JP2011173912A - Method for producing (3r, 5s)-7-substituted-3,5-dihydroxyhept-6-enoic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an intermediate which is useful as a synthetic intermediate of a cholesterol lowering agent (an HMG-CoA reducing enzyme inhibitory drug). <P>SOLUTION: An achiral amine salt of (3R, 5S)-7-substituted-3,5-dihydroxyhept-6-enoic acid represented by general formula (4) (wherein R<SP>1</SP>and R<SP>2</SP>are each a hydrogen atom and R<SP>3</SP>is a 7C-12C aralkyl group, or R<SP>1</SP>is a hydrogen atom and R<SP>2</SP>and R<SP>3</SP>are each a 3C-10C cycloalkyl group) is obtained. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a method for producing (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid, which is useful as a synthesis intermediate of a cholesterol-lowering agent (HMG-CoA reductase inhibitor). In particular, it relates to a process for producing (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid.

Conventionally, (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid is selectively selected from a mixture of optical isomers of 7-substituted-3,5-dihydroxyhept-6-enoic acid. As a method for producing the compound, a method using a chiral amine (for example, (R)-(+)-α-methylbenzylamine) is known (Bioorg. Med. Chem. Lett., 9 , 2977 ( 1999)). However, this method requires the use of a stoichiometric amount of an expensive chiral amine, and the desired (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid. It was not an industrially suitable method because the yield was as low as about 30%.

  The object of the present invention is to solve the above problems and provide an industrially suitable process for producing (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid.

The subject of the present invention is
(A) Formula (1)

7-substituted-3,5-dihydroxyhept-6-enoic acid (a mixture of optical isomers) represented by the general formula (2)

(In the formula, R ¹ , R ² and R ³ represent a hydrogen atom or a hydrocarbon group.)
Is reacted with an achiral amine represented by the general formula (3)

(In the formula, R ¹ , R ² and R ³ are as defined above.)
A first step of producing an achiral amine salt (a mixture of optical isomers) of 7-substituted-3,5-dihydroxyhept-6-enoic acid represented by
(B) Then, an achiral amine salt (optical isomer mixture) of 7-substituted-3,5-dihydroxyhept-6-enoic acid is crystallized in a solvent to obtain a compound represented by the general formula (4)

(In the formula, R ¹ , R ² and R ³ are as defined above.)
A second step for selectively obtaining an achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid represented by
(C) Further, the achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid is acidified to give a compound of formula (5)

And (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid represented by the third step It is solved by the process of -3,5-dihydroxyhept-6-enoic acid.

  According to the present invention, industrially suitable (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid, in particular (3R, 5S) -7- {2-cyclopropyl-4- A method for producing (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid can be provided.

The present invention
(A) A 7-substituted-3,5-dihydroxyhept-6-enoic acid (mixture of optical isomers) represented by the formula (1) is reacted with an achiral amine represented by the general formula (2), A first step of generating an achiral amine salt (a mixture of optical isomers) of 7-substituted-3,5-dihydroxyhept-6-enoic acid represented by the general formula (3);
(B) Then, an achiral amine salt (optical isomer mixture) of 7-substituted-3,5-dihydroxyhept-6-enoic acid was crystallized in a solvent and represented by the general formula (4) ( A second step for selectively obtaining an achiral amine of 3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid;
(C) Furthermore, the achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid is acidified to give (3R, 5S)-represented by formula (5) A third step to obtain 7-substituted-3,5-dihydroxyhept-6-enoic acid;
(3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid is produced by three steps comprising:

Subsequently, the above three steps will be described sequentially.
(A) First Step In the first step of the present invention, the 7-substituted-3,5-dihydroxyhept-6-enoic acid (optical isomer mixture) represented by the formula (1) is added to the general formula (2). Achiral amine salt of 7-substituted-3,5-dihydroxyhept-6-enoic acid represented by the general formula (3) (a mixture of optical isomers) It is.

  The 7-substituted-3,5-dihydroxyhept-6-enoic acid (optical isomer mixture) used in the first step of the present invention is represented by the above formula (1). Specifically, Formula (6)

In particular, a mixture of optical isomers comprising (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid as a main component. .

  The 7-substituted-3,5-dihydroxyhept-6-enoic acid (a mixture of optical isomers) is synthesized by, for example, a method described in JP-A-8-92217. -Dihydroxyhept-6-enoic acid ester (optical isomer mixture) can be easily obtained by hydrolysis (described in Reference Examples 1 to 3).

The achiral amine used in the first step of the present invention specifically indicates an amine having no asymmetric carbon atom. The achiral amine is represented by the above general formula (2). In the general formula (2), R ¹ , R ² and R ³ are a hydrogen atom or a hydrocarbon group, for example, a hydrogen atom; Group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group and other alkyl groups having 1 to 10 carbon atoms; cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclo A cycloalkyl group having 3 to 10 carbon atoms such as hexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group and cyclodecyl group; an aralkyl group having 7 to 12 carbon atoms such as benzyl group, phenylethyl group and phenylpropyl group; Can be mentioned. As a preferred embodiment of the above ^R 1, ^{R 2} and ^{R 3, R 3} is an aralkyl group in ^{R 1} and ^{R 2} are hydrogen atoms, ^{R 1} is ^{R 2} and ^{R 3} a hydrogen atom is a cycloalkyl group .

  The amount of the achiral amine to be used is preferably 0.5 to 2.0 mol, more preferably 0, per 1 mol of 7-substituted-3,5-dihydroxyhept-6-enoic acid (optical isomer mixture). .8 to 1.2 mol.

  The first step of the present invention is preferably performed in the presence of a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; methanol, ethanol, isopropyl alcohol, t- Alcohols such as butyl alcohol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether and tetrahydrofuran; carboxylic acid esters such as methyl acetate and ethyl acetate; methylene chloride, chloroform and dichloroethane And halogenated aliphatic hydrocarbons such as carboxylic acid esters, more preferably ethyl acetate. These solvents may be used alone or in combination of two or more.

  The amount of the solvent used is appropriately adjusted depending on the homogeneity and stirrability of the reaction solution, but is preferably 1 g of 7-substituted-3,5-dihydroxyhept-6-enoic acid (optical isomer mixture). 5 to 100 g, more preferably 10 to 50 g.

  The first step of the present invention is performed, for example, by a method such as mixing 7-substituted-3,5-dihydroxyhept-6-enoic acid (optical isomer mixture), achiral amine and solvent and stirring. Is called. The reaction temperature at that time is preferably -20 to 100 ° C, more preferably 0 to 50 ° C, and the reaction pressure is not particularly limited.

  The achiral amine salt (optical isomer mixture) of 7-substituted-3,5-dihydroxyhept-6-enoic acid obtained by the first step of the present invention can be cooled, for example, after completion of the reaction. Can be obtained as crystals.

(B) Second Step The second step of the present invention is an achiral amine of 7-substituted-3,5-dihydroxyhept-6-enoic acid represented by the general formula (3) obtained in the first step. Crystallization of a salt (a mixture of optical isomers) in a solvent yields an achiral amine of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid represented by the general formula (4) This is a step of selectively obtaining a salt.

  Examples of the solvent used in the second step of the present invention include water; alcohols such as methanol, ethanol, isopropyl alcohol and t-butyl alcohol; ethers such as diethyl ether, diisopropyl ether and tetrahydrofuran; methylene chloride and chloroform. Halogenated hydrocarbons such as benzene, toluene, xylene, etc .; Carboxylic acid esters such as methyl acetate and ethyl acetate; Nitriles such as acetonitrile and propionitrile; Acetone, methyl isobutyl ketone, etc. Ketones; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and the like, preferably ethers, ketones, amides, more preferably ethers, ketones, particularly preferably tetrahydrofuran, Me Louis Soviet-butyl ketone is used. These solvents may be used alone or in combination of two or more.

  The amount of the solvent to be used is preferably 1 to 100 g, more preferably 5 to 1 g of achiral amine salt (optical isomer mixture) of 7-substituted-3,5-dihydroxyhept-6-enoic acid. 50 g, particularly preferably 10 to 30 g.

  In the second step of the present invention, for example, the achiral amine salt (optical isomer mixture) of 7-substituted-3,5-dihydroxyhept-6-enoic acid obtained in the first step is dissolved in a solvent. After making it into a homogeneous solution (if necessary, it may be dissolved by heating), followed by cooling to precipitate crystals (crystallization). The cooling temperature in that case becomes like this. Preferably it is -50-80 degreeC, More preferably, it is -20-40 degreeC, Most preferably, it is -10-20 degreeC. If necessary, this operation may be repeated.

  The achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid obtained selectively by the second step of the present invention is filtered, for example, after crystallization is completed. Can be obtained as free crystals.

(C) Third Step The third step of the present invention is the (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-6 represented by the general formula (4) obtained in the second step. In this step, an achiral amine salt of enoic acid is acidified to obtain (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid represented by formula (5).

  The acidification in the third step of the present invention is not particularly limited as long as it is a general method for acidifying a carboxylate to obtain a free carboxylic acid, but it is preferably performed in a solvent in the presence of an acid.

  Examples of the acid used in the third step of the present invention include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Preferably, a mineral acid, more preferably hydrochloric acid or sulfuric acid is used. These acids may be used alone or in combination of two or more.

  The amount of the acid used is determined by acidifying the achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid to form a free carboxylic acid ((3R, 5S)- 7-substituted-3,5-dihydroxyhept-6-enoic acid) is not particularly limited, but (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid The amount is preferably 1.0 to 1.1 mol with respect to 1 mol of the achiral amine salt.

  The solvent used in the third step of the present invention is not particularly limited as long as it does not inhibit the reaction. For example, water; alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol; acetonitrile, propionitrile And nitriles such as alcohol, preferably alcohols, more preferably methanol and ethanol. These solvents may be used alone or in combination of two or more.

  The amount of the solvent used is appropriately adjusted depending on the homogeneity and stirrability of the reaction solution, but it can be adjusted to 1 g of an achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid. On the other hand, it is preferably 1 to 50 g, more preferably 10 to 30 g.

  In the third step of the present invention, for example, the achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid obtained in the second step, an acid and a solvent are mixed. And stirring. The temperature at that time is preferably -20 to 100 ° C, more preferably 0 to 50 ° C, and the pressure is not particularly limited.

  (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid obtained by the third step of the present invention is generally obtained by, for example, extraction, concentration, recrystallization and the like after completion of hydrolysis. Separated and purified by various methods.

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, the optical purity (enantiomeric excess (% ee) and diastereomeric excess (% de)) in the examples was performed using high performance liquid chromatography under the following analysis conditions. The optical purity of (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydrohept-6-enoic acid is determined by By heating in a group hydrocarbon solvent to give the corresponding lactone ((4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} ethenyl] -4- It was measured after derivatization to hydroxytetrahydropyran-2-one (described in Reference Examples 4 and 5 later).

Analysis conditions for high performance liquid chromatography:
(Enantiomeric excess)

(Diastereomer excess)

Reference example 1
(Synthesis of 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} 5-hydroxyhept-6-enoic acid isopropyl (mixture of optical isomers))
Into a 100-ml flask equipped with a stirrer, thermometer and dropping funnel, titanium tetraisopropoxide 6.58 g (22.0 mmol), (S) -2- {N- (3,5-di-tert- 6.70 g (21.0 mmol) of butylsalicylidene) amino} -3-methyl-1-butanol and 40 ml of methylene chloride were added and stirred at room temperature for 1 hour. Subsequently, the reaction solution was cooled to −30 ° C., and 6.36 g (20.0 mmol) of 3- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} prop-2-enal was added to methylene chloride. What was dissolved in 6 ml was added and stirred for 30 minutes. Furthermore, 2.52 g (30.0 mmol) of diketene was added and reacted for 6 hours while raising the temperature to −20 ° C.
After completion of the reaction, the obtained reaction solution was taken out, added to a mixed solution of 105.29 g (42.0 mmol) of 5.0 mass% oxalic acid aqueous solution and 50 ml of 1,2-dichloroethane, and vigorously stirred at room temperature for 1 hour. Thereafter, the organic layer was taken out, washed in the order of 50 ml of a 5.0 mass% oxalic acid aqueous solution, 50 ml of water, and 30 ml of a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. After filtration through celite, the filtrate was concentrated under reduced pressure, 50 ml of n-hexane was added to the concentrate, and the mixture was vigorously stirred for 1 hour to precipitate a solid. This was filtered and dried and isopropyl 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -5-hydroxy-3-oxohept-6-enoate (optical isomerism) as a yellow powder. Body mixture) 7.84 g was obtained (isolation yield: 85.0%).

Reference example 2
(Synthesis of 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid isopropyl (mixture of optical isomers))
7- {2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -5-hydroxy synthesized in Reference Example 1 was added to a 300-ml flask equipped with a stirrer, a thermometer and a dropping funnel. 6.91 g (15.0 mmol) of isopropyl-3-oxohept-6-enoate (optical isomer mixture), 120 ml of tetrahydrofuran and 30 ml of methanol were added and cooled to −75 ° C., and 1 mol / l diethylmethoxyboron tetrahydrofuran solution 16. 5 ml was added and stirred for 30 minutes. Next, 684 mg (18.0 mmol) of sodium borohydride was added and reacted at the same temperature for 5 hours. After completion of the reaction, 11 ml of acetic acid and 100 ml of ethyl acetate were added and stirred at room temperature for 20 minutes. The obtained reaction solution was washed with 100 ml of saturated sodium hydrogen carbonate twice and once with 50 ml of saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. To the obtained concentrate, 100 ml of methanol was added and concentrated under normal pressure heating. This operation was repeated 3 times, and isopropyl 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoate (optical isomerism) was obtained as a yellow oily substance. Body mixture) 6.60 g was obtained (isolation yield: 95.3%).
In addition, when this compound was analyzed by high performance liquid chromatography, (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept The optical purity of isopropyl-6-enoate was 73% ee and 97% de.

Reference example 3
(Synthesis of 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid (mixture of optical isomers))
7- {2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5 synthesized in Reference Example 2 was added to a 50 ml internal flask equipped with a stirrer, a thermometer and a dropping funnel. -Addition of 4.63 g (10.0 mmol) of isopropyl dihydroxyhept-6-enoate (optical isomer mixture), 10 ml of methanol and 12 ml (12.0 mmol) of 1 mol / l aqueous sodium hydroxide solution, and reaction at room temperature for 1 hour It was. After completion of the reaction, 1 mol / l hydrochloric acid was added to adjust the pH of the reaction solution to 3.5. Subsequently, after extracting twice with 10 ml of ethyl acetate, the organic layer was separated and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-ene as a pale yellow oil. 4.21 g of acid (optical isomer mixture) was obtained (isolation yield: 100%).

Example 1
(First step: 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid benzylamine salt (mixture of optical isomers) Synthesis)
7- {2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxy obtained in Reference Example 3 was added to a 50-ml flask equipped with a stirrer and a thermometer. When 4.21 g (10.0 mmol) of hept-6-enoic acid (mixture of optical isomers), 1.07 g (10.0 mmol) of benzylamine and 30 ml of ethyl acetate are added and cooled to 0 ° C. with stirring, crystals are precipitated. I came. The crystals were filtered, washed with 15 ml of ethyl acetate cooled to 0 ° C. and then dried under reduced pressure to give 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3 as colorless crystals. , 5-dihydroxyhept-6-enoic acid benzylamine salt (optical isomer mixture) 5.01 g was obtained (isolation yield: 94.9%).

Example 2
(Second step: (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid benzylamine salt Synthesis)
7- {2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxy obtained in Example 1 was placed in a 100-ml flask equipped with a stirrer and a thermometer. 4.22 g (8.00 mmol) of hept-6-enoic acid benzylamine salt (optical isomer mixture) and 84 ml of tetrahydrofuran were added, and the mixture was heated to 50 ° C. with stirring to obtain a homogeneous solution. Next, when the reaction solution was cooled to 0 ° C., crystals were precipitated, and the crystals were filtered and washed with 42 ml of tetrahydrofuran cooled to 0 ° C. This crystallization operation was repeated twice. The obtained crystals were dried under reduced pressure to give (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept as colorless crystals. 2.52 g of -6-enoic acid benzylamine salt was obtained (isolation yield: 60.0%).
In addition, (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid benzylamine salt is It is a novel compound represented by physical property values.

Melting point: 118-120 ° C
¹ H-NMR (CD ₃ OD, δ (ppm)); 1.04 to 1.07 (2H, m), 1.25 to 1.28 (2H, m), 1.28 to 1.33 (1H , M), 1.51 to 1.56 (1H, m), 2.23 to 2.29 (2H, m), 2.51 to 2.55 (1H, m), 3.76 to 3.80 (1H, m), 4.25 to 4.29 (1H, m), 5.66 (1H, dd, J = 6.3, 15.9 Hz), 6.62 (1H, dd, J = 1. 2, 15.9 Hz), 7.24-7.40 (4H, m), 7.40-7.44 (2H, m), 7.44-7.49 (5H, m), 7.58- 7.61 (1H, m), 7.91 (1H, d, J = 8.1 Hz)

Example 3
(Third step: Synthesis of (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid)
(3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3, obtained in Example 2, was added to a flask with an internal volume of 50 ml equipped with a stirrer. 2.11 g (4.00 mmol) of 5-dihydroxyhept-6-enoic acid benzylamine salt and 10 ml of methanol were added. Thereafter, 1 mol / l hydrochloric acid was added to adjust the pH of the reaction solution to 3.5. Subsequently, after extracting twice with 10 ml of ethyl acetate, the organic layer was separated and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhe as a colorless oil. 1.66 g of pt-6-enoic acid was obtained (isolation yield: 99.0%).

Reference example 4
(Synthesis of (4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} ethenyl] -4-hydroxytetrahydropyran-2-one)
(3R, 5S) -7- {2-cyclopropyl-4- (4-) obtained in Example 3 was placed in a 20-ml flask equipped with a stirrer, thermometer, reflux condenser and Dean-Stark apparatus. Fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid (1.26 g, 3.00 mmol) and toluene (5 ml) were added, and the water formed was removed at 90 to 110 ° C. while removing 2 Reacted for hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to dry the solid, and (4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) was obtained as colorless crystals. ) Quinolin-3-yl} ethenyl] -4-hydroxytetrahydropyran-2-one was obtained (isolated yield: 100%).
In addition, when this compound was analyzed by high performance liquid chromatography, (4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} ethenyl] -4- The optical purity of hydroxytetrahydropyran-2-one was 99% ee or higher and 99% de or higher.

Example 4
(First step: of 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid dicyclohexylamine salt (mixture of optical isomers) Synthesis)
7- {2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3 obtained in the same manner as in Reference Example 3 in a 50-ml flask equipped with a stirrer and a thermometer , 5-dihydroxyhept-6-enoic acid (optical isomer mixture) 4.21 g (10.0 mmol), dicyclohexylamine 1.81 g (10.0 mmol) and ethyl acetate 30 ml were added, and the mixture was cooled to 0 ° C. with stirring. Then crystals began to precipitate. The crystals were filtered, washed with 15 ml of ethyl acetate cooled to 0 ° C. and then dried under reduced pressure to give 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3 as colorless crystals. , 5-dihydroxyhept-6-enoic acid dicyclohexylamine salt (optical isomer mixture) 5.66 g was obtained (isolation yield: 94.0%).

Example 5
(Second step: (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid dicyclohexylamine salt Synthesis)
7- {2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxy obtained in Example 4 was placed in a 100-ml flask equipped with a stirrer and a thermometer. 4.81 g (8.00 mmol) of hept-6-enoic acid dicyclohexylamine salt (optical isomer mixture) and 72 ml of tetrahydrofuran were added, and the mixture was heated to 50 ° C. with stirring to obtain a homogeneous solution. Next, when the reaction solution was cooled to 0 ° C., crystals began to precipitate, and the crystals were filtered and washed with 36 ml of tetrahydrofuran cooled to 0 ° C. This crystallization operation was repeated three times. The obtained crystals were dried under reduced pressure to give (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept as colorless crystals. 2.50 g of 6-enoic acid dicyclohexylamine salt was obtained (isolation yield: 51.9%).
In addition, (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid dicyclohexylamine salt is: It is a novel compound represented by physical property values.

Melting point: 154-156 ° C
¹ H-NMR (CD ₃ OD, δ (ppm)); 1.04 to 1.07 (2H, m), 1.07 to 1.48 (6H, m), 1.51 to 1.61 (2H) M), 1.61-1.75 (2H, m), 1.75-1.93 (4H, m), 1.93-2.20 (4H, m), 2.20-2.30. (2H, m), 2.49 to 2.52 (1H, m), 3.12 to 3.20 (2H, m), 3.68 to 3.82 (1H, m), 4.20 to 4 .31 (1H, m), 5.66 (1H, dd, J = 6.3, 15.6 Hz), 6.62 (1H, dd, J = 1.2, 15.6 Hz), 7.30 to 7.34 (4H, m), 7.34 to 7.39 (2H, m), 7.55 to 7.68 (1H, m), 7.91 (1H, d, J = 8.4 Hz)

Example 6
(Third step: Synthesis of (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid)
(3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3, obtained in Example 5, was added to a 50-ml flask equipped with a stirrer. 2.41 g (4.00 mmol) of 5-dihydroxyhept-6-enoic acid dicyclohexylamine salt and 10 ml of methanol were added. Thereafter, 1 mol / l hydrochloric acid was added to adjust the pH of the reaction solution to 3.5. Subsequently, after extracting twice with 10 ml of ethyl acetate, the organic layer was separated and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhe as a colorless oil. 1.64 g of pt-6-enoic acid was obtained (isolation yield: 97.5%).

Reference Example 5
(Synthesis of (4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} ethenyl] -4-hydroxytetrahydropyran-2-one)
(3R, 5S) -7- {2-cyclopropyl-4- (4-) obtained in Example 6 was placed in a 20-ml flask equipped with a stirrer, thermometer, reflux condenser and Dean-Stark apparatus. Fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid (1.26 g, 3.00 mmol) and toluene (5 ml) were added, and the water formed was removed at 90 to 110 ° C. while removing 2 Reacted for hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to dry the solid, and (4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) was obtained as colorless crystals. ) Quinolin-3-yl} ethenyl] -4-hydroxytetrahydropyran-2-one 1.20 g (isolation yield: 99.3%).
In addition, when this compound was analyzed by high performance liquid chromatography, (4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} ethenyl] -4- The optical purity of hydroxytetrahydropyran-2-one was 99% ee or higher and 99% de or higher.

Claims (1)

General formula (4)

(In the formula, R ¹ and R ² represent a hydrogen atom and R ³ represents an aralkyl group having 7 to 12 carbon atoms, or R ¹ represents a hydrogen atom, and R ² and R ³ represent a cycloalkyl group having 3 to 10 carbon atoms. Show.)
An achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid represented by