JPH083138A - Cleavage reaction with ozone - Google Patents

Abstract

PURPOSE:To enable the reutilization of a (3S,5R)-isomer as an aldehyde derivative which is a synthetic raw material for a mavalonolactone-based compound by carrying out the ozonolysrs of the (3S,5R)-isomer that is unnecessary after optically resolving the mavalonolactone-based compound which is a racemic modification. CONSTITUTION:This cleavage reaction with ozone is carried out by a method for reacting an olefin compound of formula I {R is a carbocyclic aromatic group, a heterocyclic aromatic group or a condensed heterocyclic aromatic group having sp<2> carbon atom; Z is a group of formula II [A is CHOH or C(O); R<1> is H, a 1-4C alkyl, phenyl or an aralkyl] or formula III} or its salt with ozone and converting the compound of formula I into an aldehyde compound of the formula,, R-CHO. Furthermore, R is preferably a group of formula IV. For example, a mixed gas of ozone with oxygen is passed through ethyl (E)3,5-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)--quinolin-3-yl]-h ept-6-enoate to afford 2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-al.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an economical method for producing an optically active mevalonolactone compound, which is useful for prevention and treatment of hyperlipidemia, arteriosclerosis and the like.

[0002]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION Formula [I]

[0003]

Embedded image

[In the formula, R represents a carbocyclic aromatic group, a heterocyclic aromatic group or a condensed heterocyclic aromatic group having sp ² carbon atoms.

Z is

[0006]

[Chemical 6]

(A represents -CHOH or -C (O)-.

R ¹ represents a hydrogen atom, an optionally branched C _1-4 alkyl group, a phenyl group or an aralkyl group. )] Is a compound containing a racemate or four optical isomers, is a strong inhibitor of HMG-CoA reductase, which is a rate-limiting enzyme of cholesterol biosynthesis, and has a high lipid content. It is expected to be a drug in the prevention and treatment of blood pressure and arteriosclerosis.

The compound represented by the formula [I] is described in JP-A-1-
As described in JP-A-279866, EP-A-304063, and US-P50111930, it can be produced by the following steps.

[0010]

[Chemical 7]

A: Reduction of ester [VII] to primary alcohol [VI]. B: Oxidation to aldehyde [V]. C:
Synthesis of α, β-unsaturated carboxylic acid ester [IV]. D:
Reduction to allyl alcohol [III]. E: Enard [I
Oxidation to [I]. F: Condensation of enal [II] and a double anion of acetoacetic acid esters. G: Reduction of the carbonyl group of compound [I-4]. H: Hydrolysis of ester [I-1]. J: A process for producing mevalonolactone [I-3] by dehydrating a free hydroxy acid [I-2].

In the case of pharmaceuticals, there are many known examples in which the pharmacological activity and safety differ between the optical isomers, and it is desired to optically resolve them in order to develop better pharmaceuticals. The compound represented by the formula [I] also has two asymmetric carbons in the side chain portion Z, and since there are four optical isomers, only the (3R, 5S) isomer useful as a drug is selectively selected. Need to be synthesized.

As the method for synthesizing the (3R, 5S) form of compound [I], for example, the method described in J. E. FIG. Lynch et al., Tetra
hedron Lett. , 28 , 1385 (198
7) A method using the asymmetric aldol reaction described in T. Hi
Yama et al. Org. Chem. , 1991 , 57
52 (1991), a method using asymmetric reduction of an optically active camphor ester, T.W. Hiyama et al., Tet
rahedron Lett. , 34 , 513 (199
3) Wi with the optically active dihydroxycarboxylic acid described
Asymmetric synthesis reaction such as the method using ttig reaction,
-148237 gazette, the racemic diastereomer resolution method described in European Patent Publication 520406 (see Reference Example 1), the optical resolution method using a column for optical isomer separation (see Reference Example 2), etc. is there. However, in the case of the asymmetric synthesis method, expensive materials and high technology are required, and in the case of the resolution method, the unnecessary (3S, 5R) isomer is completely wasted, which is industrial and economical. All of these manufacturing methods have problems.

[0014]

[Means for Solving the Problems] If a method for reusing a (3S, 5R) body is established in a racemic resolution method, the inventors of the present invention will be able to complete an economical manufacturing method utilizing its simplicity. I focused my attention on the subject. As a result, (3S, 5
The present invention was completed by discovering that the R) form can be easily led to a compound [II], which is a skeleton portion of the R) form and is also a synthetic raw material. The compound [I] is a compound that requires 10 steps for its synthesis and has a large economical effect.

Further, this method can be applied to the diastereomers (3R, 5R) and (3S, 5S) which are partially by-produced when synthesizing the racemic compound [I]. It has a great merit that it can be applied to the portion that has been a purification loss until the F step.

That is, the present invention provides the formula [I]

[0017]

Embedded image

[In the formula, R represents a carbocyclic aromatic group, a heterocyclic aromatic group or a condensed heterocyclic aromatic group having sp ² carbon atoms.

Z is

[0020]

[Chemical 9]

(A represents -CHOH or -C (O)-.

R ¹ represents a hydrogen atom, an optionally branched C _1-4 alkyl group, a phenyl group or an aralkyl group. )] Is reacted with ozone to an olefin compound or a salt thereof to form an aldehyde compound.

[0023]

[Chemical 10]

[In the formula, R is the same as above. ] To the conversion method.

The olefin compound represented by the formula [I] or a salt thereof includes

[0026]

[Chemical 11]

Included are compounds represented by:

Examples of R ¹ include hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tertiary butyl group, phenyl group, benzyl group, 1-phenylethyl group and the like. .

As the salt, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, nitrogen-containing organic bases such as ammonium, trimethylamine, triethylamine, N-methylpiperidine and phenethylamine. Can be mentioned as a salt.

R represents a carbocyclic aromatic group having sp ² carbon atoms, a heterocyclic aromatic group or a condensed heterocyclic aromatic group.

Examples of the carbocyclic aromatic group are, for example,
1 to 3 selected from R ⁶ and / or R ⁷ (R ⁷ means phenyl optionally substituted by C ₁ -C ₇ alkyl group, fluoro, chloro or bromo) 1
To a phenyl group and a naphthyl group which may be substituted with 2 substituents,

[0032]

[Chemical 12]

And the like.

Examples of the heterocyclic aromatic group are, for example,
1 to 3 selected from R ⁶ , C ₁ -C ₃ alkoxymethyl, phenylcarbamoyl and / or a pyridyl group optionally substituted by 1 to 2 substituents selected from R ⁷ , a pyrimidyl group, Examples thereof include a pyrazolyl group, an imidazolyl group, a pyrrolyl group, a thienyl group and a furanyl group.

[0035]

[Chemical 13]

And the like.

The fused heterocyclic aromatic group is, for example, ₁ to 3 each selected from R ⁶ , 1 selected from C ₁ -C ₃ alkoxymethyl, phenylcarbamoyl and / or R ^7.
To an indolyl group which may be substituted with two substituents, a quinolyl group, a pyrazolopyridyl group, a thienopyridyl group, a pyrrolopyridyl group, an isoquinolinonyl group, and the like.

[0038]

Embedded image

And the like.

R ⁶ represents a C ₁ -C ₈ alkyl group or a C ₃ -C ₇ cycloalkyl group, and as C ₁ -C ₈ alkyl, methyl, ethyl, n-propyl, i-propyl, n- Butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and n-heptyl groups and the like, C ₃ -C ₇ cycloalkyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl And cycloheptyl and the like.

R ⁷ is a C ₁ -C ₇ alkyl group, fluoro,
Means phenyl optionally substituted with chloro or bromo, phenyl, 3-methylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 3,5- Diethylphenyl, 3-methyl-5-ethylphenyl, 3-n-propylphenyl, 4-n-propylphenyl, 3,5-di-n-propylphenyl, 3-i-propylphenyl, 4-i-propylphenyl , 3,5-di-i-propylphenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-
Chlorophenyl, 3,5-dichlorophenyl, 3-fluoro-4
-Chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,5-dibromophenyl and the like can be mentioned.

Particularly preferred R is

[0043]

[Chemical 15]

And the like.

The present invention will be described in detail below.

The most convenient and excellent method is to generate ozone using a commercially available ozone generator and directly introduce it into the reaction system in the form of ozone-oxygen stream. However, the method is not particularly limited to this method. Absent. The ozone is used in an amount of 0.5 to 10 equivalents, preferably 1 to 3 equivalents, relative to the raw material olefin compound. As shown in Examples 2 and 7, excessive use of ozone is likely to reduce the yield. As a matter of course, when the amount is 1 equivalent or less, the target product can be obtained, but the amount of unreacted olefin compound increases and the reaction yield decreases.

As the solvent used in the reaction, alcohol solvents such as methyl alcohol, ethyl alcohol and isopropyl alcohol are preferable, but halogen solvents such as methylene chloride, chloroform and carbon tetrachloride, pentane, hexane, heptane, cyclohexane and benzene. Hydrocarbon-based solvents such as, ether-based solvents such as ethyl ether and tetrahydrofuran, and ethyl acetate, acetone, water, acetic acid and the like can also be used.

The reaction temperature is in the range of -100 ° C to 50 ° C, preferably in the range of -77 ° C to 10 ° C, unless the solvent used solidifies. The reaction at low temperature is advantageous in order to suppress the decomposition of the quinoline aldehyde compound which is the target product and control the reaction. The reaction proceeds rapidly, and for example, even when the reaction is carried out at -77 ° C, the reaction is completed within a few minutes after the completion of the blowing of ozone (see Example 1).

Specific examples will be described below with reference to examples and reference examples.

(Example 1)

[0051]

Embedded image

Ethyl (E) 3,5-dihydroxy-7-
[2-cyclopropyl-4- (4-fluorophenyl)
-Quinolin-3-yl] -hept-6-enoate 1.
A solution of 0 g (2.2 mmole) in 100 mL of methanol was cooled to −77 ° C., and ozone-oxygen gas (ozone 10 mmole / hr) generated by an ozone generator was added to 22.
I understood for a minute. After that, through dry nitrogen gas, -73 ° C
Then, 0.5 mL of dimethyl sulfide was added, and the temperature was raised to room temperature over 1 hour. After concentrating this solution, water 40m
It was diluted with L and extracted with 50 mL of toluene. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1), and 2-cyclopropyl-4- (4-
Fluorophenyl) -quinoline-3-al 0.59 g
(2.0 mmole) was obtained.

Yield 92% ¹ HNMR (CDCl ₃ ) δ (ppm): 0.86-1.56 (m, 4H), 2.95-3.49
(m, 1H), 6.98-8.11 (m, 8H), 10.1 (s, 1H). MS (m / z): 291 (M ⁺ ), 263 (100%). (Example 2)

[0054]

[Chemical 17]

Ethyl (E) 3,5-dihydroxy-7-
[2-cyclopropyl-4- (4-fluorophenyl)
-Quinolin-3-yl] -hept-6-enoate 1.
A solution of 0 g (2.2 mmole) in 20 mL of methanol was cooled to -11 to -16 ° C, and ozone-oxygen gas (ozone 10 mmole / hr) generated by an ozone generator was generated.
For 50 minutes. The temperature was gradually raised to 20 ° C., 0.5 mL of dimethyl sulfide was added, and the mixture was stirred for 1 hour. The reaction solution was extracted twice with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and 2
-Cyclopropyl-4- (4-fluorophenyl) -quinoline-3-al 0.22 g (0.76 mmole)
I got Yield 30% (Example 3)

[0056]

Embedded image

Ethyl (E) 3,5-dihydroxy-7-
[2-cyclopropyl-4- (4-fluorophenyl)
-Quinolin-3-yl] -hept-6-enoate 1.
A solution of 0 g (2.2 mmole) in 100 mL of methanol was cooled to −19 to −20 ° C., and ozone-oxygen gas (ozone 10 mmole / h) generated by an ozone generator was generated.
r) was passed through for 33 minutes. Then, 0.5 mL of dimethyl sulfide was added at −20 ° C. through dry nitrogen gas, and the temperature was raised to room temperature over 1 hour. 140 mL of this solution in water
It was diluted with and extracted with 200 mL of ethyl acetate. The organic layer was washed twice with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated. The product is purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1),
2-cyclopropyl-4- (4-fluorophenyl)-
Quinoline-3-al 0.53 g (1.8 mmole)
I got

Yield 83% (Example 4)

[0059]

[Chemical 19]

Ethyl (E) 3,5-dihydroxy-7-
[2-cyclopropyl-4- (4-fluorophenyl)
1.0 g of (3S, 5R) -form of -quinolin-3-yl] -hept-6-enoate (87.6% ee)
A solution of (2.2 mmole) in 100 mL of methanol-
After cooling to 68 to -69 ° C, ozone-oxygen gas (ozone 10 mmole / hr) generated by an ozone generator was passed for 25 minutes. Then, through dry nitrogen gas, -68
0.5 mL of dimethyl sulfide was added at 0 ° C., and the temperature was raised to room temperature over 1 hour. After concentrating this solution, water 40
It was diluted with mL and extracted with 40 mL of toluene × 2. The organic layer was dried over anhydrous sodium sulfate and concentrated. By recrystallizing the obtained crude aldehyde compound from a mixed solution of toluene-hexane, 2-cyclopropyl-4- (4
-Fluorophenyl) -quinoline-3-al 379 m
g was obtained. The mother liquor obtained here was concentrated and the product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 2-cyclopropyl-4- (4
-Fluorophenyl) -quinoline-3-al 226.
2 mg was obtained.

Yield 605.2 mg (2.08 mmol
e) Yield 94% (Example 5)

[0062]

Embedded image

Ethyl (E) 7- [2-cyclopropyl-
4- (4-fluorophenyl) -quinolin-3-yl]
-5-Hydroxy-3-oxohept-6-enoate 1.0 g (2.2 mmole) methanol 100 mL
The solution was cooled to −65 to −75 ° C. and ozone-oxygen gas generated by an ozone generator (ozone 10 mmole /
hr) was passed for 20 minutes. Then, add 0.5 mL of dimethyl sulfide at -75 ° C. through dry nitrogen gas, and add 1
The temperature was raised to room temperature over time. The solution was concentrated, diluted with 40 mL of water, and extracted with 40 mL of toluene × 3. The light yellow solid obtained by concentration was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 0.53 g of 2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-al ( 1.8 mm
ole) was obtained.

Yield 83% Melting point 155-156 ° C (Example 6)

[0065]

[Chemical 21]

6- [2- {2-cyclopropyl-4-
(4-Fluorophenyl) -quinolin-3-yl} ethenyl] -4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 0.80 g (2 mmol)
The mixed solution of ethanol 80 mL-methanol 80 mL of e) was cooled to −60 to −72 ° C., and ozone-oxygen gas generated by an ozone generator (ozone 10 mmole /
hr) was passed for 1.5 hours. 0.5 mL of dimethyl sulfide was added at -72 ° C, and the temperature was raised to room temperature over 1 hour. The solution was concentrated, diluted with 40 mL of water, and extracted with 40 mL of toluene × 2. The yellow oil obtained after concentration was subjected to silica gel column chromatography (hexane:
2-Cyclopropyl-4- (4-fluorophenyl) -quinoline-3-by purification with ethyl acetate = 4: 1) and recrystallization from a toluene-hexane mixed solution.
165 mg (0.57 mmole) of Earl was obtained.

Yield 29% (Example 7)

[0068]

[Chemical formula 22]

(E) 3,5-dihydroxy-7- [2-
Cyclopropyl-4- (4-fluorophenyl) -quinolin-3-yl] -6-heptenoate sodium 4.21
A 428 mL ethanol solution (containing 1% water) of g (9.5 mmole) was cooled to −65 to −67 ° C., and ozone-oxygen gas (ozone 10 m
mole / hr) for 1.5 hours. 2.5 mL of dimethyl sulfide was added at -65 ° C, and the temperature was raised to 0 ° C over 1 hour. The solution was concentrated, diluted with 120 mL of water, extracted with 120 mL of toluene, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and crystallized from hexane to give 2-cyclopropyl-4- (4
-Fluorophenyl) -quinoline-3-al 791m
g (2.7 mmole) was obtained.

Yield 29% (Example 8)

[0071]

[Chemical formula 23]

(E) 3,5-dihydroxy-7- [2-
Cyclopropyl-4- (4-fluorophenyl) -quinolin-3-yl] -6-heptenoate calcium 365m
A 30 ml tetrahydrofuran solution of g (0.83 mmole) was cooled to -65 ° C, and ozone-oxygen gas (ozone 10 mmole / hr) generated by an ozone generator was generated.
For 15 minutes. Then, dry nitrogen gas was passed through for 10 minutes, 0.5 ml of dimethyl sulfide was added at -58 ° C,
The temperature was raised to 10 ° C over 1.5 hours. After concentrating this solution, 20 ml of water and 3 ml of saturated saline were added and extracted with 20 ml of toluene, and the aqueous layer was further extracted with 20 ml of toluene. The organic layer was dried over anhydrous sodium sulfate and concentrated. By purifying the product by silica gel chromatography (hexane: ethyl acetate = 3: 1), 2-
Cyclopropyl-4- (4-fluorophenyl) -quinoline-3-al 155.8 mg (0.53 mmol)
e) was obtained.

Yield 64% (Example 9)

[0074]

[Chemical formula 24]

(E) 3,5-dihydroxy-7- [2-
Cyclopropyl-4- (4-fluorophenyl) -quinolin-3-yl] -6-heptenoic acid (lactone form 4.7
%) 2.0 g (4.7 mmole) of a 200 ml methanol solution was cooled to −63 ° C., and ozone-oxygen gas generated by an ozone generator (ozone 10 mmole /
hr) was passed for 30 minutes. Then, dry nitrogen gas was passed through for 10 minutes, 1.0 ml of dimethyl sulfide was added at -60 ° C, and the temperature was raised to 23 ° C over 1 hour. After this solution was concentrated, 20 ml of water was added and extracted with 30 ml of toluene, and the aqueous layer was extracted twice with 30 ml of toluene. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give 1.15 g (3.95 mmole) of 2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-al. Obtained.

Yield 84% [Reference Example 1] Method for diastereomeric resolution of racemate (A) Synthesis of compound [(±) I] (±)-(E) 3,5-dihydroxy-7- [4-] (4
-Fluorophenyl) -2-cyclopropylquinoline-
3-yl] hept-6-enoic acid (±)-(E) ethyl-3,5-dihydroxy-7-
60 g of [4- (4-fluorophenyl) -2-cyclopropylquinolin-3-yl] hept-6-enoate was suspended in 100 mL of ethanol, and 200 mL of a 1N aqueous sodium hydroxide solution was added. As the reaction progresses,
The suspension became a homogeneous solution. After the completion of hydrolysis, 200 mL of 1N hydrochloric acid was added. This reaction solution was extracted with 500 mL of dichloromethane to obtain the target compound [(±) I].
I got

¹ H-NMR (CDCl ₃ ) δppm: 1.0-1.1 (m, 2H),
1.3-1.4 (m, 3H), 1.5-1.6 (m, 1H), 2.3-2.4 (m, 1H), 2.
51 (d, 2H, J = 6.1Hz), 2.8-3.5 (b, 3H), 4.1-4.2 (m, 1H),
4.4-4.5 (m, 1H), 5.59 (dd, 1H, J = 6.1Hz, J = 16.1Hz),
6.63 (d, 1H, J = 6.1Hz), 7.1-7.4 (m, J = 6Hz), 7.5-7.7
(m, 1H), 7.9-8.0 (m, 1H). (B) Synthesis of diastereomeric salt of compound [(-) I] (-)-(E) 3 (R) -5 (S) -dihydroxy -7
-[4- (4-Fluorophenyl) -2-cyclopropylquinolin-3-yl] hept-6-enoic acid.D (+)
Phenethylamine salt D (+) was added to a solution of the compound [(±) I] in dichloromethane.
After adding 16.2 g of phenethylamine and stirring, dichloromethane was distilled off and the residue was obtained. The residue is methyl isobutyl ketone, methyl isobutyl ketone-ethanol (1
Crystallization was repeated at 0: 1, v / v) to obtain white crystals of the diastereomer salt of the target compound [(−) I] 19.
8 g was obtained. (Melting point 144 to 147 ° C., optical purity 9
7% ee).

(C) Acquisition of optically active compound [(-) I] (-) (E) -6 (S)-[4- (4-fluorophenyl) -2-cyclopropylquinolin-3-ylethenyl]- 4 (R) -Hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (-)-(E) 3 (R) -5 (S) -dihydroxy-7
-[4- (4-Fluorophenyl) -2-cyclopropylquinolin-3-yl] hept-6-enoic acid.D (+)
To 14.08 g of the phenethylamine salt compound, 25.9 mL of 1N hydrochloric acid and 235 mL of water were added and dissolved. To this solution, 250 mL of ethyl acetate was added, and the compound [(-)
I] was extracted. The ethyl acetate solution was washed with saturated brine, and the solvent was evaporated under reduced pressure. Anhydrous toluene 250 to the residue
Add mL for 3 hours Gene Stark (Dean Sr
ark) apparatus and heated to reflux. The solvent was distilled off under reduced pressure,
The residual solid obtained was recrystallized from toluene-heptane,
6.4 g of the target compound [(-) I] was obtained. (Melting point 1
36-139 ° C).

Reference Example 2 Optical Resolution Method Using a Column for Separation of Optical Isomers 0.46 cm in inner diameter and 25 cm in length filled with a filler for optical resolution in which cellulose tris (p-chlorophenylcarbamate) is supported on silica gel carrier. Analytical column (manufactured by Daicel Chemical Industries Ltd .; CHIRALC
EL OF) using 7- [2-cyclopropyl-4-
(4-Fluorophenyl) quinolin-3-yl] -3,
Ethyl 5-dihydroxy-6-heptenoate (3R, 5
The S) body and its (3S, 5R) body were optically resolved.
The division conditions and results are as follows.

Eluent: Mixture of n-hexane / 2-propanol = 8/2 Flow rate: 1.0 ml / min Column temperature: 40 ° C. Detection: Ultraviolet absorption 254 nm Retention time; 10.1, 13.4 Volume ratio (K ₁ '); 2.37 Separation coefficient (α); 1.47 Resolution (Rs); 3.63 Elution order; (3R, 5S) form, (3S, 5R) form [Reference Example 3] Optical isomerism Optical resolution method using a column for body separation Cellulose tris (p-chlorophenylcarbamate) -supporting silica gel for optical resolution (manufactured by Daicel Chemical Industries Ltd .; CHIRALCEL)
OF, particle diameter 20 μm) filled with inner diameter 1 cm, length 2
In a simulated moving bed device consisting of eight 5 cm columns connected,
7- [2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6
-Ethyl heptenoate (3R, 5S) form and its (3S,
The 5R) racemate was supplied at 1.0 ml / min (racemic concentration 3.5 mg / ml). The simulated moving bed apparatus was operated under the following conditions.

Eluent; Mixture of n-hexane / 2-propanol = 8/2 Eluent feed rate: 7 ml / min Flow rate of adsorbate-rich fluid at outlet: 5.6 ml / min Non-adsorbate rich Flow rate of fluid withdrawal port: 2.4 ml /
Min column switching time; 21.0 min temperature; room temperature As a result, from the outlet of the fluid rich in adsorbate, (-)
-7- [2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-
The (3S, 5R) -form of 6-ethyl heptenoate is 530 pp
m, optical purity 65% ee, and from the outlet of the fluid rich in non-adsorbate, 7- [2-cyclopropyl-4- (4-
A (3R, 5S) -form of ethyl fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoate could be obtained at 894 ppm with an optical purity of 100% ee.

[0082]

Since the present invention is configured as described above, it has the following effects.

Obtained when a mevalonolactone compound which is a racemate is optically resolved, and becomes unnecessary (3S, 5
The R) form can be efficiently recovered as an aldehyde form which is a raw material for production.

Therefore, it is possible to provide an economical method for producing an optically active mevalonolactone compound.

[Brief description of drawings]

FIG. 1 is an explanatory diagram showing a simulated moving bed apparatus used in Reference Example 2.

[Explanation of symbols]

 1 to 8 unit packed bed 9 desorbed liquid supply line 10 extract withdrawal line 11 optical isomer mixture-containing liquid supply line 12 raffinate withdrawal line

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshio Ohara 722-1 Tsuboi-cho, Funabashi-shi, Chiba Central Research Laboratory, Nissan Chemical Industries, Ltd. (72) Hirokazu Ikeda 1132 (72) Inventor Tatsushi Murakami 198-1 Okiyo, Taishi-cho, Ibo-gun, Hyogo Prefecture

Claims (2)

[Claims] 1. The formula [I]: [In the formula, R represents a carbocyclic aromatic group, a heterocyclic aromatic group, or a condensed heterocyclic aromatic group having sp ² carbon atoms. Z is (A represents -CHOH or -C (O)-. R ¹ represents a hydrogen atom, an optionally branched C _1-4 alkyl group, a phenyl group or an aralkyl group.)] Reaction of olefin compound or its salt with ozone to give aldehyde compound [Wherein, R is as defined above. ] To convert. 2. R is The conversion method according to claim 1, wherein