JP2798686B2 - Suspendolide manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION INDUSTRIAL APPLICATION The present invention relates to the Caribbean fruit fly (Anastrepha suspensa lo
ew) The present invention relates to a method for producing suspenseolide, which is a component of the sex pheromone released by males, the purpose of which is to enable suspenseolide to be synthesized very easily and with high purity and high yield, and that the starting material is It is an object of the present invention to provide a method for producing suspensolide which is general-purpose and easily available, and is therefore suitable for an industrial production method as a whole.

Background of the Invention Real fly, an insect belonging to the order Diptera: Tephritidae, is small and brightly colored, with most species having mottled wings.

Adults live in the field and gather on the leaves, fruits, and buds of plants, while larvae are pests that infiltrate plants, such as those that eat leafy leaves, those that infiltrate plant stems and twigs, and those that have seeds. Some of them eat nuts and others are parasitic on raw fruits and cucumber.

Among them the Caribbean fruit fly (Anastrepha suspensa Loe)
w) is a pest that causes harmful damage to fruits such as citrus fruits in the central and northern United States. In Japan, the Caribbean fruit fly (Anastrepha suspensa Loew)
The import of citrus fruits and other parasitized parasites has been banned by the Customs Law.

(Prior art and its problems) Conventionally, this Caribbean fruit fly (Anastrepha suspensa Lo
ew), insecticides have been used to control
There was a risk of remaining on fruits such as citrus fruits.

Methods using various physiologically active substances have been studied as an effective control method instead of insecticides, and in recent years, methods using pheromones have attracted attention.

Caribbean fruit flies (Anastrepha suspensa Loew) release male pheromones and attract females.

The pheromone of the Caribbean fruit fly (Anastrepha suspensa Loew) is suspensolide (formula 4), (3Z) -3-
Nonen-1-ol (Formula 5), (3Z, 6Z) -3,6-nonadiene-1-ol (Formula 6), anastrefin (Formula 7), epianastrefin (Formula 8) It has been found that it consists of the following five components.

These Caribbean fruit flies (Anastrepha suspensa Loew)
Of the pheromones of the above, suspensolide (formula 4) is an extremely unique structure of an 11-membered lactone having two trans double bonds, so its synthesis is extremely difficult. The isolation and purification method was also very difficult due to the qualitative nature.

Mori et al.'S report (K. Mori, Y. Nakazono, Liebigs Ann. Chem.,
167, (1988)), the yield is as low as only 9.1%, and the isolation and purification method also uses a silica gel column without pre-treating the reaction solution, so that the 1000
Since it requires twice as much silica gel, it is difficult to produce it in large quantities, and it is not suitable as an industrial production method.

Furthermore, the suspension of suspense is caused by the adsorption of the suspension onto silica gel for a long time, and the decomposition of the suspension is avoided even if the column is changed to a carrier such as florisil, activated alumina, or basic alumina. The purity was low.

In view of the above circumstances, the industry has made it possible to synthesize suspensolides very easily, with high purity and high yield, and the starting materials are versatile and readily available, so that the entire process is industrially produced. It has been desired to create a method for producing a suspension suitable for the method.

(Means for Solving the Problems) The method for producing a suspension according to the present invention mainly comprises (3E, 8E) -4,8-dimethyl-10-hydroxy-3,8
After reacting decadienoic acid (formula 1) with triphenylphosphine (formula 3) in the presence of diethyl azodicarboxylate (formula 2) in an aprotic solvent, the reaction solution is concentrated. Suspending the residue in at least one low-boiling solvent, cooling the mixture to -40 ° C or lower, concentrating a filtrate obtained by filtering the suspension, and distilling the obtained residue. Therefore, all of the above-mentioned problems are solved.

Hereinafter, the configuration of the method for producing the suspension (formula 4) according to the present invention will be described in detail.

(Constitution of the Invention) In the present invention, (3E, 8E) -4,8-dimethyl-10-
Hydroxy-3,8-decadienoic acid (Formula 1) was synthesized by a method already reported (K. Mori et al., Liebigs Ann. Chem., 167,
(1988)), the ring is closed by an intramolecular esterification method.

That is, (3E, 8E) -4,8-dimethyl-10-hydroxy-3,8-decadienoic acid (formula 1) is prepared in an aprotic solvent in the presence of diethyl azodicarboxylate (formula 2). Reaction with triphenylphosphine (formula 3).

As the solvent used in this step, an aprotic solvent is preferably used.

Examples of aprotic solvents include (3E, 8E) -4,8-dimethyl-10-hydroxy-3,8-decadienoic acid (formula 1), diethyl azodicarboxylate (formula 2), and triphenylphosphine (formula 3). All aprotic solvents that dissolve are suitably used, for example, tetrahydrofuran, benzene,
Chlorobenzene, dimethylformamide, toluene, carbon tetrachloride, chloroform and the like can be mentioned, and it is particularly preferable to use benzene.

In this step, the reaction is usually performed at room temperature.

By this step, (3E, 8E) -4,8-dimethyl-10-hydroxy-3,8-decadienoic acid (formula 1) is converted into suspensolide (formula 4) through a reaction intermediate represented by the following formula 10. Become.

 This step is illustrated below.

Next, the reaction solution obtained by the above steps is concentrated, and the aprotic solvent is distilled off by means such as heat concentration, vacuum concentration, or ventilation concentration so that the suspension (formula 4) is not decomposed.

In the present invention, the reaction solution is kept at 0 ° C to 40 ° C, preferably
It is particularly desirable to concentrate under a temperature condition of 20 ° C. to 40 ° C., and it is possible to further improve the purity and yield of suspensolide (formula 4).

The reason for setting the temperature to 0 ° C. to 40 ° C. is that if the temperature is lower than 0 ° C., it takes a long time for concentration, and the efficiency is poor. If the temperature exceeds 40 ° C., suspensolide (Formula 4) generated by the reaction may be decomposed. However, the temperature is not necessarily limited to 0 ° C. to 40 ° C., and may vary depending on various conditions at the time of concentration.

Next, the residue obtained by concentrating the reaction system is suspended in at least one low-boiling solvent, cooled to −40 ° C. or lower, and then the suspension is filtered.

In the present invention, the low boiling point solvent is a solvent that does not coagulate when cooled to −40 ° C. or less and is easily distilled off when the filtrate described below is concentrated, and examples thereof include alkanes, alkenes, alkynes, and alicyclic rings. Examples include aprotic solvents such as formula hydrocarbons, aromatic hydrocarbons, organic halides, phenols, and ethers.

These low-boiling solvents may be used alone, or two or more of them may be used in combination, and a mixed solvent of n-pentane and diethyl ether is particularly preferably used.

In this step, the suspension is cooled to −40 ° C. or lower and then filtered to remove triphenylphosphine oxide (following formula 9) as a reaction product and unreacted substances.
The reason for cooling to −40 ° C. or lower is that, when the temperature exceeds −40 ° C., triphenylphosphine oxide (formula 9) dissolves in the low-boiling solvent and remains in the filtrate. This is because there is a possibility that the distillate may be distilled off together with the formula 4) and consequently lower the purity of the suspensolide (formula 4).

Ph ₃ P = O (Equation 9) Further, the filtrate obtained by filtering the suspension is concentrated to obtain a residue. In this step, too, from 0 ° C. to 40 ° C. for the reason described above.
It is particularly desirable to concentrate under a temperature condition of 20 ° C, preferably 20 ° C to 40 ° C.

 Finally, the residue obtained by concentration is distilled.

As a means for distilling the residue, distillation under normal pressure may be performed. However, it is particularly preferable to perform distillation under reduced pressure so as not to decompose the suspensolide (formula 4), usually under a vacuum of several mmHg to about 10 ⁻² mmHg. Perform at

Hereinafter, Examples, Reference Examples, and Comparative Examples of the method for producing a suspensolide (Formula 4) according to the present invention will be described.

(Example 1) (3E, 8E) -4,8-dimethyl-10-hydroxy-3,8-
After dissolving 11.2 g (52.8 mmol) of decadienoic acid and 20.9 g (79.0 mmol) of triphenylphosphine in 1.85 of dry benzene, 13.8 g (79.0 mmol) of diethyl azodicarboxylate was added dropwise at room temperature. Was stirred overnight at room temperature.

This reaction solution was concentrated under reduced pressure at a temperature of 30 ° C. to remove benzene.

The obtained residue was suspended in a mixed solvent of n-pentane and diethyl ether (100 ml, mixed volume ratio 1: 1), and the suspension was cooled to -40 ° C and filtered.

After the filtrate was again concentrated under a temperature condition of 30 ° C., the obtained residue was distilled under reduced pressure to obtain a distillate.

As a result of gas chromatographic analysis of the distillate, a peak of a main substance was observed at a retention time of 3.020 minutes, and the purity of the main substance was 94%.

The measurement was carried out using a column of PEG 20M (polyethylene glycol, molecular weight: about 20,000, length: 25 m, inner diameter: 0.2 mm), the temperature was increased from 150 ° C to 220 ° C at 10 ° C / min, and helium was used as a carrier gas. Flowed 1 ml per minute.

The absorption wave number (cm ^-1 ) of the infrared absorption spectrum of the distillate was 2990 (w), 2950 (m), 2910 (w), 28
50 (w), 1730 (s), 1660 (m), 1440 (m), 1380
(W), 1360 (w), 1335 (w), 1250 (m), 1230
(M), 1200 (m), 1120 (m), 1110 (m), 1070
(W), 1030 (w), 970 (w), and 935 (m).

The measurement was performed by dissolving a sample in carbon tetrachloride and measuring by a solution method.

Further, the δ value (ppm) of the proton nuclear magnetic resonance ( ¹ H-NMR) spectrum is 1.48 (3H, s), 1.52 (3H, s), 1.20 to
1.70 (2H, m), 1.82 (4H, m), 2.67 to 2.88 (2H, m), 4.
10-4.78 (2H, m), 4.80 (1H, dt, J = 1.0,8.0Hz), 5.03
(1H, t, J = 8.0Hz).

For the measurement, dissolve the sample in chloroform-d
The measurement was performed using a proton nuclear magnetic resonance spectrum at 400 MHz.

 The boiling point was 70 to 75 ° C at 0.5 mmHg.

From the above results, it was found that this distillate was a suspension.

The weight of the distillate was 3.08 g, and the yield was 30%.

FIG. 1 shows a gas chromatogram, FIG. 2 shows an infrared absorption spectrum, and FIG. 3 shows a 400 MHz proton nuclear magnetic resonance spectrum.

(Reference Example) The same treatment as in Example 1 was carried out, and a vacuum residue in the final step was omitted to obtain a concentrated residue.

The residue was subjected to gas chromatography analysis in the same manner as in Example 1. As a result, a suspension peak was observed at a retention time of 3.020 minutes, and the purity was 86%.

 The weight of the residue was 4.0 g, and the yield was 40%.

(Examples 2 and 3 and Comparative Example) The yield and performance of the suspension obtained by treating the suspension exactly as in Example 1 except that the temperature for cooling the suspension was changed as shown in Table 1 below. The purity of the suspension obtained by gas chromatography analysis as in Example 1 is also shown in Table 1.

(Examples 4 and 5) Except that the temperature for concentrating the reaction solution and the filtrate was changed as shown in Table 2 below, the yield of suspensolide obtained in the same manner as in Example 1 and Example 1 were obtained. Table 2 also shows the purity of the suspension obtained by gas chromatography analysis in the same manner as in Example 1.

(Effects of the Invention) As described above in detail, the method for producing a suspension according to the present invention mainly comprises (3E, 8E) -4,8-dimethyl-10-
After reacting hydroxy-3,8-decadienoic acid with triphenylphosphine in the presence of diethyl azodicarboxylate in an aprotic solvent, the reaction solution is concentrated,
The residue is suspended in at least one low-boiling solvent, cooled to −40 ° C. or lower, the filtrate obtained by filtering the suspension is concentrated, and the obtained residue is distilled. Is a method for producing suspense, which is capable of synthesizing suspense very easily and with high yield, and what is the conventional purification by column chromatography using an adsorbent such as silica gel. On the contrary, the suspension can be isolated and purified in a large amount and at a high purity of 92% or more, and the starting material is versatile and easily available. Is produced.

Further, by concentrating the reaction solution and / or the filtrate under a temperature condition of 0 ° C. to 40 ° C., a product having a conventional yield of about 9% can be produced in a high yield of about 30%. .

[Brief description of the drawings]

FIGS. 1, 2 and 3 are the gas chromatogram, the infrared absorption spectrum and the
1 shows a proton nuclear magnetic resonance spectrum at 0 MHz.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Tamaki Tachikawa 1-1-2 Shimohozumi, Ibaraki-shi, Osaka Nippon Denko Corporation (72) Inventor Mitsuru Konno 1-2-1-2 Shimohozumi, Ibaraki-shi, Osaka No. TOKYO DENKO CORPORATION (56) References Tetrahedron Let t. , 29 [50] (1988) 6565-6568 (58) Field surveyed (Int. Cl. ⁶ , DB name) C07D 313/00 CA (STN)

Claims (2)

(57) [Claims] 1. A method according to claim 1, wherein (3E, 8E) -4,8-dimethyl-10-hydroxy-3,8-decadienoic acid (formula 1) is dissolved in an aprotic solvent in diethyl azodicarboxylate (formula 2). ) In the presence of triphenylphosphine (formula 3), the reaction solution is concentrated, the residue is suspended in at least one low-boiling solvent, cooled to -40 ° C or lower, and then suspended. A method for producing a suspension (the following formula 4), comprising concentrating a filtrate obtained by filtering the liquid and distilling the obtained residue. 2. The method according to claim 1, wherein said reaction solution and / or said filtrate is kept at 0 ° C.
The method according to claim 1, wherein the concentration is performed under a temperature condition of ° C.