
3g, boiling point 115-117 ° C / 5mmHg, [α] _D = -40.2 ° (c = 1,
CHC13)) was obtained.

In a dry tetrahydrofuran solution (300 ml) of phenylmagnesium bromide prepared from magnesium (6 g) and brombenzene (40 g), while stirring at room temperature, a solution of diethyl diisopropylidene tartrate (10.7 g) in dry tetrahydrofuran (100 ml) was added. It dripped over 1 hour.
After dropping, the mixture was further stirred for 2 hours, left overnight, hydrolyzed with a saturated aqueous solution of ammonium chloride (300 ml), and extracted with benzene. The benzene layer was washed with water, then with saturated saline, dried over anhydrous magnesium sulfate, and then benzene was distilled off to obtain a colorless oily substance. Crystallization was performed by adding n-hexane (50 ml) and a small amount of benzene, and a colorless powdery (-)-(R, R) -dioxolane derivative (20
g, melting point 195-196.5 ° C [α] _D = -60.6 ° (c = 1, CHC1
3)) was obtained.

Similarly, from (-)-(S, S) -diethyl tartrate to (+)-(S, S) -dioxolane derivative (melting point 197-198
C. [.alpha.] _D = + 65.5.degree. (C = 1, CHC13)) was obtained.

[Example 1] (-)-(R, R) -dioxolane derivative (2.0 g) and 4,4a,
5,6,7,8-Hexahydro-4a-methyl-2 (3H) -naphthalenone (1.41 g) was dissolved in benzene (20 ml) with heating and allowed to stand at room temperature for 12 hours, whereby colorless prism-like crystals were deposited. This crystal was recrystallized once from (20 ml),
-(R, R) -dioxolane derivative and (-)-4,4a, 5,6,7,
1: 1 inclusion compound of 8-hexahydro-4a-methyl-2 (3H) -naphthalenone (1.71 g, melting point 190-193 ° C, [α]
_D = -101 ° (c = 1, CHC13)) was obtained as colorless prism crystals. When the crystals were heated under reduced pressure (20 mmHg) to about 200 ° C., an optically active form of the naphthalenone derivative was obtained (0.44 g, [α] _D = −219 ° (c = 1, MeOH)).

[Example 2] (-)-(R, R) -dioxolane derivative (4.66 g) and 4,4
1: 1 mixture of a, 5,6,7,8-hexahydro-2 (3H) -naphthalenone and 3,4,5,6,7,8-hexahydro-2 (1H) -naphthalenone (6.00g) Was heated and dissolved in benzene (20 ml), n-hexanone (10 ml) was added, and the mixture was allowed to stand for 12 hours, whereby colorless prismatic crystals were precipitated. When this crystal was recrystallized three times from benzene, a 1: 1 inclusion compound of (-)-dioxolane derivative and 4,4a, 5,6,7,8-hexahydro-2 (3H) -naphthalenone (2.57 g, Melting point 140-142 ° C,
[Α] _D = -60.6 ° (c = 1, CHC13)) was obtained as colorless prism crystals. This crystal under reduced pressure (20mmgHg)
When heated to about 200 ° C., optically active (−)-naphthalenone (0.62 g, [α] _D = −51.8 ° (c = 1, MeoH) was obtained.

[Example 3] (-)-(R, R) -dioxolane derivative (2.06 g) and 1,4,
5,6,7,7a-Hexahydro-2H-inden-2-one (1.20 g) was dissolved in benzene (10 ml) by heating, and then n-
Hexane (5 ml) was added and the mixture was allowed to stand for 12 hours, whereby colorless prismatic crystals were precipitated. When this crystal was recrystallized three times from benzene, a 1: 1 inclusion compound (2.1) of the (-)-dioxolane derivative and the (+)-form inden-2-one derivative was obtained.
3g, melting point 130-132 ° C, [α] _D = -40.0 ° (c = 1, CHC1
3)) was obtained as colorless prismatic crystals. When this crystal was heated to about 200 ° C. under reduced pressure (20 mmHg), the (+) form of the inden-2-one derivative (0.48 g, [α] _D = + 2
2.1 ° (c = 1, MeOH) was obtained.

[Example 4] (-)-(R, R) -dioxolane derivative (2.33 g) and 4,4
a, 5,6,7,8-Hexahydro-7a-ethyl-2 (3H)-
After naphthalenone (1.78 g) was dissolved in benzene (10 ml) by heating, n-hexane (10 ml) was added and the mixture was allowed to stand for 12 hours, whereby colorless prism-like crystals were precipitated. When this crystal was recrystallized three times from benzene, a 1: 1 inclusion compound of the (−)-dioxolane derivative and the (−) 7a-ethylnaphthalenone derivative (1.39 g, melting point 159-162 ° C., [α] _D = -83.3 ° (c = 1, CHC13)) was obtained as colorless crystals. When this crystal was heated under reduced pressure (20 mmHg) to about 200 ° C, the optically active (-) 7a-ethylnaphthalene derivative (0.38 g,
[Α] _D = -146 ° (c = 1, MeOH) was obtained.

Example 5 (−)-(R, R) -Dioxolane derivative (2.33 g) and 2,3,
7,7a-tetrahydro-7a-methyl-1H-indene-1,
After dissolving 5 (6H) -dione (1.64 g) in benzene (10 ml) by heating, n-hexane (10 ml) was added and the mixture was allowed to stand for 12 hours, whereby colorless prism crystals were precipitated. When this crystal was recrystallized three times from benzene, a 1: 1 inclusion compound (1.83 g, melting point 169-171 ° C, [α] _D =-of the (-)-dioxolane derivative and the (-)-form indendione derivative was obtained. 132 ° (c = 1, C
HC13)) was obtained as colorless plate crystals. When this crystal is heated under reduced pressure (2mmHg) to about 200 ℃, it becomes optically active (-).
The body of indendione derivative (0.47 g, [α] _D = -367 ° (c = 1, benzene) was obtained.

Example 6 (−)-(R, R) -Dioxolane derivative (2.33 g) and 3,4,
After dissolving 8,8a-tetrahydro-8a-methyl-1,6 (2H, 7H) -naphthalenedione (1.79g) in benzene (20ml) by heating, add n-hexane (10ml) and let stand for 12 hours. Colorless prismatic crystals were deposited. When this crystal was recrystallized twice from benzene, a 1: 1 inclusion compound of the (−)-dioxolane derivative and the (−)-form naphthalenedione derivative (2.30 g, melting point 186-189 ° C., [α] _D = − 81.4 ° (c =
1, CHC13)) was obtained as colorless prismatic crystals.
When this crystal was heated under reduced pressure (2 mmHg) to about 200 ° C, the optically active naphthalenedione derivative (0.64 g,
[Α] _D = −102 ° (c = 1, benzene) was obtained.

The optical purity of each of the optically active compounds divided in Examples 1 to 6 above is almost 100%.

Examples 7 to 23 The same operation as in Examples 1 to 6 was carried out by changing the compound to be resolved to obtain optically active substances having the specific optical rotations shown in Table 1.

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Claims (1)

[Claims] 1. An optically active trans-2,2-dimethyl-
α, α, α ′, α′-tetraphenyl-1,3-dioxolane-4,5-dimethanol and a racemate of an organic compound are brought into contact with each other in an organic solvent to obtain one enantiomer of the organic compound. The trans-2,2-dimethyl-α, which includes the body,
An optical resolution method characterized in that an inclusion complex of α, α ', α'-tetraphenyl-1,3-dioxolane-4,5-dimethanol is formed, separated and then decomposed. .