JPH11335328A - Production of 3,5-dihydroxy-6-oxohexanoic acid ester derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially and advantageously produce the subject derivative useful as an intermediate for a therapeutic agent for hyperlipemia by regioselectively reducing a specific derivative. SOLUTION: A 2,4-dihydroxyadipic acid ester derivative represented by formula I (R<1> is an ester, carboxyl or the like; R<2> is an alkyl, an aryl or an aralkyl; R<3> and R<4> are each H, a silyl type protecting group or the like) is regioselectively reduced to produce the objective derivative represented by formula II (e.g. t-butyl 3,5-O-isopropylidene-3,5-dihyciroxy-6-oxohexanoate). In the reduction, a hydride reducing agent, e.g. diisobutylaluminum hydride is preferably used as a reducing agent. Furthermore, the reaction is preferably conducted in, e.g. an inert aprotic solvent at -90 to -50 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a 3,5-dihydroxy-6-oxohexanoic acid ester derivative, and more particularly to a method for advantageously producing an optically active substance thereof.

[0002] Such hexanoic acid ester derivatives are
HMG- attracts attention for its action as a therapeutic agent for antilipidemia
CoA (3-hydroxy-3-methylglutaryl-CoA)
It is a compound useful as an intermediate of a reductase inhibitor.

[0003]

2. Description of the Related Art As a method for producing a 3,5-dihydroxy-6-oxohexanoic acid ester derivative, a method for oxidizing a 3,5,6-trihydroxyhexane ester derivative (JP-A-1-199945) is known. ) And a method using ozone oxidation of a styrene derivative (Journal
Of Medicinal Chemistry (J. Med. Che
m. ) 33, 2982 (1980)).

[0004]

The method of oxidizing a 3,5,6-trihydroxyhexanoic acid ester derivative and the method of utilizing ozone oxidation of a styrene derivative require relatively expensive reagents and complicated operations. Therefore, a more effective method is desired as an industrial production method of a 3,5-dihydroxy-6-oxohexanoic acid derivative.

[0005]

In view of the above circumstances, the present inventors have developed economically and practically useful 3,5-dihydroxy-6-oxohexanoic acid ester derivatives, especially optically active derivatives thereof. As a result of intensive studies on a method for producing a certain (3R, 5S) -3,5-dihydroxy-6-oxohexanoic acid ester, one of 2,4-dihydroxyadipate ester derivatives which can be easily synthesized from malic acid was obtained.
By reducing the ester group, or the carboxyl group at the 1-position, or any of its reactive derivatives,
3,5-dihydroxy-6-oxohexanoic acid ester derivative can be produced, and (2S, 4R) -2,4-dihydroxyadipate derivative synthesized using optically active L-malic acid as a starting material. By reduction, the optically active (3R, 5
The present inventors have found that S) derivatives can be produced and completed the present invention.

That is, the present invention provides a compound of the formula (I):

Embedded image (Wherein, R ¹ represents an ester group, a carboxy group or a reactive derivative of a carboxylic acid; R ² represents an alkyl group, an aryl group or an aralkyl group; R ³ and R ⁴ represent hydrogen or a silyl-type protecting group Wherein the 2,4-dihydroxyadipate derivative represented by the formula (II):

Embedded image (Wherein R ² , R ³ and R ⁴ have the same meanings as described above). A process for producing a 3,5-dihydroxy-6-oxohexanoate derivative represented by the formula:

According to the present invention, a (2S, 4R) -2,4-dihydroxyadipate derivative which can be easily synthesized from optically active L-malic acid can be effectively converted into HMG-Co.
Has a useful configuration as an intermediate for A reductase inhibitors
It can be converted to (3R, 5S) -3,5-dihydroxy-6-oxohexanoate derivative. The starting compound of the present invention, a 2,4-dihydroxyadipate derivative, is obtained by, for example, malonic acid acetonidation, followed by enrichment with malonic acid half ester, deprotection and reduction, and further, if necessary, a hydroxyl group. Can be manufactured by protecting.

The above reaction is represented by the following reaction formula.

Embedded image (Wherein, R ² and R ⁵ each represent an alkyl group, R ⁶ and R 5
⁷ represents a hydroxyl-protecting group. ).

The compound of the formula (I) is reduced to give a compound of the formula (I
In the case of producing the 3,5-dihydroxy-6-oxohexanoic acid ester derivative represented by I), examples of R ¹ include a reactive derivative of an ester group, a carboxyl group, and a carboxylic acid. Examples of the ester group include lower alkyl groups such as a methyl group, an ethyl group, and a propyl group. Examples of the reactive derivative of the carboxylic acid include an acid chloride and a mixed acid anhydride derived from the carboxylic acid.

Various reduction methods can be used depending on the type of R ¹ . For example, when R ¹ is an ester group, a hydride reducing agent such as diisobutylaluminum hydride, lithium aluminum hydride, sodium aluminum hydride, or sodium diisobutylaluminum can be used. For example, when reducing an ester to an aldehyde using diisobutylaluminum hydride,
The reaction is preferably performed at a low temperature of -90 to -50C, and an aprotic solvent such as toluene or hexane is used.

When R ¹ forms an acid chloride, various methods can be used. For example, Pd—BaSO ₄
Reduction using a catalyst as a catalyst (Rosenmund)
Can be converted to an aldehyde. When R ¹ forms a mixed acid anhydride, various methods can be used. For example, it can be converted to an aldehyde by catalytic reduction using palladium / carbon as a catalyst. When R ¹ is a carboxyl group, for example, Li
It can be converted to an aldehyde by using a borane reducing agent such as 9-BBN.

[0012]

EXAMPLES The present invention will be described in more detail with reference to the following Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 Synthesis of t-butyl 3.5-O-isopropylidene-3.5-dihydroxy-6-oxohexanoate (2S, 4R) -2,4-O-isopropylidene-2,4-
To a solution of 4.01 g (13.9 mmol) of 1-methyl 6-t-butyl dihydroxyadipate and 40 ml of toluene was added 9.6 ml of a 24% solution of diisobutylaluminum hydride in toluene at -80 ° C.
Stirred at 78 ° C. for 1 hour. After adding 50 ml of water to the reaction solution, the pH was adjusted to 2.5 by adding 1N hydrochloric acid, and the mixture was extracted with ethyl acetate (50 ml × 2).

After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting oil was purified by silica gel column chromatography (hexane: acetone = 5: 1).
430 mg of t-butyl 3,5-O-isopropylidene-3,5-dihydroxy-6-oxohexanoate were obtained (yield 12%).

¹ H NMR (DMSO-d6: CDCl ₃ = 3:
1,90 mHz): δ 1.02-2.97 (m, 8H), 1.40
(s, 9H), 2.23-2.65 (m, 2H), 3.71-4.
43 (m, 2H), 9.52 (brs, 1H)

Reference Example 1 t-butyl 4- (2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl) -3-oxo-butanoate
Synthesis of 2,2-dimethyl-5-oxo-1,3-dioxolane
Under an argon atmosphere, 2.14 g (13.2 mmol) of carbonyldiimidazole was added to a solution consisting of 2.09 g (12 mmol) of 4-acetic acid and 72.0 ml of THF at 0 ° C., and the mixture was stirred for 15 minutes, and further stirred at room temperature for 4 hours. Stirred. 5.35 g (15.6 mmol) of bis (malonic acid mono-t-butyl ester) magnesium salt was added to the obtained solution at room temperature, and the mixture was stirred for 18 hours. After THF was distilled off under reduced pressure, 100 ml of a 25% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate.

The organic layer was washed with 150 ml of a saturated aqueous solution of NaHCO ₃ and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was isolated by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give pure 4- (2,2-
3.14 g (1) of t-butyl dimethyl-5-oxo-1,3-dioxolan-4-yl) -3-oxo-butanoate
1.5 mmol) (96.0% yield).

¹ H-NMR (CDCl ₃ , 90 MHz): δ
4.71 (m, 1H),. 37 (s, 2H), 3.10 (m, 2H),
1.61 (s, 3H), 1.56 (s, 3H), 1.46 (s, 9H)

Elemental analysis: Found C 57.57%, H 7.23% Calculated C 57.34%, H 7.40% (C ₁₃ H ₂₀ O ₆ )

Reference Example 2 1-methyl 2 -hydroxy-4-oxoadipate
Synthesis of 6-tbutyl t-butyl 4- (2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl) -3-oxo-butanoate
16.30 g (60.08 mmol) of toluene 120.0 ml
After cooling to 0 ° C., 60.3 ml of sodium methoxide (1M methanol solution) was added dropwise under an argon atmosphere. After stirring at 0 ° C. for 30 minutes, 60.5 ml of 1N hydrochloric acid was added dropwise and stirred at 0 ° C. for 10 minutes. After most of the organic solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, and washed with a saturated saline solution and a phosphate buffer solution (pH 7.0).

The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was isolated by silica gel column chromatography (hexane: acetone = 2: 1) to give 13.26 g (53.85 m) of pure 1-methyl 2-hydroxy-4-oxoadipate 6-tbutyl.
mol) (89.6% yield). ¹ H-NMR (CDCl ₃ , 90 MHz): δ 4.52 (m, 1
H), 3.95 (br, 1H), 3.80 (s, 3H), 3.40 (s,
2H), 3.04 (m, 2H), 1.46 (s, 9H)

Elemental analysis: found C 53.45%, H 7.27% Calculated C 53.65%, H 7.37% (C ₁₁ H ₁₈ O ₆ )

Reference Example 3 Synthesis of 1-methyl 6-t-butyl 2,4-dihydroxyadipate THF 2.5 ml, methanol 5 ml, triethyl boron
(1M THF solution) 12 ml of the mixture was stirred for 3 hours under an argon atmosphere, cooled to -50 ° C, and 2.46 g (10 mmol) of 1-methyl 6-t-butyl 2-hydroxy-4-oxoadipate was added. A solution consisting of 2.5 ml of THF was added dropwise over 5 minutes. After stirring at −50 ° C. for 2 hours, the mixture was cooled to −78 ° C., and sodium borohydride was added.
38 g (10 mmol) were added in one portion, and the mixture was further stirred at -78 ° C for 2 hours. 3 ml of acetic acid was added dropwise to the reaction solution at -78 ° C over 15 minutes, and the mixture was further stirred for 15 minutes.

5 ml of water was added to the obtained mixture,
Stir for 5 minutes. After evaporating the organic layer under reduced pressure, ethanol 1
After 0 ml was further added and 1.5 ml of a 10% hydrogen peroxide solution was slowly added, the mixture was stirred at room temperature for 30 minutes. After adding 30 ml of a 5% aqueous sodium sulfite solution and stirring at room temperature for 30 minutes, the pH was adjusted to 6 by adding 20% sodium hydroxide. Extracted with CH ₂ Cl ₂ (50 ml × 2).

After collecting the organic layers and drying over sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was isolated by silica gel column chromatography (hexane: acetone = 4: 1) to give 1.97 g of 2,4-dihydroxyadipate 1-.
Methyl 6-t-butyl (1.93 mmol) was obtained (yield 79).
%).

¹ H-NMR (CDCl ₃ , 90 MHz): δ
4.32 (m, 2H), 3.76 (s, 3H), 3.61 (br, 2
H), 2.42 (m, 2H), 1.97 (m, 2H), 1.46 (s,
9H)

Elemental analysis: found C 53.37%, H 8.23% calculated C 53.21%, H 8.12% (C ₁₁ H ₂₀ O ₆ )

Reference Example 4 Synthesis of 2-methoxycarbonyl-4-t-butoxycarbonylmethyl-6,6-dimethyl-1,5-dioxane 4.98 g of 1-methyl-6-t-butyl 2,4-dihydroxyadipate (20.01 mmol) and methylene chloride 21 in a mixed solution, 9.6 ml (78 mmol) of dimethoxypropane, p
2.01 g (8 mmol) of pyridinium toluenesulfonate
Was added, and the mixture was stirred under reflux for 1 hour, and then stirred at 40 ° C. for 3 hours while removing methanol by azeotropic distillation. After concentration under reduced pressure, the obtained residue was dissolved in ethyl acetate, poured into water, and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: acetone =
Purification by 3: 1) gave 4.89 g (17.01 mmol) of pure 2-methoxycarbonyl-4-t-butoxycarbonylmethyl-6,6-dimethyl-1,5-dioxane (yield 85). %).

¹ H-NMR (CDCl ₃ , 90 MHz): δ
4.70-4.17 (m, 2H), 3.76 (s, 3H), 2.4
1 (br, 2H), 2.13-1.56 (m, 2H), 1.46 (m,
15H)

Elemental analysis: found C 58.38%, H 8.42% calculated C 58.31%, H 8.39% (C ₁₄ H ₂₄ O ₆ )

Claims (4)

[Claims] 1. A compound of the formula (I): (R ¹ represents an ester group, a carboxyl group, or a reactive derivative of a carboxylic acid; R ² represents an alkyl group, an aryl group, or an aralkyl group; R ³ and R ⁴ represent hydrogen or a silyl-type protecting group; A 2,4-dihydroxyadipate derivative represented by the formula (II): which represents an alkyl group which may form a ring. (Wherein R ² , R ³ and R ⁴ have the same meanings as described above.) A method for producing a 3,5-dihydroxy-6-oxohexanoate derivative represented by the formula: 2. The process according to claim 1, wherein the 2,4-dihydroxyadipate diester derivative is regioselectively reduced using a hydride reducing agent. 3. The process according to claim 1, wherein the 2,4-dihydroxyadipate diester derivative is regioselectively reduced using diisobutylaluminum hydride as a reducing agent. 4. An optically active (2S, 4R) derivative is reduced as a 2,4-dihydroxyadipate derivative to obtain a (3R, 5S) -3,5-dihydroxy-6-oxohexanoate derivative. The method according to claim 1.