Title of Invention	PROCESS FOR PRODUCING 3-1-MENTHOXYPROPANE-1,2-DIOL
Abstract	A method for safely and efficiently producing high purity 3-f-menthoxypropane-1,2-diol and intermediates to be used in the method. As shown in the following reaction formula, 3-1-menthoxypropane-1,2-diol represented by the chemical formula (IV) is produced by adding 1-menthol to a 1,2-epoxy-3-halogenopropane represented by the general formula (I) (wherein X represents a halogen atom) in an organic solvent in the presence of a Lewis acid, thereby producing a 1-halogeno-3-Q-menthoxypropan-2-ol represented by the general formula (II), allowing the first intermediate to react with an alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms to produce a 1-acyloxy-2-substituted-3-1-menthoxypropan represented by the general formula (III) and then hydrolyzing the second intermediate.

Title of Invention

PROCESS FOR PRODUCING 3-1-MENTHOXYPROPANE-1,2-DIOL

Abstract

A method for safely and efficiently producing high purity 3-f-menthoxypropane-1,2-diol and intermediates to be used in the method. As shown in the following reaction formula, 3-1-menthoxypropane-1,2-diol represented by the chemical formula (IV) is produced by adding 1-menthol to a 1,2-epoxy-3-halogenopropane represented by the general formula (I) (wherein X represents a halogen atom) in an organic solvent in the presence of a Lewis acid, thereby producing a 1-halogeno-3-Q-menthoxypropan-2-ol represented by the general formula (II), allowing the first intermediate to react with an alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms to produce a 1-acyloxy-2-substituted-3-1-menthoxypropan represented by the general formula (III) and then hydrolyzing the second intermediate.

Full Text	This invention relates to a method for producing 3-4-menthoxypropane-l,2-diol useful as^ e.g., a cool-feeling agent or refreshment improving agent, and l-acyloxy-2-substituted-3- In addition, according to the invention, (2S)-3-l-raenthoxypropane-l,2-diol in which configuration of the 2-position of the propane moiety is controlled and which has more excellent refreshing feeling can be obtained with high optical purity. BACKGROUND OF THE INVEHTION 3- influence on the aroma added to the product and can add cool-feeling action to the product. Accordingly^ making use of these characteristics of 3-f-menthoxypropane-1,2-diol, it has been proposed to add 3- , a.s well as aerosol compositions for anti-inflammatory drug and analgesic use (JP-A-63-264522). Conventionally known methods for producing 3-4-menthoxypropane-l,2-diol include (i) a method in which i-menthol is made into soditun salt with metallic sodium or sodium hydride and then reacted with an allyl halide to produce 3-^-menthoxypropane-l-ene which is subsequently converted into an oxide by oxidizing it using an organic peroxide and then hydrolyzed However, in the conventional method (i), sodium salt of I-menthol is prepared using metallic sodium or sodium hydride, it has a problem of causing a danger of explosion and generation of hydrogen gas. What is more, since oxidation of 3-f-menthoxypropane-1-ene as the intermediate is carried out using an organic peroxide, it has a danger of causing explosion also from this point, so that this cannot be said as an industrially advantageous method, and there is room for further improvement from the economic point of view. Also, since the conventional method (ii) is a production method aimed at synthesizing optically active substances, it is necessary to use expensive benzyl glycidyl ether. What is more, since the finally obtained 3~ Also, in addition to these conventional methods, (iii) it has been proposed a method in which l,2-epoxy-3-f-menthoxypropane as a synthetic intermediate of 3-1-inenthoxypropane-l,2-diol is synthesized by allowing t-menthol to undergo addition reaction with a l,2-epoxy-3-halogenopropane such as epichlorohydrin in an aqueous solution in the presence of a base and a quaternary ammonium salt [French Patent 2,479,822 (1981)]. However, it is known that a l,2-epoxy-3-halogenopropan© such as epichlorohydrin is unstable and apt to be decomposed in the presence of an acid or base ["Dictionary of Chemistry" p. 292, published by Tokyo Kagaku Oojin (1989)]. Thus, in the case of this method in which a l,2-epoxy-3-halogenopropane is allowed to undergo the reaction in the presence of a base, the l,2-epoxy-3~halogenopropane is decomposed when the reaction is carried out for a prolonged period of time, so that it is difficult to synthesize l,2-epoxy-3- In addition, (iv) a method in which l-allyloxy-3-chloro-2-propanol as an optically active glycerol derivative is produced by allowing epichlorohydrin and allyl alcohol to undergo the reaction in the presence of an acidic catalyst has been proposed as the reaction of epichlorohydrin with an alcohol (JP-A-2-221). However, this conventional method (iv) uses only primary allyl alcohol as the alcohol to be used in the reaction, and it does not report on the application to secondary alcohols, much less on the addition reaction with menthol. Also, as another conventional method, it has been proposed (v) a method in which epichlorohydrin and alcohols are allowed to undergo the reaction in the presence of an acid catalyst and then subjected to an alkali treatment to effect ring closure, thereby converting into a glycidyl ether which is subsequently hydrolyzed, and then a glycerol ether is produced by heating the reaction mixture at a temperature of from 100 to 230°C in the presence of a salt formed from a strongly basic compound and a weakly acidic compound (JP-A-2000-212114) . However, in the case of this method, it is necessary to heat the reaction mixture at a high temperature of from 100 to 230°C, particularly from 150 to 200°C, in the presence of a salt formed from a strongly basic compound and a weakly acidic compound, in order to decompose the organic halogen contained in the hydrolysa,te of the glycidyX ether, so that this is not an efficient method. What is more, the alcohols used in this method are primary alcohols represented by a general formula: R-(OA)p-OH (wherein R represents a saturated or unsaturated, straight- or branched-chain hydrocarbon radical having from 1 to 36 carbon atoms, A represents an alkylene group having from 2 to 4 carbon atoms, and p is a number of from 0 to 100), and there is no disclosure on the use of secondary alcohols, much less on the use of menthol. SUMMARY OF THE INVENTION An object of the invention is to provide a method by which 3- Another object of the invention is to provide a synthetic intermediate useful in obtaining high purity 3-t-menthoxypropane-1,2-diol. still another object of the invention is to provide an efficient method for producing an intermediate useful in obtaining 3-l-menthoxypropane-l,2-diol, A further object of the invention is to provide a method by which (2S)-3-l-menthoxypropane-l,2-diol whose configuration of the 2-position of the propane moiety is controlled and which has more excellent refreshing feeling can be produced with a high optical purity. In order to achieve these objects, the present inventors have conducted extensive studies. As a result, they succeeded in producing a l-acyloxy-2-substituted-3-l-menthoxypropanes as novel compounds, by producing a 1-halogeno-3-l-menthoxypropan-2-ol through the addition reaction of {-menthol with a 1,2-epoxy-3-halogenopropane in an organic solvent in the presence of a Lewis acid, and allowing the thus obtained l-halogeno-3-{-menthoxypropan-2-ol to react with an aliphatic carboxylic acid alkali metal salt. After further studies, it was found that these novel l-acyloxy-2-substituted-3- Thereafter, the inventors have found that (2S)-3- position of the propane moiety is controJJed and which has more exceJJent refreshing feeling can be produced with a high optical purity, by the use of an optically active substance as the l-halogeno-3-l-menthoxypropan-2-ol, and have accomplished the invention based on these findings. (2) a method for producing 3-l-menthoxypropane-l,2-diol, which comprises reacting a l-halogeno-3-l-menthoxypropan-2-ol represented by the following -general formula (II): and subsequently hydrolyzing it to produce 3-1-menthoxypropane-l,2-diol represented by the following chemical formula (IV) : (wherein R represents an acyl group derived from the aliphatic carboxylic acid having from 1 to 5 carbon atoms, and R^ represents hydrogen atom or an acyl group derived from the aliphatic carboxylic acid having from 1 to 5 carbon atoms). Also, the invention includes as preferred embodiments, (4) the production method according to any one of the sibove items (1) to epoxy-3-halogenopropane represented by the general formula (I) and l-halogGno-3--menthoxypropan-2-ol represented by the general formula (II); (5) the production method according to any one of the above items (1) to (4), wherein configuration of the 2-position of the propane moiety is (R)-form in the l,2-epoxy-3- halogenopropane represented by the general formula (I), and configuration of the 2-position of the propane moiety is (S)-forro in the l-halogeno-3-l-inenthoxypropan-2-ol represented by the general formula (II), l-acyloxy-2-substituted-3-£-inenthoxypropane represented by the general formula (III) and 3-£-inenthoxypropane-l,2-diol represented by the general formula (IV) ; and (6) the production method according to any one of the above items (1) to (5) , wherein R^ is acetyl group and R^ is hydrogen atom or acetyl group in the general formula (III). Also, the invention is, (7) a l-acyloxy-2-substituted-3-4-menthQxypropane represented by the following general formula (III): (8) a l-acetoxy-2-substituted-3-l-menthoxypropane represented by the following general formula (Ilia): (10) a (2S) -l-acetoxy-2-siibstituted-3-l-menthoxypropane represented by the following general formula (Ilia"): (In the formulae, X is a halogen atom, R^ is an acyl group derived from an aliphatic carboxylic acid having from 1 to 5 carbon atoms, and R^ is hydrogen atom or an acyl group derived from an aliphatic carboxylic acid having from 1 to 5 carbon atoms.) That is, a novel l-halogeno-3- Examples of the halogen atom X in the 1,2--epoxy-3-halogenopropane (I) include fluorine atom, chlorine atom, bromine atom and iodine atom. Illustrative examples of the l,2-epoxy-3-halogenopropane include l,2-epoxy-3-fluoropropane (epifluorohydrin), 1,2-epoxy-3-chloropropane (epichlorohydrin), l,2-epoxy-3-bromopropane (epibromohydrin) and 1,2-epoxy-3-iodopropane (epiiodohydrin). Among them, l,2-epoxy-3-chloropropane (epichlorohydrin) or l,2-epoxy-3-bromopropane (epibromohydrin) in which the halogen atom X is chlorine atom or bromine atom is suitably used in the invention, and l,2-epoxy-3-chloropropane (epichlorohydrin) is used more suitably. Regarding the l,2-epoxy-3-halogenopropane (I) and i-menthol as the material compounds, commercial products can be used as such. In carrying out the reaction to add I-menthol to the 1,2-epoxy-3-halogenopropane {I), a method in which a Lewis acid is added to and dissolved in a solution prepared by dissolving j-menthol in an organic solvent, and then a solution prepared by dissolving the l,2-epoxy-3-halogenopropane (I) in an organic solvent is added dropwise thereto to effect the reaction. Regarding using ratio of the l,2-epoxy-3-halogenopropane (I) and (I). Also, amount of the Lewis acid to be used may be similar to the catalytically effective amount in the usual addition reaction and, generally, is preferably from sJaout 0.01 to 0.1 mol, based on 1 mol of the l,2-epoxy-3-halogenopropane (I). Illustrative exan^les of the Lewis acid include boron trifluoride ether complex, aluminum chloride, zinc chloride, zinc bromide and ferric chloride, which may be used alone or as a mixture of two or more. Among them. aliuninum chloride and/or boron trifluoride ether complex is preferably used from the viewpoint of easy handling and economically low price. As the organic solvent, an organic solvent which does not exert influence of the addition reaction of {-menthol with the l,2-epoxy-3-halogenopropane (I) is used, and its illustrative examples include aliphatic hydrocarbon solvents such as hexane, heptane and octane; alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; and petroleum ether solvents, which may be used alone or as a mixture of two or more. Among them, heptane and/or toluene is preferably used from the viewpoint of easy handling and economically low price. Amount of the organic acid to be used is, in general, preferably from about 0.5 to 5 parts by volume, more preferably from about 1 to 3 parts by volume, based on 1 part by volume of t-menthol. It is desirable to carry out the addition reaction of C-menthol to the 1,2-epoxy-3-halogenopropane (I) in an atmosphere of an inert gas such as nitrogen gas or argon gas for effecting smooth progress of the addition reaction. Also, in carrying out the addition reaction by adding an organic solvent solution of the l,2-epoxy-3-halogenopropane (I) dropwise to an organic solvent solution of {-menthol and a Lewis acid, the period of time for the dropwise addition of the 1,2-epoxy-3-halogenopropane (I)-dissolved organic solvent solution is generally preferably from about 0.5 to 10 hours, more preferably from about 1.5 to 3 hours. A temperature of preferably from about 60 to 130°C, more preferably from about 65 to 120°C, is employed as the addition reaction temperature, and the l-halogeno-3- The l-halogeno-3-{-menthoxypropan-2-ol (II) obtained by this addition reaction is stable, generally shows an oily form and can be preserved. Accordingly, the l-halogeno-3-f-menthoxypropan-2-ol then directly used in the subsequent reaction without carrying out after-treatment such as purification. In the above reaction, configuration of the 2-position of the propane structure can be controlled without racemization by the use of an optically active l,2-epoxy-3-halogenopropane (I). Illustratively, by the use of a (2R)-l,2-epoxy-3-halogenopropane {I"), it can be easily introduced into a (2S)-l-halogeno-3--inenthoxypropan-2-ol (II"). Also, when a (2S)-l,2-epoxy-3-halogenopropane (I") is used, it can be easily introduced into a (2R)-1-halogeno-3-t-menthoxypropan-2-ol {II"). By allowing the l-halogeno-3- As the alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms to be used in this reaction, a lithium, sodium or potassium salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms is suitably used. The illustrative examples thereof include lithium formate, lithium acetate, lithium propionate, lithium butyrate, lithium isobutyrate, lithium valerate, lithium isovalerate, lithium pivalate, sodium formate, sodium acetate, sodium propionate, sodi\im butyrate, sodimn isobutyrate, sodium valerate, sodium isovalerate, sodium pivalate, potassium formate, potassium acetate, potassium propionate, potassium butyrate, potassium isobutyrate, potassiiun valerate, potassium isovalerate and potassium pivalate, which may be used alone or as a mixture of two or more. Among them, one or two or more of sodium formate, potassium formate, sodium acetate and potassium acetate are preferably used, and soditun acetate is used more preferably, from the viewpoint of easy handling and economically low price. When an alkali metal salt of an aliphatic carboxylic acid having 6 or more carbon atoms or an aromatic carboxylic acid alkali metal salt is used, solid precipitation becomes considerable so that the l-acyloxy-2-substituted-3-f-menthoxypropane (III) cannot be produced smoothly. From the economical point of view, amount of the used alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms is from about 1.0 to 5.0 mol, particularly from about 1.05 to 2.0 mol, based on 1 mol of the l-halogeno-3-f-menthoxypropan-2-ol (II). It is desirable that the used alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms is in an anhydrous state, because the l-acyloxy-2-substituted-3-{-menthoxypropane (III) can be formed with a high yield and the yield becomes stable. According to the invention, a commercially available alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms can be used as such or by subjecting it to a dehydration treatment in advance. According to the invention, the reaction of the 1-halogeno-3-f-menthoxypropan-2-ol (II) with an alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms, for producing the l-acyloxy-2-substituted-3-£-menthoxypropane (III), can be carried out under joint use of an aliphatic carboxylic acid anhydride as occasion demands. As the aliphatic carboxylic acid anhydride, an aliphatic carboxylic acid anhydride having from 2 to 5 carbon atoms is suiteibly used, and its illustrative examples include acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride and pivalic anhydride, which may be used alone or as a mixture of two or more. Among them, acetic anhydride is prefersibly used. When an aliphatic carboxylic acid anhydride is jointly used, its amount to be used is preferably from 1.0 to 5.0 mol, more preferably from about 1.05 to 2.0 mol, based on 1 mol of the l-halogeno-3~ According to the invention, a commercially available aliphatic carboxylic acid anhydride can be used as such. In addition, according to the invention, the reaction of the l-halogeno-3- When the reaction is carried out in the presence of a phase transfer catalyst, a reaction rate improving effect is obtained. As the phase transfer catalyst, a quaternary ammoniiim salt is suitably used, and its illustrative examples include quaternary ammonium salts which can be industrially easily obtained, such as tetramethylammonium chloride, tetrabutylammonium bromide, tetraethylammoniiim iodide, tetrabutylammoniiuD iodide, trimethylhexadecylammonitua chloride, dimethyIdioctylammonium chloride, trimethyIbenzylammonium chloride and trioctylraethylammonium chloride, which may be used alone or as a mixture of two or more. Among them, tetramethylainraoniiim bromide is preferably used from the viewpoint of easy handling and economically low price. When production reaction of the l-acyloxy-2-substituted-3- 0.01 to 0.2 mol, more preferably from about 0.02 to 0.05 mol, based on 1 mol of the l-halogeno-3~{-menthoxypropan-2-ol (11) . A commercially available phase transfer catalyst can be used as such. Production reaction of the l-acyloxy-2-siibstituted-3-f-menthoxypropane (III) may be carried out in the absence of solvent or using a solvent. When a solvent is used, any solvent which does not significantly inhibit the production reaction of 1-acyloxy-2-substituted-3-l-menthoxypropane (III) can be used, but an organic solvent is suitably used. Illustrative examples of the suitably used organic solvent include aliphatic hydrocarbon solvents such as hexane, heptane and octane; alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; ether solvents such as diethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane and 1,3-dioxofuran; amide solvents such as dimethylformamide, dimethyl ace tamide and N-methylpyrrolidotie; and petroleum ether solvents, which may be used alone or as a mixture of two or more. Among them, dimethylformamide is preferably used from the viewpoint of smooth progress of the reaction, good handling and economically low price. Amount of the organic acid to be used is preferably from about 1 to 10 parts by volume, more preferably from about 2 to 5 parts by volume, based on 1 part by volume of the l-halogeno-3- It is desirable to carry out the production reaction of l-acyloxy-2-substituted-3- It is desirable to carry out the reaction for the production of the l-acyloxy-2-substituted-3- The reaction temperature and reaction time caji be optionally changed and adjusted depending on the kind and amount of the used alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms. The l-acyloxy-2-substituted-3- acyloxy group, or a mixture of the (III-A) and (III-B). Forming ratio of the (III-A) and (III-B) in l-acyloxy-2-substituted-3-{-roenthoxypropane (III) changes depending on the kind and amount of the alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms and the presence or absence, kind and amount of the other components which are used as occasion d^aands (e.g., an aliphatic carboxylic acid anhydride and a phase transfer catalyst) . When the reaction is carried out using only an alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms without using an aliphatic carboxylic acid anhydride and a phase transfer catalyst, ration of the l-acyloxy-3-t-menthoxypropan-2-ol (III-A) generally becomes 80% or more. On the other hand, when an aliphatic carboxylic acid anhydride is jointly used, ratio of the l,2-diacyloxy-3-£-menthoxyprcpane (III-BJ increases as the amount of the aliphatic carboxylic acid anhydride increases. The l-acyloxy-2-substltuted-3- The thus obtained l-acyloxy-2-substituted-3--menthoxypropane (III) may be preserved after purifying it l>y» S"Sfw distillation or a column chromatography treatment, or without carrying out the purification treatment, and then used by collecting it from a preservation container at the time of the production of the 3- In the reaction, when an optically active 1-halogeno-3- anhydride, it can be introduced into a (2R)-l-acyloxy-2-substituted-3-i-inenthoxypropane (III-A" ") . Illustrative examples of the l-acyloxy-2-substituted-3- By hydrolyzing the l-acyloxy-2-substituted-3-t-menthoxypropane (III) obtained by the reaction, 3-t-menthoxypropane-1,2-diol (IV) is formed. It is desirable to carry out hydrolysis of the 1-acyloxy-2-substituted-3--menthoxypropane (III) in the presence of a base. As the base to be used in the hydrolysis, hydroxides, carbonates and/or alkoxides of an alkali metal or alkaline earth metal are suitably used. Their illustrative examples include lithiiua hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodiiua carbonate and potassitun carbonate, which may be used alone or as a mixture of two or more. Among them, sodium hydroxide and/or potassium hydroxide is preferably used from the viewpoint of smooth progress of the hydrolysis and economically low price. It is desirable to add the base to the reaction system in the form of aqueous solution. It is desirable that concentration of the base aqueous solution is a high concentration of 40% by mass or more, particularly from 45 to 55% by mass, because the hydrolysis reaction smoothly progresses thereby. Amount of the base to be used is preferably from about 1.0 to 5.0 mol, particularly from about 1.5 to 3.0 mol, based on 1 mol of the l-acyloxy-2-substituted-3-l-menthoxypropane (III). It is desirable to carry out the hydrolysis reaction of l-acyloxy-2-substituted-3- mixture of two or more. Among them, methanol and/or ethanol is preferably used from the viewpoint of economically low price. Amount of the organic acid to be used is preferably from about 1 to 10 parts by volume, more preferably from about 2 to 5 parts by volume, based on 1 part by volume of the l-acyloxy-2-siibstituted-3- Ten^erature of the hydrolysis reaction of 1-acyloxy-2-substituted-3-f-menthoxypropane (III) is preferably from about 20 to 100°C, particularly from about 50 to SO^C, nd the 3-l-menthoxypropane-l,2-diol (IV) is formed by carrying out the reaction for a period of from about 0.5 to 5 hours, preferably from about 1 to 3 hours, while keeping this ten^erature. Recovery of 3-t-menthoxypropane-l,2-diol (IV) from the reaction products containing 3- neutralization of the used base as occasion demands, and then evaporating the solvent. Purification of 3-4-menthoxypropane-l,2-diol (IV) can be carried out, e.g., by distillation or a column chromatography treatment. In the hydrolysis reaction, when an optically active l-acyloxy-3-t-menthoxypropan-2-ol (III-A) is used, it can be introduced into a 3-{-menthoxypropane-l,2-diol (IV) in which configuration of the 2-position of the propane moiety is controlled can be obtained without carrying out racemization. Illustratively, when a (2S)-l-acyloxy-3-£-menthoxypropan-2-ol (III-A") is used, it can be easily introduced into a (2S)-3-f-menthoxypropane-l,2-diol (IV). Also, when a (2R)-l-acyloxy-3- Among members of the 3-e-menthoxypropane-l,2-diol (IV), a (2S)-3- can be tben easily introduced into a (2S)-l-acyloxy-2-substituted-3-l- menthoxypropane (III") by allowing it to react with an alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms, and then the (2S}-3- Making use of the characteristics of the thus obtained 3- The following describes the invention illustratively with reference to Examples, but the invention is not restricted by the following Examples. In this connection, the apparatus used for the measurement (analysis) of physical properties in the following examples is as follows. (1) Chemical purity: Gas chromatograph; "HP6890" column mfd. by HEWLETT PACKARD Column; "NEUTRABOND-1" mfd. by GL Science (inner diameter x length = 0,25 mm x 30 m) {2} Kuclear magnetic i:esonance spectrum: ^H-NMR; "DRX-500" mfd. by Brucker (500 MHz) (3) Infrared absorption spectrum (IR): Equipment: ""Nicolet AVATAR 360" mfd. by Micolet Japan Measuring method: NaCl film method (4) Mass spectrum (MS): M-80 mass spectxrometer: mfd. by Hitachi (ionization voltage 20 eV) "DIP-360" mfd. by Japan Spectroscopic Synthesis of l-chloro-3- temperature. Next, 3.5 g (26.88 mmol) of anhydrous aluminum chloride was added thereto and dissolved under stirring, and the solution was heated to 70°C. A 61 g (0.6572 mol) portion of epichlorohydrin was added dropwise to this solution at the same temperature maintaining 2 hours. After completion of the dropwise addition, the reaction was carried out at the same temperature for 7 hours. Thereafter, the reaction mixture was cooled to room temperature. ,^ Ai) The reaction mixture obtained in (1) was washed with water and then with 10% sodium carbonate aqueous solution, and n-heptane was evaporated to obtain an oily substance. By distilling this oily siibstance under a reduced pressure, 57.2 g (0.37 mol) of un-reacted {-menthol was recovered at a boiling point of from 78 to 99""C/600 Pa (4.5 mmHg), and then 117 g of l-Ghloro-3- C 1 (3^) Analytical results of the l-chloro-3-«-menthoxypropan-2-ol obtained in (2) were as follows, [ajo": -73.7° (c = 1.05, EtOH) MS (m/e): 248 (M), 165, 163, 139, 138, 123, 109, 97, 95, 83, 81, 71, 69, 57, 55, 53, 43, 41, 29, 27 IR (neat, cm"^) : 3422, 2955, 2922, 2869, 1456, 1385, 1370, 1344, 1180, 1114, 1067, 1050, 1011, 991, 974, 922, 845, 753 ^H-NMR (CDCla; 5 ppm) : 0.78 (3 H, d, J = 6.9) , 0.81 - 0.88 (2 H, m), 0.90 (3 H, d, J = 7.0), 0.93 (3 H, d, J = 6.5), 0.96 - 1.01 {1 H, m), 1.20 - 1.26 (1 H, m), 1.30 - 1.40 (1 H, broad), 1.61 - 1.66 (2 H, m), 2.09 (1 H, m), 2.14 (1 H, m), 2.52 (1 H, d, J = 5.9), 3.09 (1 H, dt, J = 10.6, 4.1), 3.44 (1 H, dd, J = 9.4, 5.2), 3.60 (1 H, dd, J = 11.0, 5.6), 3.73 (1 H, dd, J = 9.4, 5.2), 3.91 - 3.97 (1 H, m) Synthesis of l-acetoxy-3- \\ [^ The reaction mixture obtained in (1) was mixed with 30 ml of water and 50 ml of heptane to effect separation, the organic layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was recovered to obtain an oily substance. By distilling this oily substance under a reduced pressure, partially purified l-acetoxy-3-J-menthoxypropan-2-ol was obtained at a boiling point of from 111 to 120°C/25 Pa (0.19 ininHg) . Composition of this product when analyzed by the gas chromatography was composed of 5.53% by mass of 3- / j Jl3) A 15 g portion of the partially purified product obtained in (2) was purified by a silica gel column chromatography. As the developing solvent, a mixed solvent composed of ethyl acetate and hexane was used, and the mixing ratio of ethyl acetate was gradually increased from 4% by volume to 10% by volume. By this, l-acetoxy-3--menthoxypropan-2-ol was eluted with the most high purity in a fraction obtained by a developing solvent containing from 6 to 10% by volume of ethyl acetate. After separating and recovering the solvent from this fraction, the residue was distilled under a reduced pressure to obtain 7.74 g (chemical purity 99.72%) of l-acetoxy-3- \ I (4) Analytical results of the l-acetoxy-3-l-menthoxypropan-2-ol obtained in (3) were as follows. [a]D^^ -67.8° (e = 1.0, EtOH) MS {m/e): 169, 155, 139, 138, 123, 117, 97, 95, 83, 81, 69, 57, 55, 43, 41 IR (neat, cm"^) : 3461, 2955, 2869, 1743, 1456, 1371, 1344, 1181, 1110, 1044, 973, 921, 846 ^H-NMR (CDCla; 6 ppm) : 0.78 (3 H, d, J = 6.9) , 0.80 - 0.88 (2 H, m), 0.88-0.90 (3 H, d, J = 6.9), 0.91-0.92 (3 H, d, J= 6.7), 0.93 - 1.00 (1 H, m), 1.19 - 1.27 (1 H, m), 1.30 - 1.39 (1 H, broad), 1.59 - 1.68 (2 H, m), 2.04 - 2.10 (1 H, m), 2.09 (3 H, s), 2.11 - 2.18 (1 H, m), 2.59 (0.5 H, s), 2.60 (0.5 H, s), 3.04 - 3.11 (1 H, m), 3.33 (0.25 H, dd, J = 9.5, 7.8), 3.37 (0.25 H, dd, J = 9.4, 7.05), 3.62 (0.25 H, dd, J = 9.3, 7.65), 3.70 (0.25 H, dd, J = 9.4, 6.85), 3.97 (1 H, m), 4.10 - 4.19 (2 H, m) Synthesis of l-fonnyloxy-3-t-menthoxypropan-2-ol l-Formyloxy-3-t-menthoxypropan-2-ol was obtained with a yield of 60.9% by carrying out the reaction under th© same conditions as in Example 2, except that anhydrous sodium formate was used instead of anhydrous sodium acetate. Synthesis of l,2-diacetoxy-3-£-menthoxypropane f, U^ In a stream of nitrogen, 100 g of l-chloro-3-l-menthoxypropan-2-ol obtained by the method of Example 1 (chemical purity 97.86%, 393.6 mmol), 36 g (438.9 mmol) of anhydrous sodium acetate and 56.3 g (550 mmol) of acetic anhydride were put into a reaction flask (200 ml capacity) and then allowed to undergo the reaction at 135 to 145°C for 7 hours. Thereafter, the reaction mixture was cooled to room temperature. ,^ (2) The reaction mixture obtained in (1) was poured into 528 g (498 mmol) of 10% sodium carbonate aqueous solution to neutralize acetic acid and acetic anhydride. After separation of layers by adding 200 ml of toluene, the organic layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was recovered to obtain an oily substance. By distilling this oily substance under a reduced pressure, 113.5 g (chemical purity 98.3%) of 1,2-diaoetoxy-3-t-menthoxypropane was obtained as a colorless and transparent oil at a boiling point of 119""C/26 Pa (0.20 mmHg) (yield 93.4% baaed on 1-chloro-3- ( ! (3) Analytical results of the 1,2-diacetoxy-3- MS (m/e): 271, 254, 194, 181, 159, 139, 138, 117, 95, 83, 81, 69, 57, 55, 43, 41 IR (neat, cm"^) : 2960, 2920, 2870, 1750, 1245, 1225, 1115, 1050, 963, 850 ^H-NMR (CDCla; 5 ppm) : 0.76 (3 H, d, J = 7.0) , 0.80 - 0.88 (2 H, m), 0.88 {3 H, d, J = 7.1), 0.91 (3 H, d, J = 6.5), 0.93 - 0.99 (1 H, m), 1.18 - 1.25 (1 H, m), 1.33 (1 H, m), 1.60 - 1.66 (2 H, m), 2.01 - 2.07 (1 H, m), 2.05 (3 H, s), 2.07 (3 H, s), 2.13 (1 H, m), 3.03 (1 H, m), 3.40 - 3.46 {1 H, m), 3.71 - 3.76 (1 H, m), 4.15 - 4.21 (1 H, m), 4.31 - 4.35 (1 H, m), 5.09 - 5.18 (1 H, m) Synthesis of 3-l-menthoxypropane-l,2-diol "rs. .) In a stream of nitrogen, 100 g of l-ehloro-3--menthoxypropan-2-ol obtained by the method of Example 1 (chemical purity 97.86%, 395.1 mmol), 35.65 g (434.6 mmol) of anhydrous sodium acetate and 2.547 g (7.9 mmol) of tetrabutylammonium bromide were put into a reaction flask (300 ml capacity) and then allowed to undergo the reaction at 150 to 160°C for 5 hours. Thereafter, the reaction mixture was cooled to 50°C or less. b) J^ In a stream of nitrogen, the reaction mixture cooled to 50°C or less obtained in (1) was mixed with a mixed solution prepared in advance from 18.91 g (472.75 mmol) of sodium hydroxide, 85.1 ml of water and 85.1 ml of methanol, and the resulting mixture was heated under reflux for 1 hour. After completion of the reaction, this was again heated to evaporate methanol. Thereafter, this was cooled to 50°C or less, mixed with 750 ml of water and 150 ml of toluene to effect separation of layers, the thus obtained organic layer was washed twice with 10% brine and dried with anhydrous magnesium sulfate, and then the solvent was recovered to obtain an oily substance. By distilling this oily substance under a reduced pressure, 88.17 g (chemical purity 97.09%) of 3- a boiling point of from 112 to 118°C/26 Pa (0.20 mmHg) {yield 94.2% based on l-chloro-3-4-menthoxypropan-2-ol). f C ) {35 Analytical results of the 3-/-inenthoxypropane-1,2-diol obtained in (2) were as follows. [alo": -84.17° {c = 1.03, EtOB) MS (m/e) : 230 (M) , 215, 169, 155, 139, 138, 123, 109, 97, 95, 83, 81, 71, 69, 57, 55, 43, 41 IR {neat, cm"^) : 3385, 2954, 2869, 1455, 1369, 1349, 1240, 1185, 1110, 1091, 1054, 920, 850 ^H-NMR {CDCI3; 6 ppm) : 0.77 (3 H, d, J = 7.0) , 0.80 - 0.88 (2 H, m), 0.88 - 0.92 {3 H, m), 0.92 - 0.99 (1 H, m), 1.19 - 1.25 {1 H, m), 1.35 (1 H, m), 1.59 - 1.66 (2 H, m), 2.06 - 2.11 (1 H, m), 2.13 (1 H, s), 2.34 - 2.60 {2 H, broad), 3.03 - 3.10 (1 H, m), 3.33 - 3.42 (1 H, m), 3.61 - 3.72 (3 H, m), 3.80 - 3.84 (1 H, m) Synthesis of 3-.f-menthoxypropane-1, 2-diol In a stream of nitrogen, 10 g of l-acetoxy-3-f-menthoxypropan-2-ol obtained by the method of Example 2 {chemical purity 99.72%, 36.60 mmol), 1.76 g (43.9 mmol) of sodium hydroxide, 10 ml of water and 10 ml of methanol were put into a reaction flask {100 ml capacity) and then heated under reflux for 1 hour. Thereafter, this was treated by the S2uae method of Example 3 {2) to obtain 8.15 g {chemical purity 98.8%) of 3- Synthesis of 3-l-menthoxypropane-l,2-diol In a stream of nitrogen, 10 g of 1,2-diacetoxy-3-f-menthoxypropane obtained by the method of Example 4 (chemical purity 98.3%, 32.24 mmol), 3.10 g (77.38 mmol) of soditun hydroxide, 10 ml of water and 10 ml of methanol were put into a reaction flasic (100 ml capacity) and then heated under reflux for 1 hour. Thereafter, this was treated by the same method of Example 3(2) to obtain 7.15 g (chemical purity 97.8%) of 3- Synthesis of (2S)-l-chloro-3-l-menthoxypropan-2-ol (■ {X) Xn a stream of nitrogen, 8.5 g (54.53 mmol) of {-menthol (mfd. by TaJcasago International Corporation), 6.5 ml of n-heptane and 219 mg (1.64 mmol) of anhydrous aluminum chloride were put into a reaction flask (30 ml capacity) and dissolved under stirring, and the solution was heated to 70""C. A 3.8 g (41 mmol) portion of (2R)-(-)-epichlorohydrin (mfd. by Daiso, optical purity 99% ee) was added dropwise to this solution at the same temperature maintaining 2 hours. After completion of the dropwise addition, the reaction was carried out at the same tanperature for 5 hours. Thereafter, the reaction mixture was cooled to room temperature. This reaction mixture was washed with water and dried with anhydrous magnesium sulfate, and then the solvent was recovered to obtain an oily substance. This oily substance was distilled under a reduced pressure to recover f-menthol and then further distilled to obtain 6-8 g of {2S)-l-chloro-3- menthoxypropan-2-ol (chemical purity 97.74%) as a colorless and transparent oil (yield 65.07% based on epichlorohydrin) at a boiling point of 101°C/36 Pa (0.27 mmHg) . _})) J^ Analytical results of the (2S)-l-chloro-3- [ale": -85.98^ (c = 1.02, EtOH) ^H-NMR (CDCI3; 5 ppm) : 0.78 (3 H, d, J = 6.9), 0.81 - 0.88 (2 H, m), 0.90 (3 H, d, J = 7.3), 0.92 (3 H, d, J = 6.6), 0.94 - 1.10 (1 H, m), 1.21 - 1.27 (1 H, m), 1.35 (1 H, m, broad), 1.59-1.67 (2 H, m), 2.06-2.10 (1 H, m), 2.11 - 2.17 (1 H, m), 2.54 (1 H, d, J = 5.8), 3.10 (1 H, dt, J = 10.6, 4.2), 3.42 (1 H, dd, J = 9.5, 5.1), 3.59 (1 H, dd, J =11.0, 5.7), 3.65 (1 H, dd, J = 11.0, 5.8), 3.73 (1 H, dd, J = 9.5, 4.5), 3.93 (1 H, m) Synthesis of (2S)-3-«-menthoxypropane-l ,2-diol A" } ii) In a stream of nitrogen, 5 g of (2S)-l-chloro-3-{-menthoxypropan-2-ol obtained by the method of Example 8 (chemical purity 97.47%, 19.60 mmol), 1.77 g (21.6 mmol) of anhydrous sodium acetate and 126 mg (0.4 mmol) of tetrabutylammonium bromide were put into a reaction flask (10 ml capacity) and then allowed to undergo the reaction at 160°C for 4 hours. Thereafter, the reaction mixture was cooled to 50°C or less. ,y ifZ) In a stream of nitrogen, the reaction mixture cooled to 50°C or less obtained in (1) was mixed with 944 mg (23.6 mmol) of sodium hydroxide and 10 ml of 50% aqueous ethanol prepared in advance, and the resulting mixture was heated under reflux for 2.5 hours. After completion of the reaction, ethanol was evaporated under a reduced pressure. Thereafter, this was mixed with 150 ml of heptane to effect separation of layers, the thus obtained organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate, and then the solvent was recovered to obtain an oily substance. By distilling this oily stibstance under a reduced pressure, 3.63 g (chemical purity 97.06%) of (2S)-3--menthoxypropane-l,2-diol was obtained as a colorless and transparent oil at a boiling point of 125°C/41 Pa (0.31 mmHg) (yield 78.06% based on (2S)-1-chloro-3-*-menthoxypropan-2-ol). ( I p) Analytical results of the (2S)-3-«-menthoxypropane-l,2-diol obtained in (2) were as follows. [a]D^^ -89.41° (a = 1.02, EtOH) ^H-HMR (CDCI3; 5 ppm) : 0.18 (3 H, d, J = T.O), 0.81 - 0. BB (2 H, m) , 0.90 (3 H, d, J = 7.2), 0.92 (3 H, d, J = 6.6), 0.93 - 1.00 {X H, m> , 1.21 - 1.27 (1 H, m>, 1.35 (1 H, m, broad), 1.59 - 1.68 (2 H, m), 2.07 - 2.11 (1 H, m), 2.11 - 2.17 (1 H, m), 2.49 (1 H, s), 3.08 (1 H, dt, J = 7.0, 4.1), 3.37 (1 H, dd, J = 9.4, 6.1), 3.65 (1 H, dd, J = 11.5, 5.5), 3.72 (2 H, dd) , 3,83 (1 H, m.) Ol {4) A mixed solution of 210 mg (0.913 mmol) of (2S)-3-«-menthoxYpropane-l,2-diol obtained in (2), 100 mg (1.19 mmol) of n-pentanal and 2 ml of hexane was mixed with 10 mg of p-toluenesTilfonic acid monohydrate and heated under reflux for 1 hour. This was cooled to room temperature, neutralized with 5% sodium carbonate aqueous solution, washed with water and then subjected to a gas chromatography analysis by employing the following conditions to find that its optical purity was 99.30%. GLC analysis: Column: Neutrabound-1, 0.25 mm x 30 (mfd. by G L Science) Column temperature: 180 to 240°C (programming rate: 4 °C/minute) Detection temperature; 240°C According to the method of the invention, 3-t~ menthoxypropane-l,2-diol useful, e.g., as a cool-feeling agent and a refrigerant improving agent, can be produced safely by a simple operation with high yield and high purity without using unstable and explosion-causing materials such as metallic sodium, sodium hydride and peroxides, so that this is an industrially advantageous method. Also, according to the invention, (2S)-3~t-inenthoxypropane-l ,2-diol in which configuration of the 2-position of the propane structure is controlled and which has more excellent refreshing feeling can be obtained with high optical purity by the use of an optically active 1,2-epoxy-3-halogenopropane (I) as the material. Also, according to the invention, a l-halogeno-3- Also, according to the invention, a l-acyloxy-2-substituted-3-l-menthoxypropane as a novel intermediate for the production of 3- In addition, the novel l-acyloxy-2-substituted-3- While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the scope thereof. L • "" ■ This application is based on Japanese patent application No. 2001-124134 filed April 23, 2001, the entire contents thereof being hereby incorporated by reference. We Claim: I. A process for producing 3-I-menthoxypropane-l,2-dio!, which comprise adding l-menthol to a l,2-epoxy-3-halogenopropane represented by the following general formula (I) : (where-.n R represents an acyl group derived from the aliphatic carboxylic acid having from 1 to 5 carbon atoms, and R^ represents hydrogen atom or an acyl group derived from the aliphatic carboxylic acid having from 1 to 5 carbon atoms), and then hydrolyzing the I-acyioxy-2-substituted-3-i-menthoxypropane in the presence of a base at a temperature ranging from 20 to 100°C for a period of 0.5 to 5 hours to produce 3-l-menthoxypropane-1.2-diol represented by the following chemical formula (IV): 2. The process for producing 3-l-menthoxypropane-l,2-diol, according to caim !, wherein X is chlorine atom in the l,2-epoxy-3-halogenopropane represented by the general formula (I) and l-ha!ogeno-3-l-menthoxypropan-2-ol represented by the general formula (TI). 3. The process for producing 3-l-menthoxypropane-l,2-diol, according to claim 1, wherein configuration of the 2-position of the propane moiety is (R)-form in the 1,2-epoxy-3-halogenopropane represented by the general formula (I), and configuration of the 2-position of the propane moiety is (S)-form in the l-halogeno-3-1-menthoxypropan-2-ol represented by the general formula (II), l-acyloxy-2-substituted-3-l-menthoxypropane represented by the general formula (III) and 3-1-menthoxypropane-1, 2-diol represented by the general formula(IV). 4. The process for producing 3-l-menthoxypropane-l,2-diol, according to claim 1, wherein R1 is acetyl group and R2 is hydrogen atom or acetyl group in the general formula {III). 5. The process for producing 3-l-menthoxypropane-l,2-diol, according to claim 1, wherein the Lewis acid is atleast one selected from boron trifluoride ether complex, aluminum chloride, zinc chloride, zinc bromide and ferric chloride. 6. The process for producing 3-l-menthoxypropane-l,2-diol, according to claim 1, wherein the base is the acid catalyst at least one selected from lithium hydf-oxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate & potassium carbonate. 7. A process for producing 3-l-menthoxypropane-l,2-diol, substantially as herein described and exemplified.

Full Text

This invention relates to a method for producing 3-4-menthoxypropane-l,2-diol useful as^ e.g., a cool-feeling agent or refreshment improving agent, and l-acyloxy-2-substituted-3- In addition, according to the invention, (2S)-3-l-raenthoxypropane-l,2-diol in which configuration of the 2-position of the propane moiety is controlled and which has more excellent refreshing feeling can be obtained with high optical purity.
BACKGROUND OF THE INVEHTION
3-
influence on the aroma added to the product and can add cool-feeling action to the product. Accordingly^ making use of these characteristics of 3-f-menthoxypropane-1,2-diol, it has been proposed to add 3- , a.s well as aerosol compositions for anti-inflammatory drug and analgesic use (JP-A-63-264522).
Conventionally known methods for producing 3-4-menthoxypropane-l,2-diol include (i) a method in which i-menthol is made into soditun salt with metallic sodium or sodium hydride and then reacted with an allyl halide to produce 3-^-menthoxypropane-l-ene which is subsequently converted into an oxide by oxidizing it using an organic peroxide and then hydrolyzed However, in the conventional method (i), sodium salt of I-menthol is prepared using metallic sodium or sodium hydride, it has a problem of causing a danger of explosion

and generation of hydrogen gas. What is more, since oxidation of 3-f-menthoxypropane-1-ene as the intermediate is carried out using an organic peroxide, it has a danger of causing explosion also from this point, so that this cannot be said as an industrially advantageous method, and there is room for further improvement from the economic point of view.
Also, since the conventional method (ii) is a production method aimed at synthesizing optically active substances, it is necessary to use expensive benzyl glycidyl ether. What is more, since the finally obtained 3~ Also, in addition to these conventional methods, (iii) it has been proposed a method in which l,2-epoxy-3-f-menthoxypropane as a synthetic intermediate of 3-1-inenthoxypropane-l,2-diol is synthesized by allowing t-menthol to undergo addition reaction with a l,2-epoxy-3-halogenopropane such as epichlorohydrin in an aqueous solution in the presence of a base and a quaternary ammonium salt [French Patent 2,479,822 (1981)]. However, it is known that a l,2-epoxy-3-halogenopropan© such as

epichlorohydrin is unstable and apt to be decomposed in the presence of an acid or base ["Dictionary of Chemistry" p. 292, published by Tokyo Kagaku Oojin (1989)]. Thus, in the case of this method in which a l,2-epoxy-3-halogenopropane is allowed to undergo the reaction in the presence of a base, the l,2-epoxy-3~halogenopropane is decomposed when the reaction is carried out for a prolonged period of time, so that it is difficult to synthesize l,2-epoxy-3- In addition, (iv) a method in which l-allyloxy-3-chloro-2-propanol as an optically active glycerol derivative is produced by allowing epichlorohydrin and allyl alcohol to undergo the reaction in the presence of an acidic catalyst has been proposed as the reaction of epichlorohydrin with an alcohol (JP-A-2-221). However, this conventional method (iv) uses only primary allyl alcohol as the alcohol to be used in the reaction, and it does not report on the application to secondary alcohols, much less on the addition reaction with menthol.
Also, as another conventional method, it has been proposed (v) a method in which epichlorohydrin and alcohols are allowed to undergo the reaction in the presence of an acid catalyst and then subjected to an alkali treatment to effect ring closure, thereby converting into a glycidyl ether which is subsequently hydrolyzed, and then a glycerol

ether is produced by heating the reaction mixture at a temperature of from 100 to 230°C in the presence of a salt formed from a strongly basic compound and a weakly acidic compound (JP-A-2000-212114) . However, in the case of this method, it is necessary to heat the reaction mixture at a high temperature of from 100 to 230°C, particularly from 150 to 200°C, in the presence of a salt formed from a strongly basic compound and a weakly acidic compound, in order to decompose the organic halogen contained in the hydrolysa,te of the glycidyX ether, so that this is not an efficient method. What is more, the alcohols used in this method are primary alcohols represented by a general formula: R-(OA)p-OH (wherein R represents a saturated or unsaturated, straight- or branched-chain hydrocarbon radical having from 1 to 36 carbon atoms, A represents an alkylene group having from 2 to 4 carbon atoms, and p is a number of from 0 to 100), and there is no disclosure on the use of secondary alcohols, much less on the use of menthol.
SUMMARY OF THE INVENTION
An object of the invention is to provide a method by which 3- Another object of the invention is to provide a synthetic intermediate useful in obtaining high purity 3-t-menthoxypropane-1,2-diol.

still another object of the invention is to provide an efficient method for producing an intermediate useful in obtaining 3-l-menthoxypropane-l,2-diol,
A further object of the invention is to provide a method by which (2S)-3-l-menthoxypropane-l,2-diol whose configuration of the 2-position of the propane moiety is controlled and which has more excellent refreshing feeling can be produced with a high optical purity.
In order to achieve these objects, the present inventors have conducted extensive studies. As a result, they succeeded in producing a l-acyloxy-2-substituted-3-l-menthoxypropanes as novel compounds, by producing a 1-halogeno-3-l-menthoxypropan-2-ol through the addition reaction of {-menthol with a 1,2-epoxy-3-halogenopropane in an organic solvent in the presence of a Lewis acid, and allowing the thus obtained l-halogeno-3-{-menthoxypropan-2-ol to react with an aliphatic carboxylic acid alkali metal salt. After further studies, it was found that these novel l-acyloxy-2-substituted-3- Thereafter, the inventors have found that (2S)-3-
position of the propane moiety is controJJed and which has more exceJJent refreshing feeling can be produced with a high optical purity, by the use of an optically active substance as the l-halogeno-3-l-menthoxypropan-2-ol, and have accomplished the invention based on these findings.

(2) a method for producing 3-l-menthoxypropane-l,2-diol, which comprises reacting a l-halogeno-3-l-menthoxypropan-2-ol represented by the following -general formula (II):

and subsequently hydrolyzing it to produce 3-1-menthoxypropane-l,2-diol represented by the following chemical formula (IV) :

(wherein R represents an acyl group derived from the aliphatic carboxylic acid having from 1 to 5 carbon atoms, and R^ represents hydrogen atom or an acyl group derived from the aliphatic carboxylic acid having from 1 to 5 carbon atoms).
Also, the invention includes as preferred embodiments,
(4) the production method according to any one of the sibove
items (1) to epoxy-3-halogenopropane represented by the general formula
(I) and l-halogGno-3-*-menthoxypropan-2-ol represented by the general formula (II);
(5) the production method according to any one of the above
items (1) to (4), wherein configuration of the 2-position
of the propane moiety is (R)-form in the l,2-epoxy-3-
halogenopropane represented by the general formula (I), and
configuration of the 2-position of the propane moiety is

(S)-forro in the l-halogeno-3-l-inenthoxypropan-2-ol represented by the general formula (II), l-acyloxy-2-substituted-3-£-inenthoxypropane represented by the general formula (III) and 3-£-inenthoxypropane-l,2-diol represented by the general formula (IV) ; and
(6) the production method according to any one of the above
items (1) to (5) , wherein R^ is acetyl group and R^ is
hydrogen atom or acetyl group in the general formula (III).
Also, the invention is,
(7) a l-acyloxy-2-substituted-3-4-menthQxypropane
represented by the following general formula (III):

(8) a l-acetoxy-2-substituted-3-l-menthoxypropane represented by the following general formula (Ilia):

(10) a (2S) -l-acetoxy-2-siibstituted-3-l-menthoxypropane represented by the following general formula (Ilia"):

(In the formulae, X is a halogen atom, R^ is an acyl group derived from an aliphatic carboxylic acid having from 1 to 5 carbon atoms, and R^ is hydrogen atom or an acyl group derived from an aliphatic carboxylic acid having from 1 to 5 carbon atoms.)
That is, a novel l-halogeno-3- Examples of the halogen atom X in the 1,2--epoxy-3-halogenopropane (I) include fluorine atom, chlorine atom, bromine atom and iodine atom. Illustrative examples of the l,2-epoxy-3-halogenopropane include l,2-epoxy-3-fluoropropane (epifluorohydrin), 1,2-epoxy-3-chloropropane (epichlorohydrin), l,2-epoxy-3-bromopropane (epibromohydrin) and 1,2-epoxy-3-iodopropane (epiiodohydrin). Among them, l,2-epoxy-3-chloropropane (epichlorohydrin) or l,2-epoxy-3-bromopropane (epibromohydrin) in which the halogen atom X is chlorine atom or bromine atom is suitably used in the invention, and

l,2-epoxy-3-chloropropane (epichlorohydrin) is used more suitably.
Regarding the l,2-epoxy-3-halogenopropane (I) and i-menthol as the material compounds, commercial products can be used as such.
In carrying out the reaction to add I-menthol to the 1,2-epoxy-3-halogenopropane {I), a method in which a Lewis acid is added to and dissolved in a solution prepared by dissolving j-menthol in an organic solvent, and then a solution prepared by dissolving the l,2-epoxy-3-halogenopropane (I) in an organic solvent is added dropwise thereto to effect the reaction.
Regarding using ratio of the l,2-epoxy-3-halogenopropane (I) and (I).
Also, amount of the Lewis acid to be used may be similar to the catalytically effective amount in the usual addition reaction and, generally, is preferably from sJaout 0.01 to 0.1 mol, based on 1 mol of the l,2-epoxy-3-halogenopropane (I).
Illustrative exan^les of the Lewis acid include boron trifluoride ether complex, aluminum chloride, zinc chloride, zinc bromide and ferric chloride, which may be used alone or as a mixture of two or more. Among them.

aliuninum chloride and/or boron trifluoride ether complex is preferably used from the viewpoint of easy handling and economically low price.
As the organic solvent, an organic solvent which does not exert influence of the addition reaction of {-menthol with the l,2-epoxy-3-halogenopropane (I) is used, and its illustrative examples include aliphatic hydrocarbon solvents such as hexane, heptane and octane; alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; and petroleum ether solvents, which may be used alone or as a mixture of two or more. Among them, heptane and/or toluene is preferably used from the viewpoint of easy handling and economically low price.
Amount of the organic acid to be used is, in general, preferably from about 0.5 to 5 parts by volume, more preferably from about 1 to 3 parts by volume, based on 1 part by volume of t-menthol.
It is desirable to carry out the addition reaction of C-menthol to the 1,2-epoxy-3-halogenopropane (I) in an atmosphere of an inert gas such as nitrogen gas or argon gas for effecting smooth progress of the addition reaction.
Also, in carrying out the addition reaction by adding an organic solvent solution of the l,2-epoxy-3-halogenopropane (I) dropwise to an organic solvent solution of {-menthol and a Lewis acid, the period of time for the

dropwise addition of the 1,2-epoxy-3-halogenopropane (I)-dissolved organic solvent solution is generally preferably from about 0.5 to 10 hours, more preferably from about 1.5 to 3 hours.
A temperature of preferably from about 60 to 130°C, more preferably from about 65 to 120°C, is employed as the addition reaction temperature, and the l-halogeno-3- The l-halogeno-3-{-menthoxypropan-2-ol (II) obtained by this addition reaction is stable, generally shows an oily form and can be preserved.
Accordingly, the l-halogeno-3-f-menthoxypropan-2-ol
then directly used in the subsequent reaction without carrying out after-treatment such as purification.
In the above reaction, configuration of the 2-position of the propane structure can be controlled without racemization by the use of an optically active l,2-epoxy-3-halogenopropane (I). Illustratively, by the use of a (2R)-l,2-epoxy-3-halogenopropane {I"), it can be easily introduced into a (2S)-l-halogeno-3-*-inenthoxypropan-2-ol (II"). Also, when a (2S)-l,2-epoxy-3-halogenopropane (I") is used, it can be easily introduced into a (2R)-1-halogeno-3-t-menthoxypropan-2-ol {II").
By allowing the l-halogeno-3- As the alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms to be used in this reaction, a lithium, sodium or potassium salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms is suitably used. The illustrative examples thereof include lithium formate, lithium acetate, lithium propionate, lithium butyrate, lithium isobutyrate, lithium valerate, lithium isovalerate, lithium pivalate, sodium formate, sodium acetate, sodium propionate, sodi\im butyrate, sodimn isobutyrate, sodium valerate, sodium

isovalerate, sodium pivalate, potassium formate, potassium acetate, potassium propionate, potassium butyrate, potassium isobutyrate, potassiiun valerate, potassium isovalerate and potassium pivalate, which may be used alone or as a mixture of two or more. Among them, one or two or more of sodium formate, potassium formate, sodium acetate and potassium acetate are preferably used, and soditun acetate is used more preferably, from the viewpoint of easy handling and economically low price.
When an alkali metal salt of an aliphatic carboxylic acid having 6 or more carbon atoms or an aromatic carboxylic acid alkali metal salt is used, solid precipitation becomes considerable so that the l-acyloxy-2-substituted-3-f-menthoxypropane (III) cannot be produced smoothly.
From the economical point of view, amount of the used alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms is from about 1.0 to 5.0 mol, particularly from about 1.05 to 2.0 mol, based on 1 mol of the l-halogeno-3-f-menthoxypropan-2-ol (II).
It is desirable that the used alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms is in an anhydrous state, because the l-acyloxy-2-substituted-3-{-menthoxypropane (III) can be formed with a high yield and the yield becomes stable.

According to the invention, a commercially available alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms can be used as such or by subjecting it to a dehydration treatment in advance.
According to the invention, the reaction of the 1-halogeno-3-f-menthoxypropan-2-ol (II) with an alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms, for producing the l-acyloxy-2-substituted-3-£-menthoxypropane (III), can be carried out under joint use of an aliphatic carboxylic acid anhydride as occasion demands.
As the aliphatic carboxylic acid anhydride, an aliphatic carboxylic acid anhydride having from 2 to 5 carbon atoms is suiteibly used, and its illustrative examples include acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride and pivalic anhydride, which may be used alone or as a mixture of two or more. Among them, acetic anhydride is prefersibly used.
When an aliphatic carboxylic acid anhydride is jointly used, its amount to be used is preferably from 1.0 to 5.0 mol, more preferably from about 1.05 to 2.0 mol, based on 1 mol of the l-halogeno-3~ According to the invention, a commercially available aliphatic carboxylic acid anhydride can be used as such.

In addition, according to the invention, the reaction of the l-halogeno-3- When the reaction is carried out in the presence of a phase transfer catalyst, a reaction rate improving effect is obtained.
As the phase transfer catalyst, a quaternary ammoniiim salt is suitably used, and its illustrative examples include quaternary ammonium salts which can be industrially easily obtained, such as tetramethylammonium chloride, tetrabutylammonium bromide, tetraethylammoniiim iodide, tetrabutylammoniiuD iodide, trimethylhexadecylammonitua chloride, dimethyIdioctylammonium chloride,
trimethyIbenzylammonium chloride and trioctylraethylammonium chloride, which may be used alone or as a mixture of two or more. Among them, tetramethylainraoniiim bromide is preferably used from the viewpoint of easy handling and economically low price.
When production reaction of the l-acyloxy-2-substituted-3-
0.01 to 0.2 mol, more preferably from about 0.02 to 0.05 mol, based on 1 mol of the l-halogeno-3~{-menthoxypropan-2-ol (11) .
A commercially available phase transfer catalyst can be used as such.
Production reaction of the l-acyloxy-2-siibstituted-3-f-menthoxypropane (III) may be carried out in the absence of solvent or using a solvent.
When a solvent is used, any solvent which does not significantly inhibit the production reaction of 1-acyloxy-2-substituted-3-l-menthoxypropane (III) can be used, but an organic solvent is suitably used. Illustrative examples of the suitably used organic solvent include aliphatic hydrocarbon solvents such as hexane, heptane and octane; alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; ether solvents such as diethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane and 1,3-dioxofuran; amide solvents such as dimethylformamide, dimethyl ace tamide and N-methylpyrrolidotie; and petroleum ether solvents, which may be used alone or as a mixture of two or more. Among them, dimethylformamide is preferably used from the viewpoint of smooth progress of the reaction, good handling and economically low price.

Amount of the organic acid to be used is preferably from about 1 to 10 parts by volume, more preferably from about 2 to 5 parts by volume, based on 1 part by volume of the l-halogeno-3- It is desirable to carry out the production reaction of l-acyloxy-2-substituted-3- It is desirable to carry out the reaction for the production of the l-acyloxy-2-substituted-3- The reaction temperature and reaction time caji be optionally changed and adjusted depending on the kind and amount of the used alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms.
The l-acyloxy-2-substituted-3-
acyloxy group, or a mixture of the (III-A) and (III-B). Forming ratio of the (III-A) and (III-B) in l-acyloxy-2-substituted-3-{-roenthoxypropane (III) changes depending on the kind and amount of the alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms and the presence or absence, kind and amount of the other components which are used as occasion d^aands (e.g., an aliphatic carboxylic acid anhydride and a phase transfer catalyst) . When the reaction is carried out using only an alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms without using an aliphatic carboxylic acid anhydride and a phase transfer catalyst, ration of the l-acyloxy-3-t-menthoxypropan-2-ol (III-A) generally becomes 80% or more. On the other hand, when an aliphatic carboxylic acid anhydride is jointly used, ratio of the l,2-diacyloxy-3-£-menthoxyprcpane (III-BJ increases as the amount of the aliphatic carboxylic acid anhydride increases.
The l-acyloxy-2-substltuted-3- The thus obtained l-acyloxy-2-substituted-3-*-menthoxypropane (III) may be preserved after purifying it l>y» S"Sfw distillation or a column chromatography treatment, or without carrying out the purification treatment, and then used by collecting it from a

preservation container at the time of the production of the 3- In the reaction, when an optically active 1-halogeno-3-
anhydride, it can be introduced into a (2R)-l-acyloxy-2-substituted-3-i-inenthoxypropane (III-A" ") .
Illustrative examples of the l-acyloxy-2-substituted-3- By hydrolyzing the l-acyloxy-2-substituted-3-t-menthoxypropane (III) obtained by the reaction, 3-t-menthoxypropane-1,2-diol (IV) is formed.
It is desirable to carry out hydrolysis of the 1-acyloxy-2-substituted-3-*-menthoxypropane (III) in the presence of a base. As the base to be used in the hydrolysis, hydroxides, carbonates and/or alkoxides of an

alkali metal or alkaline earth metal are suitably used. Their illustrative examples include lithiiua hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodiiua carbonate and potassitun carbonate, which may be used alone or as a mixture of two or more. Among them, sodium hydroxide and/or potassium hydroxide is preferably used from the viewpoint of smooth progress of the hydrolysis and economically low price.
It is desirable to add the base to the reaction system in the form of aqueous solution. It is desirable that concentration of the base aqueous solution is a high concentration of 40% by mass or more, particularly from 45 to 55% by mass, because the hydrolysis reaction smoothly progresses thereby.
Amount of the base to be used is preferably from about 1.0 to 5.0 mol, particularly from about 1.5 to 3.0 mol, based on 1 mol of the l-acyloxy-2-substituted-3-l-menthoxypropane (III).
It is desirable to carry out the hydrolysis reaction of l-acyloxy-2-substituted-3-
mixture of two or more. Among them, methanol and/or ethanol is preferably used from the viewpoint of economically low price.
Amount of the organic acid to be used is preferably from about 1 to 10 parts by volume, more preferably from about 2 to 5 parts by volume, based on 1 part by volume of the l-acyloxy-2-siibstituted-3- Ten^erature of the hydrolysis reaction of 1-acyloxy-2-substituted-3-f-menthoxypropane (III) is preferably from about 20 to 100°C, particularly from about 50 to SO^C, *nd the 3-l-menthoxypropane-l,2-diol (IV) is formed by carrying out the reaction for a period of from about 0.5 to 5 hours, preferably from about 1 to 3 hours, while keeping this ten^erature. Recovery of 3-t-menthoxypropane-l,2-diol (IV) from the reaction products containing 3-
neutralization of the used base as occasion demands, and then evaporating the solvent. Purification of 3-4-menthoxypropane-l,2-diol (IV) can be carried out, e.g., by distillation or a column chromatography treatment.
In the hydrolysis reaction, when an optically active l-acyloxy-3-t-menthoxypropan-2-ol (III-A) is used, it can be introduced into a 3-{-menthoxypropane-l,2-diol (IV) in which configuration of the 2-position of the propane moiety is controlled can be obtained without carrying out racemization. Illustratively, when a (2S)-l-acyloxy-3-£-menthoxypropan-2-ol (III-A") is used, it can be easily introduced into a (2S)-3-f-menthoxypropane-l,2-diol (IV). Also, when a (2R)-l-acyloxy-3- Among members of the 3-e-menthoxypropane-l,2-diol (IV), a (2S)-3- can be tben easily introduced into a (2S)-l-acyloxy-2-substituted-3-l-

menthoxypropane (III") by allowing it to react with an alkali metal salt of an aliphatic carboxylic acid having from 1 to 5 carbon atoms, and then the (2S}-3- Making use of the characteristics of the thus obtained 3-
The following describes the invention illustratively with reference to Examples, but the invention is not restricted by the following Examples.
In this connection, the apparatus used for the measurement (analysis) of physical properties in the following examples is as follows. (1) Chemical purity:
Gas chromatograph; "HP6890" column mfd. by HEWLETT PACKARD
Column; "NEUTRABOND-1" mfd. by GL Science (inner diameter x length = 0,25 mm x 30 m) {2} Kuclear magnetic i:esonance spectrum:
^H-NMR; "DRX-500" mfd. by Brucker (500 MHz)
(3) Infrared absorption spectrum (IR):
Equipment: ""Nicolet AVATAR 360" mfd. by Micolet Japan Measuring method: NaCl film method
(4) Mass spectrum (MS):
M-80 mass spectxrometer: mfd. by Hitachi (ionization voltage 20 eV) "DIP-360" mfd. by Japan Spectroscopic Synthesis of l-chloro-3-
temperature. Next, 3.5 g (26.88 mmol) of anhydrous aluminum chloride was added thereto and dissolved under stirring, and the solution was heated to 70°C. A 61 g (0.6572 mol) portion of epichlorohydrin was added dropwise to this solution at the same temperature maintaining 2 hours. After completion of the dropwise addition, the reaction was carried out at the same temperature for 7 hours. Thereafter, the reaction mixture was cooled to room temperature.
,^ Ai) The reaction mixture obtained in (1) was washed with water and then with 10% sodium carbonate aqueous solution, and n-heptane was evaporated to obtain an oily substance. By distilling this oily siibstance under a reduced pressure, 57.2 g (0.37 mol) of un-reacted {-menthol was recovered at a boiling point of from 78 to 99""C/600 Pa (4.5 mmHg), and then 117 g of l-Ghloro-3- C 1 (3^) Analytical results of the l-chloro-3-«-menthoxypropan-2-ol obtained in (2) were as follows, [ajo": -73.7° (c = 1.05, EtOH)
MS (m/e): 248 (M*), 165, 163, 139, 138, 123, 109, 97, 95, 83, 81, 71, 69, 57, 55, 53, 43, 41, 29, 27

IR (neat, cm"^) : 3422, 2955, 2922, 2869, 1456, 1385, 1370, 1344, 1180, 1114, 1067, 1050, 1011, 991, 974, 922, 845, 753 ^H-NMR (CDCla; 5 ppm) : 0.78 (3 H, d, J = 6.9) , 0.81 - 0.88 (2 H, m), 0.90 (3 H, d, J = 7.0), 0.93 (3 H, d, J = 6.5), 0.96 - 1.01 {1 H, m), 1.20 - 1.26 (1 H, m), 1.30 - 1.40 (1 H, broad), 1.61 - 1.66 (2 H, m), 2.09 (1 H, m), 2.14 (1 H, m), 2.52 (1 H, d, J = 5.9), 3.09 (1 H, dt, J = 10.6, 4.1), 3.44 (1 H, dd, J = 9.4, 5.2), 3.60 (1 H, dd, J = 11.0, 5.6), 3.73 (1 H, dd, J = 9.4, 5.2), 3.91 - 3.97 (1 H, m) Synthesis of l-acetoxy-3- \\ [^ The reaction mixture obtained in (1) was mixed with 30 ml of water and 50 ml of heptane to effect separation, the organic layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was recovered to obtain an oily substance. By distilling this oily substance under a reduced pressure, partially purified l-acetoxy-3-J-menthoxypropan-2-ol was obtained at a boiling point of from 111 to 120°C/25 Pa

(0.19 ininHg) . Composition of this product when analyzed by the gas chromatography was composed of 5.53% by mass of 3- / j Jl3) A 15 g portion of the partially purified product obtained in (2) was purified by a silica gel column chromatography. As the developing solvent, a mixed solvent composed of ethyl acetate and hexane was used, and the mixing ratio of ethyl acetate was gradually increased from 4% by volume to 10% by volume. By this, l-acetoxy-3-*-menthoxypropan-2-ol was eluted with the most high purity in a fraction obtained by a developing solvent containing from 6 to 10% by volume of ethyl acetate. After separating and recovering the solvent from this fraction, the residue was distilled under a reduced pressure to obtain 7.74 g (chemical purity 99.72%) of l-acetoxy-3- \ I (4) Analytical results of the l-acetoxy-3-l-menthoxypropan-2-ol obtained in (3) were as follows. [a]D^^ -67.8° (e = 1.0, EtOH)
MS {m/e): 169, 155, 139, 138, 123, 117, 97, 95, 83, 81, 69, 57, 55, 43, 41

IR (neat, cm"^) : 3461, 2955, 2869, 1743, 1456, 1371, 1344, 1181, 1110, 1044, 973, 921, 846
^H-NMR (CDCla; 6 ppm) : 0.78 (3 H, d, J = 6.9) , 0.80 - 0.88 (2 H, m), 0.88-0.90 (3 H, d, J = 6.9), 0.91-0.92 (3 H, d, J= 6.7), 0.93 - 1.00 (1 H, m), 1.19 - 1.27 (1 H, m), 1.30 - 1.39 (1 H, broad), 1.59 - 1.68 (2 H, m), 2.04 - 2.10 (1 H, m), 2.09 (3 H, s), 2.11 - 2.18 (1 H, m), 2.59 (0.5 H, s), 2.60 (0.5 H, s), 3.04 - 3.11 (1 H, m), 3.33 (0.25 H, dd, J = 9.5, 7.8), 3.37 (0.25 H, dd, J = 9.4, 7.05), 3.62 (0.25 H, dd, J = 9.3, 7.65), 3.70 (0.25 H, dd, J = 9.4, 6.85), 3.97 (1 H, m), 4.10 - 4.19 (2 H, m)
Synthesis of l-fonnyloxy-3-t-menthoxypropan-2-ol
l-Formyloxy-3-t-menthoxypropan-2-ol was obtained with a yield of 60.9% by carrying out the reaction under th© same conditions as in Example 2, except that anhydrous sodium formate was used instead of anhydrous sodium acetate. Synthesis of l,2-diacetoxy-3-£-menthoxypropane
f, U^ In a stream of nitrogen, 100 g of l-chloro-3-l-menthoxypropan-2-ol obtained by the method of Example 1 (chemical purity 97.86%, 393.6 mmol), 36 g (438.9 mmol) of anhydrous sodium acetate and 56.3 g (550 mmol) of acetic anhydride were put into a reaction flask (200 ml capacity) and then allowed to undergo the reaction at 135 to 145°C

for 7 hours. Thereafter, the reaction mixture was cooled to room temperature.
,^ (2) The reaction mixture obtained in (1) was poured into 528 g (498 mmol) of 10% sodium carbonate aqueous solution to neutralize acetic acid and acetic anhydride. After separation of layers by adding 200 ml of toluene, the organic layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was recovered to obtain an oily substance. By distilling this oily substance under a reduced pressure, 113.5 g (chemical purity 98.3%) of 1,2-diaoetoxy-3-t-menthoxypropane was obtained as a colorless and transparent oil at a boiling point of 119""C/26 Pa (0.20 mmHg) (yield 93.4% baaed on 1-chloro-3- ( ! (3) Analytical results of the 1,2-diacetoxy-3- MS (m/e): 271, 254, 194, 181, 159, 139, 138, 117, 95, 83, 81, 69, 57, 55, 43, 41
IR (neat, cm"^) : 2960, 2920, 2870, 1750, 1245, 1225, 1115, 1050, 963, 850
^H-NMR (CDCla; 5 ppm) : 0.76 (3 H, d, J = 7.0) , 0.80 - 0.88 (2 H, m), 0.88 {3 H, d, J = 7.1), 0.91 (3 H, d, J = 6.5), 0.93 - 0.99 (1 H, m), 1.18 - 1.25 (1 H, m), 1.33 (1 H, m), 1.60 - 1.66 (2 H, m), 2.01 - 2.07 (1 H, m), 2.05 (3 H, s), 2.07 (3 H, s), 2.13 (1 H, m), 3.03 (1 H, m), 3.40 - 3.46 {1

H, m), 3.71 - 3.76 (1 H, m), 4.15 - 4.21 (1 H, m), 4.31 -
4.35 (1 H, m), 5.09 - 5.18 (1 H, m)
Synthesis of 3-l-menthoxypropane-l,2-diol
"rs.
.) In a stream of nitrogen, 100 g of l-ehloro-3-*-menthoxypropan-2-ol obtained by the method of Example 1 (chemical purity 97.86%, 395.1 mmol), 35.65 g (434.6 mmol) of anhydrous sodium acetate and 2.547 g (7.9 mmol) of tetrabutylammonium bromide were put into a reaction flask (300 ml capacity) and then allowed to undergo the reaction at 150 to 160°C for 5 hours. Thereafter, the reaction mixture was cooled to 50°C or less.
b) J^ In a stream of nitrogen, the reaction mixture cooled to 50°C or less obtained in (1) was mixed with a mixed solution prepared in advance from 18.91 g (472.75 mmol) of sodium hydroxide, 85.1 ml of water and 85.1 ml of methanol, and the resulting mixture was heated under reflux for 1 hour. After completion of the reaction, this was again heated to evaporate methanol. Thereafter, this was cooled to 50°C or less, mixed with 750 ml of water and 150 ml of toluene to effect separation of layers, the thus obtained organic layer was washed twice with 10% brine and dried with anhydrous magnesium sulfate, and then the solvent was recovered to obtain an oily substance. By distilling this oily substance under a reduced pressure, 88.17 g (chemical purity 97.09%) of 3-
a boiling point of from 112 to 118°C/26 Pa (0.20 mmHg) {yield 94.2% based on l-chloro-3-4-menthoxypropan-2-ol). f C ) {35 Analytical results of the 3-/-inenthoxypropane-1,2-diol obtained in (2) were as follows. [alo": -84.17° {c = 1.03, EtOB)
MS (m/e) : 230 (M*) , 215, 169, 155, 139, 138, 123, 109, 97, 95, 83, 81, 71, 69, 57, 55, 43, 41
IR {neat, cm"^) : 3385, 2954, 2869, 1455, 1369, 1349, 1240, 1185, 1110, 1091, 1054, 920, 850
^H-NMR {CDCI3; 6 ppm) : 0.77 (3 H, d, J = 7.0) , 0.80 - 0.88 (2 H, m), 0.88 - 0.92 {3 H, m), 0.92 - 0.99 (1 H, m), 1.19
- 1.25 {1 H, m), 1.35 (1 H, m), 1.59 - 1.66 (2 H, m), 2.06
- 2.11 (1 H, m), 2.13 (1 H, s), 2.34 - 2.60 {2 H, broad), 3.03 - 3.10 (1 H, m), 3.33 - 3.42 (1 H, m), 3.61 - 3.72 (3 H, m), 3.80 - 3.84 (1 H, m)
Synthesis of 3-.f-menthoxypropane-1, 2-diol In a stream of nitrogen, 10 g of l-acetoxy-3-f-menthoxypropan-2-ol obtained by the method of Example 2 {chemical purity 99.72%, 36.60 mmol), 1.76 g (43.9 mmol) of sodium hydroxide, 10 ml of water and 10 ml of methanol were put into a reaction flask {100 ml capacity) and then heated under reflux for 1 hour. Thereafter, this was treated by the S2uae method of Example 3 {2) to obtain 8.15 g {chemical purity 98.8%) of 3-
Synthesis of 3-l-menthoxypropane-l,2-diol
In a stream of nitrogen, 10 g of 1,2-diacetoxy-3-f-menthoxypropane obtained by the method of Example 4 (chemical purity 98.3%, 32.24 mmol), 3.10 g (77.38 mmol) of soditun hydroxide, 10 ml of water and 10 ml of methanol were put into a reaction flasic (100 ml capacity) and then heated under reflux for 1 hour. Thereafter, this was treated by the same method of Example 3(2) to obtain 7.15 g (chemical purity 97.8%) of 3- Synthesis of (2S)-l-chloro-3-l-menthoxypropan-2-ol
(■ {X) Xn a stream of nitrogen, 8.5 g (54.53 mmol) of {-menthol (mfd. by TaJcasago International Corporation), 6.5 ml of n-heptane and 219 mg (1.64 mmol) of anhydrous aluminum chloride were put into a reaction flask (30 ml capacity) and dissolved under stirring, and the solution was heated to 70""C. A 3.8 g (41 mmol) portion of (2R)-(-)-epichlorohydrin (mfd. by Daiso, optical purity 99% ee) was added dropwise to this solution at the same temperature maintaining 2 hours. After completion of the dropwise addition, the reaction was carried out at the same tanperature for 5 hours. Thereafter, the reaction mixture was cooled to room temperature. This reaction mixture was washed with water and dried with anhydrous magnesium

sulfate, and then the solvent was recovered to obtain an
oily substance. This oily substance was distilled under a
reduced pressure to recover f-menthol and then further
distilled to obtain 6-8 g of {2S)-l-chloro-3- menthoxypropan-2-ol (chemical purity 97.74%) as a colorless
and transparent oil (yield 65.07% based on epichlorohydrin)
at a boiling point of 101°C/36 Pa (0.27 mmHg) .
_})) J^ Analytical results of the (2S)-l-chloro-3- [ale": -85.98^ (c = 1.02, EtOH)
^H-NMR (CDCI3; 5 ppm) : 0.78 (3 H, d, J = 6.9), 0.81 - 0.88
(2 H, m), 0.90 (3 H, d, J = 7.3), 0.92 (3 H, d, J = 6.6),
0.94 - 1.10 (1 H, m), 1.21 - 1.27 (1 H, m), 1.35 (1 H, m,
broad), 1.59-1.67 (2 H, m), 2.06-2.10 (1 H, m), 2.11 -
2.17 (1 H, m), 2.54 (1 H, d, J = 5.8), 3.10 (1 H, dt, J =
10.6, 4.2), 3.42 (1 H, dd, J = 9.5, 5.1), 3.59 (1 H, dd, J
=11.0, 5.7), 3.65 (1 H, dd, J = 11.0, 5.8), 3.73 (1 H, dd,
J = 9.5, 4.5), 3.93 (1 H, m)
Synthesis of (2S)-3-«-menthoxypropane-l ,2-diol
A" } ii) In a stream of nitrogen, 5 g of (2S)-l-chloro-3-{-menthoxypropan-2-ol obtained by the method of Example 8
(chemical purity 97.47%, 19.60 mmol), 1.77 g (21.6 mmol) of anhydrous sodium acetate and 126 mg (0.4 mmol) of tetrabutylammonium bromide were put into a reaction flask
(10 ml capacity) and then allowed to undergo the reaction

at 160°C for 4 hours. Thereafter, the reaction mixture was cooled to 50°C or less.
,y ifZ) In a stream of nitrogen, the reaction mixture cooled to 50°C or less obtained in (1) was mixed with 944 mg (23.6 mmol) of sodium hydroxide and 10 ml of 50% aqueous ethanol prepared in advance, and the resulting mixture was heated under reflux for 2.5 hours. After completion of the reaction, ethanol was evaporated under a reduced pressure. Thereafter, this was mixed with 150 ml of heptane to effect separation of layers, the thus obtained organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate, and then the solvent was recovered to obtain an oily substance. By distilling this oily stibstance under a reduced pressure, 3.63 g (chemical purity 97.06%) of (2S)-3-*-menthoxypropane-l,2-diol was obtained as a colorless and transparent oil at a boiling point of 125°C/41 Pa (0.31 mmHg) (yield 78.06% based on (2S)-1-chloro-3-*-menthoxypropan-2-ol).
( I p) Analytical results of the (2S)-3-«-menthoxypropane-l,2-diol obtained in (2) were as follows.
[a]D^^ -89.41° (a = 1.02, EtOH)
^H-HMR (CDCI3; 5 ppm) : 0.18 (3 H, d, J = T.O), 0.81 - 0. BB
(2 H, m) , 0.90 (3 H, d, J = 7.2), 0.92 (3 H, d, J = 6.6),
0.93 - 1.00 {X H, m> , 1.21 - 1.27 (1 H, m>, 1.35 (1 H, m, broad), 1.59 - 1.68 (2 H, m), 2.07 - 2.11 (1 H, m), 2.11 -
2.17 (1 H, m), 2.49 (1 H, s), 3.08 (1 H, dt, J = 7.0, 4.1),

3.37 (1 H, dd, J = 9.4, 6.1), 3.65 (1 H, dd, J = 11.5, 5.5), 3.72 (2 H, dd) , 3,83 (1 H, m.)
Ol {4) A mixed solution of 210 mg (0.913 mmol) of (2S)-3-«-menthoxYpropane-l,2-diol obtained in (2), 100 mg (1.19 mmol) of n-pentanal and 2 ml of hexane was mixed with 10 mg of p-toluenesTilfonic acid monohydrate and heated under reflux for 1 hour. This was cooled to room temperature, neutralized with 5% sodium carbonate aqueous solution, washed with water and then subjected to a gas chromatography analysis by employing the following conditions to find that its optical purity was 99.30%.
GLC analysis:
Column: Neutrabound-1, 0.25 mm x 30 (mfd. by G L Science)
Column temperature: 180 to 240°C (programming rate: 4 °C/minute)
Detection temperature; 240°C
According to the method of the invention, 3-t~ menthoxypropane-l,2-diol useful, e.g., as a cool-feeling agent and a refrigerant improving agent, can be produced safely by a simple operation with high yield and high purity without using unstable and explosion-causing materials such as metallic sodium, sodium hydride and peroxides, so that this is an industrially advantageous method.

Also, according to the invention, (2S)-3~t-inenthoxypropane-l ,2-diol in which configuration of the 2-position of the propane structure is controlled and which has more excellent refreshing feeling can be obtained with high optical purity by the use of an optically active 1,2-epoxy-3-halogenopropane (I) as the material.
Also, according to the invention, a l-halogeno-3- Also, according to the invention, a l-acyloxy-2-substituted-3-l-menthoxypropane as a novel intermediate for the production of 3- In addition, the novel l-acyloxy-2-substituted-3-
While the invention has been described in detail
and with reference to specific embodiments thereof, it will
be apparent to one skilled in the art that various changes
and modifications can be made therein without departing
from the scope thereof. L • "" ■
This application is based on Japanese patent application No. 2001-124134 filed April 23, 2001, the entire contents thereof being hereby incorporated by reference.

We Claim:
I. A process for producing 3-I-menthoxypropane-l,2-dio!, which comprise adding l-menthol to a l,2-epoxy-3-halogenopropane represented by the following general formula (I) :

(where-.n R represents an acyl group derived from the aliphatic carboxylic acid having from 1 to 5 carbon atoms, and R^ represents hydrogen atom or an acyl group derived from the aliphatic carboxylic acid having from 1 to 5 carbon atoms),
and then hydrolyzing the I-acyioxy-2-substituted-3-i-menthoxypropane in the presence of a base at a temperature ranging from 20 to 100°C for a period of 0.5 to 5 hours to produce 3-l-menthoxypropane-1.2-diol represented by the following chemical formula (IV):

2. The process for producing 3-l-menthoxypropane-l,2-diol, according to caim !, wherein X is chlorine atom in the l,2-epoxy-3-halogenopropane represented by the general formula (I) and l-ha!ogeno-3-l-menthoxypropan-2-ol represented by the general formula (TI).
3. The process for producing 3-l-menthoxypropane-l,2-diol, according to claim 1, wherein configuration of the 2-position of the propane moiety is (R)-form in the 1,2-epoxy-3-halogenopropane represented by the general formula (I), and configuration of the 2-position of the propane moiety is (S)-form in the l-halogeno-3-1-menthoxypropan-2-ol represented by the general formula (II), l-acyloxy-2-substituted-3-l-menthoxypropane represented by the general formula (III) and 3-1-menthoxypropane-1, 2-diol represented by the general formula(IV).

4. The process for producing 3-l-menthoxypropane-l,2-diol, according to claim 1,
wherein R1 is acetyl group and R2 is hydrogen atom or acetyl group in the general
formula {III).
5. The process for producing 3-l-menthoxypropane-l,2-diol, according to claim 1,
wherein the Lewis acid is atleast one selected from boron trifluoride ether complex,
aluminum chloride, zinc chloride, zinc bromide and ferric chloride.
6. The process for producing 3-l-menthoxypropane-l,2-diol, according to claim 1, wherein the base is the acid catalyst at least one selected from lithium hydf-oxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate & potassium carbonate.
7. A process for producing 3-l-menthoxypropane-l,2-diol, substantially as herein described and exemplified.

Documents:

0271-mas-2002 abstract-duplicate.pdf

0271-mas-2002 abstract.pdf

0271-mas-2002 claims-duplicate.pdf

0271-mas-2002 claims.pdf

0271-mas-2002 correspondence-others.pdf

0271-mas-2002 correspondence-po.pdf

0271-mas-2002 description (complete)-duplicate.pdf

0271-mas-2002 description (complete).pdf

0271-mas-2002 form-1.pdf

0271-mas-2002 form-19.pdf

0271-mas-2002 form-26.pdf

0271-mas-2002 form-3.pdf

0271-mas-2002 form-5.pdf

0271-mas-2002 others.pdf

0271-mas-2002 petition.pdf

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Patent Number

200758

Indian Patent Application Number

271/MAS/2002

PG Journal Number

08/2007

Publication Date

23-Feb-2007

Grant Date

02-Jun-2006

Date of Filing

11-Apr-2002

Name of Patentee

M/S. TAKASAGO INTERNATIONAL CORPORATION

Applicant Address

37-1 KAMATA 5 CHOME, OHTA-KU, TOKYO 144 8721,

Inventors:

#	Inventor's Name	Inventor's Address
1	TERUYOSHI AKIYAMA	C/O TAKASAGO INTERNATIONAL CORPORATION CENTRAL RESEARCH LABORATORY, 4-11 NISHIYAWATA 1 CHOME, HIRATSUKA-SHI, KANAGAWA 254-0073,
2	TAKASHI MIURA	C/O TAKASAGO INTERNATIONAL CORPORATION CENTRAL RESEARCH LABORATORY, 4-11 NISHIYAWATA 1 CHOME, HIRATSUKA-SHI, KANAGAWA 254-0073,
3	TOSHIMITSU HAGIWARA	C/O TAKASAGO INTERNATIONAL CORPORATION CENTRAL RESEARCH LABORATORY, 4-11 NISHIYAWATA 1 CHOME, HIRATSUKA-SHI, KANAGAWA 254-0073,
4	AKIRA AMANO	C/O TAKASAGO INTERNATIONAL CORPORATION CENTRAL RESEARCH LABORATORY, 4-11 NISHIYAWATA 1 CHOME, HIRATSUKA-SHI, KANAGAWA 254-0073,

PCT International Classification Number

A61K 7/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2001-124134	2001-04-23	Japan