JPH04316538A - Production of optically active 3,5-anti-dihydroxycarboxylic acid ester derivative - Google Patents

Abstract

PURPOSE:To efficiently obtain a large amount of a new optically active 3,5-anti- dihydroxycarboxylic acid ester derivative having an extremely application range as an intermediate for physiologically active substance such as compacting relative compound useful as an treating agent for hyperlipemia and an intermediate for functional substance. CONSTITUTION:OH of an optical activator shown by formula I (R<1> and R<2> are alkyl, alkenyl, alkynyl, aryl or aralkyl; * is asymmetric carbon) is protected by a conventional procedure, the activator is hydrolyzed under a basic condition to readily give an optical activator shown by formula VI (R<5> is protecting group). Then this compound shown by formula VI is reacted with N,N'- carbonylimidazole to give an imidazolite, which is reacted with magnesium malonate to give an optical activator shown by formula VII (R<4> is in group in R<1> and R<2>) in high yield. Then the OH protecting group is deprotected and the resulting substance is highly stereo-selectively reduced by using a reducing agent to give an optical activator shown by formula I-1. Further, the compound shown by formula I-1 is reacted with 2,2-dimethoxypropane to readily give an optical activator shown by formula I-2.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to a general formula using a specific optically active 3-hydroxycarboxylic acid ester.

0002
]

[C3]

(In the formula, R1 and R4 are an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or an aralkyl group, and R3 is hydrogen or together represents an isopropylidene group. * represents an asymmetric carbon.) The present invention relates to a method for producing an optically active 3,5-anti-dihydroxycarboxylic acid ester derivative represented by: The optically active 3,5-anti-dihydroxycarboxylic acid ester derivative represented by the general formula (I) is a very useful compound as a synthetic intermediate for various physiologically active substances and functional substances. for example,
Using this compound as an intermediate, compactin analogs useful as therapeutic agents for hyperlipidemia can be synthesized.

0004

[Prior Art] 3,5-dihydroxycarboxylic acid ester derivatives have four optical isomers ((3R,5R)-, (3S,5S)-, (
3R,5S)- and (3S,5R)-isomers exist, but in order for the target product to exhibit sufficient physiological activity and function, it is necessary to synthesize one specific isomer as an optically active form. .

Regarding the synthesis method of optically active 3,5-syn-dihydroxycarboxylic acid ester derivatives ((3R,5R)- or (3S,5S)- derivatives), (1) Addition of acetoacetate dianion to aldehyde. (Kathawala et al., Helvetica C
himica Acta, 69, 803 (1986
)), (2) cis -cyclohexane-1,3,5
- Methods starting from triols (Prasad et al.,
Tetrahedron Lett. , 25, 48
89 (1984)), (3) A method for reducing the β,δ-diketoester obtained by the reaction with an acetoacetate dianion and N-methoxyN-methylamide (Hanamoto et al., Tetrahedron L
ett. , 29, 6467 (1988)), (4)
A method starting from optically active (R)- or (S)-malic acid (Prasad et al., Tetrahedron
: Asymmetry, 1, 307 (1990)
), and many other methods are known.

On the other hand, optically active 3,5-anti-dihydroxycarboxylic acid ester derivatives ((3R,5S)
- or (3S,5R)-form) as a method for synthesis using optically active (R)- or (S)-malic acid as a starting material (Prasad et al., Tetrahedron:
Asymmetry, 1, 307 (1990)),
■A method using an aldol reaction between optically active (R)-2-hydroxy-1,2,2-triphenylethyl acetate and an optically active aldehyde (Mahler et al., Che.
m. Ber. 121, 2035 (1988)),
■ Method using yeast reduction (Sato et al., Can. J.
Chem. , 65, 2732 (1987)),■
A method that combines yeast reduction and chemical reduction (Chris
Ten et al., J. Chem. Soc. , Chem.
Commn. , 1988, 264) are only known.

[0007] Method ① uses an excess of expensive LDA and also reacts with lithium t-butyl acetate at -78°C.
This requires low-temperature conditions. Method (2) also requires a low temperature condition of -130 °C during the aldol reaction,
Furthermore, it is difficult to obtain an asymmetric source, making it impractical. ■
The method requires a low temperature condition of -78°C in the two steps of ester reduction and lithium ethyl acetate addition reaction, and because the stereoselectivity of the addition reaction is low, it is necessary to induce the lactone form and chromatographic separation. Is required.

[0008] Method (1) is more practical than methods (2) to (2), but yeast reduction is not suitable for large-scale synthesis, and the optical purity of the reduction product is low. Furthermore, the yield of the carbon enrichment reaction is low. As mentioned above, most of the methods are far from being practical on an industrial level.

[0009]

[Problems to be Solved by the Invention] From the above, it is possible to easily produce optically active 3,5-anti-dihydroxycarboxylic acid ester derivatives that are useful in a wide range of applications as intermediates for the synthesis of physiologically active substances and functional substances. There was a strong demand for legal development. The present inventors have made extensive studies to achieve the objective of efficiently obtaining a large amount of optically active 3,5-anti-dihydroxycarboxylic acid ester derivatives.
Optically active 3,5-anti- represented by the general formula (I)
The present invention was accomplished by discovering a method for efficiently producing large amounts of dihydroxycarboxylic acid ester derivatives.

0010

[Means for Solving the Problems] The present invention provides the general formula

00
11]

[C4]

Optically active 3-hydroxycarboxylic acid esters represented by the formula (wherein R1 and R2 are an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or an aralkyl group, and * represents an asymmetric carbon), Optical activity 5 is achieved by carbonization reaction in which magnesium malonate is reacted.
-Hydroxy-3-ketocarboxylic acid ester is obtained and from this compound the general formula

[0013]

[C5]

(In the formula, R1 and R4 are an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or an aralkyl group, and R3 is hydrogen or together represents an isopropylidene group. * represents an asymmetric carbon.) This is a method for producing an optically active 3,5-anti-dihydroxycarboxylic acid ester derivative, which is characterized by obtaining a compound represented by: Next, the present invention will be described in detail. The optically active 3,5-anti-dihydroxycarboxylic acid ester derivative (I) of the present invention can be produced according to the following reaction steps.

[0015]

[C6]

(wherein R1, R2 and R4 are an alkyl group, an alkenyl group, an alkynyl group, an aryl group,
or represents an aralkyl group, and R5 represents a protecting group. *
indicates an asymmetric carbon. ) The compound represented by (IV), which is a starting material, is obtained by optically resolving racemic 3-hydroxycarboxylic acid ester using lipase (R).
-, (S)-isomers can be obtained with high optical purity (Japanese Patent Application Laid-Open No. 2-219598).

Next, the compound represented by formula (V) can be easily synthesized by protecting the hydroxyl group of the compound represented by formula (IV) according to a conventional method. Examples of protecting groups include tetrahydropyranyl group, t-butyldimethylsilyl group, benzyl group, methoxyethoxymethyl group, and the like. For example, a tetrahydropyranyl group can be easily introduced by reaction with 3,4-dihydro-2H-pyran using pyridinium p-toluenesulfonate or the like as a catalyst.

The compound represented by formula (V) can be easily converted into the compound represented by formula (VI) by hydrolysis under basic conditions. Examples of the base used in the reaction include sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like. As the reaction solvent, no solvent, an alcoholic solvent such as methanol or ethanol, or a mixed solvent of these and water can be used. The reaction temperature is suitably -20°C to -50°C, particularly preferably 0°C to 25°C.

The compound represented by formula (VII) is a compound represented by formula (V
A good yield can be obtained by reacting the compound represented by I) with N,N'-carbonyldiimidazole to form an imidazolide, and then reacting it with magnesium malonate prepared from malonic acid monoalkyl ester and a magnesium compound. You can get it at Examples of the magnesium compound used in the reaction include magnesium halides such as magnesium chloride and magnesium bromide, and alkylmagnesium halides such as isopropylmagnesium chloride and isopropylmagnesium bromide. As the reaction solvent, ether solvents such as tetrahydrofuran and ether can be used. The reaction temperature is -30
℃~50℃ is suitable, particularly preferably 0℃~25℃
It is.

The compound represented by formula (VII) can be obtained by deprotecting the hydroxyl group by an appropriate method.
II) It can be easily converted into the compound represented by: For example, a compound whose hydroxyl group is protected with a tetrahydropyranyl group is deprotected under acidic conditions. Examples of acids used in the reaction include acetic acid, hydrochloric acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, and the like. As the reaction solvent, alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran, or mixed solvents of these and water can be used. The reaction temperature is suitably -20°C to 100°C, particularly preferably 0°C to 50°C.

The compound represented by formula (I-1) (in which R3 is hydrogen in formula (I)) is obtained by highly stereoselectively converting the compound represented by formula (VIII) using an appropriate reducing agent. It can be obtained by reduction. Examples of reducing agents used in the reaction include tetramethylammonium borohydride, tetrabutylammonium borohydride, sodium borohydride, tetramethylammonium triacetoxyborohydride, tetrabutylammonium triacetoxyborohydride, sodium triacetoxyborohydride. Examples include hydride. As a reaction solvent, acetic acid,
A lower carboxylic acid such as propionic acid or a mixed solvent of these with acetonitrile, tetrahydrofuran, acetone, etc. can be used, and the proportion of acetic acid in this case is 10% or more of the total, more preferably 50% or more. The reaction temperature is suitably -78°C to 50°C, particularly preferably -40°C to 25°C.

Finally, the compound represented by formula (I-1) is prepared by reacting it with 2,2-dimethoxypropane using pyridinium p-toluenesulfonate or the like as a catalyst. (where R3 is an isopropylidene group) can be easily derived. By the above operations, optically active (3R,5S)- or (
3S,5R)-3,5-dihydroxycarboxylic acid ester derivatives (I) can be obtained.

Optical activity 3,5 obtained as above
The names of typical -anti-dihydroxycarboxylic acid ester derivatives are shown below. Methyl (3R,5S)-3,5-dihydroxyhexanoate, Ethyl (3R,5S)-3,5-dihydroxyhexanoate, Propyl (3R,5S)-3,5-dihydroxyhexanoate, (3R,5S) Isopropyl -3,5-dihydroxyhexanoate, butyl (3R,5S)-3,5-dihydroxyhexanoate.

Methyl (3R,5S)-3,5-dihydroxyheptanoate, Ethyl (3R,5S)-3,5-dihydroxyheptanoate, Propyl (3R,5S)-3,5-dihydroxyheptanoate, (3R ,5S)-3,5-
Isopropyl dihydroxyheptanoate, (3R,5S)
Butyl -3,5-dihydroxyheptanoate. Methyl (3R,5S)-3,5-dihydroxyoctanoate, Ethyl (3R,5S)-3,5-dihydroxyoctanoate, Propyl (3R,5S)-3,5-dihydroxyoctanoate, (3R,5S) Isopropyl -3,5-dihydroxyoctanoate, butyl (3R,5S)-3,5-dihydroxyoctanoate.

(3R,5S)-3,5-dihydroxy-
Methyl 6-methylheptanoate, (3R,5S)-3,5
-Ethyl dihydroxy-6-methylheptanoate, (3R
,5S)-3,5-dihydroxy-6-methylheptanoate propyl, (3R,5S)-3,5-dihydroxy-
Isopropyl 6-methylheptanoate, (3R,5S)-
Butyl 3,5-dihydroxy-6-methylheptanoate.

(3R,5S)-3,5-dihydroxy-
Methyl 6-heptenoate, (3R,5S)-3,5-dihydroxy-6-octenoate, (3R,5S)-3
, methyl 5-dihydroxy-6-heptate, (3R,
5S)-3,5-dihydroxy-6-methyl octoate, (3R,5S)-3,5-dihydroxy-5-phenylpentanoate methyl, (3R,5S)-3,5-dihydroxy-6-phenylpentane Methyl acid, (3R,5S
)-methyl 3,5-dihydroxy-7-phenylpentanoate.

Methyl (3S,5R)-3,5-dihydroxyhexanoate, Ethyl (3S,5R)-3,5-dihydroxyhexanoate, Propyl (3S,5R)-3,5-dihydroxyhexanoate, (3S ,5R)-3,5-
Isopropyl dihydroxyhexanoate, (3S,5R)
Butyl -3,5-dihydroxyhexanoate. (3S,5R)-3,5-dihydroxyheptanoate methyl, (3S,5R)-3,5-dihydroxyheptanoate ethyl, (3S,5R)-3,5-dihydroxyheptanoate propyl, (3S,5R) Isopropyl -3,5-dihydroxyheptanoate, butyl (3S,5R)-3,5-dihydroxyheptanoate.

Methyl (3S,5R)-3,5-dihydroxyoctanoate, Ethyl (3S,5R)-3,5-dihydroxyoctanoate, Propyl (3S,5R)-3,5-dihydroxyoctanoate, (3S ,5R)-3,5-
Isopropyl dihydroxyoctanoate, (3S,5R)
Butyl -3,5-dihydroxyoctanoate. (3S,5R)-3,5-dihydroxy-6-methylheptanoate, ethyl (3S,5R)-3,5-dihydroxy-6-methylheptanoate, (3S,5R)-3
, propyl 5-dihydroxy-6-methylheptanoate,
Isopropyl (3S,5R)-3,5-dihydroxy-6-methylheptanoate, butyl (3S,5R)-3,5-dihydroxy-6-methylheptanoate.

(3S,5R)-3,5-dihydroxy-
Methyl 6-heptenoate, (3S,5R)-3,5-dihydroxy-6-octenoate, (3S,5R)-3
, methyl 5-dihydroxy-6-heptate, (3S,
5R)-3,5-dihydroxy-6-methyl octoate, (3S,5R)-3,5-dihydroxy-5-phenylpentanoate methyl, (3S,5R)-3,5-dihydroxy-6-phenylpentane Methyl acid, (3S,5R
)-methyl 3,5-dihydroxy-7-phenylpentanoate.

(3R,5S)-3,5-O-isopropylidenehexanoate, (3R,5S)-3,5-O
-Ethyl isopropylidenehexanoate, (3R,5S)
-3,5-O-isopropylidenehexanoate propyl,
Isopropyl (3R,5S)-3,5-O-isopropylidenehexanoate, butyl (3R,5S)-3,5-O-isopropylidenehexanoate.

(3R,5S)-3,5-O-isopropylideneheptanoate methyl, (3R,5S)-3,5-O
-Ethyl isopropylidene heptanoate, (3R,5S)
-3,5-O-isopropylidene propyl heptanoate,
Isopropyl (3R,5S)-3,5-O-isopropylideneheptanoate, (3R,5S)-butyl-3,5-O-isopropylideneheptanoate.

(3R,5S)-3,5-O-isopropylideneoctanoate methyl, (3R,5S)-3,5-O
-Ethyl isopropylidene octanoate, (3R,5S)
-3,5-O-isopropylidene propyl octoate,
Isopropyl (3R,5S)-3,5-O-isopropylideneoctanoate, (3R,5S)-butyl-3,5-O-isopropylideneoctanoate.

(3R,5S)-3,5-O-isopropylidene-6-methylheptanoate, (3R,5S)
-3,5-O-isopropylidene-6-methylheptanoate ethyl, (3R,5S) -3,5-O-isopropylidene-6-methylheptanoate propyl, (3R,5S)
Isopropyl -3,5-O-isopropylidene-6-methylheptanoate, (3R,5S)-butyl-3,5-O-isopropylidene-6-methylheptanoate.

(3R,5S)-3,5-O-isopropylidene-6-methyl heptenate, (3R,5S)-3,
Methyl 5-O-isopropylidene-6-octenoate, (
3R,5S)-3,5-O-isopropylidene-6-methyl heptate, (3R,5S)-3,5-O-isopropylidene-6-methyl octoate, (3R,5S)-
Methyl 3,5-O-isopropylidene-5-phenylpentanoate, (3R,5S)-methyl 3,5-O-isopropylidene-6-phenylpentanoate, (3R,5S)
Methyl -3,5-O-isopropylidene-7-phenylpentanoate.

(3S,5R)-3,5-O-isopropylidenehexanoate methyl, (3S,5R)-3,5-O
-ethyl isopropylidenehexanoate, (3S,5R)
-3,5-O-isopropylidenehexanoate propyl,
Isopropyl (3S,5R)-3,5-O-isopropylidenehexanoate, butyl (3S,5R)-3,5-O-isopropylidenehexanoate.

(3S,5R)-3,5-O-isopropylideneheptanoate methyl, (3S,5R)-3,5-O
-isopropylidene ethyl heptanoate, (3S,5R)
-3,5-O-isopropylidene propyl heptanoate,
(3S,5R)-3,5-O-isopropylideneheptanoate isopropyl, (3S,5R)-3,5-O-isopropylideneheptanoate butyl, (3S,5R)-3,
Methyl 5-O-isopropylideneoctanoate, (3S,
5R)-ethyl-3,5-O-isopropylideneoctanoate, (3S,5R)-3,5-O-isopropylideneoctanoate propyl, (3S,5R)-3,5-O-isopropylideneoctanoate isopropyl , (3S, 5R)
-3,5-O-isopropylidenebutyl octanoate.

(3S,5R)-3,5-O-isopropylidene-6-methylheptanoate, (3S,5R)
-3,5-O-isopropylidene-6-methylheptanoate ethyl, (3S,5R) -3,5-O-isopropylidene-6-methylheptanoate propyl, (3S,5R)
Isopropyl -3,5-O-isopropylidene-6-methylheptanoate, (3S,5R)-butyl-3,5-O-isopropylidene-6-methylheptanoate.

(3S,5R)-3,5-O-isopropylidene-6-methyl heptenoate, (3S,5R)-3,
Methyl 5-O-isopropylidene-6-octenoate, (
3S,5R)-3,5-O-isopropylidene-6-methyl heptate, (3S,5R)-3,5-O-isopropylidene-6-methyl octoate, (3S,5R)-
Methyl 3,5-O-isopropylidene-5-phenylpentanoate, (3S,5R)-methyl 3,5-O-isopropylidene-6-phenylpentanoate, (3S,5R)
-3,5-O-isopropylidene-7-phenylpentanoate methyl and the like.

[0039]

[Effects of the Invention] The effects of the present invention are listed below. 1. Because the reaction can be carried out under mild conditions from 0°C to around room temperature,
No special equipment required. 2. Easy to operate.

3. A product with high optical purity can be obtained. 4. Starting materials are readily available. In other words, the production method of the present invention efficiently produces optically active 3,5-anti-dihydroxycarboxylic acid ester derivatives, which are useful compounds with an extremely wide range of applications as intermediates for the synthesis of physiologically active substances and functional substances. This is an excellent method for obtaining large quantities.

[0041]

EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited by these Examples. Example 1 Production process 1 of methyl (3R,5S)-3,5-dihydroxyheptanoate and methyl (3R,5S)-3,5-O-isopropylideneheptanoate 9.1 g of methyl dl-3-hydroxypentanoate , 29.0 g of Tricaproin, and 3.0 g of Lipase Amano P was stirred at 38° C. for 70 hours. After removing lipase by suction filtration, purification was performed by distillation to obtain (S)-(
3.8 g of methyl +)-3-hydroxypentanoate and 5.7 g of methyl (R)-(+)-3-hexanoyloxypentanoate were obtained as a distillation residue. (S)-(+)-
A mixture of 2.3 g of methyl 3-hydroxypentanoate, 7.0 g of tricaproin, and 1.0 g of Lipase Amano P,
The mixture was stirred again at 38°C for 70 hours. After removing lipase by suction filtration, purification was performed by distillation to obtain (S)-(+
0.9 g of methyl )-3-hydroxypentanoate and 0.4 g of methyl (R)-(+)-3-hexanoyloxypentanoate were obtained as a distillation residue. (S)-(+)-3 by NMR using Eu(hfc)3 as a shift reagent
- When the optical purity of methyl hydroxypentanoate was assayed, it was found to be about 99% ee. of this compound
The 1H NMR chart supported the structure well.

Further, the physical property values were as follows. Boiling point: 62.5-63.5℃/6mmHg Specific optical rotation: +
37.9° (cl.46, CHCl3). Step 2 31.70 g of methyl (S)-3-hydroxypentanoate
(240 mmol), 3,4-dihydro-2H-pyran 30.56 g (363 mmol), methylene chloride 3
Pyridinium p-toluenesulfonate (hereinafter abbreviated as PPTS) 6.1 to 00 ml of the mixture under ice cooling.
1 g (24.3 mmol) (dissolved in a small amount of methylene chloride) was added and stirred at room temperature for 6 hours. The reaction mixture was poured into brine (300 ml) and ethyl acetate (200 ml x 4
) was extracted. The extract was mixed with water and saturated saline (100 ml each)
) and then dried over anhydrous magnesium sulfate. Filtration and solvent distillation were performed to obtain 54.76 g of crude methyl (S)-3-tetrahydropyranyloxypentanoate.

This compound was identified by 1H NMR chart analysis. 1H NMR (CDCl3) data is shown below. 1H NMR: δ0.9 (dt, 3H), 1.3
-2.1 (m, 8H), 2.3-2.9 (m, 2
H), 3.3-4.2 (m, 2H), 3.7 (s,
3H), 4.0 (quint, 1H), 4.6
-5.0 (m, 1H). Step 3 10.18 g (44.6 mmol) of crude methyl (S)-3-tetrahydropyranyloxypentanoate was dissolved in 22.3 ml of methanol, and 44.6 ml (89 mmol) of 10% aqueous potassium hydroxide solution was dissolved under ice cooling. 2 mmol) was added dropwise. The mixture was stirred for 4 hours under ice cooling and further stirred for 30 minutes at room temperature. The reaction mixture was neutralized with 6N hydrochloric acid (14.9 ml) and then extracted with methylene chloride (150 ml x 4). The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to give crude (S)-3-tetrahydropyranyloxypentanoic acid 8.
．． 81 g was obtained.

This compound was identified by 1H NMR chart analysis. 1H NMR (CDCl3) data is shown below. 1H NMR: δ0.9 (dt, 3H), 1.3
-2.1 (m, 8H), 2.3-2.9 (m, 2
H), 3.3-3.7 (m, 1H), 3.7-4.
2 (m, 1H), 4.0 (quint, 1H),
4.6-5.1 (m, 1H), 9.8 (brs, 1
H).

Step 4: 8.81 g (43.6 mmol) of crude (S)-3-tetrahydropyranyloxypentanoic acid was dissolved in 88 ml of tetrahydrofuran, and 10.86 g (N,N'-carbonyldiimidazole) was dissolved under ice cooling. 67.0 mmol) was added thereto and stirred at room temperature for 20 hours to obtain imidazolide. Malonic acid monomethyl ester 10.34g (87.6mm
ol) in 100 ml of tetrahydrofuran, and 4.86 g (51.0 mmol) of magnesium chloride was added under ice cooling.
added. Next, 14 ml of triethylamine (100
mmol) dropwise to keep the internal temperature below 10℃,
The mixture was stirred at the same temperature for 1 hour. After the imidazolide was added dropwise, the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into water (200 ml) containing 54 g of ammonium chloride, and extracted with ethyl acetate (100 ml x 4). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, water, and saturated brine (50 ml each), and then dried over anhydrous magnesium sulfate. The mixture was filtered and the solvent was distilled off to obtain 13.20 g of crude methyl (S)-3-oxo-5-tetrahydropyranyloxyheptanoate. It was purified by silica gel column chromatography (heptane:ethyl acetate 10:1→5:1) to obtain 8.98 g (34.8 mmol) of methyl (S)-3-oxo-5-tetrahydropyranyloxyheptanoate. The total yield from methyl (S)-3-hydroxypentanoate obtained in Step 1 was 78%.

This compound was identified by 1H NMR chart analysis. 1H NMR (CDCl3) data is shown below. 1H NMR: δ0.9 (dt, 3H), 1.3
-2.0 (m, 8H), 2.3-3.0 (m, 2
H), 3.2-4.2 (m, 5H), 3.7 (s,
3H), 4.5-4.8 (m, 1H). Step 5 P
-Toluenesulfonic acid monohydrate 8.68g (45.6m
mol) (dissolved in a small amount of water) was added dropwise, and the mixture was stirred at the same temperature for 5 hours. The reaction mixture was mixed with water (180 g) containing 39 g of baking soda.
ml) and extracted with ethyl acetate (100 ml x 4). The extract was diluted with saturated sodium bicarbonate solution, water, and saturated saline (50 m each).
After sequentially washing with 1), it was dried over anhydrous magnesium sulfate. After filtration and evaporation, the crude (S)-3-oxo-5-
5.78 g of methyl hydroxyheptanoate was obtained.

This compound was identified by 1H NMR chart analysis. 1H NMR (CDCl3) data is shown below. 1H NMR: δ1.0(t, 3H), 1.3-
1.8 (m, 2H), 2.6-2.8 (m, 2H
), 3.0(brs, 1H), 3.5(s, 2H
), 3.7(s, 3H), 3.8-4.2(m,
1H). Step 6 Add a mixed solution of 35 ml of acetonitrile and 47 ml of acetic acid,
Tetramethylammonium borohydride 6.1 under ice cooling
Add 2g (68.8mmol) little by little and let it cool for 30 minutes at room temperature.
Stir for a minute. Subsequently, under ice-cooling, 7.03 g of crude methyl (S)-3-oxo-5-hydroxyheptanoate (40
．． 4 mmol) was added dropwise, and the mixture was stirred at the same temperature for 6 hours. The reaction mixture was added dropwise to water (140 ml) containing 85 g of sodium bicarbonate, and extracted with ethyl acetate (140 ml x 4). The extract was washed successively with saturated aqueous sodium bicarbonate, water, and saturated brine (70 ml each), and then dried over anhydrous magnesium sulfate. The mixture was filtered and the solvent was distilled off to obtain 5.30 g of crude methyl (3R,5S)-3,5-dihydroxyheptanoate.

This compound was identified by 1H NMR chart analysis. 1H NMR (CDCl3) data is shown below. 1H NMR: δ0.9(t, 3H), 1.3-
1.9 (m, 4H), 2.3-2.7 (m, 2H
), 3.4-4.0 (m, 1H), 3.7 (s,
3H), 4.1-4.6 (m, 1H). Step 7 5.30 g (30.1 mmol) of crude methyl (3R,5S)-3,5-dihydroxyheptanoate was dissolved in 37.0 ml of methylene chloride, and 37.0 ml (303 mmol) of 2,2-dimethoxypropane was dissolved under ice cooling. ), PPTS 0
．． 78 g (3.1 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was poured into brine (100ml) and extracted with methylene chloride (75ml x 4). Add the extract to water,
After washing successively with saturated brine (50 ml each), it was dried over anhydrous magnesium sulfate. The residue obtained by filtration and evaporation of the solvent was dissolved again in 12.0 ml of methylene chloride, and the mixture was cooled with ice for 2.
2-dimethoxypropane 12.0ml (98.4mmo
1), 0.26 g (1.0 mmol) of PPTS was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution (
50 ml) and extracted with methylene chloride (75 ml x 4). The extract was washed successively with water and saturated brine (50 ml each), and then dried over anhydrous magnesium sulfate. filtration,
The solvent was distilled off to obtain 5.81 g of crude methyl (3R,5S)-3,5-O-isopropylideneheptanoate. Purification by distillation yielded 4.33 g (20.0 mmo) of methyl (3R,5S)-3,5-O-isopropylideneheptanoate
l) was obtained. (S)-3-oxo-5 obtained in step 4
The total yield from methyl -tetrahydropyranyloxyheptanoate was 46%.

As a result of analysis by capillary gas chromatography, this compound has a (3R,5S)-isomer and a (3S
, 5S)-isomer at a ratio of approximately 9:1. This compound was identified by 1H NMR chart analysis. 1HN
MR (CDCl3) data is shown below. 1H NMR: δ0.9(t, 3H), 1.2-
2.0 (m, 4H), 1.3 (s, 3H), 1
．． 4 (s, 3H), 2.5 (dd, 1H), 2.
5 (dd, 1H), 3.7 (s, 3H), 3.
7 (quint, 1H), 4.2 (quint,
1H).

Further, the physical property values were as follows. Boiling point: 79°C/2mmHg Specific optical rotation: +37.0° (cl.064, CHCl3
). Example 2 Production step 1 of methyl (3R,5S)-3,5-dihydroxyheptanoate and methyl (3R,5S)-3,5-O-isopropylideneheptanoate (S obtained in step 1 of Example 1) )-Methyl 3-hydroxypentanoate 770 mg (5.83 mmol), t-
Butyldimethylsilyl chloride 1.34g (8.89
mmol), imidazole 600 mg (8.81 mm
ol) and dimethylformamide (8 ml) was stirred at room temperature for 17 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution (80 ml).
) and extracted with ethyl acetate (80 ml x 4). The extract was washed successively with water and saturated brine (100 ml each), and then dried over anhydrous magnesium sulfate. The mixture was filtered and the solvent was distilled off to obtain 1.71 g of crude methyl (S)-3-t-butyldimethylsilyloxypentanoate. Silica gel column chromatography (heptane:ethyl acetate 20:1
) to obtain 1.39 g (5.64 mmol) of methyl (S)-3-t-butyldimethylsilyloxypentanoate.
I got it. Yield 97%.

This compound was identified by 1H NMR chart analysis. 1H NMR (CDCl3) data is shown below. 1H NMR: δ0.1 (s, 6H), 0.8-
1.1 (m, 3H), 0.9 (s, 9H), 1
．． 4-1.7 (m, 2H), 2.4 (d, 2H),
3.7(s, 3H), 4.1(quint, 1
H). Step 2 1.39 g (5.64 mmol) of methyl (S)-3-t-butyldimethylsilyloxypentanoate was dissolved in 2.9 ml of methanol, and 5.7 ml (11.4 mmol) of 10% aqueous potassium hydroxide solution was added under ice cooling. ) was dropped. The mixture was stirred for 4 hours under ice cooling and further stirred for 30 minutes at room temperature. The reaction mixture was neutralized with 6N hydrochloric acid (1.9 ml) and then diluted with ether (1.9 ml).
00ml x 4). The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to obtain crude (S)-3-
t-butyldimethylsilyloxypentanoic acid 1.30g
I got it.

This compound was identified by 1H NMR chart analysis. 1H NMR (CDCl3) data is shown below. 1H NMR: δ0.1 (sx2, 6H), 0.
8-1.2 (m, 3H), 0.9 (s, 9H),
1.4-1.9(m, 2H), 2.5(d, 2H
), 4.1(quint, 1H), 9.6(br
s, 1H). Step 3 800 mg (3.47 mmol) of crude (S)-3-t-butyldimethylsilyloxypentanoic acid was dissolved in 9 ml of tetrahydrofuran, and N,N' was dissolved under ice cooling.
- Carbonyldiimidazole 860 mg (5.30 mm
ol) was added and stirred at room temperature for 20 hours to obtain imidazolide.

1.06 g of malonic acid monomethyl ester (
8.98 mmol) and 13.8 m of tetrahydrofuran
1 of isopropylmagnesium bromide under ice-cooling.
．． 13.2 ml of 5 M tetrahydrofuran solution (19.
8 mmol) was added dropwise and stirred at the same temperature for 30 minutes, at room temperature for 30 minutes, and further at 45° C. for 30 minutes. The mixture was cooled with ice again, and the imidazolide was added dropwise, followed by stirring at room temperature for 24 hours. The reaction mixture was poured into 1N hydrochloric acid (50 ml) and extracted with ethyl acetate (50 ml x 4). The extract was washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated brine (50 ml each), and then dried over anhydrous magnesium sulfate. Filtration, evaporation of solvent,
780 mg of crude methyl (S)-3-oxo-5-t-butyldimethylsilyloxyheptanoate was obtained. Purified by silica gel column chromatography (heptane:ethyl acetate 20:1), (S)-3-oxo-5-
Methyl t-butyldimethylsilyloxyheptanoate 58
0 mg (2.01 mmol) was obtained. The total yield from methyl (S)-3-t-butyldimethylsilyloxypentanoate obtained in Step 1 was 58%.

This compound was identified by 1H NMR chart analysis. 1H NMR (CDCl3) data is shown below. 1H NMR: δ0.0 (sx2, 6H), 0.
6-1.1 (m, 3H), 0.8 (s, 9H),
1.1-1.8 (m, 2H), 2.6 (ddx2,
2H), 3.4(s, 2H), 3.7(s,
3H), 4.1 (quint, 1H).

Step 4 Methyl (S)-3-oxo-5-t-butyldimethylsilyloxyheptanoate 350 mg (1.21 mmol)
46% hydrofluoric acid-acetonitrile (5:95)
The mixture was dissolved in 3.1 ml of the mixed solution and stirred for 1 hour under ice cooling. The reaction mixture was poured into ice water (30 ml) and ethyl acetate (
30 ml x 4). Add the extract to saturated sodium bicarbonate solution, water,
After washing successively with saturated saline (30 ml each), it was dried over anhydrous magnesium sulfate. After filtration and evaporation, the crude (S
)-3-oxo-5-hydroxyheptanoate methyl 30
0 mg was obtained. The product was then purified by silica gel column chromatography (heptane:ethyl acetate 5:1→3:1) to obtain 140 mg (0.80 mmol) of methyl (S)-3-oxo-5-hydroxyheptanoate. Yield 66%.

The 1H NMR chart of this compound matched that obtained in step 5 of Example 1. Step 5 Add (S) to a mixed solution of 1 ml of acetonitrile and 1 ml of acetic acid.
-Methyl 3-oxo-5-hydroxyheptanoate 130
mg (0.75 mmol) and add 1.04 mg (0.75 mmol) of tetramethylammonium triacetoxyborohydride under ice cooling.
g (3.95 mmol) and stirred at the same temperature for 4 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (50 ml) and extracted with ethyl acetate (50 ml x 4). After washing the extract with saturated sodium bicarbonate solution, water, and saturated saline solution (25 ml each),
Dry over anhydrous magnesium sulfate. The mixture was filtered and the solvent was distilled off to obtain 120 mg of crude methyl (3R,5S)-3,5-dihydroxyheptanoate.

The 1H NMR chart of this compound matched that obtained in step 6 of Example 1. Step 6 Dissolve 120 mg (0.68 mmol) of crude methyl (3R,5S)-3,5-dihydroxyheptanoate in 2 ml of methylene chloride, and add 2 ml (16.4 mmol) of 2,2-dimethoxypropane and 40 mg of PPTS under ice cooling. (
0.16 mmol) was added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (50 ml) and extracted with ethyl acetate (50 ml x 4). The extract was washed successively with water and saturated brine (50 ml each), and then dried over anhydrous magnesium sulfate. After filtration and evaporation, the crude (3R,
130 mg of methyl 5S)-3,5-O-isopropylideneheptanoate was obtained. Purified by silica gel column chromatography (heptane:ethyl acetate 20:1),
80 mg (0.37 mmol) of methyl 3R,5S)-3,5-O-isopropylideneheptanoate was obtained. Process 4
The total yield from methyl (S)-3-oxo-5-hydroxyheptanoate obtained in (S) was 50%.

As a result of analysis by capillary gas chromatography, this compound has a (3R,5S)-isomer and a (3S
, 5S)-isomer at a ratio of about 9:1. The 1H NMR chart of this compound matched that obtained in Step 7 of Example 1. Example 3 Production process 1 of methyl (3S,5R)-3,5-dihydroxyheptanoate and methyl (3S,5R)-3,5-O-isopropylideneheptanoate (R )-(+)-Methyl 3-hexanoyloxypentanoate 5.7 g, 1,2-dichloroethane 48 ml, ethanol 48 ml, sulfuric acid 0.
After refluxing 9 ml of the mixture for 40 hours, water and ethyl acetate were added and stirred. The separated organic layer was washed successively with saturated aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The mixture was filtered and the solvent was distilled off to obtain 2.8 g of crude methyl (R)-(-)-3-hydroxypentanoate. Purified by distillation,
Methyl (R)-(-)-3-hydroxypentanoate 1.
8g was obtained. Optical purity was assayed by NMR using Eu(hfc)3 as a shift reagent and found to be approximately 95%ee.
Met. The 1H NMR chart of this compound well supported its structure.

Further, the physical property values were as follows. Boiling point: 62.5-63.5℃/6mmHg Specific optical rotation: -
35.5° (cl.55, CHCl3). Step 2 Methyl (R)-3-hydroxypentanoate 10.12g
(76.6 mmol), 3,4-dihydro-2H-pyran 9.76 g (116 mmol), methylene chloride 100
ml of the mixture under ice-cooling, add 2.05 g of PPTS (8.
16 mmol) (dissolved in a small amount of methylene chloride),
Stirred at room temperature for 6 hours. The reaction mixture was diluted with brine (100 m
1) and extracted with ethyl acetate (100 ml x 4). The extract was washed successively with water and saturated brine (50 ml each), and then dried over anhydrous magnesium sulfate. The mixture was filtered and the solvent was distilled off to obtain 16.75 g of crude methyl (R)-3-tetrahydropyranyloxypentanoate.

This compound was identified by 1H NMR chart analysis. 1H NMR (CDCl3) data is shown below. 1H NMR: δ0.9 (dt, 3H), 1.3
-2.1 (m, 8H), 2.3-2.9 (m, 2
H), 3.3-4.2 (m, 2H), 3.7 (s,
3H), 4.0 (quint, 1H), 4.6
-5.0 (m, 1H). Step 3 10.07 g (46.6 mmol) of crude methyl (R)-3-tetrahydropyranyloxypentanoate was dissolved in 23.3 ml of methanol, and 46.6 ml (93.6 mmol) of a 10% aqueous potassium hydroxide solution was dissolved under ice cooling. 2 mmol) was added dropwise. The mixture was stirred for 4 hours under ice cooling and further stirred for 30 minutes at room temperature. The reaction mixture was neutralized with 6N hydrochloric acid (14.9 ml) and then extracted with methylene chloride (150 ml x 4). The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to give crude (R)-3-tetrahydropyranyloxypentanoic acid 9.
．． 25g was obtained.

This compound was identified by 1H NMR chart analysis. 1H NMR (CDCl3) data is shown below. 1H NMR: δ0.9 (dt, 3H), 1.3
-2.1 (m, 8H), 2.3-2.9 (m, 2
H), 3.3-3.7 (m, 1H), 3.7-4.
2 (m, 1H), 4.0 (quint, 1H),
4.6-5.1 (m, 1H), 9.8 (brs,
1H).

Step 4: 12.84 g (63.5 mmol) of crude (R)-3-tetrahydropyranyloxypentanoic acid was dissolved in 128 ml of tetrahydrofuran, and 15.54 g (95 mmol) of N,N'-carbonyldiimidazole was dissolved under ice cooling. .8 mmol)
was added and stirred at room temperature for 20 hours to obtain imidazolide. Malonic acid monomethyl ester 15.07g (128m
mol) in 300 ml of tetrahydrofuran, and dissolved 6.91 g (72.6 mmol) of magnesium chloride under ice-cooling.
l) was added. Next, 20 ml of triethylamine (1
43 mmol) was added dropwise so as to keep the internal temperature below 10°C, and the mixture was stirred at the same temperature for 1 hour. After the imidazolide was added dropwise, the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into water (300 ml) containing 54 g of ammonium chloride, and extracted with ethyl acetate (150 ml x 4). 1N extract
After sequentially washing with hydrochloric acid, saturated aqueous sodium bicarbonate, water, and saturated brine (75 ml each), it was dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave 21.92 g of crude methyl (R)-3-oxo-5-tetrahydropyranyloxyheptanoate. Purified by silica gel column chromatography (heptane:ethyl acetate 10:1→5:1), (R)-3
11.53 g (44.6 mmol) of methyl -oxo-5-tetrahydropyranyloxyheptanoate was obtained. The total yield from methyl (R)-3-hydroxypentanoate obtained in Step 1 was 70%.

This compound was identified by 1H NMR chart analysis. 1H NMR (CDCl3) data is shown below. 1H NMR: δ0.9 (dt, 3H), 1.3
-2.0 (m, 8H), 2.3-3.0 (m, 2
H), 3.2-4.2 (m, 5H), 3.7 (s,
3H), 4.5-4.8 (m, 1H). Step 5 9.52 g (36.9 mmol) of methyl (R)-3-oxo-5-tetrahydropyranyloxyheptanoate,
To a mixture of 95 ml of methanol and 47.5 ml of water was added 9.13 g (48 ml) of p-toluenesulfonic acid monohydrate under ice cooling.
．． 0 mmol) (dissolved in a small amount of water) was added dropwise, and the mixture was stirred at the same temperature for 5 hours. The reaction mixture was mixed with water containing 40 g of baking soda (
200 ml) and extracted with ethyl acetate (100 ml x 4). The extract was mixed with saturated sodium bicarbonate solution, water, and saturated saline (5 each
0 ml) and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the crude (R)-3-oxo-
6.20 g of methyl 5-hydroxyheptanoate was obtained.

This compound was identified by 1H NMR chart analysis. 1H NMR (CDCl3) data is shown below. 1H NMR: δ1.0(t, 3H), 1.3-
1.8 (m, 2H), 2.6-2.8 (m, 2H
), 3.0(brs, 1H), 3.5(s, 2H
), 3.7(s, 3H), 3.8-4.2(m,
1H). Step 6 Add 5.0% tetramethylammonium borohydride to a mixed solution of 31ml of acetonitrile and 41.4ml of acetic acid under ice cooling.
39 g (60.6 mmol) was added little by little and stirred at room temperature for 30 minutes. Then, under ice cooling, crude (R)-3-
Methyl oxo-5-hydroxyheptanoate 6.20g (
35.6 mmol) was added dropwise and stirred at the same temperature for 7 hours. The reaction mixture was added dropwise to water (100 ml) containing 61 g of sodium bicarbonate, and extracted with ethyl acetate (100 ml x 4). The extract was washed successively with saturated aqueous sodium bicarbonate, water, and saturated brine (50 ml each), and then dried over anhydrous magnesium sulfate. filtration,
The solvent was distilled off to obtain 4.40 g of crude methyl (3S,5R)-3,5-dihydroxyheptanoate.

This compound was identified by 1H NMR chart analysis. 1H NMR (CDCl3) data is shown below. 1H NMR: δ0.9(t, 3H), 1.3-
1.9 (m, 4H), 2.3-2.7 (m, 2H
), 3.4-4.0 (m, 1H), 3.7 (s, 3
H), 4.1-4.6 (m, 1H). Step 7 4.40 g (25.0 mmol) of crude methyl (3S,5R)-3,5-dihydroxyheptanoate was dissolved in 30.5 ml of methylene chloride, and 30.5 ml (250 mmol) of 2,2-dimethoxypropane was dissolved under ice cooling. ), PPTS
1.31 g (5.2 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was poured into brine (100ml),
Extracted with ethyl acetate (75 ml x 4). Add the extract to water,
After washing successively with saturated brine (50 ml each), it was dried over anhydrous magnesium sulfate. The residue obtained by filtration and evaporation of the solvent was dissolved again in 10 ml of methylene chloride and diluted with 2,2
-dimethoxypropane 10ml (82.0mmol),
Add 0.44g (1.8mmol) of PPTS,
The mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution (50%
ml) and extracted with methylene chloride (75 ml x 4). The extract was washed successively with water and saturated brine (50 ml each), and then dried over anhydrous magnesium sulfate. The mixture was filtered and the solvent was distilled off to obtain 5.69 g of crude methyl (3S,5R)-3,5-O-isopropylideneheptanoate. Purified by distillation to obtain 3.48 g (16.1 mmol) of methyl (3S,5R)-3,5-O-isopropylideneheptanoate.
) obtained. (R)-3-oxo-5 obtained in step 4
The total yield from methyl -tetrahydropyranyloxyheptanoate was 44%.

As a result of analysis by capillary gas chromatography, this compound has a (3S,5R)-isomer and a (3R
, 5R)-isomer at a ratio of about 9:1. This compound was identified by 1H NMR chart analysis. 1H N
MR (CDCl3) data is shown below. 1H NMR: δ0.9(t, 3H), 1.2-
2.0 (m, 4H), 1.3 (s, 3H), 1
．． 4 (s, 3H), 2.5 (dd, 1H), 2.
5 (dd, 1H), 3.7 (s, 3H), 3.
7 (quint, 1H), 4.2 (quint,
1H) In addition, the physical property values were as follows.

Boiling point: 82°C/2mmHg Specific rotation: -3
3.3° (cl.106, CHCl3).

Claims (1)

[Claims] Claim 1: Represented by the general formula [Formula 1] (wherein R1 and R2 represent an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or an aralkyl group. * represents an asymmetric carbon) Optical activity 3-
An optically active 5-hydroxy-3-ketocarboxylic acid ester is obtained from the hydroxycarboxylic acid ester by a carbonization reaction in which magnesium malonate is reacted, and from this compound, the general formula [Chemical formula 2] (wherein R1 and R4 are an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or an aralkyl group,
R3 represents hydrogen or together represents an isopropylidene group. * indicates an asymmetric carbon. ) A method for producing an optically active 3,5-anti-dihydroxycarboxylic acid ester derivative, the method comprising obtaining a compound represented by: