JP3852083B2 - Method for producing 2-methoxycyclohexanone - Google Patents

Description

何れも（ＲＳ)−２−メトキシシクロヘキサノールの転化率が低く、（ＲＳ)−２−メトキシシクロヘキサノンの選択率の低かった。
【００２５】
比較例７
実施例１と同様の装置に（ＲＳ)−２−メトキシシクロヘキサノール１１．４ｇ（０．１モル）、メチルエチルケトン７ｇ、及び１０％硫酸水溶液２５ｇ（２６ミリモル）を仕込み、２０〜２５℃ にて攪拌した。有効塩素１２．５％の次亜塩素酸ナトリウム水溶液６１ｇを約２時間で添加し、更に３０分間攪拌を継続した。ＧＣで分析した結果、（ＲＳ)−２ーメトキシシクロヘキサノールの転化率は９８％であり、（ＲＳ)−２−メトキシシクロヘキサノンが９３％生成していた。次いで実施例１と同様にしてクロロホルムで（ＲＳ)−２−メトキシシクロヘキサノンを抽出したが、メチルエチルケトンがクロル化された催涙性の強い化合物が副生物しており、後処理の操作性に支障があった。ここで使用したメチルエチルケトンの４０℃ に於ける水への溶解度は５ｗｔ％以上である。
【００２６】
比較例８
メチルエチルケトンに替えてトルエンを使用し、比較例６と同様に反応させた。ＧＣ分析した結果、（ＲＳ)−２−メトキシシクロヘキサノンの転化率は４５％、（ＲＳ)−２−メトキシシクロヘキサノールの収率は４２％と低かった。更に、トルエンのクロル化物が副生する為に、（ＲＳ)−２−メトキシシクロヘキサノールの精製には高段数の精留塔が必要であった。ここで使用したトルエンと水に対する２０℃ での（ＲＳ)−２−メトキシシクロヘキサノールの分配は水に大きく偏っており、トルエンへの分配比は１以下である。
【００２７】
比較例９
２５％硫酸を４０ｇ添加し、その他は実施例１と同様にして反応させた。反応液をＧＣで分析すると（ＲＳ）−２−メトキシシクロヘキサノールが２４％残存していた。
【００２８】
【発明の効果】
１．本発明によれば、２−メトキシシクロヘキサノールを次亜ハロゲン酸アルカリ金属塩またはアルカリ土類金属塩で酸化する際に、特定の有機化合物と鉱酸を共存させる事により、高収率で、容易にケトンを製造することができる。ここで、有機化合物とはアルキルクロライドまたはジエチルエーテルを意味する。
【００２９】
２．更に光学活性脂環式アルコールを原料に使用すれば、ラセミ化を併発する事なく光学活性脂環式ケトンを製造することができる。
【００３０】
３．原料の２級アルコールと生成物であるケトンは近接した沸点を持つ化合物である事が多いが、本発明の方法では原料の２級アルコールの転化率を１００％にする事が容易であり、従って高純度のケトンを容易に得ることができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical important methoxy cyclohexanone and pesticides raw materials, particularly relates to the preparation of optically active 2-methoxy cyclohexanone, hypohalous acid and more particularly a 2-methoxy cyclohexanol in a water solvent In producing 2-methoxycyclohexanone by reacting with an alkali metal salt or the like, 2-methoxycyclohexanone is obtained in high yield by coexisting an organic compound having specific physical properties and a specific amount of mineral acid. . Further, when optically active 2-methoxycyclohexanol is used as a raw material, optically active 2-methoxycyclohexanone is produced without accompanying racemization.
[0002]
[Prior art]
Conventionally, various methods for obtaining an alicyclic ketone by oxidizing an alicyclic alcohol with hypohalous acid are known. For example, (1) a method of reacting cycloheptanol with sodium hypochlorite in the presence of a quaternary ammonium salt (Tetrahedron Letter (1976), 20,1641), (2) optically active menthol in a glacial acetic acid solvent. Method of obtaining optically active menthone by reaction with sodium hypochlorite (J. Org. Chem., (1980), 45, 2030), (3) Cycloalkanol and hypohalous acid in water and water miscible solvent A method of obtaining an alicyclic alcohol by reacting with an alkali metal salt of alkali acid or alkaline earth metal hypohalite at a pH of 6 or less (Japanese Patent Laid-Open No. 4-21629) (4) Optically active 2-alkoxycyclohexanol A method of obtaining optically active 2-alkoxycycloalkanone by oxidation with a source of halogenous acid or hypohalous acid (GB 2283971) is known.
[0003]
However, the method (1) has disadvantages such as an increase in cost due to the addition of a quaternary ammonium salt and a complicated isolation operation. The method (2) is excellent as a method for obtaining optically active menthone without reducing the optical purity, but has the disadvantage that the product isolation operation becomes complicated because glacial acetic acid is used as a solvent. Since the method (3) reacts in a solvent miscible with water, there is a drawback that the product isolation operation becomes complicated. In the reaction in the presence of a ketone, which is the most preferred embodiment of the method (4), a by-product in which the α-position of the added ketone is chlorinated is produced. For example, when acetone, methyl ethyl ketone, etc. are used, there is tearing properties, and α-haloketone, which is highly toxic to the human body, is produced as a by-product, and the purity of the product deteriorates. May cause health problems.
[0004]
[Problems to be solved by the invention]
In the present invention, when 2-methoxycyclohexanol is reacted with an alkali metal hypohalite or an alkaline earth metal hypohalite, a by-product that is harmful to the human body is generated in a short time with a high yield. It is to provide an industrial method for producing 2-methoxycyclohexanone without any problems. Furthermore, when optically active 2-methoxycyclohexanol is used, it is providing the industrial manufacturing method of optically active 2-methoxycyclohexanone which does not combine racemization.
[0005]
[Means for Solving the Problems]
As a result of intensive studies on the production method of 2-methoxycyclohexanone, the present inventors have surprisingly found that 2-methoxycyclohexanol and an alkali metal hypohalite or alkaline earth metal hypohalite in an aqueous solvent. When reacting, an aliphatic compound with specific physical properties and a specific amount of mineral acid coexist to generate by-products that are high in yield, good operability, and harmful to the human body in a short time. can produce a 2-methoxy cyclohexanone without, in particular, when the optically active 2-methoxy-cyclohexanol was used as the starting material, the present invention found that can produce an optically active 2-methoxy cyclohexanone to suppress racemization Was completed.
[0006]
That is, the present invention provides 2-methoxycyclohexanol (hereinafter sometimes referred to as “secondary alcohol” or “alicyclic alcohol”) and alkali metal hypohalite or alkaline earth metal hypohalite in water. When producing 2-methoxycyclohexanone by reacting in a solvent, 2-methoxycyclohexanone (hereinafter referred to as “alicyclic ketone” or “ketone”) in which an aliphatic compound having specific physical properties and a specific amount of mineral acid coexist. In some cases) . Here, the aliphatic compound having specific physical properties means an aliphatic compound selected from alkyl chloride and diethyl ether . The amount of mineral acid to coexist herein, means that it is 0.1 to 0.8 equivalents relative to 2-methoxy cyclohexanol. Furthermore, when optically active 2-methoxycyclohexanol is used as a starting material, it is a method for producing optically active 2-methoxycyclohexanone .
[0007]
DETAILED DESCRIPTION OF THE INVENTION
The secondary alcohol used as a raw material, a 2-methoxy cyclohexanol Sano Le. Further, the optically active cycloaliphatic alcohols, optically active 2-methoxy cyclohexanol Sano Le can be preferably used.
[0008]
The other raw material alkali metal hypohalite or alkaline earth metal hypohalite is sodium hypochlorite, sodium hypobromite, potassium hypochlorite, potassium hypobromite, hypochlorous acid. Examples thereof include calcium chlorate and calcium hypobromite, preferably sodium hypochlorite, sodium hypobromite, potassium hypochlorite and potassium hypobromite, particularly preferably hypochlorite. Sodium acid. As 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 there is much salt content in the sodium hypohalite aqueous solution, there is no problem in the reaction, 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 adjust the amount of mineral acid added to the oxidation reaction solution.
[0009]
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 1 to 2 equivalents, preferably 1 to 1.3 equivalents of the starting alicyclic alcohol. If it is less than 1 equivalent, the reaction becomes immature, and if it exceeds 2 equivalents, not only will the raw material cost increase, but side reactions may occur due to excess hypohalous acid, or decomposition of hypohalous acid in the post-treatment step of the reaction. It must be operated and is not advantageous. In addition, when reaction is progressing favorable by the method of this invention, the usage-amount of hypohalous acid is 1-1.15 equivalent.
[0010]
The fat aliphatic compounds you added, is 1 or more distribution ratio of secondary alcohol at 20 ° C. is to water, and an organic compound solubility is 5 wt% or less to the in water 40 ° C. Those selected from alkyl chloride and diethyl ether are used . Here, the distribution ratio means that secondary alcohol is added to water having the same weight as that of the aliphatic compound, stirred for 10 minutes, and then allowed to stand for separation to analyze the concentration of both layers. It is a ratio of the concentration of alcohol, and the distribution ratio is defined as 1 or more when the concentration in the organic solvent is higher than the concentration in water . For example if dichloromethane, chloroform, tetrachloromethane, monochloroethane, 1,1-dichloroethane, 1,2-dichloroethane, alkyl chlorides or diethyl ethers such as 1,1,1 over trichloroethane. Particularly preferred are dichloromethane, chloroform, monochloroethane, 1,1-dichloroethane and 1,2-dichloroethane. The amount of lipid compound 0.1-3 times normal are secondary alcohols, preferably 0.2 to same weight. When the addition amount is 0.1 weight times or less, the effect is not exhibited, the reaction rate is slowed, and the by-products are increased. Further, even if it is 3 times by weight or more, the reaction rate is slow, which is not preferable.
[0011]
The mineral acid to be added is preferably sulfuric acid, hydrochloric acid or phosphoric acid. The amount used is 0.1 to 0.8 equivalent, preferably 0.2 to 0.8 equivalent, of the secondary alcohol as a raw material. When the amount is less than 0.1 equivalent, the pH of the reaction solution becomes 3 or more due to the added alkali metal hypohalite, which not only slows the reaction rate but also increases by-products. On the other hand, when the amount is 2 equivalents or more, the decomposition of hypohalous acid is promoted, and the amount of alkali metal hypohalous acid salt required to make the conversion rate of the secondary alcohol 100% increases, which is not preferable because the cost increases. However, if the aqueous alkali metal hypohalite solution contains a large amount of free alkali, an acid corresponding to the amount of alkali already mixed in is added at the beginning of the reaction, or is added sequentially during the reaction. To do. Here, the equivalent of acid is 1 equivalent of 2 moles when sulfuric acid is used per mole of alicyclic alcohol, 1 mole is 1 equivalent when hydrochloric acid, and 1 mole is 3 equivalents when phosphoric acid is used. means. The mineral acid used here may be used as an aqueous solution. The concentration is preferably 2 to 25% by weight aqueous solution, more preferably 5 to 15% by weight. If it is 2% or less, the concentration of the reaction solution is lowered and the production efficiency is deteriorated, and if it is 25% or more, the reaction solution at the initial stage of the reaction is small and the operability is poor, the reaction temperature is difficult to control, and by-products are increased. Absent.
[0012]
As the reaction mode, a secondary alcohol, an organic compound, and a mineral acid are charged all at once, and an aqueous solution of an alkali metal hypohalite or an alkaline earth metal hypohalite is added dropwise with stirring. Further, when the initial concentration of the mineral acid aqueous solution is high or when the amount of the organic compound to be added is small, a secondary alcohol or a mineral acid aqueous solution can be sequentially added during the reaction to react.
[0013]
The reaction temperature is 0 to 30 ° C., preferably 15 to 25 ° C., from the stability of hypohalous acid generated in the reaction solution. When the temperature is lower than 0 ° C, the oxidation reaction is delayed, and when the temperature is higher than 30 ° C, hypohalous acid is decomposed. In particular, when an optically active alicyclic alcohol is used, it is preferable to react at 30 ° C. or lower in order to suppress the racemization reaction.
The added alkali metal hypohalous acid salt immediately becomes hypohalous acid upon contact with a mineral acid, and then reacts instantaneously upon contact with an 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.
[0014]
After confirming the completion of the reaction, the excess hypohalous acid is decomposed. For example, sodium bisulfite or sodium sulfite may be added until the potassium iodide starch test paper does not turn blue-violet.
[0015]
The ketone thus obtained is isolated from the reaction solution by a conventional method. For example, after extracting from a reaction mixture with an organic solvent, the method of distilling and refine | purifying after removing a solvent, or the method of refine | purifying and isolating an extract by column chromatography etc. are mentioned.
[0016]
【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 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.
[0017]
Example 1
In a 500 ml four-necked flask equipped with a thermometer, dropping funnel, condenser and stirrer, 13.0 g (0.1 mol) of (RS) -2-methoxycyclohexanol, 7 g of dichloromethane, 30 g of 10% aqueous sulfuric acid (30 mmol) Was stirred at 20 to 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 (RS) -2-methoxycyclohexanol had disappeared, 2 g of sodium hydrogen sulfite was added with stirring, and the potassium iodide starch test paper turned blue-violet. I confirmed not to. Extraction was performed twice with 50 g of dichloromethane, and the dichloromethane layers were combined, washed with 30 g of saturated brine, and then concentrated and distilled to obtain 11.5 g (90 mmol) of (RS) -2-methoxycyclohexanone. The chemical purity was 99.8%. The dichloromethane used here has a partition ratio with water at 20 ° C. of 1 or more, and the solubility in water at 40 ° C. is 5 wt% or less.
[0018]
Reference example 1
In the same apparatus as in Example 1, 11.4 g (0.1 mol) of (RS) -2-methylcyclohexanol, 7 g of 1,2-dichloroethane, 20 g of 20% sulfuric acid aqueous solution (20 mmol) were charged at 20 to 25 ° C. Was stirred. 145 g of sodium hypochlorite aqueous solution containing 5.6% effective chlorine was added in about 3 hours, and stirring was further continued for 30 minutes. As a result of analyzing the reaction solution by GC, 95% of (RS) -2-methylcyclohexane was produced. The 1,2-dichloroethane used here has a partition ratio with water at 20 ° C. of 1 or more, and its solubility in water at 40 ° C. is 5 wt% or less.
[0019]
Reference example 2
(RS) -4-methylcyclohexanol (11.4 g, 0.1 mol), chloroform (10 g), 10% aqueous sulfuric acid solution (20 g, 20 mmol) were charged in the same apparatus as in Example 1, and the mixture was stirred at 20-25 ° C. . 145 g of sodium hypochlorite aqueous solution containing 5.6% effective chlorine was added in about 3 hours, and stirring was further continued for 30 minutes. As a result of analyzing the reaction solution by GC, 94% of (RS) -4-methylcyclohexanone was produced. The chloroform used here has a partition ratio with water at 20 ° C. of 1 or more, and the solubility in water at 40 ° C. is 5 wt% or less.
[0020]
Example 2
The reaction was conducted in the same manner as in Example 1 using 13.0 g (0.1 mol) of (S) -2-methoxycyclohexanol having an optical purity of 99% ee, and 11.2 g of (S) -2-methoxycyclohexanone (88 Mmol). The chemical purity was 99.8%, the optical purity was 99% ee, and no racemization occurred in the reaction.
[0021]
Example 3
The same apparatus as in Example 1 was charged with 3.9 g (30 mmol) of (RS) -2-methoxycyclohexanol, 7 g (19 mmol) of 10% hydrochloric acid and 2 g of diethyl ether, and a 12.3% aqueous hypochlorous acid solution. Was added dropwise and reacted in the same manner as in Example 1. As a result of analyzing the reaction solution by GC, 95% of (RS) -2-methoxycyclohexanone was produced. The diethyl ether used here has a partition ratio with water at 20 ° C. of 1 or more, and the solubility in water at 40 ° C. is 5 wt% or less.
[0022]
Comparative Example 1
The reaction was carried out in the same manner as in Example 1 except that 10% sulfuric acid was not added. The reaction mixture and analyzed by GC (RS) -2- methoxy cyclohexanone had generated 1.7%.
[0023]
Comparative Examples 2-6
In the same apparatus as in Example 1, 11.4 g (0.1 mol) of (RS) -2-methoxycyclohexanol, the compounds shown in Table 1, and 40 g (41 mmol) of 10% sulfuric acid aqueous solution were charged. Stir at ℃. 65 g of an aqueous sodium hypochlorite solution containing 12.5% effective chlorine was added in about 2 hours, and stirring was continued for another 30 minutes. The results are shown in Table 1. The organic compounds methanol and acetonitrile added here have a solubility in water at 40 ° C. of 5 wt% or more, and the distribution of (RS) -2-methoxycyclohexanol in cyclohexane and water at 20 ° C. is largely biased to water. The distribution ratio to cyclohexane is 1 or less.
[0024]
[Table 1]

In either case, the conversion rate of (RS) -2-methoxycyclohexanol was low, and the selectivity of (RS) -2-methoxycyclohexanone was low.
[0025]
Comparative Example 7
In the same apparatus as in Example 1, 11.4 g (0.1 mol) of (RS) -2-methoxycyclohexanol, 7 g of methyl ethyl ketone, and 25 g (26 mmol) of 10% sulfuric acid aqueous solution were charged and stirred at 20 to 25 ° C. did. 61 g of an aqueous sodium hypochlorite solution containing 12.5% effective chlorine was added in about 2 hours, and stirring was further continued for 30 minutes. As a result of GC analysis, the conversion rate of (RS) -2-methoxycyclohexanol was 98%, and 93% (RS) -2-methoxycyclohexanone was produced. Next, (RS) -2-methoxycyclohexanone was extracted with chloroform in the same manner as in Example 1. However, a strong tearing compound in which methyl ethyl ketone was chlorinated was a by-product, which hindered the operability of post-treatment. It was. The solubility of methyl ethyl ketone used here in water at 40 ° C. is 5 wt% or more.
[0026]
Comparative Example 8
Toluene was used instead of methyl ethyl ketone, and the reaction was carried out in the same manner as in Comparative Example 6. As a result of GC analysis, the conversion rate of (RS) -2-methoxycyclohexanone was 45%, and the yield of (RS) -2-methoxycyclohexanol was as low as 42%. Furthermore, since a chlorinated product of toluene is produced as a by-product, a rectifying column having a high number of stages is required for purification of (RS) -2-methoxycyclohexanol. The distribution of (RS) -2-methoxycyclohexanol at 20 ° C. with respect to toluene and water used here is largely biased to water, and the distribution ratio to toluene is 1 or less.
[0027]
Comparative Example 9
40 g of 25% sulfuric acid was added, and the others were reacted in the same manner as in Example 1. When the reaction solution was analyzed by GC, 24% (RS) -2-methoxycyclohexanol remained.
[0028]
【The invention's effect】
1. According to the present invention, when 2-methoxycyclohexanol is oxidized with a hypohalous acid alkali metal salt or an alkaline earth metal salt, a specific organic compound and a mineral acid are allowed to coexist with a high yield. A ketone can be produced. Here, the organic compound means alkyl chloride or diethyl ether .
[0029]
2. Furthermore, if an optically active alicyclic alcohol is used as a raw material, an optically active alicyclic ketone can be produced without accompanying racemization.
[0030]
3. The raw material secondary alcohol and the product ketone are often compounds having close boiling points, but in the method of the present invention, the conversion of the raw material secondary alcohol can be easily made 100%. High purity ketones can be easily obtained.

Claims (4)

In producing 2-methoxycyclohexanone by reacting 2-methoxycyclohexanol with an alkali metal hypohalite or alkaline earth metal hypohalite in an aqueous solvent, selected from alkyl chloride and diethyl ether A method for producing 2-methoxycyclohexanone, wherein an aliphatic compound and 0.1 to 0.8 equivalents of a mineral acid are allowed to coexist with 2-methoxycyclohexanol. The method for producing 2-methoxycyclohexanone according to claim 1, wherein 2-methoxycyclohexanol is optically active 2-methoxycyclohexanol, and 2-methoxycyclohexanone is optically active 2-methoxycyclohexanone. 3. 2-methoxy according to claim 1 or 2 , characterized in that the alkyl chloride is dichloromethane, chloroform, tetrachloromethane, monochloroethane, 1,1-dichloroethane, 1,2-dichloroethane or 1,1,1-trichloroethane. A method for producing cyclohexanone. The method for producing 2-methoxycyclohexanone according to any one of claims 1 to 3 , wherein the mineral acid is sulfuric acid, hydrochloric acid or phosphoric acid.