JPH0592964A - Purification of optically active 4-substituted lactones - Google Patents

Abstract

PURPOSE:To very readily obtain 4-substituted lactones having a sufficiently high optical purity in high yield. CONSTITUTION:The lactone ring of a 4-substituted lactone is once cleaved by hydrolysis to obtain its hydroxycarboxylic acid derivative. The resultant hydroxycarboxylic acid derivative is subsequently repeatedly recrystallized and purified to a high optical-purity hydroxycarboxylic acid derivative. The purified hydroxycarboxylic acid derivative is then lactonized again in an acid condition, thus affording the objective high optical-purity 4-substituted lactone, e.g. a compound of the formula.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for purifying optically active 4-substituted lactones.

[0002]

2. Description of the Related Art Many physiologically active substances differ greatly in the expression of physiological activity due to the difference in optical isomers.

Among such physiologically active substances, for example,
(R, Z) -5-tetradecene-4-olide, which is a sex pheromone of the bean beetle (Popilia japonica), which is a harmful insect that eats fruit trees such as grapes and turf, is useful as an attractant excellent in attracting and killing the bean beetle. is there.

The general formula (I) of (R, Z) -5-tetradecene-4-olide is shown in Chemical formula 1.

[0005]

[Chemical 1]

Such research on (R, Z) -5-tetradecene-4-olide (I) has been extensively conducted by Dr. Tamlinson of the US Department of Agriculture. According to their research, the double bond existing in the side chain of (R, Z) -5-tetradecene-4-olide (I) is required to be in the cis configuration for the activity to be expressed. Yes, the trans form has no inhibitory activity. On the other hand, regarding the asymmetric carbon atom at the 4-position, it is known that only the (R) form exhibits activity and the (S) form does not. Furthermore, it has been confirmed that the (S) form strongly inhibits the activity of the (R) form. Therefore, in order to efficiently and effectively attract and kill beetles, the double bond of the side chain must not have the trans configuration and must not contain the (S) form. .. In other words, effective attraction and killing of Japanese beetles requires the use of (R, Z) -5-tetradecene-4-olide (I) having extremely high optical and chemical purities.

Conventionally, (R, Z) -5-tetradecene-4
-As a method for producing the orido (I), for example, (1) 1-
The acetylenic ketoester synthesized from the decin derivative was converted into (2S, 3R)-(+)-4-dimethylamino-
1,2-Diphenyl-3-methyl-2-butanol [Aldrich Chemical Co. , Made of chiral (Chir
ald)] and a method of asymmetric reduction in the presence of Li-olide 1H ₄ [S. Senda and K.K. Mori,
Agric. Biol. Chem. , 47, 2595
(1983)] or (2) (R) -glutamic acid via butyrolactone and using the Wittig reaction [R. E. Dootle, et al. Che
m. Ecol. , 6, 473 (1980)] and the like are known.

[0008]

However, (R, Z) -5-tetradecene-4 obtained by the conventional production method.
-Olide (I) was not always sufficient in chemical purity or optical purity. For example, (R, Z) -5-tetradecene-4-olide (I) obtained by the method (2) had a chemical purity of 80% and an optical purity of 88%.

Further, (R, Z) -5-tetradecene-
4-Olide (I) is obtained as an oily substance. Therefore, it does not crystallize and is difficult to purify as it is. Therefore, in order to further increase the optical purity, a method of purifying by repeating recrystallization after forming a salt using a reagent such as a chemically active amine in the intermediate step or the final step of the manufacturing process, or with urea or the like. After the adduct is formed, it is purified by a method for purifying it.

However, in these purification methods, since expensive reagents must be used, the manufacturing cost becomes high. Further, there are problems that the above-mentioned purification process is complicated and that the purification is not always sufficient.

Here, (R, Z) -5-tetradecene-
Although 4-olide has been described as an example, the above problems are common to physiologically active substances belonging to 4-substituted lactones. For example, a compound having a basic skeleton of a substituted lactone such as (R) -4-hexanolide, which is a pheromone of the snail, and (R, Z) -6-dodecene-4-olide, which is an odorous substance of Kuroo deer, is also used. I have a similar problem.

[0012] The present invention has been made in view of the above points, and is capable of purifying 4-substituted lactones having a high recovery rate and a high optical purity by an extremely simple method without using an expensive reagent. An object of the present invention is to provide a method for purifying 4-substituted lactones that can be obtained.

[0013]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that crystallization is difficult.
The inventors have found that a hydroxycarboxylic acid derivative obtained by hydrolyzing a -substituted lactone is easily crystallized, and completed the present invention. That is, the present invention provides a step of hydrolyzing a 4-substituted lactone to obtain a hydroxycarboxylic acid derivative, a step of recrystallizing the hydroxycarboxylic acid derivative, and a step of recrystallizing the hydroxycarboxylic acid derivative under lactone. The method for purifying an optically active 4-substituted lactone is characterized by comprising:

The present invention will be described in more detail below.

Examples of 4-substituted lactones to be purified in the present invention include (R, Z) -5-tetradecene-
Pheromones such as 4-olide and (R) -4-hexanolide, and odorants such as (R, Z) -6-dodecene-4-olide are physiologically active substances having a basic skeleton of 4-substituted lactone such as odorants. ..

First, a 4-substituted lactone is hydrolyzed to cleave the lactone ring to obtain a hydroxycarboxylic acid derivative. Here, the 4-substituted lactone can be hydrolyzed by a generally known hydrolysis method. For example, to a solution of sodium metal dissolved in dry methanol, after the crude product was added dropwise and stirred, excess water was added,
It can be performed by further stirring. Further, it can be carried out in a solvent such as water or methanol using a metal hydroxide such as sodium hydroxide.

Next, the hydroxycarboxylic acid derivative is recrystallized to increase the optical purity of the hydroxycarboxylic acid derivative. Here, recrystallization of the hydroxycarboxylic acid derivative can be repeated as necessary until a crystal of the hydroxycarboxylic acid derivative having a sufficiently high optical purity is obtained.

Next, the purified hydroxycarboxylic acid derivative is lactonized again under acidic conditions to obtain a 4-substituted lactone having high optical purity.

[0019]

According to the method for purifying an optically active 4-substituted lactone of the present invention, a hydroxycarboxylic acid derivative obtained by hydrolyzing a 4-substituted lactone and once cleaving the lactone ring can be easily crystallized. Thereby, the optical purity and the chemical purity of the hydroxycarboxylic acid derivative can be easily increased by repeating the recrystallization.

[0020]

EXAMPLES Hereinafter, the case where the method for purifying an optically active 4-substituted lactone of the present invention is applied to the purification of (R, Z) -5-tetradecene-4-olide will be described.

First, R. E. Doodle, eta
1, J.I. Chem. Ecol. , 6, 473 (198
According to the production method disclosed in (0), a crude product of (R, Z) -5-tetradecene-4-olide (hereinafter referred to as a crude product) was obtained using (R) -glutamic acid as a starting material. The crude product is an oily substance, and its purity is 80% in chemical purity and 88 in optical purity by gas chromatographic analysis.
%Met.

Next, 1.7 g of sodium metal was dissolved in 50 ml of dry methanol, and this solution was maintained at 15 to 20 ° C. with stirring. Then, 17 g of the crude product was dropped into this solution and stirred at 20 ° C. for 2 hours. Next, 33 ml of water was added to this solution while being careful not to exceed 20 ° C., and the mixture was further stirred for 1 hour. The reaction solution was poured into an excessive amount of ice water, and the aqueous layer was extracted several times with ether. Next, 2-3 wt% of dilute hydrochloric acid was added to this aqueous layer while cooling with ice water, slowly and carefully until the pH reached about 4. After this time, the reaction was extracted several times with ether. Then, the extract is washed with water, dried over anhydrous sodium sulfate, and then concentrated,
12.5 g of crude crystals of (R, Z) -4-hydroxy-5-tetradecenoic acid were obtained.

Next, 12.5 g of the obtained crude crystals of (R, Z) -4-hydroxy-5-tetradecenoic acid were dissolved in 25 ml of dry ether, and further dried n-hexane 125
ml was added. The solution was left in the refrigerator overnight. The precipitated crystals were filtered and dried in a desiccator to obtain scaly crystals 9.4g. Furthermore, 34 ml of dry ether
Then, by recrystallizing at room temperature using a mixed solution of 34 ml of dry n-hexane, 7.6 g of white scale-like crystals of (R, Z) -4-hydroxy-5-tetradecenoic acid were obtained.

The obtained (R, Z) -4-hydroxy-5
-The physical properties of the white scale-like crystals of tetradecenoic acid are as follows.

[Α] _D ²³ + 16.0 ° (c = 0.85, CHCl ₃ ) Melting point: 64.5-65.5 ° C. IR (KBr): ν max 3210 (br), 3008 (s), 2958 (s), 2922 (s),
2856 (s), 2680 (m), 1717 (s), 1470 (m), 1
441 (s), 1075 (m), 1056 (m) ¹ H-NMR (CDCl ₃ ): δ 0.89 (3H, t, J = 6.9Hz), 1.15
1.42 (14H, m), 1.71-1.98 (2H,
m), 1.98-2.17 (2H, m), 2.48 (2
H, t, J = 7.2 Hz), 4.46-4.58 (1H,
m), 5.33-5.43 (1H, m), 5.47-
5.58 (1H, m).

Next, 7.6 g of the obtained white scale-like crystals of (R, Z) -4-hydroxy-5-tetradecenoic acid and 0.5 g of paratoluenesulfonic acid were dissolved in 50 ml of ether and then for 2 hours. Heated to reflux. The reaction solution was allowed to cool, then washed successively with water and an aqueous sodium carbonate solution, and dried over anhydrous sodium sulfate. The dried reaction solution was concentrated to give (R, Z) -5-tetradecene-4-olide 7.0.
5 g was obtained.

The obtained (R, Z) -5-tetradecene-
The purity of 4-olid was determined by gas chromatography analysis.
It has a chemical purity of 99.7% or more and an optical rotation of [α] _D ^23.
_{-70.4 (c = 1.0, CHCl 3} ) was.

[0028]

As described above, according to the method for purifying an optically active 4-substituted lactone of the present invention, the 4-substituted lactone is hydrolyzed to once cleave the lactone ring, thereby facilitating recrystallization. By purifying in the form of a novel hydroxycarboxylic acid derivative, 4-substituted lactones having a sufficiently high optical purity can be obtained very simply, with a high recovery rate, without using an expensive reagent. It has a remarkable effect.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroshi Kawakami 6-2 Umegaoka, Midori-ku, Yokohama-shi, Kanagawa Japan Tobacco Inc. Life Science Institute (72) Inventor Katsuya Matsumoto 6-2, Umegaoka, Midori-ku, Yokohama-shi, Kanagawa Japan Tobacco Inc. Life Science Research Institute (72) Inventor Hajime Hajime 2 6 Umegaoka, Midori-ku, Yokohama-shi, Kanagawa Japan Tobacco Inc. Life Science Research Institute (72) Ino Mikio Ono 3 Midorigaoka, Hamura-cho, Nishitama-gun, Tokyo Chome 5-8 Fuji Flavor Co., Ltd. (72) Inventor Kazumi Ogata 3-5-8 Fuji Flavor Co., Ltd. Midorigaoka, Hamura-cho, Nishitama-gun, Tokyo

Claims (1)

[Claims] 1. A step of hydrolyzing a 4-substituted lactone to obtain a hydroxycarboxylic acid derivative, a step of recrystallizing the hydroxycarboxylic acid derivative, and a lactonization of the recrystallized hydroxycarboxylic acid derivative under acidic conditions. The method for purifying an optically active 4-substituted lactone, comprising: