Production of optically active ketone

Process for producing an optically active ester by reaction of a racemic alcohol with an optically active amino or tartaric acid derivative, a process for producing an optically active alcohol by hydrolysis of the optically active ester, a process for converting an alcohol into a ketone by oxidation, a method for stably storing an optically active ketone, and a new optically active amino acid ester and a new optically active tartaric acid ester.

TECHNICAL FIELD
 The present invention relates to a process for producing an optically
 active ketone which is an important intermediate for medicines and
 agricultural chemicals. More particularly, the present invention relates
 to a process for producing an optically active ester by reaction of a
 racemic alcohol with an optically active amino acid derivative or
 optically active tartaric acid derivative, to a process for producing an
 optically active alcohol by hydrolysis of said optically active ester, to
 a process for converting an alcohol into a ketone by oxidation, to a
 method for stably storing an optically active ketone, and to a new
 optically active amino acid ester and a new optically active tartaric acid
 ester.
 BACKGROUND ART
 (1) Production of optically active alcohol: There have been known several
 processes for, production of optically active alcohols. For example, (1)
 symmetric hydrolysis of an carboxylate ester of racemic alcohol by an
 enzyme (Agric. Biol. Chem., 46, 757 (1982)); (2) asymmetric hydrogenation
 if a ketone as a precursor by an enzyme (Nippon Kagaku Zasshi, 1315
 (1983)); and (3) asymmetric reduction of a ketone as a precursor by an
 asymmetric catalyst and hydrogen (J. Am. Chem. Soc., 101, 3129 (1979)).
 These processes are favorable to production of optically active alcohols
 but have their respective disadvantages. Process (1) needs an expensive
 enzyme and often involves difficulty in obtaining alcohols of high optical
 purity due to the enzyme's optical selectivity which greatly varies
 depending on the desired compound. Process (2) also needs an expensive
 enzyme and generally suffers the low enzymatic, activity. Process (3)
 needs an expensive asymmetric catalyst and involves difficulty in
 obtaining alcohols of high optical purity.
 (2) Esterifying reaction: There have been known several processes for
 producing optically active alicyclic alcohol derivatives. For example, (1)
 reaction of a racemic cyclohexanol derivative with propionic acid (to give
 an ester), followed by enzymatic resolution by lipase (Synthesis 1137
 (1990)); and (2) reaction of racemic alcohol with phthalic anhydride (to
 give a racemic carboxylic acid), followed by optical resolution by the aid
 of optically active .alpha.-phenylethylamine and subsequent hydrolysis to
 give an optically active alcohol (European Patent No. 656344). These
 processes are superior in production of optically active alicyclic alcohol
 derivatives but have their respective disadvantages. Process (1) needs an
 expensive enzyme and involves difficulty in obtaining alicyclic alcohol
 derivatives of high optical purity due to the enzyme's optical selectivity
 which greatly varies depending on the desired compound. Process (2) needs
 complex steps of synthesizing a phthalic acid derivative, forming a
 diastereomer salt with optically active .alpha.-phenylethylamine, and
 performing optical resolution.
 (3) Oxidation of an alcohol to produce a ketone: There have been known
 several processes for producing an alicyclic ketone from in alicyclic
 alcohol by oxidation with a hypohalous acid. For example, (1) reaction of
 cycloheptanol with sodium hypochlorite in the presence of a quaternary
 ammonium salt (Tetrahedron Letter (1976), 2, 1641); (2) reaction a
 optically active menthol with sodium hypochlorite in glacial acetic acid
 (as a solvent) to give optically active menthone (J. Org. Chem., (1980),
 45, 2030); (3) reaction of cycloalkanol with alkali metal (or alkaline
 earth metal) hypohalite at pH 6 or below in water and water-miscible
 solvent to give an alicyclic alcohol (Japanese Patent Laid-open No.
 211629/1992); and (4) reaction of optically active 2-alkoxycyclohexanol
 with hypohalous acid or a source thereof to give an optically active
 2-alkoxycycloalkanone (GB 2283971).
 These processes have their respective disadvantages. Process (1) needs a
 quaternary ammonium salt (which adds to the production cost) and a complex
 step to separate the reaction product. Process (2) needs A complex step to
 separate the reaction product as the result of using glacial acetic acid
 as a solvent, although it efficiently yields the desired product without
 decrease in optical purity. Process (3) needs a complex step to separate
 the reaction product because of reaction in a water-miscible solvent.
 Process (4) gives rise to an undesirable by-product when the reaction is
 carried out in the presence of a ketone according to the most preferable
 embodiment. This by-product is a ketone with its .alpha.-position
 chlorinated. In the case where the ketone is acetone or methyl ethyl
 ketone, the by-product is .alpha.-chloroketone which is highly toxic to
 human bodies and possesses tearing properties. It aggravates the purity of
 the reaction product and has an adverse effect on the health of operators
 in the case of commercial production.
 In addition, the optically active 2-alkoxycycloalkanone produced by the
 above-mentioned process decreases in chemical purity and undergoes
 racemization if it is stored at room temperature (about 30.degree. C.)
 after purification by distillation. Although the optically active
 .alpha.-substituted cyclic ketone is unstable, nothing is known about the
 method of stabilizing it.
 DISCLOSURE OF THE INVENTION
 The present invention was completed to eliminate the above-mentioned
 disadvantages involved in the prior art technology. Accordingly, it is an
 object of the present invention to provide a process for reacting a
 racemic alcohol with an optically active amino acid derivative or tartaric
 acid derivative, thereby producing optically active esters, to provide a
 process for hydrolyzing them, thereby giving optically active alcohols, to
 provide a process for oxidizing the alcohols into ketones, to provide a
 method for stably storing the optically active ketones, and to provide a
 new optically active amino acid ester and tartaric acid ester.

BEST MODE FOR CARRYING OUT THE INVENTION
 Synthesis of amino acid esters
 According to the present invention, amino acid esters are synthesized from
 racemic alcohols exemplified below.
 alkyl secondary alcohols such as methylethyl alcohol.
 aralkyl alcohols such as .alpha.-phenylethyl alcohol.
 alicyclic alcohols such as 2-methoxycyclohexanol.
 heterocyclic alcohols such as 1-ethyl-3-hydroxypyridine and
 N-benzyl-3-pyrrolidinol.
 primary alcohols such as N-methyl-2-pyrrolidine ethanol.
 diols such is 1-phenyl-1,3-propanediol.
 In addition, racemic alcohols include not only a mixture of R-form and
 S-form in equal amounts but also a mixture containing S-form or R-form in
 an amount more than 50% and less than 99%.
 The optically active amino acids used in the present invention may be
 either those of S-configuration or those of R-configuration depending on
 the intended use. Although natural L-.alpha.-amino acids are desirable
 because of their ready commercial availability at low prices, it is also
 possible to use non-natural amino acids. Examples of amino acids are shown
 below.
 natural amino acids such as L-alanine, L-phenylalanine, L-proline,
 L-valine, L-isoleucine, and L-leucine.
 non-natural amino acids such as D-alanine, D-phenylalanine, D-proline,
 D-valine, D-isoleucine, D-leucine, L-pyrrolidone-5-carboxylic acid,
 D-phenylglycine, D-pyrrolidone-5-carboxylic acid, and L-phenylglycine.
 heterocyclic amino acids such as L-indoline-2-carboxylic acid and
 D-indoline-2-carboxylic acid.
 These amino acids may be used as such or after conversion into an acyl
 derivative or sulfonyl derivative by N-substitution of the amino group in
 consideration of reactivity and resolution efficiency. Acyl derivatives of
 amino acids include, for example, those which are modified with any of
 alkylcarbonyl group (such as acetyl, propionyl, and butyroyl),
 arylcarbonyl group (such as benzoyl, toluoyl, and chlorobenzoyl),
 aralkylcarbonyl group (such as benzylcarbonyl, phenethylcarbonyl, and
 chlorobenzyl-carbonyl), and benzyloxycarbonyl group. Sulfonyl derivatives
 of amino acids include, for example, those which are modified with any of
 alkylsulfonyl group (such as methanesulfonyl and ethanesulfonyl),
 arylsulfonyl group (such as benzenesulfonyl, toluenesulfonyl, and
 chlorobenzenesulfonyl), and aralkylsulfonyl group (such as benzylsulfonyl,
 phenethylsulfonyl, and chlorobenzylsulfonyl).
 The ester of the optically active amino acid and racemic alcohol can be
 produced by the ordinary processes such as reacting the optically active
 amino acid (in the form of acid halide) with the racemic alcohol, reacting
 the optically active amino acid with the racemic alcohol in the presence
 of an esterifying catalyst, and reacting the optically active amino acid
 (in the form of acid anhydride) with the racemic alcohol.
 (2) Synthesis of optically active tartaric acid ester
 The tartaric a id ester in the present invention may be synthesized from an
 optically active tartaric acid derivative anhydride of either L-form or
 D-form, depending on the intended use. A natural L-tartaric acid
 derivative anhydride is desirable because of its ready availability at a
 low price, However, it is also possible to use a D-tartaric acid
 derivative anhydride Examples include O,O'-diacetyl-L-tartaric acid,
 O,O'-diacetyl-D-tartaric acid, O,O'-dibenzyl-L-tartaric acid,
 O,O'-benzyl-D-tartaric acid, O,O'-dibenzoyl-L-tartaric acid,
 O,O'-benzoyl-D-tartaric acid, O,O'-ditoluoyl-L-tartaric acid,
 O,O'-ditoluoyl-D-tartaric acid, O,O'-di(parachlorobenzoyl)-L-tartaric
 acid, O,O'-di(parachlorobenzoyl)-D-tartaric acid,
 O,O'-di(3,4-dimethylbenzoyl)-L-tartaric acid,
 O,O'-di(3-dimethylbenzoyl)-D-tartaric acid,
 O,O'-di(methoxybenzoyl)-L-tartaric acid, and
 O,O'-di(methoxybenzoyl)-D-tartaric acid.
 The reaction between the optically active tartaric acid derivative
 anhydride and the racemic secondary alcohol is carried out in a solvent or
 in the presence of a Lewis acid without solvent. Examples of the Lewis
 acid include aluminum chloride, zinc chloride, and iron chloride, with the
 last being preferable from the standpoint of easy operation. It should be
 used in an amount of 0.01-20 mol %, preferably 0.1-10 mol %, of the amount
 of the racemic secondary alcohol derivative.
 Solvents are not specifically restricted so long as they are not involved
 in the reaction. Preferred examples of solvents include aromatic
 hydrocarbons (such as benzene, toluene, and xylene) and alkyl halide (such
 as dichloromethane and chloroform).
 The reaction temperature should be 0-150.degree. C., preferably room
 temperature to 120.degree. C. Reaction at low temperatures takes a long
 time and reaction at high temperatures gives rise to impurities.
 The present invention permits easy synthesis of a tartrate ester from a
 racemic alcohol and an optically active tartaric acid derivative
 anhydride.
 (3) Diastereomer resolution of optically active ester
 According to the present invention, the optically active amino acid ester
 or tartaric acid ester prepared as mentioned above undergoes diastereomer
 resolution in the following manner. There are several ways for optical
 resolution. For example, separation by crystallization that utilizes a
 difference in solubility, separation by passage through a column, and
 separation by the aid of a quasi moving bed. Their selection depends on
 the desired product.
 Crystallization employs as a solvent water, alcohols, aliphatic
 hydrocarbons, aromatic hydrocarbons, ketones, ethers, and mixtures
 thereof. Columns are filled with silica gel, modified silica gel, zeolite,
 alumina, or the like. Quasi moving beds are effective for column
 separation in commercial production. Developing solvents should be
 chemically stable. Their examples include aromatic hydrocarbons (such as
 benzene and toluene), halogenated hydrocarbons (such as dichloromethane
 and chloroform), alicyclic hydrocarbons (such as cyclohexane and
 cyclooctane), and acetonitrile. Their selection depends on the kind of the
 amino acid ester and tartaric acid ester and also on the filler used. They
 may be used alone or in combination with one another.
 According to the present invention, a racemic alcohol an optically active
 amino acid or tartaric acid derivative anhydride are easily synthesized
 into an amino acid ester or tartaric acid ester, which is subsequently
 converted into an optically active tartaric acid ester of high optical
 purity by diastereomer resolution or into an optically active alicyclic
 alcohol derivative (which is an important intermediate for medicines) by
 hydrolysis.
 (4) New optically active ester
 The new optically active ester of the present invention is an optically
 active amino acid ester or tartaric acid ester which is obtained from an
 amino acid ester or tartaric acid ester by diastereomer resolution.
 Incidentally, the expression "optically active tartaric acid ester"
 implies a mixture of esters in which either the (S)-form or the (R) form
 of the alicyclic alcohol accounts for more than 80% of the total.
 (5) Hydrolysis of optically active esters
 According to the present invention, following diastereomer resolution, the
 optically active amino acid esters are hydrolyzed so as to produce the
 desired optically active alcohols. This hydrolysis may be accomplished by
 use of either acid or alkali; but it should be carried out such that the
 desired alcohols do not undergo racemization. This object is achieved by
 reaction with an aqueous solution of mineral acid (such as sulfuric acid,
 and hydrochloric acid) or an aqueous solution of alkali (such as sodium
 hydroxide, potassium hydroxide, sodium carbonate; and sodium hydrogen
 carbonate). Water as a medium may be used in combination with an organic
 solvent such as methanol, isopropanol, acetone, toluene and chloroform.
 The temperature for hydrolysis ranges from room temperature to 100.degree.
 C. at which racemization will not occur. (It depends on the rate of
 hydrolysis of individual compounds.) The thus obtained optically active
 alcohols are recovered from the reaction liquid by solvent extraction (for
 separation from the optically active amino acids) and subsequent
 distillation.
 Likewise, the optically active tartaric acid ester which has undergone
 diastereomer resolution is hydrolyzed so as to give the desired optically
 active alicyclic alcohol derivative. The hydrolysis of the ester group may
 be accomplished by either acid or alkali; but it should be carried out
 such that the desired alcohols do not undergo racemization. This object is
 achieved by reaction with an aqueous solution of mineral acid (such as
 sulfuric acid and hydrochloric acid) or an aqueous solution of alkali
 (such as sodium hydroxide, potassium hydroxide, sodium carbonate, and
 sodium hydrogen carbonate). Water as a medium may be used in combination
 with an organic solvent such as methanol, isopropanol, acetone, toluene,
 and chloroform. The temperature for hydrolysis ranges from room
 temperature to 100.degree. C. at which racemization will not occur. (It
 depends on the rate of hydrolysis of individual compounds.) Hydrolysis by
 an alkaline aqueous solution involves the simultaneous hydrolysis of the
 acyl group of O,O'-diacyltartaric acid, giving rise to tartaric acid.
 Hydrolysis by an aqueous solution of mineral acid involves the slow
 hydrolysis of the acyl group of O,O'-diparatoluoyltartaric acid or
 O,O'-dibenzoyltartaric acid (under at certain condition of hydrolysis),
 giving rise to O,O'-diparatoluoyltartaric acid or O,O'-dibenzoyltartaric
 acid which can be recovered for reuse.
 The thus obtained optically active alicyclic alcohol derivatives are
 recovered from the reaction liquid by solvent extraction (for separation
 from the optically active tartaric acid or derivatives thereof) and
 subsequent distillation.
 The present invention permits the easy production of an optically active
 alcohol of high optical purity from a racemic alcohol, aid also permits
 the recycling of the recovered optically active amino acid or tartaric
 acid.
 (6) Oxidation of alcohol
 In the present invention, the oxidation of an alcohol to produce a ketone
 involves as reactants an alicyclic alcohol hypohalite, aliphatic compound,
 and mineral acid.
 Preferred examples of the alicyclic alcohol include cycloalkanols (such as
 cyclopentanol, cyclohexanol, cycloheptanol, and cyclooctanol),
 alkyl-substituted cycloalkanol (such as 2-methylcyclohexanol and
 3-methylcyclooctanol), and alkoxycycloalkanol (such as
 2-methoxycyclohexanol). Preferred examples of the optically active
 alicyclic alcohol include optically active alkyl-substituted cycloalkanol
 (such as optically active 2-methylcyclohexanol and optically active
 3-methylcyclooctanol) and optically active alkoxycycloalkanol (such as
 optically active 2-methoxycyclohexanol).
 Preferred examples of the alkali metal or alkaline earth metal hypohalite
 include sodium hypochlorite, sodium hypobromite, potassium hypochlorite,
 potassium hypobromite, calcium hypochlorite, and calcium hypobromite. The
 former four are preferable and the first one is particularly preferable.
 Sodium hypochlorite may be used in the form of commercially available
 aqueous solution (5-14% concentrator). A dilute aqueous solution lower
 than 5% causes the reaction liquid to decrease in concentration, leading
 to an increased production cost. The aqueous solution of sodium
 hypochlorite may contain sodium chloride in any amount but should not
 contain free alkali (such as sodium hydroxide and potassium hydroxide) in
 an amount more than 1%. Excess free alkali should be neutralized
 beforehand; otherwise, it is necessary to adjust the amount of mineral
 acid to be added to the reaction liquid for oxidation.
 The amount of alkali metal hypohalite to be used may be determined by the
 amount of effective chlorine. It is also affected by tie composition of
 the reaction system, the kind of the alicyclic alcohol, and the reaction
 temperature. Usually it s about 1-2 equivalents, preferably 1-1.3
 equivalents, of the alicyclic alcohol. An amount less than 1 equivalent
 results in premature reactions, and an amount more than 2 equivalents
 leads to a high material cost and side reactions and the necessity of
 decomposing hypohalous acid after the reaction, An adequate amount of
 hypochlorous acid is 1-1.15 equivalents if the reaction proceeds
 satisfactorily.
 The aliphatic compound is characterized by a partition ratio (defined
 below) greater than 1 and a solubility less than 5 wt % in water at
 40.degree. C. (To determine the partition ratio, a sample of alicyclic
 alcohol is dissolved in a sample of aliphatic compound and water (of the
 same amount as aliphatic compound). After stirring for 10 minutes, the,
 solution is allowed to stand at. 20.degree. C. until the solution
 separates into two layers. The concentrations of alicyclic alcohol in the
 organic and aqueous layers are determined, and their ratio is calculated.
 A partition ratio greater than 1 means that the alicyclic alcohol is
 present more in the organic layer than in the aqueous layer.)
 Preferred examples of the aliphatic compound include alkyl chloride (such
 as dichloromethane, chloroform, tetrachloromethane, monochloroethane,
 1,1-dichloroethane, 1,2-dichloroethane, and 1,1,1- trichloroethane) and
 ethers (such as diethyl ether). Those except for the third and last ones
 are particularly desirable. (Their selection depends on the kind of
 alicyclic alcohol used). The amount of the aliphatic compound varies
 depending on the kind of alicyclic alcohol used; it is usually 0.1-3,
 preferably 0.2-1, times as much as alicyclic alcohol (by weight), An
 amount less than the minimum specified above is not enough to produce the
 desired effect at an adequate reaction rate without by-products. An amount
 more than the maximum specified above retards the reaction rate.
 Preferred examples of the mineral acid include sulfuric acid, hydrochloric
 acid, and phosphoric acid in the form of aqueous solution. The mineral
 acid is used in an amount of 0.1-2 equivalents, preferably 0.2-0.8
 equivalents, of the alicyclic alcohol used. An amount less than 0.1
 equivalent is not enough to keep the reaction liquid acid (below pH 3) in
 opposition to the action of the alkali metal hypohalite which increases
 pH. This leads to a slow reaction rate and an increase in by-products. An
 amount more than 2 equivalents promotes the decomposition of hypohalous
 acid, making it necessary to increase the amount of alkali metal
 hypochlorite required to achieve 100% conversion of the alicyclic alcohol.
 This leads to an increased production cost. In the case where alkali metal
 hypohalite (in the form of aqueous solution) contains a large amount of
 free alkali; it is necessary to add an acid in an amount corresponding to
 the amount of free alkali at the initial stage or intermediate stage of
 reaction. One mol of sulfuric acid for one mol of alicyclic alcohol equals
 2 equivalents. One mol of hydrochloric acid for one mol of alicyclic
 alcohol equals 1 equivalent. One mol of phosphoric acid for one mol of
 alicyclic alcohol equals 3 equivalents. The concentration of the aqueous
 solution of mineral acid should be 2-25 wt % preferably 5-15 wt %. A
 dilute aqueous solution of mineral acid (lower than 2%) lowers the
 concentration of the reaction liquid, aggravating the productivity. A
 concentrated aqueous solution of mineral acid (higher than 25%) results in
 too small an amount of reaction liquid for smooth operation in the initial
 stage of reaction. This presents difficulties in controlling the reaction
 temperature and increases by-products.
 The reaction may be carried out by charging the alicyclic alcohol,
 aliphatic compound, and mineral acid ( aqueous solution) all at once and
 then adding dropwise the aqueous solution of alkali metal or alkaline
 earth metal hypohalite with stirring. It is also possible to add gradually
 the alicyclic alcohol and mineral acid (in aqueous solution) during
 reaction in the case where the mineral acid (in aqueous solution) has a
 high concentration in the initial stage or the amount of the aliphatic
 compound is small.
 The reaction temperature should be 0-30.degree. C., preferably
 15-25.degree. C., to keep stable the hypohalous acid which is formed in
 the reaction liquid. A reaction temperature lower than 0.degree. C. leads
 to a slow rate of oxidation. A reaction temperature higher than 30.degree.
 C. leads to the decomposition of hypohalous acid. In the case where an
 optically active aliphatic alcohol is used, it is desirable to keep the
 reaction temperature below 30.degree. C. so as to suppress racemization.
 The alkali metal hypohalite added to the reaction system becomes hypohalous
 acid immediately upon contact with the mineral acid, and the hypohalous
 acid immediately reacts with the alicyclic alcohol upon contact with it.
 Therefore, the reaction time substantially equals the time required for
 the aqueous solution of alkali metal hypohalite to be added. The reaction
 is followed by aging for about 30 minutes.
 After the reaction is complete, excess hypohalous acid is decompose by
 adding, sodium hydrogensulfite until the reaction solution does not change
 potassium iodide starch paper into purple any longer.
 The thus obtained alicyclic ketone is isolated from the reaction mixture in
 the usual way, such as extraction with an organic solvent, followed by
 solvent removal and distillation for purification, or followed by column
 chromatography for isolation and purification. In the case where the
 ketone is an optically active one, it is desirable to carry cut the
 following procedure to prevent racemization.
 If there remains excess hypohalous acid, add alkali metal hydrogensulfite
 or alkali metal sulfite until the reaction solution does not change
 potassium iodide starch paper into purple any longer. (Alkali metal
 hydrogensulfite includes sodium hydrogensulfite, potassium
 hydrogensulfite, and lithium hydrogensulfite. Alkali metal sulfite
 includes sodium sulfite, potassium sulfite, and lithium sulfite.) They may
 be used in the form of aqueous solution or powder. The amount to be added
 depends on the amount of hypohalous acid remaining in the reaction system,
 It can be judged by visually observing that potassium iodide starch paper
 does not change into purple any longer.
 The reaction solution containing the thus obtained alicyclic ketone is
 adjusted to PH 7.1-10, preferably PH 7.5-9, and then allowed to stand for
 0.01-5 hours at 0-40.degree. C. so as to decompose impurities unstable to
 bases. Preferred bases for PH adjustment include alkali metal hydroxide
 (such as sodium hydroxide, potassium hydroxide, and lithium hydroxide),
 alkali metal hydrogen carbonate (such as sodium hydrogen carbonate and
 potassium hydrogen carbonate), and alkali metal carbonate (such as sodium
 carbonate and potassium carbonate), Excessive alkalization (higher than pH
 10) is not desirable because of the possibility of some optically active
 alicyclic ketones undergoing racemization.
 The thus obtained reaction liquid undergoes extraction for separation of
 the desired optically active alicyclic ketone. Solvents for extraction are
 not specifically restricted so long as they are separable from water and
 capable of extracting the optically active alicyclic ketone without
 reacting with it. Examples of such solvents include ethers (such as
 dimethyl ether), ketones (such as methyl isobutyl ketone), hydrocarbons
 (such as cyclohexane and toluene), and alkyl halides (such as chloroform
 and dichloroethane.
 After extraction, the extract containing the optically active alicyclic
 ketone is washed with a saturated aqueous solution of sodium chloride, (if
 necessary) dehydrated with magnesium sulfate or the like, concentrated,
 and distilled under reduced pressure.
 According to the present invention, an alicyclic alcohol is oxidized with
 sodium hypochlorite in the presence of an aliphatic compound and a mineral
 acid. This procedure permits easy production of alicyclic ketone in high
 yields. The alicyclic ketone is characterized by immiscibility with water
 and a partition ratio in water greater than 1 (for the alicyclic alcohol
 as the starting material).
 Using an optically active alicyclic alcohol as the starting material offers
 the advantage that it is possible to produce the desired optically active
 alicyclic ketone without racemization.
 The alicyclic alcohol as the starting material and the alicyclic ketone as
 the reaction product usually have their respective melting points close to
 each other. Nevertheless, according to the present invention, it is
 possible to easily achieve 100% conversion for the alicyclic alcohol and
 hence it is possible to easily obtain the desired alicyclic ketone of high
 purity.
 Moreover, according to the present invention, the optically active
 alicyclic alcohol is oxidized with a hypochlorite under an acidic
 condition, thereby converting it into an optically active alicyclic
 ketone, and distilling it under a basic condition, thereby giving an
 optically active alicyclic ketone of high purity with good storage
 stability.
 (7) Storing Method
 Since an optically active .alpha.-ketone is subject to racemization, it is
 desirable to store or stabilize it in the following manner.
 (i) Storage in the absence of halogen.
 (ii) Storage out of contact with oxygen.
 (iii) Storage out of contact with metal.
 (iv) Storage out of contact with acids and bases.
 (v) Storage out of contact with inorganic oxides.
 (vi) Storage in a condition created by combination of the above.
 (i) Storage in the absence of halogen. This means that the environment for
 storage should not contain halogen in such an amount as to subject the
 optically active .alpha.-substituted cyclic ketone to racemization during
 its storage. In other words, the amount of halogen should be less than 500
 ppm, preferably less than 200 ppm, of the optically active
 .alpha.-substituted cyclic ketone. The amount of halogen is determined by
 refluxing (with heating) a sample in 1N aqueous solution of sodium
 hydroxide and subsequently performing potentiometric titration.
 Storing the optically active .alpha.-substituted cyclic ketone in the
 presence of a halogen-free solvent (after thorough stirring) produces good
 results. Examples of the halogen-free solvent include ketones (such as
 2-butane), nitriles (such as acetonitrile), aliphatic hydrocarbons (such
 as hexane and octane), alicyclic hydrocarbons (such as cyclohexane),
 aromatic hydrocarbons (such as toluene), esters (such as ethyl acetate),
 ethers (such as diethyl ether and dioxane), and deoxygenated water). Of
 these examples, hydrocarbons and ethers are preferable. The concentration
 of the optically active .alpha.-substituted cyclic ketone in the solvent
 may range from 10 to 99 wt %. A solution with concentrations lower than 10
 wt % is too bulky for efficient storage. A solution with concentrations
 higher than 99 wt % does not produce the effect of adding the solvent. The
 storage temperature varies depending on the quality of the distilled
 starting material and the optical and chemical purity required after
 storage. Storage at 20.degree. C. will prevent the optical and chemical
 purity from decreasing by more than 3% even after storage for 60 days.
 Storage may be under pressure, normal pressure, or reduced pressure. A
 dark place or a container shielded from ultraviolet rays should preferably
 be used for storage.
 (ii) Storage out of contact with oxygen. This is accomplished by blowing an
 oxygen-free inert gas into the purified product, thereby expelling oxygen
 completely, and then replacing the atmosphere in the container with an
 inert gas, or by expelling dissolved oxygen from the product in vacuo and
 then keeping the container evacuated or keeping the container filled with
 an inert gas (after introduction of an inert gas to break vacuum). The
 inert gas is any gas that does not react with the optically active
 .alpha.-substituted cyclic ketone. It is exemplified by nitrogen, helium,
 and argon. The inert gas atmosphere means any inert gas atmosphere in
 which the content of oxygen is less than 5%, preferably less than 1%.
 Storage may be under pressure, normal pressure, or reduced pressure.
 Storage at 20.degree. C. will prevent the optical and chemical purity from
 decreasing by more than 1% even after storage for 60 days. A dark place or
 a container shielded from ultraviolet rays should preferably be used for
 storage. To ensure a better stability, it is recommended to mix the
 product with a halogen-free solvent (mentioned in (i) above) before
 storage in the atmosphere of inert gas.
 (iii) Storage out of contact with metal. This is accomplished by storing
 the purified product in a glass container or a drum coated with
 halogen-free resin in place of a metal container or a stainless steel
 drum. In addition, it is not desirable to use a metal column and packing
 for rectification. Contact with metal promotes racemization and chemical
 degradation. Metals that have marked effects are iron, manganese, nickel,
 copper and zinc and alloys thereof.
 (iv) Storage out of contact with acids and bases. This object is achieved
 when water has pH 3.5-7.5, preferably pH 4.5-7.5, that is in contact with
 the optically active .alpha.-substituted cyclic ketone. It is desirable to
 exclude inorganic acids (such as sulfuric acid and hydrochloric acid),
 inorganic bases (such as sodium hydrogen carbonate and sodium hydroxide),
 and organic bases (such as amines). The last one reacts with the
 carboxylic group in the optically active .alpha.-substituted cyclic ketone
 to lower the chemical purity.
 The above-mentioned methods should preferably be used in combination with
 one another so as to keep stable the optically active .alpha.-substituted
 cyclic ketone which is unstable. That is, rectification should be carried
 out by using a glass-lined bubble cap tower or a glass-lined rectifying
 column containing plastic or glass packing (non-metal packing), and the
 distillate should be collected in glass containers or plastic-coated drums
 and stored under an inert gas atmosphere. Preferably, rectification should
 be carried out by using a glass-lined bubble cap tower or a glass-lined
 rectifying column containing plastic or glass packing (non-metal packing),
 the distillate should be diluted with a halogen-free solvent, and the
 resulting solution should be placed in glass containers or plastic-coated
 drums and stored under an inert gas atmosphere.
 Storage may be under pressure, normal pressure, or reduced pressure. The
 storage temperature depends on the desired purity. Storage at 10.degree.
 C. will prevent the optical and chemical purity from decreasing by more
 than 1% even after storage for 60 days.
 Despite the above-mentioned procedure, racemization may take place if there
 are some kinds of impurities in trace amounts. In such a case, contact
 with an inorganic oxide prevents racemization and permits stable storage
 without chemical deterioration.
 The optically active .alpha.-substituted ketone includes optically active
 aliphatic .alpha.-substituted ketones (such as optically active
 3-methyl-2-oxoheptane), optically active alicyclic .alpha.-substituted
 ketones (such as optically active menthol and optically active
 2-methoxycyclohexanol), and optically active aralkyl .alpha.-substituted
 ketones (such as optically active 2-methylpropylphenylketone). These
 compounds may be present in an organic solvent after extraction from the
 oxidation reaction solution, or in a concentrated solution remaining after
 solvent removal by distillation under reduced pressure from the organic
 extract layer, or in a vacuum distillate of said concentrated solution.
 Their concentration ranges from 1 to 99.9%. The inorganic oxide for
 contact includes, for example, zeolite and silica gel, which are capable
 of adsorbing polar substances. (Those which become a strong acid or a
 strong base in the system cannot be used.) Zeolite may be either natural
 zeolite or artificial zeolite, such as "Zeoram A-5" commercially available
 as molecular sieve from Toso Co., Ltd. An example of silica gel is
 "Wakogel C-200" from Wako Pure Chemical Industries, Ltd. These inorganic
 ozides may be used as such or after pretreatment for better effects.
 Pretreatment may be accomplished by heating at 100.degree. C. for above
 (for drying) under reduced pressure, or by firing at 400.degree. C. or
 above in an electric furnace.
 The inorganic oxide may be brought into contact with the optically active
 .alpha.-substituted ketone by simply adding batchwise the former to the
 latter or by passing the latter through a column filled with the former.
 Either method may be used depending on the object. In the case of
 batchwise addition, the amount of the inorganic oxide should be 0.1-30 wt
 %, preferably 1-10 wt %, of the amount of the optically active
 .alpha.-substituted ketone, depending on the mode of storage, the amount
 of impurities, and the storage temperature. After the inorganic oxide has
 been added to the optically active .alpha.-substituted ketone (which may
 be present in an organic solvent or may contain an organic solvent as
 mentioned above), it is necessary to stir thoroughly but is not necessary
 to continue stirring. After stirring, the inorganic oxide (which has
 adsorbed impurities to promote racemization) may be filtered out or left
 in the system. After contact with the inorganic oxide, the optically
 active .alpha.-substituted ketone should be at 30.degree. C. or below,
 preferably 10.degree. C. or below, depending on the kind of the product
 and the desired optical and chemical purity of the product. In the case
 where the optically active .alpha.-substituted ketone is present in an
 extract of an organic solvent (which is not yet purified by distillation
 under reduced pressure) or in a concentrated solution remaining after
 solvent removal (by vacuum distillation) from the organic layer of the
 extract, the storage temperature should be lower than 0.degree. C.,
 preferably lower than -10.degree. C. After contact with the inorganic
 oxide, the optically active .alpha.-substituted ketone should preferably
 be stored in vacuo or under an atmosphere of inert gas, such as nitrogen,
 helium, and argon, so as to avoid contact with oxygen.
 According to the present invention, it is possible to keep chemically and
 optically stable the optically active .alpha.-substituted ketone which is
 chemically and optically unstable.
 The optically active alcohol and optically active ketone obtained as
 mentioned above are useful as intermediates for organic reactions,
 particularly for preparing medicines and agricultural chemicals.
 EXAMPLES
 The invention will be described in more detail with reference to the
 following examples and comparative examples, which are not intended to
 restrict the scope of the invention.
 (Production of Amino Acid Ester)
 In this example, the analysis for optical purity by HPLC is carried out
 under the following basic conditions, although the eluent may vary in
 composition depending on individual compounds.
 Column: Intersil ODS (made by G. L. Science)
 Eluent: a mixture of 0.5% aq. solutions of phosphoric acid and acetonitrile
 in a ratio of from 20:80 to 80:20.
 Flow rate: 2 ml/min
 EXAMPLE 1
 A 500-ml four-mouth flask equipped with a thermometer, dropping funnel,
 condenser, and stirrer was charged with 27 g (0.1 mol) of
 N-benzoyl-L-phenylalanine and 300 ml of toluene. The flask was further
 charged with 13 g of thionyl chloride by dropwise addition over 30 minutes
 with stirring at 80-85.degree. C. Stirring was continued for 1 hour. After
 the reaction was complete, the reaction solution was concentrated under
 reduced pressure and unreacted thionyl chloride and hydrochloric acid were
 removed. To the concentrated solution were added 14.3 g (0.11 mol) of
 trans-2-methoxycyclohexanol and 100 ml of toluene. After reaction at
 80-90.degree. C. for 2 hours, the reaction solution was concentrated under
 reduced pressure to give a mixture of
 (1S)-(N-benzoyl-L-phenylalaninyloxy)-(2S)-methoxycyclohexane and
 (1R)-(N-benzoyl-L-phenylalanyloxy)-(2R)-methoxycyclohexane. The
 concentrated solution was dissolved (with heating) in 150 ml of methanol
 added thereto, and the solution was cooled to room temperature and
 precipitates were filtered out. After drying, there was obtained 15.2 g of
 crystals. The crystals were found to be composed of
 (1S)-(N-benzoyl-L-phenylalanyloxy)-(2S)-methoxycyclohexane and
 (1R)-(N-benzoyl-L-phenylalanyloxy)-(2R)-methoxycyclohexane in a molar
 ratio of 4.6/1. The crystals were recrystallized from 200 ml of methanol
 to give 11.2 g of crystals composed of
 (1S)-(N-benzoyl-L-phenylalanyloxy)-(2S)-methoxycyclohexane and
 (1R)-(N-benzoyl-L-phenylalanyloxy)-(2R)-methoxycyclohexane in a molar
 ratio of 100/1. The
 (1S)-(N-benzoyl-L-phenylalanyloxy)-(2S)-methoxycyclohexane gave an NMR
 chart and an IR chart as shown in FIGS. 1 and 2, respectively. The NMR
 analysis was carried out by using JMMN-EX90 made by Nippon Denshi, with
 the same dissolved in CDCl3. The IR analysis was carried out by using
 SYSTEM 2000 made by Perkin-Elmer (KBr tablet method).
 The crystals were dissolved in a mixture of 44 ml of 1N aqueous solution of
 sodium hydroxide and 20 ml of methanol, and the solution was kept at
 40.degree. C. for 2 hours to effect hydrolysis. The reaction solution was
 concentrated under reduced pressure to remove most ethanol. The
 concentrated solution was extracted three times with 20 ml of chloroform,
 and the extract was concentrated to give 3.7 g of
 (1S)-hydroxy-(2S)-methoxycyclohexane, which has an optical purity of 98%
 ee.
 The aqueous layer remaining after extraction was made acidic and filtered
 out to recover crystals of N-benzoyl-L-phenylalanine. After drying, the
 recovered N-benzoyl-L-phenylalanine was reused to give the same results of
 resolution as mentioned above.
 (Resolution of Amino Acid Ester)
 EXAMPLE 2
 Reaction was carried out between 27 g (0.1 mol) of
 N-benzoyl-L-phenylalanine and 13 g of thionyl chloride in the same manner
 as in Example 1. The reaction solution was concentrated under reduced
 pressure. The concentrated solution was given 13.4 g (0.11 mol) of
 .alpha.-phenylethyl alcohol and 100 ml of toluene, and reaction was
 carried out at 80-90.degree. C. for 2 hours. After the reaction was
 complete, the reaction solution was concentrated and then given 50 ml of
 isopropanol. Resulting crystals were filtered off and recrystallized twice
 from 100 ml of isopropanol. The thus obtained crystals were hydrolyzed (in
 the same manner as in Example 1) and the resulting hydrolyzate was
 extracted with chloroform to give 5.2 g of .alpha.-phenylethyl alcohol.
 The optical purity of the S-form was 97% ee.
 EXAMPLE 3
 The same apparatus as used in Example 1 was charged with 23.8 g (0.1 mol)
 of N-paranitrobenzoyl-L-alanine, 14.3 g (0.11 mol) of
 trans-2-methoxycyclohexanol, and 200 ml of toluene. After stirring at
 80-85.degree. C., 13 g of thionyl chloride was added dropwise over 1 hour.
 Stirring was continued for 1 hour. The reaction solution was concentrated
 under reduced pressure. The residues were given 100 ml of isopropanol,
 followed by stirring at room temperature for 1 hour. Crystals that had
 separated out was filtered off. On hydrolysis with 2N aqueous solution of
 sodium hydroxide, there was obtained 5.2 g of trans-2-methoxycyclohexanol.
 The optical purity of the (R,R)-form was 58% ee.
 EXAMPLE 4
 The same apparatus as used in Example 1 was charged with 31.2 g (0.1 mol)
 of N-tosyl-L-phenylalanine, 14.3 g (0.11 mol) of
 trans-2-methoxycyclohexanol, 200 ml of toluene, and 1 g of
 paratoluenesulfonic acid. The reactants were heated under reflux for 5
 hours. The reaction solution was concentrated and the residues were
 recyrstallized twice from 50 ml of isopropanol. Thus there was obtained
 12.5 g of (1S)-(N-tosyl-L-phenylalanyloxy)-(2S)-methoxycyclohexane, which
 has an optical purity of 99% ee. This sample gave an NMR chart and an IR
 chart as shown in FIGS. 3 and 4, respectively. (Conditions for NMR and IR
 analyses are the same as those in Example 1.)
 EXAMPLE 5
 The procedure of Example 1 was repeated for reaction between 27 g (0.1 mol)
 of N-benzoyl-L-phenylalanine and 13 g of thionyl chloride. The reaction
 solution was concentrated under reduced pressure. The concentrated
 solution was reacted with 13.4 g (0.11 mol) of .alpha.-phenylethylalcohol
 and 100 ml of toluene at 80-90.degree. C. for 2 hours. After the reaction
 was complete, the reaction solution was concentrated and the concentrated
 solution underwent chromatographic separation by the aid of a column
 (filled with 100 ml of silica gel) and a developing solvent consisting of
 cyclohexane and ethyl acetate in a ratio of 93:7 by volume. The fraction
 that had been eluted first was concentrated and then hydrolyzed to give
 4.2 g of .alpha.-phenylethylalcohol. The optical purity of the S-form was
 92% ee.
 (Production of Tartaric Acid Ester)
 In this example, the analysis for optical purity by HPLC was carried out
 under the following basic conditions, although the elutent may vary in
 composition depending on individual compounds.
 Column: CAPSELL PAK SG 120, 4.6 mm in diameter, 150 mm long (made by
 Shiseido Co., Ltd.)
 Eluent: a mixture of 0.05% aq. solutions of phosphoric acid and
 acetonitrile in a ratio of 55:45.
 Flow rate: 1 ml/min
 Detector: UV 254 nm
 EXAMPLE 6
 A 500-ml four-mouth flask equipped with a thermometer, dropping funnel,
 condenser, and stirrer was charged with 47.8 g (0.13 mol) of
 diparatoluoyl-L-tartaric acid anhydride, 13.0 g (0.1 mol) of
 (RS)-2-methoxycyclohexanol, 1.2 g of anhydrous iron trichloride, and 300
 ml of toluene. After heating under reflux for 10 hours, the reaction
 solution was analyzed by liquid chromatography. The result of analysis
 indicated the formation of diparatoluoyl-L-tartaric
 acid-mono(2-methoxy)cyclohexyl ester (92%).Time for peak detection was 35
 minutes in the case of (R)-2-methoxycyclohexanol ester and 37 minutes in
 the case of (S)-2-methoxycyclohexanol ester. These analytical data suggest
 that the tartaric acid ester formed is composed of (R)-form and (S)-form
 in a ratio of approximately 1/1. The reaction solution was filtered to
 separate the diparatoluoyl-L-tartaric acid anhydride remaining unreacted.
 The filtrate was concentrated and subjected to column chromatography
 (using a column filled with silica gel "Kieselgel 60", 60-230 mesh, made
 of Merck). Chromatographic separation was carried out by using a mixture
 of acetonitrile and cyclohexane in varied ratios. Thus there was obtained
 9.5 g of diparatoluoyl-L-tartaric acid-mono(R)-2-methoxycyclohexyl ester.
 Analysis by liquid chromatography indicated that the optical purity of the
 (R)-ester if 98% ee. This compound gave an 1H-NMR chart (CDCl.sub.3) and
 an MS spectrum as shown in FIGS. 5 and 6, respectively.
 EXAMPLE 7
 A 500-ml four-mouth flask equipped with a thermometer, dropping funnel,
 condenser, and stirrer was charged with 51.0 g (0.15 mol) of
 dibenzoyl-L-tartaric acid anhydride, 13.0 g (0.1 mol) of
 (RS)-2-methoxycyclohexanol, 1.2 g of anhydrous iron trichloride, and 300
 ml of toluene. After heating under reflux for 10 hours, the reaction
 solution was analyzed by liquid chromatography. The result of analysis
 indicated the formation of dibenzoyl-L-tartaric acid-mono(2-methoxy)cyclo-
 hexyl ester (95)%. Time for peak detection was 17 minutes in the case of
 (R)-2-methoxycyclohexanol ester and 18 minutes in the case of
 (S)-2-methoxycyclohexanol ester. These analytical data suggest that the
 tartaric acid ester formed is composed of (R)-form and (S)-form in a ratio
 of approximately 1/1. The reaction solution was filtered to separate
 insoluble matter. The filtrate was concentrated and subjected to column
 chromatography (using a column filled with silica gel "Kieselgel 60",
 60-230 mesh, made by Merck). Chromatographic separation was carried out by
 using a mixture of acetonitrile and cyclohexane in varied ratios. Thus
 there was obtained 10.8 g of dibenzoyl-L-tartaric
 acid-mono(R)-2-methoxycyclohexyl ester. Analysis by liquid chromatography
 indicated that the optical purity of the (R)-ester is 96% ee. This
 compound gave an 1H-NMR chart (CDCl.sub.3) as shown in FIG. 7.
 EXAMPLE 8
 The same apparatus as used in Example 6 was charged with 2.5 g (0.02 mol)
 of .alpha.-phenylethylalcohol, 14.7 g (0.04 mol) of
 diparatoluoyl-L-tartaric acid anhydride, 37 mg of anhydrous iron
 trichloride, and 60 g of toluene. After heating under reflux for 5 hours,
 the reaction solution was analyzed by liquid chromatography. The result of
 analysis indicated the formation of diparatoluoyl-L-tartaric
 acid-mono(RS)-.alpha.-phenylethyl ester (88%). Time for peak detection was
 37 minutes in the case of (R)-.alpha.-phenylethylalcohol ester and 43
 minutes in the case of (S)-.alpha.-phenylethylalcohol ester. These
 analytical data suggest that the tartaric acid ester formed is composed of
 (R)-form and (S)-form in a ratio of approximately 1.2/1. The reaction
 solution was filtered to separate insoluble matter. The filtrate was
 concentrated and subjected to column chromatography (using a column filled
 with silica gel "Kieselgel 60", 60-230 mesh, made by Merck).
 chromatographic separation was carried out by using a mixture of
 acetonitrile and cyclohexane in varied ratios. Thus there was obtained 3.1
 g of diparatoluoyl-L-tartaric acid-mono(R)-.alpha.-phenylethylalcohol
 ester. Analysis by liquid chromatography indicated that the optical purity
 of the (R)-ester is 96% ee.
 EXAMPLE 9
 A 500-ml four-mouth flask equipped with a thermometer, dropping funnel,
 condenser, and stirrer was charged with 47.8 g (0.13 mol) of
 diparatoluoyl-L-tartaric acid anhydride, 13.0 g (0.1 mol) of
 (RS)-2-methoxycyclohexanol, 1.2 g of anhydrous iron trichloride, and 300
 ml of toluene. After heating under reflux for 10 hours, the reaction
 solution was analyzed by liquid chromatography. The result of analysis
 indicated the formation of diparatoluoyl-L-tartaric
 acid-mono(2-methoxy)cyclohexyl ester (92%). Time for peak detection was 35
 minutes in the case of (R)-2-methoxycyclohexanol ester and 37 minutes in
 the case of (S)-2-methoxycyclohexanol ester. Diparatoluoyl-L-tartaric acid
 anhydride remaining unreacted was filtered off, and the filtrate was
 concentrated and subjected to column chromatography (using a column filled
 with silica gel "Kieselgel 60", 60-230 mesh, made by Merck).
 Chromatographic separation was carried out by using a mixture of
 acetonitrile and cylohexane in varied ratios. There was obtained 9.5 g of
 diparatoluoyl-L-tartaric acid-mono(R)-2-methoxycyclohexyl ester in the
 first eluate. Analysis by liquid chromatography indicated that the ester
 is composed of (R)-form and (S)-form in a ratio of approximately 99/1.
 This compound was hydrolyzed by 30 ml in 1N aqueous solution of sodium
 hydroxide at 30.degree. C. for 5 hours with stirring. The hydrolyzate was
 extracted three times with 100 ml of dichloroethane. The extract was
 concentrated to give 2.8 g of concentrated solution containing
 (R)-2-methoxycyclohexanol. The concentrated solution was distilled under
 reduced pressure (2.6 kPa) to give 2.2 g of distillate having an angle of
 rotation of -75.degree. (c=2.10 in dichloromethane). The last eluate
 obtained by chromatographic separation was treated in the same manner as
 above to give 2.1 g of (S)-2-methoxycyclohexanol having an angle of
 rotation of +74.degree. (c=2.00 in dichloromethane).
 EXAMPLE 10
 The procedure of Example 7 was repeated to give a concentrated solution
 containing about 20 g of dibenzoyl-L-tartaric
 acid-mono(R)-2-methoxycyclohexyl ester. This concentrated solution was
 subjected to column chromatography (using a column filled with silica gel
 "Kieselgel 60", 60-230 mesh, made by Merck). chromatographic separation
 was carried out by using a mixture of acetonitrile and cyclohexane in
 varied ratios. The eluate was concentrated to give 5.8 g of
 dibenzoyl-L-tartaric acid-mono(R)-2-methoxycyclohexyl ester. The liquid
 chromatography under the above-mentioned conditions caused
 (R)-2-methoxycyclohexanol ester to be detected after 17 minutes and
 (S)-2-methoxycyclohexanol ester to be detected after 18 minutes. Results
 of analysis indicated that the concentrated solution consisted of
 (R)-ester and (S)-ester in a ratio of 98/2. Upon treatment in the same
 manner as in Example 9, followed by distillation under reduced pressure,
 there was obtained (R)-2-methoxycyclohexanol.
 (Oxidation)
 Example 11
 A 500-ml four-mouth flask equipped with a thermometer, dropping funnel,
 condenser, and stirrer was charged with 13.0 g (0.1 mol) of
 (RS)-2-methoxycyclohexanol, 7 g of dichloromethane, and 30 g of 10%
 aqueous solution of sulfuric acid (30 mmol). The reactants were stirred at
 20-25.degree. C. The flask was further charged with 60 g of aqueous
 solution of sodium hypochlorite containing 12.1% effective chlorine over
 about 1 hour. Stirring was continued for 30 minutes. The reaction solution
 was analyzed by gas chromatography to confirm that the peak due to
 (RS)-2-methoxycyclohexanol had disappeared. The reaction solution was
 given 2 g of sodium hydrogensulfite with stirring. It was confirmed that
 the reaction solution did not change potassium iodide starch paper into
 purple any longer. The reaction solution was extracted twice with 50 g of
 dichloromethane. The dichloromethane layers were combined together and
 washed with 30 g of saturated aqueous solution of sodium chloride. Upon
 concentration and distillation, there was obtained 11.5 g (90 mmol) of
 (RS)-2-methoxycyclohexanone. The chemical purity of this compound was
 99.8%. Incidentally, the dichloromethane used in this example has a
 partition ratio in water (at 20.degree. C.) greater than 1 and has a
 solubility in water (40.degree. C.) lower than 5 wt %.
 Example 12
 The same apparatus as used in Example 1 was charged with 11.4 g (0.1 mol)
 of (RS)-2-methylcyclohexanol, 7 g of 1,2-dichloroethane, and 20 g of 10%
 aqueous solution of sulfuric acid (20 mmol). The reactants were stirred at
 20-25.degree. C. The flask was further charged with 145 g of aqueous
 solution of sodium hypochlorite containing 5.6% effective chlorine over
 about 3 hours. Stirring was continued for 30 minutes. The result of
 analysis by gas chromatography indicated the formation of
 (RS)-2-methylcyclohexanone (95%). Incidentally, the 1,2-dichloroethane
 used in this example has a partition ratio in water (at 20` C.) greater
 than 1 and has a solubility in water (40.degree. C.) lower than 5 wt %.
 Example 13
 The same apparatus as used in Example 1 was charged with 11.4 g (0.1 mol)
 of (RS)-4-methylcyclohexanol, 10 g of chloroform, and 20 g of 10% aqueous
 solution of sulfuric acid (20 mmol). The reactants were stirred at
 20-25.degree. C. The flask was further charged with 145 g of aqueous
 solution of sodium hypochlorite containing 5.6% effective chlorine over
 about 3 hours. Stirring was continued for 30 minutes. The result of
 analysis by gas chromatography indicated the formation of
 (RS)-4-methylcyclohexanone (94%). Incidentally, the chloroform used in
 this example has a partition ratio in water (at 20.degree. C.) greater
 than 1 and has a solubility in water (40.degree. C.) lower than 5 wt %.
 Example 14
 The same procedure as in Example 1 was repeated to give 11.2 g (88 mmol) of
 (S)-2-methoxycyclohexanone from 13.0 g (0.1 mol) of
 (S)-2-methoxycyclohexanol having an optical purity of 99% ee. This product
 has a chemical purity of 99.8% and an optical purity of 99% ee.
 Racemization did not occur during reaction.
 Example 15
 The same apparatus as used in Example 11 was charged with 3.9 g (30 mmol)
 of (RS)-4-methylcyclohexanol, 7 g of 10% hydrochloric acid (19 mmol), and
 2 g of diethyl ether. By dropping 23 g of 12.3% aqueous solution of
 hypochlorite, reaction was carried out in the same manner as in Example 1.
 The result of analysis by gas chromatography indicated the formation of
 (RS)-2-methylcyclohexanone (95%). Incidentally, the diethyl ether used in
 this example has a partition ratio in water (at 20.degree. C.) greater
 than 1 and has a solubility in water (40.degree. C.) lower than 5 wt %.
 Comparative Example 1
 The same procedure as in Example 11 was repeated except that 10% sulfuric
 acid was not added. The result of analysis by gas chromatography indicated
 the formation of (RS)-2-methoxycyclohexanol (1.7%).
 Comparative Examples 2 to 6
 The same apparatus as used in Example 11 was charged with 11.4 g (0.1 mol)
 of (RS)-2-methoxycyclohexanol, the compound shown in Table 1, and 40 g of
 10% aqueous solution of sulfuric acid (41 mmol). The reactants were
 stirred at 20-25.degree. C. The reaction solution was given 65 g of
 aqueous solution of sodium hypochlorite containing 12.5% effective
 chlorine over about 2 hours. Stirring was continued for 30 minutes. The
 results are shown in Table 1. Incidentally, the methanol and acetonitrile
 used in these comparative examples had a solubility in water (40.degree.
 C.) higher than 5 wt %. The partition (at 20.degree. C.) of
 (RS)-2-methoxycyclohexanol is much greater in water than in cyclohexane,
 and the partition ratio for cyclohexane is lower than 1.
 TABLE 1
 Con- Yield of (RS)-2-
 Amount version methoxycyclohexanone
 Compound added (%) (%)
 Comparative None 41.9 38.7
 Example 2
 Comparative Methanol 100 g 76.5 69.3
 Example 3
 Comparative Methanol 13 g 76.2 69.3
 Example 4
 Comparative Acetonitrile 13 g 85.4 79.8
 Example 5
 Comparative Cyclohexane 30 g 10.2 8.6
 Example 6
 It is noted that in these comparative examples the conversion of
 (RS)-2-methoxycyclohexanol is low and the selectivity of
 (RS)-2-methoxycyclohexanone is low.
 Comparative Example 7
 The same apparatus as used in Example 11 was charged with 11.4 g (0.1 mol)
 of (RS)-2-methoxycyclohexanol, 7 g of methyl ethyl ketone, and 25 g of 10%
 aqueous solution of sulfuric acid (26 mmol). The reactants were stirred at
 20-25.degree. C. The reaction solution was given 61 g of aqueous solution
 of sodium hypochlorite containing 12.5% effective chlorine over about 2
 hours. Stirring was continued for 30 minutes. The result of analysis by
 gas chromatography indicated the formation of (RS)-2-methocycyclohexanone
 (93%), with the conversion of (RS)-2-methoxycyclohexanol being 98%.
 Then, the same procedure as in Example 1 was repeated to extract
 (RS)-2-methocycyclohexanol with chloroform. During extraction, the methyl
 ethyl ketone was chlorinated to give a compound having strong tearing
 properties, which hindered the subsequent operation. Incidentally, the
 methyl ethyl ketone used in this comparative example has a solubility in
 water (40.degree. C.) lower than 5 wt %.
 Comparative Example 8
 The same procedure as in Comparative Example 6 was repeated except that
 methyl ethyl ketone was replaced by toluene. The result of analysis by gas
 chromatography indicated that the conversion of
 (RS)-2-methocycyclohexanone was 45% and the yield of
 (RS)-2-methocycyclohexanol was as low as 42%. In addition, the reaction
 gave rise to chlorinated toluene as a by-producy, which made it necessary
 to use a rectifying column having a large number of plates to purify
 (RS)-2-methocycyclohexanol. The partition (at 20.degree. C.) of
 (RS)-2-methoxycyclohexanol is much greater in water than in toluene, and
 the partition ratio for toluene is lower than 1.
 Comparative Example 9
 The same procedure as in Example 11 was repeated except that 40 g of 25%
 sulfuric acid was added. The result of analysis by gas chromatography
 indicated that 24% of (RS)-2-methoxycyclohexanol remained unreacted.
 (Production of optically active ketone)
 In the following examples, the chemical purity of optically active
 alicyclic ketone was determined by gas chromatography that employs
 "Thermon 3000" as the liquid layer, and the optical purity was determined
 by gas chromatography that employs a chiral column.
 Example 16
 A 500-ml four-mouth flask equipped with a thermometer, dropping funnel,
 condenser, and stirrer was charged with 13.0 g (0.1 mol) of
 (S)-2-methoxycyclohexanol having an optical purity of 99.8% ee, 7 g of
 dichloromethane, and 30 g of 10% aqueous solution of sulfuric acid (30
 mmol). The reactants were stirred at 20-25.degree. C. The flask was
 further charged with 60 g of aqueous solution of sodium hypochlorite
 containing 12.1% effective chlorine over about 1 hour. Stirring was
 continued for 30 minutes. The reaction solution was analyzed by gas
 chromatography to confirm that the peak due to (S)-2-methoxycyclohexanol
 had disappeared. The reaction solution was given 2 g of sodium
 hydrogensulfite with stirring. It was confirmed that the reaction solution
 did not change potassium iodide starch paper into purple any longer. The
 reaction solution was extracted twice with 200 g of dichloromethane. The
 dichloromethane layers were combined together and washed with 30 g of 30%
 aqueous solution of sodium carbonate. After stirring at 20-25.degree. C.
 for 1 hour, it was confirmed that the water layer had a pH higher than
 7.5. The water layer was discharged, and the dichloromethane layer was
 washed with saturated aqueous solution of sodium chloride. Upon
 concentration and distillation, there was obtained 11.5 g (90 mmol) of
 (S)-2-methoxycyclohexanone. The chemical purity of this compound was
 99.6%. One gram of this compound was placed in a glass ample and sealed,
 with the atmosphere therein replaced with argon. The ample was heated at a
 prescribed temperature for 60 hours. After cooling to room temperature,
 the ample was opened and the content was tested for optical purity. The
 results are shown in Table 2.
 TABLE 2
 Heating temperature Optical purity
 60.degree. C. 99.6% ee
 80.degree. C. 98.9% ee
 100.degree. C. 97.3% ee
 Example 17
 Reaction was carried out in the same manner as in Example 16. After the
 peak due to (S)-2)-methoxycyclohexanol had disappeared, the reaction
 solution was given 2 g of sodium hydrogensulfite with stirring so that the
 reaction solution did not change potassium iodide starch paper into purple
 any longer. The reaction solution was adjusted to pH 2 or below with 10%
 sulfuric acid, followed by stirring at 20-25.degree. C. for 1 hour. The
 reaction solution was adjusted to pH 7.5-8 with an aqueous solution of
 sodium carbonate, followed by stirring at 20-25.degree. C. for 1 hour. The
 reaction solution was adjusted again to pH 2 or below with 10% sulfuric
 acid, followed by stirring at 20-25.degree. C. for 2 hours. The reaction
 solution was extracted three times with 100 g of toluene. The toluene
 layers were combined together and washed with a saturated aqueous solution
 of sodium chloride. After concentration and distillation in the same
 manner as in Example 1, there was obtained 10.3 g (80 mmol) of
 (S)-2-methoxycyclohexanone having a chemical purity of 99.3% and an
 optical purity of 99.6% ee. This product was heated at 60.degree. C. for
 48 hours in the same manner as in Example 16; it decreased in optical
 purity to 99.0% ee.
 Example 18
 The same procedure as in Example 16 was repeated except that the
 dichloroethylene was replaced by ethyl hexyl ketone. There was obtained
 9.9 g of (S)-2-methoxycyclohexanone having an optical purity of 99.2% ee.
 This product was heated at 60.degree. C. for 48 hours in the same manner
 as in Example 16; it decreased in optical purity to 98.5% ee.
 Comparative Example 10
 Reaction was carried out in the same manner as in Example 16. After the
 peak due to (S)-2-methoxycyclohexanol had disappeared, the reaction
 solution was given 2 g of sodium hydrogensulfite with stirring so that the
 reaction solution did not change potassium iodide starch paper into purple
 any longer. The reaction solution was extracted twice with 100 g of
 dichloroethane. The dichloroethane layers were combined together and
 washed with a saturated aqueous solution of sodium chloride. After
 concentration and distillation in the same manner as in Example 1, there
 was obtained 10.9 g (85 mmol) of (S)-2-methoxycyclohexanone having a
 chemical purity of 99.4% and an optical purity of 99.5% ee (measured
 immediately after distillation). As in Example 3, this product was sealed
 in a glass ample, with the atmosphere therein replaced with argon. The
 glass ample was heated at a prescribed temperature for 20 hours. After
 cooling to room temperature, the ample was opened and the content was
 tested for optical purity. The results are shown in Table 3.
 TABLE 3
 Heating temperature Optical purity
 20.degree. C. 75.6% ee
 40.degree. C. 38.2% ee
 60.degree. C. 11.3% ee
 (Storage of optically active ketone)
 In the following examples, the chemical purity of optically active
 2-methoxycyclohexanone was determined by gas chromatography that employs
 "Thermon 3000" as the liquid layer, and the optical purity was determined
 by gas chromatography that employs a chiral column.
 Example 19
 A sample of (S)-2-methoxycyclohexanone (having an optical purity of 98.75%
 ee and a chemical purity of 99.28%) was distilled using a glass apparatus.
 The distillate (1 g) was diluted with a prescribed solvent to give a 50 wt
 % solution. The solution was sealed in a glass ample, with the atmosphere
 therein replaced with argon. The ample was heated at 80.degree. C. for 65
 hours. After cooling to room temperature, the ample was opened and the
 content was tested for optical purity and chemical purity. The results are
 shown in Table 4.
 TABLE 4
 Solvent Optical purity (% ee) Chemical purity (%)
 None 98.05 99.07
 2-Butanone 98.58 99.27
 Acetonitrile 98.58 99.25
 Aliphatic hydrocarbon 98.57 99.28
 (bp. 100-120.degree. C.)
 Cyclohexane 98.48 99.19
 Ethyl acetate 98.39 99.15
 1,4-Dioxane 98.28 97.19
 Propylene glycol 98.26 99.87
 Water (deoxygenated) 98.14 99.07
 Toluene 98.13 98.59
 Example 20
 A sample of (S)-2-methoxycyclohexanone (the same one as in Example 19) was
 diluted with cyclohexane to give a 50 wt % solution. The solution was
 sealed in a glass ample, with the atmosphere therein replaced with argon.
 The ample was stored at room temperature (20-25.degree. C.) for one month.
 The ample was opened and the content was analyzed. The optical purity was
 98.68% ee and the chemical purity was 99.27%.
 Example 21
 A sample of (S)-2-methoxycyclohexanone (the same one as in Example 19) was
 diluted with cyclohexane to give a 50 wt % solution. The solution was
 sealed in a glass ample. The ample was stored at 20.degree. C. for 60
 days. The ample was opened and the content was analyzed. The optical
 purity was 95.89% ee and the chemical purity was 96.18%.
 Example 22
 A sample of (S)-2-methoxycyclohexanone (the same one as in Example 19) was
 sealed in a glass ample, with the atmosphere therein replaced with
 nitrogen. The ample was stored at 20.degree. C. for 60 days. The ample was
 opened and the content was analyzed. The optical purity was 98.05% ee and
 the chemical purity was 99.07%.
 Example 23
 A sample of (S)-2-methoxycyclohexanone (having an optical purity of 99.02%
 ee and a chemical purity of 99.13% ) was distilled using a glass
 apparatus. The distillate (1 g) was diluted with toluene to give a 90 wt %
 solution. The solution was sealed in a glass ample, with the atmosphere
 therein replaced with argon. The ample was stored at 10.degree. C. for 6
 months. The ample was opened and the content was analyzed. The optical
 purity was 98.08% ee and the chemical purity was 99.05%.
 Example 24
 A sample of (S)-2)-methoxycyclohexanone (the same one as in Example 19) was
 diluted with a prescribed solvent to give a 50 wt % solution. The solution
 was sealed in a glass ample, without the atmosphere therein replaced with
 inert gas. The ample was heated at 80.degree. C. for 65 hours. The ample
 was opened and the content was tested for optical purity and chemical
 purity. The results are shown in Table 5.
 TABLE 5
 Solvent Optical purity (% ee) Chemical purity (%)
 2-Butanone 98.21 96.92
 Cyclohexane 98.03 96.87
 Ethyl acetate 97.99 95.58
 Toluene 97.38 97.93
 Comparative Example 11
 A sample of (S)-2-methoxycyclohexanone (the same one as in Example 19) as
 such (without dilution) was sealed in a glass ample, without the
 atmosphere therein replaced with inert gas. The ample was heated at
 80.degree. C. for 65 hours as in Example 19. The ample was opened and the
 content was analyzed. It was found that the optical purity decreased to
 97.10% ee and the chemical purity decreased to 95.12%.
 Comparative Example 12
 A sample of (S)-2-methoxycyclohexanone (the same one as in Example 19) was
 diluted with a halogen-containing solvent to give a 50 wt % solution. The
 solution was sealed in a glass ample, with the atmosphere therein replaced
 with argon. The ample was heated at 80.degree. C. for 65 hours. The ample
 was opened and the content was tested for optical purity and chemical
 purity. The results are shown in Table 6.
 TABLE 6
 Solvent Optical purity (% ee) Chemical purity (%)
 Chlorobenzene 97.70 98.94
 1,2-Dichloroethane 9.70 96.64
 1,1,1-trichloroethane 0.00 94.50
 Comparative Example 13
 A sample of (S)-2-methoxycyclohexanone (the same one as in Example 19) as
 such (without dilution) was heated together with a piece of stainless
 steel at 80.degree. C. for 65 hours in the same manner as in Example 19.
 The ample was opened and the content was analyzed. It was found that the
 optical purity decreased to 90.43% ee and the chemical purity decreased to
 97.97%.
 Comparative Example 14
 A sample of (S)-2-methoxycyclohexanone (the same one as in Example 19) was
 diluted with an aqueous solution containing an inorganic salt, acid, or
 base to give a 50 wt % solution. The solution was sealed in a glass ample,
 with the atmosphere therein replaced with argon. The ample was heated at
 80.degree. C. for 65 hours. The ample was opened and the content was
 tested for optical purity and chemical purity. The results are shown in
 Table 7.
 TABLE 7
 Optical Chemical
 Inorganic compound purity (% ee) purity (%)
 Sodium hydrogensulfite (0.2 eq) 95.53 96.65
 Sodium sulfite (saturated aq. solution) 95.21 97.80
 Sodium chloride (saturated aq. solution) 92.76 98.80
 1N sodium hydroxide 0.00 64.34
 1N sulfuric acid 0.00 not detected
 Hydrochloric acid (0.07 eq) 0.00 17.36
 (Stabilization by inorganic oxide)
 Example 25
 A 50-ml stoppered test tube was charged with 10 g of
 (S)-2-methoxycyclohexanone (having an optical purity of 98.7% ee and a
 chemical purity of 99.2%). The sample was incorporated with 1 g of "Zeoram
 A-5" (made by Toso) which had previously been dried at 100.degree. C. for
 5 hours under reduced pressure. With the atmosphere in the test tube
 replaced with argon, the sample was stirred at room temperature for 1 hour
 and allowed to stand at 20-25.degree. C. for 7 days. The sample remained
 almost unchanged in optical purity (98.5% ee) and chemical purity (99.2%).
 By contrast, the sample without "Zeoram A-5" decreased in optical purity
 to 96.5% ee although it remained unchanged in chemical purity (99.2%).
 Example 26
 A 500-ml four-mouth flask equipped with a thermometer, dropping funnel,
 condenser, and stirrer was charged with 13.0 g (0.1 mol) of
 (S)-2-methoxycyclohexanol having an optical purity of 99.8% ee, 7 g of
 dichloromethane, and 30 g of 10% aqueous solution of sulfuric acid (30
 mmol). The reactants were stirred at 20-25.degree. C. The flask was
 further charged with 60 g of aqueous solution of sodium hypochlorite
 containing 12.1% effective chlorine over about 1 hour. Stirring was
 continued for 30 minutes. The reaction solution was analyzed by gas
 chromatography to confirm that the peak due to (S)-2-methoxycyclohexanol
 had disappeared. The reaction solution was given 2 g of sodium
 hydrogensulfite with stirring. It was confirmed that the reaction solution
 did not change potassium iodide starch paper into purple any longer. The
 reaction solution was given 30 ml of 10% aqueous solution of sodium
 carbonate, followed by stirring at 20-25.degree. C. for 1 hour. The
 reaction solution was extracted twice with 50 g of dichloromethane. The
 dichloromethane layers were combined together and washed with saturated
 aqueous solution of sodium chloride. Upon concentration, there was
 obtained 21.6 g of dichloromethane solution containing 11.5 g (90 mmol) of
 (S)-2-methoxycyclohexanone, which has an optical purity of 99.6% ee. This
 solution (10 g) was placed in a test tube and incorporated with 1 g of
 "Zeoram A-5", which had previously been dried at 100.degree. C. for 5
 hours under reduced pressure, in the same manner as in Example 25. With
 the atmosphere in the test tube replaced with argon, the sample was
 stirred at room temperature for 1 hour and allowed to stand at
 20-25.degree. C. for 7 days. The sample was found to have an optical
 purity of 98.6% ee. By contrast, the sample without "Zeoram A-5" decreased
 in optical purity to 76.1% ee.
 Example 27
 The same procedure as in Example 26 was repeated except that diethyl ether
 was used for extraction. There was obtained 20.9 g of concentrated
 solution which contained 9.8 g of (S)-2-methoxycyclohexanone having an
 optical purity of 99.6% ee. This solution (10 g) was placed in a test tube
 and incorporated with 3 g of "Wakogel C-200" (made by Wako Pure Chemical
 Industries, Ltd.), which had previously been dried at 100.degree. C. for 5
 hours under reduced pressure, in the same manner as in Example 25. With
 the atmosphere in the test tube replaced with argon, the sample was
 stirred at room temperature for 1 hour and allowed to stand at
 20-25.degree. C. for 7 days. The sample was found to have an optical
 purity of 99.0% ee. No peaks due to impurities were detected in gas
 chromatography. By contrast, the sample without "Wakogel C-200" decreased
 in optical purity to 89.3% ee.
 Example 28
 The same procedure as in Example 27 was repeated to give 23.5 g of
 concentrated solution which contained 9.6 g of (S)-2-methoxycyclohexanone
 having an optical purity of 99.6% ee. This solution (10 g) was placed in a
 test tube and incorporated with 3 g of "Wakogel C-200", which had
 previously been dried at 100.degree. C. for 5 hours under reduced
 pressure, in the same manner as in Example 25. With the atmosphere in the
 test tube replaced with argon, the sample was stirred at room temperature
 for 1 hour and allowed to stand at 20-25.degree. C. for 7 days. The sample
 was found to have an optical purity of 98.7% ee. A few peaks due to
 impurities were detected in gas chromatography, although they were not
 detected at the time of charging. By contrast, the sample without "Wakogel
 C-200" decreased in optical purity to 89.0% ee. More peaks due to
 impurities were detected in gas chromatography, although they were not
 detected at the time of charging.
 Example 29
 The same procedure as in Example 26 was repeated except that dichloroethane
 was used for extraction. There was obtained 21.9 g of concentrated
 solution which contained 12.0 g of (S)-2-methoxycyclohexanone having an
 optical purity of 95.9% ee. This solution (8 g) was placed in a test tube
 and incorporated with 2 g of "Zeoram A-5", which had previously been dried
 at 100.degree. C. for 5 hours under reduced pressure, in the same manner
 as in Example 25. With the atmosphere in the test tube replaced with
 argon, the sample was stirred at room temperature for 1 hour and allowed
 to stand at 40.degree. C. for 13 hours. The sample was found to have an
 optical purity of 95.9% ee. No peaks due to impurities were detected in
 gas chromatography. By contrast, the sample without "Zeoram A-5" decreased
 in optical purity to 87.1% ee.
 Example 30
 The concentrated solution (10 g) obtained in Example 29 was diluted with 20
 g of dichloroethane. The diluted solution was passed through a column
 filled with "Zeoram A-5" (10 g), which had previously been dried at
 100.degree. C. for 5 hours under reduced pressure. The filtrate was
 allowed to stand at 40.degree. C. for 13 hours in a container, with the
 atmosphere therein replaced with argon. The sample was found to have an
 optical purity of 95.7% ee. No peaks due to impurities were detected in
 gas chromatography.
 Exploitation in Industry
 The present invention provides an optically active amino acid ester, an
 optically active alcohol, and an optically active ketone, which are useful
 as an intermediate for medicines and agricultural chemicals.