JPH0859539A - Method for separating optical isomer of 2,2-disubstituted cyclic ketone - Google Patents

Abstract

PURPOSE: To obtain an optical isomer of a disubstituted cyclic ketone, having a high optical purity and useful as a synthetic intermediate, etc., for medicines, agrochemicals, etc., by separating either of the optical isomers of the disubstituted cyclic ketone from a specific clathrate compound. CONSTITUTION: This method for separating an optical isomer of a 2,2- disubstituted cyclic ketone comprises forming a clathrate compound from a mixture of optical isomers of the 2,2-disubstituted cyclic ketone represented by formula I [ n is 1 or 2; R<1> and R<2> are each a (substituted)1-6C alkyl or an alkoxycarbonyl] and an optically active host compound represented by formula II [m is 4 or 5; Ph is phenyl] and then separating either of the optical isomers of the 2,2-disubstituted cyclic ketone from the resultant clathrate compound.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for separating optical isomers of 2,2-disubstituted cyclic ketones. This 2,2-disubstituted cyclic ketone has a high utility value in the field of fine chemistry centering on medicines and agricultural chemicals.

[0002]

2. Prior Art and Problems to be Solved by the Invention 2, 2
-Disubstituted cyclic ketones are industrially important compounds as intermediates for various fine chemicals centering on medicines and agricultural chemicals. Particularly in the optically active form of 2,2-disubstituted cyclic ketone,
The optical isomers may have remarkably different physiological activities, and a method for easily obtaining an optically active substance has been desired. However, in ordinary chemical synthesis, an equal amount mixture of optical isomers, so-called racemate, is obtained, and it is usually difficult to obtain an optically active substance.

Conventionally, as a method for obtaining an optically active 2,2-disubstituted cyclic ketone, a method by an addition reaction of an unsaturated amino ester (tetrahedron: asymmetry,
2, 411 (1991)) and the like are known. However, with this method, it is often impossible to obtain a product having sufficient optical purity. Therefore, optical activity with high optical purity 2, 2-
There has been a need for a method of obtaining disubstituted cyclic ketones.

[0004]

Means for Solving the Problems As a result of intensive research to solve the above-mentioned problems, the present inventor selectively included one of the optical isomers of 2,2-disubstituted cyclic ketones and an optically active host compound. The present invention has been completed and the present invention has been completed. That is, according to the present invention, an inclusion compound is formed from a mixture of optical isomers of 2,2-disubstituted cyclic ketone and an optically active host compound, and from this inclusion compound, an optical isomer of 2,2-disubstituted cyclic ketone is formed. The present invention provides a method for separating optical isomers, characterized in that one of them is separated.

The 2,2-disubstituted cyclic ketone in the method of the present invention has the formula (1)

[0006]

[Chemical 3]

(In the formula, n is 1 or 2, R ¹ and R ² are the same or different, and each represents an optionally substituted alkyl group or alkoxycarbonyl group having 1 to 6 carbon atoms. The compound represented by the formula (1) is included, and these compounds give a mixture of equal amounts of optical isomers, that is, a racemic body in a usual chemical synthesis, but an optically active substance is industrially required.

In the compound represented by the above formula (1), R ¹
Examples of the alkyl group having 1 to 6 carbon atoms represented by R ² include a methyl group, an ethyl group, a propyl group, a butyl group, and the like, and examples of the substituent on the alkyl chain include a cyano group, an acetyl group, and And an alkoxycarbonyl group such as a methoxycarbonyl group. Examples of the alkoxycarbonyl group represented by R ¹ and R ² include a methoxycarbonyl group and an ethoxycarbonyl group.

The optically active host compound used in the present invention has the formula (2)

[0010]

[Chemical 4]

(Wherein m is 4 or 5 and Ph represents a phenyl group). The above formula
Since the compound represented by (2) can be easily synthesized from optically active tartaric acid, it can be obtained at a considerably low cost and can be reused.

In the method of the present invention, any method may be used to form the inclusion compound of the 2,2-disubstituted cyclic ketone and the optically active host compound. For example, 2, 2
-The di-substituted cyclic ketone racemate and the optically active host compound are dissolved in a suitable solvent at a molar ratio of about 1: 1 to 4: 1, if necessary under heating, and cooled or a solvent having low solubility is gradually added. The inclusion compound can be obtained by adding Also, the inclusion compound may be formed by mixing in the absence of a solvent. The clathrate compound obtained by the above method exhibits different physical properties (melting point, crystal form, etc.) from the starting material. However, practically, it is sufficient to achieve the desired separation, and it is not necessary to confirm the presence of the clathrate compound.

Any method may be used to obtain the optically active 2,2-disubstituted cyclic ketone from the clathrate compound. The simplest method is to heat the clathrate compound to separate the low boiling point 2,2-disubstituted cyclic ketone. The heating temperature in this case varies depending on the pressure and the boiling point of the 2,2-disubstituted cyclic ketone to be separated, but considering the stability of the optically active host compound and the 2,2-disubstituted cyclic ketone to heat, the reduced pressure It is preferable to carry out below.

Further, recrystallization is repeated at the stage of the inclusion compound, or after the 2,2-disubstituted cyclic ketone to be separated is separated, the inclusion compound is formed again using the optically active host compound. As a result, it is possible to improve the optical purity of the 2,2-disubstituted cyclic ketone.

[0015]

Although the reason why the method of the present invention is suitable for the separation of optical isomers of 2,2-disubstituted cyclic ketones is not clear, the optically active host compound used in the present invention is
It has a size and a polarity that easily interact with the 2-disubstituted cyclic ketone, and is considered to easily form an inclusion compound. Further, it is considered that the inclusion compound is selectively formed with only one of the optical isomers of the 2,2-disubstituted cyclic ketone depending on the three-dimensional structure of the optically active host compound.

[0016]

The optically active host compound used in the present invention can be repeatedly used. Furthermore, according to the method of the present invention, the optically active 2,2-disubstituted cyclic ketone can be separated by a simple operation. As a result, it becomes possible to supply a large amount of inexpensive 2,2-disubstituted cyclic ketone having high optical purity.

[0017]

EXAMPLES Next, the present invention will be described more specifically by way of examples, but the present invention is not limited to these examples.

Example 1 (-) form (1.00 g, 2.03) of a compound represented by the following formula (3)
mmol) was dissolved in ether (8 ml) with heating. Then, the racemate of the compound represented by the following formula (4) (0.88 g, 4.06 mmo
l) and hexane (8 ml) were added, and the mixture was allowed to stand for 12 hours, whereby crystals (0.81 g, colorless prisms) composed of compound (3) and compound (4) were deposited. Further, the obtained crystals (0.80 g) were recrystallized from a mixed solvent of ether-hexane to give colorless prism crystals (0.72 g). This crystal (0.58g)
When heated under reduced pressure (2 mmHg) to about 210 ° C., an optically active compound (4) (0.10 g) was obtained. The specific rotation of the compound (4) thus obtained is [α] _D = + 118.3 ° (c
It was 0.92, methanol) and the optical purity was 100% ee as measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd.).

[0019]

[Chemical 5]

Example 2 (-) form (1.00 g, 1.97) of the compound represented by the following formula (5)
mmol) was dissolved in ether (8 ml) with heating. Then, the racemate of the compound represented by the following formula (6) (0.39 g, 1.97 mmo
l) and hexane (8 ml) were added and left to stand for 12 hours, a crystal consisting of compound (5) and compound (6) (1.04 g, needle crystals)
Was deposited. Further, the obtained crystals (1.00 g) were recrystallized twice from an ether-hexane mixed solvent to obtain needle crystals (0.85 g). When this crystal (0.71g) was heated under reduced pressure (2mmHg) to about 210 ℃, an optically active compound was obtained.
(6) (0.09 g) was obtained. The specific rotation of the compound (6) thus obtained is [α] _D = −33.9 ° (c 0.57,
Indicates ethanol (HPLC) (manufactured by Daicel Chemical Industries, Ltd.)
CHIRALPAK AS) measured optical purity 92%
It was ee.

[0021]

[Chemical 6]

Example 3 (−) form of the compound represented by the above formula (5) (1.00 g, 1.97)
mmol) was dissolved in ether (8 ml) with heating. Then, the racemate of the compound represented by the following formula (7) (0.83 g, 3.94 mmo
l) and hexane (8 ml) were added and left to stand for 12 hours, a crystal consisting of compound (5) and compound (7) (0.94 g, needle crystals)
Was deposited. Further, the obtained crystals (0.88 g) were recrystallized from an ether-hexane mixed solvent three times to obtain needle crystals (0.56 g). This crystal (0.54g) was heated under reduced pressure (2mmHg) to about 210 ° C to give an optically active compound.
(7) (0.03 g) was obtained. The specific rotation of the compound (7) thus obtained is [α] _D = + 15.5 ° (c 0.2
8, Methanol), HPLC (Daicel Chemical Industry)
The optical purity was 83% ee when measured using CHIRALPAK AS manufactured by K.K.

[0023]

[Chemical 7]

Examples 4 to 10 Optical resolution was carried out in the same manner as in Examples 1 to 3 using the racemic guest compounds and optically active host compounds shown in Tables 1 and 2. The results are shown in Tables 1 and 2.

[0025]

[Table 1]

[0026]

[Table 2]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 67/48 69/608 9546-4H 69/757 B 9546-4H C 9546-4H 253/34 255 / 31 C07D 321/00 321/12 // C07M 7:00

Claims (4)

[Claims] 1. An inclusion compound is formed from a mixture of optical isomers of a 2,2-disubstituted cyclic ketone and an optically active host compound, and one of the optical isomers of the 2,2-disubstituted cyclic ketone is formed from this inclusion compound. A method for separating optical isomers, which comprises separating 2. A 2,2-disubstituted cyclic ketone is represented by the following formula (1):
The method for separating optical isomers according to claim 1, which is a compound represented by: Embedded image (In the formula, n is 1 or 2, R ¹ and R ² are the same or different and each represents an optionally substituted alkyl group or alkoxycarbonyl group having 1 to 6 carbon atoms.) 3. The optical isomerism according to claim 2, wherein the substituent of the alkyl group having 1 to 6 carbon atoms represented by R ¹ and R ² in the formula (1) is a cyano group, an acetyl group or an alkoxycarbonyl group. Body separation method. 4. The optically active host compound which forms an inclusion compound with a 2,2-disubstituted cyclic ketone is a compound represented by the following formula (2): Optical isomer separation method. Embedded image (In the formula, m is 4 or 5, and Ph represents a phenyl group.)