JP2619136B2 - Process for producing 5,6-dihydroxy-3-oxohexanoate derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial application field) The present invention relates to 5,6-dihydroxy-3-oxohexanoic acid ester derivatives, especially optically active (S) -5,6-
The present invention relates to a method for producing t-butyl dihydroxy-3-oxohexanoate.

Such 5,6-dihydroxy-3-oxohexanoic acid ester derivatives have attracted attention as a therapeutic agent for hyperlipidemia. HMG-CoA (Hydroxy methyl glutaryl-CoA)
A) Compounds useful as intermediates of reductase inhibitors.

(Prior Art) As a conventional method for producing a 5,6-dihydroxy-3-oxohexanoate derivative, a 4-position hydroxyl group of 3,4-dihydroxybutyric acid is converted to t-butyl as shown in the following reaction formula. Compounds protected with diphenylsilyl group or triphenylmethyl group were added with malonic acid half ester Mg.
A method is known in which a salt is reacted with carbonyldiimidazole (CDI) or a lithium enolate of acetic ester is acted on an ester derivative thereof (see JP-A-63-22056 and JP-A-1-199945). ).

(In the formula, Pr represents a t-butyldimethylsilyl group or a triphenylmethyl group, and R ² represents an ethyl group or a t-butyl group.) (Problems to be Solved by the Invention) In any of the above methods, the starting compounds Comparatively, the synthesis of a 3,4-dihydroxybutyric acid derivative in which the 4-hydroxyl group is protected is relatively complicated, only a compound in which the 6-hydroxyl group of the product is protected is obtained, It has points to be improved, such as the necessity of using expensive reagents, and is not necessarily practical as an industrial process for producing 5,6-dihydroxy-3-oxohexanoate derivatives.

(Problems to be Solved by the Invention) The present inventors have conducted intensive studies on a method for producing a 5,6-dihydroxy-3-oxohexanoic acid ester derivative that is economically practical in view of the above situation, By reacting a 3-hydroxy-γ-butyrolactone derivative with a lithium enolate of acetate or a zinc enolate prepared from zinc and α-bromoacetate (Reformatsky reaction), economical 5,6-dihydroxy is achieved. The inventors have found that a -3-oxohexanoic acid ester derivative can be produced, and have completed the present invention.

That is, the present invention provides a compound of the formula (I): (. In the formula, R ¹ represents hydrogen or a silyl-type protecting group) and 3-hydroxy -γ- butyrolactone derivative represented by the formula _{(II): LiCH 2 CO 2} R 2 (II) ( wherein, R ² Represents an alkyl group, an aralkyl group or an aryl group having 1 to 10 carbon atoms.) The compound is reacted with a lithium enolate of an acetic acid ester represented by the formula (III): (Wherein R ¹ and R ² are the same as described above). A novel method for producing a 5,6-dihydroxy-3-oxohexanoate derivative represented by the formula:

Further, the present invention provides a method for preparing a 3-hydroxy-γ-butyrolactone derivative represented by the formula (I) in the presence of zinc by the formula (IV) BrCH ₂ CO ₂ R ² (IV) wherein R ² is the same as defined above. ), Characterized in that it is reacted with an α-bromoacetic acid ester represented by the formula (III):
Provided is a method for producing a 3-oxohexanoic acid ester derivative.

Further, the present invention provides a compound of the formula (V), wherein the primary hydroxyl group of the 5,6-dihydroxy-3-oxohexanoic acid ester derivative represented by the formula (III) is protected. (Wherein, R ¹ and R ² are the same as above, and R ³ represents a protecting group for a hydroxyl group.) A method for producing a 5,6-dihydroxy-3-oxohexanoate derivative represented by the formula:

According to the present invention, by using optically active (S) -3-hydroxy-γ-butyrolactone as a starting material,
An (S) -5,6-dihydroxy-3-oxohexanoate derivative having a steric shape that is particularly useful as an HMG-CoA reduction inhibitor intermediate can be easily produced.

The 3-hydroxy-γ-butyrolactone derivative, which is the starting compound of the present invention, can be prepared, for example, by preparing 3-hydroxy-γ-butyrolactone from malic acid in three steps [SYNTHETIC COMMUNI.
CA-TION), 16 , 183 (1986)].
It can be produced by protecting the hydroxyl group with a silyl group or the like. As the protecting group, a silyl-type protecting group such as a trimethylsilyl group, a triethylsilyl group, and a t-butyldimethylsilyl group is preferable. The above reaction is represented by the following reaction formula: In the present invention, when a lithium enolate of an acetate is used, the acetate is t-butyl acetate,
Isopropyl acetate, ethyl acetate, methyl acetate and the like can be used, but t-butyl acetate is preferred from the viewpoint of the selectivity of the reaction and the yield.

For the preparation of lithium enolate, commonly used lithium diisopropylamide can be suitably used, for example,
Lithium diisopropylamide is prepared by the reaction of diisopropylamine and n-butyllithium,
After adding an acetate to a lithium enolate of the acetate, 4-cyano-3-hydroxybutyrate is added and reacted to give 6-cyano-5-yl.
Hydroxy-3-oxohexanoate can be synthesized. Lithium diisopropylamide and acetic ester are preferably 1 to 6 equivalents, more preferably 1.6 equivalents to the 3-hydroxy-γ-butyrolactone derivative.
It is used in a ratio of 5 to 5 equivalents.

The reaction temperature is preferably low, generally -100 ° C to 20 ° C,
Preferably, it is -80 ° C to 0 ° C.

As the solvent, preferably, tetrahydrofuran (TH
Aprotic solvents such as F) and hexane can be used, and among them, THF can be suitably used.

When a zinc enolate prepared by reacting α-bromoacetic acid ester with zinc is used, α-bromoacetic acid ester includes t-butyl α-bromoacetate, isopropyl α-bromoacetate, ethyl α-bromoacetate, α-bromoacetic acid Alkyl esters such as methyl can be used, but among them, α-tert-butyl α-bromoacetate is preferable from the viewpoint of reaction selectivity and yield. It is preferable that zinc used for the preparation of zinc enolate is activated in advance by washing with hydrochloric acid or the like, or is activated in the system by using trimethylsilyl chloride or the like.
When activating with trimethylsilyl chloride,
For example, activation is achieved by adding trimethylsilyl chloride, preferably 2 to 50% by weight, more preferably 10 to 20% by weight, based on zinc to a mixture in which zinc dust is suspended in THF or the like and stirring the mixture. . The reaction can be performed, for example, by dropping α-bromoacetate into a mixture of activated zinc, a 3-hydroxy-γ-butyrolactone derivative and an aprotic solvent such as THF, and then reacting α-bromoacetate. And zinc is used in an amount of 1 to 5 molar equivalents, preferably 1.5 to 4 equivalents to the lactone. The reaction temperature depends on the solvent used, for example, when THF is used, preferably 15 ° C to 70 ° C, more preferably 20 ° C.
Performed at ~ 65 ° C.

Examples of the protecting group for the primary hydroxyl group of 5,6-dihydroxy-3-oxohexanoate include acyl groups such as benzoyl group and acetyl group, and silyl groups such as t-butyldiphenylsilyl group and t-butyldimethylsilyl group. And ether-type protecting groups such as triphenylmethyl group. For example, when a benzoyl group is used, introduction of a desired protecting group is achieved by reacting a benzoylating agent such as benzoyl chloride in the presence of a base such as pyridine by a conventional method. The amount of benzoyl chloride used is R ¹
Is preferably 1 to 1.5 equivalents, more preferably 1 to 1.2 equivalents, in order to minimize dibenzoylation.

(Examples) Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to the examples.

Example 1 (S) -5,6-dihydroxy-3-oxohexanoic acid t
Production of -butyl To a solution consisting of 3.54 g (35 mmol) of diisopropylamine and 10 ml of THF, 21.3 ml (35 mmol) of a 15% hexane solution of n-butyllithium was added dropwise at 0 ° C. under an argon atmosphere. 0
After stirring at 30 ° C for 30 minutes, the mixture was cooled to -70 ° C, and 4.79 ml (35 mmol) of t-butyl acetate was added dropwise. After stirring at -70 ° C for 1 hour,
1.02 g of (S) -3-hydroxy-γ-butyrolactone (1
0 mmol) in 1 ml of THF was added dropwise. After stirring at -70 ° C for 2 hours, the mixture was stirred at -10 ° C for 30 minutes. The reaction solution was poured into a solution consisting of 60 ml of 1N hydrochloric acid and 60 ml of ether, and the pH of the aqueous layer was further adjusted with 1N hydrochloric acid.
Adjusted to 6.5. After liquid separation, the aqueous layer was extracted three times with 50 ml of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting oil was subjected to silica gel column chromatography (hexane: acetone =). 5: 1)
And 1.56 g of (S) -5,6-dihydroxy-
T-Butyl 3-oxohexanoate was obtained (yield 71.4).
%). ¹ H NMR (CDCl ₃ , 90 mHz): δ = 1.48 (s, 9H), 2.68−2.83
(M, 2H), 3.05-3.48 (m, 2H), 3.42 (s, 2H), 3.45-
3.68 (m, 1H), 4.02-4.6 (m, 2H).

IR (neat): 3425, 3000, 1710, 850 cm ^-1 .

[Α] _D ²⁰ = −17.25 (c = 2.14, methanol) Example 2 (S) -5,6-dihydroxy-3-oxohexanoic acid t
Preparation of -Butyl A suspension of 9.82 g (0.15 mol) of zinc powder in 40 ml of THF was added at room temperature to 1.9 ml (15 mmo) of trimethylsilyl chloride.
l) was added and the mixture was stirred for 30 minutes, and then 2.4 ml (10.5 mmol) of t-butyl α-bromoacetate was added. 4.27 g (42 mmol) of (S) -3-hydroxy-γ-butyrolactone was added, the bath temperature was raised to 65 ° C., and then α-bromo-t-butyl acetate 15.3 g was added.
ml (94.5 mmol) was added slowly over 30 minutes. After the addition was completed, the mixture was further stirred at a bath temperature of 65 ° C. for 30 minutes, the reaction solution was returned to room temperature, and 50 ml of water was added to stop the reaction. The pH of the reaction solution was adjusted to 6.8 using 20% aqueous NaOH, the precipitated solid was removed by filtration, and the filtrate was extracted three times with 100 ml of ethyl acetate. After drying the combined organic layers over anhydrous sodium sulfate,
The oily substance obtained by concentration under reduced pressure was purified using silica gel column chromatography (hexane: acetone = 5: 1) to give 2.66 g (12.2 mmol) of (S) -5,6-
There was obtained t-butyl dihydroxy-3-oxohexanoate.

Example 3 (S) -5,6-dihydroxy-6-benzoyloxy-3
Preparation of t-butyl oxohexanoate In a solution consisting of 16.8 g (77 mmol) of t-butyl (S) -5,6-dihydroxy-3-oxohexanoate and 120 ml of methylene chloride, at 0 ° C, 11.2 ml of pyridine was added. Benzoyl 1
0.2 ml was added, and the mixture was stirred at 0 ° C for 2 hours. After completion of the reaction, 38 ml of water was added, the pH was adjusted to 7 with 20% NaOH, the layers were separated, the aqueous layer was extracted with methylene chloride (120 ml × 2), and the combined organic layers were dried over anhydrous sodium sulfate. The oil obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography (hexane: acetone = 5: 1) to obtain 19.3 g (60 mmol) of (S) -5,6-dihydroxy-6-benzoyloxy. T-Butyl-3-oxohexanoate was obtained as a solid. Melting point: 67-68 ° C. ¹ H NMR (CDCl ₃ , 90 mHz): δ = 1.46 (s, 9H), 2.85 (d, 2
H, J = 6Hz), 3.09 (d, 1H, J = 4Hz), 3.42 (s, 2H), 4.3
2-4.6 (m, 3H), 7.26-7.6 (m, 3H), 8.0-8.11 (m, 2
H).

IR (KBr): 3495, 1730, 1700, 1335, 1290, 1150, 720c
m ^-1 .

(Effect of the Invention) According to the method of the present invention, a 5,6-dihydroxy-3-oxohexanoate derivative useful as an HMG-CoA reductase inhibitor intermediate can be efficiently and economically produced.

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Claims (12)

(57) [Claims] (1) Formula (I): (. In the formula, R ¹ represents hydrogen or a silyl-type protecting group) and 3-hydroxy -γ- butyrolactone derivative represented by the formula _{(II): LiCH 2 CO 2} R 2 (II) ( wherein, R ² Represents an alkyl group, an aralkyl group or an aryl group having 1 to 10 carbon atoms.) The compound is reacted with a lithium enolate of an acetic acid ester represented by the formula (III): (In the formula, R ¹ and R ² are the same as described above.) A method for producing a 5,6-dihydroxy-3-oxohexanoate derivative represented by the formula: 2. Use of 3-hydroxy-γ-butyrolactone as a 3-hydroxy-γ-butyrolactone derivative.
The method according to claim 1, wherein 5,6-dihydroxy-3-oxohexanoic acid ester is produced. 3. An optically active (S) -5,6-dihydroxy-3-oxohexanoic acid ester is produced by using optically active (S) -3-hydroxy-γ-butyrolactone as a 3-hydroxy-γ-butyrolactone derivative. The method according to claim 1 or 2, wherein 4. A lithium enolate of t-butyl acetate is used as a lithium enolate of an acetate ester.
4. The method according to any one of items 1 to 3. 5. A lithium enolate prepared by reacting t-butyl acetate with lithium diisopropylamide as a lithium enolate of an acetate ester.
5. The method according to any one of items 1 to 4. 6. A 3-hydroxy-γ-formula represented by the formula (I)
Reacting a butyrolactone derivative with an α-bromoacetic acid ester represented by the formula (IV) BrCH ₂ CO ₂ R ² (IV) (wherein R ² is the same as defined above) in the presence of zinc; 5,6-dihydroxy- represented by the formula (III)
A method for producing a 3-oxohexanoic acid ester derivative. 7. Use of 3-hydroxy-γ-butyrolactone as a 3-hydroxy-γ-butyrolactone derivative.
The method according to claim 6, wherein 5,6-dihydroxy-3-oxohexanoate is produced. 8. An optically active (S) -5,6-dihydroxy-3-oxohexanoic acid ester is produced by using optically active (S) -3-hydroxy-γ-butyrolactone as a 3-hydroxy-γ-butyrolactone derivative. The method according to claim 6 or 7, wherein 9. A t-butyl 5,6-dihydroxy-3-oxohexanoate derivative is produced by using t-butyl α-bromoacetate as α-bromoacetic ester.
The production method according to any one of the above. 10. A compound of the formula (V), wherein the primary hydroxyl group of the 5,6-dihydroxy-3-oxohexanoate derivative represented by the formula (III) produced in claim 1 or 6 is protected. ): (Wherein R ¹ and R ² are the same as above, and R ³ represents a protecting group for a hydroxyl group.) A method for producing a 5,6-dihydroxy-3-oxohexanoate derivative represented by the formula: 11. A protecting group for a primary hydroxyl group represented by the formula (VI): (In the formula, R ⁴ represents an alkyl group, an aralkyl group or an aryl group.) The production method according to claim 10, wherein an acyl group represented by the following formula is introduced. 12. The method according to claim 11, wherein a benzoyl group is introduced as an acyl group.