JPH1121261A - Stabilization of optically active alpha-substituted ketones - Google Patents

Abstract

PROBLEM TO BE SOLVED: To chemically stably preserve an optically active α-substituted ketone with preventing racemization, by adding an inorganic oxide to the ketone. SOLUTION: An inorganic oxide such as a zeolite or silica gel as a substance to adsorb a polar substance is added to an optically active α-substituted ketone of the formula (R<1> and R<2> are each a 1-8C alkyl, a 1-18C aryl, aralkyl, etc.; R<3> is a 1-4C alkyl, a halogen, etc.), which is sufficiently stirred and preserved. The preservation is carried out at <=30 deg.C in an inert gas atmosphere such as preferably nitrogen, helium or argon. The treatment may be performed by packing an inorganic oxide into a column and passing the optically active α-substituted ketone through the column.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for stabilizing optically active .alpha.-substituted ketones which are important as raw materials for pharmaceuticals and agricultural chemicals, and more particularly to a method for chemically and optically unstable ketones. The present invention relates to a method for stabilizing various optically active α-substituted ketones.

[0002]

2. Description of the Related Art Conventionally, various methods for producing optically active α-substituted ketones have been known. For example, a method of oxidizing (−)-menthol with sodium hypochlorite to obtain (−)-menthone (J. Org. Chem. 1980, 45, 2032)
-2033) or optically active 2-methoxycyclohexanol is oxidized with a hypohalous acid or a source of hypohalous acid under acidic conditions in the presence of ketones such as acetone and methyl ethyl ketone to produce optically active 2-methoxycyclohexanol. A method for obtaining cyclohexanone (GB 2283971) and the like are known. However, since these compounds are unstable compounds that are easily racemized, for example, when stored at room temperature, the optical purity and the chemical purity are reduced, which causes a problem that it is difficult to use them as raw materials for medical and agricultural chemicals. On the other hand, there is no known example relating to a method for preventing racemization of optically active α-substituted ketones and for stably storing them.

[0003]

SUMMARY OF THE INVENTION The present invention relates to an optically active α-
It is to provide a method for stably storing substituted ketones.

[0004]

Means for Solving the Problems The present inventors have studied the optical activity α
As a result of intensive studies on a method of preventing racemization of substituted ketones and preserving them stably, surprisingly, the optical activity α
-It has been found that racemization can be prevented by bringing an inorganic oxide into contact with a substituted ketone, and that the compound can be stably stored, thus completing the invention.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The optically active α-substituted ketones of the present invention can be produced by a known method. For example,
(-)-Mentone can be produced in a form maintaining optical purity by oxidizing (-)-menthol dissolved in glacial acetic acid with an aqueous solution of sodium hypochlorite.

The optically active 2-methoxycyclohexanone is obtained by adding an optically active 2-methoxycyclohexanol having an optical purity of 99.0% ee or more to a hypohalous acid or a hypohalous acid under acidic conditions in the presence of a ketone. It can be manufactured by oxidizing at the source of generation. Although there are various isolation methods, for example, in order to isolate optically active 2-methoxycyclohexanone from the oxidation reaction solution, firstly, the residual hypohalous acid in the system is visually inspected with potassium iodide starch test paper in a blue-violet color. Decompose by adding sodium bisulfite or sodium sulfite until the color no longer changes. Next, the pH of the reaction solution containing optically active 2-methoxycyclohexanone was adjusted to 7.5 to 9 in order to decompose in advance the impurities that promote unstable racemization in the base contained in the reaction solution, and then to 0.
After reacting at ４０40 ° C. for 0.05 to 5 hours, solvent extraction is performed with diethyl ether, methyl isobutyl ketone or the like.
Then, the solvent extract layer is concentrated and distilled under reduced pressure to obtain purified optically active 2-methoxycyclohexanone.

However, optically active 2-methoxycyclohexanone is a chemically and optically unstable compound, and in the presence of certain impurities, racemizes even when refrigerated at 5 to 10 ° C. Or it becomes impure. In particular, the optically active 2-methoxycyclohexanone before distillation purification by concentrating the solvent extraction layer is easily racemized,
When an inorganic base, an inorganic acid, a metal or a metal salt, or the like is mixed, racemization often occurs even in a very small amount, and may occur even when stored at −10 ° C. or lower. Furthermore, when it comes into contact with oxygen, it is oxidized and by-produces impurities such as methyl adipate. Therefore, in order to prevent an inorganic base, an inorganic acid, a metal or a metal salt from being brought into the organic extract layer, the organic extract layer is sufficiently washed and then concentrated. However, even if these operations are carried out, a very small amount may cause racemization depending on the kind of the impurity. Therefore, by bringing them into contact with and adsorbing an inorganic oxide, racemization can be prevented, and they can be stably stored without being chemically impure.

Here, the optically active α-substituted ketone is a compound represented by the above general formula (I). Specifically, optically active aliphatic α-substituted ketones such as optically active 3-methyl-2-oxoheptane, and optically active alicyclic α-substituted ketones such as optically active menthol and optically active 2-methoxycyclohexanol. And optically active aralkyl α-substituted ketones such as 1-methylpropyl phenyl ketone.

These are those in the organic solvent extract obtained by extracting the organic solvent from the oxidation reaction solution, those in the concentrate obtained by removing the solvent from the organic solvent extract layer under reduced pressure, and those obtained by distilling the concentrate under reduced pressure. Means that the concentration is 1 to 99.9
% Can be used.

As the inorganic oxide to be brought into contact, any inorganic oxide, such as zeolite or silica gel, having the ability to adsorb polar substances can be used. Can not. As the zeolite, either a natural zeolite or a synthetic zeolite can be used. For example, zeolam A-5 (manufactured by Tosoh Corporation) commercially available as molecular sieves can be used. Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.) or the like can be used as the silica gel. Although these inorganic oxides can be used as they are, it is more effective to use them after pretreatment. As the pretreatment method, 100 ° C
There are a method of heating and drying under reduced pressure, and a method of baking in an electric furnace at 400 ° C. or higher.

Examples of the method of contacting the inorganic oxide include a method of adding the above-mentioned optically active α-substituted ketone in a batch system, a method of filling the column and passing the optically active α-substituted ketone, and the like. What is necessary is just to select according to the objective. When added in a batch system, the amount of the inorganic oxide to be added varies depending on the storage form, the amount of impurities, the storage temperature and the like of the optically active α-substituted ketone.
t% to 30% by weight, preferably 1% to 10% by weight. These inorganic oxides are added to the organic solvent extract, the concentrate obtained by removing the solvent from the organic solvent extract under reduced pressure, or the optically active α-substituted ketones distilled under reduced pressure, and then sufficiently stirred, but continuously stirred. do not have to. Further, after the compound which promotes the racemization is adsorbed by sufficiently stirring, the compound may be separated by filtration or the like, or may coexist in the system as it is. The storage temperature of the optically active α-substituted ketones brought into contact with the inorganic oxide varies depending on the type of optically active α-substituted ketones, required optical purity and chemical purity, but is usually 30 ° C. or lower, preferably 10 ° C. It is as follows. In particular, in the case of an organic solvent extract before purification by vacuum distillation or a concentrated solution in which the solvent is removed from the organic solvent extract layer under reduced pressure, the temperature is 0 ° C or lower, preferably -10 ° C or lower.

Also, the optical activity α contacted with an inorganic oxide
-Preservation of substituted ketones is more effective when not in contact with oxygen. Although it can be stored in a vacuum state, it may be stored in an atmosphere of an inert gas such as nitrogen, helium, or argon.

[0013]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. still,
The chemical purity of optically active 2-methoxycyclohexanone is Th
The optical purity was determined by GC analysis using ermon3000 as a liquid layer, and the optical purity was determined by GC analysis using a chiral column.

EXAMPLE 1 10 g of distilled (S) -2-methoxycyclohexanone (optical purity: 98.7% ee, chemical purity: 99.2%) was charged into a 50 ml glass stoppered glass test tube. Then, as pretreatment, Zeolam A-5 dried under reduced pressure at 100 ° C. for 5 hours.
The mixture was purged with argon (manufactured by Tosoh Corporation), stirred at room temperature for 1 hour, and then allowed to stand at 20 ° C to 25 ° C for 7 days. The optical purity of the content was 98.5% ee, and the chemical purity was 99.2%.

Comparative Example 1 The procedure of Example 1 was repeated except that Zeorum A-5 was not added. The optical purity of the content was 96.5% ee, and the chemical purity was 99.2%.

Example 2 A 500 ml four-necked flask equipped with a thermometer, a dropping funnel, a condenser and a stirrer was charged with 99.8% e of optical purity.
13.0 g of (S) -2-methoxycyclohexanol of e
(0.1 mol), 7 g of dichloromethane and 30 g (30 mmol) of a 10% aqueous sulfuric acid solution. Stir at 20-25 ° C. 60 g of an aqueous solution of sodium hypochlorite containing 12.1% of available chlorine was added in about 1 hour, and stirring was further continued for 30 minutes. The reaction mixture was analyzed by GC, and after confirming that the peak of (S) -2-methoxycyclohexanol had disappeared, 2 g of sodium bisulfite was added with stirring. After confirming that the potassium iodide starch test paper did not turn blue-violet, 30 ml of a 10% aqueous sodium carbonate solution was added.
After the addition, the mixture was stirred at 20 to 25 ° C for 1 hour. It was then extracted twice with 50 g of dichloromethane. The dichloromethane layers were combined, washed with a saturated saline solution, and then concentrated to obtain 11.5 g of (S) -2-methoxycyclohexanone (9
0 mmol) in 21.6 g of a dichloromethane solution. The optical purity of (S) -2-methoxycyclohexanone in the concentrate was 99.6% ee. 10 g of this solution
Was charged in the same test tube as in Example 1, and 10
After addition of 1 g of Zeolam A-5 dried under reduced pressure at 0 ° C. for 5 hours, the atmosphere was replaced with argon. After stirring at room temperature for 1 hour, the mixture was allowed to stand at 20 ° C to 25 ° C for 7 days. The optical purity of the content was 98.6% ee.

Comparative Example 2 The procedure of Example 2 was repeated except that Zeorum A-5 was not added. The optical purity of the content was 76.1% ee.

Example 3 20.9 g of a concentrate was obtained in the same manner as in Example 2 except that the extraction solvent was changed to diethyl ether. This includes (S)-
9.8 g of 2-methoxycyclohexanone was contained. The optical purity of (S) -2-methoxycyclohexanone in the concentrate was 99.6% ee. 10 g of this solution
Was charged in the same test tube as in Example 1, and 10
3 g of Wakogel C-200 dried at 0 ° C. for 5 hours under reduced pressure
After the addition, the atmosphere was replaced with argon. After stirring at room temperature for 1 hour, the mixture was allowed to stand at 20 ° C to 25 ° C for 7 days. The optical purity of the content was 99.0% ee, and no impurity peak was found in the GC analysis, which was not observed at the time of preparation.

Comparative Example 3 Example 3 except that Wakogel C-200 was not added.
It was allowed to stand as above. The optical purity of the content was 89.3% ee.

Example 4 In the same manner as in Example 2, 23.5 g of a concentrate was obtained. This contained 9.6 g of (S) -2-methoxycyclohexanone. The optical purity of (S) -2-methoxycyclohexanone in the concentrate was 99.6% ee. 10 g of this solution was charged into a test tube similar to that of Example 1, and Wakogel C-20 dried at 100 ° C. for 5 hours under reduced pressure as a pretreatment.
After adding 3 g of 0, the mixture was stirred at room temperature for 1 hour without replacing with argon, and then allowed to stand at 20 ° C. to 25 ° C. for 7 days. Although the optical purity of (S) -2-methoxycyclohexanone was 98.7% ee, a plurality of impurity peaks which were not observed at the time of preparation by GC analysis were detected.

Comparative Example 4 Example 4 except that Wakogel C-200 was not added.
It was allowed to stand as above. The optical purity of the content was 89.0% ee, and more impurity peaks that were not observed during preparation by GC analysis were detected. Example 5 21.9 g of a concentrated liquid was obtained in the same manner as in Example 2 except that the extraction solvent was changed to dichloroethane. Among them, (S) -2
12.0 g of -methoxycyclohexanone was contained. The optical purity of (S) -2-methoxycyclohexanone in the concentrate was 95.9% ee. 8 g of this solution was charged into the same test tube as in Example 1, and 100
After addition of 2 g of Zeolam A-5 dried under reduced pressure at 5 ° C. for 5 hours, the atmosphere was replaced with argon. After stirring at room temperature for 1 hour, the mixture was allowed to stand at 40 ° C. for 13 hours. The optical purity of the content was 95.9% ee, and no impurity peak was found in the GC analysis, which was not observed during the preparation.

Comparative Example 5 The procedure of Example 5 was repeated except that Zeorum A-5 was not added. The optical purity of the content was 87.1% ee.

Example 6 10 g of the concentrated solution obtained in Example 5 was diluted with 20 g of dichloroethane and passed through a column filled with Zeolam A-5 (packing amount: 10 g), which was dried at 100 ° C. for 5 hours under reduced pressure as a pretreatment. . After replacing the passing solution with argon, 13
Let stand for hours. The optical purity of the content was 95.7% ee, and no impurity peak was found in the GC analysis, which was not observed at the time of preparation.

[0024]

According to the present invention, chemically and optically unstable optically active α-substituted ketones can be stored chemically and optically stably.

Claims (9)

[Claims] 1. A compound of the general formula (I) (Wherein, R ¹ and R ² are an alkyl group having 1 to 8 carbon atoms; an unsubstituted or an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group having 6 to 18 carbon atoms substituted with a halogen element, Or an aralkyl group, which may be the same or different, and R ¹ and R ² may combine to form an alkyl ring, R ³ is an alkyl group having 1 to 4 carbon atoms,
Represents an alkoxyl group or a halogen element. A method for stabilizing optically active α-substituted ketones, which comprises contacting an optically active α-substituted ketone represented by the formula (1) with an inorganic oxide. 2. The method for stabilizing optically active α-substituted ketones according to claim 1, wherein the inorganic oxide to be contacted is a substance that adsorbs a polar compound. 3. The method for stabilizing an optically active α-substituted ketone according to claim 1, wherein the inorganic compound to be contacted is zeolite or silica gel. 4. An optically active α-substituted ketone is an optically active α-substituted ketone.
4. An optically active .alpha.-substituted ketone produced by oxidizing a substituted alcohol with a halogen, a halogen acid, a hypohalous acid, or a hypohalous acid source. The method for stabilizing an optically active α-substituted ketone according to the above. 5. The optically active α-substituted ketone is an optically active α-substituted ketone.
It is a substituted alicyclic ketone, The claim 1 characterized by the above-mentioned.
5. The method for stabilizing an optically active α-substituted ketone according to any one of 4. 6. The method for stabilizing an optically active α-substituted ketone according to claim 5, wherein the optically active α-substituted alicyclic ketone is optically active α-methoxycyclohexanone. 7. An optically active α-methoxycyclohexanone produced by oxidizing optically active α-methoxycyclohexanol with a hypohalous acid or a hypohalous acid generating source. A method for stabilizing active α-substituted ketones. 8. The optically active α- according to any one of claims 1 to 7, wherein the optically active α- is stored in an inert gas atmosphere.
A method for stabilizing substituted ketones. 9. The optically active α according to claim 8, wherein the inert gas is nitrogen, helium or argon.
-Stabilization of substituted ketones.