JP3757592B2 - Process for producing optically active alicyclic ketones - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing optically active alicyclic ketones that are important as raw materials for pharmaceuticals and agricultural chemicals, and more specifically, optically active alicyclic alcohols are reacted with hypohalite aqueous solutions in acidic aqueous solutions. After being converted to an optically active alicyclic ketone, it is isolated after undergoing a basic step as necessary, and purified by distillation in the presence of a compound having an epoxy group or in the presence of a hindered amine, Moreover, this is a method for obtaining an optically active alicyclic ketone having high storage stability.
[0002]
[Prior art]
Conventionally, various methods for obtaining an optically active alicyclic ketone by oxidizing an optically active alicyclic alcohol with a hypohalite are known. For example, a method of obtaining optically active 2-alkoxycycloalkanone by oxidizing optically active 2-alkoxycyclohexanol with hypohalous acid or a source of hypohalous acid under acidic conditions in the presence of ketones (GB 2283971 ) Etc. are known. However, the optically active 2-alkoxycycloalkanone produced by the above method has a problem in storage stability, such as a decrease in chemical purity and racemization when the distilled purified product is stored at room temperature of about 30 ° C.
[0003]
[Problems to be solved by the invention]
The present invention provides a method for producing an optically active alicyclic ketone having high storage stability when an optically active alicyclic alcohol is reacted with an alkali salt of hypohalous acid under acidic conditions to produce an optically active alicyclic ketone. It is to provide.
[0004]
[Means for Solving the Problems]
As a result of intensive studies on a method for producing optically active alicyclic ketones, the present inventors have surprisingly converted optically active ketones by reacting optically active alicyclic alcohols with hypohalite in acidic aqueous solution. Subsequently, it was found that an optically active alicyclic ketone having high purity and high storage stability can be produced by distillation purification in the presence of a compound having an epoxy group or in the presence of a hindered amine. Here, it is found that the storage stability is further improved by isolating after the step of making the reaction solution basic at pH 7.1 to 10 and then purifying by distillation in the presence of a compound having an epoxy group or in the presence of a hindered amine. The present invention has been completed.
[0005]
That is, in the present invention, when an optically active alicyclic alcohol is produced by reacting an optically active alicyclic alcohol with an alkali metal hypohalite or alkaline earth metal hypohalite in an acidic aqueous solution, the reaction is completed. If necessary, it is isolated after passing through a step of making the reaction solution basic at pH 7.1 to 10, and then purified by distillation in the presence of a compound having an epoxy group or in the presence of a hindered amine, This is a method for producing an optically active alicyclic ketone having high storage stability.
[0006]
DETAILED DESCRIPTION OF THE INVENTION
The optically active alicyclic alcohol used as a raw material includes optically active alkyl-substituted cycloalkanols such as optically active 2-methylcyclohexanol and optically active 3-methylcyclooctanol, and optically active alkoxy such as optically active 2-methoxycyclohexanol. Cycloalkanols.
[0007]
The other raw material alkali metal hypohalite or alkaline earth metal hypohalite is sodium hypochlorite, sodium hypobromite, potassium hypochlorite, potassium hypobromite, Examples thereof include calcium chlorite and calcium hypobromite, preferably sodium hypochlorite, sodium hypobromite, potassium hypochlorite and potassium hypobromite, particularly preferably hypochlorous acid. Sodium chlorate. As the sodium hypochlorite, a commercially available aqueous solution may be used. Although any concentration can be used, a commercially available 5 to 14% aqueous solution can be preferably used. A dilute aqueous solution of 5% or less is not preferable because the concentration of the reaction solution becomes low and the manufacturing cost increases. Moreover, even if inorganic salts such as sodium chloride are contained in the hypohalite aqueous solution, the reaction is not hindered, but the amount of free alkali such as sodium hydroxide or potassium hydroxide is preferably less than 1%. When the amount of free alkali is large, it is necessary to neutralize the free alkali in advance or increase the amount of mineral acid added to the oxidation reaction solution.
[0008]
The amount of alkali metal hypohalite used is determined from the amount of effective chlorine, but is influenced by the composition of the reaction system, the type of alicyclic alcohol, the reaction temperature, and the like. Usually, it is about 0.5 to 2 equivalents, preferably 1 to 1.3 equivalents, of the starting alicyclic alcohol. If the amount is more than 2 equivalents, not only will the raw material cost increase, but side reactions may occur due to excess hypohalous acid, and the operation of decomposing hypohalous acid must be carried out in the post-treatment step of the reaction. I can't say. In addition, when reaction is progressing favorable by the method of this invention, the usage-amount of hypohalous acid is 1-1.15 equivalent.
[0009]
The mineral acid to be added is preferably a sulfuric acid aqueous solution, a hydrochloric acid aqueous solution or a phosphoric acid aqueous solution. The amount used is 0.1 to 3 equivalents, preferably 0.2 to 2 equivalents, of the starting alicyclic alcohol.
[0010]
An organic compound may be added during the reaction. For example, primary alcohols such as methanol, ethers, ketones, alkyl halides, alkyl nitriles such as acetonitrile, and alkyl carboxylic acids such as acetic acid.
[0011]
The reaction mode includes optically active alicyclic alcohol, mineral acid aqueous solution, and when necessary, an organic compound is added all at once, while stirring, alkali metal hypohalite or hypohalous acid. An aqueous solution of an alkaline earth metal salt may be dropped. In addition, when the initial charge concentration of the mineral acid aqueous solution is high or when the amount of the organic compound to be added is small, the alicyclic alcohol or the mineral acid aqueous solution can be sequentially added during the reaction to react.
[0012]
The reaction temperature is 0 to 40 ° C., preferably 15 to 30 ° C., from the stability of hypohalous acid generated in the reaction solution. When the temperature is lower than 0 ° C, the oxidation reaction is slowed. When the temperature is higher than 40 ° C, hypohalous acid is decomposed. In particular, the reaction is preferably performed at 30 ° C. or lower in order to suppress the racemization reaction.
The added alkali metal hypohalite or alkaline earth metal hypohalite contacts with mineral acid to immediately become hypohalous acid, and then reacts instantaneously when contacted with alicyclic alcohol. Therefore, the reaction time is substantially the addition time of the aqueous alkali hypohalite solution, and the aging time is about 30 minutes.
[0013]
After confirming the completion of the reaction, the isolation operation is performed.
[0014]
If excess hypohalous acid remains, an alkali metal hydrogen sulfite or an alkali metal sulfite is added as needed until the potassium iodide starch test paper does not turn blue-violet. Here, the alkali metal bisulfite is sodium hydrogen sulfite, potassium hydrogen sulfite, lithium hydrogen sulfite and the like. The alkali metal sulfite is sodium sulfite, potassium sulfite, lithium sulfite, or the like. The alkali metal bisulfite or alkali metal sulfite to be added may be used as an aqueous solution, or may be added in a powder state. The amount used is determined by the amount of hypohalous acid remaining in the system, but is an amount that does not cause the potassium iodide starch test paper to turn blue-purple visually.
[0015]
The optically active alicyclic ketone is isolated from the reaction solution thus obtained by extraction. Any extraction solvent can be used as long as it is separated from water and has the ability to extract optically active alicyclic ketones and does not react. For example, ethers such as diethyl ether, ketones such as methyl isobutyl ketone, hydrocarbons such as cyclohexane and toluene, and halogenated alkyls such as chloroform and dichloroethane can be used. The reaction solution for extraction may be alkaline to acidic, but is preferably neutral or acidic. This depends on the type of alicyclic ketone as the target product, but the distribution to the organic solvent is generally larger on the acidic side and the amount of impurities brought into the organic layer is often reduced.
[0016]
The extract containing the optically active alicyclic ketone is washed with saturated saline, and if necessary, dehydrated with a dehydrating agent such as magnesium sulfate, and then the solvent is concentrated. Next, distillation is performed under reduced pressure in the presence of a compound having an epoxy group or in the presence of a hindered amine.
[0017]
Since the compound having an epoxy group used in the present invention needs to be separated from the target optically active alicyclic ketone by distillation, it is a compound having a higher boiling point than that of the optically active alicyclic ketone, preferably a boiling point at normal pressure. Is preferably 30 ° C. or more higher than the optically active alicyclic ketone. For example, a reaction product of epichlorohydrin and phenol or bisphenol A may be used instead of a single compound. In addition, a plurality of epoxy groups may be present in the molecule. The addition amount is 0.001 to 0.2 times by weight, preferably 0.001 to 0.1 times by weight, with respect to the optically active alicyclic ketone.
[0018]
The hindered amine used in the present invention is a compound (HALS) known as a light stabilizer for resins, such as bis (2,2,6,6-tetramethyl-4-piperidinyl) sebacate (trade name Tinuvin 770). Ciba Geigy). The addition amount is 0.001 to 0.2 times by weight, preferably 0.001 to 0.1 times by weight, with respect to the optically active alicyclic ketone.
[0019]
As described above, a stable optically active alicyclic ketone can be obtained by purifying an optically active alicyclic ketone isolated from an oxidation reaction solution by extraction or the like in the presence of a compound having an epoxy group or a hindered amine according to the above. However, when the operation is performed after the step of making the oxidation reaction solution basic, the stability of the optically active alicyclic ketone is further improved. That is, the reaction liquid containing an optically active alicyclic ketone is adjusted to pH 7.1 to 10, preferably pH 7.5 to 9, and then reacted at 0 to 40 ° C. for 0.01 to 5 hours to be unstable to the base. Decompose impurities. Bases added here are alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate. Salts are preferred. A pH of 10 or higher is not preferable because racemization may occur depending on the type of optically active alicyclic ketone. If the reaction temperature is higher than 40 ° C, racemization may occur, and if it is less than 0 ° C, the effect may not be exhibited, which is not preferable. Moreover, although reaction time is based also on the kind of alicyclic ketone, it is 0.01 to 5 hours normally, More preferably, it is 0.01 to 3 hours. Isolating and concentrating the optically active alicyclic ketone by extraction from the reaction solution thus obtained, and obtaining a stable optically active alicyclic ketone by distillation under reduced pressure in the presence of a compound having an epoxy group or a hindered amine. Can do.
[0020]
【Example】
EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these. The chemical purity of the optically active alicyclic ketone was determined by GC analysis using Thermo 3000 as a liquid layer, and the optical purity was determined by GC analysis using a chiral column.
[0021]
Example 1
In a 500 ml four-necked flask equipped with a thermometer, a dropping funnel, a condenser and a stirrer, 13.0 g (0.1 mol) of (S) -2-methoxycyclohexanol having an optical purity of 99.8% ee, 7 g of dichloromethane, Charge 30 g (30 mmol) of 10% sulfuric acid aqueous solution. Stir at 20-25 ° C. 60 g of sodium hypochlorite aqueous solution containing 12.1% effective chlorine was added in about 1 hour, and stirring was further continued for 30 minutes. The reaction solution 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-purple, it was extracted twice with 200 g of dichloromethane. The dichloromethane layers were combined, washed with saturated brine, and concentrated. To the concentrate, 0.6 g of a bisphenol A type epoxy compound (manufactured by Toto Kasei Co., Ltd., trade name: YD-128) was added and stirred at 70 ° C. for 1 hour, followed by distillation under reduced pressure (S ) -2-Methoxycyclohexanone (11.5 g, 90 mmol) was obtained. The chemical purity was 99.1% and the optical purity was 99.7% ee. 1 g of the obtained (S) -2-methoxycyclohexanone was charged into a glass ampoule, purged with argon, sealed, and heated at 60 ° C. for 60 hours. As a result of cooling to room temperature, opening the ampule and analyzing (S) -2-methoxycyclohexanone, the chemical purity was 99.0% and the optical purity was 99.0%.
[0022]
Example 2
A phenylglycidyl ether compound (manufactured by Sanko Chemical Co., Ltd., OPP-G) instead of the bisphenol A type epoxy compound of Example 1 (trade name: YD-128, manufactured by Toto Kasei Co., Ltd.) 11.5 g (90 mmol) of (S) -2-methoxycyclohexanone was obtained in the same manner as in Example 1 except that 0.2 g was added. The chemical purity was 99.2% and the optical purity was 99.6% ee. 1 g of the obtained (S) -2-methoxycyclohexanone was charged into a glass ampoule, purged with argon, sealed, and heated at 70 ° C. for 60 hours. As a result of cooling to room temperature, opening the ampule and analyzing (S) -2-methoxycyclohexanone, the chemical purity was 99.0% and the optical purity was 99.1% ee.
[0023]
Example 3
Instead of the bisphenol A type epoxy compound of Example 1 (trade name: YD-128, manufactured by Toto Kasei Co., Ltd.), bis (2,2,6,6-tetramethyl-4-piperidinyl) sebacate ( 11.0 g (86 mmol) of (S) -2-methoxycyclohexanone was obtained in the same manner as in Example 1, except that 0.3 g of Ciba Geigy Co., Ltd., Tinuvin 770) was added. The chemical purity was 99.2% and the optical purity was 99.5% ee. 1 g of the obtained (S) -2-methoxycyclohexanone was charged into a glass ampoule, purged with argon, sealed, and heated at 80 ° C. for 15 hours. As a result of cooling to room temperature, opening the ampule and analyzing (S) -2-methoxycyclohexanone, the chemical purity was 99.0% and the optical purity was 99.0% ee.
[0024]
Example 4
In a 500 ml four-necked flask equipped with a thermometer, dropping funnel, condenser and stirrer, 13.0 g (0.1 mol) of (S) -2-methoxycyclohexanol having an optical purity of 99.8% ee, 7 g of dichloroethane, Charge 30 g (30 mmol) of 10% sulfuric acid aqueous solution. Stir at 20-25 ° C. 60 g of sodium hypochlorite aqueous solution containing 12.1% effective chlorine was added in about 1 hour, and stirring was further continued for 30 minutes. The reaction solution 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-purple, an aqueous sodium carbonate solution was added to adjust the pH to 7.5 to 9, and the mixture was stirred at 20 to 25 ° C. for 1 hour. After adjusting the pH to 2 or less again with 10% sulfuric acid, the mixture was stirred at 20 to 25 ° C. for 2 hours and extracted with 100 g of toluene three times. The toluene layers were combined, washed with saturated brine, and concentrated. After adding 0.2 g of a bisphenol A type epoxy compound (trade name: YD-128, manufactured by Toto Kasei Co., Ltd.) to the concentrate, the mixture was stirred at 70 ° C. for 1 hour and then distilled under reduced pressure (S) 11.5 g (90 mmol) of -2-methoxycyclohexanone was obtained. The chemical purity was 99.1% and the optical purity was 99.7% ee. 1 g of the obtained (S) -2-methoxycyclohexanone was charged into a glass ampoule, purged with argon, sealed, and heated at 80 ° C. for 15 hours. As a result of cooling to room temperature, opening the ampule and analyzing (S) -2-methoxycyclohexanone, the chemical purity was 99.1% and the optical purity was 99.3% ee.
[0025]
Comparative Example 1
In the same manner as in Example 1, 11.5 g (90 mmol) of (S) -2-methoxycyclohexanone was obtained by distillation under reduced pressure without adding an epoxy compound to the concentrate. The chemical purity was 99.1% and the optical purity was 99.0% ee. 1 g of the obtained (S) -2-methoxycyclohexanone was charged into a glass ampoule, purged with argon, sealed, and heated at 60 ° C. for 60 hours. As a result of cooling to room temperature, opening the ampule and analyzing (S) -2-methoxycyclohexanone, the chemical purity was 99.0%, but the optical purity was 77.8% ee.
[0026]
【The invention's effect】
According to the present invention, when an optically active alicyclic alcohol is oxidized with a hypohalite under acidic conditions to produce an optically active alicyclic ketone, in the presence of a compound having an epoxy group during distillation or in the presence of a hindered amine By purifying under distillation, an optically active alicyclic ketone having high purity and high storage stability can be obtained. Furthermore, after isolation through a basic step, an optically active alicyclic ketone having higher storage stability can be obtained by distillation purification in the presence of a compound having an epoxy group during distillation or in the presence of a hindered amine. .

Claims (7)

The following general formula (I)

(Here, R represents an alkyl group having 1 to 8 carbon atoms and an alkoxyl group having 1 to 8 carbon atoms, and the bonding position of the substituent is a carbon atom different from the bonding position of the hydroxyl group. N is 0 to 3) And an optically active alicyclic alcohol represented by the following general formula (II):

(Wherein R represents an alkyl group having 1 to 8 carbon atoms and an alkoxyl group having 1 to 8 carbon atoms, and n represents 0 to 3). Wherein the compound is purified by distillation in the presence of a compound containing an epoxy group or a hindered amine.

(Wherein R represents an alkyl group having 1 to 8 carbon atoms and an alkoxyl group having 1 to 8 carbon atoms, and n represents 0 to 3), and a method for producing a stable optically active alicyclic ketone represented by . The optically active alicyclic alcohol is represented by the following general formula (III)

(Wherein R represents an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, and the bonding position of the substituent is the 2nd position or the 3rd position). The optically active alicyclic ketone is represented by the following general formula (IV)

(Where R represents an alkyl group having 1 to 8 carbon atoms and an alkoxyl group having 1 to 8 carbon atoms, and the bonding position of the substituent is the 2nd or 3rd position). The method for producing a stable optically active alicyclic ketone according to claim 1. 3. The stable optically active alicyclic ring according to claim 1, wherein the optically active alicyclic alcohol is optically active 2-methoxycyclohexanol and the optically active alicyclic ketone is optically active 2-methoxycyclohexanone. A method for producing formula ketones. The method for producing a stable optically active alicyclic ketone according to any one of claims 1 to 3, wherein the boiling point of the compound having an epoxy group is not less than the boiling point of the alicyclic ketone at normal pressure. . The method for producing a stable optically active alicyclic ketone according to any one of claims 1 to 3, wherein the hindered amine is bis (2,2,6,6-tetramethyl-4-piperidyl) sebacate. . The method for producing a stable optically active alicyclic ketone according to any one of claims 1 to 5, further comprising a step of making the reaction solution basic after completion of the oxidation reaction. The method for producing a stable optically active alicyclic ketone according to claim 6, wherein the pH of the reaction solution is 7.1 to 10 in the step of making basic.