JPH0525089A - Production of 2-hydroxy acid derivative - Google Patents

Abstract

PURPOSE:To effectively and economically produce the subject compound useful as a synthetic intermediate for various drugs, agricultural chemicals, etc., by reacting a 2-hydroxyacetic acid derivative with a metal alkoxide. CONSTITUTION:A compound of formula I (X, Y are H, alkyl. aralkyl, etc., or X and Y form a ring together; A is a functional group not reactive with an metal alkoxide) is reacted with a metal alkoxide (e.g. sodium methoxide, sodium ethoxide or a combination of a base such as a metal hydride with an alcohol) in a solvent such as THF preferably at -80 to 60 deg.C to produce the objective compound of formula II (R<1> is alkyl aralkyl, aryl, etc.; P is H, OH- protecting group) examplified by 2-hydroxy-4-oxyadipic acid 1-methyl-6-t-butyl ester.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel method for producing a 2-hydroxy acid derivative. The 2-hydroxy acid derivative is a useful synthetic intermediate for various drugs, agricultural chemicals, physiologically active substances and the like.

[0002]

2. Description of the Related Art Conventionally, as a one-step conversion method from an acetal derivative of 2-hydroxy acid to a 2-hydroxy acid ester, a method by treating with alcohol under acidic conditions has been known. It could not be used for a substrate having at the same time a functional group, such as or a tetrahydropyranyl group, which easily changes under acidic conditions. Examples of the two-step conversion method include a method in which a hydrolysis reaction is performed to convert the acetal portion to α-hydroxycarboxylic acid and then a normal esterification reaction is performed, but it takes time and effort.

[0003]

In view of such circumstances, the present inventors have earnestly studied an effective and economical one-step conversion method from an acetal derivative of 2-hydroxy acid to a 2-hydroxy acid ester. As a result, they have found a practical new production method of 2-hydroxy acid ester and completed the present invention.

That is, the present invention uses the formula (1):

[Chemical 5] (In the formula, X and Y each independently represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, or X and Y jointly form a ring. A is any functional group which does not react with a metal alkoxide. Of a 2-hydroxy acid derivative represented by the formula (2):

[Chemical 6] (In the formula, R ¹ represents an alkyl group, an aralkyl group, an aryl group or a silyl group, P represents a hydrogen atom or a protective group of a hydroxyl group, and A represents the same meaning as described above.) Regarding manufacturing method.

In particular, A is the formula (7):

[Chemical 7] (In the formula, R ² represents a hydrogen atom, an alkyl group, an aralkyl group, an aryl group or a silyl group.) Formula (4):

[Chemical 8] (Wherein R ¹ , R ² and P have the same meanings as described above) 2
A hydroxy acid derivative, or A is of formula (8):

[Chemical 9] (In the formula, Q represents a hydrogen atom or a hydroxyl-protecting group. R
² has the same meaning as above. ) Is a formula (6):

[Chemical 10] (In the formula, R ¹ , R ² , P and Q have the same meanings as described above.) The present invention relates to a method for producing a 2-hydroxy acid derivative.

As examples of X and Y in the present invention, (X, Y) are each independently a hydrogen atom; methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s.
alkyl groups such as ec-butyl, t-butyl, pentyl, hexyl, heptyl and octyl groups; aralkyl groups such as benzyl group and p-nitrobenzyl group; aryl groups such as phenyl group and tolyl group , Or a combination thereof, or an acetal-type protecting group in which X and Y together form a ring, or one of X and Y is a hydrogen atom, an alkyl group, an aralkyl group, etc., and the remaining one is methoxy or ethoxy. And an orthoester type protecting group such as an alkoxy group such as propoxy, isopropoxy, butoxy, phenoxy and the like.

Examples of the protective group for the hydroxyl group as P or Q include "Protective Groups in Organic Synthesis" and "Protective Groups".
in Organic Synthesis "Theodor W. Gr.
eene), John Wiley and Sons (J
OHN WILEY & SONS), pp. 10-72, 1981. That is, for example, ester type protecting groups such as acetyl group and benzoyl group, benzyl group, ether type protecting groups such as p-nitrobenzyl group, alkyl groups such as trityl group, trimethylsilyl, triethylsilyl,
Triisopropylsilyl, t-butyldimethylsilyl,
Isobutyldimethylsilyl, thexyldimethylsilyl,
Examples thereof include silyl type protecting groups such as t-butyldiphenylsilyl group, carbonic acid ester type protecting groups such as t-butoxycarbonyl group and benzyloxycarbonyl group.

Examples of R ¹ are alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl and octyl groups; benzyl group and p-type group. Aralkyl groups such as nitrobenzyl group; aryl groups such as phenyl group and tolyl group; trimethylsilyl, triethylsilyl, triisopropylsilyl, t-
Examples thereof include silyl groups such as butyldimethylsilyl, isobutyldimethylsilyl, thexyldimethylsilyl, and t-butyldiphenylsilyl groups.

Examples of R ² are hydrogen atom; methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Alkyl groups such as sec-butyl, t-butyl, pentyl, hexyl, hebutyl, octyl groups; aralkyl groups such as benzyl group and p-nitrobenzyl group;
Aryl groups such as phenyl group and tolyl group; silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, isobutyldimethylsilyl, thexyldimethylsilyl, t-butyldiphenylsilyl group, etc. To be

The relations of the compounds in the present invention are represented by the formulas, for example, as follows.

[Chemical 11]

The compound (3), which can be easily derived from malic acid or the like by a known method, can be easily compounded by the esterification reaction of the present invention without affecting other functional groups such as ester group and keto group (4). Compound (6) is obtained by introducing the compound into a compound (6), then subjecting it to a reduction reaction, and further introducing a protecting group if necessary. Alternatively, compound (3) is first subjected to a reduction reaction to give compound (5), and then compound (6) is extremely easily produced by the esterification reaction of the present invention. The compound (6) can be made into an extremely useful intermediate in the production of various HMG-CoA reductase inhibitors by, for example, selectively reducing the 1-position ester group.

Further, the compound (1) in the present invention,
(2), (3), (4), (5) and (6) have an asymmetric carbon at the 2-position, and in compounds (5) and (6) the carbon at the 4-position is also an asymmetric carbon. , The present invention is (2R),
(2S) or (2R, 4R), (2R, 4S),
It includes all the methods for producing (2S, 4R), all optically active isomers of (2S, 4S), a mixture thereof in any proportion, and a racemic compound. By using optically active malic acid and further improving the reduction method, compounds (1), (2),
The optically active substances (3), (4), (5) and (6) can be produced. Especially when L-malic acid is used, HMG-C
It is possible to efficiently construct the (2S, 4R) configuration important for oA reductase inhibitor synthesis by asymmetric induction reduction.

The manufacturing method of the present invention will be described in detail below. The 2-hydroxy acid derivative (1) which is the starting material in the present invention can be easily derived from 2-hydroxy acid. For example, first, a 2-hydroxy acid may be reacted with various ketones, aldehydes, orthoesters or the like to simultaneously protect the hydroxyl group of 2-hydroxy acid and the carboxylic acid at the 1-position (eg, tetrahedron letters (Tetrahe).
doron Lett. ) 28 , 1685 (198)
7), Tetrahedron 4
0 , 1313 (1984), etc.). For example, for the carboxylic acid moiety at the 4-position of the malic acid derivative obtained by the acetonide conversion of malic acid, it is possible to increase the carbon by 2 carbons by the carbonization reaction that is usually used, and for example, carbonyldiimidazole and chloroformate. The compound (3) can be obtained by converting the compound into an active ester using, for example, or converting it into an acid chloride with thionyl chloride, and then reacting it with a two-carbon carbonaceous agent such as Mg enolate.

Conversion of compound (1) to compound (2),
For example, in order to convert the compound (3) to the compound (4) and the compound (5) to the compound (6), the acetal (3) can be treated with a metal alkoxide to effect the esterification in one step. As the metal alkoxide, a general metal alkoxide such as sodium ethoxide, sodium methoxide, potassium methoxide, and potassium ethoxide can be used, and a base such as a metal hydride or metal amide or an organic metal and various alcohols can be used. You may use the metal alkoxide prepared by combination. As the reaction solvent at that time, a corresponding alcohol may be used, or THF, toluene, ether,
An aprotic solvent such as dioxane may be used or they may be combined.

The reaction temperature can be selected from a wide range from the freezing point to the boiling point of the solvent, but it is -80 because of its simple operation.
The range of 60 ° C to 60 ° C is preferable.

For converting the compound (3) to the compound (5) or from the compound (4) to the compound (6), a general reduction reaction such as a reduction reaction with a metal hydride or a catalytic hydrogenation reaction can be used.

In each step, if necessary,
A protective group for the hydroxyl groups of P and Q can be introduced. These can be carried out by a known method, for example, in the compound (6), P and Q together form an isopropylidene group from 1,3-diol in which P and Q are both hydrogen atoms. In order to carry out the acetal type protection, acetone and sulfuric acid or dimethoxypropane and pyridinium p-toluenesulfonate may be allowed to act.

The compound (6) can be used as an extremely useful intermediate in the production of HMG-CoA reductase inhibitors. For example, when the 1-position is an ester, it can be easily converted into an alcohol or an aldehyde by a reduction reaction. For example, by using an inexpensive and easily usable reducing agent such as sodium borohydride, the 3,5,6-trihydroxyhexanoic acid derivative can be produced very simply and safely. Further, in order to produce a 3,5-dihydroxy-6-oxo-hexanoic acid derivative, a compound (6) in which the 1-position is a carboxylic acid is prepared by an appropriate treatment and then introduced into an acid chloride, followed by hydrogenation. The aldehyde can be converted to an aldehyde by the reaction, or after the compound (6) having an ester at the 1-position is prepared, it can be converted to an aldehyde by a reduction reaction or a reduction reaction and a subsequent oxidation reaction.

In order to isolate the compounds (1) to (6), any method generally used in organic chemistry can be used, and the compounds (1) to (6) can be purified by extraction, silica gel column chromatography, distillation or the like. It is also possible to proceed to the next step from each step without purifying each compound.

[0020]

EXAMPLES The present invention will be further described below with reference to examples and reference examples, but the present invention is not limited thereto.

[0021]Example 1   4- (2,2-dimethyl-5-oxo-1,3-dio
Xylan-4-yl) -3-oxobutanoic acid t-butyl
Manufacturing

[Chemical 12] 2,2-Dimethyl-5-oxo-1,3-dioxolane-4-acetic acid 2.09 g (12 mmol) in THF 72.
To the solution in 0 ml, under an argon atmosphere, 2.14 g (13.2 mmol) of carbonyldiimidazole was added at 0 ° C., and the mixture was stirred for 15 minutes and then at room temperature for 4 hours. Bis (malonic acid mono-t-butyl ester) was added to the resulting solution.
Magnesium salt (5.35 g, 15.6 mmol) was added at room temperature, and the mixture was stirred for 18 hours. After distilling off THF under reduced pressure,
100 ml of 25% citric acid aqueous solution was added, and the mixture was extracted with ethyl acetate. 150 ml of the organic layer is saturated NaHCO ₃
It was washed with an aqueous solution, dried over sodium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give pure 4-
(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl) -3-oxobutanoic acid t-butyl
3.14 g (11.5 mmol) was obtained. Yield 96.1
%

¹ H-NMR (90 MHz, CDC
l ₃ ): δ 4.71 (m, 1H), δ 3.37 (s, 2)
H), δ 3.10 (m, 2H), δ 1.61 (s, 3
H), δ1.56 (s, 3H), δ1.46 (s, 9
H) Elemental analysis: analytical value C57.57%, H 7.23% calculated value C57.34%, H 7.40% (C ₁₃ H
₂₀ O ₆ )

[0023]Example 2   2-hydroxy-4-oxoadipic acid 1-methyl
  Production of 6-t-butyl

[Chemical 13] 4- (2,2-dimethyl-5) obtained in the same manner as in Example 1
-Oxo-1,3-dioxolan-4-yl) -3-oxobutanoic acid t-butyl 16.30 g (60.08 m)
To a solution of (mol) in 120.0 ml of toluene, 60.3 ml of sodium methoxide (1M methanol solution) was added dropwise at 0 ° C. under an argon atmosphere over 10 minutes. 0
After stirring for 30 minutes at 0 ° C, 60.5 ml of 1N hydrochloric acid was added dropwise, and the mixture was stirred for 10 minutes at 0 ° C. Most of the organic solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate and washing with saturated saline and a phosphate buffer solution (pH 7.0). The organic layers were combined, dried over sodium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: acetone =
2: 1) to give pure 2-hydroxy-4-
1-Methyl 6-t-butyl oxoadipate 1
Obtained 4.26 g (57.91 mmol). Yield 96.
4%

¹ H-NMR (90 MHz, CDC
l ₃ ): δ4.52 (m, 1H), δ3.95 (br,
1H), δ3.80 (s, 3H), δ3.40 (s, 2)
H), δ3.04 (m, 2H), δ1.46 (s, 9
H) Elemental analysis: Analytical value C53.45%, H 7.27% Calculated value C53.65%, H 7.37% (C ₁₁ H ₁₈
O ₆ )

[0025]Example 3   2-Hydroxy-4-oxoadipate 1-ethyl
  Production of 6-t-butyl

[Chemical 14] 4- (2,2-dimethyl-5) obtained in the same manner as in Example 1
T-Butyl-oxo-1,3-dioxolan-4-yl) -3-oxobutanoate 16.30 g (60.08)
mmol) of toluene 120.0 ml-ethanol 6
4.91 g (79.10 mm) of sodium ethoxide was added to a solution in a mixed solvent of 0.0 ml at 0 ° C. under an argon atmosphere.
ol) was added dropwise. After stirring at 0 ° C for 30 minutes, 80.5 ml of 1N hydrochloric acid was added dropwise, and the mixture was stirred at 0 ° C for 10 minutes. Most of the organic solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate and washing with saturated saline and a phosphate buffer solution (pH 7.0). The organic layers are combined and dried over sodium sulfate,
It was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: acetone = 2: 1) to give pure 2-hydroxy-4-oxoadipate 1-ethyl 6-t-butyl 14.02 g (53.85 mmo).
l) was obtained. Yield 89.6%

¹ H-NMR (90 MHz, CDC
l ₃ ): δ4.52 (m, 1H), δ4.30 (q, 2)
H), δ3.43 (s, 2H), δ3.20 (m, 2)
H), δ2.96 (br, 1H), δ1.46 (s, 9
H), δ1.28 (t, 3H) Elemental analysis: analytical value C 55.44%, H 7.70
% Calculated values C 55.37%, H 7.75% (C ₁₂
H ₂₀ O ₆₎

[0027]Example 4   2-Hydroxy-4-oxoadipic acid 1-isop
Production of ropyl 6-t-butyl

[Chemical 15] Sodium hydride (60% in oil) under argon atmosphere
6.0 g (150 mmol) was washed with hexane, dried, and then mixed with 170 ml of THF. The mixture was cooled to 0 ° C. and 30 ml of isopropanol was added dropwise to form a yellow solution. 4- (2,2 obtained in Example 1
-Dimethyl-5-oxo-1,3-dioxolane-4-
Yl) -3-oxobutanoic acid t-butyl 13.62
g (50.00 mmol) was dissolved in 100.0 ml of toluene, cooled to 0 ° C., and the above yellow solution was added dropwise.
After stirring at 0 ° C for 30 minutes, 60.0 ml of 1N hydrochloric acid was added dropwise, and the mixture was stirred at 0 ° C for 10 minutes. Most of the organic solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate and washing with saturated saline and a phosphate buffer solution (pH 7.0). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. Pure 2-hydroxy-4 was obtained by subjecting the residue to silica gel column chromatography (hexane: acetone = 2: 1).
There was obtained 11.07 g (40.35 mmol) of 1-isopropyl 6-t-butyl -oxoadipate. Yield 80.7%

¹ H-NMR (90 MHz, CDC
l ₃ ): δ5.12 (m, 1H), δ4.47 (m, 1)
H), δ3.43 (s, 2H), δ3.25 (br, 1
H), δ3.00 (m, 2H), δ1.46 (s, 9
H), δ1.30 (s, 3H), δ1.23 (s, 3)
H) Elemental analysis: analytical value C 56.84%, H 8.02
% Calculated value C 56.92%, H 8.08% (C ₁₃
H ₂₂ O ₆₎

[0029]Example 5   4- (2,2-dimethyl-5-oxo-1,3-dio
Xylan-4-yl) -3-hydroxybutanoic acid t-
Butyl production

[Chemical 16] 4- (2,2-dimethyl-obtained in the same manner as in Example 1
5-oxo-1,3-dioxolan-4-yl) -3-
T-Butyl oxobutanoate 10.88 g (40.0
mmol) in 20 ml of THF and then at -78 ° C.
Then, a mixed solution of THF 96.0 ml-BEt ₃ (1M THF solution) 56.0 ml was added dropwise over 45 minutes.
After stirring at −78 ° C. for 50 minutes, 1.51 g (40.0 mmol) of sodium borohydride was added at once, and the mixture was further stirred at −78 ° C. for 4 hours, then poured into 0 ° C. 1N hydrochloric acid, and extracted with ethyl acetate. And washed with saturated saline.
The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give pure 4-
There was obtained 6.08 g (22.16 mmol) of t-butyl (2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl) -3-hydroxybutanoate. Yield 55
%

¹ H-NMR (90 MHz, CDC
l ₃ ): δ 4.71 (m, 1H), δ 4.28 (br,
1H), δ3.40 (m, 1H), δ2.50 (m, 2)
H), δ2.00 (m, 2H), δ1.61 (s, 3
H), δ1.56 (s, 3H), δ1.46 (s, 9
H) Elemental analysis: analysis C57.07%, H 8.13% Calculated C56.92%, H 8.08% (C 13 H
₂₂ O ₆ )

[0031]Example 6   2,4-Dihydroxyadipic acid 1-methyl 6-
Production of t-butyl

[Chemical 17] 4- (2,2-dimethyl-5-oxo-obtained in Example 5
1,3-dioxolan-4-yl) -3-hydroxybutanoic acid t-butyl 5.49 g (20.0 mmol)
Was dissolved in 40.0 ml of toluene, and 30.0 ml of sodium methoxide (1M methanol solution) was added dropwise at 0 ° C. under an argon atmosphere. After stirring at 0 ° C for 30 minutes, 30.5 ml of 1N hydrochloric acid was added dropwise, and the mixture was stirred at 0 ° C for 10 minutes. Most of the organic solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate, a saturated saline solution and a phosphate buffer solution (pH 7.
Washed with 0). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. Pure 2,4-dihydroxyadipic acid 1- was obtained by subjecting the residue to silica gel column chromatography (hexane: acetone = 2: 1).
Methyl 6-t-butyl 3.69 g (14.9 mmo
l) was obtained. Yield 74.3%

¹ H-NMR (90 MHz, CDC
l ₃ ): δ4.33 (m, 2H), δ3.76 (s, 3)
H), δ3.61 (br, 2H), δ2.42 (m, 2)
H), δ1.97 (m, 2H), δ1.46 (s, 9
H) Elemental analysis: Analytical value C 53.29%, H 8.10.
% Calculated values C 53.21%, H 8.12% (C ₁₁
H ₂₀ O ₆₎

[0033]Example 7   4- (2-methyl-5-oxo-1,3-dioxola
(N-4-yl) -3-oxo-butanoic acid t-butyl
Manufacturing of

[Chemical 18] 2-Methyl-5-oxo-1,3-dioxolane-4-
Acetate 8.01 g (50 mmol) in THF 300.0 m
To the solution in 1 under an argon atmosphere, 8.92 g (55 mmol) of carbonyldiimidazole was added at 0 ° C. and stirred for 15 minutes, and then stirred at room temperature for 4 hours. 22.27 mg (65 mmol) of bis (malonic acid mono t-butyl ester) magnesium salt was added to the obtained solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO ₃ , dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give pure 4-
(2-methyl-5-oxo-1,3-dioxolane-4
-Yl) -3-oxo-butanoic acid t-butyl 9.80
g (38 mmol) was obtained. Yield 75.9%

¹ H-NMR (90 MHz, CDC
l ₃ ): δ5.96-5.53 (m, 1H), δ4.6
7 (m, 1H), δ 3.40 (s, 2H), δ 3.13
(M, 2H), δ1.56 (d, 3H), δ1.46
(S, 9H) Elemental analysis: analytical value C 55.99%, H 6.95
% Calculated value C 55.80%, H 7.03% (C ₁₂
H ₁₈ O ₆ )

[0035]Example 8   2-hydroxy-4-oxoadipic acid 1-methyl
  Production of 6-t-butyl

[Chemical 19] 4- (2-methyl-5-oxo-1,3 obtained in Example 7
-Dioxolan-4-yl) -3-oxo-butanoic acid
5.16 g (20.0 mmol) of t-butyl was dissolved in 40.0 ml of toluene, and sodium methoxide (1M methanol solution) 20.5 was added at 0 ° C. under an argon atmosphere.
ml was added dropwise over 10 minutes. After stirring at 0 ° C for 30 minutes, 21.0 ml of 1N hydrochloric acid was added dropwise, and the mixture was stirred at 0 ° C for 10 minutes. Most of the organic solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate, a saturated saline solution and a phosphate buffer solution (pH 7.
Washed with 0). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: acetone = 2: 1) to give pure 1-methyl 6-t-butyl 2-hydroxy-4-oxoadipic acid 4.39 g (17.83 mmo).
l) was obtained. Yield 89.2%

¹ H-NMR was in accordance with Example 2. Elemental analysis: analytical value C 53.59%, H 7.45
% Calculated values C 53.65%, H 7.37% (C ₁₁
H ₁₈ O ₆ )

Reference Example The following is an intermediate 3,5-0-isopropylidene-3,5,6 of an HMG-CoA synthesis inhibitor using the method of the present invention.
An example of synthesizing -t-butyl trihydroxyhexanoate is shown.

[0038]Reference example 1   2,4-Dihydroxyadipic acid 1-methyl 6-
t-Butyl production THF 133.05 ml, methanol 66.52 ml,
BEt₃(1M THF solution) 72.71 ml
The mixture was stirred at room temperature for 1 hour under a Lgon atmosphere. 2-hydroxy
Ci-4-oxoadipic acid 1-methyl 6-t-butyl
12.79 g (51.94 mmol) of THF
After dissolving in 2 ml, it was cooled to -78 ° C and
The solution was added dropwise over 45 minutes. Stir at -78 ° C for 50 minutes
After stirring, 2.26 g of sodium borohydride (59.
72 mmol) at once and further at −78 ° C. for 3 hours
It was stirred. Acetic acid-methanol (1: 1) mixed solution 54 m
l was added dropwise to the reaction solution at −78 ° C. over 15 minutes,
It was stirred for another 15 minutes. The mixture obtained is treated with 5% ammonium chloride.
It was poured into 511 ml of monium and stirred for 15 minutes. pH 7.
After adjusting to 5, the organic layer was distilled off under reduced pressure. 10 at room temperature
Adjust the pH to 7 after adding 104 ml of hydrogen peroxide solution
Then, 312 ml of 5% sodium sulfite aqueous solution was added,
After stirring at room temperature for 40 minutes, extract with ethyl acetate.
It was The organic layers are combined and dried over sodium sulfate, and then distilled under reduced pressure.
I left. Silica gel column chromatography (
Xane: acetone = 2: 1)
2,4-Dihydroxyadipate 1-methyl 6-t-
Obtained 11.22 g (45.19 mmol) of butyl.
Yield 87%

¹ H-NMR was in accordance with Example 6. Elemental analysis: analytical value C 53.37%, H 8.23
% Calculated value C 53.21%, H 8.12% (C ₁₁ H
₂₀ O ₆ )

[0040]Reference example 2   2-methoxycarbonyl-4-t-butoxycarbonyl
Rumethyl-6,6-dimethyl-1,5-dioxane
Manufacturing 2,4-Dihydroxyadipic acid 1-methyl 6-t
-Butyl 4.98 g (20.02 mmol) and methyl chloride
In the mixed solution of Tylene 21, dimethoxypropane 9.6m
1 (78 mmol), pyridini p-toluenesulfonate
2.01 g (8 mmol) of sodium was added, and under reflux condition for 1 hour.
While stirring, then azeotropically removing methanol
The mixture was stirred at 40 ° C for 3 hours. After concentration under reduced pressure, the obtained residue is
After dissolving in ethyl acetate, pour into water and extract with ethyl acetate
did. The organic layers are collected, dried over sodium sulfate, and concentrated under reduced pressure.
Contracted. Silica gel column chromatography (
Xane: acetone = 3: 1) to give pure 2
-Methoxycarbonyl-4-t-butoxycarbonylme
Chill-6,6-dimethyl-1,5-dioxane 4.8
9 g (17.01 mmol) was obtained. Yield 85%

¹ H-NMR (90 MHz, CDC
_{l 3): δ4.70-4.17 (m,} 2H), δ3.7
6 (s, 3H), δ2.41 (m, 2H), δ2.13
-1.56 (m, 2H), δ 1.46 (m, 15H) Elemental analysis: analytical value C 58.38%, H 8.42
% Calculated value C 58.31%, H 8.39% (C ₁₄ H
₂₄ O ₆ )

[0042]Reference example 3   3,5-0-isopropylidene-3,5,6-trihi
Production of t-butyl droxyhexanoate 2-methoxycarbonyl-4-t-butoxycarbonyl
Methyl-6,6-dimethyl-1,5-dioxane 2.8
Dissolve 8 g (10 mmol) in 160 ml of methanol
And then sodium borohydride 1.89 g (50 mmo
l) at once, and at room temperature under argon atmosphere for 12 hours
It was stirred. After the methanol was distilled off under reduced pressure, water was added at 0 ° C,
The pH was adjusted to 7 with 1N hydrochloric acid and extracted with ethyl acetate.
It was The organic layers were collected, dried over sodium sulfate, and evaporated under reduced pressure.
did. The residue is purified by silica gel column chromatography (hexane
Pure by applying Sun: Ethyl acetate = 3: 1)
3,5-0-isopropylidene-3,5,6-trihydr
2.27 g (8.7 mm) of t-butyl roxyhexanoate
ol) was obtained. Yield 87%

¹ H-NMR (90 MHz, CDC
l ₃ ): δ 4.43-3.82 (m, 2H), δ 3.6
8-3.44 (m, 2H), [delta] 2.71-2.32.
(M, 3H), δ 1.82-1.5 (m, 2H), δ
1.47 (s, 9H), δ 1.45 (d, 6H, J = 4)
Hz) Elemental analysis: analytical value C 59.97%, H 9.46
% Calculated value C 59.98%, H 9.29% (C ₁₃ H
₂₄ O ₅ )

[0044]Reference example 4   (3R, 5S) -3,5-0-isopropylidene-
T-Butyl 3,5,6-trihydroxyhexanoate
Manufacturing of 4- (2,2-dimethyl-5-oxo-in Example 1
1,3-dioxolan-4-yl) -3-oxo-buta
As a raw material in the production of t-butyl acid salt, L-li
(4S) -2,2-Dimethyl-5 derived from ngoic acid
-Oxo-1,3-dioxolane-4-acetic acid 2.09 g
The same operation as in Example 1 is performed using (12 mmol).
As a result, 4- (2,2-dimethyl-5-oxo-1,
3-dioxolane- (4S) -4-yl) -3-oxo
T-Butyl butanoate was prepared and subsequently Example 2
And by performing the same operation as in Reference Examples 1 to 3 (3
R, 5S) -3,5-0-isopropylidene-3,5
T-Butyl 6-trihydroxyhexanoate was produced.

¹ H-NMR coincided with Reference Example 3. Elemental analysis: analytical value C 60.10%, H 9.21
% Calculated value C 59.98%, H 9.29% (C ₁₃ H
₂₄ O ₅ )

[Chemical 20]

[0046]

EFFECTS OF THE INVENTION By using the novel production method of the present invention, it becomes possible to efficiently produce an 2-hydroxy acid ester from an acetal derivative of 2-hydroxy acid, which is effective and economical, and further, HMG-CoA. It enables efficient production of synthetic intermediates for reductase inhibitors (1-methyl 6-t-butyl 2-hydroxy-4-oxoadipate, etc.).

Claims (13)

[Claims] 1. Formula (1): (In the formula, X and Y each independently represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, or X and Y jointly form a ring. A is any functional group which does not react with a metal alkoxide. Represented by the formula (2): embedded image which comprises reacting a 2-hydroxy acid derivative represented by the formula (2) with a metal alkoxide. (In the formula, R ¹ represents an alkyl group, an aralkyl group, an aryl group or a silyl group, P represents a hydrogen atom or a protective group of a hydroxyl group, and A represents the same meaning as described above.) Manufacturing method. 2. A is of formula (7): (In the formula, R ² is a hydrogen atom, an alkyl group, an aralkyl group,
Represents an aryl group or a silyl group. The manufacturing method of Claim 1 which is a group shown by these. 3. A is of formula (8): (In the formula, Q represents a hydrogen atom or a hydroxyl-protecting group. R
² has the same meaning as above. The manufacturing method of Claim 1 which is a group shown by these. 4. The production method according to claim 1, wherein X is a methyl group and Y is a hydrogen atom or a methyl group. 5. The production method according to claim 2, wherein R ² is an alkyl group having 1 to 4 carbon atoms. 6. The method according to claim ^{2, wherein} R ² is a t-butyl group.
The production method according to any one of 1. 7. The production method according to claim 3, wherein Q is a hydrogen atom. 8. The production method according to claim 2, wherein R ¹ is an alkyl group having 1 to 4 carbon atoms. 9. The production method according to claim 2, wherein R ¹ is a methyl group, an ethyl group or an isopropyl group. 10. As the metal alkoxide, when R ¹ is a methyl group, sodium methoxide or potassium methoxide, when it is an ethyl group, sodium ethoxide or potassium ethoxide, or when it is an isopropyl group, sodium isopropoxy. The manufacturing method according to any one of claims 1 to 9, wherein a cord is used. 11. A metal alkoxide prepared by combining an alcohol and a base is used as the metal alkoxide.
10. The method according to any one of 9 to 9. 12. The method according to claim 11, wherein a metal hydride is used as the base. 13. The method according to claim 12, wherein sodium hydride is used as the metal hydride.