JPH02212482A - Production of suspensolide - Google Patents

Abstract

PURPOSE:To obtain the title compound of high purity in high yield by allowing a specific compound to react with triphenyl phosphine in the presence of diethyl azodicarboxylate in an aprotic solvent, then subjecting the reaction mixture to concentration, suspension, cooling, further filtration, concentration and distillation. CONSTITUTION:(3E,8E)-4,8-Dimethyl-10-hydroxy-3,8-decadienoic acid of formula I is allowed to react with triphenyl phosphine of formula III in an aprotic solvent, preferably benzene, in the presence of diethyl azodicarboxylate at room temperature. Then, the reaction mixture is concentrated with heat at 0 to 40 deg.C, the residue is suspended in a low boiling solvent, preferably a mixed solvent of n-pentane and diether, cooled down to -40 deg.C, the suspension is filtered, the filtrate is concentrated again at 0 to 40 deg.C and the residue is distilled, preferably under vacuum to give the subject compound of formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) This invention is applicable to Caribbean fruit flies (An, astrepha).
Regarding a method for producing suspensolide, which is a component of the sex pheromone released by males of the 5us-#ttrtsa Loam), the purpose is to be able to synthesize suspensolide extremely easily and with high purity and high yield; Moreover, the present invention provides a method for producing a suspenselide in which the starting materials are versatile and easily available, and the entire process is therefore suitable for industrial production.

(Background of the Invention) Fruit flies, which are insects belonging to the order Diptera and the family Fruitfly, are small and brightly colored, and most types have markings on their wings.

Adults live outdoors and gather on the leaves, fruits, and buds of plants, while larvae are pests that sneak into plants, including those that eat the mesophyll, those that sneak into the stems and buds of plants, and those that sneak into seeds. There are some that bite into fruits and nuts, and others that are parasitic on raw fruits, cucurbits, etc.

Among them, the Caribbean fruit fly (Anastrepha su
spgytsa Loe- is a pest that causes severe damage to fruits such as citrus fruits in the central and northern parts of the United States, and in Japan, this Caribbean fruit fly (Anas
In order to prevent the invasion and spread of tr-gph (1suspgnsa latw), the import of parasitic citrus fruits and the like is completely prohibited under the Customs Act.

(Prior art and its problems) Conventionally, this Caribbean fruit fly (Anastrepha 5
Insecticides have been used as a means to exterminate P. us-perlsa Loew, but there is a fear that they may remain on fruits such as citrus fruits.

Methods using various physiologically active substances have been studied as effective control methods in place of insecticides, and in recent years, methods using pheromones have been attracting attention.

Caribbean fruit fly (Anastrtpha suspgn)
sa Late), males emit pheromones to attract females.

Caribbean fruit fly (Anastrepha 5usptn)
sa Loew)'s 7 eromons are Suspense Ride (
The following formula 4), (3z)-3-/quin-1-ol (the following formula 5
), (32,62)-3,6-nonadien-1-ol (formula ○ below), anastrefin (formula 7 below), and evianastrefin (formula 8 below). ing.

--OHc formula 6) These Caribbean fruit flies (Anastrepha 5us
Among the pheromones of pensaLoaII+), suspendensolide (formula 4) has a very unique structure of an 11-membered ring lactone with two trans double bonds.
The synthesis was extremely difficult, and the isolation and purification methods were also extremely difficult due to the instability caused by the structure.

Report by Mori et al. (K, Mori, Y, Nakaxono,
Liebigs Ann.

Chem, 167, (198B)), the yield was only 9.1%, and the isolation and purification method involved separating the reaction solution using a silica gel column without pretreating the substrate. Since it requires a huge amount of silica gel, 500 to too many times the amount of silica gel, it is difficult to produce in large quantities, and therefore it is not suitable as an industrial production method.

Furthermore, as the suspension is adsorbed onto silica gel for a long period of time, the decomposition of the suspension occurs, and even if the column carrier is changed to a carrier such as Florisil, activated alumina, or basic alumina, decomposition of the suspension can be avoided. The purity was low.

In view of the above-mentioned circumstances, the industry believes that it is possible to synthesize suspensolide very easily, with high purity and high yield, and that the starting materials are versatile and easily available. It has been desired to create a method for producing suspensolide suitable for this method.

(Means for Solving the Problems) The method for producing a suspensolide according to the present invention mainly comprises (3B, 8B)-4,8-dimethyl-10-hydroxy-3°8-decadienoic acid (formula l below). , in an aprotic solvent, diethyl azodicarboxylate (formula 2
) in the presence of triphenylphosphine (formula 3 below), the reaction solution is concentrated, the residue is suspended in at least one low boiling point solvent, and after cooling to below -40°C, this suspension is A suspensolide (formula 4 below) characterized by concentrating the filtrate obtained by filtering the liquid and distilling the obtained residue
This manufacturing method solves all of the above problems.

In this invention, (32,8E)-4,8-dimethyl-10-hydroxy-3,8-decadienoic acid (formula l
) using a previously reported method (K, Mori et al.
,, Liebigs Ann.

The ring is closed by an intramolecular esterification method according to Che+a, 167, (1988)).

That is, (3B, 8B) -4,8-dimethyl-10
-Hydroxy-3,8-decadienoic acid (Formula 1) is reacted with triphenylphosphine (Formula 3 below) in the presence of diethyl azodicarboxylate (Formula 2 below) in an aprotic solvent.

Ph2 (Formula 3) Hereinafter, the structure of the method for producing suspensolide (Formula 4) according to the present invention will be described in detail.

(Structure of the Invention) P Ph3 (Formula 3) As the solvent used in this step, an aprotic solvent is preferably used.

As an aprotic solvent, (3E, 8E) -4,8
Any aprotic solvent that dissolves -dimethyl-10-hydroxy-3,8-decadienoic acid (formula 1), diethyl azodicarboxylate (formula 2), and triphenylphosphine (formula 3) is preferably used, Examples include tetrahydrofuran, benzene, chlorobenzene, dimethylformamide, toluene, carbon tetrachloride, chloroform, etc.
It is particularly desirable to use benzene.

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

Through this step, (38,8E)-4,8-dimethyl-10-hydroxy-3,8-decadienoic acid (Formula 1) passes through the reaction intermediate shown in the following Formula 10, and then suspendensolide (
Equation 4) This process is illustrated below.

Next, the reaction solution obtained through the above steps is concentrated,
The aprotic solvent is distilled off by means such as heating concentration, reduced pressure concentration, ventilation concentration, etc. to such an extent that the suspendolide (formula 4) is not decomposed.

In this invention, it is particularly desirable to concentrate the reaction solution under a temperature condition of 0°C to 40°C, preferably 20°C to 40°C, to further improve the purity and yield of suspendolide (Formula 4). becomes possible.

The reason for setting the temperature to 0°C to 40°C is that if it is less than 0°C, it will take a long time to concentrate, resulting in poor efficiency; if it exceeds 40°C, there is a risk that the suspendolide (Formula 4) produced by the reaction will decompose. However, the temperature is not necessarily limited to θ°C to 40°C, and may be determined as appropriate since it varies depending on various conditions during concentration.

Next, the residue obtained by concentrating the reaction system is suspended in at least one low boiling point solvent, cooled to below -40'C, and then this suspension is filtered.

In this invention, a low boiling point solvent is a solvent that does not solidify when cooled to -40'C or lower and is easily distilled off during the concentration of the filtrate described below, such as alkanes, alkenes, alkynes, ring rings. Examples include aprotic solvents such as formula hydrocarbons, aromatic hydrocarbons, organic halides, phenols, and ethers.

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

In this step, the reason why the suspension is cooled to below -40°C and then filtered is to remove the reaction product triphenylphosphine oxide (formula 9 below) and unreacted substances.
The reason for cooling to below -40°C is that when the temperature exceeds -40°C, triphenylphosphine oxide (Formula 9) dissolves in the low boiling point solvent and remains in the filtrate, and during the distillation described later, This is because it may be distilled out together with formula 4), resulting in a decrease in the purity of suspendolide (formula 4).

Ph5P=O (Formula 9) Furthermore, the filtrate obtained by filtering the suspension is concentrated to obtain a residue, but in this step as well, for the above-mentioned reasons, the temperature is 0°C to 40°C.
It is particularly desirable to concentrate under temperature conditions of 20°C to 40'C.

Finally, the residue obtained by concentration is distilled.

As a means of distilling the residue, distillation at normal pressure may be used, but
It is particularly preferable to distill under reduced pressure so that the suspendolide (Formula 4) does not decompose, and usually at a temperature of several mmHg to 10 mmHg.
The test is carried out under a vacuum of about +aHg.

Examples, reference examples, and comparative examples of the method for producing suspensolide (Formula 4) according to the present invention are shown below.

(Example 1) (3E, 8E) -4,8-dimethyl-10-hydroxy-3,8-decadienoic acid 11.2 g (52.8 m
mol) and triphenylphosphine 20.9g (79,
After dissolving 0m mol) in 1.85j' of dry benzene, 13.8g of diethyl azodicarboxylate (79°0m mol) was dissolved in 1.85j' of dry benzene.
mol) was added dropwise at room temperature, and the reaction solution was stirred overnight at room temperature.

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

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

After concentrating the filtrate again at a temperature of 30°C, the resulting residue was distilled under reduced pressure to obtain a distillate.

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

The measurement was performed using PEG 20M (polyethylene glycol,
Molecular weight approximately 20,000, length 25m1 inner diameter 012111fill
) using a column with a temperature of 150°C at 0°C per minute.
to 220° C., and helium was flowed at l/min as a carrier gas.

In addition, the absorption wave number of the infrared absorption spectrum of this distillate (
am-') is 2990 (W), 2950 (m),
2910(w), 2850(W), 1730(s)
, 1660 (m) , 1440 (m) , 1380 (W
), 1360(w), 1335(w), 1250
(m), 1230 (m), 1200 (m), 112
0(m) , 1110(m) , 101070(,10
1030(,970(w), 935(m)).

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

Furthermore, the δ value (ppm) of the proton nuclear magnetic resonance ('H-NMR) spectrum is 1.48 (3H, s), 1.52
(3H, s), 1.20-1.70 (2B, m), 1
．． 82 (4H, m), 2.67-2.88 (2H, m
), 4, 10-4.78 (2H, m), 4.80 (IH
,dt, J=1.0.8.0Hz), 5,03(IH
, t+J=8.0).

For measurement, the sample was dissolved in chloroform-d and the frequency was set to 4.
The measurement was performed using a proton nuclear magnetic resonance spectrum at 00 MHz.

The boiling point was 70 to 75°C at 0.5 mm) Ig.

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

The weight of this distillate is 3.08g, and the yield is 30%.
Met.

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

(Reference Example) A concentrated residue was obtained by processing in exactly the same manner as in Example 1, omitting the final step of vacuum distillation.

As a result of gas chromatographic analysis of this residue in the same manner as in Example 1, a peak of suspendolide was observed at a retention time of 3.020 minutes, and its purity was 86%.

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

(Examples 2 and 3 and Comparative Examples) Yield and performance of suspendolide obtained by processing in exactly the same manner as in Example 1, except that the temperature at which the suspension was cooled was changed as shown in Table 1 below. The purity of the suspendolide as determined by the same gas chromatographic analysis as in Example 1 is also listed in Table 1.

Table 1 (Examples 4 and 5) The yield and yield of suspendolide obtained by processing in exactly the same manner as in Example 1, except that the temperature at which the reaction solution and filtrate were concentrated was changed as shown in Table 2 below. The purity of the suspendolide as determined by the same gas chromatography analysis as in Example 1 is also listed in Table 2.

Table 2 (Effects of the Invention) As detailed above, the method for producing suspensolide according to the present invention mainly uses (3B, 8B)-4,8-dimethyl-10-hydroxy-3,8-decadienoic acid, After reacting with triphenylphosphine in the presence of diethyl azodicarboxylate in an aprotic solvent, the reaction solution was concentrated, the residue was suspended in at least one low boiling point solvent, and cooled to below -40°C. This suspension is then filtered, the resulting filtrate is concentrated, and the resulting residue is distilled.This method allows for the production of suspensolide very easily and in high yield. Furthermore, unlike conventional purification using column chromatography using adsorbents such as silica gel,
Production of suspensolide in which suspensolide can be isolated and purified in large quantities with a high purity of 92% or more, and in which the starting materials are versatile and easily available, and therefore the entire process is suitable for industrial production methods. It has the effect of being a method.

Furthermore, by concentrating the reaction solution and/or the filtrate under temperature conditions of 0° C. to 40° C., it is possible to produce a product with a high yield of about 30%, compared to the conventional yield of about 9%. .

[Brief explanation of the drawing]

Figures 1, 2, and 3 are the gas chromatogram, infrared absorption spectrum, and 4
10 shows a proton nuclear magnetic resonance spectrum diagram at 00 MHz.

Claims (2)

[Claims] (1) (3E,8E)-4,8-dimethyl-10-hydroxy-3,8-decadienoic acid (formula 1 below) was added to diethyl azodicarboxylate (formula 2 below) in an aprotic solvent.
) in the presence of triphenylphosphine (formula 3 below), the reaction solution is concentrated, the residue is suspended in at least one low boiling point solvent, and after cooling to below -40°C, this suspension is A suspensolide (formula 4 below) characterized by concentrating the filtrate obtained by filtering the liquid and distilling the obtained residue
manufacturing method. (2) The method for producing suspensolide (formula 4) according to claim (1), characterized in that the reaction solution and/or the filtrate are concentrated under a temperature condition of 0°C to 40°C. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Formula 1) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Formula 2) PPh_3 (Formula 3) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Formula 4)