JPH04349894A - Production of optically active alcohol - Google Patents

Abstract

PURPOSE:To effectively produce the subject compound useful as an intermediate for synthesizing drugs by subjecting racemic acetylene alcohol compounds and a fatty acid to an asymmetric esterification reaction in the presence of a lipase to selectively esterify one of the racemic compounds. CONSTITUTION:Racemic alcohol compounds of formula I (R<1> is proton, saturated straight chain hydrocarbon such methyl; R<2> is saturated straight chain hydrocarbon such as methyl, unsaturated hydrocarbon such as vinyl; but R<1>not equal to R<2>) and a fatty acid of formula: R<3>-COOH (R<3> is saturated straight chain hydrocarbon, aromatic hydrocarbon such as phenyl, etc.) are subjected to an asymmetric esterification reaction in the presence of a lipase in an organic solvent to produce an optically active alcohol fatty acid ester of formula II, followed by separating and recovering another optically active alcohol of formula III which has not been esterified in the above step from the optically active ester.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing optically active acetylene alcohol from racemic acetylene alcohol by an asymmetric esterification 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, medicines, agricultural chemicals, etc.).

0002

BACKGROUND OF THE INVENTION In recent years, optically active alcohols have attracted attention as synthetic intermediates for fine chemicals such as pharmaceuticals, agricultural chemicals, and liquid crystals. Optically active acetylene alcohol is a compound with particularly high utility value,
It is used in the synthesis of prostaglandins and antibacterial agents. As a method for producing acetylene alcohol, reduction of ketone using lithium aluminum halide modified with binaphthol (J. Am. Chem. Soc. 106
, 6717 (1984)) and a method of optical resolution by forming an inclusion compound with an alkaloid such as brucine (Tetrahedron Lett. 2).
2, 4669 (1981), Israel J.
Chem. , 25, 338 (1985)). Although these chemical production methods provide high optical purity, they all use expensive reagents and require extreme reaction conditions.

On the other hand, recently, various methods for producing optically active substances using enzymes have been proposed. This method is considered to be an industrially promising process because the reaction conditions are mild and relatively inexpensive crude enzymes can be used. However, there are almost no known examples of using enzymes to produce optically active acetylene alcohols having an acetylene group at an asymmetric carbon in the molecule.

0004

[Problems to be Solved by the Invention] In view of the above circumstances, the present invention has been made as a result of intensive studies on a method for producing optically active acetylene alcohol using an enzyme. When various lipolytic enzymes are allowed to act in an organic solvent, one of the racemic acetylene alcohols is selectively esterified by an asymmetric esterification reaction, thereby converting the racemic alcohol into an optically active ester and the other one. The present inventors have discovered that it is possible to separate these into optically active alcohols, leading to the completion of the present invention.

[0005]

[Means for Solving the Problems] That is, the present invention provides the general formula

[0006]

[C4]

(In the formula, R1 is a saturated straight-chain hydrocarbon group such as proton, methyl, ethyl, etc., and R2 is methyl,
Saturated linear hydrocarbon groups such as ethyl and propyl; branched saturated hydrocarbon groups such as isopropyl, isobutyl and isopentyl; unsaturated hydrocarbon groups such as vinyl, allyl and isopropenyl; and aromatic carbon groups such as phenyl and benzyl. Indicates a hydrogen group. However, racemic alcohol represented by R1 ≠ R2 ) and general formula R3 -COOH (2)
(In the formula, R3 is a saturated straight-chain hydrocarbon group such as methyl, ethyl, propyl, a branched saturated hydrocarbon group such as isopropyl, isobutyl, isopentyl, or an unsaturated hydrocarbon group such as vinyl, allyl, isopropenyl, etc.) Indicates aromatic hydrocarbon groups such as phenyl and benzyl.)
By adding a lipolytic enzyme or a bacterial cell containing a lipolytic enzyme to an organic solvent containing various fatty acids represented by the formula, the general formula

[0008]

[C5]

Fatty acid ester of optically active alcohol represented by

0010

[C6]

This is a method for producing an optically active ester and an optically active alcohol, which is characterized by separating and recovering the other optically active alcohol that has not been esterified. The present invention dissolves various racemic acetylene alcohols, which can be obtained at low cost through synthetic chemistry, and fatty acids, which can be obtained at low cost, in an organic solvent, and performs an asymmetric esterification reaction using a lipolytic enzyme to obtain one of the optically active molecules of the alcohol. This ester and the other optically active alcohol that has not been esterified are separated by column chromatography, fractional distillation, fractional extraction, etc.
This is a method for producing optically active acetylene alcohol to be recovered.

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

[0013]

[Chemical 7]

[0014]

[Chemical formula 8]

[0015]

[Chemical formula 9]

Furthermore, as the fatty acids used in the present invention, various straight chain fatty acids such as valeric acid, hexanoic acid, heptanoic acid, and octanoic acid, as well as fatty acids having side chains, can be used. It is desirable to select an appropriate one based on properties, reaction conditions, etc. The lipolytic enzyme used in the present invention is not particularly limited, but esterase is typically used. Lipase is usually used as the esterase, and depending on its origin and type, it is derived from Candida genus, Mucor genus, etc.
Genus, Rhizopus, Aspergillus, Arthrobacter (
Genus Arthrobacter, Pseudomonas (Ps
It may be of microbial origin, such as those of the genus Eudomonas, or of animal origin, such as pig pancreas, or of plant origin.

The asymmetric esterification reaction of the present invention can be carried out in various organic solvents, such as hexane, isopropyl ether, and toluene. The concentrations of acetylene alcohol and fatty acid in the reaction can be appropriately selected depending on the activity of the enzyme and other conditions, but are usually in the range of 0.01 to 0.5 mol each, preferably 0.05 to 0.2 mol. used. The amount of enzyme used can vary depending on its type and activity, but it is usually 1 to 1000 mg/ml, preferably 5 to 100 mg/ml.

The reaction temperature is not particularly limited as long as it is at the action temperature of the enzyme, but it is usually preferably 4°C to 50°C. The progress of the reaction can be monitored by gas chromatography analysis.

[0019]

[Examples] The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited by these Examples to the extent that it does not go beyond the gist of the invention. Example 1 1-pentyn-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 AY (Amano Pharmaceutical Co., Ltd.) 4
g was added thereto, and the mixture was stirred at 200 rpm for 100 hours at 30°C, and the reaction was terminated when the remaining 1-pentyn-3-ol in the reaction solution was reduced to 50% of the initial level. 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. To stop the reaction, the reaction solution was filtered through a membrane filter. This was done by filtering to remove the lipase. Next, the filtrate was extracted with ion-exchanged water, and this aqueous layer was further extracted with ether.
1-pentyn-3-ol was separated and purified by distilling the ether layer. By this operation, 1-pentyne-3
-ol 0.27 g (21% yield) and 1.84 g (yield 90%) of valeric acid ester of 1-pentyn-3-ol.
) was obtained.

Example 2 The same procedure as in Example 1 was carried out at 30° C. for 120 hours at 200 rpm, except that 2.94 g (30 mmol) of 1-hexyn-3-ol was used as the acetylene alcohol.
The 1-hexyne-3- remaining in the reaction solution was stirred with
When the amount of ol reaches 50% of the starting amount, the reaction is stopped in the same manner as in Example 1, and then the filtrate is extracted with water, the aqueous layer is extracted with ether, and the ether layer is distilled under reduced pressure. By this, 0.32 g of 1-hexyn-3-ol (
(Yield: 22%) and 2.07 g (Yield: 92%) of valerate ester of 1-hexyn-3-ol.

Example 3 Stirring was carried out at 200 rpm for 220 hours at 30° C. in the same manner as in Example 2 except that 3.36 g (30 mmol) of 1-heptyn-3-ol was used as the acetylene alcohol. The reaction was stopped when the amount of remaining 1-heptyn-3-ol reached 50% of the starting amount, and a 4% aqueous sodium bicarbonate solution was added to the filtrate to remove the aqueous layer. Unreacted valeric acid was removed, and then the hexane layer was distilled under reduced pressure to obtain 1-heptine-3.
-ol and ester were separated and purified. Result 1-
Heptyn-3-ol 0.78g (yield 46%), 1-
2.16 g (yield: 88%) of heptyn-3-ol valerate ester was obtained.

Example 4 The same procedure as in Example 2 was carried out except that 3.79 g (30 mmol) of 1-octyne-3-ol was used as the acetylene alcohol, at 30° C. for 150 hours at 200 rpm.
The 1-octyne-3- remaining in the reaction solution was stirred with
The reaction was stopped when the amount of ol reached 50% of the starting amount, and the remaining 1-octyn-3-ol and the produced ester were separated and produced in the same manner as in Example 2. As a result, 0.174 g (yield: 94%) of 1-octyn-3-ol and 2.3 g (yield: 87%) of valeric acid ester of 1-octyn-3-ol were obtained.

Example 5 The optical purity of the optically active acetylene alcohols obtained in Examples 1 to 4 was determined using an HPLC column manufactured by Daicel Industries, Ltd. (trade name: CHIRALCELOD) and 1H-NMR. Determination of optical purity using the column was performed by dissolving acetylene alcohol in hexane/2-propanol in a volume ratio of 9/1 and using hexane/2-propanol in a volume ratio of 9/1 as an eluent.
Analysis was performed with an I detector. The determination of optical purity by 1H-NMR was performed using CD of each acetylenic alcohol.
Dissolve in Cl3, perform 1H-NMR measurement, and determine the peak of H (methine) bonded to the asymmetric carbon. Then, the shift reagent {[Tris
3-(heptafluoropropylhydr
roxymethylene)-(+) campha
[rato] Praseodium (III) der
When the 1H-NMR measurement is performed again after adding the CDCl3 solution of ivative}, the peak of methine is shifted to the higher magnetic field side by the shift reagent and is divided into two parts corresponding to the quantitative ratio of its optical isomers. Therefore, its optical purity was determined from the intensity of the separated peaks. Table 1 shows the results.

Table 1 Example 6 The same procedure as in Example 1 was carried out at 30° C. for 120 hours at 200 rpm, except that Lipase PS (manufactured by Amano Pharmaceutical Co., Ltd.) was used as the enzyme and heptanoic acid was used as the fatty acid.
When the amount of 1-pentyn-3-ol in the reaction solution reaches 50% of the initial amount of the reaction, the alcohol remaining in the reaction solution and the generated ester are added in the same manner as in Example 1. was separated and purified.

Example 7 The same procedure as in Example 1 was carried out, except that 2.94 g (30 mmol) of 1-hexyn-3-ol was used as the acetylene alcohol, at 30° C. for 220 hours, at 200 rpm.
1-hexyne-3 remaining in the reaction solution was stirred at
When the amount of -ol reached 50% of the initial amount of the reaction, the alcohol remaining in the reaction solution and the produced ester were separated and purified in the same manner as in Example 2.

Example 8 The same procedure as in Example 6 was carried out, except that 3.36 g (30 mmol) of 1-heptyn-3-ol was used as the acetylene alcohol, at 30° C. for 600 hours, at 200 rpm.
1-heptine-3 remaining in the reaction solution was stirred at
When the amount of -ol reached 50% of the initial amount of the reaction, the alcohol remaining in the reaction solution and the produced ester were separated and purified in the same manner as in Example 3.

Example 9 The same procedure as in Example 6 was repeated except that 3.79 g (30 mmol) of 1-octyne-3-ol was used as the acetylene alcohol at 30° C. for 500 hours at 200 rpm.
The 1-octyne-3 remaining in the reaction solution was stirred at
When the amount of -ol reached 50% of the initial amount of the reaction, the alcohol remaining in the reaction solution and the produced ester were separated and purified in the same manner as in Example 4.

Example 10 The optical purity of each acetylene alcohol obtained in Examples 6 to 9 was determined in the same manner as in Example 5. The results are shown in Table 2. Table 2 Examples 11 to 14 Racemic acetylene alcohol as raw material: 1-pentyn-3-ol (Example 11), 1-hexyn-3-ol (Example 12), 1-heptyn-3-ol (Example 13) Using 1-octin-3-ol (Example 14) and 10 g of Lipase B-4 (Nagase Seikagaku Kogyo), synthesize an ester in the same manner as in Example 6, and each acetylene alcohol starts the reaction. When the alcohol content decreased to 50%, the remaining alcohol and the produced ester were separated and purified, and the optical purity of each acetylene alcohol obtained was determined in the same manner as in Example 5. The results are shown in Table 3.

Table 3 Example 15 5-methyl-1-hexyn-3-ol 3.4 g (3
0 mmol), 3.1 g (30 mmol) of valeric acid were dissolved in 300 ml of water-saturated hexane, 4 g of Lipase AY (Amano Pharmaceutical Co., Ltd.) was added thereto, and the mixture was heated at 30°C for 120 hours for 200 ml of water-saturated hexane.
Stirring was performed at rpm, and when 5-methyl-1-hexyn-3-ol in the reaction solution decreased to 50% of the initial level, a portion of the reaction solution was taken and added to an HPLC column manufactured by Daicel Corporation (CHIRACEL OD). ) gives 5-methyl-1-
The optical purity of hexyn-3-ol was determined. As a result, the optical purity of 5-methyl-1-hexyn-3-ol in the reaction solution was 19.4%.

Example 16 4-ethyl-1-hexyn-3-ol 3.8g (3
0 mmol), 3.1 g (30 mmol) of valeric acid were dissolved in 300 ml of water-saturated hexane, 4 g of Lipase AY (Amano Pharmaceutical Co., Ltd.) was added thereto, and the mixture was heated at 30°C for 120 hours for 200 ml of water-saturated hexane.
Stir at rpm, and when 4-ethyl-1-hexyn-3-ol in the reaction solution has decreased to 50% of the initial level, take a portion of the reaction solution, and add the reaction solution in the same manner as in Example 11. The optical purity of 4-ethyl-1-hexyn-3-ol was determined. As a result, the optical purity of 4-ethyl-1-hexyn-3-ol in the reaction solution was 31.2%.

[0031]

Effects of the Invention According to the present invention, optically active acetylene alcohols useful as pharmaceuticals, agricultural chemicals, and synthetic intermediates thereof can be efficiently produced from various racemic acetylene alcohols that can be obtained synthetically and at low cost.

Claims (1)

[Claims] Claim 1: General formula [Formula 1] (wherein, R1 is a saturated straight-chain hydrocarbon group such as proton, methyl, or ethyl, and R2 is a saturated straight-chain hydrocarbon group such as methyl, ethyl, or propyl, or , represents a branched saturated hydrocarbon group such as isopropyl, isobutyl, isopentyl, an unsaturated hydrocarbon group such as vinyl, allyl, isopropenyl, or an aromatic hydrocarbon group such as phenyl, benzyl.However, R1 ≠ R2) Racemic alcohol represented by the general formula R3 -COOH (2)
(In the formula, R3 is a saturated straight-chain hydrocarbon group such as methyl, ethyl, propyl, a branched saturated hydrocarbon group such as isopropyl, isobutyl, isopentyl, or an unsaturated hydrocarbon group such as vinyl, allyl, isopropenyl, etc.) Indicates aromatic hydrocarbon groups such as phenyl and benzyl.)
By adding a lipolytic enzyme to an organic solvent containing various fatty acids represented by the formula and asymmetric ester synthesis, a fatty acid ester of an optically active alcohol represented by the general formula [Chemical formula 2] and a fatty acid ester of the general formula [Chemical formula 3] are synthesized. ] A method for producing an optically active alcohol, which comprises separating and recovering the other optically active alcohol that has not been esterified.