KR102659019B1 - Synthesis method of sex pheromon cis-7,8-epoxy-2-methyloctadecane in Lymantria dispar - Google Patents

Abstract

The present invention relates to a method for synthesizing cis-7,8-epoxy-2-methyloctadecane, a sex pheromone of the gypsy moth, in particular using 3-butynol as a starting material and Ni(OAc) ₂ as a catalyst. This relates to a method for mass synthesizing cis-7,8-epoxy-2-methyloctadecane, a gypsy moth pheromone, through reduction and Grignard reactions. The synthesis method of the present invention includes (a) synthesizing tetradec-3-yn-1-ol from 3-butynol; (b) synthesizing cis-tetradec-3-en-1-ol by partial hydrogenation under Ni(oAc) ₂ catalyst; (c) synthesizing cis-2-methyloctadec-7-ene through Grignard reaction with isopentylmagnesium bromide; and (d) an epoxidation reaction to synthesize cis-7,8-epoxy-2-methyloctadecane. The present invention uses 3-butynol as a starting material and a catalytic reduction reaction and Grignard reaction using inexpensive Ni(OAc) ₂ instead of expensive Pd as a catalyst to produce cis-7,8-epoxy, a gypsy moth sex pheromone. -2-Methyloctadecane can be synthesized in large quantities. 7,8-Epoxy-2-methyloctadecane synthesized according to the present invention can be used as an attractant in traps using gypsy moth sex pheromone to more easily monitor the occurrence of gypsy moths outdoors, and based on this, it can be used in farms, etc. By distributing traps in large quantities, it is possible to control the pest gypsy moth in an environmentally friendly way that does not use chemical pesticides.

Description

Synthesis method of sex pheromon cis-7,8-epoxy-2-methyloctadecane in Lymantria dispar}

The present invention relates to a method for synthesizing cis-7,8-epoxy-2-methyloctadecane, a sex pheromone of the gypsy moth, and more specifically, using 3-butynol as a starting material and Ni(OAc) ₂ as a catalyst. This relates to a method for mass synthesizing cis-7,8-epoxy-2-methyloctadecane, a gypsy moth pheromone, using catalytic reduction reaction and Grignard reaction.

The gypsy moth ( Lymantria dispar , Gypsy moth) is a species belonging to the Lepidoptera family Mothidae and is the most damaging forest pest worldwide (Leonard, 1974). It is native to Asia and Europe, including Korea, but is also a pest that has been introduced into North America and causes great damage to oak trees (Pogue and Schaefer, 2007; GBIF Secretariat, 2019). There have been cases in Korea where large-scale outbreaks occurred and caused damage at a local level. In particular, in 2020, it occurred in large numbers in 19 types of fruit trees and trees in almost all regions except the Jeolla region, causing damage to 6,183 ha in 10 cities and provinces (Jung et al., 2020). In particular, the winter mortality rate of gypsy moths is decreasing due to abnormally high temperatures in winter, and the occurrence of gypsy moths is increasing.

Gypsy moths not only cause damage to forests, but also cause large numbers of larvae and moths to appear in urban parks near forests, causing damage to city residents by causing skin itching and disgust in humans. In addition, as the frequency of gypsy moths entering farmland around forests where gypsy moths occur increases, damage to crops such as fruit trees is expected. Therefore, predictive analysis and comprehensive control measures for provocative outbreaks of gypsy moth are urgently needed (Hwang et al., 2021).

The sex attractant pheromone of the gypsy moth is cis-7,8-epoxy-2-methyloctadecane {cis-7,8-epoxy-2-methyloctadecane; (±)-Disparlure}, and the optical isomer (+)-enantiomer {(+)-Enantiomer} or (-)-Disparlure{(-)-Disparlure} was found to be involved in sexual attraction. (Bierl et al. 1970, Iwaki 1974).

In particular, pheromones are a means of communication between species and are host-specific, so there is growing interest in technologies that use them to control pests in an ecologically friendly manner. Disparlure, a synthetic pheromone of the gypsy moth, has an excellent attraction effect and is therefore used for control purposes such as density monitoring (Tayler et al. 1991. Cater et al. 1994) and mating disturbance (Leonhardt et al. 1996). there is.

The known synthetic method for synthesizing cis-7,8-epoxy-2-methyloctadecane is as follows (Sheads et al. 1973).

First, 5-methyl 1-hexene is brominated and 1-dodecyne is converted into 1-bromo-5-methyl hexane. After coupling, it is reduced with a palladium (Pd) catalyst to synthesize Z-2-methyl-7-octadecene. Finally, epoxidation is performed to synthesize the target compound, cis-7,8-epoxy-2-methyloctadecane {(±)-disparure}. The core of this synthesis method is the process of reducing a triple bond to a (Z) double bond using a palladium (Pd) catalyst. The reaction of reducing a triple bond to a double bond by catalytic reduction generally involves trans isomerism. Therefore, there is a problem that it is not easy to make the production rate of the original (Z) isomer more than 90% and it is not easy to separate the two isomers by physical methods. In addition, there is a problem that palladium (Pd), which is used as a catalyst for (Z) selectivity, is expensive and the reproducibility of the reaction is poor.

Republic of Korea Patent Publication No. 10-2010-0135557 Republic of Korea Patent Publication No. 10-2022-0075797

Hwang, H.S, Lee, Y.S, Lee, H.A, Choi, D.S, Lee, K.Y, 2021. Natural Enemies of the Asian Gypsy Moth, Lymantria dispar asiatica (Lepidoptera: Erebidae) and the Genetic Variation Analysis of L. dispar Multiple Nucleopolyhedrovirus Korean J. Appl. Entomol. 60(4): 379-386 Jung, J.K., Nam, Y., Kim, D., Lee, S.H., Lim, J.H., Choi, W.I., Kim, E.S., 2020. Tree-crown defoliation caused by outbreak of forest insect pests in Korea during 2020. Korean J Appl. Entomol. 59, 409-410. Leonard, D.E., 1974. Recent developments in ecology and control of the gypsy moth. Annu. Rev. Entomol. 19, 197-229. Pogue, M.G., Schaefer, P.W., 2007. A Review of Selected Species of Lymantria Hubner [1819] Including Three New Species (Lepidoptera: Noctuidae: Lymantriinae). Department of Agriculture Forest Health Technology Enterprise Team, Washington, DC, US GBIF Secretariat, 2019. GBIF Backbone Taxonomy. Checklist dataset https://doi.org/10.15468/39omei accessed via GBIF. org (accessed on 4 Aug 2020). Bierl, B. A., M. Beroza, and C. W. Collier. 1970. Potent sex attractant of the gypsy moth: its isolation, identification, and synthesis. Science 170: 87-89. Iwaki, S., S. Marumo, T. Satio, M. Yamada, and K. katagiri. 1974. Synthesis and activity of optically active disparlure. J. Am. Chem. Soc. 96:1842-1844 Tylor, R.A. J., M.L. McManus, and C.W. Pitts. 1991. The absolute efficiency of gypsy moth, Lymantria dispar (Lepidoptera: Lymantriidae), milk-carton pheromone traps. Bulletin of Entomological Research 81: 111-118. Carter, M.R. F.W. Ravlin, and M.L. McManus. 1994. Estimating gypsy moth (Lepidoptera: Lymantriidae) egg mass density using male months captured in pheromone-baited, milk-carton trap. Environ. Entomol. 23:556-561 Leonharadt, B.A., V.C. Mastro, D.S Leonard, W. McLane, R.C. Reardon, and K.W Thorpe. 1996. Control of low-density gypsy moth (Leidoptera: Lymantriidae) populations by mating disruption with pheromone. J. Chem. Ecol. 22: 1255-1272. Sheads, R. E., and Morton Beroza. “Preparation of tritium-labeled disparlure, the sex attractant of the gypsy moth.” Journal of agricultural and food chemistry 21.5 (1973): 751-753.

In the present invention, 3-butynol is used as a starting material, and cis-7,8-epoxy, the sex pheromone of the gypsy moth, is produced through a catalytic reduction reaction and Grignard reaction using inexpensive Ni(OAc) ₂ instead of expensive Pd as a catalyst. The purpose is to provide a method for synthesizing -2-methyloctadecane in large quantities.

In order to achieve the above object, in the present invention,

(a) synthesizing tetradec-3-yn-1-ol by introducing a protecting group into the -OH group of 3-butynol, reacting it with 1-halodecane, and then removing the protecting group;

(b) synthesizing cis-tetradec-3-en-1-ol by partial hydrogenation of tetradec-3-yn-1-ol under a Ni(oAc) ₂ catalyst;

(c) synthesizing cis-2-methyloctadec-7-ene by tosylating the -OH group of cis-tetradec-3-en-1-ol and then subjecting it to Grignard reaction with isopentylmagnesium bromide; and

(d) cis-7, a sex pheromone of the gypsy moth, comprising the step of synthesizing cis-7,8-epoxy-2-methyloctadecane by epoxidizing cis-2-methyloctadec-7-ene, A method for synthesizing 8-epoxy-2-methyloctadecane is provided.

In the above synthesis method, step (a) is preferably performed by introducing a protecting group into the -OH group of 3-butynol, reacting it with 1-bromodecane, and then removing the protecting group to produce tetradec-3-yn-1-ol. synthesize. The protecting group is preferably -OTHP group.

In the above synthesis method, the step of removing the protecting group is preferably,

Dissolving 2-(tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran obtained by reaction with 1-bromodecane in methanol as a solvent;

Mixing 2-(tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran and p-toluenesulfonic acid dissolved in methanol and reacting with stirring for 3 to 6 hours at room temperature;

removing the solvent;

Extracting with an extraction solvent;

Washing and concentrating the extracted organic layer; and

and purifying the concentrated residue.

In the above synthesis method, step (b) is preferably,

Dissolving Ni(oAc) ₂ and NaBH ₄ in the solvent ethanol, respectively;

Mixing Ni(oAc) ₂ and NaBH ₄ dissolved in methanol with stirring;

Mixing ethylenediamine and tetradec-3-yn-1-ol in the mixture, injecting hydrogen and reacting with stirring at room temperature for 4 to 8 hours;

removing the solvent;

Extracting with an extraction solvent;

Washing and concentrating the extracted organic layer; and

and purifying the concentrated residue.

In the above synthesis method, step (c) is preferably,

Cis-tetradec-3-en-1-ol was reacted with p-toluenesulfonyl chloride to synthesize cis-tetradec-3-en-1-yl 4-methylbenzenesulfonate, and then reacted with isopentylmagnesium bromide. Cis-2-methyloctadec-7-ene is synthesized through Grignard reaction.

In the above synthesis method, step (d) is preferably,

Cis-2-methyloctadec-7-ene is reacted with mCPBA to synthesize cis-7,8-epoxy-2-methyloctadecane.

The step (d) is more preferably,

Reacting cis-2-methyloctadec-7-ene and methylene chloride with stirring for 8 to 15 minutes;

Next, adding mCPBA and methylene chloride at 0°C and reacting with stirring at room temperature for 4 to 8 hours;

Next, adding NaHCO ₃ (sodium bicarbonate) aqueous solution and stirring for 10 to 20 minutes;

Next, extraction with NaHCO ₃ aqueous solution added;

Washing and concentrating the extracted organic layer; and

and purifying the concentrate obtained by the concentration.

The present invention uses 3-butynol as a starting material and cis-7, the sex pheromone of the gypsy moth, through a catalytic reduction reaction and Grignard reaction using inexpensive Ni(OAc) ₂ as a catalyst instead of the expensive Pd used conventionally. , 8-Epoxy-2-methyloctadecane is synthesized in large quantities.

7,8-Epoxy-2-methyloctadecane synthesized according to the present invention can be used as an attractant in traps using the sex pheromone of the gypsy moth to more easily monitor the occurrence of gypsy moths outdoors, and based on this, farmers can more easily monitor the occurrence of gypsy moths in the field. By distributing traps in large quantities, it is possible to control the gypsy moth, a pest, in an environmentally friendly way that does not use chemical pesticides.

In the present invention, the method for synthesizing cis-7,8-epoxy-2-methyloctadecane, a sex pheromone of gypsy moth, includes steps (a) to (d) below.

(a) synthesizing tetradec-3-yn-1-ol by introducing a protecting group into the -OH group of 3-butynol, reacting it with 1-halodecane, and then removing the protecting group;

(b) synthesizing cis-tetradec-3-en-1-ol by partial hydrogenation of tetradec-3-yn-1-ol under a Ni(oAc) ₂ catalyst;

(c) synthesizing cis-2-methyloctadec-7-ene by tosylating the -OH group of cis-tetradec-3-en-1-ol and then subjecting it to Grignard reaction with isopentylmagnesium bromide; and

(d) Synthesizing cis-7,8-epoxy-2-methyloctadecane by epoxidizing cis-2-methyloctadec-7-ene.

Hereinafter, the present invention will be described in detail for each step.

1. Step (a): Synthesis of tetradec-3-yn-1-ol from 3-butynol

Tetradec-3-yn-1-ol is synthesized by introducing a protecting group to the -OH group of 3-butynol, reacting it with 1-halodecane, and then removing the protecting group. The 1-halodecane is preferably 1-bromodecane. As the protecting group, for example, -OTHP group can be introduced. A preferred example of this step is shown in Scheme 1 below.

[Scheme 1]

The specific synthesis process according to the preferred embodiment is as follows.

(1) Introduction of protecting group

First, in order to introduce a protecting group, 3-butynol, pyridinium p-toluenesulfonate, and 3,4-dihydro-2H-pyran ( 3,4-Dihydro-2H-pyran) is added and reacted to synthesize 2-(but-3-yn-1-yloxy)tetrahydro-2H-pyran.

3-Butynol is used by dissolving it in methylene chloride, a solvent. It is preferable to mix 3-butynol with methylene chloride as a solvent and stir for 8 to 15 minutes to dissolve 3-butynol in methylene chloride. It is more preferable to stir for 10 minutes.

When 3-butynol is completely dissolved in methylene chloride, mix pyridinium p-toluenesulfonate and 3,4-dihydro-2H-pyran while maintaining the temperature at 0°C and react while stirring at room temperature for 3 to 6 hours. I order it. It is more preferable to stir for 4 hours.

At this time, it is advisable to check the progress of the reaction using TLC (Thin-Layer Chromatography).

When the reaction is completed, the pressure is reduced and the solvent, methylene chloride, is removed. After removing the solvent, extraction is performed with an extraction solvent, the extracted organic layer is washed and concentrated, and the concentrated residue is purified to obtain 2-(but-3-yn-1-yloxy)tetrahydro-2H-pyran.

At this time, it is preferable to use EtoAc (Ethyl acetate)/H ₂ 0/NaHCO ₃ /NaCl as the extraction solvent, and the concentrated residue is preferably purified using a silica gel column (hexane/ether: 9/1). .

(2) Reaction with 1-bromodecane

2-(but-3-yn-1-yloxy)tetrahydro-2H-pyran, THF (Tetrahydrofuran), hexamethylphosphoramide, n-butyllithium (n- 2-(tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran is synthesized by reacting butyllithium) and 1-bromodecane.

First, 2-(but-3-yn-1-yloxy)tetrahydro-2H-pyran, THF, and hexamethylphosphoramide were mixed and reacted, and n-butyllithium was mixed and reacted, 1- Bromodecane is mixed and reacted to obtain 2-(tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran.

2-(but-3-yn-1-yloxy)tetrahydro-2H-pyran, THF and hexamethylphosphoramide are 2-(but-3-yn-1-yloxy)tetrahydro-2H-pyran THF is mixed first, then hexamethylphosphoramide is added and reacted with stirring for 8 to 15 minutes. It is more preferred to stir for about 10 minutes.

The reacted 2-(but-3-yn-1-yloxy)tetrahydro-2H-pyran, THF and hexamethylphosphoramide were mixed with n-butyllithium while maintaining the temperature at -40°C and incubated for 8 to 15 minutes. React while stirring. After reaction, the temperature is raised to 0°C and stirred for 25 to 40 minutes, then cooled to -40°C. It is more preferable to stir for 30 minutes.

After cooling again to -40°C, 1-bromodecane is mixed and reacted with stirring for 13 to 18 hours at room temperature. It is more preferable to stir for 15 hours.

At this time, it is advisable to check the progress of the reaction using TLC.

When the reaction is completed, an appropriate amount of water (H ₂ O) is slowly mixed. After mixing with water, extraction is performed with an extraction solvent, the extracted organic layer is washed and concentrated, and the concentrated residue is purified to obtain 2-(tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran. .

At this time, it is preferable to use EtoAc/H ₂ O/NaCl as the extraction solvent, and purify the concentrated residue using a silica gel column (hexane/ether: 20/1).

(3) Removal of protecting group

Tetradec-3-yn-1-ol is synthesized by reacting 2-(tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran obtained above with p-Toluenesulfonic acid. .

2-(Tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran is used by dissolving it in methanol, a solvent. Mix 2-(tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran with methanol as a solvent and stir for 8 to 15 minutes to dissolve 2-(tetradec-3-yn-1-yloxy) in methanol. si) It is desirable to dissolve tetrahydro-2H-pyran. It is more preferable to stir for 10 minutes.

When 2-(tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran is completely dissolved in methanol, p-toluenesulfonic acid is mixed and reacted with stirring at room temperature for 3 to 6 hours. It is more preferable to stir for 4 hours.

At this time, it is advisable to check the progress of the reaction using TLC.

When the reaction is completed, the pressure is reduced and the solvent, methanol, is removed. After removing the solvent, extraction is performed with an extraction solvent, the extracted organic layer is washed and concentrated, and the concentrated residue is purified to obtain tetradec-3-yn-1-ol.

It is preferable to use NaHCO ₃ when removing the solvent by reducing the pressure. It is preferable to use ether/H ₂ O/NaCl as an extraction solvent, and purify the concentrated residue using a silica gel column (hexane/EtOAC: 9/1).

2. Step (b): Synthesis of cis-tetradec-3-en-1-ol

Tetradec-3-yn-1-ol obtained above is subjected to partial hydrogenation under a Ni(oAc) ₂ catalyst to synthesize cis-tetradec-3-en-1-ol. A preferred example of this step is shown in Scheme 2 below.

[Scheme 2]

This step is preferably:

Dissolving Ni(oAc) ₂ and NaBH ₄ in the solvent ethanol, respectively;

Mixing Ni(oAc) ₂ and NaBH ₄ dissolved in methanol with stirring;

Mixing ethylenediamine and tetradec-3-yn-1-ol in the mixture, injecting hydrogen and reacting with stirring at room temperature for 4 to 8 hours;

removing the solvent;

Extracting with an extraction solvent;

Washing and concentrating the extracted organic layer; and

and purifying the concentrated residue.

A preferred embodiment will be described in detail.

First, Ni(oAc) ₂ and NaBH ₄ are mixed, and ethylenediamine and tetradec-3-yn-1-ol are mixed into this mixture and hydrogen is injected to react.

Ni(oAc) ₂ and NaBH ₄ are each used by dissolving in ethanol, a solvent. Mix Ni(oAc) ₂ and NaBH ₄ and stir for 4 to 8 minutes. It is more preferable to stir for 5 minutes.

Ethylenediamine and tetradec-3-yn-1-ol are mixed in this mixture, hydrogen is injected, and the mixture is stirred to react. It is preferable to stir at room temperature for 4 to 8 hours, and more preferably for 5 hours.

At this time, it is advisable to check the progress of the reaction using TLC.

When the reaction is completed, the solvent is removed by filtration. After removing the solvent, extraction is performed with an extraction solvent, the extracted organic layer is washed and concentrated, and the concentrated residue is purified to obtain cis-tetradec-3-en-1-ol.

It is preferable to use ether during filtration, ether/H ₂ O/NaCl as an extraction solvent, and purify the concentrated residue using a silica gel column (hexane/ether: 4/1).

3. Step (c): Synthesis of cis-2-methyloctadec-7-ene

The -OH group of cis-tetradec-3-en-1-ol obtained above is tosylated and subjected to Grignard reaction with isopentylmagnesium bromide to synthesize cis-2-methyloctadec-7-ene. A preferred example of this step is shown in Scheme 3 below.

[Scheme 3]

This step is preferably:

Cis-tetradec-3-en-1-ol was reacted with p-toluenesulfonyl chloride to synthesize cis-tetradec-3-en-1-yl 4-methylbenzenesulfonate, and then reacted with isopentylmagnesium bromide. Cis-2-methyloctadec-7-ene is synthesized through Grignard reaction.

A preferred embodiment will be described in detail.

Cis-tetradec-3-en-1-ol, pyridine, and p-toluensulfony chloride are reacted to produce cis-tetradec-3-en-1-yl 4-methylbenzenesulfo. Synthesize Nate.

Cis-tetradec-3-en-1-ol and pyridine are first mixed, then p-toluenesulfony chloride is added and reacted with stirring. It is preferable to stir at room temperature for 4 to 7 hours, and more preferably for 5 hours.

At this time, it is advisable to check the progress of the reaction using TLC.

When the reaction is completed, the solvent is removed after filtering with ether, extraction is performed with an extraction solvent, the extracted organic layer is washed and concentrated, and the concentrated residue is purified to produce cis-tetradec-3-en-1- 4-methylbenzenesulfonate is obtained. At this time, it is preferable to use ether/H ₂ O/Na ₂ SO ₄ as the extraction solvent, and it is preferable to purify using a silica gel column (hexane/EtOAC: 9/1).

Cis-tetradec-3-en-1-yl 4-methylbenzenesulfonate thus obtained is reacted with Grignard Reagent to synthesize cis-2-methyloctadec-7-ene.

Grignard reagent is synthesized by slowly adding a mixture of 1-bromo-3-methylbutane and THF to a mixture of Mg and I ₂ and heating and stirring until it boils and discolors.

The synthesized Grignard reagent is slowly added to cis-tetradec-3-en-1-yl 4-methylbenzenesulfonate and THF and reacted with stirring. At this time, it is preferable to carry out the reaction at a temperature of -10°C. It is preferable to stir for 8 to 15 minutes, and more preferably for 10 minutes.

After stirring, 0.1M Li ₂ CuCl ₄ was added and reacted with stirring. It is preferable to stir at room temperature for 2 to 5 hours, and more preferably for 3 hours.

At this time, it is advisable to check the progress of the reaction using TLC.

When the reaction is completed, NH ₄ Cl (ammonium chloride) aqueous solution is mixed until it turns blue, extracted with an extraction solvent, the extracted organic layer is washed and concentrated, and the concentrated residue is purified to produce cis-2-methylocta. Get Deck-7-N.

It is preferable to use ethyl ether/NH ₄ Cl/NaCl as an extraction solvent, and it is preferable to purify using a silica gel column (100% hexane).

4. Step (d): Synthesis of cis-7,8-epoxy-2-methyloctadecane (±)-Disparlure)

Cis-2-methyloctadec-7-ene obtained above is subjected to an epoxidation reaction to synthesize cis-7,8-epoxy-2-methyloctadecane. A preferred example of this step is shown in Scheme 4 below.

[Scheme 4]

This step is preferably:

Cis-2-methyloctadec-7-ene is reacted with mCPBA to synthesize cis-7,8-epoxy-2-methyloctadecane.

This step is more preferably:

Reacting cis-2-methyloctadec-7-ene and methylene chloride with stirring for 8 to 15 minutes;

Next, adding mCPBA and methylene chloride at 0°C and reacting with stirring at room temperature for 4 to 8 hours;

Next, adding NaHCO ₃ (sodium bicarbonate) aqueous solution and stirring for 10 to 20 minutes;

Next, extraction with NaHCO ₃ aqueous solution added;

Washing and concentrating the extracted organic layer; and

and purifying the concentrate obtained by the concentration.

A preferred embodiment of this step will be described in detail.

Cis-2-methyloctadec-7-ene, methylene chloride, and mCPBA (Meta-Chloroperoxybenzoic acid) are reacted to synthesize cis-7,8-epoxy-2-methyloctadecane.

First, cis-2-methyloctadec-7-ene and methylene chloride are reacted with stirring. It is preferable to stir for 8 to 15 minutes, and more preferably for 10 minutes.

After reaction, set the temperature to 0°C, add mCPBA and methylene chloride, and react with stirring at room temperature. It is preferable to stir for 4 to 8 hours, and more preferably for 6 hours.

At this time, it is advisable to check the progress of the reaction using TLC.

When the reaction is completed, NaHCO ₃ (sodium bicarbonate) aqueous solution is added and stirred for 10 to 20 minutes, extracted with the NaHCO ₃ aqueous solution added, the extracted organic layer is washed and concentrated, and the concentrated residue is purified and purified. -7,8-epoxy-2-methyloctadecane is obtained.

It is preferable to purify using a silica gel column (hexane/EtOAC: 20/1).

The present invention will be described in more detail through examples below. These examples illustrate the present invention and the scope of the present invention is not limited thereto.

[Example]

Reagents, Devices and Instruments

Nuclear magnetic resonance spectra were performed using an Avance Digital 500 MHz Spectrometer (Bruker, Ettlingen, Germany). For tube chromatography, silica gel 60 (Merck KGaA, Darmstadt, Germany) was used. Reagents were purchased from Sigma-Aldrich (Merck KGaA, Darmstadt, Germany) and Sejin-Ci (Tokyo chemical industry, Tokyo, Japan) and used without purification, and solvents were used without purification or after purification by distillation. Gas chromatographic analysis of the synthesized pheromone component was performed in an oven using YL 6500 GC (Youngin Chromass, Gyeonggi-do, Korea) and TG-5Ms (30m × 0.25mm I.D., 0.25㎛) (Thermo scientific, United States of America). The analysis was performed at a temperature of 125°C, a flow rate of 1.0 ㎖/min, and an injection sample volume of 1 ㎕.

<Example 1>

Cis-7,8-epoxy-2-methyloctadecane {(±)-Disparlure)} was synthesized as follows.

[Scheme 5]

Reagents and conditions:

(i) 1eq of 3-butynol, 0.0083eq of PPTs, 1.5eq of DHP, MC, rt, 4hr, 81%

(ii) 1.3eq of 1-bromodecane, 1.25eq of 1.6M BuLi, HMPA, THF, rt, 15hr, 61%

(iii) 0.1eq of PTSA, MeOH, NaHCO ₃ , rt, 2hr, 71.3%

(iv) 0.1667eq of NaBH4, 0.1667eq of Ni(oAc)2, 95%EtOH, 0.42eq of Ethylenediamine, rt, 5hr, 78%

(v) 1.5eq of P-toluensulfony chloride, Pyridine, rt, 5hr, 87%

(ⅵ) Grignard reagent - 5eq of 1-bromo-3-methylbutane, 7.5eq of Mg,, I _2, THF, 0.01eq of 0.1M Li ₂ CuCl ₄ , THF, rt, 3hr, 48%

(ⅶ) 1.22eq of MCPBA, MC, rt, 6hr, 38%

Each process (i) to (vii) will be described below.

(i) Synthesis of 2-(but-3-yn-1-yloxy)tetrahydro-2H-pyran

3-Butynol (10.74 g, 0.153 mol) was added to the flask, methylene chloride (107.4 ml) as a solvent was added, and the mixture was stirred for 10 minutes. While maintaining the temperature of the flask at 0°C, pyridinium p-toluenesulfonate (0.32 g, 0.001 mol) and 3,4-dihydro-2H-pyran (20.85 ml, 0.191 mol) were added and stirred at room temperature for 4 hours. and reacted.

The progress of the reaction was checked by TLC. After completion, the solvent was removed under reduced pressure, extracted with EtoAc/H ₂ 0/NaHCO ₃ /NaCl, the extracted organic layer was washed and concentrated, and the concentrated residue was purified on a silica gel column (hexane). /ether:4/1) to obtain 2-(but-3-yn-1-yloxy)tetrahydro-2H-pyran (Compound 2) (19.14 g, 81%).

The NMR analysis results of 2-(but-3-yn-1-yloxy)tetrahydro-2H-pyran (Compound 2) are as follows:

^1H NMR (CDCl ₃ , 500MHz) δ 4.65 (dd, J =4.2, 3.0Hz, 1H), 3.93-3.80 (m, 2H), 3.62-3.48 (m, 2H), 2.50 (td, J =7.0, 2.6Hz, 2H), 1.98 (d, J =5.3Hz, 1H), 1.89-1.78 (m, 1H), 1.77-1.67(m, 1H), 1.66-1.47(m, 4H) ; ¹³ C NMR (CDCl ₃ , 126 MHz) δ 98.79, 69.18, 65.53, 62.24, 30.55, 25.43, 19.96, 19.41

(ii) Synthesis of 2-(tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran

(But-3-yn-1-yloxy)tetrahydro-2H-pyran (Compound 2) (19.14 g, 0.124 mol) and THF (478.52 ml) were mixed in the flask, and HMPA (28.54 ml) was added. Stirred for 10 minutes. While maintaining the temperature of the flask at -40°C, 1.6M n-butyllithium (97 mL, 0.155 mol) was mixed and stirred for 10 minutes. The temperature of the stirred flask was maintained at 0°C and stirred for 30 minutes. After stirring, the mixture was cooled again to -40°C, 1-bromodecane (35.68 g, 0.161 mol) was added, and the reaction was stirred at room temperature for 15 hours.

The progress of the reaction was confirmed by TLC and the reaction was terminated. After the reaction was completed, an appropriate amount of H ₂ O was slowly added. After adding H ₂ O, extraction was performed with EtoAc/H ₂ O/H ₂ O/NaCl, the extracted organic layer was washed and concentrated, and the concentrated residue was purified using a silica gel column (hexane/ether: 20/1). 2-(Tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran (Compound 3) (18.52 g, 61%) was obtained.

The NMR analysis results of 2-(tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran (Compound 3) are as follows:

^1H NMR (CDCl ₃ , 500MHz) 4.65 (dd, J =4.2, 3.0Hz, 1H), 3.89 (ddd, J =11.2 8.2, 3.1Hz, 1H), 3.79 (dt, J =9.6, 7.2Hz, 1H) ), 3.57-3.47 (m, 2H), 2.46 (tt, J =7.3, 2.4Hz, 2H), 2.13 (tt, J = 7.1, 2.4Hz, 2H), 1.83 (dtt, J =13.2, 5.6, 2.6 Hz, 1H), 1.76-1.67(m, 1H), 1.64-1.58 (m, 2H), 1.58-1.54 (m, 1H), 1.54-1.49 (m, 2H), 1.49-1.42 (m, 2H), 1.37 (dd, J =10.7, 5.3 Hz, 1H), 1.35-1.24 (m, 13H), 0.88(t, J =7.0Hz, 3H) ; ¹³ C NMR (CDCl ₃ , 126MHz) δ 98.72, 81.41, 76.72, 66.27, 62.17, 31.92, 30.61, 29.59 (d, J =5.9Hz), 29.27 (d, J =17.7Hz), 28.95 (d, J = 19.3Hz), 25.48, 22.70, 20.26, 19.45, 18.77, 14.12

(iii) Synthesis of tetradec-3-yn-1-ol

2-(Tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran (Compound 3) (18.52 g, 0.062 mol) and methanol (277.5 ml) as a solvent were mixed in the equipped flask and incubated for 10 minutes at room temperature. After stirring for several minutes, p-toluenesulfonic acid (1.44 g, 0.007 mol) was mixed and stirred at room temperature for 2 hours.

The progress of the reaction was confirmed by TLC. After completion, NaHCO ₃ (16.66 g) was mixed and the solvent was removed under reduced pressure. Extracted with ether/H ₂ O/NaCl, washed and concentrated the extracted organic layer, and purified the concentrated residue with a silica gel column (hexane/EtOAC: 9/1) to produce tetradec-3-yn-1-ol ( Compound 4) (11.36 g, 71.3%) was obtained.

The NMR analysis results of tetradec-3-yn-1-ol (compound 4) are as follows:

^1H NMR (CDCl ₃ , 500MHz) δ 3.68 (t, J =6.2, 2H), 2.43 (tt, J =6.2, 2.4 Hz, 2H), 2.16 (tt, J =7.2, 2.4Hz, 2H), 1.53 -1.44 (m, 2H), 1.41-1.33(m, 2H), 1.33-1.23(m, 13H), 0.91-0.85 (m, 3H) ; ¹³ C NMR (CDCl ₃ , 126MHz) δ 82.84, 76.25, 61.40, 31.92, 29.69-29.25(m), 29.25-28.83(m), 23.22, 22.70, 18.75, 14.12

(iv) Synthesis of cis-tetradec-3-en-1-ol

Ethanol (50.4 ml) was added to dissolve Ni(oAc) ₂ (0.98 g, 0.004 mol) in a flask, and ethanol (5.04 ml) was added to NaBH ₄ (0.15 g, 0.004 mol) in another flask to dissolve them. The mixture was placed in a 2-neck flask and stirred for about 5 minutes. Ethylenediamine (0.67 mL, 0.011 mol) and tetradec-3-yn-1-ol (5.04 g, 0.024 mol) were added to the mixed 2-neck flask, then hydrogen (H ₂ ) was injected and incubated at room temperature for 5 hours. The reaction was carried out while stirring.

The progress of the reaction was confirmed by TLC, and after completion, it was filtered with ether using Celite545. After filtration, the solvent was removed, extracted with ether/H ₂ O/NaCl, the extracted organic layer was washed and concentrated, and the concentrated residue was purified using a silica gel column (hexane/ether:４/1) to obtain cis-tetra Dec-3-en-1-ol (Compound 5) (4g, 78%) was obtained.

The NMR analysis results of cis-tetradec-3-en-1-ol (compound 5) are as follows:

^1H NMR (CDCl ₃ , 500MHz) δ 5.61-5.51 (m, 1H), 5.41-5.31 (m, 1H), 3.64 (t, J =6.5, 2H), 2.37-2.29 (m, 2H), 2.06 ( qd, J =7.3, 1.6Hz, 2H), 1.38-1.29(m, 4H), 1.29-1.27(m, 4H), 1.27 (d, J =4.4Hz, 9H), 0.91-0.85 (m, 3H) ; ¹³ C NMR (CDCl ₃ , 126 MHz) δ 133.57, 124.94, 62.36, 31.93, 30.83, 29.81-29.26 (m), 27.40, 22.70, 14.12

(v) Synthesis of cis-tetradec-3-en-1-yl 4-methylbenzenesulfonate

Cis-Tetradec-3-en-1-ol (Compound 5) (4 g, 0.018 mol) and pyridine (24 ml) were mixed in the equipped flask, and p-toluenesulfonyl chloride (5.38 g, 0.028 mol) was added. did. The reaction was stirred at room temperature for 5 hours.

The progress of the reaction was checked by TLC, and when the reaction was completed, the pressure was reduced to remove the solvent. Extracted with ether/H ₂ O/Na ₂ SO ₄ , the extracted organic layer was washed and concentrated under reduced pressure, and the concentrated residue was purified using a silica gel column (hexane/EtOAC: 9/1) to produce cis-tetradec-3- En-1-yl 4-methylbenzenesulfonate (Compound 6) (6g, 87%) was obtained.

The NMR analysis results of cis-tetradec-3-en-1-yl 4-methylbenzenesulfonate (Compound 6) are as follows:

^1H NMR (CDCl ₃ , 500MHz) δ 7.82-7.76 (m, 2H), 7.37-7.31 (m, 2H), 5.52-5.43 (m, 1H), 5.26-5.17 (m, 1H), 4.00 (t, J =7.0H, 2H), 2.45 (s, 3H), 2.39 (qd, J =7.1, 1.5Hz, 2H), 1.95 (qd, J =7.2, 1.7Hz, 2H), 1.34-1.27(m, 3H) ), 1.25 (d, J =3.0Hz, 12H), 0.91-0.85 (m, 3H) ; ¹³ C NMR (CDCl ₃ , 126MHz) δ 144.65, 134.01, 133.30, 129.80, 127.95, 122.57, 69.81, 31.92, 29.72-29.19 (m), 27.32, 27.10, 22.69, 21 .63, 14.12

(vi) Synthesis of cis-2-methyloctadec-7-ene

Add Mg (6g, 1.151mol) and an appropriate amount of I ₂ to a 2-neck flask and place it on a heating stirrer. 1-Bromo-3-methylbutane (23.2g, 0.153mol) and THF (72ml) were added to the other flask. The mixture was mixed and slowly added to a flask equipped with a heating stirrer, heated and stirred until it boiled and discolored.

The Grignard reagent thus prepared was mixed with cis-tetradec-3-en-1-yl 4-methylbenzenesulfonate (compound 6) (6 g, 0.016 mol) and THF (42 ml), and the flask was maintained at -10°C. It was slowly added and stirred for 10 minutes. After stirring, 0.1M Li ₂ CuCl ₄ (1.98 g, 0.0001 mol) was mixed and reacted with stirring for 3 hours at room temperature.

The progress of the reaction was checked by TLC, and after the reaction was completed, NH ₄ Cl aqueous solution was added until it turned blue. Extracted with ethyl ether/NH ₄ Cl/NaCl, the extracted organic layer was washed and concentrated under reduced pressure, and the concentrated residue was purified using a silica gel column (hexane 100%) to produce cis-2-methyloctadec-7-ene (compound 7) (3.91g, 48%) was obtained.

The NMR analysis results of cis-2-methyloctadec-7-ene (compound 7) are as follows:

^1H NMR (CDCl ₃ , 500MHz) δ 5.35 (ddd, J =5.5, 4.4, 1.1 Hz, 2H), 2.06-1.98 (m, 4H), 1.51 (dqd, J =13.2, 6.6, 2.5 Hz, 2H) , 1.37-1.31 (m, 3H), 1.31-1.22 (m, 22H), 1.21-1.11 (m, 4H), 0.87 (ddd, J =6.6, 5.3, 1.5Hz, 16H) ; ¹³ C NMR (CDCl ₃ , 126MHz) δ 129.91 (d, J =5.8Hz), 39.12, 38.93, 31.60, 30.05, 29.89-29.50 (m), 29.35 (d, J =4.3Hz), 27.99, 27.69, 27.34 -27.01 (m), 22.79-22.56(m), 14.11

(vii) Synthesis of cis-7,8-epoxy-2-methyloctadecane {(±)-Disparlure)}

Methylene chloride (52 ml) was added to cis-2-methyloctadec-7-ene (Compound 7) (2 g, 0.007 mol) and stirred for 10 minutes. The temperature was set to 0°C, mCPBA (1.21 g, 0.009 mol) was added together with methylene chloride (31.4 ml), and the mixture was stirred at room temperature for 6 hours to react.

The progress of the reaction was confirmed by TLC, and after the reaction was completed, NaHCO ₃ aqueous solution was added, stirred for 10 to 20 minutes, and extracted as NaHCO ₃ was added. After extraction, the extracted organic layer was washed and concentrated under reduced pressure, and the concentrated residue was purified using a silica gel column (hexane/EtOAC: 20/1) to produce cis-7,8-epoxy-2-methyloctadecane {(±)- Disparlure)} (Compound 1) (0.4g, 38%) was obtained.

The NMR analysis results of cis-7,8-epoxy-2-methyloctadecane are as follows:

¹ H NMR (CDCl ₃ , 500MHz) δ 2.91 (td, J =4.6, 3.0Hz, 2H), 1.59-1.46 (m, 7H), 1.46 -1.37 (m, 3H), 1.36(d, J =7.8Hz) , 3H) 1.32-1.25 (m, 12H), 1.19 (dt, J =10.7, 7.1 Hz, 2H), 0.88 (t, J =6.9Hz, 10H), ; ¹³ C NMR (CDCl ₃ , 126MHz) δ 57.25 (d, J =1.6Hz), 38.93, 31.92, 29.71-29.27 (m), 28.01-27.69 (m), 27.34, 26.88, 26.62, 22.78-22.54 (m) , 14.12

Claims (8)

(a) synthesizing tetradec-3-yn-1-ol by introducing a protecting group into the -OH group of 3-butynol, reacting it with 1-halodecane, and then removing the protecting group;
(b) synthesizing cis-tetradec-3-en-1-ol by partially hydrogenating tetradec-3-yn-1-ol under a Ni(oAc) ₂ catalyst;
(c) synthesizing cis-2-methyloctadec-7-ene by tosylating the -OH group of cis-tetradec-3-en-1-ol and then subjecting it to Grignard reaction with isopentylmagnesium bromide; and
(d) cis-7, a sex pheromone of the gypsy moth, comprising the step of synthesizing cis-7,8-epoxy-2-methyloctadecane by epoxidizing cis-2-methyloctadec-7-ene, Method for synthesizing 8-epoxy-2-methyloctadecane. According to paragraph 1,
The step (a) is characterized in that tetradec-3-yn-1-ol is synthesized by introducing a protecting group into the -OH group of 3-butynol, reacting it with 1-bromodecane, and then removing the protecting group. Method for synthesizing cis-7,8-epoxy-2-methyloctadecane, the sex pheromone of the gypsy moth. According to paragraph 1,
Step (a) is characterized in that tetradec-3-yn-1-ol is synthesized by introducing -OTHP group as a protecting group to the -OH group of 3-butynol, reacting with 1-bromodecane, and then removing the protecting group. A method of synthesizing cis-7,8-epoxy-2-methyloctadecane, a gypsy moth sex pheromone. According to paragraph 3,
The process of removing the protecting group is,
Dissolving 2-(tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran obtained by reaction with 1-bromodecane in methanol as a solvent;
Mixing 2-(tetradec-3-yn-1-yloxy)tetrahydro-2H-pyran and p-toluenesulfonic acid dissolved in methanol and reacting with stirring for 3 to 6 hours at room temperature;
removing the solvent;
Extracting with an extraction solvent;
Washing and concentrating the extracted organic layer; and
A method for synthesizing cis-7,8-epoxy-2-methyloctadecane, a sex pheromone of gypsy moth, comprising the step of purifying the concentrated residue. According to paragraph 1,
In step (b),
Dissolving Ni(oAc) ₂ and NaBH ₄ in the solvent ethanol, respectively;
Mixing Ni(oAc) ₂ and NaBH ₄ dissolved in ethanol while stirring;
Mixing ethylenediamine and tetradec-3-yn-1-ol in the mixture, injecting hydrogen and reacting with stirring at room temperature for 4 to 8 hours;
removing the solvent;
Extracting with an extraction solvent;
Washing and concentrating the extracted organic layer; and
A method for synthesizing cis-7,8-epoxy-2-methyloctadecane, a sex pheromone of gypsy moth, comprising the step of purifying the concentrated residue. According to paragraph 1,
In step (c), cis-tetradec-3-en-1-ol is reacted with p-toluenesulfonyl chloride to synthesize cis-tetradec-3-en-1-yl 4-methylbenzenesulfonate. Afterwards, cis-2-methyloctadec-7-ene is synthesized through Grignard reaction with isopentylmagnesium bromide. Cis-7,8-epoxy-2-methyloctadecane, a sex pheromone of the gypsy moth, is Synthesis method. According to paragraph 1,
The step (d) is a sex pheromone of the gypsy moth, characterized in that cis-7,8-epoxy-2-methyloctadecane is synthesized by reacting cis-2-methyloctadec-7-ene with mCPBA. Method for synthesizing cis-7,8-epoxy-2-methyloctadecane. According to paragraph 1,
In step (d),
Reacting cis-2-methyloctadec-7-ene and methylene chloride with stirring for 8 to 15 minutes;
Next, adding mCPBA and methylene chloride at 0°C and reacting with stirring at room temperature for 4 to 8 hours;
Next, adding NaHCO ₃ (sodium bicarbonate) aqueous solution and stirring for 10 to 20 minutes;
Next, extraction with NaHCO ₃ aqueous solution added;
Washing and concentrating the extracted organic layer; and
A method for synthesizing cis-7,8-epoxy-2-methyloctadecane, a sex pheromone of gypsy moth, comprising the step of purifying the concentrate obtained by the concentration.