JP2958665B2 - Optically active 3,5-anti-dihydroxycarboxylic acid ester derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to optically active 3,5-anti-dihydroxycarboxylic acid ester derivatives.

[0002]

2. Description of the Related Art The optically active 3,5-anti-dihydroxycarboxylic acid ester derivative of the present invention is a novel compound synthesized for the first time by the present inventors. This novel compound is a very useful compound as an intermediate for synthesizing various physiologically active substances and functional substances. For example, a compactin analog useful as a therapeutic drug for hyperlipidemia can be synthesized using the present compound as an intermediate.

[0003]

SUMMARY OF THE INVENTION Optically active 3,5-anti-dihydroxycarboxylic acid ester derivatives have an extremely wide range of applications as intermediates for synthesizing physiologically active substances and functional substances. The development of the law was strongly desired. The present inventors have conducted intensive studies to achieve the objective of efficiently obtaining this optically active substance in a large amount. As a result, the present inventors have found a production method for efficiently producing the optically active substance in a large amount, and have found a novel optically active substance by this production method. , 5-anti-dihydroxycarboxylic acid ester derivatives.

[0004]

Means for Solving the Problems The optical activity 3 of the present invention
5-anti-dihydroxycarboxylic acid ester and optically active 3,5-anti-O-isopropylidenecarboxylic acid ester are represented by the following general formulas (Ia ), (IIa) and (IIb).

[0005]

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[0006]

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(Wherein R ¹ and R ² each represent an alkyl group having 1 to 20 carbon atoms ).
R, 5S) -3,5-dihydroxyhexanoate,
Propyl (3R, 5S) -3,5-dihydroxyhexanoate, isopropyl (3R, 5S) -3,5-dihydroxyhexanoate, butyl (3R, 5S) -3,5-dihydroxyhexanoate.

Methyl (3R, 5S) -3,5-dihydroxyheptanoate, propyl (3R, 5S) -3,5-dihydroxyheptanoate, isopropyl (3R, 5S) -3,5-dihydroxyheptanoate, (3R , 5S)-
Butyl 3,5-dihydroxyheptanoate. Propyl (3R, 5S) -3,5-dihydroxyoctanoate, isopropyl (3R, 5S) -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, (3
R, 5S) -3,5-dihydroxy-6-methylheptanoate propyl, (3R, 5S) -3,5-dihydroxy-6-methylheptanoate isopropyl, (3R, 5S)
Butyl-3,5-dihydroxy-6-methylheptanoate.

(3R, 5S) -3,5-O-isopropyl
Methyl lidenhexanoate, (3R, 5S) -3,5-O
-Ethyl isopropylidenehexanoate,

(3R, 5S) -3,5-O-isopropyl
Propylidenehexanoate, (3R, 5S) -3,5-
Isopropyl O-isopropylidenehexanoate.

[0012] (3R, 5S) -3,5-O- isopropylidene-hexanoic acid butyl, (3R, 5S) -3,5- O
-Methyl isopropylideneheptanoate, (3R, 5S)
Ethyl-3,5-O-isopropylideneheptanoate,
(3R, 5S) -3,5-O-isopropylideneheptanoate propyl, (3R, 5S) -3,5-O-isopropylideneheptanoate isopropyl, (3R, 5S)-
Butyl 3,5-O-isopropylideneheptanoate.

Methyl (3R, 5S) -3,5-O-isopropylideneoctanoate, (3R, 5S) -3,5-O
-Ethyl isopropylideneoctanoate, (3R, 5S)
Propyl-3,5-O-isopropylideneoctanoate,
Isopropyl (3R, 5S) -3,5-O-isopropylideneoctanoate, butyl (3R, 5S) -3,5-O-isopropylideneoctanoate.

Methyl (3R, 5S) -3,5-O-isopropylidene-6-methylheptanoate, (3R, 5S)
Ethyl -3,5-O-isopropylidene-6-methylheptanoate, (3R, 5S) -3,5-O-isopropylidene-6-methylheptanoate, (3R, 5S)
Isopropyl-3,5-O-isopropylidene-6-methylheptanoate, butyl (3R, 5S) -3,5-O-isopropylidene-6-methylheptanoate.

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

Methyl (3S, 5R) -3,5-O-isopropylideneheptanoate, (3S, 5R) -3,5-O
-Ethyl isopropylideneheptanoate, (3S, 5R)
Propyl -3,5-O-isopropylideneheptanoate,
Isopropyl (3S, 5R) -3,5-O-isopropylideneheptanoate, butyl (3S, 5R) -3,5-O-isopropylideneheptanoate.

Methyl (3S, 5R) -3,5-O-isopropylideneoctanoate, (3S, 5R) -3,5-O
-Ethyl isopropylideneoctanoate, (3S, 5R)
Propyl-3,5-O-isopropylideneoctanoate,
Isopropyl (3S, 5R) -3,5-O-isopropylideneoctanoate, butyl (3S, 5R) -3,5-O-isopropylideneoctanoate.

Methyl (3S, 5R) -3,5-O-isopropylidene-6-methylheptanoate, (3S, 5R)
Ethyl-3,5-O-isopropylidene-6-methylheptanoate, (3S, 5R) -3,5-O-isopropylidene-6-methylheptanoate, (3S, 5R)
Isopropyl-3,5-O-isopropylidene-6-methylheptanoate and butyl (3S, 5R) -3,5-O-isopropylidene-6-methylheptanoate.

Next, a method for producing the compound of the present invention will be described. The optically active 3,5-anti-dihydroxycarboxylic acid ester derivatives (Ia, Ib, IIa, IIb) of the present invention are produced by using the racemic 3-hydroxycarboxylic acid ester (III) as a starting material according to the following reaction steps. I can do it.

[0020]

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(Wherein R ¹ , R ² and R ^{3 each} have 1 to 2 carbon atoms)
0 represents an alkyl group, and R ⁴ represents a protecting group. * Represents an asymmetric carbon. The compound represented by the formula (IV) is obtained by optically resolving a racemic 3-hydroxycarboxylic acid ester (III) using a lipase to give (R)-,
(S) -Each body can be obtained with good optical purity (Japanese Patent Application No. 1-397297).

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

The compound represented by the formula (V) can be easily converted to the compound represented by the 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 or 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 the formula (VII) is obtained by reacting the compound represented by the formula (VI) with N, N'-carbonyldiimidazole to give imidazolide, and then reacting a monoalkyl malonate with a magnesium compound. By reacting with magnesium malonate adjusted from the above, a good yield can be obtained. Examples of the magnesium compound used in the reaction include magnesium halides such as magnesium chloride and magnesium bromide, and alkyl magnesium halides such as isopropyl magnesium chloride and isopropyl magnesium bromide. As a reaction solvent, ether solvents such as tetrahydrofuran and ether can be used. Reaction temperature is -30 ° C to 50 ° C
Is suitable, and particularly preferably 0 ° C to 25 ° C.

The compound represented by the formula (VII) can be easily converted to the compound represented by the formula (VIII) by removing the protecting group for the hydroxyl group by an appropriate method. For example, a compound in which a hydroxyl group is protected by a tetrahydropyranyl group is deprotected under acidic conditions. Examples of the acid used for the reaction include acetic acid, hydrochloric acid, p-toluenesulfonic acid, and pyridinium p-toluenesulfonate.
As the reaction solvent, alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran,
Alternatively, a mixed solvent 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 the formula (Ia, Ib) is represented by the formula (VI)
The compound represented by II) can be obtained by highly stereoselective reduction using an appropriate reducing agent. Examples of the reducing agent used in the reaction include tetramethylammonium borohydride, tetrabutylammonium borohydride, sodium borohydride, tetramethylammonium triacetoxyborohydride, tetrabutylammonium triacetoxyborohydride, sodium triacetoxyborohydride Hydride and the like. As the reaction solvent, acetic acid, lower carboxylic acids such as propionic acid, or a mixed solvent thereof with acetonitrile, tetrahydrofuran, acetone or the like can be used, and the ratio of acetic acid in that case is 10% or more of the whole, more preferably. Is more than 50%. The reaction temperature is suitably from −78 ° C. to 50 ° C., particularly preferably from −40 ° C. to 25 ° C.

Finally, the compound represented by the formula (Ia, Ib) is represented by the formula (IIa, IIb) by reacting with 2,2-dimethoxypropane using pyridinium p-toluenesulfonate or the like as a catalyst. It can be easily led to a compound. By the above operation, optical activity (3R, 5S)
Or (3S, 5R) -3,5-dihydroxycarboxylic acid ester derivatives (formulas (Ia, Ib) and (IIa, IIb)) can be obtained.

[0028]

The optically active 3,5-anti-dihydroxycarboxylic acid ester derivative of the present invention can be a useful compound having a very wide range of applications as an intermediate for synthesizing physiologically active substances and functional substances. For example, a compactin analog useful as a therapeutic agent for hyperlipidemia using the present compound as an intermediate can be easily synthesized.

[0029]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention. Example 1 Preparation of methyl (3R, 5S) -3,5-dihydroxyheptanoate and methyl (3R, 5S) -3,5-O-isopropylideneheptanoate Step 1 9.1 g of methyl dl-3-hydroxypentanoate, A mixture of 29.0 g of tricaproin and 3.0 g of lipase amano P was added
Stirred for hours. After removing lipase by suction filtration,
Purification was performed by distillation, and 3.8 g of methyl (S)-(+)-3-hydroxypentanoate and (R)-as a distillation residue were obtained.
5.7 g of methyl (+)-3-hexanoyloxypentanoate
I got 2.3 g of methyl (S)-(+)-3-hydroxypentanoate, 7.0 g of tricaproin, 1.0 g of lipase amano P
Was again stirred at 38 ° C. for 70 hours. After removing lipase by suction filtration, purification is performed by distillation,
Methyl (S)-(+)-3-hydroxypentanoate 0.9
g and 0.4 g of methyl (R)-(+)-3-hexanoyloxypentanoate 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. ¹ HN of the compound
The MR chart well supported the structure.

The physical properties were as follows. Boiling point: 62.5-63.5 ° C./6 mmHg Specific rotation: + 37.9 ° (cl. 46, CHCl ₃ ). Step 2 31.70 g of methyl (S) -3-hydroxypentanoate (240 mm
ol), 30.56 g of 3,4-dihydro-2H-pyran (363 mmo
l) Pyridinium p-toluenesulfonate (hereinafter abbreviated as PPTS) in a mixture of 300 ml of methylene chloride under ice cooling.
6.11 g (24.3 mmol) (dissolved in a small amount of methylene chloride) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was added to a saline solution (300 m
l) and extracted with ethyl acetate (200 ml x 4). The extract was washed sequentially with water and saturated saline (100 ml each), and then dried over anhydrous magnesium sulfate. Filtration and solvent evaporation gave 54.76 g of crude methyl (S) -3-tetrahydropyranyloxypentanoate.

This compound was identified by ¹ H NMR chart analysis. ¹ H NMR (CDCl ₃ ) data is shown below. ¹ H NMR: δ 0.9 (dt, 3H), 1.3-2.1 (m, 8H), 2.3-2.9
(m, 2H), 3.3-4.2 (m, 2H), 3.7 (s, 3H), 4.0 (quint, 1
H), 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 of a 10% aqueous potassium hydroxide solution (89.2 mmol
l) was added dropwise. The mixture was stirred for 4 hours under ice cooling and further for 30 minutes at room temperature. The reaction mixture was neutralized with 6N hydrochloric acid (14.9 ml) and extracted with methylene chloride (150 ml × 4). The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off.
8.81 g of -3-tetrahydropyranyloxypentanoic acid was obtained.

This compound was identified by ¹ H NMR chart analysis. ¹ H NMR (CDCl ₃ ) data is shown below. ¹ H NMR: δ 0.9 (dt, 3H), 1.3-2.1 (m, 8H), 2.3-2.9
(m, 2H), 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 Crude (S) -3-tetrahydropyranyloxypentanoic acid (8.81 g, 43.6 mmol) was dissolved in tetrahydrofuran (88 ml), and N, N'-carbonyldiimidazole (10.8 g) was dissolved under ice-cooling.
6 g (67.0 mmol) was added and the mixture was stirred at room temperature for 20 hours to obtain imidazolide.

Malonic acid monomethyl ester 10.34 g (87.6 m
mol) was dissolved in 100 ml of tetrahydrofuran, and 4.86 g (51.0 mmol) of magnesium chloride was added under ice cooling. Subsequently, 14 ml (100 mmol) of triethylamine was added dropwise so that the internal temperature was kept at 10 ° C. or lower, and the mixture was stirred at the same temperature for 1 hour. After dropping the imidazolide, 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 × 4). The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water, and saturated saline (50 ml each), and dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent yielded 13.20 g of crude methyl (S) -3-oxo-5-tetrahydropyranyloxyheptanoate. Silica gel column chromatography (heptane: ethyl acetate 10: 1 →
5: 1), and 8.98 g (34.8 mmol) of methyl (S) -3-oxo-5-tetrahydropyranyloxyheptanoate
I got The total yield from methyl (S) -3-hydroxypentanoate obtained in Step 1 was 78%.

This compound was identified by ¹ H NMR chart analysis. ¹ H NMR (CDCl ₃ ) data is shown below. ¹ H NMR: δ 0.9 (dt, 3H), 1.3-2.0 (m, 8H), 2.3-3.0
(m, 2H), 3.2-4.2 (m, 5H), 3.7 (s, 3H), 4.5-4.8 (m, 1
H). Step 5 8.98 g (34.8 mmol) of methyl (S) -3-oxo-5-tetrahydropyranyloxyheptanoate, 90 ml of methanol,
To a mixture of 45 ml of water, p-toluenesulfonic acid 1 was added under ice-cooling.
8.68 g (45.6 mmol) of hydrate (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 poured into water (180 ml) containing 39 g of sodium bicarbonate, and extracted with ethyl acetate (100 ml × 4). Extract solution is saturated aqueous sodium bicarbonate, water, saturated saline (50 ml each)
, And dried over anhydrous magnesium sulfate. Filtration and solvent evaporation gave 5.78 g of crude methyl (S) -3-oxo-5-hydroxyheptanoate.

This compound was identified by ¹ H NMR chart analysis. ¹ H NMR (CDCl ₃ ) data is shown below. ¹ H 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 To a mixed solution of 35 ml of acetonitrile and 47 ml of acetic acid was added under ice-cooling,
6.12 g (68.8 mmo) of tetramethylammonium borohydride
l) was added in small portions and stirred at room temperature for 30 minutes. Subsequently, under ice-cooling, 7.03 g (40.4 mmol) of crude methyl (S) -3-oxo-5-hydroxyheptanoate 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 × 4). The extract was washed sequentially with saturated aqueous sodium hydrogen carbonate, water, and saturated saline (70 ml each), and dried over anhydrous magnesium sulfate. Filtration, solvent evaporation,
5.30 g of crude methyl (3R, 5S) -3,5-dihydroxyheptanoate were obtained.

The compound was identified by ¹ H NMR chart analysis. ¹ H NMR (CDCl ₃ ) data is shown below. ¹ H NMR: δ 0.9 (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, 1
H). Step 7 The crude methyl (3R, 5S) -3,5-dihydroxyheptanoate (5.30 g, 30.1 mmol) was dissolved in methylene chloride (37.0 ml), and under ice-cooling, 2,2-dimethoxypropane (37.0 ml, 303 mmol) was added.
l) and 0.78 g (3.1 mmol) of PPTS were added, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into saline (100 ml) and extracted with methylene chloride (75 ml × 4). Extract the extract with water, saturated saline (each
50 ml), and dried over anhydrous magnesium sulfate. The residue obtained by filtration and evaporation of the solvent was re-methylene chloride 1
Dissolved in 2.0 ml and cooled under ice-cooling to 2,2-dimethoxypropane 12.
0 ml (98.4 mmol) and 0.26 g (1.0 mmol) of PPTS were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (50 ml) and extracted with methylene chloride (75 ml × 4). The extract was washed sequentially with water and saturated saline (50 ml each), and dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave the crude (3
5.81 g of methyl (R, 5S) -3,5-O-isopropylideneheptanoate were obtained. Purify by distillation, (3R, 5
S) Methyl 3,5-O-isopropylideneheptanoate
4.33 g (20.0 mmol) were obtained. (S) -3 obtained in step 4
The total yield from methyl-oxo-5-tetrahydropyranyloxyheptanoate was 46%.

As a result of analysis by capillary gas chromatography, the product was identified as (3R, 5S) -form and (3R, 5S) -form.
Approximately 9: 1 mixture with (S, 5S) -form. This compound was identified by ¹ H NMR chart analysis. ¹ H NMR
(CDCl ₃ ) data is shown below. ¹ H NMR: δ 0.9 (t, 3H), 1.2-2.0 (m, 4H), 1.3 (s, 3
H), 1.4 (s, 3H), 2.5 (dd, 1H), 2.5 (dd, 1H), 3.7 (s, 3
H), 3.7 (quint, 1H), 4.2 (quint, 1H) The physical properties were as follows.

Boiling point: 79 ° C./2 mmHg Specific rotation: + 37.0 ° (cl.064, CHCl ₃ ). Example 2 Preparation of methyl (3R, 5S) -3,5-dihydroxyheptanoate and methyl (3R, 5S) -3,5-O-isopropylideneheptanoate Step 1 Obtained in Step 1 of Example 1 ) 770 mg (5.83 mmol) of methyl 3-hydroxypentanoate, 1.34 g (8.89 mmol) of t-butyldimethylsilyl chloride, 600 m of imidazole
A mixture of g (8.81 mmol) and 8 ml of dimethylformamide was stirred at room temperature for 17 hours. The reaction mixture was saturated with aqueous sodium bicarbonate (80 ml)
And extracted with ethyl acetate (80 ml × 4). The extract was washed sequentially with water and saturated saline (100 ml each), and then dried over anhydrous magnesium sulfate. Filtration and solvent evaporation gave 1.71 g of crude methyl (S) -3-t-butyldimethylsilyloxypentanoate. Purify by silica gel column chromatography (heptane: ethyl acetate 20: 1),
1.39 g (5.64 mmol) of methyl (S) -3-t-butyldimethylsilyloxypentanoate was obtained. 97% yield.

This compound was identified by ¹ H NMR chart analysis. ¹ H NMR (CDCl ₃ ) data is shown below. ¹ H NMR: δ 0.1 (s, 6H), 0.8-1.1 (m, 3H), 0.9 (s, 9
H), 1.4-1.7 (m, 2H), 2.4 (d, 2H), 3.7 (s, 3H), 4.1 (qui
nt, 1H). 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 a 10% aqueous potassium hydroxide solution was added under ice-cooling.
Was added dropwise. The mixture was stirred for 4 hours under ice cooling and further for 30 minutes at room temperature. The reaction mixture was neutralized with 6N hydrochloric acid (1.9 ml) and extracted with ether (100 ml × 4). The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to obtain crude (S) -3-
1.30 g of t-butyldimethylsilyloxypentanoic acid were obtained.

This compound was identified by ¹ H NMR chart analysis. ¹ H NMR (CDCl ₃ ) data is shown below. ^{1 H 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 (brs, 1H). Step 3 Crude (S) -3-t-butyldimethylsilyloxypentanoic acid (800 mg, 3.47 mmol) was dissolved in tetrahydrofuran (9 ml), and N, N'-carbonyldiimidazole was dissolved under ice-cooling.
860 mg (5.30 mmol) was added, and the mixture was stirred at room temperature for 20 hours to obtain imidazolide.

Malonic acid monomethyl ester 1.06 g (8.98 mm
ol) was dissolved in 13.8 ml of tetrahydrofuran, 13.2 ml (19.8 mmol) of a 1.5 M solution of isopropylmagnesium bromide in tetrahydrofuran was added dropwise under ice cooling, and the mixture was added at the same temperature for 30 minutes and at room temperature.
The mixture was stirred for 30 minutes and further at 45 ° C. for 30 minutes. After ice-cooling again, the above-mentioned imidazolide was added dropwise, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into 1N hydrochloric acid (50 ml), and ethyl acetate (50 ml) was added.
× 4). The extract was washed sequentially with water, saturated aqueous sodium hydrogen carbonate, water and saturated saline (50 ml each), and dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave crude (S) -3-
780 mg of methyl oxo-5-t-butyldimethylsilyloxyheptanoate were obtained. Purification by silica gel column chromatography (heptane: ethyl acetate 20: 1) (S)
580 mg (2.01 mmol) of methyl 3-oxo-5-t-butyldimethylsilyloxyheptanoate was obtained. The total yield from methyl (S) -3-t-butyldimethylsilyloxypentanoate obtained in Step 1 was 58%.

This compound was identified by ¹ H NMR chart analysis. ¹ H NMR (CDCl ₃ ) data is shown below. ¹ H 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 4 350 mg (1.21 mmol) of methyl (S) -3-oxo-5-tert-butyldimethylsilyloxyheptanoate was added to 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 added to ice water (30 m
l) and extracted with ethyl acetate (30 ml × 4). The extract was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated saline (30 ml each), and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, 300 mg of crude methyl (S) -3-oxo-5-hydroxyheptanoate was obtained. Purification by silica gel column chromatography (heptane: ethyl acetate 5: 1 → 3: 1) gave 140 mg (0.80 mmol) of methyl (S) -3-oxo-5-hydroxyheptanoate. Yield 66%.

The ¹ H NMR chart of this compound was identical to that obtained in Step 5 of Example 1. Step 5 (S) -3 was added to a mixed solution of 1 ml of acetonitrile and 1 ml of acetic acid.
Methyl oxo-5-hydroxyheptanoate 130 mg (0.75
mmol), and 1.04 g (3.95 mmol) of tetramethylammonium triacetoxyborohydride was added thereto under ice cooling, followed by stirring at the same temperature for 4 hours. The reaction mixture was saturated with aqueous sodium bicarbonate (50 ml)
And extracted with ethyl acetate (50 ml × 4). The extract was washed successively with saturated aqueous sodium hydrogen carbonate, water, and saturated saline (25 ml each),
Dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, 120 mg of crude methyl (3R, 5S) -3,5-dihydroxyheptanoate was obtained.

The ¹ H NMR chart of this compound was identical to that obtained in Step 6 of Example 1. Step 6 120 mg (0.68 mmol) of crude methyl (3R, 5S) -3,5-dihydroxyheptanoate was dissolved in 2 ml of methylene chloride, and 2 ml (16.4 mmol) of 2,2-dimethoxypropane were dissolved under ice-cooling.
l), PPTS (40 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (50 ml) and extracted with ethyl acetate (50 ml × 4). The extract was washed sequentially with water and saturated saline (50 ml each), and dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave crude (3R, 5S)-
130 mg of methyl 3,5-O-isopropylideneheptanoate
I got Purify by silica gel column chromatography (heptane: ethyl acetate 20: 1) to give (3R, 5S)-
Methyl 3,5-O-isopropylideneheptanoate 80 mg
(0.37 mmol) was obtained. The total yield from methyl (S) -3-oxo-5-hydroxyheptanoate obtained in Step 4 is
50%.

As a result of analysis by capillary gas chromatography, the product was identified as (3R, 5S) -isomer and (3R, 5S) -isomer.
Approximately 9: 1 mixture with (S, 5S) -form. The ¹ H NMR chart of this compound was consistent with that obtained in Step 7 of Example 1. Example 3 Production of Methyl (3S, 5R) -3,5-Dihydroxyheptanoate and (3S, 5R) -3,5-O-isopropylideneheptanoate Step 1 The (R) obtained in Step 1 of Example 1 A mixture of 5.7 g of methyl-(+)-3-hexanoyloxypentanoate, 48 ml of 1,2-dichloroethane, 48 ml of ethanol and 0.9 ml of sulfuric acid was prepared.
After refluxing for 40 hours, water and ethyl acetate were added and stirred. The separated organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave 2.8 g of crude methyl (R)-(-)-3-hydroxypentanoate.
I got Purification by distillation gave 1.8 g of methyl (R)-(-)-3-hydroxypentanoate. When optical purity was assayed by NMR using Eu (hfc) ₃ as a shift reagent, it was about 95% ee. The ¹ H NMR chart of this compound well supported the structure.

The physical properties were as follows. Boiling point: 62.5-63.5 ° C./6 mmHg Specific rotation: −35.5 ° (cl. 55, CHCl ₃ ). Step 2 10.12 g of methyl (R) -3-hydroxypentanoate (76.6 m
mol), 9.76 g of 3,4-dihydro-2H-pyran (116 mmo
l), 100 ml of methylene chloride, 2.05 g of PPTS under ice cooling
(8.16 mmol) (dissolved in a small amount of methylene chloride) and the mixture was stirred at room temperature for 6 hours. Pour the reaction mixture into saline (100 ml),
Extracted with ethyl acetate (100 ml × 4). The extract was washed sequentially with water and saturated saline (50 ml each), and dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave crude (R) -3-
16.75 g of methyl tetrahydropyranyloxypentanoate was obtained.

This compound was identified by ¹ H NMR chart analysis. ¹ H NMR (CDCl ₃ ) data is shown below. ¹ H NMR: δ 0.9 (dt, 3H), 1.3-2.1 (m, 8H), 2.3-2.9
(m, 2H), 3.3-4.2 (m, 2H), 3.7 (s, 3H), 4.0 (quint, 1
H), 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 (93.2 mmol) of a 10% aqueous potassium hydroxide solution was added under ice-cooling.
l) was added dropwise. The mixture was stirred for 4 hours under ice cooling and further for 30 minutes at room temperature. The reaction mixture was neutralized with 6N hydrochloric acid (14.9 ml) and extracted with methylene chloride (150 ml × 4). The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off.
9.25 g of -3-tetrahydropyranyloxypentanoic acid was obtained.

This compound was identified by ¹ H NMR chart analysis. ¹ H NMR (CDCl ₃ ) data is shown below. ¹ H NMR: δ 0.9 (dt, 3H), 1.3-2.1 (m, 8H), 2.3-2.9
(m, 2H), 3.3-3.7 (m, 1H), 3.7-4.2 (m, 1H), 4.0 (quin
t, 1H), 4.6-5.1 (m, 1H), 9.8 (brs, 1H). Step 4 Crude (R) -3-tetrahydropyranyloxypentanoic acid (12.84 g, 63.5 mmol) was dissolved in tetrahydrofuran (128 ml), and N, N'-carbonyldiimidazole (15.5) was dissolved under ice cooling.
4 g (95.8 mmol) was added, and the mixture was stirred at room temperature for 20 hours to obtain imidazolide.

Malonic acid monomethyl ester 15.07 g (128 mm
ol) was dissolved in 300 ml of tetrahydrofuran, and 6.91 g (72.6 mmol) of magnesium chloride was added under ice cooling. Subsequently, 20 ml (143 mmol) of triethylamine was added dropwise so that the internal temperature was kept at 10 ° C. or lower, and the mixture was stirred at the same temperature for 1 hour. After dropping the imidazolide, 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 × 4). The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and saturated saline (75 ml each), and dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave 21.92 g of crude methyl (R) -3-oxo-5-tetrahydropyranyloxyheptanoate. Silica gel column chromatography (heptane: ethyl acetate 10: 1 →
5: 1), and 11.53 g (44.6 mmol) of methyl (R) -3-oxo-5-tetrahydropyranyloxyheptanoate
I got The total yield from methyl (R) -3-hydroxypentanoate obtained in Step 1 was 70%.

This compound was identified by ¹ H NMR chart analysis. ¹ H NMR (CDCl ₃ ) data is shown below. ¹ H NMR: δ 0.9 (dt, 3H), 1.3-2.0 (m, 8H), 2.3-3.0
(m, 2H), 3.2-4.2 (m, 5H), 3.7 (s, 3H), 4.5-4.8 (m, 1
H). Step 5 Methyl (R) -3-oxo-5-tetrahydropyranyloxyheptanoate 9.52 g (36.9 mmol), methanol 95 ml,
To a mixture of 47.5 ml of water was added dropwise 9.13 g (48.0 mmol) of p-toluenesulfonic acid monohydrate (dissolved in a small amount of water) under ice-cooling.
The mixture was stirred at the same temperature for 5 hours. The reaction mixture was poured into water (200 ml) containing 40 g of sodium bicarbonate, and extracted with ethyl acetate (100 ml × 4). The extract was washed with saturated aqueous sodium bicarbonate, water, and saturated saline (50 ml each)
, And dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave 6.20 g of crude methyl (R) -3-oxo-5-hydroxyheptanoate.

This compound was identified by ¹ H NMR chart analysis. ¹ H NMR (CDCl ₃ ) data is shown below. ¹ H 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 To a mixed solution of acetonitrile 31 ml and acetic acid 41.4 ml was added ice-cooled tetramethylammonium borohydride 5.39 g (60.6 mmol
l) was added in small portions and stirred at room temperature for 30 minutes. Then, under ice-cooling, 6.20 g (35.6 mmol) of crude methyl (R) -3-oxo-5-hydroxyheptanoate was added dropwise, and the mixture was 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 × 4). The extract was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated saline (50 ml each), and dried over anhydrous magnesium sulfate. Filtration, solvent evaporation,
4.40 g of crude methyl (3S, 5R) -3,5-dihydroxyheptanoate was obtained.

This compound was identified by ¹ H NMR chart analysis. ¹ H NMR (CDCl ₃ ) data is shown below. ¹ H NMR: δ 0.9 (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, 1
H). Step 7 The crude methyl (3S, 5R) -3,5-dihydroxyheptanoate (4.40 g, 25.0 mmol) was dissolved in methylene chloride (30.5 ml), and 2,2-dimethoxypropane (30.5 ml, 250 mmol) was dissolved under ice-cooling.
l) and 1.31 g (5.2 mmol) of PPTS were added, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into brine (100 ml) and extracted with ethyl acetate (75 ml × 4). Extract the extract with water, saturated saline (each
(50 ml) and dried over anhydrous magnesium sulfate. The residue obtained by filtration and evaporation of the solvent was methylene chloride again.
and 2,2-dimethoxypropane 10 ml (8
2.0 mmol) and 0.44 g (1.8 mmol) of PPTS were added, followed by stirring at room temperature for 5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (50 ml) and extracted with methylene chloride (75 ml × 4). The extract was washed sequentially with water and saturated saline (50 ml each), and then dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave the crude (3S, 5
R) Methyl -3,5-O-isopropylideneheptanoate
5.69 g were obtained. Purified by distillation (3S, 5R) -3,
3.48 g of methyl 5-O-isopropylideneheptanoate (16.1
mmol). (R) -3-oxo- obtained in step 4
The total yield from methyl 5-tetrahydropyranyloxyheptanoate was 44%.

As a result of analysis by capillary gas chromatography, the product was identified as (3S, 5R) -isomer and (3S, 5R) -isomer.
(R, 5R) -form. This compound was identified by ¹ HNMR chart analysis. ¹ H NMR
(CDCl ₃ ) data is shown below. ¹ H NMR: δ 0.9 (t, 3H), 1.2-2.0 (m, 4H), 1.3 (s, 3
H), 1.4 (s, 3H), 2.5 (dd, 1H), 2.5 (dd, 1H), 3.7 (s, 3
H), 3.7 (quint, 1H), 4.2 (quint, 1H) The physical properties were as follows.

Boiling point: 82 ° C./2 mmHg Specific rotation: −33.3 ° (cl. 106, CHCl ₃ ).

──────────────────────────────────────────────────の Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07C 69/675 C07D 319/06 CA (STN) REGISTRY (STN) WPI / L (QUESTEL)

Claims (2)

(57) [Claims] [Claim 1] (In the formula, R ¹ and R ² each represent an alkyl group having 1 to 20 carbon atoms.) An optically active 3,5-anti-dihydroxycarboxylic acid ester represented by the formula: ## STR2 ## (In the formula, R ¹ and R ² each represent an alkyl group having 1 to 20 carbon atoms .) An optically active 3,5-anti-O-isopropylidenecarboxylic acid ester represented by the formula: