JP2007291122A - Method for producing (s)-5-substituted-5-hydroxy-3-oxopentanoate derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a (S)-5-substituted-5-hydroxy-3-oxopentanoate derivative by an industrially suitable simple method in a high optical purity and in a high isolation yield. <P>SOLUTION: This method for producing the (S)-5-substituted-5-hydroxy-3-oxopentanoate derivative is characterized by reacting an aldehyde compound with a diketone in the presence of an amine and a titanium complex obtained by the reaction of tetraisopropoxy titanium with an optically active Schiff base such as (S)-2-[N-(3,5-di-t-butylsalicylidene)amino]-3-methyl-1-butanol in an organic solvent. When the aldehyde compound is benzaldehyde, the obtained compound is isopropyl (S)-5-phenyl-5-hydroxy-3-oxopentanoate. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a process for producing (S) -5-substituted-5-hydroxy-3-oxopentanoic acid ester derivatives. (S) -5-substituted-5-hydroxy-3-oxopentanoic acid ester derivatives, especially (S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -5 -Hydroxy-3-oxohept-6-enoic acid ester is a useful compound as a synthetic intermediate of a blood cholesterol lowering agent (HMG-CoA reductase inhibitor).

Conventionally, as a method for producing an (S) -5-substituted-5-hydroxy-3-oxopentanoic acid ester derivative by reacting an aldehyde compound with diketene in the presence of a titanium complex, 3- [2-cyclopropyl -4- (4-Fluorophenyl) quinolin-3-yl] -prop-2-en-1-al and diketene were reacted with (S)-in an optical purity of 78% ee and an isolated yield of 72%. Methods for producing ethyl 7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -5-hydroxy-3-oxohept-6-enoate are disclosed (eg, patent literature) 1). However, the optical purity and isolation yield of the target product obtained by this method were never satisfactory.
JP-A-8-92217

  The object of the present invention is to solve the above-mentioned problems and to obtain the desired (S) -5-substituted-5-hydroxy-3-oxopentane by a simple method with high optical purity and high isolation yield. The present invention provides a process for producing an industrially suitable (S) -5-substituted-5-hydroxy-3-oxopentanoic acid ester derivative to obtain an acid ester derivative.

  The subject of this invention is general formula (1).

(In the formula, R ¹ represents a hydrocarbon group, and R ² , R ³ and R ⁴ represent a hydrogen atom or a hydrocarbon group.)
And an optically active Schiff base represented by the general formula (2)

(In the formula, R ⁵ represents a hydrocarbon group.)
And a titanium complex obtained by reacting with a titanium compound represented by formula (3)

(Wherein R ⁶ , R ⁷ and R ⁸ represent a hydrocarbon group.)
In the presence of an amine of formula (4)

(In the formula, R ⁹ represents a hydrocarbon group or a heterocyclic group which may have a substituent.)
Wherein the aldehyde compound represented by the formula is reacted with a diketene in an organic solvent (5)

(Wherein R ⁵ and R ⁹ are as defined above.)
(S) -5-substituted-5-hydroxy-3-oxopentanoic acid ester derivatives represented by

  According to the present invention, the desired (S) -5-substituted-5-hydroxy-3-oxopentanoic acid ester derivative can be obtained by a simple method with high optical purity and high isolation yield, which is industrially suitable. The present invention provides a process for producing (S) -5-substituted-5-hydroxy-3-oxopentanoic acid ester derivatives.

The optically active Schiff base used in the reaction of the present invention is represented by the general formula (1). In the general formula (1), R ¹ is a hydrocarbon group, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, etc. An alkyl group having 1 to 10 carbon atoms (including these isomers); cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group A cycloalkyl group having 3 to 10 carbon atoms such as cyclodecyl group; an aralkyl group having 7 to 12 carbon atoms such as benzyl group, phenethyl group and phenylpropyl group (note that these groups include various isomers); Examples thereof include aryl groups having 6 to 10 carbon atoms such as phenyl group, tolyl group, xylyl group, and naphthyl group (these groups include various isomers).

R ² , R ³ and R ⁴ are a hydrogen atom or a hydrocarbon group. Examples of the hydrocarbon group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, C1-C10 alkyl groups such as octyl group, nonyl group, decyl group (note that these groups include various isomers); cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclohexane C3-C10 cycloalkyl groups such as heptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group; aralkyl groups having 7-12 carbon atoms such as benzyl group, phenethyl group, phenylpropyl group, etc. An aryl group having 6 to 10 carbon atoms such as a phenyl group, a tolyl group, a xylyl group, a naphthyl group (these groups are represented by various isomers). Body).).

In the most preferable embodiment of R ¹ , R ² , R ³ and R ⁴ , R ¹ is an isopropyl group, R ² is a hydrogen atom, and R ³ and R ⁴ are t-butyl groups.

  The amount of the optically active Schiff base to be used is preferably 0.2 to 2 mol, more preferably 0.5 to 1.5 mol, with respect to 1 mol of the titanium compound.

The titanium compound used in the reaction of the present invention is represented by the general formula (2). In the general formula (2), R ⁵ is a hydrocarbon group, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, etc. An alkyl group having 1 to 10 carbon atoms (including these isomers); cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group A cycloalkyl group having 3 to 10 carbon atoms such as cyclodecyl group; an aralkyl group having 7 to 12 carbon atoms such as benzyl group, phenethyl group and phenylpropyl group (note that these groups include various isomers); Examples thereof include aryl groups having 6 to 10 carbon atoms such as phenyl group, tolyl group, xylyl group and naphthyl group (these groups include various isomers). Preferably, it is an isopropyl group.

  The amount of the titanium compound used is preferably 0.1 to 5 mol, more preferably 0.2 to 3 mol, relative to 1 mol of the aldehyde compound.

The titanium complex used in the reaction of the present invention can be synthesized according to the method described in J. Org. Chem., 58 , 1515 (1993). For example, the above optically active Schiff base and titanium compound can be synthesized. It can be obtained by reacting in an organic solvent. In addition, the produced | generated titanium complex can be used for reaction, without isolating.

The amine used in the reaction of the present invention is represented by the general formula (3). In the general formula (3), R ⁶ , R ⁷ and R ⁸ are hydrocarbon groups, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, An alkyl group having 1 to 10 carbon atoms such as a nonyl group and a decyl group (these groups include various isomers); a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, A cycloalkyl group having 3 to 10 carbon atoms such as a cyclooctyl group, a cyclononyl group, and a cyclodecyl group; an aralkyl group having 7 to 12 carbon atoms such as a benzyl group, a phenethyl group, and a phenylpropyl group. An aryl group having 6 to 10 carbon atoms such as a phenyl group, a tolyl group, a xylyl group, and a naphthyl group (note that these groups include various isomers). In a preferred embodiment, (1) R ⁶ , R ⁷ and R ⁸ are all ethyl groups, (2) R ⁶ and R ⁷ are isopropyl groups, and R ⁸ is an ethyl group. R ⁶ , R ⁷ and R ⁸ are not simultaneously a cycloalkyl group, a benzyl group or an aryl group.

  The amount of the amine used is preferably 0.01 to 3 mol, more preferably 0.02 to 2 mol, relative to 1 mol of the aldehyde compound.

  The organic solvent used in the reaction of the present invention is not particularly limited as long as it does not inhibit the reaction. For example, alcohols such as methanol, ethanol, isopropyl alcohol and t-butyl alcohol; diethyl ether, diisopropyl ether, tetrahydrofuran and the like Ethers; Aliphatic hydrocarbons such as hexane, heptane and cyclohexane; Halogenated aliphatic hydrocarbons such as methylene chloride and chloroform; Aromatic hydrocarbons such as benzene, toluene and xylene; Methyl acetate, ethyl acetate, etc. Carboxylic acid esters; Nitriles such as acetonitrile and propionitrile; Ketones such as acetone and methyl isobutyl ketone; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; 1,3-dimethylimidazolidine And ureas such as 2-one That is, preferably ethers, aromatic hydrocarbons, aliphatic hydrocarbons, more preferably ethers, aromatic hydrocarbons, aromatic hydrocarbons are used particularly preferably. In addition, you may use these organic solvents individually or in mixture of 2 or more types.

  The amount of the solvent used is appropriately adjusted depending on the uniformity and stirrability of the reaction solution, but is preferably 1 to 50 g, more preferably 3 to 20 g, relative to 1 g of the aldehyde compound.

The aldehyde compound used in the reaction of the present invention is represented by the general formula (5). In the general formula (5), R ⁹ is a hydrocarbon group or a heterocyclic group which may have a substituent. Examples of the hydrocarbon group include methyl groups, ethyl groups, propyl groups, butyl groups, pentyl groups, hexyl groups, heptyl groups, octyl groups, nonyl groups, decyl groups and other alkyl groups (in addition, these groups include various groups). Including isomers); cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group; vinyl group, allyl group, propenyl group, Alkenyl groups such as butenyl groups; Aralkyl groups such as benzyl groups, phenethyl groups, and phenylpropyl groups (these groups include various isomers); Aryls such as phenyl groups, tolyl groups, xylyl groups, and naphthyl groups Groups (note that these groups include various isomers). Examples of the heterocyclic group include furyl, benzofuryl, thienyl, pyrrolyl, pyridyl, quinolyl, pyrimidyl, piperidyl, morpholyl, thiazolyl, benzothiazolyl, imidazolyl, triazolyl, and the like. Can be mentioned.

  The hydrocarbon group or heterocyclic group may have a substituent. Examples of the substituent include a substituent formed through a carbon atom, a substituent formed through an oxygen atom, a substituent formed through a nitrogen atom, a substituent formed through a sulfur atom, and a halogen atom.

  Examples of the substituent formed through the carbon atom include alkyl groups such as methyl group, ethyl group, propyl group, butyl group, pentyl group, and hexyl group; cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cyclobutyl. Cycloalkyl groups such as groups; alkenyl groups such as vinyl groups, allyl groups, propenyl groups, cyclopropenyl groups, cyclobutenyl groups, cyclopentenyl groups; quinolyl groups, pyridyl groups, pyrrolidyl groups, pyrrolyl groups, furyl groups, thienyl groups, etc. Heterocyclic group: aryl group such as phenyl group, tolyl group, fluorophenyl group, xylyl group, biphenyl group, naphthyl group, anthryl group, phenanthryl group; acetyl group, propionyl group, acryloyl group, pivaloyl group, cyclohexylcarbonyl group, benzoyl Group, naphthoyl group Acyl group such as toluoyl group (may be acetalized); carboxyl group; alkoxycarbonyl group such as methoxycarbonyl group and ethoxycarbonyl group; aryloxycarbonyl group such as phenoxycarbonyl group; halogenation such as trifluoromethyl group An alkyl group; and a cyano group. These groups include various isomers.

  Examples of the substituent formed through the oxygen atom include a hydroxyl group; an alkoxyl group such as a methoxyl group, an ethoxyl group, a propoxyl group, a butoxyl group, a pentyloxyl group, a hexyloxyl group, a heptyloxyl group, and a benzyloxyl group; Aryloxyl groups such as phenoxyl group, toluyloxyl group, naphthyloxyl group and the like can be mentioned. These groups include various isomers.

  Examples of the substituent formed through the nitrogen atom include a primary amino group such as a methylamino group, an ethylamino group, a butylamino group, a cyclohexylamino group, a phenylamino group, or a naphthylamino group; a dimethylamino group, diethylamino Groups, dibutylamino groups, methylethylamino groups, methylbutylamino groups, diphenylamino groups, secondary amino groups such as N-methyl-N-methanesulfonylamino groups; morpholino groups, piperidino groups, piperazinyl groups, pyrazolidinyl groups, pyrrolidino A heterocyclic amino group such as a group or an indolyl group; an imino group. These groups include various isomers.

  Examples of the substituent formed through the sulfur atom include a mercapto group; a thioalkoxyl group such as a thiomethoxyl group, a thioethoxyl group, and a thiopropoxyl group; a thiophenoxyl group, a thiotoluyloxyl group, and a thionaphthyloxyl group. Thioaryloxyl group and the like. These groups include various isomers.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  The amount of diketene used in the reaction of the present invention is preferably 1 to 3 mol, more preferably 1 to 2 mol, relative to 1 mol of the aldehyde compound.

  In the reaction of the present invention, for example, a Schiff base and a titanium compound are mixed and reacted to form a titanium complex, and then an amine, an aldehyde compound, a diketene and an organic solvent are mixed and reacted with stirring. It is done by the method. The reaction temperature at that time is preferably −150 to 50 ° C., more preferably −100 to 30 ° C., particularly preferably −80 to 20 ° C., and the reaction pressure is not particularly limited.

  By the reaction of the present invention, an (S) -5-substituted-5-hydroxy-3-oxopentanoic acid ester derivative is obtained as a final product. For example, after completion of the reaction, filtration, concentration, recrystallization, It is isolated and purified by general methods such as crystallization, distillation, column chromatography and the like.

Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
In addition, optical purity (enantiomeric excess (% ee)) measurement in Examples and Comparative Examples and quantitative analysis in Reference Examples were performed using high performance liquid chromatography under the following analysis conditions.

Analytical conditions for high performance liquid chromatography;
(Optical purity measurement)
Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries)
4.6mmφ × 250mm
Column temperature: 30 ° C
Elution solvent: n-hexane / isopropyl alcohol / diethylamine (= 94.9 / 5.0 / 0.1 (volume ratio))
Flow rate: 0.5ml / min.
Detection wavelength: 254nm

(Quantitative analysis)
Column: Inertsil ODS-3V (manufactured by GL Science)
4.6mmφ × 250mm
Column temperature: 40 ° C
Elution solvent: acetonitrile / 0.02 mol / l citrate buffer (= 2/1 (volume ratio)) (pH 3.3)
Flow rate: 1.0ml / min.
Detection wavelength: 254nm

Reference Example 1 (Synthesis of (S) -2- [N- (3,5-di-t-butylsalicylidene) amino] -3-methyl-1-butanol in toluene solution)
To a 100 ml flask equipped with a stirrer, thermometer, reflux condenser and Dean-Stark apparatus, in a nitrogen atmosphere, 7.37 g (31.5 mmol) of 3,5-di-t-butyl-2-hydroxybenzaldehyde, (S) -2-Amino-3-methyl-1-butanol (3.26 g, 31.6 mmol) and toluene (40 ml) were added, and the mixture was reacted under reflux (90-110 ° C.) for 1 hour while removing the water produced. After completion of the reaction, the reaction solution was cooled to room temperature and 40 ml of a toluene solution of (S) -2- [N- (3,5-di-t-butylsalicylidene) amino] -3-methyl-1-butanol ( (S) -2- [N- (3,5-di-t-butylsalicylidene) amino] -3-methyl-1-butanol (containing 10.0 g (31.5 mmol)) was obtained.

Example 1 (Synthesis of isopropyl (S) -5-phenyl-5-hydroxy-3-oxopentanoate)
Titanium tetraisopropoxide (9.87 g, 33.0 mmol) was added to a 200-ml flask equipped with a stirrer, a thermometer, and a dropping funnel with a side tube, and then synthesized in Reference Example 1 (S) -2- [ 40 ml of toluene solution of N- (3,5-di-t-butylsalicylidene) amino] -3-methyl-1-butanol ((S) -2- [N- (3,5-di-t-butyl) Salicylidene) amino] -3-methyl-1-butanol (containing 10.0 g (31.5 mmol)) is slowly added dropwise so that the temperature of the reaction solution does not exceed 30 ° C., and reacted at room temperature for 1 hour to form a titanium complex. Synthesized. Thereafter, the reaction solution was cooled to −20 ° C., a solution of 3.18 g (30.0 mmol) of benzaldehyde dissolved in 50 ml of toluene was slowly added and stirred for 30 minutes. Further, 0.42 ml (3.00 mmol) of triethylamine and 3.28 g (39.0 mmol) of diketene were added in this order, and the mixture was reacted at −20 ° C. for 8 hours. After completion of the reaction, the obtained reaction solution was added to a mixed solution of 5.0% by mass oxalic acid aqueous solution 100 ml, isopropyl alcohol 50 ml and ethyl acetate 50 ml, and vigorously stirred at room temperature for 1 hour. Thereafter, the organic layer was taken out, washed with 50 ml of a 5.0% by mass oxalic acid aqueous solution, 50 ml of water, and 30 ml of a saturated aqueous sodium hydrogen carbonate solution in that order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (filler; Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: toluene / ethyl acetate = 9/1 (volume ratio)). As a result, 5.78 g (23.5 mmol) of isopropyl (S) -5-phenyl-5-hydroxy-3-oxopentanoate was obtained as a pale yellow oily substance (optical purity: 81.7% ee, isolated yield: 78.2%). .

Comparative Example 1 (Synthesis of isopropyl (S) -5-phenyl-5-hydroxy-3-oxopentanoate)
In Example 1, the reaction was performed in the same manner as in Example 1 except that triethylamine was not added. As a result, 5.95 g (23.8 mmol) of isopropyl (S) -5-phenyl-5-hydroxy-3-oxopentanoate was obtained (optical purity: 79.2% ee, isolated yield: 79.3%).

Example 2 (Synthesis of isopropyl (S) -7-phenyl-5-hydroxy-3-oxohept-6-enoate)
In Example 1, the reaction was carried out in the same manner as in Example 1 except that the aldehyde compound was changed to 3.69 g (30.0 mmol) of cinnamaldehyde. As a result, 6.50 g (23.6 mmol) of isopropyl (S) -7-phenyl-5-hydroxy-3-oxohept-6-enoate was obtained as a pale yellow oil (optical purity: 82.8% ee, isolated yield). Rate: 78.5%).

Comparative Example 2 (Synthesis of isopropyl (S) -7-phenyl-5-hydroxy-3-oxohept-6-enoate)
In Example 2, the reaction was performed in the same manner as in Example 2 except that triethylamine was not added. As a result, 6.29 g (22.8 mmol) of isopropyl (S) -7-phenyl-5-hydroxy-3-oxohept-6-enoate was obtained (optical purity: 79.4% ee, isolated yield: 76.0%). .

Example 3 (Synthesis of (S) -5- (pyridin-3-yl) -5-hydroxy-3-oxopentanoic acid isopropyl)
In Example 1, the reaction was carried out in the same manner as in Example 1 except that the aldehyde compound was changed to 3.21 g (30.0 mmol) of nicotine aldehyde. As a result, 5.74 g (22.9 mmol) of isopropyl (S) -5- (pyridin-3-yl) -5-hydroxy-3-oxopentanoate was obtained as a pale yellow oil (optical purity: 79.4% ee, Isolated yield: 76.2%).
Note that isopropyl (S) -5- (pyridin-3-yl) -5-hydroxy-3-oxopentanoate is a novel compound represented by the following physical property values.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.35 (6H, d), 1.92 (2H, m), 2.00 (1H, s), 2.10 (1H, s), 2.40 (2H, m), 3.85 (1H, m), 4.31 (1H, m), 4.50 (1H, m), 7.42 (1H, t), 7.90 (1H, d), 8.55 (1H, d), 8.70 (1H, s)
CI-MS (m / e); 252 (MH), 234 (M-OH)

Comparative Example 3 (Synthesis of isopropyl (S) -5- (pyridin-3-yl) -5-hydroxy-3-oxopentanoate)
In Example 3, the reaction was performed in the same manner as in Example 3 except that triethylamine was not added. As a result, 5.81 g (23.1 mmol) of isopropyl (S) -5- (pyridin-3-yl) -5-hydroxy-3-oxopentanoate was obtained (optical purity: 76.4% ee, isolated yield: 77.1%).

Example 4 (Synthesis of (S) -7- (2-isopropyl-4-phenylquinolin-3-yl) -5-hydroxy-3-oxohept-6-enoic acid isopropyl)
Example 1 except that the aldehyde compound was changed to 9.03 g (30.0 mmol) of 3- (2-isopropyl-4-phenylquinolin-3-yl) -prop-2-en-1-al in Example 1. The reaction was carried out in the same manner as above. As a result, 11.5 g (25.9 mmol) of isopropyl (S) -7- (2-isopropyl-4-phenylquinolin-3-yl) -5-hydroxy-3-oxohept-6-enoate was obtained as a pale yellow oil. (Optical purity: 85.3% ee, isolated yield: 86.3%).
Note that isopropyl (S) -7- (2-isopropyl-4-phenylquinolin-3-yl) -5-hydroxy-3-oxohept-6-enoate is a novel compound represented by the following physical properties. .

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.29 (6H, d), 1.39 (6H, d), 1.63 (2H, m), 2.00 (1H, s), 2.10 (1H, s), 2.40 (2H, m), 3.12 (1H, m), 3.85 (1H, m), 3.90 (1H, m), 4.31 (1H, m), 6.25 (1H, d), 6.62 (1H, d), 7.22 ~ 7.32 (3H, m), 7.39-7.48 (3H, m), 7.60 (1H, t), 7.69 (1H, d), 8.02 (1H, d)
CI-MS (m / e); 446 (MH), 428 (M-OH)

Comparative Example 4 (Synthesis of (S) -7- (2-isopropyl-4-phenylquinolin-3-yl) -5-hydroxy-3-oxohept-6-enoic acid isopropyl)
In Example 4, the reaction was performed in the same manner as in Example 4 except that triethylamine was not added. As a result, 11.8 g (26.5 mmol) of isopropyl (S) -7- (2-isopropyl-4-phenylquinolin-3-yl) -5-hydroxy-3-oxohept-6-enoate was obtained (optical purity). : 79.9% ee, isolated yield: 88.2%).

Example 5 (Synthesis of (S) -7- (2-isopropyl-4-phenylquinolin-3-yl) -5-hydroxy-3-oxohept-6-enoic acid isopropyl)
The reaction was conducted in the same manner as in Example 4 except that triethylamine was changed to 0.52 ml (3.00 mmol) of diisopropylethylamine in Example 4. As a result, 11.7 g (26.3 mmol) of isopropyl (S) -7- (2-isopropyl-4-phenylquinolin-3-yl) -5-hydroxy-3-oxohept-6-enoate was obtained as a pale yellow oil. (Optical purity: 83.2% ee, isolated yield: 87.5%).

  According to the present invention, the desired (S) -5-substituted-5-hydroxy-3-oxopentanoic acid ester derivative can be obtained by a simple method with high optical purity and high isolation yield, which is industrially suitable. A method for producing a (S) -5-substituted-5-hydroxy-3-oxopentanoic acid ester derivative can be provided.

Claims (4)

General formula (1)

(In the formula, R ¹ represents a hydrocarbon group, and R ² , R ³ and R ⁴ represent a hydrogen atom or a hydrocarbon group.)
And an optically active Schiff base represented by the general formula (2)

(In the formula, R ⁵ represents a hydrocarbon group.)
And a titanium complex obtained by reacting with a titanium compound represented by formula (3)

(Wherein R ⁶ , R ⁷ and R ⁸ represent a hydrocarbon group.)
In the presence of an amine of formula (4)

(In the formula, R ⁹ represents a hydrocarbon group or a heterocyclic group which may have a substituent.)
Wherein the aldehyde compound represented by the formula is reacted with a diketene in an organic solvent (5)

(Wherein R ⁵ and R ⁹ are as defined above.)
(S) -5-substituted-5-hydroxy-3-oxopentanoic acid ester derivatives represented by   The process for producing a (S) -5-substituted-5-hydroxy-3-oxopentanoic acid ester derivative according to claim 1, wherein the organic solvent is an aromatic hydrocarbon. Formula (6)

(S) -5- (Pyridin-3-yl) -5-hydroxy-3-oxopentanoic acid isopropyl represented by Formula (7)

(S) -7- (2-Isopropyl-4-phenylquinolin-3-yl) -5-hydroxy-3-oxohept-6-enoic acid isopropyl represented by