JP3988528B2 - Process for producing optically active 5-hydroxy-3-ketoester - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an optically active 5-hydroxy-3-containing 1,3-bis- (trimethylsiloxy) -1-alkoxy-but-1,3-diene, which is useful as an intermediate for producing pharmaceuticals and agricultural chemicals. The present invention relates to a method for producing a ketoester.
[0002]
[Prior art]
A method for producing an optically active 5-hydroxy-3-ketoester by asymmetric aldol reaction between 1,3-bis- (trimethylsiloxy) -1-methoxy-buta-1,3-diene and an aldehyde is disclosed in A. Soriente et al. (Tetrahedron: Asymmetry, 11, 255-2258 (2000), Tetrahedron: Asymmetry, 12, 959-963 (2001)).
[0003]
According to this method, in the presence of a complex formed from chiral 1,1′-bi-2-naphthol (hereinafter referred to as “BINOL”) and a tetravalent titanium compound, and molecular sieves, 1 , 3-bis- (trimethylsiloxy) -1-methoxy-buta-1,3-diene can be reacted to produce an optically active 5-hydroxy-3-ketoester.
[0004]
However, this method has a problem that the yield of 5-hydroxy-3-ketoester produced varies greatly depending on the chiral BINOL or aldehyde used in the reaction, or due to subtle differences in conditions. ing. For example, 1,3-bis- (trimethylsiloxy) -1-methoxy-buta-1,3-diene and cinnamaldehyde are reacted in the presence of (R)-(+)-BINOL to yield 92 % Yields 5-hydroxy-3-ketoesters, whereas yields are reduced to 68% when reacted in the presence of (S)-(−)-BINOL. .
[0005]
In addition, when forming a complex from chiral BINOL and a tetravalent titanium compound, it is carried out at an extremely low reaction temperature of −78 ° C. When industrialized as it is, the complexity of operation, capital investment, etc. There is a problem in practicality in terms of cost.
[0006]
[Problems to be solved by the invention]
The present invention provides a method for producing an optically active 5-hydroxy-3-ketoester with high yield and high purity.
[0007]
[Means for Solving the Problems]
In light of the above problems, the present inventors have conducted extensive studies on a method for producing optically active 5-hydroxy-3-ketoesters. As a result, when this asymmetric aldol reaction is carried out in the presence of a lithium compound, a high yield and a high yield can be obtained. Knowing that optically active 5-hydroxy-3-ketoesters can be obtained with purity, the present invention has been completed.
[0008]
That is, the gist of the present invention is to provide a 1,3-diene compound represented by the general formula (1) in a reaction medium containing a chiral 1,1'-bi-2-naphthol compound and a tetravalent titanium compound.
[0009]
[Chemical formula 5]
[0010]
(Wherein R¹And R²Each independently represents an alkyl or aryl group having 1 to 10 carbon atoms,
R^ThreeRepresents an optionally substituted alkyl group or an optionally substituted aryl group;
R^FourRepresents a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group. )
Aldehyde represented by general formula (2)
[0011]
[Chemical 6]
(Wherein R^FiveRepresents an optionally substituted hydrocarbon group or heterocyclic group, and n represents an integer of 0 or 1. )
And an optically active 5-hydroxy-3-ketoester represented by the general formula (3)
[0012]
[Chemical 7]
[0013]
(Wherein R^Three, R^Four, R^FiveAnd n are as defined above. )
In the method for producing a lithium compound in a reaction medium.
[0014]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
(1,3-diene compound represented by the general formula (1))
In the 1,3-diene compound represented by the general formula (1), R¹And R²Each independently represents an alkyl group having 1 to 10 carbon atoms or an aryl group.
[0015]
Examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group, nonyl group, decyl group, cyclohexyl group and the like. And a linear or branched alkyl group having 1 to 10 carbon atoms, preferably a linear alkyl group, particularly preferably a linear or branched alkyl group having 1 to 4 carbon atoms. is there.
[0016]
As said aryl group, a phenyl group or a naphthyl group is mentioned, Among these, Preferably it is a phenyl group.
Where 3 R¹And R²May be the same or different from each other.
SiR in general formula (1)¹ _ThreeGroup and SiR² _ThreePreferable specific examples of the group include a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a triphenylsilyl group, a diphenylmethylsilyl group, and a dimethylphenylsilyl group, and a trimethylsilyl group is particularly preferable.
[0017]
R^ThreeRepresents an optionally substituted alkyl group or an optionally substituted aryl group.
Examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group, nonyl group, decyl group, cyclohexyl group and the like. The chain or cyclic alkyl group of these is mentioned, Among these, Preferably it is a C1-C10 thing.
[0018]
Examples of the aryl group include a phenyl group and a naphthyl group.
The substituent for the alkyl group and aryl group is not particularly limited as long as it does not adversely affect the reaction. For example, halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; methyl group, ethyl group Alkyl groups such as propyl group and butyl group; alkoxy groups such as methoxy group, ethoxy group, propoxy group and butoxy group; aryl groups such as phenyl group, halophenyl group, alkyl-substituted phenyl group and alkoxy-substituted phenyl group .
[0019]
R above^ThreePreferred is an alkyl group having 1 to 6 carbon atoms, a benzyl group or a phenyl group, more preferred is a methyl group, an ethyl group or a benzyl group, and particularly preferred is a methyl group or an ethyl group.
R^FourRepresents a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group.
[0020]
Examples of the optionally substituted alkyl group and the optionally substituted aryl group include the above R^ThreeThe thing similar to what was described as description of this is mentioned.
R above^FourOf these, a hydrogen atom or an alkyl group having 1 to 6 carbon atoms is preferable, a hydrogen atom, a methyl group or an ethyl group is more preferable, and a hydrogen atom is particularly preferable.
Preferred examples of the 1,3-diene compound include those obtained by combining the preferred ranges of the above-mentioned substituents. Among these, R¹And R²Are all methyl or ethyl, R^ThreeIs a methyl group or an ethyl group, R^FourAre more preferred, particularly R¹, R²And R^ThreeAre all methyl groups, R^FourA compound in which is a hydrogen atom is preferred.
[0021]
(Aldehyde represented by general formula (2))
In the aldehyde represented by the general formula (2), R^FiveRepresents an optionally substituted hydrocarbon group or heterocyclic group, and n represents an integer of 0 or 1.
The hydrocarbon group may be either a chain or a ring, and examples of the chain hydrocarbon group include a methyl group, an ethyl group, a vinyl group, an ethynyl group, a propyl group, an isopropyl group, and a propenyl group. Allyl group, isopropenyl group, propynyl group, butyl group, t-butyl group, s-butyl group, isobutyl group, butenyl group, butadienyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group or decyl group Examples of the cyclic hydrocarbon group include a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a cycloheptyl group, a phenyl group, and a naphthyl group which may be wholly or partially hydrogenated.
[0022]
The hydrocarbon group preferably has 1 to 20 carbon atoms.
The heterocyclic group may be either saturated or unsaturated, for example, furyl group, pyrrolyl group, pyrrolidinyl group, pyrrolinyl group, imidazolyl group, imidazolidinyl group, imidazolyl group, thienyl group, pyranyl group, pyridyl group. , A benzofuranyl group, an indolyl group, a chromenyl group, an isochromenyl group, a quinolyl group, an isoquinolyl group, or the like, which has 1 to 3 heteroatoms and about 4 to 13 carbon atoms.
[0023]
The substituent that these hydrocarbon group or heterocyclic group may have is not particularly limited as long as it does not adversely affect the present reaction. For example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom Halogen atoms such as methyl group, alkyl groups such as ethyl group, propyl group and butyl group; alkoxy groups such as methoxy group, ethoxy group, propoxy group and butoxy group; alkoxycarbonyl groups such as methoxycarbonyl group and ethoxycarbonyl group; Aryloxy groups such as phenoxy group, methylphenoxy group and naphthyloxy group; aryloxycarbonyl groups such as phenoxycarbonyl group; N-alkylcarbamoyl groups such as N-methylcarbamoyl group; N-aryls such as N-phenylcarbamoyl group Rucarbamoyl group; acyloxy group such as acetoxy group and benzoyloxy group Group; or substituted with a substituent selected from the above-mentioned halogen atom, alkyl group, alkoxy group, alkoxycarbonyl group, aryloxy group, aryloxycarbonyl group, N-alkylcarbamoyl group, N-arylcarbamoyl group and acyloxy group And a phenyl group which may be present.
[0024]
As the aldehyde, those having a molecular weight of 1000 or less, preferably 750 or less are usually used.
In the reaction of the aldehyde with the 1,3-diene compound, it is usually used in a theoretical amount or more, for example, 0.8 times mole or more, preferably 1 time mole or more. However, since excessive use of aldehyde is not preferable in terms of economy, it is usually used in a range of 4 times mol or less, preferably 2.5 times mol or less.
[0025]
(Chiral BINOL compound)
As the chiral BINOL compound, any compound that can be used in the asymmetric aldol reaction can be used. Specific examples include compounds represented by the following general formula (4).
[0026]
[Chemical 8]
[0027]
R⁶, R⁷, R⁸And R⁹Each independently represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an alkenyl group, a nitro group, a cyano group or a phenyl group which may have a substituent.
Examples of the substituent that the phenyl group may have include a halogen atom, a lower alkyl group, and a lower alkoxy group.
[0028]
As a chiral BINOL compound, in view of the cost and the effect on the reaction, R⁶, R⁷, R⁸And R⁹It is sufficient that all of these are hydrogen atoms.
The chiral BINOL compound is preferably used in an amount of 0.1 to 50 mol% with respect to the aldehyde. If it is less than 0.1 mol%, both yield and optical purity are lowered. Moreover, even if it exceeds 50 mol%, the yield and optical purity are not affected. However, since a chiral BINOL compound is expensive, it is not economically practical.
[0029]
(Tetravalent titanium compound)
As the tetravalent titanium compound, any compound that can be used in the asymmetric aldol reaction together with the chiral BINOL compound can be used. Specific examples include titanium tetrachloride, dichlorodialkoxytitanium, dibromodialkoxytitanium, and tetraalkoxytitanium. Among these, tetraalkoxy titanium, particularly tetraalkoxy titanium having an alkoxy group having 1 to 10 carbon atoms is preferable. The alkoxy group is more preferably a lower alkoxy group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, or a t-butoxy group, and is particularly preferable as a tetravalent titanium compound. Is titanium tetraisopropoxide.
[0030]
The tetravalent titanium compound is preferably used in an equimolar amount with respect to the BINOL compound, that is, 0.1 to 50 mol% with respect to the aldehyde.
(Lithium compound)
This production method comprises a 1,3-diene compound represented by the general formula (1) and a general formula (1) in a reaction medium containing a chiral 1,1′-bi-2-naphthol compound and a tetravalent titanium compound. In reacting the aldehyde represented by 2), a lithium compound is contained in the reaction medium.
[0031]
Examples of lithium compounds include metal lithium; lithium fluoride, lithium chloride, lithium bromide, lithium iodide, lithium t-butoxide, lithium carbonate, lithium nitrate, lithium sulfate, lithium phosphate, lithium tetraborate, lithium tetrafluoroborate. Lithium salts such as lithium acetate, lithium oxalate and lithium trifluoromethanesulfonate; and organic lithiums such as methyl lithium, butyl lithium and phenyl lithium, among which lithium salts are preferred, lithium alkoxides or halogens being more preferred Lithium chloride, more preferably lithium chloride or lithium t-butoxide, and particularly preferably lithium chloride.
[0032]
The lithium compound is usually used in an amount of 0.01 mol% or more, preferably 0.1 mol% or more, more preferably 1 mol% or more, and particularly preferably 2 mol% or more with respect to the aldehyde. In addition, it is sufficient that the lithium compound is added to some extent, and even if it is used in excess, there are problems in terms of cost and removal of the lithium compound after the reaction. Hereinafter, it is particularly preferably used in the range of 50 mol% or less.
[0033]
(Reaction form)
When the 1,3-diene compound represented by the general formula (1) and the aldehyde represented by the general formula (2) are reacted by the production method according to the present invention, a chiral BINOL compound is previously contained in the reaction medium. It is preferable to add a tetravalent titanium compound to form a catalyst. Usually, a chiral BINOL compound and a tetravalent titanium compound are added to a reaction medium in an atmosphere of an inert gas such as nitrogen or argon, and then a 1,3-diene compound and an aldehyde are added thereto and reacted.
[0034]
The lithium compound is usually added to the reaction medium before the addition of the 1,3-diene compound or aldehyde, or is added to the reaction medium at the same time as or after the addition of these raw materials. Among these, it is preferable to add to the reaction medium before the addition of the 1,3-diene compound or aldehyde, or to add them simultaneously with the addition of these raw materials.
As the reaction medium, any one used in the asymmetric aldol reaction can be used. For example, aliphatic hydrocarbons such as hexane, heptane and octane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran (hereinafter referred to as “THF”), diisopropyl ether and dimethoxyethane; dichloromethane, chloroform and the like And nitrile compounds such as acetonitrile and propionitrile. Of these, ethers such as THF are preferred.
[0035]
The amount of solvent used is generally affected by whether the substrate is crystalline or highly viscous, so it can be set arbitrarily according to the type of substrate, and even part of it can be dissolved. Although it does not matter as long as it is within the range, it is usually 1% by weight or more, preferably 3% by weight or more, and 80% by weight as the substrate concentration of the aldehyde from the viewpoint of the effect of stirring efficiency or the effect of the pot efficiency. % Or less, preferably 50% by weight or less, particularly preferably 20% by weight or less.
[0036]
The reaction can be carried out at any temperature from −78 ° C. to the boiling point of the reaction medium, but is usually −40 ° C. or higher, preferably 0 ° C. or higher, more preferably 5 ° C. or higher, from the reaction operation and industrial viewpoint. Particularly preferably, it is performed at 10 ° C. or higher.
(Hydroxyl-containing compound)
In this reaction, it is more preferable in terms of reaction rate and optical purity to contain a specific amount of a compound containing a hydroxyl group in the reaction medium in addition to BINOL.
[0037]
Examples of the compound having a hydroxyl group include water; chain or cyclic alcohols such as methanol, trifluoromethyl alcohol, ethanol, propanol and benzyl alcohol; or phenols such as phenol and naphthol which may have a substituent. It is done.
The alcohols preferably have 1 to 10 carbon atoms, and the phenols preferably have 1 to 20 carbon atoms.
[0038]
Examples of the substituent for phenols include a halogen atom, an alkyl group, an alkoxy group, an alkenyl group, a nitro group, and a cyano group.
The compound having a hydroxyl group may be used alone or a mixture of those selected from the above group.
The compound having a hydroxyl group is preferably water or phenols, and particularly preferably water.
[0039]
The compound having a hydroxyl group is used in an amount of 0.5 equivalents or more, preferably 0.7 equivalents or more, particularly preferably 1 equivalent or more with respect to the chiral BINOL compound in terms of the amount of hydroxyl groups. However, if there are too many compounds having a hydroxyl group, the complex catalyst formed by the tetravalent titanium compound and the chiral 1,1′-bi-2-naphthol compound will be deactivated. , Preferably 5 equivalents or less, particularly preferably 2 equivalents or less.
[0040]
The compound containing a hydroxyl group may be added to a reaction medium containing a chiral BINOL compound and a tetravalent titanium compound, but a reaction medium containing a hydroxyl group-containing compound in advance may be used. In particular, when the compound having a hydroxyl group is water, a water-containing solvent such as water-containing THF may be used as it is if the water content is appropriate.
[0041]
In order to adjust the amount of the compound having a hydroxyl group in the reaction medium, a substance having an adsorption or dehydration action may be added to the system.
Examples of the substance having an adsorption or dehydrating action include zeolite, activated carbon, silica gel, activated alumina, anhydrous sodium sulfate, anhydrous magnesium sulfate, and anhydrous calcium chloride. Among these, a substance selected from the group consisting of zeolite, silica gel, anhydrous sodium sulfate, anhydrous magnesium sulfate and anhydrous calcium chloride is preferable, and synthetic zeolites such as those commercially available as molecular sieves 3A, 4A, 5A, 13X and the like are particularly preferable. preferable. Among them, it is preferable to use powdery molecular sieves, particularly molecular sieves 4A type powdery molecular sieves. These synthetic zeolites are preferably used after being calcined at 250 degrees or more for 12 hours or more.
[0042]
As a reaction form, a chiral BINOL compound and a tetravalent titanium compound may be added to a reaction medium in which the amount of a compound having a hydroxyl group is adjusted in advance, or after adding a chiral BINOL compound to the reaction medium, a tetravalent titanium is added. The amount of the compound having a hydroxyl group in the reaction medium may be adjusted after adding the chiral BINOL compound and the tetravalent titanium compound to the reaction medium. A method of adding a chiral BINOL compound and a tetravalent titanium compound to a reaction medium in which the amount of the compound having a hydroxyl group is adjusted in advance, or after adding a chiral BINOL compound and a tetravalent titanium compound to a reaction medium containing almost no hydroxyl group compound And a method of adding a predetermined amount of a compound having a hydroxyl group to the reaction medium.
[0043]
After completion of the reaction, an aqueous catalyst solution is deactivated by adding and stirring an acidic aqueous solution such as trifluoroacetic acid to the cooled reaction solution as necessary, and then an alkaline aqueous layer such as a saturated aqueous sodium hydrogen carbonate solution. The target product can be obtained by extracting the target product using ethyl acetate and an organic solvent such as ethyl acetate, and then performing ordinary purification operations such as column chromatography and crystallization.
[0044]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to a following example, unless the summary is exceeded.
The product structure is¹Confirmed by 1 H-NMR. The optical purity was calculated as enantiomeric excess (% ee) by high performance liquid chromatography (HPLC) analysis using a column for optical isomer separation. The HPLC conditions for optical purity test are described below.
Column; Chiralpak AD (manufactured by Daicel Chemical Industries, Ltd.)
Eluent: n-hexane / ethanol / diethylamine = 90/10 / 0.1%
Flow rate: 1.0 mL / min
Detection wavelength: 254 nm
[0045]
[Expression 1]
In the reaction, a sufficiently dried reagent and solvent were used in advance.
[0046]
Example 1
(S)-(−)-BINOL 143 mg (0.5 mmol), titanium tetraisopropoxide 142 mg (0.5 mmol), and THF 12 mL were charged into a glass flask having an internal volume of 200 mL, and stirred at room temperature for 15 minutes. Next, 2.0 g of molecular sieves (4A, powder, manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred at room temperature for 1 hour. To this solution was added a solution of 660 mg (5 mmol) of cinnamaldehyde in THF (5 mL), and the mixture was stirred at room temperature for 1 hour, and 2.74 g of 1,3-bis- (trimethylsiloxy) -1-ethoxy-but-1,3-diene. A solution of (10 mmol) in THF (5 mL) and 21 mg (0.5 mmol) of lithium chloride were sequentially added, and the mixture was stirred at room temperature for 5 hours. After cooling the reaction solution to 0 ° C., a solution of 3.5 g of trifluoroacetic acid in water (25 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through celite, and 100 mL of ethyl acetate was added to the filtrate. The aqueous layer was made alkaline with a saturated aqueous sodium hydrogen carbonate solution, and then separated to obtain an organic layer. The obtained ethyl acetate solution was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off ethyl acetate under reduced pressure was purified by column chromatography to obtain the corresponding optically active 5-hydroxy-3-ketoester. The yield was 99% and the optical purity was 99% ee.
[0047]
Example 2
(S)-(−)-BINOL 143 mg (0.5 mmol), titanium tetraisopropoxide 142 mg (0.5 mmol), and THF 12 mL were charged into a glass flask having an internal volume of 200 mL and stirred at room temperature for 15 minutes. Next, 2.0 g of molecular sieves (4A, powder, manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred at room temperature for 1 hour. To this solution was added a solution of 660 mg (5 mmol) of cinnamaldehyde in THF (5 mL), and the mixture was stirred at room temperature for 1 hour, and 2.74 g of 1,3-bis- (trimethylsiloxy) -1-ethoxy-but-1,3-diene. A solution of (10 mmol) in THF (5 mL) and 21 mg (0.5 mmol) of lithium chloride were sequentially added, and the mixture was stirred at room temperature for 5 hours. After the reaction solution was filtered through celite, THF was distilled off under reduced pressure. Toluene 3.6 mL, 36% hydrochloric acid 0.13 g and water 0.6 mL were added, and the mixture was stirred at room temperature for 1 hour. The precipitated white solid was taken out and dissolved in a mixed solution of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer obtained by liquid separation was washed with saturated brine and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by column chromatography to obtain the corresponding optically active 5-hydroxy-3-ketoester. The yield was 99% and the optical purity was 99% ee.
[0048]
Example 3
(S)-(−)-BINOL 143 mg (0.5 mmol), titanium tetraisopropoxide 142 mg (0.5 mmol), and THF 12 mL were charged into a glass flask having an internal volume of 200 mL and stirred at room temperature for 15 minutes. Next, 500 mg of molecular sieves (4A, powder, manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred at room temperature for 1 hour. To this solution was added a solution of 660 mg (5 mmol) of cinnamaldehyde in THF (5 mL), and the mixture was stirred at room temperature for 1 hour, and 2.74 g of 1,3-bis- (trimethylsiloxy) -1-ethoxy-but-1,3-diene. A solution of (10 mmol) in THF (5 mL) and 21 mg (0.5 mmol) of lithium chloride were sequentially added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was cooled to −78 ° C., 4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through celite, and 100 mL of ethyl acetate was added to the filtrate. The aqueous layer was made alkaline with a saturated aqueous sodium hydrogen carbonate solution, and then separated to obtain an organic layer. The obtained ethyl acetate solution was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off ethyl acetate under reduced pressure was purified by column chromatography to obtain the corresponding optically active 5-hydroxy-3-ketoester. The yield was 99% and the optical purity was 99% ee.
[0049]
Example 4
In Example 1, instead of 2.0 g of molecular sieves, 2.0 g of anhydrous magnesium sulfate (manufactured by Wako Pure Chemical Industries, Ltd.) was used, and the corresponding optically active 5-hydroxy-3-hydroxy was used in the same manner as in Example 1. Ketoester was obtained. The yield was 99% and the optical purity was 71% ee.
[0050]
Example 5
In Example 1, instead of 2.0 g of molecular sieves, 2.0 g of anhydrous sodium sulfate (manufactured by Wako Pure Chemical Industries) was used, and the corresponding optically active 5-hydroxy-3-hydroxy was used in the same manner as in Example 1. Ketoester was obtained. The yield was 99% and the optical purity was 73% ee.
[0051]
Example 6
In Example 1, the corresponding optically active 5-hydroxy-3-ketoester was obtained in the same manner as in Example 1, except that 500 mg of molecular sieves was used instead of 2.0 g of molecular sieves. The yield was 99% and the optical purity was 99% ee.
[0052]
Example 7
In Example 1, (R)-(+)-BINOL was used instead of (S)-(-)-BINOL, and 500 mg of molecular sieves was used instead of 2.0 g of molecular sieves. The corresponding optically active 5-hydroxy-3-ketoester was obtained. The yield was 99% and the optical purity was 99% ee.
[0053]
Example 8
In Example 1, the corresponding optically active 5-hydroxy-3-ketoester was obtained in the same manner as in Example 1 except that 531 mg (5 mmol) of benzaldehyde was used instead of 660 mg (5 mmol) of cinnamaldehyde. The yield was 99% and the optical purity was 99% ee.
[0054]
Example 9
Example 1 is the same as Example 1 except that 500 mg of molecular sieves is used instead of 2.0 g of molecular sieves, and 480 mg (5 mmol) of 3-furylaldehyde is used instead of 660 mg (5 mmol) of cinnamaldehyde. An optically active 5-hydroxy-3-keto ester was obtained. The yield was 99% and the optical purity was 99% ee.
[0055]
Example 10
500 ml of dehydrated THF (manufactured by Wako Pure Chemical Industries, Ltd.) containing 3 g of sodium benzophenone ketyl as a solvent was refluxed for 12 hours, and THF whose water content was confirmed to be <5 ppm by Karl Fischer moisture measurement was used.
In a glass flask with an internal volume of 100 mL, 143 mg (0.5 mmol) of (S)-(−)-BINOL, 142 mg (0.5 mmol) of titanium tetraisopropoxide and 12 mL of THF were charged and stirred at room temperature for 10 minutes. Next, 10 mg (0.55 mmol) of water was added and stirred at room temperature for 15 minutes. Further, 21 mg (0.5 mmol) of lithium chloride was added and stirred at room temperature for 15 minutes. To this solution was added a solution of 660 mg (5 mmol) of cinnamaldehyde in THF (5 mL), and the mixture was stirred at room temperature for 1 hour, and 2.74 g of 1,3-bis- (trimethylsiloxy) -1-ethoxy-but-1,3-diene ( 10 mmol) in THF (5 mL) was added and stirred at room temperature for 5 hours. After cooling the reaction solution to 0 ° C., a solution of 3 g of trifluoroacetic acid in water (25 mL) was added and stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added thereto to make the aqueous layer alkaline, and then liquid separation extraction was performed twice with 100 ml of ethyl acetate to obtain an organic layer. The obtained ethyl acetate solution was washed with saturated brine and dried over anhydrous sodium sulfate. Furthermore, the residue obtained by distilling off ethyl acetate under reduced pressure was purified by column chromatography to obtain the corresponding optically active 5-hydroxy-3-ketoester. The obtained product had a yield of 99% and an optical purity of 99% ee.
[0056]
Example 11
Addition of 21 mg (0.5 mmol) of lithium chloride after addition of 2.74 g (10 mmol) of 1,3-bis- (trimethylsiloxy) -1-ethoxy-buta-1,3-diene in THF (5 mL) The same operation as in Example 10 was performed. The obtained optically active 5-hydroxy-3-ketoester had a yield of 99% and an optical purity of 99% ee.
[0057]
Example 12
500 ml of dehydrated THF (manufactured by Wako Pure Chemical Industries, Ltd.) containing 3 g of sodium benzophenone ketyl as a solvent was refluxed for 12 hours, and THF whose water content was confirmed to be <5 ppm by Karl Fischer moisture measurement was used.
In a glass flask with an internal volume of 100 mL, 143 mg (0.5 mmol) of (S)-(−)-BINOL, 142 mg (0.5 mmol) of titanium tetraisopropoxide and 12 mL of THF were charged and stirred at room temperature for 10 minutes. Next, 10 mg (0.55 mmol) of water was added, and the mixture was stirred at room temperature for 15 minutes. Then, 500 mg of molecular sieves (4A, powder, manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was further stirred at room temperature for 15 minutes. Further, 21 mg (0.5 mmol) of lithium chloride was added and stirred at room temperature for 15 minutes. To this solution was added a solution of 660 mg (5 mmol) of cinnamaldehyde in THF (5 mL), and the mixture was stirred at room temperature for 10 minutes, and 2.74 g of 1,3-bis- (trimethylsiloxy) -1-ethoxy-but-1,3-diene ( 10 mmol) in THF (5 mL) was added and stirred at room temperature for 5 hours. After cooling the reaction solution to 0 ° C., a solution of 3.5 g of trifluoroacetic acid in water (25 mL) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added thereto to make the aqueous layer alkaline, and then liquid separation extraction was performed twice with 100 ml of ethyl acetate to obtain an organic layer. The obtained ethyl acetate solution was washed with saturated brine and dried over anhydrous sodium sulfate. Furthermore, the residue obtained by distilling off ethyl acetate under reduced pressure was purified by column chromatography to obtain the corresponding optically active 5-hydroxy-3-ketoester. The obtained product had a yield of 99% and an optical purity of 99% ee.
[0058]
Further, as Comparative Example 1, except that lithium chloride was not added, the results obtained when the corresponding optically active 5-hydroxy-3-ketoester was obtained in the same manner as in Example 12, The results when the corresponding optically active 5-hydroxy-3-ketoester was obtained in the same manner as in Example 12 except that lithium was not added are shown in the following table.
[0059]
From these results, it can be seen that the presence of the lithium compound improves the optical purity of the product.
[0060]
[Table 1]
[0061]
Example 13
After carrying out the reaction in the same manner as in Example 10, THF was distilled off from this reaction solution under reduced pressure, 3.6 ml of toluene, 0.13 g of 36% hydrochloric acid and 0.6 ml of water were added to the residue, Stir for hours. The precipitated white solid was taken out and dissolved in a mixed solution of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer obtained by liquid separation was washed with saturated brine and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by column chromatography to obtain the corresponding optically active 5-hydroxy-3-ketoester. The obtained product had a yield of 99% and an optical purity of 99% ee.
[0062]
Example 14
500 ml of dehydrated THF (manufactured by Wako Pure Chemical Industries, Ltd.) containing 3 g of sodium benzophenone ketyl as a solvent was refluxed for 12 hours, and THF whose water content was confirmed to be <5 ppm by Karl Fischer moisture measurement was used.
After adding 21 mg (0.5 mmol) of lithium chloride and stirring for 15 minutes at room temperature, 2.74 g (10 mmol) of 1,3-bis- (trimethylsiloxy) -1-ethoxy-but-1,3-diene was added to this solution. THF (5 mL) was added, and the same operation as in Example 10 was performed except that 660 mg (5 mmol) of cinnamaldehyde in THF (5 mL) was immediately added and stirred at room temperature for 5 hours. The obtained optically active 5-hydroxy-3-ketoester had a yield of 99% and an optical purity of 99% ee.
[0063]
Example 15
In Example 10, the same operation as in Example 10 was performed except that (R)-(+)-BINOL was used instead of (S)-(−)-BINOL, and the corresponding optical activity 5- Hydroxy-3-ketoester was obtained. The obtained product had a yield of 99% and an optical purity of 99% ee.
[0064]
Example 16
In Example 10, the corresponding optically active 5-hydroxy-3-ketoester was obtained in the same manner as in Example 10 except that 531 mg (5 mmol) of benzaldehyde was used instead of 660 mg (5 mmol) of cinnamaldehyde. The yield was 96% and the optical purity was 99% ee.
[0065]
Example 17
In Example 10, the corresponding optically active 5-hydroxy-3-keto ester was obtained in the same manner as in Example 10, except that 480 mg (5 mmol) of 3-furylaldehyde was used instead of 660 mg (5 mmol) of cinnamaldehyde. The yield was 99% and the optical purity was 99% ee.
[0066]
Example 18
In Example 10, instead of 660 mg (5 mmol) of cinnamaldehyde, 561 mg (5 mmol) of thiophene-2-carbaldehyde was used, and the corresponding optically active 5-hydroxy-3-ketoester was obtained in the same manner as in Example 10. Obtained. The yield was 86% and the optical purity was 99% ee.
[0067]
Example 19
In Example 10, the corresponding optically active 5-hydroxy-3-ketoester was used in the same manner as in Example 10, except that 611 mg (5 mmol) of 3- (2-furyl) acrolein was used instead of 660 mg (5 mmol) of cinnamaldehyde. Got. The yield was 91% and the optical purity was 99% ee.
[0068]
Example 20
In Example 10, the corresponding optically active 5-hydroxy-3-ketoester was obtained in the same manner as in Example 10 except that instead of 660 mg (5 mmol) of cinnamaldehyde, 781 mg (5 mmol) of 1-decanal was used. The yield was 79% and the optical purity was 99% ee.
[0069]
Example 21
In Example 10, the corresponding optically active 5-hydroxy-3-keto ester was obtained in the same manner as in Example 10, except that 811 mg (5 mmol) of 4-methoxycinnamaldehyde was used instead of 660 mg (5 mmol) of cinnamaldehyde. . The yield was 88% and the optical purity was 97% ee.
[0070]
Example 22
In Example 10, the corresponding optically active 5-hydroxy-3-keto ester was obtained in the same manner as in Example 10, except that 886 mg (5 mmol) of 4-nitrocinnamaldehyde was used instead of 660 mg (5 mmol) of cinnamaldehyde. . The yield was 89% and the optical purity was 97% ee.
[0071]
Example 23
In Example 10, 1,3-bis- (trimethylsiloxy) -1-tarsha was replaced with 2.74 g (10 mmol) of 1,3-bis- (trimethylsiloxy) -1-ethoxy-but-1,3-diene. The corresponding optically active 5-hydroxy-3-ketoester was obtained in the same manner as in Example 10 except that 3.03 g (10 mmol) of butyl-buta-1,3-diene was used. The yield was 99% and the optical purity was 99.5% ee.
[0072]
Example 24
In Example 10, the corresponding optically active 5-hydroxy-3-ketoester was obtained in the same manner as in Example 10, except that 51 mg (0.55 mmol) of phenol was used instead of 10 mg (0.55 mmol) of water. The yield was 86% and the optical purity was 91% ee.
[0073]
Example 25
In Example 10, the corresponding optically active 5-hydroxy-3-keto ester was obtained in the same manner as in Example 10, except that 51 mg (0.55 mmol) of pentafluorophenol was used instead of 10 mg (0.55 mmol) of water. It was. The yield was 95% and the optical purity was 98% ee.
[0074]
【The invention's effect】
According to the present invention, 5-hydroxy-3-ketoester can be stably produced with high optical purity and high yield.

Claims (8)

In a reaction medium containing a chiral 1,1′-bi-2-naphthol compound and a tetravalent titanium compound, the 1,3-diene compound represented by the general formula (1)
(Wherein R ¹ and R ² each independently represents an alkyl group having 1 to 10 carbon atoms or an aryl group,
R ³ represents an optionally substituted alkyl group or an optionally substituted aryl group;
R ⁴ represents a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group. ) Aldehyde represented by general formula (2)
(Wherein R ⁵ represents an optionally substituted hydrocarbon group or heterocyclic group, and n represents an integer of 0 or 1) to react with the optical compound represented by the general formula (3). Active 5-hydroxy-3-ketoester
(Wherein R ³ , R ⁴ , R ⁵ and n have the same meanings as described above), wherein the reaction medium contains a lithium compound. The process according to claim 1, wherein the chiral 1,1'-bi-2-naphthol compound is represented by the following general formula (4).
(Wherein R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a trialkylsilylethynyl group, an optionally substituted alkyl group or a substituted group) Represents an optionally substituted alkoxy group, an optionally substituted alkenyl group, an optionally substituted phenyl group or an optionally substituted heterocyclic group.)   The method according to claim 1 or 2, wherein the lithium compound is a lithium salt.   The production method according to claim 3, wherein the lithium compound is used in an amount of 0.01 to 200 mol% with respect to the aldehyde. In the reaction medium, in addition to the chiral 1,1′-bi-2-naphthol compound, water or an optionally substituted phenol is added to the chiral 1,1′-bi-2-naphthol compound. It contains 0.5-10 equivalent, The method in any one of the Claims 1 thru | or 4 characterized by the above-mentioned. In a reaction medium containing a chiral 1,1′-bi-2-naphthol compound and a tetravalent titanium compound in advance, the 1,3-diene compound represented by the general formula (1) and the general formula (2) the process according to any one of claims 1 to 5, characterized in that to perform the reaction by adding an aldehyde represented. A lithium compound is added to a reaction medium to which a chiral 1,1′-bi-2-naphthol compound and a tetravalent titanium compound are added in advance, and then a 1,3-diene represented by the general formula (1) is added thereto. the method according to any one of claims 1 to 5 compounds and aldehyde were added, characterized in that to perform the reaction. Water contained in addition to the chiral 1,1′-bi-2-naphthol compound or the chiral 1,1′-bi-2-naphthol compound and the tetravalent titanium compound in addition to the chiral 1,1′-bi-2-naphthol compound The amount of phenol which may have a substituent is adjusted to 0.5 to 10 equivalents with respect to the chiral 1,1′-bi-2-naphthol compound, and then this is represented by the general formula (1). The method according to any one of claims 1 to 5 , wherein the reaction is carried out by adding the 1,3-diene compound represented by the formula, the aldehyde represented by the general formula (2) and a lithium compound.