JPH0584094A - Method for producing optically active alcohol - Google Patents

Abstract

PURPOSE:To obtain the title compound useful for medicines inexpensively and efficiently independently of a concrete reaction condition by subjecting an acetylene alcohol of racemic modification and a fatty acid vinyl ester to asymmetric transesterification reaction in the presence of a lipid hydrolyzing enzyme. CONSTITUTION:First, an acetylene alcohol of racemic modification of formula I (R<1> is proton or 1-12C saturated straight-chain hydrocarbon; R<2> is 1-12C saturated straight-chain hydrocarbon or 1-12C unsaturated hydrocarbon with the proviso that R<1>=R<2>) and a fatty acid vinyl ester (e.g. vinyl laurate or vinyl caparate) of formula II (R<3> is 1-12C unsaturated hydrocarbon, aromatic hydrocarbon, etc.) are blended in an organic solvent (e.g. hexane) to give a solution. Then, the solution is mixed with a lipid hydrolyzing enzyme (usually lipase) and subjected to asymmetric transesterification reaction to give an optically active alcohol fatty acid ester of formula III and to simultaneously collect unreacted optically alcohol of formula I by optical resolution.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active acetylene alcohol from a racemic alcohol by an asymmetric transesterification reaction. The optically active acetylene alcohol and its ester obtained by the present invention are important as synthetic intermediates for other useful optically active compounds (liquid crystal compounds, pharmaceuticals, agricultural chemicals, etc.).

[0002]

2. Description of the Related Art Recently, an optically active alcohol has been attracting attention as a synthetic intermediate for fine chemicals such as pharmaceuticals, agricultural chemicals and liquid crystals. The optically active acetylene alcohol is a compound having a particularly high utility value among them, and is used for the synthesis of prostaglandins and antibacterial agents. As a chemical method for producing acetylene alcohol, reduction of a ketone with lithium aluminum halide modified with binaphthol (J. Am. Chem. Soc. 106, 671
7 (1984)) or a method of optical resolution by forming an inclusion compound with an alkaloid such as brucine (Tetrahedr
on Lett.22,4669 (1981), Israel J. Chem., 25,338 (1985))
and so on.

On the other hand, recently, various methods for producing an optically active substance using an enzyme have been proposed. The production method using an enzyme is considered to be an industrially promising process because the reaction conditions are mild and relatively inexpensive crude enzyme can be used. It is said that ester hydrolysis reaction using a lipolytic enzyme, ester synthesis reaction, transesterification reaction, etc. can be mainly used for the production of asymmetric alcohol. Of these, J.Org.
Chem., 53,3127 (1988), J.Org.Chem., 53,6130 (1988), Tetr
ahedron Lett., 30,6189 (1989), Tetrahedron Lett., 30,1
The transesterification reaction using a vinyl ester as an acyl donor disclosed in 917 (1989), etc., has been applied to the kinetic optical resolution of asymmetric alcohols such as meso-1,3-diol and 2-halo-1-allyl alcohol. It is said to be suitable.
However, the reaction rate and the optical yield of the product strongly depend on the type of solvent, the reaction temperature, the structure of the substrate, etc., and have not been established as a general-purpose method. In addition, to the knowledge of the present inventors, no examples have been disclosed to which an enzyme was used for producing an optically active acetylene alcohol having an acetylene group at an asymmetric carbon in the molecule.

[0004]

Chemical production methods such as reduction of ketones and formation of inclusion compounds with alkaloids give high optical purity, but all require large amounts of expensive reagents. It is not always satisfactory as an industrial production method such as requiring extreme reaction conditions. We tried to produce optically active acetylene alcohol by ester synthesis reaction using lipolytic enzyme, but it takes a long time to complete the reaction, and the optical purity of the separated and collected optically active acetylene alcohol is low, and it is practical. The manufacturing method was not satisfactory. In view of the above situation, as a result of repeated intensive studies on a method for producing an optically active acetylene alcohol using a lipolytic enzyme,
When various lipolytic enzymes are allowed to act in an organic solvent in the presence of the above-mentioned racemic alcohol and fatty acid vinyl ester, the asymmetric ester and the other optically active alcohol are brought to a higher optical purity in a short time. They found that they can be divided, and completed the present invention.

As is clear from the above description, the object of the present invention is a method of optically resolving racemic alcohol by using a lipolytic enzyme and a fatty acid vinyl ester, the effect of which strongly depends on specific reaction conditions. It is to provide a general-purpose and practical optical resolution method of racemic acetylene alcohol that does not do so.

[0006]

Means for Solving the Problems That is, the present invention provides (1) a general formula

[0007]

[Chemical 5]

(In the formula, R ¹ is a proton or a saturated linear hydrocarbon group having 1 to 12 carbon atoms, and R ² is 1 carbon atom.
To 12 saturated linear hydrocarbon groups, branched saturated hydrocarbon groups, unsaturated hydrocarbon groups having 1 to 12 carbon atoms or aromatic hydrocarbon groups, provided that R1 ≠ R2) Racemic alcohol and general formula

[0009]

[Chemical 6]

(In the formula, R ³ is a saturated straight chain hydrocarbon group having 1 to 12 carbon atoms, a branched saturated hydrocarbon group having 1 to 12 carbon atoms, or an unsaturated hydrocarbon group having 1 to 12 carbon atoms. Group or an aromatic hydrocarbon group) is mixed in an organic solvent to form a solution, and a lipolytic enzyme or cells containing the lipolytic enzyme is added to the solution to perform asymmetric transesterification. By the general formula

[0011]

[Chemical 7]

A fatty acid ester of an optically active alcohol represented by the general formula

[0013]

[Chemical 8]

A process for producing an optically active ester and an optically active alcohol, characterized in that the other optically active alcohol which has not been transesterified is obtained.

(2) The method according to item (1), wherein a lipase is used as the lipolytic enzyme. (3) 1-pentyn-3-ol, 1-hexyn-3-ol, 1-heptin-3- as racemic alcohol
The production method according to the above (1), wherein any one selected from all, 1-octin-3-ol and 5-methyl-1-hexyn-3-ol is used. (4) Vinyl laurate as a fatty acid vinyl ester,
The production method according to the above (1), wherein any one selected from vinyl caprate and vinyl caproate is used. (5) The production method according to (1) above, wherein one or more selected from hexane, isopropyl ether, and toluene are used as the organic solvent.

According to the present invention, various racemic acetylene alcohols that can be obtained synthetically at a low cost, and fatty acid vinyl esters that can be obtained at a low price in the same manner as an inexpensive solvent are dissolved in an organic solvent. This is a method for producing an optically active acetylene alcohol in which a fatty acid ester of one optically active substance is produced and the other optically active alcohol which has not been transesterified with this ester is obtained.

The present invention will be described in detail below. Specific examples of the optically active acetylene alcohol of the general formula (4) produced in the present invention include the followings.

[0018]

[Chemical 9]

[0019]

[Chemical 10]

[0020]

[Chemical 11]

[0021]

[Chemical formula 12]

[0022]

[Chemical 13]

[0023]

[Chemical 14]

[0024]

[Chemical 15]

[0025]

[Chemical 16]

As the fatty acid vinyl ester used in the present invention, various linear fatty acid vinyl esters such as vinyl laurate, vinyl caprate and vinyl caproate, and fatty acid vinyl ester having a side chain can be used. However, it is desirable to select an appropriate one from the substrate specificity of the enzyme, the reaction conditions and the like.

The lipolytic enzyme used in the present invention is not particularly limited, but an esterase is typically used. Lipase is usually used as the esterase, and its origin is
Depending on the type, the genus Candida , Muco
r) genus, Rhizopus (Rhizopus) genus Aspergillus (Asperg
illus genus, Arthrobacter genus, Pseudomonas genus, and the like, or animal origin such as porcine pancreas, or plant origin. Specific examples are shown in Table 1.

[0028]

[Table 1]

The asymmetric transesterification reaction of the present invention can be carried out in various organic solvents, and examples thereof include hexane, isopropyl ether and toluene. The concentrations of the acetylene alcohol and the fatty acid vinyl ester in the reaction can be appropriately selected depending on the activity of the enzyme and other conditions, but are usually 0.01 to
It is used in an amount of 0.5 mol, preferably 0.01 to 0.1 mol. The enzyme may be used in various amounts depending on its type and activity, but it is usually 1 to 1000 mg /
ml, preferably 5-100 mg / ml.
The reaction temperature is not particularly limited as long as it is the action temperature of the enzyme, but usually 4 to 50 ° C is desirable. The progress of the reaction can be followed by performing analysis by gas chromatography.

[Examples] The present invention will be described in more detail below with reference to Examples, but the present invention is not limited to these Examples without departing from the scope of the invention. Example 1 1-pentyne-3-ol 2.53 g (30 mmo
l) and 6.78 g (30 mmol) of vinyl laurate are dissolved in 300 ml of hexane, 4 g of Lipase AY30 (Amano Pharmaceutical Co., Ltd.) is added, and the mixture is stirred at 200 rpm for 5 hours at 30 ° C. The reaction was terminated when the amount of pentin-3-ol was reduced to 50% at the start of the reaction. The amount of 1-pentyn-3-ol in the reaction solution was calculated by analyzing the reaction solution by gas chromatography using an SBS-100 column manufactured by Shinwa Kako Co., Ltd., and the reaction was stopped by stopping the reaction solution with a membrane filter. It was carried out by filtering with-to remove the lipase. Next, the filtrate is extracted with ion-exchanged water, and this aqueous layer is further extracted with ether,
1-Pentin-3-ol was separated and purified by distilling the ether layer. By this operation, 0.33 g (yield 24%) of (R) -1-pentyn-3-ol and (S)
3. Lauric acid ester of -1-pentyn-3-ol 4.
20 g (yield 90%) was obtained.

Example 2 The same procedure as in Example 1 was repeated except that 1.94 g (30 mmol) of 1-hexyne-3-ol was used as the acetylene alcohol, and the mixture was stirred at 30 rpm at 200 rpm for 40 hours. The reaction was stopped in the same manner as in Example 1 when the amount of 1-hexyne-3-ol remaining in the reaction solution reached about 50% of the start of the reaction, and the filtrate was then deionized water. After extraction with water, the aqueous layer is extracted with ether, and the ether layer is distilled under reduced pressure to obtain (R) -1-hexyne-3-
0.38 g (yield 26%) of ole and 4.47 g (yield 92%) of lauric acid ester of (S) -1-hexyne-3-ol were obtained.

Example 3 The same procedure as in Example 2 was repeated except that 1-heptin-3-ol (3.36 g, 30 mmol) was used as the acetylene alcohol, and the mixture was stirred at 30 ° C. for 40 hours at 200 rpm. The reaction was stopped in the same manner as in Example 1 when the amount of 1-heptin-3-ol remaining in the reaction solution reached 50% of the start of the reaction. Then, the filtrate was concentrated, subjected to silica gel column chromatography, and eluted with a hexane: ethyl acetate (9: 1) solution to separate and obtain the produced ester, which was further eluted with ethyl acetate to remove unreacted alcohol. Recovered. As a result, (R) -1-heptin-3-ol 0.82 g (yield 48.8%), (S)-
Lauric acid ester of 1-heptin-3-ol 4.5
6 g (yield 90%) was obtained.

Example 4 Example 1 was repeated except that 3.36 g (30 mmol) of 1-octyne-3-ol was used as the acetylene alcohol.
In the same manner as in Example 1, stirring was carried out at 30 ° C. for 20 hours at 200 rpm, and when the amount of 1-octyne-3-ol remaining in the reaction solution reached 50% of the start of the reaction, the same as in Example 1. Then, the reaction was stopped, and the remaining 1-octyne-3-ol and the produced ester were separated and purified in the same manner as in Example 3. As a result, (R) -1-octyne-3-o-
1.72 g (yield 91%), (S) -1-octyne-
3-ol lauric acid ester 4.66 g (yield 88
%) Was obtained.

Example 5 The same procedure as in Example 1 was repeated except that 5-methyl-1-hexyne-3-ol (3.36 g, 30 mmol) was used as the acetylene alcohol.
The mixture was stirred at 0 rpm, and when 5-methyl-1-hexyne-3-ol in the reaction solution was reduced to 50% at the start of the reaction, the reaction was stopped in the same manner as in Example 1, and the remaining 5 -Methyl-1-hexyne-3-ol and the produced ester were separated and purified in the same manner as in Example 3. as a result,
(R) -5-methyl-1-hexyne-3-ol 1.5
1 g (yield 90%) and 4.71 g (yield 93%) of (S) -5-methyl-1-hexyne-3-ol lauric acid ester were obtained.

Example 6 The optical purity of the optically active acetylene alcohols obtained in Examples 1 to 5 was determined with a HPLC column (trade name CHIRALCEL OD) manufactured by Daicel Industries, Ltd.
The optical purity was determined using the column by dissolving the obtained alcohol in hexane / 2-propanol at a volume ratio of 9/1 and using an RI detector with the same solvent as the eluent. The results are shown in Table 2.

[0036]

[Table 2]

Comparative Example 1 1-pentyne-3-ol 2.53 g (30 mmol)
, 2.1 g (30 mmol) of valeric acid was dissolved in 300 ml of water-saturated hexane, and lipase AY30 (Amano Pharmaceutical Co., Ltd.) 4
g, and the mixture was stirred at 30 ° C. for 100 hours at 200 rpm, and when the residual 1-pentyne-3-ol in the reaction solution was reduced to 50% at the start of the reaction, the same procedure as in Example 1 was performed. (R) -alcohol and (S) -remaining in the reaction solution
The ester was separated and purified.

Comparative Example 2 The same procedure as in Comparative Example 1 was repeated except that 1-hexyne-3-ol (2.94 g, 30 mmol) was used as the acetylene alcohol, and the mixture was stirred at 30 ° C. for 120 hours at 200 rpm. When the residual 1-hexyne-3-ol in the reaction solution was reduced to 50% at the start of the reaction, the (R) -alcohol and ((R) -alcohol and () remaining in the reaction solution were obtained in the same manner as in Example 2. The S) -ester was separated and purified.

Comparative Example 3 The same procedure as in Comparative Example 1 was repeated except that 1-heptin-3-ol (3.36 g, 30 mmol) was used as the acetylene alcohol, and the mixture was stirred at 30 ° C. for 220 hours at 200 rpm. The reaction was stopped when the residual 1-heptin-3-ol in the reaction solution decreased to 50% at the start of the reaction, 4% aqueous sodium bicarbonate solution was added to the filtrate, and the aqueous layer was removed. Unreacted valeric acid in the filtrate was removed, and then the hexane layer was distilled under reduced pressure to separate and purify (R) -alcohol and (S) -ester.

Comparative Example 4 The same procedure as in Comparative Example 1 was repeated except that 1.79 g (30 mmol) of 1-octyne-3-ol was used as the acetylene alcohol, and the stirring was carried out at 200 rpm at 30 ° C. for 150 hours. When the residual 1-octyne-3-ol in the reaction solution was reduced to 50% at the start of the reaction, (R) -alcohol and ((R) -alcohol and () remaining in the reaction solution were obtained in the same manner as in Comparative Example 3. The S) -ester was separated and purified.

Comparative Example 5 The same procedure as in Comparative Example 1 was repeated except that 5-methyl-1-hexyne-3-ol (3.36 g, 30 mmol) was used as the acetylene alcohol.
Stirring was carried out at 00 rpm, and the residual 5-methyl-
When 1-hexyne-3-ol was reduced to 50% at the start of the reaction, the (R) -alcohol and (S) -ester remaining in the reaction solution were separated in the same manner as in Comparative Example 3. Purified.

Comparative Example 6 The optical purity of each acetylene alcohol obtained in Comparative Examples 1 to 5 was determined in the same manner as in Example 6. The results are shown in Table 2.

[0043]

[Table 3]

Example 7 As in Example 1, except that Lipase PS (Amano Pharmaceutical Co., Ltd.) was used as the enzyme, at 30 ° C. for 5 hours at 200 rpm.
When the amount of 1-pentyne-3-ol in the reaction solution reached 50% of the start of the reaction, it was left in the reaction solution in the same manner as in Example 1 (R)-. The alcohol and the produced (S) -ester were separated and purified.

Example 8 Except that toluene was used as the solvent, stirring was carried out at 200 ° C. for 20 hours at 30 ° C. in the same manner as in Example 7, and the amount of 1-pentyn-3-ol in the reaction solution was changed. At 50% of the starting point, the (R) -alcohol remaining in the reaction solution and the produced (S) were obtained in the same manner as in Example 1.
-The ester was separated and purified.

Example 9 In the same manner as in Example 7, except that 2.94 g (30 mmol) of 1-hexyne-3-ol was used as the acetylene alcohol, stirring was carried out at 200 rpm for 24 hours at 30 ° C. When the amount of 1-hexyne-3-ol remaining in the reaction solution reached about 50% at the start of the reaction, (S) -alcohol remained in the reaction solution in the same manner as in Example 2. And (R) -ester were separated and purified.

Example 10 Stirring was carried out at 200 rpm for 24 hours at 30 ° C. in the same manner as in Example 7 except that 3.36 g (30 mmol) of 1-heptin-3-ol was used as the acetylene alcohol. When the amount of 1-heptin-3-ol remaining in the reaction solution reached about 50% of the start of the reaction, (S) -alcohol remained in the reaction solution in the same manner as in Example 3. And (R) -ester were separated and purified.

Example 11 The same procedure as in Example 7 was repeated except that 3.79 g (30 mmol) of 1-octyne-3-ol was used as the acetylene alcohol, and the mixture was stirred at 200 rpm for 20 hours at 30 ° C. When the amount of 1-octyne-3-ol remaining in the reaction solution reached about 50% at the start of the reaction, (S) -alcohol remained in the reaction solution in the same manner as in Example 4. And (R) -ester were separated and purified.

Example 12 The same procedure as in Example 7 was repeated except that 5-methyl-1-hexyne-3-ol (3.36 g, 30 mmol) was used as the acetylene alcohol at 20 ° C. for 20 hours.
The mixture was stirred at 0 rpm, and when 5-methyl-1-hexyne-3-ol in the reaction solution decreased to 50% at the start of the reaction, it remained in the reaction solution as in Example 5 (S). -Alcohol and (R) -ester were separated and purified.

Example 13 The optical purity of each acetylene alcohol obtained in Examples 7 to 12 was determined in the same manner as in Example 6. The results are shown in Table 3.

[0051]

[Table 3]

Comparative Example 7 The reaction liquid was stirred at 200 ° C. for 120 hours at 30 ° C. in the same manner as in Comparative Example 1 except that Lipase PS (Amano Pharmaceutical Co., Ltd.) was used as the enzyme and heptanoic acid was used as the fatty acid. When the residual 1-pentyn-3-ol in the reaction solution was reduced to 50% at the start of the reaction, the (R) -alcohol and (S) -ester remaining in the reaction solution were separated and purified in the same manner as in Example 1. did.

Comparative Example 8 The same procedure as in Comparative Example 7 was repeated except that 2.94 g (30 mmol) of 1-hexyne-3-ol was used as the acetylene alcohol, and the mixture was stirred at 200 ° C. for 220 hours at 30 ° C. When the residual 1-hexyn-3-ol of the above was reduced to 50% at the start of the reaction, the (S) -alcohol and (R) -ester remaining in the reaction solution were separated and purified in the same manner as in Example 2. ..

Comparative Example 9 The same procedure as in Comparative Example 7 was conducted except that 1-heptin-3-ol (3.36 g, 30 mmol) was used as the acetylene alcohol, and the mixture was stirred at 30 ° C. for 600 hours at 200 rpm to prepare a reaction solution. Of the residual 1-heptin-3-ol of 50% of the reaction start was stopped, the reaction was stopped by adding a 4% sodium bicarbonate aqueous solution to the filtrate, and removing the aqueous layer. Unreacted heptonic acid was removed, and then the hexane layer was distilled under reduced pressure to separate and purify (S) -alcohol and (R) -ester.

Comparative Example 10 The same procedure as in Comparative Example 1 was repeated except that 1.79 g (30 mmol) of 1-octyne-3-ol was used as the acetylene alcohol. When the amount of residual 1-octyne-3-ol was reduced to 50% at the start of the reaction, the (R) -alcohol and (S) -ester remaining in the reaction solution were separated and purified in the same manner as in Comparative Example 3. ..

Comparative Example 11 The optical purity of each acetylene alcohol obtained in Comparative Examples 7 to 10 was determined in the same manner as in Example 6. The results are shown in Table 5.

[0057]

[Table 5]

[0058]

INDUSTRIAL APPLICABILITY According to the present invention, an optically active acetylene alcohol useful as a medicine, a pesticide and a synthetic intermediate thereof can be efficiently produced from various racemic acetylene alcohols which can be obtained synthetically and inexpensively.

[Table 4]

Claims (5)

[Claims] 1. A general formula: (In the formula, R ¹ is a proton or a saturated linear hydrocarbon group having 1 to 12 carbon atoms, and R ² is a saturated linear hydrocarbon group having 1 to 12 carbon atoms or a saturated saturated hydrocarbon group having a branch. A hydrogen group, an unsaturated hydrocarbon group having 1 to 12 carbon atoms or an aromatic hydrocarbon group, provided that a racemic alcohol represented by R ¹ ≠ R ² ) and a general formula: (In the formula, R ³ is a saturated straight-chain hydrocarbon group having 1 to 12 carbon atoms, a branched saturated hydrocarbon group having 1 to 12 carbon atoms, or an unsaturated hydrocarbon group having 1 to 12 carbon atoms, or an aromatic group. A fatty acid vinyl ester represented by the formula (1), which is an aromatic hydrocarbon group, is mixed in an organic solvent to form a solution, and a lipolytic enzyme is added to the solution to perform asymmetric transesterification to give an optically active alcohol represented by the general formula. To produce a fatty acid ester of [Chemical 4] A method for producing an optically active alcohol, which comprises optically resolving the other optically active alcohol which has not been transesterified and is represented by the general formula. 2. The production method according to claim 1, wherein lipase is used as the lipolytic enzyme. 3. As racemic alcohol, 1-pentyn-3-ol, 1-hexyne-3-ol, 1-heptin-3-ol, 1-octin-3-ol or 5 is used.
The method according to claim 1, wherein any one selected from -methyl-1-hexyn-3-ol is used. 4. The method according to claim 1, wherein any one selected from vinyl laurate, vinyl caprate and vinyl caproate is used as the fatty acid vinyl ester. 5. The method according to claim 1, wherein one or more selected from hexane, isopropyl ether and toluene are used as the organic solvent.