JPH0434532B2 - - Google Patents

Description

[Detailed description of the invention]

Technical field The present invention provides a novel compound having optical activity, 1.
6-diphenyl-2,4-hexadiyne-1,6
-Regarding a method for producing a diol derivative (hereinafter sometimes referred to as a diacetylene diol derivative). Prior Art For the resolution of racemates, a diastereomer method using an optically active resolving reagent is generally used industrially. Commonly used conventional resolving agents include optically active amines such as brucine, optically active acids such as camphorsulfonic acid, and optically active alcohols such as menthol. After forming a salt or ester with the racemate to be separated into diastereomers, fractional crystallization is performed using the difference in solubility to separate each diastereomer, which is then neutralized or hydrolyzed. This is a method for separating each antipode of the desired racemic body. However, most conventional dividing agents are naturally produced and expensive.
In addition to being difficult to obtain in large quantities, racemates forming diastereomers are limited depending on the type of resolving reagent, so the development of resolving reagents having various optical activities is desired. Purpose and Structure of the Invention In view of the above-mentioned circumstances, the present inventors have carried out intensive research with the aim of finding a new method for producing optically active compounds. We have successfully developed a new method for producing -diphenyl-2,4-hexadiyne-1,6-diol derivatives. (In the formula, R represents a butyl group, a tolyl group, a naphthyl group, or a halogenated phenyl group.) The optically active diacetylene diol derivative of the above general formula () has the general formula () It can be produced by dimerizing an optically active phenylpropargyl alcohol derivative represented by the formula (wherein R is as defined above) in the coexistence of pyridine, cuprous chloride, and oxygen. DETAILED DESCRIPTION OF THE INVENTION The optically active diacetylene diol derivative of the general formula () described above can be produced from the corresponding ketone in the following manner. That is, first, the corresponding ketone of the general formula () (wherein R is as defined above) and sodium acetylide (NaC≡CH) are reacted in liquid ammonia under normal pressure to synthesize a racemic body of a phenylpropargyl alcohol derivative represented by the general formula (), and then For example, this racemic body can be obtained from Japanese Patent Application No. 57-33011 (Showa
The product was obtained by contacting with l-brucine and l-sparteine in an organic solvent by the method described in the specification of Japanese Patent Application No. 57-164969 (filed on September 24, 1982). The optically active phenylpropargyl alcohol derivative of the general formula () can be obtained by separating the resulting diastereomers using the difference in solubility and then decomposing them. The optically active phenylpropargyl alcohol derivative of the general formula () can also be prepared by reacting the racemic form of the phenylpropargyl alcohol derivative of the general formula () with acetic anhydride or acetic chloride to obtain the corresponding O-acetylphenylpropargyl alcohol. After synthesizing the derivative (racemate), only the l-enantiomer is asymmetrically hydrolyzed, for example, in the presence of an esterase produced by a microorganism of the genus Bacillus or Rhodotorula to obtain the desired optically active phenylpropargyl alcohol. derivatives can be obtained. The following general formula () obtained in this way
The optically active diacetylene diol derivative of the general formula () can be synthesized by dissolving the optically active phenylpropargyl alcohol derivative in an organic solvent and dimerizing it in the presence of pyridine, cuprous chloride and oxygen. can. Optically active phenylpropargyl alcohol derivative of general formula () (hereinafter referred to as monoacetylene alcohol derivative)
Examples of organic solvents that dissolve is acetone.
The amount used is suitably 10 to 50 ml, preferably 10 to 25 ml, per 10 g of optically active monoacetylene alcohol. A catalytic amount of cuprous chloride (1/20 to 1/100 mol) was added to the optically active monoacetylene alcohol derivative solution prepared in this way, and pyridine was added at a volume ratio of 1/10 to 1/50 to the organic solvent. and react at room temperature for 10 to 20 hours while blowing oxygen at a rate of 50 to 300 ml/hour. After the reaction, the organic solvent is removed, the residue is washed with petroleum ether, and the crystals are collected by filtration. After dissolving this crystal in benzene and washing with hydrochloric acid water or sulfuric acid water,
By drying the benzene layer and removing benzene, an optically active diacetylene diol represented by the general formula () can be obtained. The optically active diacetylene diol thus obtained forms inclusion compounds with various racemic pairs and includes only one enantiomer at that time, so it has uses as a new optical resolution agent. Those that form clathrate compounds with this optically active diacetylene diol include malic acid, mandelic acid, pipecolic acid, carvone, menthol, pantoyl lactone, β-lactones, β-lactams, γ-lactones, γ-
lactams, δ-lactones, δ-lactams,
Examples include ε-lactones, ε-lactams, sulfoxides, ketones, and the like. Of these,
In 4- to 7-membered ring lactones, lactams, ketones, sulfoxides, menthol, pantoyl lactone, etc., only one enantiomer is selectively included and crystallized. Regarding the separation conditions in detail, the appropriate molar ratio of the optically active form of (-)-diacetylene diol and the racemic compound to be separated is 1:4 to 1:10. Considering the ratio and optical purity, it is sufficient to provide 4 mol of the racemic compound per 1 mol of diacetylene diol. As the separation solvent, it is preferable to use one in which diacetylene diol and the racemic compound are dissolved and the solubility of the clathrate compound formed therein is low. Such solvents include tetrahydrofuran,
Methyl alcohol is suitable for the separation of menthol and pantoyllactone, methyl alcohol is suitable for the separation of sulfoxides, and ether-petroleum ether mixed solvent is suitable for the separation of ketones. The separation temperature is room temperature, and the time required for crystallization is 10 to 48 hours for lactones and lactams, 4 to 10 days for pantoyl lactone and l-menthol, 2 to 72 hours for sulfoxides, and 5 to 15 hours for ketones. It is. To isolate the desired optically active guest molecule from the clathrate, there are two methods: vacuum distillation, column chromatography,
There is a method based on exchange of guest compounds, which may be selected arbitrarily depending on the guest molecule. Examples Examples of the present invention will be described below, but it goes without saying that the scope of the present invention is not limited to these examples. Example 1 In a flask with a shoulder, molasses 1% by weight, corn steep liquor 2.5% by weight, ammonium sulfate 0.5% by weight
and inorganic salt mixture ( _MgSO4・_7H2O20g ,
FeSO ₄・7H ₂ O5g, CaCl ₂ 2g, MnCl ₂・4H ₂ O0.2
After sterilizing 100 ml of medium (PH7.0) containing 1) 1 ml of distilled water containing 0.1 g of NaMoO ₄ 2H ₂ O and 0.1 g of NaCl, Rhodotorula minuta (IFO-
0378) was inoculated from a slant medium with two platinum loops and incubated at 30℃ for 94 hours.
Culture was performed with back and forth shaking for hours. The bacterial cells collected from this culture solution by centrifugation were washed twice with distilled water to obtain washed bacterial cells. This was further freeze-dried to obtain freeze-dried bacterial cells. 50 mg of this freeze-dried cellulose was suspended in 20 ml of water (PH7.0), and 0.5% by weight of O-acetyl-1-o-
The mixture was mixed and suspended with 100 ml of a solution of chlorophenyl-1-phenylpropargyl alcohol in n-heptane, and reacted at 30° C. for 48 hours with stirring. The bacterial cells were separated from the reaction solution, the aqueous layer and the n-heptane layer were separated, and the n-heptane layer was dried with Glauber's salt, and then the n-heptane was removed. The remaining crystals were subjected to column chromatography using Wakogel C-300 and developed with chloroform to separate the hydrolysis product 1-o-chlorophenyl-1-phenylpropargyl alcohol and the unreacted O-acetyl derivative. . The former [α] ²⁵ _D (CH ₃ OH1%)
was -129°. The optically active (-)-1-o-
48 g of chlorophenyl-1-phenyl-propargyl alcohol was dissolved in a mixture of 100 ml acetone and 10 ml pyridine, 862 mg of cuprous chloride was added, and the mixture was heated at room temperature while passing oxygen through the reaction solution at a flow rate of 200 ml/hour.
Reacted for 16 hours. Acetone and pyridine were removed from the reaction solution, and the resulting pale blue crystals were dissolved in benzene, washed with a 12% aqueous hydrochloric acid solution, and then with water, and the benzene layer was dried with sodium sulfate. When benzene was removed, 43 g of white crystals were obtained. This is 1,6-di(chlorophenyl)-1,6-diphenyl-2,4-hexadiyn-1,6-diol, [α] ²⁵ _D = -122° (1% CH ₃ OH), and the melting point is The temperature was 127-129℃. Examples 2-6 Optical activity 1 synthesized according to the method described in Example 1
-Various derivatives of phenylpropargyl alcohol were subjected to dimerization reactions in exactly the same manner as in Example 1. Table 1 shows the [α] ²⁵ _D and melting point of each diacetylene diol derivative obtained.

[Table] Example 7 Optically active (-)-1,6-di(o-chlorophenyl)-1,6-diphenyl- synthesized in Example 1
2,4-hexadiyne-1,6-diol [α]
30 g of ²⁵ _D = -122° (CH ₃ OH 1%) was dissolved in 75 ml of tetrahydrofuran. When 26 g of racemic γ-valerolactone was dissolved in this solution and left at room temperature for 2 days, white crystals were precipitated. The crystals were collected by filtration and petroleum ether methyl alcohol (3:
After washing with the mixed solvent of 1) and drying, place it in a distillation pot.
When heated to 80° C. under a reduced pressure of 2 mHg, 7.6 g of optically active γ-valerolactone was obtained. [α] ²⁵ _D = 10.7° (neat). Example 8 Optically active (-)-1,6-di-(o-chlorophenyl)-1,6-diphenyl- synthesized in Example 2
10g of 2,4-hexadiyne-1,6-diol
Dissolve in 30 ml of methyl alcohol and add to this solution
When 8.2 g of methyl ethyl sulfoxide was dissolved and left at room temperature for 2 days, white crystals were obtained. This was collected by filtration and dried to obtain 11 g of an inclusion compound containing two molecules of methyl ethyl sulfoxide with a melting point of 102-116°C and [α] ²⁵ _D = -31.4° (1% CH ₃ OH). Put this in a distillation pot and reduce the pressure to 100mHg under a reduced pressure of 20mHg.
The mixture was heated to 0.degree. C., and optically active methyl ethyl sulfoxide was isolated. Example 9 When optical resolution of α-amino-ε-caprolactam was attempted in exactly the same manner as in Example 1, 48
By standing for a period of time, crystals of an clathrate compound containing α-amino-ε-caprolactam were obtained. The crystals were subjected to column chromatography using ethyl acetate as a developing solvent, and optically active α-amino-
δ-caprolactam was confirmed. Example 10 19.2 g of optically active (-)-1,6-di-(o-chlorophenyl)-1,6-diphenyl-2,4-hexadiyn-1,6-diol and 17.8 g of 3-methylcyclohexanone were added to ether petroleum. It was dissolved in 100 ml of a mixed solvent of ether (volume ratio 1:1) and allowed to stand at room temperature for 6 hours, resulting in the precipitation of white crystals.
After collecting the crystals by filtration, they were recrystallized again from a mixed solvent of ether and petroleum ether (volume ratio 1:1). After repeating the recrystallization operation twice, the precipitated crystals were collected by filtration. 11.6 g of crystals of the clathrate thus obtained were placed in a distillation pot and distilled at normal pressure, resulting in optically active (+)-3-methylcyclohexanone.
3.3g was obtained. [α] ²⁵ _D was +9.5° (CHCl ₃ 1%).

Claims (1)

[Claims] 1 General formula () (In the formula, R represents a butyl group, a tolyl group, a naphthyl group, or a halogenated phenyl group) dimerizing an optically active phenylpropargyl alcohol derivative in the coexistence of pyridine, cuprous chloride, and oxygen. A general formula () characterized by (wherein R is as defined above) optically active 1,6-diphenyl-
Method for producing 2,4-hexadiyne-1,6-diol derivative.