JPH0570393A - Production of optically active alcohol - Google Patents

Abstract

PURPOSE:To efficiently produce the subject compound useful as a production intermediate, etc., by reacting a specified alcohol with a specified carboxylic acid ester and a specified carboxylic acid in a specified condition. CONSTITUTION:The objective compound of formula IV having the opposite configuration to the alcohol represented by formula I is obtained by reacting a mixture of an optically active alcohol represented by formula I (* is asymmetric carbon) and an optically active carboxylic acid ester expressed by formula II (R<1> is lower alkyl; ** is asymmetric carbon) and having the opposite configuration to that of the above-mentioned alcohol with a carboxylic acid represented by formula III (R<2> is H, lower alkyl or phenyl) in the presence of diethyl azodicarboxylate and triphenylphosphine or tributylphosphine and subsequently carrying out hydrolysis at a weakly acidic or basic condition.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an optically active alcohol. More specifically, it relates to a method for producing an optically active alcohol represented by the following formula (9).

[0002]

BACKGROUND OF THE INVENTION Alcohols represented by the following formula 9 are known as important alcohol components of ether compounds having excellent pest control activity. (JP-A-60-215671) It is also known that the pest control activity of this ether compound is several times better than the racemic or (R) -form of the (S) -form. .. Therefore, it is desired to develop a practical method for producing one of the optical isomers, which is an alcohol represented by the following chemical formula 9. Conventionally, there is a method of dividing by utilizing the asymmetric discrimination ability of a living body such as the asymmetric hydrolysis action of an enzyme.
-176592, this method involves the formation of an alcohol derivative having almost the same amount of alcohol as one of the optical isomers, and an alcohol derivative having a configuration opposite to that of the alcohol, resulting in efficient separation. It is not always sufficient from an industrial point of view due to the necessity of equipment.

[0003]

[Means for Solving the Problems] Under such circumstances,
The present inventors have conducted various studies on the production method of the optically active alcohol represented by the following general formula 9, wherein an optically active alcohol and a carboxylic acid ester of the alcohol having a configuration opposite to that of the alcohol are used. It was found that an alcohol having one steric configuration can be efficiently obtained by reacting the mixture of 1) with a specific reaction reagent and then hydrolyzing the mixture under specific conditions, and completed the present invention. That is, the present invention is represented by Formula 6

[Chemical 6] [In the formula, * represents an asymmetric carbon. ] And an optically active alcohol represented by the following general formula:

[Chemical 7] [In the formula, R ¹ represents a lower alkyl group, and ** represents an asymmetric carbon. ] And a mixture with an optically active carboxylic acid ester represented by the following general formula:

[Chemical 8] [In the formula, R ² represents a hydrogen atom, a lower alkyl group or a phenyl group. ] The carboxylic acid represented by the following, after reacting in the presence of diethyl azodicarboxylate and triphenylphosphine or tributylphosphine, followed by hydrolysis under mildly acidic conditions or basic conditions, Formula 9 having a configuration opposite to that of the alcohol represented by Formula 1

[Chemical 9] [In the formula, ** represents an asymmetric carbon. ] The manufacturing method of optically active alcohol shown by these is provided. Furthermore, the present invention provides the general formula

[Chemical 10] [In the formula, R ¹ represents a lower alkyl group. ] To an esterase produced by a microorganism or an animal pancreatic esterase on the racemic carboxylic acid ester represented by the following formula to asymmetrically hydrolyze the esterase and the optically active alcohol represented by the formula: A mixture with an optically active carboxylic acid ester represented by the general formula (7) having a steric configuration is introduced, and then the mixture and the carboxylic acid represented by the general formula (8) are combined with diethyl azodicarboxylate and triphenylphosphine. Alternatively, the reaction is carried out in the presence of tributylphosphine, followed by hydrolysis under mildly acidic conditions or basic conditions.
Also provided is a method for producing an optically active alcohol represented by the formula (9), which has a configuration opposite to that of the alcohol represented by the formula (6). Examples of the lower alkyl group for R ¹ in Chemical formulas 7 and 10 include a methyl group, an ethyl group, a propyl group, and a butyl group. Examples of the lower alkyl group for R ² in Chemical formula 8 include a methyl group, an ethyl group, a propyl group, and a butyl group. According to the present invention, the carboxylic acid ester of one of the optical isomers, which is a by-product in the optical resolution method using esterase, can be directly and efficiently converted into the alcohol represented by the formula 9 having the opposite configuration without separation. Therefore, the optically active alcohol represented by the formula 9 can be advantageously produced on an industrial scale. Hereinafter, the present invention will be described in detail.

In the present invention, a mixture of an optically active alcohol represented by the formula (6) and an optically active carboxylic acid ester represented by the general formula (7) and a carboxylic acid represented by the general formula (8) are mixed with diethyl azo. When reacting in the presence of dicarboxylate and triphenylphosphine or tributylphosphine, the reaction temperature is
It is usually in the range of -20 to 50 °. In the reaction,
Usually, chain ethers such as diethyl ether and ethylene glycol dimethyl ether, tetrahydrofuran,
Aliphatic ethers such as dioxane, lower aliphatic ketones such as acetone and methyl ethyl ketone, and organic solvents such as aprotic polar solvents such as dimethylformaldehyde and dimethylsulfoxide are used. With respect to the amount of the reagent used, the amount of the carboxylic acid represented by the general formula 9 used, diethyl azodicarboxylate, triphenylphosphine or tributylphosphine is not particularly limited, and the optical amount represented by the general formula 9 is used. It may be 1 mol or more for each mol of the active alcohol, but 1 to 2 mol of each is usually sufficient for the purpose. The reaction liquid after the reaction as described above may be concentrated if necessary, and the product after the reaction may be taken out by a usual means such as extraction with an organic solvent or distillation and used for the next hydrolysis. it can.

The hydrolysis reaction can be carried out under mildly acidic conditions or basic conditions. The reagents used are:
Examples of the weakly acidic conditions include mineral acids such as sulfuric acid and nitric acid, sulfonic acids and the like, and examples of the basic conditions include inorganic bases such as potassium carbonate, sodium hydroxide and ammonia, and organic bases such as sodium ethoxide. The reaction temperature range is usually 0 to 100 ° C. Further, in the hydrolysis reaction, the use of an organic solvent other than water is not essential, but if necessary, for example, tetrahydrofuran, alicyclic ethers such as dioxane, acetone, lower aliphatic ketones such as methyl ethyl ketone, dimethyl. An aprotic polar solvent such as formamide or dimethyl sulfoxide, a protic polar solvent such as methanol or ethanol, or an organic solvent that is mutually soluble in water can be used together. Also, an appropriate buffer can be used. After the reaction, the reaction solution is concentrated if necessary, and then the desired optically active alcohol represented by the formula 9 can be easily obtained by a usual means such as extraction with an organic solvent. If necessary, it can be further purified by silica gel chromatography or the like.

An esterase produced by a microorganism or an animal pancreatic esterase is allowed to act on the racemic carboxylic acid ester represented by the general formula (10), which is expressed by the optically active alcohol represented by the general formula (6) and the general formula (7). When asymmetrically hydrolyzing to a carboxylic acid ester, a microorganism that produces an esterase derived from a microorganism to be used is an esterase having the ability to asymmetrically hydrolyze a racemic carboxylic acid ester represented by the general formula (10). There is no particular limitation as long as it is a producing microorganism (here, esterase means esterase in a broad sense including lipase.) Specific examples of such microorganisms include Pseudomonas spp. Chromobacter
ium), Arthrobacter (genus Arthrobacter), Alcaligenes (genus Alcaligenes), Candida (Candida)
Genus, genus Achromobacter, genus Nocardia, flavobacterium
um), Tolulopsis, Brevibacterium, Bacillus
Examples thereof include microorganisms belonging to the genera Escherichia, Micrococcus, Hansenula, and Mucor. Representative strain names belonging to each of these genera are exemplified below, but the microorganisms used in the present invention are not limited to these examples. (1) Nocardia erythroporis IFO-12682 and Nocardia erythroporis IFO-12320 (2) Arthrobacter simplex IFO-12069 Arthrobacter simplex (3) Flavobacterium arboressens IFO-3750 Flavobacterium arborescens (4) Torulopsis candy IFO-0380 Torulopsis candida (5) Brevibacterium ammoniagenes (6) Bacillus licheniformis IFO-12197 Bacillus licheniformis (7) Baltis spherica IFO-3528 Bacillus sphaelicus (8) 3301 Escherichia coli (9) Hansenula saturnus IFO-0117 Hansenula saturnus (10) Micrococcus varians IFO-3765 Micrococcus varians (11) Chromobacterium viscosum ATCC-6918 Chromobacterium viscosum (12) Pseudomonas fu Luoressence IFO-3081 Pseudomonas fluorescens (13) Arthrobacter ureafaciens (14) Alcaligenes faecalis (15) Candida utilis (16) Bacter Species ATCC-21910 Achrombacter sp. (17) Mucor pusillus IFO-9856 Mucor pusillus All of these strains are American Type Culure Collect.
ion (ATCC) or the Fermentation Research Institute (IFO) of Osaka City, and can be obtained from these preservation organizations. In addition, some of these esterases originating from microorganisms are commercially available and can be easily obtained. Specific examples of commercially available esterases include Pseudomonas lipase (manufactured by Amano Pharmaceuticals), Mucor lipase (lipase M-AP (manufactured by Amano Pharmaceuticals)), and Candida cylindracese lipase (lipase MY).
(Manufactured by Meito Sangyo), lipase of alkaline genus (Lipase PL (manufactured by Meito Sangyo)), lipase of Achromobacter (lipase AL (manufactured by Meito Sangyo), lipase of Arthrobacter (lipase joint BSL ( Joint liquor refinement)),
Similarly, lipases of the genus Arthrobacter (manufactured by Shin Nippon Chemical Industry Co., Ltd.), lipases of the genus Chromobacterium (manufactured by Toyo Brewing Co.) and the like can be mentioned. The esterase derived from animal organs has an ability to asymmetrically hydrolyze racemic organic carboxylic acid ester represented by the general formula 10 (here, esterase means a broadly defined esterase including lipase). ), And is not particularly limited. Specific examples of such esterases include pancreatin derived from porcine pancreas and steapsin derived from piglet pancreas. In the esterase derived from microbial origin or animal organs as described above, when carried out on an industrial scale, it is preferable to use an esterase derived from microorganism because of its easy availability. Among them, Pseudomonas spp. In terms of asymmetric yield, Mucor, Chromobacterium, Escherichia
seherichia) genus, Arthrobacter genus,
The genus Alcaligenes, Bacillus
Esterases produced by microorganisms belonging to the genus Nocardia are preferred. Cultivation of the esterase-producing microorganism used is usually carried out by liquid culture according to a conventional method to obtain a culture solution. For example, sterilized liquid medium [malt extract for yeasts and yeasts, yeast extract medium (peptone 5.0 g, soluble starch 10.0 g per liter of water)
g, malt extract 3.0 g, and yeast extract 3.0 g to adjust the pH to 6.2), and a sterilized liquid medium for actinomycetes (1 g water, soluble starch 10.0 g, NZ amine (type A) 2 0.0g, meat extract 1.0g and yeast extract
Dissolve 1.0 g to pH 7.2), sterilized liquid medium for bacteria (1 g water, dissolve soluble starch 10.0 g, peptone 5.0 g and yeast extract 5.0 g to pH 6.8) )] Is inoculated with a microorganism, and usually reciprocal or rotary shaking culture is performed at 20 to 40 ° C. for 1 to 3 days. Moreover, you may perform solid culture as needed. Furthermore, in such culture,
The amount of enzyme produced can also be improved by adding natural oils and fats such as olive oil and soybean oil, and nonionic surfactants such as polyoxyethylene sorbitan monooleate as inducers to the medium.

The asymmetric hydrolysis in this step is carried out by a culture solution in which the above microorganism is cultivated, cells separated from the culture solution, a culture filtrate containing esterase, or crude cells separated from the cells or the culture filtrate by various enzyme separation methods. It is carried out by mixing an esterase, a purified esterase and an esterase-containing extract or concentrated solution, or an aqueous solution containing an animal organ-derived esterase with an organic carboxylic acid ester represented by the general formula 10 and stirring or shaking. Also, immobilized cells or immobilized esterase can be used. As a condition for carrying out asymmetric hydrolysis, a reaction temperature of 10 to 70 ° C. is suitable, and a thermostable esterase obtained by culturing a thermophilic bacterium or a thermophilic bacterium cultivates 50 to 65 ° C. 20 to 50 ° C. is preferable for a culture solution or an esterase having no heat resistance. The reaction time is usually 3 to 70 hours, but the reaction time can be shortened by increasing the reaction temperature or increasing the amount of enzyme. The pH during the reaction is preferably 8 to 11 for the culture solution of an alkaliphilic bacterium or alkaline esterase, and 5 to 8 for a culture solution of a non-alkalophilic microorganism or an esterase having no alkali tolerance. Further, it is preferable to use a buffer solution to neutralize the organic carboxylic acid generated by hydrolysis and keep the pH constant during the reaction, or to drop an aqueous alkaline solution with the progress of the reaction. Examples of the buffer solution include buffer solutions of inorganic acid salts such as sodium phosphate and potassium phosphate, and buffer solutions of organic acid salts such as sodium acetate and sodium citrate. General formula that is a substrate
The use concentration of the organic carboxylic acid ester represented by Chemical formula 10 is 0.5 to 80% by weight with respect to the reaction solution, and 10 to 50% by weight is suitable for industrial implementation. The general formula 10
The carboxylic acid ester represented by is a conventional method for producing an ester, for example, a method of reacting 1- (4-phenoxyphenoxy) propan-2-ol with an anhydride of an organic carboxylic acid or an organic carboxylic acid chloride in the presence of an organic base. It can be easily produced by reacting with.

[0008]

The present invention will be described in more detail with reference to the following examples, but the present description is not limited thereto. In the following examples, 1- (4-phenoxyphenoxy)
The optical isomer ratio of propan-2-ol was measured by high performance liquid chromatography (column: Sumipax OA-1000) using an optically active column after reacting with 3,5-dinitrophenyl isocyanate to give a carbamate derivative. It is a value. Example 1 (I) 3N was added to 180 g of a 0.2 M potassium phosphate aqueous solution.
An aqueous solution of sodium hydroxide was added to adjust a pH 6.5 buffer solution. To this buffer, 0.60 g of Pseudomonas esterase (Amano P) was added, and then racemic 1- (4-
Phenoxyphenoxy) propan-2-yl acetate (20.0 g) was added, and the pH was adjusted with 3N aqueous sodium hydroxide solution.
The mixture was vigorously stirred at 40 ° C. for 24 hours while controlling at 6.5 ± 0.2. Then, the reaction solution was extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated,
(R) -1- (4-phenoxyphenoxy) propane-
18.2 g of a mixture of 2-ol and (S) -1- (4-phenoxyphenoxy) propan-2-yl acetate (contents of 50.6% and 49.4% respectively) were obtained. A part of the above mixture was separated by silica gel column chromatography to obtain (R) -1- (4-phenoxyphenoxy) propan-2-ol and (S) -1- (4-
Phenoxyphenoxy) propan-2-ol and (S)
The result of the optical isomer ratio analysis of -1- (4-phenoxyphenoxy) propan-2-yl acetate was as follows: 1- (4-phenoxyphenoxy) propan-2-ol (R) -form / (S) -form Body = 98.7: 1.3 1- (4-phenoxyphenoxy) propan-2-yl acetate (after hydrolysis, analyzed as alcohol) (R) -body / (S) -body = 0.7: 99.3. (II) Dissolve 2.66 g of the mixture obtained in (I) and 2.63 g of triphenylphosphine in 20 ml of diethyl ether, then add 1.76 g of diethyl azodicarboxylate and acetic acid.
A solution of 0.63 g dissolved in 10 ml of diethyl ether
It was added dropwise at 25 ° C over 15 minutes. After stirring at the same temperature for 8 hours, the mixture was concentrated. The resulting product was stirred as 30 g of an aqueous solution of 5% potassium carbonate in 80% methanol at 25 ° C. for 21 hours. The reaction solution was neutralized with 5% hydrochloric acid, concentrated to about half volume, and then extracted with diethyl ether. The diethyl ether layer was dried over anhydrous sodium sulfate, concentrated, and then subjected to crude column chromatography packed with silica gel in order to remove triphenylphosphine oxide and diethyl hydrazine dicarboxylate, and then (S)-
1- (4-phenoxyphenoxy) propan-2-ol 2.37 g (yield; 96.9%, [α] _D ²⁵ ; + 17.1 ° (c
= 2.38, chloroform)) was obtained. The product was characterized by racemic 1 in the characteristics of retention time by IR, NMR spectrum and gas chromatography, except for the optical property.
Consistent with-(4-phenoxyphenoxy) propan-2-ol. The optical isomer ratio analysis of the obtained 1- (4-phenoxyphenoxy) propan-2-ol was (R) -form / (S) -form = 2.7: 97.3.

[0009]

Industrial Applicability According to the method of the present invention, only the alcohol represented by the formula 9 having one steric configuration can be efficiently obtained, and the alcohol can be advantageously produced even on an industrial scale.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location C12P 41/00 F 8828-4B // A01N 31/16 8930-4H C07B 55/00 B 7419-4H 61/00 300

Claims (2)

[Claims] 1. Formula 1 [In the formula, * represents an asymmetric carbon. ] And an optically active alcohol represented by the following general formula: [In the formula, R ¹ represents a lower alkyl group, and ** represents an asymmetric carbon. ] And a mixture with an optically active carboxylic acid ester represented by the following general formula: [In the formula, R ² represents a hydrogen atom, a lower alkyl group or a phenyl group. ] The carboxylic acid represented by the following, after reacting in the presence of diethyl azodicarboxylate and triphenylphosphine or tributylphosphine, followed by hydrolysis under mildly acidic conditions or basic conditions, A compound having a configuration opposite to that of the alcohol represented by the formula: [In the formula, ** represents an asymmetric carbon. ] The manufacturing method of optically active alcohol shown by these. 2. Formula 5: [In the formula, R ¹ represents a lower alkyl group. ] The racemic carboxylic acid ester represented by the formula [1] is allowed to react with an esterase produced by a microorganism or an animal pancreatic esterase to asymmetrically hydrolyze the esterase and the optically active alcohol represented by the formula 1 according to claim 1; The compound is led to a mixture with the optically active carboxylic acid ester represented by the general formula (2) having a configuration opposite to that of the alcohol, and then the mixture and the compound represented by the general formula (3) according to the first claim. It is characterized in that it is reacted with a carboxylic acid to be reacted in the presence of diethyl azodicarboxylate and triphenylphosphine or tributylphosphine, and then hydrolyzed under mildly acidic conditions or basic conditions. The method for producing an optically active alcohol represented by the general formula (4) according to claim 1, which has a configuration opposite to that of the alcohol represented by the general formula (1) according to claim 1.