JPH1045672A - Method for producing optically active 4-hydroxy-3-methylbutanoic acid t-butyl ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce optically active 4-hydroxy-3-methylbutanoic acid t-butyl ester, which is an effective intermediate for producing optically active pharmaceuticals and agriculturally active agricultural chemicals, in a stable state and with good yield. To provide. SOLUTION: The optically active 3-carboxybutanoic acid t-butyl ester is reduced using a borane complex to obtain the following formula (1)
To produce optically active 4-hydroxy-3-methylbutanoic acid t-butyl ester represented by the formula: t-C ₄ H ₉ OOCCH ₂ C ^* H (CH ₃ ) CH ₂ OH (1) (In the formula, ^* indicates that the carbon is an asymmetric carbon.)

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an optically active drug,
Optical activity 4 which is an intermediate used for optically active pesticides
-Hydroxy-3-methylbutanoic acid t-butyl ester.

[0002]

2. Description of the Related Art An optically active 4-hydroxy-3-methylbutanoic acid ester is synthesized by reducing an optically active 3-carboxybutyric acid methyl ester with a borane complex such as a borane-dimethylsulfide complex. A method for selectively reducing only the carboxyl group without using the method (Biosci. Biotech. Biochem., 57 (2) 265)
(1993)).

However, when 4-hydroxy-3-methylbutanoic acid ester is produced according to the above method, the obtained 4-hydroxy-3-methylbutanoic acid methyl ester is unstable and easily converted to β-methyl-γ-butyrolactone. It has been found to have drawbacks. According to subsequent studies by the present inventors, it was found that t-butyl ester instead of methyl ester was extremely stable unless acidic conditions were used. However,
When producing optically active 4-hydroxy-3-methylbutanoic acid t-butyl ester, a conventional borane complex decomposes because a t-butyl ester group unstable to acidic conditions exists in addition to a reducing carboxyl group. Easy to do,
An effective synthesis method has been desired.

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a method for producing an optically active 4-hydroxy-3-methylbutanoic acid t-butyl ester, which is an effective intermediate for producing optically active pharmaceuticals and agriculturally active agricultural chemicals, in a stable state. It is an object of the present invention to provide a method for producing a high yield.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies on a method for producing optically active 4-hydroxy-3-methylbutanoic acid t-butyl ester. The inventors have found a method for selectively reducing the ester while maintaining the stereo structure, and have completed the present invention.

That is, the gist of the present invention is to provide an optically active 4-hydroxy-formula represented by the following formula (1), characterized in that optically active 3-carboxybutanoic acid t-butyl ester is reduced using a borane complex. A method for producing t-butyl 3-methylbutanoate. t-C ₄ H ₉ OOCCH ₂ C ^* H (CH ₃ ) CH ₂ OH (1) (In the formula, ^* indicates that the carbon is an asymmetric carbon.)

[0007]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Specific examples of the borane complex used in the present invention include borane-tetrahydrofuran,
Examples thereof include borane-dimethyl sulfide, borane-dimethylamine, borane-trimethylamine, borane-triethylamine, and borane-pyridine. Among these, the borane-tetrahydrofuran complex is preferred from the viewpoints of the problem of odor, the reducing power of the complex and the yield of the final product.

[0008] The borane-tetrahydrofuran complex can be prepared, for example, by dissolving gaseous borane in tetrahydrofuran.
Industrially, it can be usually prepared by adding boron trifluoride to a suspension of an alkali metal borohydride in tetrahydrofuran and filtering off sodium borofluoride precipitated.

The alkali metal borohydride used in preparing the borane-tetrahydrofuran complex by adding boron trifluoride to a suspension of the alkali metal borohydride in tetrahydrofuran includes sodium borohydride, lithium borohydride and the like. Is mentioned. here,
The amount of the alkali metal borohydride used for boron trifluoride can be arbitrarily set. However, under the reaction conditions exceeding 120% of the equivalent value, the excess alkali metal borohydride is not effectively used, which is uneconomical.
Under the reaction conditions at a usage amount of 100% or less of the equivalent value, the components inside the alkali metal borohydride particles in suspension are not effectively used for the reaction with boron trifluoride. It is difficult to prevent. As a result, the acid-unstable t-butyl ester group is decomposed and a side reaction is caused by reduction, thereby lowering the purity of the product. Therefore, it is preferable to use an excess amount of the alkali metal borohydride with respect to boron trifluoride, for example, in the range of 102 to 120% of the equivalent value.

[0010] The concentration of the borane complex in the reaction solution in the reduction reaction is not particularly limited. In consideration of handling properties, it is preferable to carry out the reaction using a complex of about 1 mol / L. However, in order to enhance the productivity, it is effective to use a borane complex of 1 mol / L or more and raise the concentration of the reactant to effect the reaction. There is. However, if the concentration of the reactants is too high, not only does the viscosity of the reaction solution increase, making control of the reaction difficult,
Since a large amount of solids is generated in the post-treatment, the recovery rate may decrease. Therefore, when practicing the present invention, it is preferable to set the concentration of the borane complex between 0.5 and 3.0 mol / L.

The reaction temperature is 0 ° C. to suppress side reactions.
The temperature is preferably set to the following, particularly preferably −25 ° C. or lower.However, the viscosity increases as the concentration of the borane complex increases, so that the reaction temperature may be increased to about 25 ° C. as the reaction proceeds. No problem.

In the reaction, a borane complex is produced in advance, and the cooled optically active 3- (3) -borane complex is used as a raw material.
A method of dropping t-butyl carboxybutanoate is generally used, and this method is also preferable in order to prevent side reactions.

The reaction solvent is particularly preferably an ether solvent such as tetrahydrofuran and dimethoxyethane.

When the post-treatment is carried out under acidic conditions, β-methyl-
There is a possibility that by-products of γ-butyrolactone and decomposition of t-butyl ester may occur. In addition, since a racemization reaction may occur under basic conditions, a method of inactivating the borane complex by adding methanol is most preferable.

The target product can be obtained by distilling off the solvent or low-boiling components such as methanol after the post-treatment of the reaction solution. However, when the alcohol is by-produced, the product is purified by, for example, hexane or ethyl acetate. Dissolved in a solvent such as chloroform, methyl ethyl ketone, etc.
Can be removed or reduced by washing with an alkali. When aldehyde remains,
After methanol is added to inactivate the borane complex, the aldehyde can be reduced by adding an alkali metal borohydride in an equimolar amount or more to the remaining aldehyde.

[0016]

The present invention will be described below by way of examples.

Example 1 31.2 g of sodium borohydride was suspended in 1 L of anhydrous tetrahydrofuran. 123 ml of boron trifluoride-diethyl ether complex was gradually added thereto under ice cooling,
After stirring for 1 hour, the precipitated sodium borofluoride was separated by filtration under a nitrogen stream (the amount of sodium borohydride was 1.1 equivalents to boron trifluoride).

In 90 ml of the borane-tetrahydrofuran complex solution prepared as described above, t-butyl (R) -3-carboxybutanoate (optical purity 98% ee) was added.
A solution prepared by dissolving 1.3 g in 30 ml of anhydrous tetrahydrofuran was added dropwise at 2 to 5 ° C. under ice-cooling.
Allowed to react for hours. After the reaction, methanol 10
0 ml was gradually added under ice cooling. The obtained reaction solution was concentrated to obtain 9.3 g of crude (R) -4-hydroxy-3-methylbutanoic acid t-butyl ester. Analysis by liquid chromatography revealed that (R) -4-hydroxy-
97.0% of 3-methylbutanoic acid t-butyl ester,
(R) -methylsuccinic acid 0.1%, (R) -2-methyl-1,4-butanediol 2.1%, unknown substance 0.8% (liquid chromatography conditions: column ODS-
120A (manufactured by Tosoh) 4.6 mmφ × 25 cm, mobile phase acetonitrile / water / phosphoric acid = 40/60 / 0.1,
Flow rate 1.0 ml / min, detection UV 220 nm). In addition,
(R) -2-Methyl-1,4-butanediol was analyzed by liquid chromatography after inducing tosylate by a conventional method (liquid chromatography conditions: column O).
DS-120A (manufactured by Tosoh) 4.6mmφ × 25cm,
Mobile phase acetonitrile / water / phosphoric acid = 70/30 /
0.1, flow rate 1.0ml / min, detection UV254n
m).

The above crude product was dissolved in 200 ml of ethyl acetate, washed twice with 50 ml of a 10% aqueous sodium carbonate solution, and the organic layer was dried over anhydrous sodium sulfate and concentrated to obtain (R) -4- Hydroxy-3-methylbutanoic acid t-butyl ester (98% ee optical purity;
After induction to (R) -β-methyl-γ-butyrolactone, the optical rotation was measured and determined. [Α] _D ²⁰ = + 24.4
9.1 g of 6 ゜ (c = 2, methanol) was obtained (yield: 8).
7%).

Example 2 A borane-tetrahydrofuran complex prepared in Example 1 using 1.2 equivalents (120%) of sodium borohydride was used, and (S) -3-
Carboxybutanoic acid t-butyl ester (optical purity 97
% Ee) When the same operation as in Example 1 was performed except that 10.2 g was used, (s) -4-hydroxy-3-methylbutanoic acid t-butyl ester (optical purity 97% e
e; After induction into (S) -β-methyl-γ-butyrolactone, the optical rotation was measured and determined. [Α] _D ²⁰ = −23.
8.0 g (28% (c = 4, methanol)) was obtained (85% yield).

Example 3 The same operation as in Example 1 was carried out except that a borane-tetrahydrofuran complex prepared using 28.4 g of sodium borohydride (1.0 equivalent to boron trifluoride) was used. As a result, 10.0 g of a crude product was obtained. As a result of the analysis, the target compound was 80.2%, (R) -methylsuccinic acid was 9.8%, (R) -methyl-1,4-butanediol was 7.6%, and the unknown was 2.4%. Was.

[0022]

Industrial Applicability The present invention provides an optically active intermediate which is an effective intermediate for producing optically active pharmaceuticals, optically active agricultural chemicals and the like.
This has the effect that hydroxy-3-methylbutanoic acid t-butyl ester can be produced in a stable state with good yield. In particular, borane prepared using an alkali metal borohydride in an amount exceeding the equivalent value with respect to boron trifluoride-
If a tetrahydrofuran complex is used, it can be produced with higher yield.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Keiichi Sakashita Mitsubishi Rayon Co., Ltd. 2-3-1 Kyobashi, Chuo-ku, Tokyo

Claims (3)

[Claims] 1. An optically active 4-hydroxy-formula represented by the following formula (1), wherein the optically active 3-carboxybutanoic acid t-butyl ester is reduced using a borane complex.
A method for producing t-butyl 3-methylbutanoate. t-C ₄ H ₉ OOCCH ₂ C ^* H (CH ₃ ) CH ₂ OH (1) (In the formula, ^* indicates that the carbon is an asymmetric carbon.) 2. The method according to claim 1, wherein the borane complex is a borane-tetrahydrofuran complex. 3. The method according to claim 2, wherein the borane-tetrahydrofuran complex is prepared by using an alkali metal borohydride in an amount exceeding the equivalent value to boron trifluoride.