JP2003137870A - Method for producing 3,5-dioxo-6-heptenoic acid derivatives, and intermediate therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrially effective method for producing esters of 3,5-dioxo-6-heptenoic acid which are raw materials for synthesizing esters of (3R,5S)-(E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-3,5-dih ydroxyhept-6- enoic acid. SOLUTION: This method for producing the esters of the (6E)-7-[2- cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dioxoheptenoic acid comprises subjecting 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbonaldehyde and the esters of the 3,5-dioxohexanoic acid to a condensation reaction. The production method takes a path passing ester of 7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3- yl]-3,5-dioxoheptenoic acid having a substituent such as a hydroxy group and a halogen atom at the 7-position as an intermediate of the condensation reaction in the production method. The new intermediate compound is also provided.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to (3R, 5S)-
Necessary for the synthesis of (E) -7- [2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-yl] -3,5-dihydroxyhept-6-enoic acid esters,
The present invention relates to a new method for producing a β-diketocarboxylic acid ester derivative represented by the general formula (C). General formula
(3R, 5S) derived from the compound represented by (C)
-(E) -7- [2-Cyclopropyl-4- (4-fluorophenyl) -quinolin-3-yl] -3,5-dihydroxyhept-6-enoic acid is disclosed in JP-A 1-27986.
No. 6, 3-hydroxy-
It inhibits 3-methylglutaryl-CoA reductase and is useful as a blood cholesterol lowering agent.

[0002]

2. Description of the Related Art (3R, 5S)-(E) -7- [2-Cyclopropyl-4- (4-fluorophenyl) -quinolin-3-yl] -3,5-dihydroxyhept-6-ene As a method for industrially producing an acid, a carbonyl group of a β-hydroxyketoester obtained by subjecting an enal and a ketoester to a condensation reaction is reduced (JP-A-1-27).
9866 Publication and Journal of Chroma
tography A, 832 (1999) p55-6
5) Methods are known. However, in these methods, since the reaction product becomes an optical isomer mixture, it is necessary to separate and purify only the desired optically active compound by chromatography in the final step. Separation of isomers in the final step causes a lot of loss and cannot be said to be an industrially inexpensive and efficient production method. On the other hand, β represented by the general formula (C)
-If the diketocarboxylic acid ester is stereoselectively reduced, the amount of the isomer is small, which is desirable. However, the diketocarboxylic acid ester is used as a raw material in JP-A-6-329679, and the specific production method is Not listed.

[0003]

Therefore, the advent of a method for efficiently producing β-diketocarboxylic acid esters, which are the compounds represented by the general formula (C), which are the above-mentioned useful raw materials, has been desired.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have condensed a compound represented by the formula (A) with a compound represented by the general formula (B). By reacting, a compound represented by the general formula (C) can be produced, and a dehydration reaction of the compound represented by the general formula (D), which is a production intermediate of the condensation reaction, can be carried out simply and easily. The inventors have found that the compound represented by formula (C) can be efficiently derived, and have completed the present invention.

That is, the gist of the present invention is the following formula (A):

[Chemical 8] 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3-carbaldehyde represented by the following general formula
(B)

[Chemical 9] (In the formula, R ¹ represents a hydrogen atom, an alkyl group, an aralkyl group or an aryl group.) The compound represented by the following general formula (C) is characterized in that it is subjected to a condensation reaction.

[Chemical 10] (Wherein R ¹ has the same meaning as described above).

Another subject matter of the present invention is the following general formula (D):

[Chemical 11] (In the formula, R ¹ has the same meaning as described above. R ² represents a hydroxyl group, a halogen atom, a silyloxy group, a sulfonyloxy group, an acyloxy group, an alkoxycarbonyloxy group, an alkylthiocarbonyloxy group, an alkoxythiocarbonyloxy group, or A compound represented by the general formula (C) or a salt thereof is characterized in that R ² is eliminated from the compound represented by the formula (1) which represents an alkylthiothiocarbonyloxy group or a salt thereof. . A further gist of the present invention resides in a compound represented by the general formula (D), which is a novel compound.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. The method for producing the compound represented by the general formula (C) or a salt thereof according to the present invention is 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3 represented by the formula (A).
-Carboxaldehyde [hereinafter referred to as compound (A)] and a compound represented by the general formula (B) [hereinafter referred to as compound (B)] are subjected to a condensation reaction. In the general formula (B), the substituent R ¹ is a hydrogen atom; a straight chain such as a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group,
A branched or cyclic alkyl group; an aralkyl group such as a benzyl group or a phenethyl group; or a phenyl group, a mesityl group,
An aryl group such as a naphthyl group is shown, among which an alkyl group having 1 to 4 carbon atoms or a phenyl group is preferable, and a methyl group or an ethyl group is particularly preferable.

The condensation reaction between the compound (A) and the compound (B) can be carried out by the same operation as what is called the so-called aldol reaction, and is usually performed under a nitrogen gas or an inert gas atmosphere. A method in which a base is added to a solution containing (B) and then a solution containing the compound (A) is added dropwise to the solution is preferably performed. Examples of the base used in the condensation reaction include alkali metal or alkaline earth metal hydrides such as sodium hydride, potassium hydride and calcium hydride; alkyl lithium reagents such as n-butyl lithium and tertiary butyl lithium; Grignard reagents such as t-butyl magnesium chloride; alkali metal alkoxides such as sodium ethoxide; NaN
Examples thereof include H _{2 and the} like, as well as solid bases such as oxides of alkaline earth metals such as magnesium oxide.
Of these, alkali metal or alkaline earth metal hydrides and NaNH ₂ are preferable, alkali metal hydrides are more preferable, and sodium hydride is particularly preferable.

The amount of the base used is usually 1.5 equivalents or more, preferably 2 equivalents or more based on the compound (B), but if used in an excessively large amount, a side reaction may occur and the yield may decrease. Therefore, it is usually used in the range of 10 equivalents or less. Of these, the preferred range is 2-3 equivalents, and particularly preferred is 2-2.7 equivalents.

The reaction is usually carried out using a solvent, and the solvent is an aromatic hydrocarbon solvent such as toluene, benzene or xylene; an ether solvent such as methyl-t-butyl ether, dimethoxyethane or tetrahydrofuran; Halogenated hydrocarbon solvents such as methylene; aprotic solvents such as N, N-dimethylformamide can be used. Among these, preferred solvents have a dielectric constant of 2.5 or higher at 20 ° C, more preferably 5 That is all. Specific examples of the preferred solvent include tetrahydrofuran,
Examples thereof include dimethoxyethane, N, N-dimethylformamide and N, N-dimethylimidazolidinone, and tetrahydrofuran is particularly preferable. The amount of the solvent used is usually about 0.5 to 100 times the volume of the reaction substrate, and from the industrial viewpoint, it is preferably 20 times or less.

As the reaction procedure, the compound (A) may be added after mixing the base and the compound (B), or the mixture of the base and the compound (B) may be added to the compound (A). Alternatively, a mixture of the compounds (A) and (B) in a base may be added, or a base may be added to the mixture of the compounds (A) and (B). . Although the reaction proceeds with any of the operations, it is preferably a method of mixing the base and the compound (B) and then adding the compound (A) thereto. The reaction is -50 ° C to 100 ° C, preferably-
The reaction may be carried out at a temperature of 20 ° C to 40 ° C for usually 30 minutes or longer, preferably 1 hour or longer, and the temperature may be raised if necessary.
After completion of the reaction, the compound (C) can be obtained by adding water, acetic acid, ammonium chloride or the like to the reaction system to stop the reaction, and then performing usual isolation / purification operations such as washing with water and separation / extraction.

The acid addition salt of the compound (C) of the present invention is, after the termination of the above reaction, washed with water, and if necessary, the organic phase obtained by liquid separation and extraction is concentrated and / or cooled, and an acid is added and stirred. You can get it. Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as p-toluenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid. Of these, hydrochloric acid and organic acids are preferable, and particularly preferable are:
It is hydrochloric acid. As a reaction operation, a method of adding dropwise a solution of compound (C) diluted with a solvent such as ethyl acetate in an amount of about equimolar amount to the compound (C) is usually preferable. Although the dropping temperature depends on the solubility of the acid addition salt of the compound (C) in the solvent, it is usually 60
The acid addition salt of compound (C) can be isolated according to a usual crystallization operation, such as cooling at or below 0 ° C., cooling and concentration after dropping, if necessary. When R ¹ is a hydrogen atom in the general formula (C), an ammonium salt or an amine addition salt can be obtained by using ammonia or amines instead of the above acid.

In the production method of the present invention, the above compound (A) is used.
In the condensation reaction of the compound (B) with the compound (B), by selecting a base and a solvent to be used, the following general formula (D)

[Chemical 12] (In the formula, R ¹ has the same meaning as described above. R ² represents a hydroxyl group, a halogen atom, a silyloxy group, a sulfonyloxy group, an acyloxy group, an alkoxycarbonyloxy group, an alkylthiocarbonyloxy group, an alkoxythiocarbonyloxy group, or Compound (C) can also be produced after passing through a compound represented by an alkylthiothiocarbonyloxy group) [hereinafter referred to as compound (D)] or a salt thereof.

The substituent R ¹ of the above compound (D) is the same as those described above, and R ² is a hydroxyl group; a halogen atom such as a chlorine atom or a bromine atom; a trimethylsilyloxy group, a tert-butyldimethylsilyloxy group, etc. Silyloxy group; sulfonyloxy group such as methanesulfonyloxy group and paratoluenesulfonyloxy group; acyloxy group such as acetoxy group and propionyloxy group; alkoxycarbonyloxy group such as methoxycarbonyloxy group and vinyloxycarbonyloxy group; methylthiocarbonyl An alkylthiocarbonyloxy group such as an oxy group; an alkoxythiocarbonyloxy group such as a methoxythiocarbonyloxy group; or an alkylthiothiocarbonyloxy group such as a methylthiothiocarbonyloxy group. A hydroxyl group, a sulfonyloxy group or an acyloxy group is preferable, an acyloxy group is more preferable, and an acetoxy group is particularly preferable. Examples of the preferred combination of substituents for the compound (D) include a combination of preferred R ¹ and R ² mentioned in the description of the above substituents.

Of the above compounds (D), the following general formula (E) is one in which the substituent R ² is a hydroxyl group.

[Chemical 13] The compound represented by the formula (wherein R ¹ has the same meaning as above) [hereinafter referred to as the compound (E)] is preferably used as a base used in the condensation reaction of the compound (A) and the compound (B). Is an alkali metal or alkaline earth metal hydride in combination with an alkyllithium reagent, or diisopropylaminomagnesium bromide, particularly preferably Na.
It can be obtained by using H in combination with n-BuLi.

When an alkali metal or alkaline earth metal hydride and an alkyllithium reagent are used together as the base, the amount of the alkali metal or alkaline earth metal hydride used is equivalent to that of the compound (A). Before and after the molar amount, the amount of alkyllithium used was 1.
Used around 5 to 2.5 equivalents. As the solvent, it is possible to use the same as those mentioned in the description of the condensation reaction, preferably tetrahydrofuran, dimethoxyethane, N, N-dimethylformamide, N, N-dimethylimidazolidinone or dichloromethane. Can be mentioned. Also, the reaction operation can be performed in the same manner as described in the above description of the condensation reaction.

The above compound (E) has keto-enol tautomerism and exists in the form of both of the following compounds in the solvent such as in the reaction system. After the passage, the enol form mainly exists.

[Chemical 14]

Although the compound (C) or a salt thereof can be directly obtained by dehydrating the compound (E) thus obtained, the following hydroxyl group of the compound (E) is converted into another functional group which can be a leaving group. General formula (F)

[Chemical 15] (In the formula, X represents a halogen atom, a silyloxy group, a sulfonyloxy group, an acyloxy group, an alkoxycarbonyloxy group, an alkylthiocarbonyloxy group, an alkoxythiocarbonyloxy group, or an alkylthiothiocarbonyloxy group.) Compound [below,
Compound (C) can also be obtained via compound [F]. At that time, the compound (F) may be isolated, but the reaction can be continuously performed without isolation. The compounds (E) and (F) may be isolated as an acid addition salt using an organic acid in the same manner as the above method.

When the compound (C) is directly obtained from the compound (E) by a dehydration reaction, the dehydration reaction is carried out in the presence of an acid.
Examples of the acid to be used include p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, sulfuric acid, hydrochloric acid, acetic acid, boric acid and other Bronsted acids, copper (II) chloride, chloride
(I) Examples include Lewis acids such as copper, copper iodide, bismuth chloride, copper triflate, and scandium triflate, and solid acids such as silica gel and zeolite. The amount of the acid used is 0.01-fold molar equivalent or more, preferably 0.05-fold molar equivalent to 100 molar equivalents, relative to compound (E).

In the present dehydration reaction, a dehydrating agent may be allowed to coexist. However, in this dehydration reaction, an intramolecular ring-closing reaction with the carbonyl group at the 3-position occurs as a side reaction, so that the by-product is ring-opened. In order to do so, some amount of water is required in the system. Therefore, it is preferable to add the dehydrating agent after the reaction has proceeded to some extent. Examples of the dehydrating agent used include dicyclohexylcarbodiimide (DCC), acetic anhydride, magnesium sulfate, silica gel, molecular sieves and other dehydrating agents usually used in dehydration reactions, and acetic anhydride and molecular sieves are preferred. In this reaction, the water generated in the reaction may be distilled off under normal pressure or reduced pressure conditions to carry out the reaction, or in combination with a dehydrating agent.

The reaction solvent is an aromatic hydrocarbon solvent such as toluene, benzene or xylene; a chain or cyclic aliphatic hydrocarbon solvent such as hexane, cyclohexane or heptane; an ether such as methyl-t-butyl ether or tetrahydrofuran. System solvent; ester solvent such as ethyl acetate;
Halogenated hydrocarbon solvents such as methylene chloride; protic polar solvents such as methanol, ethanol, isopropyl alcohol and acetic acid can be used, and preferably tetrahydrofuran, toluene, benzene or methylene chloride,
Tetrahydrofuran or toluene is particularly preferable. In addition, since there is a problem of intramolecular ring closure reaction which is a side reaction as described above, it is possible to use a water-containing solvent. The amount of the solvent used is usually 0.5 times the volume of the reaction substrate
About 100 times the capacity is used, and from this point of view, from the industrial viewpoint, it is preferable that the capacity is 20 times or less.

The dehydration reaction can be carried out usually by dissolving the compound (E) in the above-mentioned solvent and at a reaction temperature of -20 to 180 ° C, preferably 0 to 120 ° C for the purpose of suppressing the production amount of by-products. . Further, the usual azeotropic dehydration operation can be performed in combination, and preferably, when the conversion becomes constant, water is added and the azeotropic dehydration operation is performed again. After completion of the reaction, the compound (C) or a salt thereof can be obtained by the same isolation / purification operations as separation extraction and the like as described above.

When the hydroxyl group of the compound (E) is converted into another functional group X which can be a leaving group and then the functional group X is eliminated to obtain the compound (C), the substitution reaction to the functional group X is Depending on the type of the functional group X, the substitution can be performed by a commonly used introduction method. For example, specifically
In the case of a halogen atom such as a chlorine atom and a bromine atom, a halogenating agent such as phosphorus bromide, thionyl chloride, and sulfuryl chloride, and in the case of a silyloxy group, a corresponding silyl chloride,
In the case of a sulfonyloxy group such as a methanesulfonyloxy group or a p-toluenesulfonyloxy group, a method of reacting the corresponding sulfonyl chloride or sulfonic anhydride in the presence of a base can be mentioned. In the case of an acyloxy group such as an acetoxy group or a propionyloxy group, there may be mentioned a method of reacting the corresponding acid chloride, acid anhydride or vinyl ester in the presence of an acid or a base, if necessary. Further, in the case of an alkoxycarbonyloxy group, an alkylthiocarbonyloxy group, an alkoxythiocarbonyloxy group and an alkylthiothiocarbonyloxy group, there may be mentioned a method of reacting the corresponding chloride in the presence of a base, if necessary.

The functional group X of the compound (F) thus obtained
The elimination reaction of is carried out in the presence of a base, under heating, or under a combination thereof. As the base to be used, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal or alkaline earth metal carbonates or bicarbonates such as potassium carbonate and sodium hydrogen carbonate; alkali metal such as sodium hydride Inorganic bases such as hydrides or metal alcoholates such as sodium methoxide, sodium ethoxide, potassium t-butoxide; triethylamine, 1,8-diazabicyclo [5.
Amines such as 4.0] -7-undecene, 1,5-diazabicyclo [4.3.0] -5-nonene; pyridine,
Examples thereof include organic bases such as picoline, lutidine, N, N-dimethylaminopyridine, and other pyridines, preferably alkali metal bicarbonates, alkali metal alcoholates, tertiary amines or pyridines, and particularly preferably carbonic acid. Sodium hydrogen, sodium ethoxide, triethylamine, pyridine or N, N-dimethylaminopyridine.

The elimination reaction is usually carried out at a reaction temperature of room temperature or higher, preferably at 50 to 180 ° C, particularly preferably at 80 to 120 ° C. As a reaction mode for obtaining the compound (C) from the compound (E) via the compound (F), a base is allowed to coexist in the reaction solution of the substitution reaction for the functional group X, if necessary, and the reaction solution is left as it is. By heating,
It is industrially preferable because the substitution reaction and the elimination reaction can be carried out in one pot. The compound (C) and its salt, which are the products obtained by this elimination reaction, can be obtained by the same usual isolation and purification operations as described above, such as washing with water and separation extraction, after the completion of the above reaction. .

In the present invention, the compound (D) obtained by the above condensation reaction is a novel compound and is described in the above (3).
R, 5S)-(E) -7- [2-Cyclopropyl-4-
(4-Fluorophenyl) -quinolin-3-yl]-
It is a compound useful as a raw material for synthesizing 3,5-dihydroxyhept-6-enoic acid esters. Further, the compound (C) or a salt thereof obtained by the production method of the present invention is a carbonyl group by a known stereoselective reduction reaction using a microorganism, a chiral boron-based reducing agent or the like with respect to the carbonyl group in the compound. The corresponding dihydroxycarboxylic acid can be obtained by reducing the group and, if necessary, performing a deesterification reaction in the presence of an alkali. By treating the dihydroxycarboxylic acid thus obtained with an alkali metal such as sodium hydroxide or calcium chloride, an alkaline earth metal and / or salts thereof, (3
R, 5S)-(E) -7- [2-Cyclopropyl-4-
(4-Fluorophenyl) -quinolin-3-yl]-
Salts of 3,5-dihydroxyhept-6-enoic acid can be prepared. This compound is useful as a blood cholesterol lowering agent as described above.

[0027]

The present invention will be further described below with reference to examples, but the present invention is not limited to these examples as long as the gist thereof is not exceeded. (Example 1)

[Chemical 16]

Oily, 60% sodium hydride 2.40
g and tetrahydrofuran 200 ml, while maintaining the internal temperature at 2 ° C or lower, 3,5-dioxohexanoic acid ethyl ester 10.3 g and tetrahydrofuran 40 m
1 of the mixed solution was added dropwise over 20 minutes. After reacting at -10 ° C for 50 minutes, 75 ml of 1.6 M hexane solution of n-butyllithium was added dropwise over 40 minutes while keeping the internal temperature at -20 to -15 ° C, and reacted at internal temperature of 2 ° C or lower for 40 minutes. Let While keeping the internal temperature at -15 ° C or lower, 2-cyclopropyl-4- (4-fluorophenyl) quinoline-
A mixed solution of 3-carbaldehyde (11.7 g) and tetrahydrofuran (80 ml) was added dropwise over 40 minutes, and the mixture was mixed at 10 ° C or lower for 1
Reacted for hours. While maintaining the internal temperature at 5 ° C or lower, 14.4 ml of acetic acid and 40 ml of toluene were added to the reaction system, and then washed successively with 100 ml of water and 100 ml of saturated saline.
After distilling off the solvent, hexane 100 m was added to the obtained residue.
1, 5 ml of ethyl acetate were added to crystallize, and this was collected by filtration,
Dried, 7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -7-hydroxy-
3,5-Dioxoheptanoic acid ethyl ester 16.6 g
(Yield 89%) was obtained. The NMR of the compound is as follows. ¹ H-NMR (CDCl ₃ ): 1.11 (2H, m), 1.13 (1H,
m), 1.27 (3H, t, J = 10), 1.76 (1H, m), 2.40 (1H,
m), 2.48 (2H, ABq, J = 66,14), 2.69 (2H, ABq, J = 52,1
6), 2.78 (1H, m), 3.30 (1H, m), 4.18 (2H, m), 5.25
(1H, d, J = 3), 5.58 (1H, dd, J = 12,4), 7.16-7.26 (5
H, m), 7.33 (1H, dd, J = 7,7), 7,61 (1H, dd, J = 7,7),
7.93 (1H, d, J = 7)

(Example 2)

[Chemical 17]

20.0 g of 7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -7-hydroxy-3,5-dioxoheptanoic acid ethyl ester obtained in Example 1 Was dissolved in 120 ml of toluene, 10 g of silica gel and 8 g of anhydrous magnesium sulfate were added, and the mixture was reacted at 95 ° C. for 16 hours. After removing the silica gel and the inorganic salt of the reaction system, the solvent was distilled off, and the obtained residue was purified by column chromatography (developing solvent; hexane: ethyl acetate = 2: 1) to obtain (6E) -7. −
[2-cyclopropyl-4- (4-fluorophenyl)
8.4 g (yield 44%) of quinolin-3-yl] -3,5-dioxoheptenoic acid ethyl ester was obtained. The NMR of the compound is as follows. ¹ H-NMR (CDCl ₃ ): 1.09 (2H, m), 1.28 (3H,
t, J = 7), 1.40 (2H, m), 2.38 (1H, m), 3.40 (2H, s),
4.20 (2H, q, J = 7), 5.51 (1H, s), 6.02 (1H, d, J = 1
6), 7.16-7.26 (4H, m), 7.30-7.40 (2H, m), 7.70
(1H, d, J = 16), 7.63 (1H, m), 7.97 (1H, m)

(Example 3) Ethyl 7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -7-hydroxy-3,5-dioxoheptanoate obtained in Example 1 A mixture of 5.0 g of ester, 10 ml of toluene, and 0.37 g of anhydrous p-toluenesulfonic acid was added at 110 ° C.
Was reacted for 3 hours. After washing the reaction system with aqueous sodium hydrogen carbonate, the obtained organic layer was concentrated, and the obtained residue was subjected to column chromatography (developing solvent; hexane: ethyl acetate =
2: 1) and purified (6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dioxoheptenoic acid ethyl ester.
0 g (63% yield) was obtained.

Example 4 Ethyl 7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -7-hydroxy-3,5-dioxoheptanoate obtained in Example 1. 0.50 g of ester, 20 ml of toluene,
A mixture of 0.037 g of anhydrous p-toluenesulfonic acid was reacted under reduced pressure at an internal temperature of 105 ° C. for 1 hour while distilling off water produced by the reaction by azeotropic distillation with toluene. After returning to normal pressure, 0.097 g of water was added to the reaction system and reacted at 90 ° C. for 10 minutes, then again under reduced pressure conditions and an internal temperature of 105.
The reaction was carried out at 0 ° C for 1 hour while distilling off water. The reaction system was analyzed by high performance liquid chromatography (6E) -7-
[2-cyclopropyl-4- (4-fluorophenyl)
It was confirmed that 0.37 g (yield 78%) of quinolin-3-yl] -3,5-dioxoheptenoic acid ethyl ester was produced.

Example 5 Ethyl 7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -7-hydroxy-3,5-dioxoheptanoate obtained in Example 1 0.01 g of sulfuric acid was added to a mixed solution of 0.2 g of ester and 2 ml of vinyl acetate, and the mixture was reacted under heating under reflux for 5 hours. The reaction system was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, the resulting organic layer was concentrated, and the obtained residue was purified by column chromatography (developing solvent; hexane: ethyl acetate = 2: 1). , (6E) -7- [2-Cyclopropyl-4- (4-fluorophenyl) quinoline-3-
Ile] -3,5-dioxoheptenoic acid ethyl ester (0.14 g, yield 73%) was obtained.

Example 6 Ethyl 7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -7-hydroxy-3,5-dioxoheptanoate obtained in Example 1 A mixed solution of 2.0 g of ester, 10 ml of acetic acid, 0.66 g of acetic anhydride and 0.01 g of N, N-dimethyl-4-aminopyridine was reacted at 90 ° C. for 4 hours. The reaction system was diluted with ethyl acetate, washed with water and aqueous sodium hydrogen carbonate, the obtained organic layer was concentrated, and the obtained residue was crystallized with hexane to give (6E) -7- [2-cyclopropyl. −
4- (4-fluorophenyl) quinolin-3-yl]-
3,5-dioxoheptenoic acid ethyl ester 1.55 g
(Yield 80%) was obtained.

Example 7 Ethyl 7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -7-hydroxy-3,5-dioxoheptanoate obtained in Example 1. 0.250 g of the ester was dissolved in 5 ml of a 4 mol / L hydrochloric acid / ethyl acetate solution, and stirring was continued at 20 ° C. for 12 hours. The reaction system was analyzed by high performance liquid chromatography, and (6E) -7- [2-cyclopropyl-4-
(4-Fluorophenyl) quinolin-3-yl] -3,
5-dioxoheptenoic acid ethyl ester 0.198 g
It was confirmed that the corresponding amount (yield 82%) was generated.

(Example 8) In a mixed solution of oil, 60% sodium hydride (1.37 g) and tetrahydrofuran (10 ml), while keeping the internal temperature at 20 ° C, 2,5-dioxohexanoic acid ethyl ester (2.36 g) and tetrahydrofuran 10 ml of the mixed solution was added dropwise over 5 minutes. After stirring at that temperature for 1 hour, 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3-carbaldehyde 2.0
A mixed solution of 1 g and 20 ml of tetrahydrofuran was added dropwise over 20 minutes. After stirring for 4 hours, the reaction solution was added to 3.09 g of acetic acid and 20 ml of water to stop the reaction. It is extracted with 40 ml of ethyl acetate, and the organic phase is 20 ml of saturated saline.
It was washed with and dried over 2 g of anhydrous sodium sulfate. When the obtained organic phase is analyzed, it is the target product (6E) -7-
[2-cyclopropyl-4- (4-fluorophenyl)
2.52 g (yield 82%) of quinolin-3-yl] -3,5-dioxoheptenoic acid ethyl ester was obtained. After distilling off the solvent, 4 mol / L hydrochloric acid / ethyl acetate solution (1.7 ml) was added to the obtained residue at room temperature. After the crystals were formed, the temperature was cooled to 5 ° C., and the crystals were collected by filtration and dried to obtain (6E) -7- [2-cyclopropyl-4- (4-
Fluorophenyl) quinolin-3-yl] -3,5-dioxoheptenoic acid ethyl ester hydrochloride 2.49 g
(Yield 75%) was obtained.

[0037]

EFFECTS OF THE INVENTION According to the present invention, (3R, 5S)-(E) -7- [2-
Cyclopropyl-4- (4-fluorophenyl) -quinolin-3-yl] -3,5-dihydroxyhept-6-
The 3,5-dioxo-6-heptenoic acid ester, which is a raw material for the synthesis of enoic acid esters, can be industrially easily produced.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Manabu Katsuta             1000 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa             Within Mitsubishi Chemical Corporation (72) Inventor Akemi Hosokawa             1000 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa             Within Mitsubishi Chemical Corporation (72) Inventor Yoichi Matsumoto             1000 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa             Within Mitsubishi Chemical Corporation (72) Inventor Yuzo Kasuga             1000 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa             Within Mitsubishi Chemical Corporation (72) Inventor Naoyuki Watanabe             1000 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa             Within Mitsubishi Chemical Corporation F-term (reference) 4C031 BA07

Claims (4)

[Claims] 1. The following formula (A): 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3-carbaldehyde represented by the following general formula
(B) [Chemical 2] (In the formula, R ¹ represents a hydrogen atom, an alkyl group, an aralkyl group or an aryl group.) A condensation reaction is carried out with a compound represented by the following general formula (C): (In the formula, R ¹ has the same meaning as described above.) A method for producing a compound or a salt thereof. 2. A process for producing a compound represented by the general formula (C) or a salt thereof by a condensation reaction between the compound represented by the formula (A) and the compound represented by the general formula (B). As an intermediate, the following general formula (D): (In the formula, R ¹ has the same meaning as described above, and R ² represents a hydroxyl group, a halogen atom, a silyloxy group, a sulfonyloxy group, an acyloxy group, an alkoxycarbonyloxy group, an alkylthiocarbonyloxy group, an alkoxythiocarbonyloxy group, or The compound according to claim 1, which represents an alkylthiothiocarbonyloxy group, or a salt thereof. 3. The following general formula (D): (In the formula, R ¹ and R ² have the same meanings as described above.) R ² is eliminated from the compound represented by the formula or a salt thereof, and the following general formula (C): (In the formula, R ¹ has the same meaning as described above.) A method for producing a compound or a salt thereof. 4. The following general formula (D): (In the formula, R ¹ and R ² have the same meanings as described above.).