JP3006748B2 - Process for producing optically active 7-substituted pyridyl-3,5-dihydroxy-hept-6-enoic acid ester derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel process for producing optically active 7-substituted pyridyl-3,5-dihydroxy-hept-6-enoic acid ester derivatives. Optically active 7-substituted pyridyl-3,5-dihydroxy-hept-6-enoic ester derivatives are blood cholesterol lowering agents (4-hydroxy-3-
Methylglutaryl-5- (HMG) Co-A reductase inhibitor] is useful as an intermediate during synthesis.

The optically active 7-substituted pyridyl-3,5-dihydroxy-hept-6-enoic acid ester derivatives which are the object compounds of the present invention, for example, 3R, 5S-(+)-(E) -7-
[4- (4-fluorophenyl) -2,6-diisopropyl-5-
(Methoxymethyl-pyrid-3-yl) -3,5-dihydroxy-
Journal of Medicinal Chemistry (Hourna-6-enoic acid n-butyl ester)
l of Medicinal Chemistry,
1985, vol. 28, no. 3, R3,5S-(+)-having 4-hydroxy-3-methylglutaryl-5- (HMG) Co-A reductase inhibitory activity according to the method described in P.3, 347-358). (E) -7- [4- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethyl
-Pyrid-3-yl] -3,5-dihydroxy-hept-6-enoic acid.

[0003]

2. Description of the Related Art Conventionally, as a method for reacting an aldehyde with diketene to obtain the corresponding 5-hydroxy-3-oxo-hept-6-enoic acid ester derivatives, there are the following methods. Chemistry Letters (Chemistry Le
terts, 1975, pp. 161-164), cinnamaldehyde and diketene are reacted as aldehydes in the presence of titanium tetrachloride to give methyl 5-hydroxy-3-oxo-7-phenyl-6-heptenoate. A method of making is disclosed. However, this method is a racemic production method. Chemistry Express (Chemistry Express)
Express, 1991, vol. 3, 193
On page 196), similar benzaldehydes, benzaldehyde and diketene are reacted in the presence of trivalent samarium iodide to give methyl 5-hydroxy-3-oxo-5-.
A method for producing phenylpentanoate is disclosed. However, this method is a racemic production method.

[0004] Therefore, any of the known production methods,
This is a method for producing a racemic body, not a method for synthesizing an optically active form.

[0005]

The present inventor has proposed that (E) -3- [4- (4-fluorophenyl) -2,6-
Diisopropyl-5-methoxymethyl-pyrid-3-yl)
As a result of studying the use of prop-2-en-1-al, diketene and a titanium complex were reacted in an organic solvent to produce an optically active 7-substituted pyridyl-5-hydroxy-3-oxo-
A hept-6-enoic acid ester derivative was obtained, and further subjected to syn reduction to give an optically active 7-substituted pyridyl-3,5-
The present invention has been completed by finding that a dihydroxy-hept-6-enoic acid ester derivative can be obtained.

The present invention relates to (E) -3- [4- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl] -prop-2-en-1-a -Optically active 7- by reacting thiol, diketene and titanium complex in an organic solvent
An optically active 7-substituted pyridyl-3,5-dihydroxy-hept-6-ene is obtained by preparing a substituted pyridyl-5-hydroxy-3-oxo-hept-6-enoic acid ester derivative and subjecting the compound to syn reduction. An object is to provide a method for efficiently obtaining an acid ester derivative.

[0007]

According to the present invention, there is provided a compound represented by the general formula (1):

[0008]

Embedded image

(Where R¹Represents an alkyl group, and n represents an integer.
Represents an arbitrary integer selected from the numbers 0, 1, 2, 3, and 4
Then R^TwoRepresents a hydrogen atom, an alkyl group, or a phenyl group;
R^Three, R ^FourRepresents a hydrogen atom or an alkyl group independently of each other
Then R^Two, R^Three, R^FourCannot be hydrogen atoms at the same time
) And an optically active Schiff base represented by the general formula (2)

[0010]

Embedded image

(Wherein R ⁵ represents an alkyl group or a phenyl group) and a titanium complex obtained by reacting with a titanium compound represented by the formula (E) -3- [4- (4-fluorophenyl)
-2,6-diisopropyl-5-methoxymethyl-pyrido-3-
Yl] -prop-2-en-1-al is reacted with diketene in an organic solvent in the general formula (3)

[0012]

Embedded image

Wherein R ⁶ represents an alkyl group or a phenyl group, an optically active 7-substituted pyridyl-5-hydroxy-3-oxo-hept-6-enoic ester derivative represented by the formula: General formula (4) after syn reduction

Embedded image (Wherein, R ⁶ has the same meaning as described above).
Optically active 7-substituted pyridyl-3,5-dihydroxy-hept-6, characterized by forming an enoate derivative
-It relates to a method for producing an enoate derivative.

The main reactions in the production method of the present invention can be represented, for example, by the following reaction (1) represented by reaction formula (1) and reaction (2) represented by reaction formula (2). The reaction (1) represented by the reaction formula (1) is a reaction of the optically active Schiff base represented by the general formula (1) and the general formula (2)
And a titanium complex obtained by reacting with a titanium compound represented by the formula: (E) -3- [4- (4-fluorophenyl) -2,6-
Diisopropyl-5-methoxymethyl-pyrid-3-yl)
-Production of optically active 7-substituted pyridyl-5-hydroxy-3-oxo-hept-6-enoic acid ester derivatives by reacting prop-2-en-1-al with diketene in an organic solvent How to

Reaction formula (1)

[0016]

Embedded image

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meaning as described above)

As R ¹ in the optically active Schiff base represented by the general formula (1) used in the reaction (1) of the production method of the present invention, for example, an alkyl group having 1 to 10 carbon atoms can be mentioned. Is a methyl group, an ethyl group, a propyl group (including each isomer), a butyl group (including each isomer), a pentyl group (including each isomer), and more preferably a tert-butyl group.

Examples of n include integers of 0, 1, 2, and 4, preferably 0, 1, and 2, and more preferably 1. The replacement position is arbitrary.

Examples of R ² include a hydrogen atom and a phenyl group, for example, an alkyl group having 1 to 10 carbon atoms.
Preferably a methyl group, an ethyl group, a propyl group (including each isomer), a butyl group (including each isomer), a pentyl group (including each isomer), more preferably a methyl group,
These are an ethyl group and an isopropyl group.

R ³ and R ⁴ each independently represent a hydrogen atom, for example, an alkyl group having 1 to 10 carbon atoms, preferably a hydrogen atom, a methyl group, an ethyl group,
A propyl group (including each isomer), a butyl group (including each isomer), and a pentyl group (including each isomer), and more preferably a hydrogen atom. The above R ² , R ³ , R
⁴ is not a hydrogen atom at the same time.

The Schiff base is a Journal of Organic Chemistry (Journal of Organic Chemistry).
rganic Chemistry, 1993, 58
Vol., Pp. 1515 to 1522). For example, (S) -2- [N- (3-
tert-Butylsalicylidene) amino] -3-methyl-1-butanol is (S) -2-amino-3-methyl-1-butano-
To 3-tert-butylsalicylaldehyde in a methanol solution in the presence of sodium sulfate.

As R ⁵ in the titanium compound represented by the general formula (2) used in the reaction (1) of the production method of the present invention, a phenyl group, for example, an alkyl group having 1 to 10 carbon atoms can be mentioned. Represents a methyl group, an ethyl group, a propyl group (including each isomer), a butyl group (including each isomer), a pentyl group (including each isomer), a hexyl group (including each isomer), a heptyl group ( Including each isomer)
And more preferably an ethyl group, a propyl group (including each isomer), a butyl group (including each isomer), and a pentyl group (including each isomer). The “titanium compound represented by the general formula (2)” having such R ⁵ is preferably a titanium tetraalkoxide, and is titanium tetraisopropoxide, titanium tetra n-butoxide, titanium tetraethoxide, titanium tetra n-oxide. Propoxide, titanium tetraisopentoxide, titanium tetraneopentoxide, and titanium tetra-1-ethylpropoxide are more preferred.

In the reaction (1) of the production method of the present invention, a compound having only one of the optical isomers is used as the optically active Schiff base. In that case, the 7-substituted pyridyl with optical activity corresponding to the optical isomer of the Schiff base used
-5-Hydroxy-3-oxo-hept-6-enoic acid ester derivative can be obtained.

A titanium complex obtained by reacting a Schiff base with a titanium compound is a journal of Organic
Chemistry (Journal of Organic
Chemistry, 1993, vol. 58, 1515-
P. 1522). For example, the titanium complex can be produced by reacting an optically active Schiff base with a titanium tetraalkoxide in a methylene chloride solution. The produced titanium complex can be used for the reaction without separation.

The optically active 7-substituted pyridyl-5-hydroxy-3-oxo- represented by the general formula (3) which is the target compound (1) produced in the reaction (1) of the production method of the present invention.
R ⁶ in the hept-6-enoic ester derivative is R ⁵
And an alkyl group or a phenyl group having the same meaning as described above. The general formula (3) having such R ⁵
May be determined by the above-mentioned titanium compound.

The optically active compound represented by the general formula (3)
7-substituted pyridyl-5-hydroxy-3-oxo-hept-6-
There are keto-form and enol-form tautomers in the enic ester derivative, and the optically active tautomer in the production method of the present invention is present.
7-substituted pyridyl-5-hydroxy-3-oxo-hept-6-
The enoate derivative may be either a keto form or an enol form.

(E) -3- [4- (4-Fluorophenyl) -2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl]-used in the reaction (1) of the production method of the present invention. Prop-2-en-1-al can be produced according to the method described in JP-A-1-216974.

The amount of the titanium compound represented by the general formula (2) used in the reaction (1) of the production method of the present invention is 0.8 to 0.8 mol per mol of the optically active Schiff base.
It is sufficient that the amount is a ratio of 1.2 mol.
An amount that gives a ratio of 1.15 mol is preferred.

(E) -3- [4- (4-Fluorophenyl) -2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl]-used in the reaction (1) of the production method of the present invention. Prop-2-en-1-al may be used in an amount of usually 0.1 to 15 mol per 1 mol of the Schiff base, and especially 0.2 to 10 mol. A ratio amount is preferred. As an addition method, it may be added as it is,
It may be dissolved in an organic solvent described below and added.

The diketene used in the reaction (1) of the production method of the present invention may be used in such an amount that the amount is usually 0.1 to 15 mol per mol of the Schiff base, and particularly 0. It is preferably in an amount of 2 to 10 mol.

The organic solvent used in the reaction (1) of the production method of the present invention is not particularly limited as long as it does not participate in the reaction since it is also used as a reaction solvent. Solvents, aromatic hydrocarbon organic solvents such as benzene, toluene and xylene, ether organic solvents such as diethyl ether, diisopropyl ether and tetrahydrofuran, nitrile organic solvents such as acetonitrile and propionitrile, methanol And alcohol-based solvents such as ethanol, ethanol and propanol.

The amount of the organic solvent used in the reaction (1) of the production method of the present invention is not particularly limited, but is usually 0.01 to 100 times (weight ratio) based on the optically active Schiff base. It is sufficient that the amount is the ratio of
An amount that gives a ratio of 50 times (weight ratio) is preferable.
An amount that gives a ratio of 20 times (weight ratio) is more preferable.

The reaction temperature of the reaction (1) in the production method of the present invention is as follows:
Although it depends on the amount and type of organic solvent used,
Usually, it is -150 ° C to 40 ° C, preferably -120 ° C to 30 ° C, more preferably -100 ° C to 20 ° C. The reaction (1) of the production method of the present invention can be performed under a condition in which an inert gas such as a nitrogen gas, a helium gas, or an argon gas is passed, and the inert gas used is a nitrogen gas, an argon gas. Is preferred.

In the reaction (1) of the production method of the present invention, the desired compound (1) is prepared from the reaction mixture containing the optically active 7-substituted pyridyl-5-hydroxy-3-oxo-hept-6-enoic acid ester derivative. ) May be performed by a combination of ordinary washing and separation operations. For example, a dilute acid aqueous solution or a dilute alkali aqueous solution is added to the reaction mixture, and the mixture is stirred, extracted with an organic solvent, and then subjected to silica gel column chromatography. It is preferable to obtain the target compound by a method such as purification in-.

As the dilute acid aqueous solution used for obtaining the target compound (1), an aqueous solution of an inorganic acid such as hydrochloric acid, nitric acid or sulfuric acid, or an aqueous solution of an organic acid such as oxalic acid or acetic acid can be used. Preferably, oxalic acid is used.
As the diluted alkaline aqueous solution, an aqueous solution of an alkali metal carbonate such as aqueous sodium bicarbonate or sodium carbonate is usually used.
An aqueous solution of an alkali metal hydroxide such as an aqueous sodium hydroxide solution, an aqueous ammonia solution, or the like can be used, and an aqueous sodium bicarbonate solution is preferably used.

The concentration of the dilute acid aqueous solution or dilute alkali aqueous solution to be used is not particularly limited.
The concentration is from M to 10M, preferably from 0.1M to 8M. The amount of the dilute acid aqueous solution or dilute alkali aqueous solution to be used in the reaction mixture varies depending on the concentration and type of the dilute acid aqueous solution or dilute alkali aqueous solution. ~ 50
Times (volume ratio), preferably 2 to 25 times (volume ratio).

The reaction (2) represented by the reaction formula (2) in the production method of the present invention is a reaction of the optically active 7-substituted pyridyl-5-hydroxy-3-oxo-hept-6- optical compound obtained in the reaction (1). This is a method for producing an optically active 7-substituted pyridyl-3,5-dihydroxy-hept-6-enoic acid ester derivative by subjecting the enoic acid ester derivative to syn reduction.

Reaction formula (2)

[0040]

Embedded image

The syn reduction in the reaction (2) refers to optically active 7-substituted pyridyl-5-hydroxy-3-oxo-hept-6.
-Refers to a method for producing an optically active 7-substituted pyridyl-3,5-dihydroxy-hept-6-enoic ester derivative from an enoic ester derivative in the presence of a metal hydride in an organic solvent.

The optically active 7-substituted pyridyl represented by the general formula (3) used in the reaction (2) of the production method of the present invention.
As the -5-hydroxy-3-oxo-hept-6-enoic acid ester derivative, those obtained in the reaction (1) can be used.

Examples of the metal hydride used in the reaction (2) of the production method of the present invention include metal borohydride compounds such as sodium borohydride, lithium borohydride and zinc borohydride. Sodium borohydride is preferred.

The amount of the metal hydride used in the reaction (2) of the production method of the present invention is an optically active 7-substituted pyridyl-5-hydroxy-3-oxo-hept-6-enoic acid ester derivative. It is sufficient that the amount is usually 0.3 to 15 mol per mol, and the amount is preferably 0.8 to 10 mol.

In the reaction (2) of the production method of the present invention, an additive can be used together with the metal hydride. Examples of the additives include trialkylboranes such as triethylborane and tributylborane, and dialkylalkoxyboranes such as diethylmethoxyborane and diethylethoxyborane, and preferred is diethylmethoxyborane.

The amount of the additive used in the reaction (2) of the production method of the present invention is an optically active 7-substituted pyridyl-5-hydroxy-3-oxo-hept-6-enoic ester derivative 1. The amount is usually 0.1 to 15 mol, preferably 0.3 to 10 mol, per mol.

The organic solvent used in the reaction (2) of the production method of the present invention is not particularly limited as long as it does not participate in the reaction. For example, halogen-based organic solvents such as methylene chloride and chloroform, benzene, toluene and xylene And organic solvents such as diethyl ether, diisopropyl ether and tetrahydrofuran, and alcohol organic solvents such as methanol, ethanol and isopropanol. Can be methano-
Alcohol-based organic solvents such as ethanol, ethanol and isopropanol, diethyl ether, diisopropyl ether,
Ether organic solvents such as tetrahydrofuran are preferred, and methanol and tetrahydrofuran are more preferred.
The organic solvent used in the reaction (2) of the production method may be a single organic solvent or a mixed solvent composed of a plurality of organic solvents. In this case, the mixing ratio is arbitrary.

The amount of the organic solvent used in the reaction (2) of the production method of the present invention is determined based on the amount of the optically active 7-substituted pyridyl-5-hydroxy-3-oxo-hept-6-enoic acid ester derivative. On the other hand, the amount is usually 0.01 to 100 times (weight ratio), and preferably 0.1 to 50 times (weight ratio).

The reaction temperature in the reaction (2) of the production method of the present invention varies depending on the type and amount of the metal hydride used, but is usually from -130 to 25 ° C, and from -100 to 5 ° C.
Is preferred.

The optically active 7-substituted pyridyl-3,5-dihydroxy-heptone represented by the general formula (4), which is the target compound (2), produced in the reaction (2) of the production method of the present invention.
R ⁶ in the -6-enoic acid ester derivative has the same meaning as described above. The general formula (4) having such R ⁶
May be determined by the above-mentioned titanium compound.

In the reaction (2) of the production method of the present invention, the target compound (2) is converted from the reaction mixture containing the formed optically active 7-substituted pyridyl-3,5-dihydroxy-hept-6-enoic acid ester derivative. The method of obtaining may be performed by combining ordinary washing operations and separation operations.For example, the reaction mixture is diluted by adding an organic solvent, and after removing the inorganic base by washing with water or the like, purification is performed by silica gel column chromatography. It is preferable to obtain the target compound by a method or the like.

The optically active 7-substituted pyridyl-3,5-dihydroxy-hept-6 obtained in the reaction (2) of the production method of the present invention.
-For example, Journal of Medicinal Chemistry (Journal of Medicinal Chemistry)
Medical Chemistry, 1985
Year, Volume 28, No. 3, pp. 347-358) or according to the reference examples.
-Methylglutaryl-5- (HMG) Co-A Reductor
3R, 5S-(+)-(E) -7-
[4- (4-fluorophenyl) -2,6-diisopropyl-5-
(Methoxymethyl-pyrid-3-yl) -3,5-dihydroxy-
Hept-6-enoic acid can be produced.

According to the present invention, a titanium complex obtained by reacting an optically active Schiff base with a titanium compound and (E) -3- [4- (4-fluorophenyl) -2,6- Diisopropyl-5-methoxymethyl-pyrid-3-yl] -prop
-2-en-1-al is reacted with diketene in an organic solvent to produce an optically active 7-substituted pyridyl-5-hydroxy-3-oxo-hept-6-enoic acid ester derivative, By performing the syn reduction, the optically active 7-substituted pyridyl-3,5-dihydroxy-hept-6-enoic acid ester derivative as the target compound can be produced without performing optical resolution.

[0053]

Examples are shown below. The optical purity (% ee) in Examples and Reference Examples was determined by performing HPLC analysis described below. The analysis conditions are as follows: column; CHIRALPAK
AD, elution solvent; (hexane: ethanol = 95: 5)
+ 0.1% trifluoroacetic acid, flow rate; 1.0 ml / mi
n, detection wavelength; 254 nm. Optically active 7-substituted pyridyl-5-hydroxy-3-oxo-hept-6-enoic acid ester derivatives may exist as a mixture of keto-enol compounds, but all compounds have optical purity. Are the same value.

Example 1 After heating and drying under reduced pressure, (S) -2- [N- (3-tert-butylsalicylidene) amino] -3-methyl-1-butano was introduced into a Schlenk tube into which argon gas had been introduced. -1.45g
(5.5 mmol), 10 ml of methylene chloride and 1.7 ml (5.0 mmol) of titanium tetra-n-butoxide.
Was added and stirred and mixed at room temperature for 1 hour. After cooling the Schlenk tube to −20 ° C., (E) -3- [4- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethyl-
Pyrid-3-yl] -prop-2-en-1-al 1.78
g (5.0 mmol) and stirred for 5 minutes, and then 0.77 ml (10 mmol) of diketene was added.
The reaction was carried out by stirring for 67 hours while maintaining the temperature at 20 ° C. The obtained reaction mixture was mixed with 50 ml of methylene chloride and 0.24 M
The mixture was added to a mixed solution of 50 ml of aqueous sodium bicarbonate, and stirred vigorously for 2 hours to obtain a two-layer solution. The resulting two-layer solution was separated, and the aqueous layer was extracted three times with methylene chloride (15 m in order).
1, 5 ml and 5 ml were used. ) To obtain a methylene chloride extract. The methylene chloride layer and the methylene chloride extract were combined to obtain a methylene chloride solution. The methylene chloride solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off.
Silica gel chromatography (elution solvent: hexane:
(Ethyl acetate = 75:25) to give 5S- (E) -7
-[4- (4-fluorophenyl) -2,6-diisopropyl-5
-Methoxymethyl-pyrid-3-yl] -5-hydroxy-3
-Oxo-hept-6-enoic acid n-butyl ester 2.0
4 g was obtained (optical purity: 65% ee, (E) -3- [4- (4-
Yield based on (fluorophenyl) -2,6-diisopropyl-5-methoxymethyl-5-pyrid-3-yl] -prop-2-en-1-al: 79%).

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.93 ppm (t, J = 7.3 Hz, 3H) 1.235 ppm (d, J = 6.4 Hz, 3H) 1.240 ppm (d, J) = 6.8 Hz, 3H) 1.32 ppm (d, J = 6.8 Hz, 6H) 1.38 ppm (qt, J = 7.3 Hz, 7.9 Hz,
2H) 1.63 ppm (tt, J = 6.8 Hz, 7.8 Hz,
2H) 2.42 ppm (dd, J = 2.9 Hz, 16.1 H)
z, 1H) 2.45 ppm (dd, J = 6.4 Hz, 16.1 H
z, 1H) 2.4-2.5 ppm (m, 1H) 3.19 ppm (s, 3H) 3.26 ppm (qq, J = 6.4 Hz, 6.8 Hz,
1H) 3.35 ppm (qq, J = 6.4 Hz, 6.8 Hz,
1H) 3.40 ppm (s, 2H) 4.05 ppm (s, 2H) 4.14 ppm (t, J = 6.8 Hz, 2H) 4.4 to 4.6 ppm (m, 1H) 5.24 ppm (dd, J = 5.9Hz, 16.1H
z, 1H) 6.34 ppm (dd, J = 1.5 Hz, 16.1 H
z, 1H) 7.0-7.2 ppm (m, 4H)

Example 2 5S- (E) -7 obtained in Example 1 under an argon atmosphere
-[4- (4-fluorophenyl) -2,6-diisopropyl-5
-Methoxymethyl-pyrid-3-yl] -5-hydroxy-3
-Oxo-hept-6-enoic acid n-butyl ester 2.0
0 g (optical purity: 65% ee) were mixed with 30 ml of dry tetrahydrofuran and 7.5 of dry methanol.
It was dissolved in a mixed solvent 1 with milliliter and cooled to -75 ° C. to obtain a mixed solution 1. While stirring the obtained mixed solution vigorously, 4.3 ml of a 1.0 M solution of diethylmethoxyborane in tetrahydrofuran (4.3 mmol) was added.
1) was added dropwise, and the mixture was stirred at -75 ° C for 15 minutes. Then, 162 mg (4.3 mmol) of sodium borohydride was added, and the mixture was stirred and reacted at -75 ° C for 4 hours. After adding 3.9 ml of acetic acid to the obtained reaction mixture to terminate the reaction, the reaction mixture was diluted with 100 ml of ethyl acetate and stirred at room temperature. The diluted solution obtained was diluted with saturated aqueous sodium bicarbonate 1
After washing with a mixed solvent 2 of 2 ml and 48 ml of water (the mixed solvent 2 was renewed and the same operation was performed three times), the extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a concentrate 1. Obtained. To the obtained concentrate 1, 15 ml of methanol and 4 microliter of concentrated hydrochloric acid were added and dissolved, followed by concentration under reduced pressure to obtain a concentrate 2 (the same operation was performed 5 times). The obtained concentrate 2 is purified by silica gel chromatography [elution solvent; hexane: ethyl acetate = 70: 30] to obtain 3R, 5S- (E).
-7- [4- (4-fluorophenyl) -2,6-diisopropyl
-5-methoxymethyl-pyrid-3-yl] -3,5-dihydroxy-hept-6-enoic acid n-butyl ester 1.67 g
[5S- (E) -7- [4- (4-fluorophenyl)
-2,6-diisopropyl-5-methoxymethyl-pyrido-3-
Yl] -5-hydroxy-3-oxo-hept-6-enoic acid
-Yield based on butyl ester: 83%].

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.94 ppm (t, J = 7.3 Hz, 3H) 1.1 to 1.8 ppm (m, 2H) 1.23 ppm (d, J = 6) 0.84 Hz, 3H) 1.24 ppm (d, J = 6.8 Hz, 3H) 1.32 ppm (d, J = 6.8 Hz, 6H) 1.38 ppm (qt, J = 7.3 Hz, 7.8 Hz,
2H) 1.63 ppm (tt, J = 6.8 Hz, 7.8 Hz,
2H) 2.40 ppm (dd, J = 4.4 Hz, 16.1 H)
z, 1H) 2.42 ppm (dd, J = 7.8 Hz, 16.1 H
2.9-3.0 ppm (m, 1H) 3.18 ppm (s, 3H) 3.29 ppm (sept, J = 6.8 Hz, 1H) 3.35 ppm (sept, J = 6.8 Hz, 3. 1H) 3.5-3.7 ppm (m, 1H) 4.0-4.1 ppm (m, 1H) 4.05 ppm (s, 2H) 4.12 ppm (t, J = 6.8 Hz, 2H) 2 to 4.4 ppm (m, 1H) 5.25 ppm (dd, J = 6.4 Hz, 16.1 H)
z, 1H) 6.30 ppm (dd, J = 1.0 Hz, 16.1 H
z, 1H) 7.0-7.2 ppm (m, 4H)

Reference Example 1 3R, 5S- (E) -7- [4- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl] obtained in Example 2 -3,5-dihydroxy-hept-6
-522 mg (1.01 mm) of n-butyl enoate
ol) in 1 ml of ethanol and dissolve in ethanol.
Solution was obtained. To the resulting ethanol solution was added 2 ml of a 1N aqueous sodium hydroxide solution, and the mixture was added at room temperature for 3 hours.
The reaction was stirred for 0 minutes. 1N-
After neutralizing the aqueous solution with 2 ml of hydrochloric acid, 10 ml of methylene chloride was added and the solvent was extracted twice to obtain a methylene chloride layer. The obtained methylene chloride layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off. 3R, 5S- (E) -7- [4- (4-fluorophenyl) -2,6-diisopropyl- 5-methoxymethyl-pyrid-3-yl] -3,5-dihydroxy-hept-6-enoic acid 4
59 mg were obtained. [3R, 5S- (E) -7- [4- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl] -3,5-dihydroxy-hept-6-
Yield based on n-butyl enoate: 99%].

Reference Example 2 3R, 5S- (E) -7- [4- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl] obtained in Reference Example 1. -3,5-dihydroxy-hept-6
20 ml of toluene was added to 459 mg of enic acid and dissolved to obtain a toluene solution. After adding 10 microliters of trifluoroacetic acid to the obtained toluene solution,
The mixture was reacted by stirring at 80 ° C. for 30 minutes. After cooling the obtained reaction solution to room temperature (20 ° C.), it was concentrated under reduced pressure to obtain a concentrated solution. The obtained concentrate is subjected to silica gel chromatography [elution solvent: hexane: ethyl acetate = 50: 5.
0] and purified by 4R, 6S- (E) -6- [4- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethyl-pyrid-3-ylethenyl] -4-hydroxy-3 , 4,5,6
366 mg of tetrahydro-2H-pyran-2-one were obtained [3R, 5S- (E) -7- [4- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethyl-pyrido]
-3-yl] -3,5-dihydroxy-hept-6-enoic acid: yield: 83%, optical purity: 65% ee].

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.24 ppm (d, J = 6.8 Hz, 6H) 1.315 ppm (d, J = 6.4 Hz, 3H) 1.320 ppm (d, J) = 6.8 Hz, 3H) 1.4-1.6 ppm (m, 1H) 1.5-1.7 ppm (m, 1H) 1.6-1.8 ppm (m, 1H) 2.5-2.7 ppm (M, 2H) 3.19 ppm (s, 3H) 3.27 ppm (qq, J = 6.4 Hz, 6.8 Hz,
1H) 3.36 ppm (sept, J = 6.8 Hz, 1H) 4.05 ppm (d, J = 10.3 Hz, 1H) 4.06 ppm (d, J = 9.8 Hz, 1H) 4.1-4. 2 ppm (m, 1H) 5.0 to 5.1 ppm (m, 1H) 5.27 ppm (dd, J = 5.9 Hz, 16.1H
z, 1H) 6.40 ppm (dd, J = 1.5 Hz, 16.1 H)
z, 1H) 7.0-7.2 ppm (m, 4H)

The preferred embodiments of the present invention are as follows.

1) The above-mentioned optically active 7-substituted pyridyl-3,5-dihydroxy-heptone, wherein R ^{1 in the} formula (1) is an optically active Schiff base representing an alkyl group having 1 to 5 carbon atoms.
Production method of -6-enoic ester derivative.

2) The above-mentioned production method, wherein n in the general formula (1) is an optically active Schiff base represented by an integer of 0 to 2.

3) The above-mentioned production method, wherein R ^{2 in the} general formula (1) is an optically active Schiff base representing an alkyl group having 1 to 5 carbon atoms.

4) The above-mentioned production method, wherein R ³ and R ^{4 in} the general formula (1) are a hydrogen atom and an optically active Schiff base representing an alkyl group having 1 to 5 carbon atoms.

5) The above method, wherein R ^{5 in the} general formula (2) is a titanium compound having 1 to 7 carbon atoms.

6) R ¹ and R ^{2 in} the general formula (1) ^each have 1 carbon atom
And n represents an integer of 0 to 2;
³ , R ⁴ is a hydrogen atom, an optically active Schiff base having an alkyl group having 1 to ⁵ carbon atoms, and R ^{5 in the} general formula (2) is a titanium compound having an alkyl group having 1 to 7 carbon atoms. The above manufacturing method.

7) The above-mentioned production method, wherein R ^{1 in the} general formula (1) is an optically active Schiff base representing a tert-butyl group.

8) The above-mentioned production method, wherein n in the general formula (1) is an optically active Schiff base having an integer of 1.

9) The above-mentioned production method, wherein R ^{2 in the} general formula (1) is an optically active Schiff base representing an alkyl group having 1 to 3 carbon atoms.

10) The above-mentioned production method, wherein R ³ and R ^{4 in} the general formula (1) are optically active Schiff bases each representing a hydrogen atom.

11) R ^{5 in the} general formula (2) has 2 to ⁵ carbon atoms
The production method described above, which is a titanium compound showing an alkyl group of

12) In the general formula (1), R ¹ represents a tert-butyl group, R ² represents an alkyl group having 2 to 3 carbon atoms, and n
Represents an integer of 1, R ³ and R ⁴ are optically active Schiff bases each representing a hydrogen atom, and R ^{5 in the} general formula (2) has 2 carbon atoms.
The above-mentioned production method, which is a titanium compound showing an alkyl group of from 5 to 5.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-3-93773 (JP, A) JP-A-2-286648 (JP, A) JP-A-7-126217 (JP, A) Tetrahedron, Vol. 50 , No. 15, p. 4385-4398 (1994). Med. Chem. Vol. 28, No. 3, p. 347-358 (1985) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 213/55 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula (1) (Wherein, R ¹ represents an alkyl group, n is an integer 0, 1,
2, 3 and indicates any integer selected from 4, R ² is a hydrogen atom, an alkyl group, a phenyl group, R ^3, R ⁴ independently of one another are hydrogen, an alkyl group, R ^2, R
³ and R ⁴ are not hydrogen atoms at the same time) and an optically active Schiff base represented by the general formula (2): (Wherein, R ⁵ represents an alkyl group or a phenyl group) and a titanium complex obtained by reacting with a titanium compound represented by the formula (E) -3- [4- (4-fluorophenyl) -2,
6-diisopropyl-5-methoxymethyl-pyrido-3
-Yl] -prop-2-en-1-al is reacted with diketene in an organic solvent to obtain a compound represented by the general formula (3): (In the formula, R ⁶ represents an alkyl group or a phenyl group.) An optically active 7-substituted pyridyl-5-hydroxy-3
-Oxo-hept-6-enoic acid ester derivative is produced and subjected to syn reduction to obtain a compound of the general formula (4). (Wherein, R ⁶ has the same meaning as described above), wherein an optically active 7-substituted pyridyl-3,5-dihydroxy-hept-6-enoic acid ester derivative is produced. Of a 7-substituted pyridyl-3,5-dihydroxy-hept-6-enoic acid ester derivative.