JP4611226B2 - Method for producing (R) -1-octen-3-ol - Google Patents

Description

  The present invention relates to a method for industrially advantageously producing natural (R) -1-octen-3-ol contained in mushrooms having high added value that is useful as a perfume ingredient.

  1-octen-3-ol has a matsutake-like fragrance and is widely used as a fragrance ingredient for matsutake flavor and the like. On the other hand, it has been confirmed that the optically active 1-octen-3-ol has a significantly different aroma between the R-form and the S-form. The R-form has a strong and typical matsutake-like aroma at a threshold of about 1 ppm, whereas the S-form only has a weak and dusty grass-like aroma at a threshold of about 100 ppm (Non-patent Document 1). . However, 1-octen-3-ol contained in mushrooms has an R-form of 78 to 94% e.e. e. Therefore, in order to reproduce the aroma of mushrooms such as matsutake in a natural flavor in a formulated fragrance, 1-octene having the same optical purity as that of nature is known. It is desirable to use -3-ol, so 78-94% e.e. e. There is a demand for a method for industrially and efficiently producing R-form 1-octen-3-ol having an optical purity of a certain degree.

As a method for producing optically active 1-octen-3-ol, for example, methyl β-hydroxyoctanoate is formed from β-keto-methyl octoate using a ruthenium-binap catalyst, and further three steps are performed. A method for producing optically active 1-octen-3-ol (Non-patent Document 3), and a method for producing optically active 1-octen-3-ol from linoleic acid using mushroom lipoxygenase (Non-patent Document 4). ) A method of esterifying an alkanol or alkenol having a secondary hydroxyl group in an organic solvent using porcine pancreatic esterase (Non-patent Document 5), a lipase for racemic 1-octen-3-ol Alkenyl esters (eg vinyl acetate, vinyl octoate, laurin as acyl donors in the presence) Asymmetric acylation using vinyl acid, isopropenyl acetate) or acid anhydride (for example, acetic anhydride, butyric anhydride), and from the mixture containing the acylated product and the unreacted product, (R)- A process for producing (R) -1-octen-3-ol comprising separating 1-octen-3-ol (Patent Document 1) and the like are known.
Patent No. 36386643 Nozaki Norio, "Chemistry", Volume 48, 814 (1993) A. Mosandl, “Z. Lebensm. Unters. Forsch.”, 186, p. 417 (1988) Yamamoto, “Takasago Perfume Time Report”, Volume 109, Page 10 (1993) W. Grosch et al., “PPOGRES IN FLAVOR RESEARCH 1984”, Proceedings of the 4th Weurman Flavor Symposium, p. 253 (1984) P. Schreier et al., “Flavor Precursors”, ACS Symposium series 490, p. 32 (1992)

However, the asymmetric synthesis method of optically active 1-octen-3-ol using the binup catalyst described in Non-Patent Document 3 has a long synthesis step and is not practical. In addition, the method of producing optically active 1-octen-3-ol from mushroom lipoxygenase from linoleic acid described in Non-Patent Document 4 has a significantly low yield of 1-octen-3-ol, and is practical. Is hard to say. The method for obtaining an optically active substance by asymmetric esterification in an organic solvent using porcine pancreatic esterase described in Non-Patent Document 5 is that the optical purity and enantiomeric selectivity of the obtained optically active 1-octen-3-ol are high. Low and not satisfactory. The method of performing asymmetric acylation on the racemic 1-octen-3-ol described in Patent Document 1 using an acyl donor in the presence of lipase and separating unreacted products generally has low enantiomeric selectivity, In order to obtain high selectivity, it is necessary to use a lipase derived from Candida antarctica as a lipase (see Patent Document 1). However, since this enzyme is expensive, it is costly in industrial production. Disadvantageous. In addition, purification of the target product is performed by silica gel column chromatography, but purification by silica gel column chromatography is industrially unsuitable from the viewpoint of cost and operation, and industrially uses silica gel column chromatography. In such a case, a large amount of developing solvent is required, and it cannot be said that the environment is good.

  Therefore, conventionally, development of the manufacturing method of optically active 1-octen-3-ol more advantageous industrially is desired.

  The present inventors perform asymmetric acylation of racemic 1-octen-3-ol using an acyl donor in the presence of lipase to separate unreacted (R) -1-octen-3-ol. As a result of intensive studies to solve the above-mentioned drawbacks in the method, when vinyl butyrate is used as the acyl donor, the product (S) -1-octen-3-yl butyrate and the residual substrate (R ) 1-octen-3-ol, and the remaining 3 components of vinyl butyrate can be distilled easily and completely by distillation, and it is found that it is extremely industrially advantageous in terms of cost and operation. Thus, the present invention has been completed.

  Thus, the present invention uses vinyl butyrate as the acyl donor in the asymmetric acylation of racemic 1-octen-3-ol with lipase, thereby converting (S) -1-octen-3-ol to (S) -1-octen-3-yl butyrate is selectively converted, and unreacted (R) -1-octen-3-ol is separated from the resulting reaction mixture by distillation (R ) -1-Octen-3-ol is provided.

  In the present invention, (R) -1-octene-3 having high optical purity is characterized in that the above method is repeated for (R) -1-octen-3-ol obtained by the above production method. -To provide a method for producing oars.

  The method of the present invention is cost-effective because a racemic 1-octen-3-ol can be asymmetrically acylated using an inexpensive lipase that is readily available. In addition, according to the method of the present invention, (R) -1-octen-3-ol can be separated from the reaction mixture by a simple distillation purification operation, so that it can be processed in a large amount in a short time even on an industrial scale. It can be carried out, and it can be drastically reduced in terms of cost and operation, and has excellent effects such as no adverse environmental impact.

  Hereinafter, the present invention will be described in more detail. In the present specification, the term “(R) -1-octen-3-ol” includes not only pure (R) -1-octen-3-ol but also (R) -1-octene-3. -Ole predominate, eg about 40% e. e. The term “(S) -1-octen-3-ol” is used to encompass the above, and not only pure (S) -1-octen-3-ol but also (S) -1 Predominately octen-3-ol, eg about 40% e. e. It is used in the meaning including the above.

本発明は、ラセミ体の１−オクテン−３−オールをアシルドナーの存在下にリパーゼを用いて不斉アシル化することにより、（Ｓ）−１−オクテン−３−オールをエステルに変え、未反応の（Ｒ）−１−オクテン−３−オールを分離することによって、香料として有用な（Ｒ）−１−オクテン−３−オールを製造する方法において、アシルドナーとして酪酸ビニルを使用する点に本質的特徴を有するものである。

In the present invention, racemic 1-octen-3-ol is asymmetrically acylated using lipase in the presence of an acyl donor to change (S) -1-octen-3-ol into an ester, Essentially in the use of vinyl butyrate as the acyl donor in a process for producing (R) -1-octen-3-ol useful as a fragrance by separating (R) -1-octen-3-ol It has characteristics.

  As the acyl donor in the asymmetric acylation using the above lipase, Patent Document 1 states that carboxylic acid alkyl esters, carboxylic acid alkenyl esters, and carboxylic acid anhydrides can be used. Specifically, Examples are given only with vinyl acetate, vinyl octoate, vinyl laurate, acetic anhydride and butyric anhydride.

  When vinyl acetate having a small number of carbon atoms is used as the acyl donor, the product (S) -1-octen-3-yl acetate and the unreacted residual substrate (R) -1-octen-3-ol The boiling points are close, and it is practically impossible to completely fractionate by distillation. On the other hand, when vinyl octanoate or vinyl laurate having a large number of carbons is used as the acyl donor, the product acylated product and unreacted residual substrate can be separated by distillation, but the residual substrate is (R) -1- It is very difficult to completely fractionate octen-3-ol and vinyl octoate or vinyl laurate by distillation.

  On the other hand, when acetic anhydride or butyric anhydride is used as an acyl donor, the reaction rate is slow and the reaction takes too much time, which is not industrially advantageous.

  However, when vinyl butyrate not described in Patent Document 1 is used as an acyl donor in the present invention, surprisingly, (S) -1-octen-3-yl butyrate as an acylation product and unreacted residual substrate are present. (R) -1-octen-3-ol and the residual acyl donor vinyl butyrate can be completely separated from each other by a simple distillation method, and the desired (R) -1-octene- It was found that 3-ol can be obtained with high optical purity.

  In the method of the present invention, the amount of vinyl butyrate used as the acyl donor is not particularly limited, but is usually 0.5 to 5 mol, particularly 1 to 3 mol per 1 mol of racemic 1-octen-3-ol. It can be in the molar range.

The lipase that can be used in the present invention is not particularly limited as long as it has a certain degree of enantiomeric selectivity. For example, lipase derived from Candida antarctica, lipase A derived from Aspergillus niger, Pseudomonas sp. . Lipase AK derived from Candida rugosa, lipase AY derived from Candida rugosa, lipase PS derived from Burkholderia cepacia, Alcaligenes sp. Origin lipase QL and the like. Among them, lipase PS derived from Burkholderia cepacia is suitable because it is easily available, is inexpensive, and has a relatively high enantiomeric selectivity. The amount of these lipases used depends on the enzyme activity, but is usually 0.001 to 0.2 parts by weight, preferably 0.01 parts by weight per 1 part by weight of racemic 1-octen-3-ol. It can be in the range of ~ 0.1 part by weight.

  Racemic 1-octen-3-ol used as a starting material is known per se and can be easily obtained as a commercial product. The asymmetric acylation reaction can be usually carried out in an organic solvent inert to the reaction. Examples of the organic solvent that can be used in this case include cyclohexane, n-hexane, n-heptane, toluene, tert- Examples include butanol, ethyl ether, tetrahydrofuran, and carbon tetrachloride. Among them, nonpolar solvents such as cyclohexane, n-hexane, n-heptane, and toluene are particularly preferable. The amount of these organic solvents used may be any amount that dissolves at least raw material racemic 1-octen-3-ol and vinyl butyrate. Specifically, for example, racemic 1-octen-3-ol and butyric acid are used. It can be in the range of 1 to 20 times the capacity, preferably 2 to 10 times the capacity of the total amount of vinyl.

  The asymmetric acylation reaction of racemic 1-octen-3-ol can be performed at a temperature at which the lipase is not deactivated, for example, at a temperature of 80 ° C. or lower, preferably within a range of about 20-30 ° C.

  The resulting reaction mixture is filtered to remove the lipase, for example, washed with an alkaline aqueous solution or water as necessary, and dried, and then the solvent is distilled off under reduced pressure using an appropriate means such as an evaporator. Remove most of the solvent by methods such as distillation, distillation column, condenser, distillate fraction collector, thermometer, and a tank equipped with a stirrer equipped with a stirrer to distill off the solvent under normal or reduced pressure. As a result, a crude product containing acylated product (S) -1-octen-3-yl butyrate, unreacted residual substrate (R) -1-octen-3-ol and unreacted vinyl butyrate is obtained.

  This crude product can easily separate and recover (R) -1-octen-3-ol of high optical purity by distillation without using complicated separation and purification means such as chromatography. This is a significant advantage and a great feature of the method of the present invention.

  The above crude product can be distilled using a normal distillation apparatus, and industrially, it can be used using a multistage distillation column. As the distillation column, if it has a column length and the number of theoretical plates sufficient to fractionate (S) -1-octen-3-yl butyrate, (R) -1-octen-3-ol and vinyl butyrate There is no limitation in particular, and the distillation apparatus normally used industrially can be used similarly. Specifically, for example, a multistage distillation column having 5 to 30 stages is used in a reflux flow of 1: 1 to 20: 1. Can be manipulated by ratio. Moreover, although the temperature and degree of vacuum during distillation are not strictly limited, the degree of vacuum is usually within the range of 0.2 to 30 kPa, and the temperature is the applicable degree of vacuum (R). A temperature at which -1-octen-3-ol is distilled from the top of the column can be employed.

  Thus, high optical purity, eg 40-99% e.e. e. (R) -1-octen-3-ol can be obtained.

  According to the present invention, in order to further increase the optical purity of the obtained (R) -1-octen-3-ol, the above-described operation is optionally performed on the obtained (R) -1-octen-3-ol. Can be repeated (hereinafter referred to as reprocessing operation). That is, the (R) -1-octen-3-ol obtained above was asymmetrically acylated again using vinyl butyrate as an acyl donor in the presence of lipase, and the resulting reaction mixture was distilled to obtain high optical properties. Purity, eg 80% e.e. e. The above (R) -1-octen-3-ol can be obtained.

  According to the method of the present invention, for the separation and recovery of (R) -1-octen-3-ol from the reaction mixture, a cost-effective distillation method capable of performing a large amount of processing in a short time is used. Therefore, even if the reprocessing operation is performed, the cost is not significantly increased.

  Next, a preferred embodiment of the method of the present invention will be described.

ラセミ体の１−オクテン−３−オールと該１−オクテン−３−オール １モルあたり０．５〜５モルの酪酸ビニルを反応フラスコに採取し、これに有機溶媒を加え、攪拌子や撹拌羽根などで撹拌し、よく混合する。得られる混合溶液に、該１−オクテン−３−オールを基準にしてリパーゼを０．１〜２０％、好ましくは１〜１０％加え、４〜８０℃、好ましくは２０〜３０℃の温度で２〜９６時間撹拌を続ける。次いでリパーゼを濾別し、濾液をアルカリ水溶液、例えば１〜１０％炭酸水素ナトリウム水溶液、次いで水または１％ないし飽和食塩水で順次洗浄し乾燥した後、例えばエバポレーターを用い減圧下に有機溶媒の大半を留去し、残留液（粗製物）を多段蒸留塔を用いて蒸留し、（Ｒ）−１−オクテン−３−オールを分別する。

Racemic 1-octen-3-ol and 0.5 to 5 moles of vinyl butyrate per mole of 1-octen-3-ol are collected in a reaction flask, an organic solvent is added thereto, and a stirrer or stirring blade is added. Stir etc. and mix well. To the resulting mixed solution, 0.1 to 20%, preferably 1 to 10% of lipase is added based on the 1-octen-3-ol, and 2 at a temperature of 4 to 80 ° C, preferably 20 to 30 ° C. Continue stirring for -96 hours. The lipase is then filtered off, and the filtrate is washed successively with an alkaline aqueous solution, such as 1-10% aqueous sodium hydrogen carbonate solution, then with water or 1% to saturated saline, and dried. Is distilled off and the residual liquid (crude product) is distilled using a multistage distillation column to fractionate (R) -1-octen-3-ol.

  The (R) -1-octen-3-ol thus obtained can be used as a raw material for various blended fragrances including Matsutake flavor and mushroom flavor.

  Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples.

Example 1
Racemic 1-octen-3-ol (350 g, 2.73 mol), vinyl butyrate (350 g, 3.07 mol) and n-heptane (3.5 L) are placed in a 5 L flask, stirred at 35 ° C., -Octen-3-ol and vinyl butyrate were dissolved. Lipase PS (manufactured by Amano Enzyme) (17.5 g) was added thereto and dispersed uniformly, followed by stirring at 30 ° C. for 48 hours. The conversion rate from 1-octen-3-ol to 1-octen-3-yl butyrate after the reaction was 49.0%. The lipase was filtered off from the reaction solution, the filtrate was washed twice with 10% aqueous soda ash (850 g) and once with water, dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate was used with a rotary evaporator. The solvent n-heptane and most of the vinyl butyrate were distilled off to obtain a crude product.

Solvent evaporation conditions using a rotary evaporator
Steam temperature Decompression degree
33 → 47 ° C. to 11 kPa (mainly removes n-heptane)
47 → 70 ° C 11 → 5 kPa (mainly vinyl butyrate is distilled off)

  When the internal temperature reached 70 ° C. and the degree of vacuum became 5 kPa, the solvent recovery was terminated to obtain a crude product (crude product yield 416.5 g).

  The obtained crude product was subjected to precision distillation in a flask equipped with a multistage distillation column (5 theoretical plates), a condenser, a distillate distiller, a thermometer, a vacuum line and a stirrer.

  The temperature was gradually raised under the conditions of a degree of vacuum of 3.0 kPa and a reflux ratio of 5: 1. First, the remaining vinyl butyrate was distilled off. Since the distillation rate became slow when the column top temperature rose to 80 ° C., fraction 1 was defined as the column top temperature up to 80 ° C. When the heating was further continued, the distillation rate increased from the time when the temperature exceeded 80 ° C., and stable distillation of (R) -1-octen-3-ol occurred. Since the distillation rate rapidly decreased from the time when the tower top temperature exceeded 85 ° C., the tower top temperature up to 85 ° C. was designated as fraction 2, and the rest thereafter was designated as fraction 3. The temperature was raised to 120 ° C., but the distillate was slight. The distillation conditions and results are shown in Table 1.

１−オクテン−３−オールの純度及び香気評価よりフラクション２（８０〜８５℃／３．０ｋＰａの留分）を本発明品１とした（収量１７２．５ｇ）。蒸留残渣は２２０．４ｇであった。本発明品１の（Ｒ）−１−オクテン−３−オールの化学純度は９９．８％、光学純度は５４．６％ｅ．ｅ．であった。

From the purity and aroma evaluation of 1-octen-3-ol, fraction 2 (80 to 85 ° C./3.0 kPa fraction) was designated as Product 1 (yield 172.5 g). The distillation residue was 220.4g. The chemical purity of (R) -1-octen-3-ol of the product 1 of the present invention is 99.8%, and the optical purity is 54.6% e.e. e. Met.

  The distillation residue (S) -1-octen-3-yl butyrate has a chemical purity of 96.7% and an optical purity of 60.8% e.e. e. Met.

Example 2
(R) -1-octen-3-ol (optical purity 54.6% ee, 150 g, 1.17 mol), vinyl butyrate (150 g, 1.32 mol) and n-heptane obtained in Example 1 (1.5 L) was placed in a 5 L flask and stirred at 35 ° C. Lipase PS (manufactured by Amano Enzyme) (7.5 g) was added thereto and dispersed uniformly, followed by stirring at 30 ° C. for 48 hours. The conversion rate from 1-octen-3-ol to 1-octen-3-yl butyrate after the reaction was 40.0%. The enzyme was filtered off from the reaction solution, and the filtrate was washed twice with 10% aqueous soda ash (365 g) and once with water, dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate was filtered using a rotary evaporator. The solvent n-heptane and most of the vinyl butyrate were distilled off to obtain a crude product.

Solvent evaporation conditions using a rotary evaporator
Steam temperature Decompression degree
33 → 48 ° C. to 11 kPa (mainly removes n-heptane)
48 → 70 ° C 11 → 5 kPa (mainly vinyl butyrate is distilled off)

  When the internal temperature reached 70 ° C. and the degree of vacuum became 5 kPa, the solvent recovery was terminated to obtain a crude product (crude product yield 180.6 g).

The resulting crude product was subjected to precision distillation in the same manner as in Example 1 in a flask equipped with a multistage distillation column (theoretical plate number: 10), a condenser, a distillation fraction receiver, a thermometer, a vacuum line and a stirrer. . Table 2 shows the distillation conditions and results.

１−オクテン−３−オールの純度及び香気評価よりフラクション２（８０〜８５℃／２．７ｋＰａの留分）を本発明品２とした（収量７３．５ｇ）。蒸留残渣は９９．０ｇであった。本発明品２の（Ｒ）−１−オクテン−３−オールの化学純度は９９．８％、光学純度は９１．０％ｅ．ｅ．であった。

From the purity and aroma evaluation of 1-octen-3-ol, fraction 2 (80 to 85 ° C./2.7 kPa fraction) was designated as Product 2 of the present invention (yield 73.5 g). The distillation residue was 99.0 g. The chemical purity of (R) -1-octen-3-ol of the product 2 of the present invention is 99.8%, and the optical purity is 91.0% e.e. e. Met.

Comparative Example 1
In Example 1, the same operation as in Example 1 was performed except that vinyl acetate (264 g, 3.07 mol) was used instead of vinyl butyrate (350 g, 3.07 mol), at 80 to 85 ° C./3.0 kPa. 300 g of distilled (R) -1-octen-3-ol was obtained.

  The obtained (R) -1-octen-3-ol had a chemical purity of 64.8% and contained 35.0% (S) -1-octen-3-yl acetate as an impurity.

Comparative Example 2
In Example 1, operation similar to Example 1 was performed except using vinyl octoate (523 g, 3.07 mol) instead of vinyl butyrate (350 g, 3.07 mol), and 80 to 85 ° C./3.0 kPa. To obtain 230 g of (R) -1-octen-3-ol.

  The chemical purity of the obtained (R) -1-octen-3-ol was 84.8% and contained 15.0% vinyl octoate as an impurity.

Comparative Example 3
In Example 1, the same operation as Example 1 was carried out except that acetic anhydride (157 g, 1.54 mol) was used instead of vinyl butyrate (350 g, 3.07 mol), and the mixture was stirred at 30 ° C. for 48 hours. It was. The conversion rate from 1-octen-3-ol to 1-octen-3-yl acetate after the reaction was 10.0%.

Comparative Example 4
In Example 1, the same operation as Example 1 was carried out except that butyric anhydride (243 g, 1.54 mol) was used instead of vinyl butyrate (350 g, 3.07 mol), and the mixture was stirred at 30 ° C. for 48 hours. It was. The conversion rate from 1-octen-3-ol to 1-octen-3-yl butyrate after the reaction was 7.5%.

Claims (2)

  In the asymmetric acylation of racemic 1-octen-3-ol using lipase, vinyl butyrate is used as an acyl donor, whereby (S) -1-octen-3-ol is preferentially (S) -1-octen-3-yl butyrate, and unreacted (R) -1-octen-3-ol is separated from the resulting reaction mixture by distillation. (R) -1-octene- A method for producing 3-ol.   (R) -1-octene having a high optical purity, characterized in that the method according to claim 1 is repeated for (R) -1-octen-3-ol obtained by the method according to claim 1. A process for producing -3-ol.