A sustained-release pheromone preparation for Migdorus phryanus and a method for controlling it using the same.

Abstract

This invention relates to Migdolus flyanus, which uses industrially synthesizable 2-methyl-N-(2'-methylbutyl)butanamide. Almonds fryan The objective is to provide a sustained-release pheromone formulation targeting ) and a control method using the same. [Solution] The present invention provides a sustained-release pheromone formulation targeting Migdorus huryanus, comprising at least an isomer mixture (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide and a biodegradable polymer container for storing the isomer mixture. The present invention also provides a method for controlling Migdorus huryanus, comprising at least the step of installing the sustained-release pheromone formulation in a field at an installation density of 1 to 50,000 units / ha and releasing the isomer mixture in the sustained-release pheromone formulation into the field at an release rate of 0.05 g to 3 g / day / ha.

Description

Technical Field

[0001] The present invention relates to a sustained-release pheromone preparation of Migdolus fryanus( Migdolus fryanus ) and a control method using the same.

Background Art

[0002] Migdolus fryanus( Migdolus fryanus ; hereinafter also referred to as "MFLB"), a kind of longhorn beetle belonging to the family Cerambycidae of the order Coleoptera, is distributed mainly in South America and is a very serious pest economically because it causes great damage to sugarcane.

[0003] The larvae of this species damage the underground part of sugarcane, and the adults also live in the soil except during mating behavior. Therefore, the control effect by conventional insecticide spraying is not sufficient. In addition, due to the residue of insecticides on crops caused by the use of insecticides and / or the impact on the environment or health, the development of new control technologies such as the mating disruption method using sex pheromone substances and the mass trapping method is required.

[0004] The sex pheromone of MFLB was identified by Leal et al. as 2-methyl-N-(2’-methylbutyl)butanamide (the naming of the compound will be described later) (Non-Patent Document 1). From the analysis results of chiral-phase GC (Chiral phase gas chromatography) of a mixture of two types of diastereomers of the natural product and the synthetic product, the absolute configuration of the asymmetric carbon atom (position 2; the position number will be described later) on the acid moiety side was determined to be S. Although the absolute configuration of the asymmetric carbon atom (position 2’) on the amine residue side could not be analytically proven, it was predicted to be S based on biosynthetic reasoning, and the natural product was identified (presumed) as the (2S,2’S)-isomer. In addition, in the field attraction test, both the (2S,2’R / S)-isomer, which is a synthetic product, and the (2S,2’S)-isomer, which is a natural product, showed attraction activity (Non-Patent Document 1 and Patent Document 1).

[0005] As synthetic examples of the sex pheromone of MFLB, the synthesis of four possible diastereomers by Santangelo et al. (Non-Patent Document 2) and the synthesis by A.E.G. Santana et al. (Patent Document 2) have been reported.

[0006] Here, in the above prior art documents, even when the same compound is shown, the nomenclature and the method of assigning position numbers are different. Therefore, the nomenclature and position numbers used in the present application will be explained in advance.

[0007] The following formula (1)

Chemical formula

[0008] [ka] (In the formula, a wedged bond represents absolute configuration.) [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] International Publication No. 96 / 19919 [Patent Document 2] Brazilian Patent Application Publication No. 102017000486 Specification [Non-patent literature]

[0010] [Non-Patent Document 1] WSLeal et al., Experientia, 50, 853 (1994) [Non-Patent Document 2] EMSantangelo et al., Synthetic Communications, 31, 3685 (2001) [Overview of the project] [Problems that the invention aims to solve]

[0011] Until now, the vast majority of insects targeted for the development of mating disruptors have been moths of the order Lepidoptera, with only a few known examples in scale insects of the order Hemiptera and beetles. Sex pheromones in moths are mainly alcohols, acetate esters, aldehydes, and hydrocarbons, and even including other taxonomic groups, there are no examples of amide compounds like MFLB's sex pheromones being commonly used as mating disruptors.

[0012] Generally, sustained-release pheromone preparations, especially mating disruptors, are required to continuously release a constant amount of the active ingredient throughout the period when adult insects of the target species emerge. Common containers for pheromone preparations include tubes and aerosol cans. While it is presumed that a method of filling MFLB pheromone material into aerosol cans or automatic sprayers and periodically spraying the MFLB pheromone material into the field is applicable, the use of aerosol cans and automatic sprayers presents significant hurdles for users due to their high cost, the limited number of installation points raising concerns about a substantial decrease in pheromone concentration in the field due to malfunctions, and the potential for theft due to the conspicuous nature of mechanical devices.

[0013] Therefore, the present inventors attempted to provide a sustained-release pheromone formulation using a polymer container, such as a tubular container, which is inexpensive and allows for relatively easy control of pheromone concentration in the field.

[0014] However, when tests were conducted using formulations containing 2-methyl-N-(2'-methylbutyl)butanamide in containers made of high-density polyethylene (HDPE) and ethylene-vinyl acetate copolymer (EVA), which have been used as containers for conventional sustained-release pheromone formulations, it was found that 2-methyl-N-(2'-methylbutyl)butanamide was hardly released and did not function as a communication disruptor (see Comparative Examples 1 and 2 of this specification). Furthermore, although the occurrence period of MFLB is said to be less than two weeks, the timing of occurrence varies considerably depending on temperature changes, so in reality, a release period of 3 to 4 months is required. One reason why there have been no examples of communication disruption using the above amide compounds is thought to be that it has been difficult to sustainably release the pheromone substance within the desired period in a formulation that can actually be applied in the field.

[0015] Furthermore, when applying sex pheromone substances with isomers to pest forecasting and / or control technologies such as communication disruption, non-natural isomers can significantly reduce the attractive activity and / or communication disruption effect of the pheromone. Regarding MFLB sex pheromone substances, it has been shown that both the natural (2S,2'S)-isomer and the synthetic (2S,2'R / S)-isomer exhibit attractive activity (Non-Patent Literature 1 and Patent Literature 1), but there is no information on the biological activity of other isomers.

[0016] Furthermore, for MFLB control methods using sex pheromone substances to become widespread, it is important that pheromone preparations are priced to be acceptable to the market. Since selectively synthesizing a single stereoisomer with biological activity is economically costly, if a mixture of isomers that can be synthesized more cheaply can be expected to have an attractive or mating disruptive effect, then using such a mixture would be more economical.

[0017] The present invention has been made in view of the above circumstances, and aims to provide a sustained-release pheromone formulation targeting MFLB using 2-methyl-N-(2'-methylbutyl)butanamide and a control method using the same. [Means for solving the problem]

[0018] The inventors of the present invention conducted diligent research to solve the above problems and found that by filling a biodegradable resin tube with (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide, an isomer mixture of MFLB sex pheromone substances, and installing it in the field, a release period necessary and sufficient for controlling MFLB can be obtained, and that even an isomer mixture of sex pheromone substances can be observed to have a communication disruption effect on MFLB, leading to the present invention.

[0019] According to one aspect of the present invention, a sustained-release pheromone formulation targeting MFLB is provided, comprising at least an isomer mixture (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide and a biodegradable polymer container for housing the isomer mixture. Furthermore, according to one aspect of the present invention, there is a sustained-release pheromone formulation targeting Migdolus fryanus, comprising at least an isomer mixture (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide and a biodegradable polymer container for housing the isomer mixture, wherein the biodegradable polymer is an aliphatic polyester.

[0020] Furthermore, in another aspect of the present invention, a method for controlling MFLB is provided, which includes at least the step of installing the sustained-release pheromone preparation in a field at a density of 1 to 50,000 units / ha and releasing the isomer mixture in the sustained-release pheromone preparation into the field at a release rate of 0.05 g to 3 g / day / ha. [Effects of the Invention]

[0021] According to the present invention, a sustained-release pheromone formulation according to the present invention provides a release period that is necessary and sufficient for controlling MFLBs, and even a mixture of isomers of sex pheromone substances can exert a communication disruption effect on MFLBs. [Brief explanation of the drawing]

[0022]

Figure 1

Figure 2

[0023] The embodiments of the present invention will be described in detail below, but the present invention is not limited to these embodiments.

[0024] This paper describes a sustained-release pheromone formulation of MFLB using the isomer mixture (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide, and a method for producing the same.

[0025] <Sustained-release pheromone preparation using (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide, an isomer mixture> A sustained-release pheromone preparation according to the present invention comprises at least an isomer mixture (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide (hereinafter also referred to as "MFLB pheromone substance") and a biodegradable polymer container for housing the isomer mixture. The sustained-release pheromone preparation encompasses embodiments as an attractant and a mating disruptor.

[0026] The isomer mixture (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide is represented by the following formula (1). The (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide (1) contains four stereoisomers, as shown below: (2R,2'R)-2-methyl-N-(2'-methylbutyl)butanamide represented by the following formula (2R,2'R)-(1); (2R,2'S)-2-methyl-N-(2'-methylbutyl)butanamide represented by the following formula (2R,2'S)-(1); (2S,2'R)-2-methyl-N-(2'-methylbutyl)butanamide represented by the following formula (2S,2'R); and (2S,2'S)-2-methyl-N-(2'-methylbutyl)butanamide represented by the following formula (2S,2'S).

[0027] [ka]

[0028] The isomer mixture (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide may be synthesized, for example, according to the preparation examples described in this specification, or according to other preparation methods.

[0029] In a mixture containing isomers of (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide, the relative abundance of the four isomers can vary depending on the conditions of the synthesis reaction and the post-synthesis treatment. Specifically, the ratio of (2R,2'R)-2-methyl-N-(2'-methylbutyl)butanamide:(2R,2'S)-2-methyl-N-(2'-methylbutyl)butanamide:(2S,2'R)-2-methyl-N-(2'-methylbutyl)butanamide:(2S,2'S)-2-methyl-N-(2'-methylbutyl)butanamide may vary within the range of 23-27:23-27:23-27:23-27, but is not limited to these values.

[0030] A mixture containing isomers of (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide may contain impurities other than (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide that are unavoidable during production. These unavoidable impurities include, for example, the starting materials used in the synthesis reaction, the catalyst, and by-products generated by the synthesis reaction (including, for example, decomposition products).

[0031] Furthermore, the sustained-release pheromone formulation according to the present invention may contain additives such as antioxidants, ultraviolet absorbers, diluents, and polymerization inhibitors.

[0032] Examples of antioxidants include 2,6-di-tert-butyl-4-methylphenol, butylhydroxytoluene, butylhydroxyanisol, hydroquinone, and vitamin E.

[0033] Examples of the UV absorber include 2-(2'-hydroxy-3'-tert-butyl-5'-methylphenyl)-5-chlorobenzotriazole, 2-hydroxy-4-octoxybenzophenone, 2-(3,5-di-t-butyl-2-hydroxyphenyl)-5-chlorobenzotriazole, and 2,5'-di-tert-butylhydroquinone.

[0034] Examples of the diluent include dodecyl acetate, tetradecyl acetate, hexadecylate, 1-dodecanol, 1-tetradecanol, and 1-hexadecanol.

[0035] Examples of polymerization inhibitors include 2,2'-methylenebis(4-methyl-6-t-butylphenol).

[0036] The amount of each additive added varies depending on the usage environment of the sustained-release pheromone preparation, but is preferably 0.1 to 5.0 parts by mass per 100 parts by mass of the pheromone substance in the MFLB.

[0037] Each additive may be used in combination of two or more types.

[0038] Furthermore, commercially available additives can be used for each of these components.

[0039] The container for the sustained-release pheromone preparation is not particularly limited as long as it is made of a biodegradable polymer and is capable of housing the pheromone substance of the MFLB in a manner that allows it to release.

[0040] The biodegradable polymer is not particularly limited as long as it can permeate the pheromone substance of MFLB, and from the viewpoint of grade diversity, price, moldability and / or mechanical strength, it is preferable to use aliphatic polyester, aromatically modified aliphatic polyester, or a combination thereof (blended polymer). The blended polymer may be a combination of two or more aliphatic polyesters, or a combination of two or more aromatically modified aliphatic polyesters.

[0041] Examples of aliphatic polyesters include polybutylene succinate, polybutylene malonate, butylene adipate, polybutylene pentanoate, polybutylene octanoate, polybutylene butenoate, polycaprolactone, and copolymers of aliphatic polyesters such as polyethylene succinate adipate, polypropylene succinate adipate, and polybutylene succinate adipate. From the viewpoint of the plasticity of the molded product, polybutylene succinate and polybutylene succinate adipate are preferred. In addition, the similar physical properties of the two polymers are another reason for this preference.

[0042] Examples of the aromatically modified aliphatic polyester include copolymers of aromatically modified aliphatic polyesters such as polybutylene terephthalate and polybutylene succinate terephthalate.

[0043] The blended polymer is preferably a combination of polybutylene succinate and polycaprolactone, or a combination of polybutylene adipate and polycaprolactone, and its mass ratio (polybutylene succinate or polybutylene adipate:polycaprolactone) is preferably less than 100:greater than 0 to 45:55, more preferably 95:5 to 45:55, and even more preferably 90:10 to 70:30. The blended polymer may also be a combination of polybutylene terephthalate and polybutylene succinate terephthalate, or a combination of polybutylene succinate and polybutylene terephthalate.

[0044] The above-mentioned biodegradable polymer may contain antioxidants and / or ultraviolet absorbers to prevent degradation.

[0045] Examples of antioxidants include phenol-based antioxidants such as ethylenebis(oxyethylene)bis(3-(5-tert-butyl-4-hydroxy-m-tolyl)propionate and octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate; sulfur-based antioxidants such as didodecyl 3,3'-thiodipropionate; and phosphorus-based antioxidants such as tris(2,4-di-tert-butylphenyl)phosphi.

[0046] Examples of UV absorbers include benzotriazol-based UV absorbers such as 2-(2'-hydroxy-3'-tert-butyl-5'-methylphenyl)-5-chlorobenzotriazol, and benzophenone-based UV absorbers such as 2-hydroxy-4-octoxybenzophenone.

[0047] The amount of each of the antioxidant and the ultraviolet absorber added is preferably more than 0 parts by mass and up to 3 parts by mass per 100 parts by mass of the biodegradable polymer.

[0048] Each additive may be used in combination of two or more types.

[0049] Furthermore, commercially available additives can be used for each of these components.

[0050] To prevent degradation of the pheromone substance of MFLB from ultraviolet light, the above biodegradable polymer may contain colorants such as inorganic and organic colorants.

[0051] Examples of inorganic colorants include iron oxide, chromium oxide, titanium oxide, and carbon black.

[0052] Examples of organic colorants include polycyclic pigments such as quinacridone red, phthalocyanine blue, and phthalocyanine green; and azo pigments such as monoazo yellow and disazo orange.

[0053] The amount of colorant added is preferably more than 0 parts by weight and up to 3 parts by weight, and more preferably more than 0 parts by weight and up to 1 part by weight, based on 100 parts by weight of the biodegradable polymer, from the viewpoint of solvent resistance and / or light resistance.

[0054] From the viewpoint of improving processability, an anti-blocking agent and / or a lubricant may be added to the above biodegradable polymer.

[0055] Examples of blocking inhibitors include metal salts of higher fatty acids such as calcium stearate, barium stearate, stearic acid, zinc stearate, and magnesium stearate; and inorganic powders such as silica, talc, and diatomaceous earth.

[0056] Examples of lubricants include hydrocarbons such as liquid paraffin; alcohols such as stearyl alcohol; higher fatty acids such as stearic acid, behenic acid, and 12-hydroxystearic acid; esters such as glycerin monostearate, glycerin monooleate, and butyl stearate; polyhydric alcohol partial esters such as triethylene glycol; natural waxes such as paraffin; fatty acid amides such as stearamide, oleamide, erucamide, methylenebisstearate, and ethylenebisstearate; and polymers such as polyethylene.

[0057] From the viewpoint of compatibility with the biodegradable polymer and / or weather resistance, the amount of each of the blocking inhibitor and lubricant added is preferably more than 0 parts by mass and up to 30 parts by mass per 100 parts by mass of the biodegradable polymer.

[0058] Furthermore, the above-mentioned biodegradable polymer may be a commercially available product or a synthesized one.

[0059] The container for the sustained-release pheromone preparation is not particularly limited as long as it can stably hold the pheromone substance of the MFLB and allow the pheromone substance of the MFLB to be released into the atmosphere, but examples include caps, tubes, laminated bags, capsules, beads, bottles, and ampoules. The container may be permeable to the pheromone substance of the MFLB in at least a part or all of it.

[0060] From the viewpoint of uniformity in the release of pheromone substances in MFLBs, a sustained-release pheromone preparation in a tubular container is preferred as a communication disruptor, with an inner diameter of preferably 0.5 to 2.5 mm and a surface area of ​​preferably 600 to 4000 mm². 2 The film thickness is preferably 0.3 to 0.8 mm, and the length is preferably 0.01 to 100 m, more preferably 0.02 to 20 m, and even more preferably 0.2 to 10 m.

[0061] For sustained-release pheromone preparations that use containers other than tubular containers, the film thickness is preferably 0.01 to 0.1 mm, from the viewpoint that increased film thickness leads to increased rigidity and thus poorer handling.

[0062] Regarding the amount of pheromone substance loaded onto the MFLB in the sustained-release pheromone preparation, there are no particular limitations on the attractant as long as it exhibits attractant activity, but it is preferably in the range of 10 μg to 100 mg. Regarding the communication disruptor, there are no particular limitations as long as an airborne pheromone concentration is ensured in the field that prevents males from distinguishing female pheromones, but it is preferably 10 mg or more per sustained-release pheromone preparation.

[0063] One method for controlling MFLB is to use the above-mentioned sustained-release pheromone preparation containing MFLB pheromone substances as an attractant and / or mating disruptor. When used as an attractant, for example, it can be used as a material for outbreak forecasting or mass trapping, which includes setting it in insect traps such as delta, wing, bucket, funnel, pitfall, funnel-type, and sticky traps and installing them in the field to attract and kill adult insects.

[0064] When used as a mating disruption agent, a control method is suggested that includes at least the step of installing the above-mentioned sustained-release pheromone preparation in the field at a density of 1 to 50,000 units / ha and releasing the pheromone substance from the preparation into the field at a rate of 0.05 g to 3 g / day / ha. This release makes it possible to disrupt mating. The installation location of the sustained-release pheromone preparation may be off the ground, but since adult MFLBs live in the soil except during mating behavior, the soil surface is preferred.

[0065] The number of mating disruptors installed in the field varies depending on their shape, but preferably 1 to 50,000 per hectare, more preferably 2 to 10,000 per hectare, and even more preferably 50 to 3,000 per hectare, and they are used to control pests by disrupting the mating behavior of male and female adult insects.

[0066] The release period of the pheromone substance is preferably set according to the emergence period of adult MFLBs and the range of its annual variation. The emergence period of adult MFLBs is approximately two weeks, but the rate of larval growth is affected by temperature, so it is known that there can be a difference of 3 to 4 months from year to year. Therefore, in one embodiment of the present invention, it is preferable to use a sustained-release pheromone formulation that has a release period of 3 to 4 months on the soil surface, and it is even preferable to use a sustained-release pheromone formulation that has a longer release period of 5 to 6 months.

[0067] As a guideline for the release period, a sustained-release pheromone preparation that maintains a release amount of 0.5 mg / day / unit or more 70 to 80 days after installation is preferred. [Examples]

[0068] The present invention will be described in more detail below with reference to preparation examples and embodiments, but the present invention is not limited thereto. The purity of the raw materials, products, and intermediates will be expressed as %GC, using values ​​obtained by gas chromatography (GC) analysis. The isomer ratio of the products and intermediates will be expressed using the area ratio obtained from GC analysis. GC conditions: GC: Simadzu GC-2025, Column: 5%Ph-Me silicone 25mx0.25mmφx0.25μm, Carrier gas: He, Detector: FID. The yield is the converted yield value based on %GC. Since the starting materials used in the reaction and the product obtained from the reaction are not necessarily 100% pure, the converted yield (%) is calculated as follows: Converted yield (%) = [(Weight of product obtained from the reaction × %GC) / Molecular weight of product] ÷ [(Weight of starting materials in the reaction × %GC) / Molecular weight of starting materials] × 100. Note that the detection sensitivity of gas chromatography differs depending on the compound, so the converted yield may exceed 100%, especially when the starting materials or product are crude products. For spectral analysis of the compounds, the crude product was purified as needed.

[0069] <(2S,2'S)-2-methyl-N-(2'-methylbutyl)butanamide: Synthesis of (2S,2'S)-(1)> [ka] (In the formula, Ph represents a phenyl group. The same applies below.)

[0070] Preparation Example 1: Synthesis of (2S,αR)-2-methylbutyl-α-phenylethylamine:(2S,αR)-(2a) [when Ar=Ph=phenyl group in general formula (2)] [ka]

[0071] Under a nitrogen atmosphere, a mixture of 52.8 g of (S)-2-methylbutyl=p-toluenesulfonate, synthesized from (S)-2-methylbutanol (99.1% S, 98.2% ee) by a conventional method, and 70.6 g of (R)-α-phenylethylamine (~100% ee) was stirred at 90-100°C for 17 hours. The cooled reaction mixture was diluted with 100 ml of tert-butyl=methyl=ether, then poured into a 5% sodium hydroxide aqueous solution to separate the organic layer, and the aqueous layer was extracted with tert-butyl=methyl=ether. The concentrated residue of the combined organic layers was distilled under reduced pressure to recover 39 g of (R)-α-phenylethylamine, and then 37.6 g of the target product (2S,αR)-(2a) (99.3% GC, yield 90%; fractional yield 92%) was obtained.

[0072] (2S,αR)-2-methylbutyl-α-phenylethylamine:(2S,αR)-(2a):C 13 H 21 N [ka]

[0073] Colorless oil. Boiling point: 67℃ / 0.3kPa. Specific rotation: [α] D 22 +67.5 (c=1.0, CHCl3). IR(D-ATR):ν=3083,3063,2960,2925,2874,2810,1603,1463,1452,1369,1305,1210,1128,1028,910,760,700,597,555cm -1 . 1H-NMR (600 MHz, CDCl3): δ = 0.85 (3H, t, J = 7.4 Hz), 0.88 (3H, d, J = 6.7 Hz), 1.07 - 1.15 (1H, m), 1.2 - 1.8 (1H, NH, broad), 1.32 - 1.41 (1H, m), 161.35 (3H, d, J = 6.6 Hz), 1.45 - 1.54 (1H, m), 2.18 (1H, dd, J = 11.5, 7.7 Hz), 2.45 (1H, dd, J = 11.5, 5.5 Hz), 3.73 (1H, q, J = 6.6 Hz), 7.21 - 7.25 (1H, m), 7.30 - 7.35 (4H, m) ppm.

[0074] The above 1 Among the signals of the H-NMR spectrum, the signals derived from the two diastereotopic hydrogen atoms at the 1-position of the major diastereomer (2S,αR)-(2a) are δ = 2.18 (1H, dd, J = 11.5, 7.7 Hz), 2.45 (1H, dd, J = 11.5, 5.5 Hz). The signal at the 1-position of the minor diastereomer (2R,αR)-(2a) [this diastereomer is derived from the opposite enantiomer present in trace amounts in the starting material (S)-2-methylbutanol, i.e., (R)-2-methylbutanol] is observed at δ = 2.31 (1H, dd, J = 11.5, ~6.6 Hz), 2.33 (1H, dd, J = 11.5, ~6.6 Hz). From the integration values of these peaks, the stereochemistry at the 2-position was estimated to be major:minor = (2S,αR):(2R,αR) = 98.54:1.46 (estimated by calculation). Note that the calculation excluded the C satellite peaks that overlap in this chemical shift region. 13 The C satellite peaks were excluded.

Chemical Structure

[0075] This isomer ratio indicates that the stereochemistry of the chiral center at position 2 of the starting material is maintained without isomerization. Furthermore, it was shown that if optically pure α-phenylethylamine is used as a starting material, the absolute stereochemistry and optical purity of the chiral center at position 2 can be determined within the compound itself without conversion to another derivative. 13 C-NMR (150MHz, CDCl3): δ=11.53,17.87,24.70,27.76,35.15,54.06,58.58,126.71(2C),126.88,128.49(2C),146.17ppm. GC-MS (EI, 70eV): 30, 41, 51, 65, 77, 91, 105 (base peak), 118, 134, 176, 191 (M + ).

[0076] Preparation Example 2: Synthesis of (2S,2'S,αR)-2-methyl-N-(2-methylbutyl)-N-(α-phenylethyl)butanamide:(2S,2'S,αR)-(3a) [when Ar=Ph in general formula (3)] [ka]

[0077] Under a nitrogen atmosphere, 10.25 g of ice-cold (S)-2-butanoic acid (99.3% S, 98.5% ee), 30.5 g of triethylamine, and 80 ml of tetrahydrofuran were mixed and 26.9 g of diphenyl phosphoryl chloride was added dropwise over 5 minutes at 15°C or below. The mixture was stirred at 7°C for 10 minutes, then at room temperature for 20 minutes. The resulting crystals were removed by Celite filtration, and the cake was washed with 30 ml of tetrahydrofuran. While stirring the combined filtrate under a nitrogen atmosphere at room temperature, 18.0 g of (2S, αR)-(2a) obtained in Preparation Example 1 and 61 g of triethylamine were added and stirred at 72-75°C for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue from which tetrahydrofuran and triethylamine had been removed was dissolved in diethyl ether. The ether solution was washed with dilute hydrochloric acid, water, saturated sodium bicarbonate aqueous solution, and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target product (2S,2'S,αR)-(3a) 23.98 g (93.8~98.8% GC, yield 91%).

[0078] (2S,2'S,αR)-2-methyl-N-(2-methylbutyl)-N-(α-phenylethyl)butanamide:(2S,2'S,αR)-(3a):C 18 H 29 NO [ka]

[0079] Colorless oil. Specific rotation: [α] D 22 +105.0 (c=1.0, CHCl3). IR(D-ATR):ν=3063,3030,2963,2933,2874,1737,1639,1496,1463,1417,1379,13 01,1271,1231,1207,1185,1157,1117,1088,1049,1028,970,911,787,745,699cm -1 . 1H-NMR (600MHz, CDCl3): δ=0.74(3x0.55H,d,J=6.7Hz),0.771(3x0.45H,t,J=7.3Hz),0.772( 3x0.45H,d,J=6.7Hz),0.78(3x0.55H,t,J=7.3Hz),0.84-0.90(0.55H,m),0.89(3H,t,J=7.4 Hz),0.90-0.99(0.45H,m),1.07(3x0.45H,d,J=6.8Hz),1.11(3x0.55H,d,J=6.7Hz),1.12-1 .29(2x0.55H+0.45H,m),1.39-1.47(0.45H+0.55H,m),1.52-1.58(0.45H,m)1.56(3x0.55H, d,J=7.2Hz),1.65(3x0.45H,d,J=7.1Hz),1.66-1.75(0.55H,m),1.75-1.84(0.45H,m),2.63 (0.55H,hex-like,J=~6.8Hz),2.67(0.45H,hex-like,J=6.8Hz),2.88(0.45H,dd,J=13.6,8 .4,Hz),2.91(0.55H,dd,J=15.1,8.5Hz),3.04(0.55H,dd,J=15.1,7.0Hz),3.23(0.45H,dd, J=13.6,6.6Hz),5.16(0.45H,q,J=7.0Hz),5.83(0.55H,q,J=7.1Hz),7.21-7.36(5H,m)ppm.

[0080] 1 In 1H-NMR, diastereomers, which are tautomers, were found in the CDCl3 solution of the sample in a ratio of approximately 55:45, each giving a separate peak. This phenomenon is due to the fact that this is an amine with three different substituents on the nitrogen atom, and the sp3 hybridized nitrogen atom, including the lone pair of electrons, acts as a chiral center. Because of the steric hindrance of the bulky substituents, rapid inversion is prevented, resulting in the existence of diastereomers due to the chirality of the nitrogen atom, as shown in the equation below. For each hydrogen atom in these diastereomers, coefficients were used to represent 0.55H and 0.45H, respectively, so that the total is 29H. These coefficients are equivalent to the integral values. [ka] (In the formula, : represents a lone pair of electrons.)

[0081] 13 ¹¹¹ NMR (150 MHz, CDCl3): δ = 11.62, 11.73 , 12.12 ,12.38, 17.07 , 17.16 ,17.44, 17.63 ,18.25,19.39, 27.08 ,27.48,27.55, 27.67 ,34.05, 35.18 , 37.82 ,38.53,49.80, 50.54 , 52.56 ,55.31,126.93(2C), 127.27 ,127.54, 127.84(2C) , 128.34(2C) ,128.69(2C),141.55, 141.65 , 177.76 178.11 ppm. 13 In 1C-NMR, the diastereomers formed by the above-mentioned chiral nitrogen atoms each yielded a different signal. The signals assigned to the diastereomer with the higher abundance are underlined. GC-MS (EI, 70eV): 41, 57, 79, 105 (base peak), 120, 134, 156, 177, 204, 218, 275 (M + ).

[0082] Preparation Example 3: Synthesis of (2S,2'S)-2-methyl-N-(2-methylbutyl)butanamide:(2S,2'S)-(1) [ka]

[0083] Under a nitrogen atmosphere, a mixture of 3.90 g of (2S,2'S,αR)-(3a) obtained in Preparation Example 2 and 14.0 g of formic acid was heated at 70-75°C for 12 hours while stirring. After the reaction mixture was cooled to 50°C, a distillation head was attached to the reaction vessel and the mixture was distilled under reduced pressure. As a fraction, after the excess formic acid and α-phenylethyl formate, the target product (2S,2'S)-(1) 1.89 g (92.0% GC, yield 79%) was obtained.

[0084] (2S,2'S)-2-methyl-N-(2-methylbutyl)butanamide:(2S,2'S)-(1):C 10 H 21 NO [ka]

[0085] Colorless oil. Specific rotation: [α] D 25 +23.3 (c=3.0, CH3CH2OCH2CH3). IR(D-ATR):ν=3297,3087,2963,2932,2876,1732,1645,1553,1462,1381,1269,1236,1108,968,765,699cm -1 . 1 H-NMR (600MHz, CDCl3): δ=0.89(3H,d,J=6.7Hz),0.897(3H,t,J=7.5Hz),0.899 (3H,t,J=7.5Hz),1.13(3H,d,J=6.9Hz),1.12-1.19(1H,m),1.35-1.46(2H,m), 1.49-1.59(1H,m),1.62-1.70(1H,m),2.02-2.14(1H,m),3.09(1H,dt-like,J= ~13.4,~6.5Hz),3.17(1H,dt-like,J=~13.4,~6.0Hz),5.46(1H,NH,br.s)ppm. the above 1Among the signals in the H-NMR spectrum, the signal at position 1 for the major diastereomer (2S,2'S)-(1) [and more precisely, a trace amount of (2R,2'R)-(1)] is δ=3.09 (1H,dt-like, J=~13.4,~6.5Hz) and 3.17 (1H,dt-like, J=~13.4,~6.0Hz), and the corresponding trace amounts of the minor diastereomer are The corresponding signals for the teleomers (2R,2'S)-(1) and (2S,2'R)-(1) were observed at δ=3.04 (1H,dt-like,J=~13.4,~7Hz) and 3.23 (1H,dt-like,J=~13.4,~7Hz), and from the integral values ​​of these peaks, the stereochemistry was [(2S,2'S)+(2R,2'R)]:[(2R,2'S)+(2S,2'R)]=91:9. 13 C-NMR (150MHz, CDCl3): δ=11.42,12.11,17.31,17.80,27.15,27.52,35.10,43.63,45.00,176.56ppm. GC-MS (EI, 70eV): 41, 57 (base peak), 71, 85, 102, 114, 128, 143, 156, 171 (M + ). Chiral phase GC: HP 7890B, Column: Cyclosil-B 30m x 0.25mmφ x 0.25μm, 130℃ const., Carrier gas: He 1mL / min, Inj: 220℃, Detector: FID 230℃: 6.56% (Rt 17.57 min), 93.43% (Rt 18.11 min). In this GC, the peak due to the acyl group-side chiral center, i.e., the stereochemistry at position 2, was separated. Therefore, the ratio was [(2R,2'R)+(2R,2'S)]:[(2S,2'S)+(2S,2'R)] = 93.43:6.56.

[0086] the above 1From the diastereomer ratio of the 1H-NMR spectrum and the stereochemistry ratio of the 2 position of the chiral phase GC, the stereochemistry ratio of the 2' position can be calculated. As shown below, the 2 position is 93.44%S and the 2' position is 97.19%S (i.e., 90.99%de, 99.80%ee), demonstrating that the manufacturing method of the present invention allows for the synthesis of the target product with high optical purity without racemization or epimerization. [ka]

[0087] <(2S,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide:(2S,2'RS)-(1) synthesis> [ka]

[0088] Preparation Example 4: Synthesis of (2RS,αR)-2-methylbutyl-α-phenylethylamine:(2RS,αR)-(2a) [a 50:50 mixture of (2R,αR)-(2a) and (2S,αR)-(2a), where Ar=Ph in general formula (2)] [ka]

[0089] Using 135 g of (±)-2-methylbutyl=p-toluenesulfonate instead of (S)-2-methylbutyl=p-toluenesulfonate as in Preparation Example 1, 96.3 g of the target product (2RS,αR)-(2a) (99.7% GC, yield 90%; total yield of fractions 93%) was obtained by the same procedure as in Preparation Example 1.

[0090] (2RS,αR)-2-methylbutyl-α-phenylethylamine:(2RS,αR)-(2a)[50:50 mixture of (2R,αR)-(2a) and (2S,αR)-(2a)]:C 13 H 21 N [ka]

[0091] Colorless oil. Boiling point: 69℃ / 0.3kPa. Specific rotation: [α] D 26 +59.3 (c=1.0, CHCl3). IR(D-ATR):ν=3083,3062,3025,2960,2925,2874,2810,1603,1493,1452,1369,1305,1210,1127,1028,910,760,700,597,555cm -1 . 1 H-NMR (600MHz, CDCl3): δ=0.846(3x0.5H,t,J=7.4Hz),0.850(3x0.5H,t,J=7.4Hz),0.87(3x0.5H,d,J=~6Hz ),0.88(3x0.5H,d,J=~6Hz),1.06-1.16(1H,m),1.2-1.6(1H,NH,br.),1.32-1.46(1H,m),1.35(3H,d,J=6.6H z), 1.46-1.54 (1H,m), 2.18 (0.5H,dd,J=11.5,7.7Hz), 2.31 (0.5H,dd,J=11.5,6.6Hz), 2.33 (0.5H,dd,J=11.5,6.6Hz), 2.45 (0.5H,dd,J=11.5,5.5Hz), 3.73 (1H,q,J=6.6Hz), 7.21-7.25 (1H,m), 7.30-7.35 (4H,m) ppm. A coefficient was used to set each hydrogen atom of the two diastereomers to 0.5H, and the total was described to be 21H. This coefficient is equivalent to the integral value. Below, the diastereomer mixture is described. 1 The description of H-NMR should be the same. 13¹¹C-NMR (150MHz, CDCl3): δ = 11.32 (0.5C), 11.52 (0.5C), 17.81 (0.5C), 17.86 (0.5C), 24.64 (0.5C), 24.72 (0.5C), 27.40 (0.5C), 27.75 (0.5C), 35.11 (0.5C), 35.16 (0.5C), 54.06 (0.5C), 54.12 (0.5C), 58.57 (0.5C), 58.62 (0.5C), 126.70 (2C), 126.86 (1C), 128.47 (2C), 146.22 (1C) ppm. A coefficient was used to set each carbon atom of the two diastereomers to 0.5C, resulting in a total of 13C. This coefficient does not necessarily correlate with peak intensity or integral value. Below, for diastereomer mixtures... 13 The description of the 1C-NMR spectrum should be the same. GC-MS (EI, 70eV): 30, 41, 51, 65, 77, 91, 105 (base peak), 118, 134, 176, 191 (M + ).

[0092] The specific rotations of (R)-α-phenylethylamine:(R)-(4a) used in the reaction and the excess recovered after the reaction are as follows, indicating that racemization did not proceed and that the recovered product can be used. (R)-(4a):[α] used D 26 +38.7 (neat) Recovered (R)-(4a):[α] D 26 +40.1 (neat)

[0093] Preparation Example 5: Synthesis of (2S,2'RS,αR)-2-methyl-N-(2-methylbutyl)-N-(α-phenylethyl)butanamide:(2S,2'RS,αR)-(3a) [a 50:50 mixture of (2S,2'R,αR)-(3a) and (2S,2'S,αR)-(3a), where Ar=Ph in general formula (3)] [ka]

[0094] Instead of (2S,αR)-(2a) obtained in Preparation Example 1, 14.0 g of (2RS,αR)-(2a) obtained in Preparation Example 4 and 7.10 g of (S)-2-butanoic acid (98.9%S, 97.9%ee) were used, and the target product (2S,2'RS,αR)-(3a) 13.35 g (96.4%GC, yield 67%; fractional yield 70%) was obtained by the same procedure as in Preparation Example 2.

[0095] (2S,2'RS,αR)-2-methyl-N-(2-methylbutyl)-N-(α-phenylethyl)butanamide:(2S,2'RS,αR)-(3a)[50:50 mixture of (2S,2'R,αR)-(3a) and (2S,2'S,αR)-(3a)]:C 18 H 29 NO [ka]

[0096] Colorless oil. Specific rotation: [α] D 26 +97.3 (c=1.0, CHCl3). IR(D-ATR):ν=3063,3030,2964,2933,2874,1639,1496,1463,1418,1380,12 71,1231,1207,1186,1156,1119,1089,1049,1028,968,912,787,758,699cm -1 . 1H-NMR (600MHz, CDCl3): δ=0.65-0.82(6H,m),0.86-0.92(3H,m),0.97-1.35(~6H,m),1.37 -1.48(1H,m),1.56(3x0.55H,br.d,J=~7Hz),1.65(3x0.45H,d,J=~7Hz),1.72-1.84(~1H, m),2.57-2.66(0.55H,m),2.66-2.73(0.45H,m),2.84-3.07(1.55H,m),3.17-3.27(0.45H ,m),5.11-5.21(0.45H,m),5.79-5.93(0.55H,2xq-like,J=7.0Hz),7.21-7.37(5H,m)ppm.

[0097] the above 1 The 1H-NMR spectrum showed a very complex overlap of spectra from four sets of diastereomers, due to the presence of a diastereomer from the 2' position and a diastereomer from the chiral nitrogen atom in a ratio of approximately 55:45. This made complete peak assignment impossible. However, two of these four sets of spectra closely matched those of (2S,2'S,αR)-2-methyl-N-(2-methylbutyl)-N-(α-phenylethyl)butanamide obtained in Preparation Example 2. The remaining two sets of spectra originated from (2S,2'R,αR)-2-methyl-N-(2-methylbutyl)-N-(α-phenylethyl)butanamide.

[0098] 13 C-NMR(150MHz,CDCl3):δ=11.619, 11.623 ,11.70, 11.74 , 12.12 ,12.21, 12.38 ,12.40,16.83, 17.066 ,17.070, 17.16 ,17.22, 17.45 , 17.63 ,17.75, 18.25 ,18.30,19.38, 19.39 , 27.08 ,27.26, 27.48 , 27.55 ,27.582,27.584,27.670, 27.673 ,34.05 ,34.60, 35.18 ,35.26, 37.83 ,37.96, 38.53 ,38.54,49.37, 49.81 ,50.37, 50.54 ,52.45, 52.57 , 55.32 ,55.40, 126.93 ,127.01, 127.27 ,127.28, 127.54 ,127.57, 127.84 ,127.90, 128.35 ,128.37, 128.69 ,128.70,141.53, 141.54 ,141.58, 141.64 , 177.76 ,177.80, 178.13 178.14 ppm. the above 13 In the 1C-NMR spectrum, the signals assigned to the two diastereomers of (2S,2'S,αR)-2-methyl-N-(2-methylbutyl)-N-(α-phenylethyl)butanamide are underlined, while those of the other two diastereomers of (2S,2'R,αR)-2-methyl-N-(2-methylbutyl)-N-(α-phenylethyl)butanamide are shown without underlining. GC-MS (EI, 70eV): 41, 57, 79, 105 (base peak), 120, 134, 156, 177, 204, 218, 275 (M + ).

[0099] Preparation Example 6: Synthesis of (2S,2'RS)-2-methyl-N-(2-methylbutyl)butanamide:(2S,2'RS)-(1) [a 50:50 mixture of (2S,2'R)-(1) and (2S,2'S)-(1)] [ka]

[0100] Under a nitrogen atmosphere, a mixture of 1.00 g of (2S,2'RS,αR)-2-methyl-N-(2-methylbutyl)-N-(α-phenylethyl)butanamide obtained in Preparation Example 5 and 35 ml of formic acid was stirred at 50-60°C for 5 hours and at room temperature for 16 hours. The reaction mixture was diluted with tert-butyl methyl ether, and after washing, drying, and concentration, the mixture was purified by silica gel column chromatography to obtain the target product (2S,2'RS)-(1) 0.54 g (99.8% GC, 90% yield).

[0101] (2S,2'RS)-2-methyl-N-(2-methylbutyl)butanamide:(2S,2'RS)-(1)[50:50 mixture of (2S,2'R)-(1) and (2S,2'S)-(1)]:C 10 H 21 NO [ka]

[0102] Colorless oil. Specific rotation: [α] D 23 +19.5 (c=3.3, CH3CH2OCH2CH3). IR(D-ATR):ν=3296,3089,2963,2931,2876,1645,1553,1462,1381,1269,1236,1108,968,766,704cm -1 . 1 H-NMR (600MHz, CDCl3): δ=0.87-0.93(9H,m),1.12-1.19(1H,m),1.13(3H,d,J=6.9Hz) ,1.34-1.46(2H,m),1.50-1.59(1H,m),1.62-1.70(1H,m),2.05-2.13(1H,m),3.04(0. 5H,dt-like,J=~13.4,~7Hz),3.09(0.5H,dt-like,J=~13.4,~6.5Hz),3.17(0.5H,dt- like,J=~13.4,~6.0Hz),3.23(0.5H,dt-like,J=~13.4,~7Hz)5.48(1H,NH,br.s)ppm. 13 C-NMR (150MHz, CDCl3): δ=11.40(0.5C),11.42(0.5C),12.11,17.29(0.5C),17.31(0.5C),17.80,27.15,27.52,35.10,43.62,45.01,176.57ppm. GC-MS (EI, 70eV): 41, 57 (base peak), 71, 85, 102, 114, 128, 143, 156, 171 (M + ). Chiral phase GC (under the same conditions as preparation example 3): 3.92% (Rt 17.51 ​​min), 96.08% (Rt 17.97 min).

[0103] The stereochemistry at position 2 was determined to be 96.1% S by chiral phase GC, demonstrating that the target product can be synthesized with high optical purity using this method. [ka]

[0104] <(2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide:(2RS,2'RS)-(1) synthesis 1> [ka]

[0105] Preparation Example 7: Synthesis of (2RS,2'RS)-2-methyl-N-(2-methylbutyl)butanamide:(2RS,2'RS)-(1) [a 25:25:25:25 mixture of (2R,2'R)-(1), (2R,2'S)-(1), (2S,2'R)-(1), and (2S,2'S)-(1)] Under a nitrogen atmosphere, 0.50 g of ice-cold (±)-2-butanoic acid, 1.20 g of 1-methylimidazole, and 20 ml of acetonitrile were mixed and stirred at room temperature, to which 1.44 g of diphenylphosphoryl chloride was added. After stirring at room temperature for 3.5 hours, 0.93 g of (2RS,αR)-2-methylbutyl-α-phenylethylamine obtained in Preparation Example 4 was added while cooling with water, and the mixture was stirred at 90-95°C for 36 hours. The reaction mixture was diluted with tert-butyl methyl ether, washed, dried, and concentrated to obtain the crude product (2RS,2'RS,αR)-(3a) 1.21 g (90.9% GC, yield 82%).

[0106] The obtained crude product (2RS,2'RS,αR)-(3a) 1.21 g was used in place of (2S,2'S,αR)-2-methyl-N-(2-methylbutyl)-N-(α-phenylethyl)butanamide in Preparation Example 3, and the target product (2RS,2'RS)-(1) 0.745 g (99.4-100% GC, yield 99%) was obtained by the same procedure as in Preparation Example 3.

[0107] (2RS,2'RS)-2-methyl-N-(2-methylbutyl)butanamide:(2RS,2'RS)-(1)[(2R,2'R)-(1) and (2R,2'S)-(1) and (2S,2'R)-(1) and (2S,2'S)-(1) in a ~25:25:25:25 mixture]:C 10 H 21 NO [ka]

[0108] Colorless oil. The various spectra of this substance were identical to those of (2S,2'RS)-2-methyl-N-(2-methylbutyl)butanamide:(2S,2'RS)-(1) in Preparation Example 6. 1In 1H-NMR, the signal at the 1' position was observed at δ=3.04 (0.5H, dt-like, J=~13.4,~7Hz), 3.09 (0.5H, dt-like, J=~13.4,~6.5Hz), 3.17 (0.5H, dt-like, J=~13.4,~6.0Hz), and 3.23 (0.5H, dt-like, J=~13.4,~7Hz) ppm, but NH:δ=5.48 When decoupling was performed by irradiating with (br.s) ppm, the δ changed to 3.04 (0.5H,dd,J=13.4,7.3Hz), 3.09 (0.5H,dd,J=13.4,7.2Hz), 3.18 (0.5H,dd,J=13.4,6.1Hz), and 3.23 (0.5H,dd,J=13.4,6.1Hz) ppm, and could be separated as non-overlapping peaks. Of these peaks, δ=3.04 and 3.23 were (2R * ,2'R * For the diastereomers of (2R,2'R)-(1) [i.e., (2R,2'R)-(1) and / or (2S,2'S)-(1)], δ=3.09 and 3.18 are (2R * ,2'S * It was assigned to the diastereomer of )-(1)[(2R,2'S)-(1) and / or (2S,2'R)-(1)]. 1 It has been shown that the diastereomer ratio of [(2R,2'R)+(2S,2'S)]:[(2R,2'S)+(2S,2'S)] can be determined by 1H-NMR. For example, this was applied to the determination of the isomer purity in Preparation Example 3 described above.

[0109] Chiral phase GC: HP 7890B, Column: Cyclosil-B 30mx0.25mmφx0.25μm, 116℃+0.4℃ / min const., Carrier gas: He 1mL / min, Inj: 200℃, Detector: FID 230℃: 49.90% (Rt 37.70 min), 50.10% (Rt 38.01 min). The peaks due to the stereochemistry at position 2 were separated in a 1:1 ratio. This demonstrated that the diastereomer ratio of [(2S,2'S)+(2S,2'R)]:[(2R,2'R)+(2R,2'S)] could be determined. For example, this was applied to the isomer purity determination in Examples 3 and 6 above.

[0110] <(2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide:(2RS,2'RS)-(1) synthesis 2> [ka]

[0111] Preparation Example 8: Synthesis of (2RS,2'RS)-2-methyl-N-(2-methylbutyl)butanamide:(2RS,2'RS)-(1) [a mixture of (2R,2'R)-(1), (2R,2'S)-(1), (2S,2'R)-(1), and (2S,2'S)-(1) in a ratio of approximately 25:25:25:25] Under a nitrogen atmosphere, a mixture of 1,201.29 g (98.51% GC) of (±)-α-phenylethylamine and 882.36 g (89.40% GC; containing 9.7% toluene) of (±)-2-methylbutyl=p-toluenesulfonate was stirred at 85°C for 62 hours. After cooling the reaction mixture, it was diluted with toluene, washed, dried, and concentrated, followed by vacuum distillation to obtain the intermediate (2RS,αRS)-(2a) 543.05 g (99.29% GC, yield 87%, fractionation yield 95%).

[0112] (2RS,αRS)-2-methylbutyl-α-phenylethylamine:(2RS,αRS)-(2a):A mixture of (2R,αR)-(2a), (2R,αS)-(2a), (2S,αR)-(2a), and (2S,αS)-(2a) in a ratio of approximately 25:25:25:25, where Ar=Ph in general formula (2):C 13 H 21 N [ka]

[0113] Colorless oil. Boiling point: 108℃ / 0.2kPa. The various spectra of this substance were identical to those of (2RS,αR)-2-methylbutyl-α-phenylethylamine:(2RS,αR)-(2a) in Preparation Example 4.

[0114] The mixture of 538.11 g of (2RS,αRS)-(2a), 704.15 g of pyridine, and 270 g of tetrahydrofuran was cooled on ice under a nitrogen atmosphere, and 503.18 g of (±)-2-methylbutyryl chloride was added dropwise at a temperature below 15°C while stirring. The reaction mixture was heated and stirred at 55°C for 15 hours. After cooling the reaction mixture, water was added and it was extracted with toluene. After washing, drying, and concentrating the organic layer, it was concentrated under reduced pressure to obtain the crude intermediate product (2RS,2'RS,αRS)-(3a) 783.89 g (98.22% GC, quantitative yield).

[0115] The crude product (2RS,2'RS,αRS)-(3a) was obtained in a mixture of 783.52 g, 0.78 g of 4-tert-butylcatechol, and 3,858 g of formic acid, which were stirred under a nitrogen atmosphere at 60°C for 24 hours. After cooling, the reaction mixture was diluted with toluene, washed, dried, and concentrated, and then distilled under reduced pressure to obtain the target product (2RS,2'RS)-(1) in 345.3 g (99.52% GC, yield 73%, fractionation yield 85%).

[0116] (2RS,2'RS)-2-methyl-N-(2-methylbutyl)butanamide:(2RS,2'RS)-(1)[a 25:25:25:25 mixture of (2R,2'R)-(1), (2R,2'S)-(1), (2S,2'R)-(1), and (2S,2'S)-(1)]:C 10 H 21 NO [ka]

[0117] Colorless oil. Boiling point: 110-113°C / 0.1kPa. The various spectra of this substance were identical to those of (2S,2'RS)-2-methyl-N-(2-methylbutyl)butanamide:(2S,2'RS)-(1) in Preparation Example 6.

[0118] <Sustained-release pheromone preparation containing (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide>

[0119] Example 1 A pheromone preparation containing the MFLB pheromone substance was prepared as follows. To 100 parts by mass of the pheromone substance prepared according to Preparation Example 8, namely (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide:(2RS,2'RS)-(1) [a 25:25:25:25 mixture of (2R,2'R)-(1), (2R,2'S)-(1), (2S,2'R)-(1), and (2S,2'S)-(1)], 2 parts by mass each of BHT (2,6-di-tert-butyl-4-methylphenol) and HBMCBT (2-(2'-hydroxy-3'-tert-butyl-5'-methylphenyl)-5-chlorobenzotriazole) were added and mixed to prepare a raw material for a pheromone formulation. The pheromone preparation was manufactured by encapsulating approximately 180 mg of this pheromone preparation active ingredient in a tubular container made of polybutylene succinate (BioPBS FD92PB, manufactured by Mitsubishi Chemical Corporation) with an inner diameter of 0.84 mm, a wall thickness of 0.45 mm, and a length of 200 mm. Next, the obtained pheromone preparation was placed in a constant temperature bath maintained at a wind speed of 0.3 m / s and a temperature of 30°C, and the amount of pheromone substance released from the pheromone preparation was calculated by measuring the weight loss over the elapsed days. The results are shown in Figure 1. Furthermore, the amount released 77 days after installation was 0.68 mg / day / unit. The amount released was defined as the weight loss of the pheromone preparation.

[0120] Example 2 A pheromone preparation was manufactured in the same manner as in Example 1, except that the container material was changed to a blend polymer of polybutylene succinate (BioPBS FD92PB, manufactured by Mitsubishi Chemical Corporation) and polycaprolactone (Capa6800, manufactured by Ingevity) in a mass ratio of 85:15. The amount of pheromone substance released from the pheromone preparation was calculated under the same conditions as in Example 1. The results are shown in Figure 1. Furthermore, the amount of pheromone substance released 77 days after installation was 0.92 mg / day / unit.

[0121] Example 3 A pheromone preparation was manufactured in the same manner as in Example 2, except that the container material was changed to a blend polymer of polybutylene succinate (BioPBS FD92PB, manufactured by Mitsubishi Chemical Corporation) and polycaprolactone (Capa6800, manufactured by Ingevity) in a mass ratio of 70:30. The amount of pheromone substance released from the pheromone preparation was then calculated under the same conditions as in Example 1. The results are shown in Figure 1. Furthermore, the amount of pheromone substance released 77 days after installation was 0.97 mg / day / unit.

[0122] Comparative Example 1 A pheromone preparation was manufactured in the same manner as in Example 1, except that the container was changed to a tube-shaped container made of high-density polyethylene (HDPE) with an inner diameter of 0.84 mm, a wall thickness of 0.35 mm, and a length of 200 mm. The amount of pheromone substance released from the pheromone preparation was then calculated under the same conditions as in Example 1. The results are shown in Figure 1. Furthermore, the amount of pheromone substance released 77 days after installation was 0.00 mg / day / unit.

[0123] Comparative Example 2 A pheromone preparation was manufactured in the same manner as in Example 1, except that the container was changed to a tube-shaped container made of ethylene-vinyl acetate copolymer (EVA) containing 2% by mass of vinyl acetate units, with an inner diameter of 0.84 mm, a wall thickness of 0.35 mm, and a length of 200 mm. The amount of pheromone substance released from the pheromone preparation was calculated under the same conditions as in Example 1. The results are shown in Figure 1. Furthermore, the amount of pheromone substance released 77 days after installation was 0.04 mg / day / unit.

[0124] Comparative Example 3 A pheromone formulation was manufactured in the same manner as in Example 2, except that the pheromone substance of MFLB was replaced with N,N-diethyl-3-methylbenzamide (DEET) in the active ingredient for formulation. The amount of pheromone substance released from the pheromone formulation was then calculated under the same conditions as in Example 1. The results are shown in Figure 2. N,N-diethyl-3-methylbenzamide (DEET) belongs to the same amide compound group as the pheromone substance of MFLB. Furthermore, the amount of pheromone substance released 77 days after installation was 0.11 mg / day / unit.

[0125] Comparative Example 4 A pheromone formulation was manufactured in the same manner as in Comparative Example 1, except that DEET was used instead of MFLB as the pheromone substance in the active ingredient for formulation. The amount of pheromone substance released from the pheromone formulation was then calculated under the same conditions as in Example 1. The results are shown in Figure 2. Furthermore, the amount released 77 days after installation was 0.23 mg / day / unit.

[0126] Comparative Example 5 A pheromone formulation was manufactured in the same manner as in Comparative Example 2, except that DEET was used instead of MFLB pheromone substance in the active ingredient for formulation. The amount of MFLB pheromone substance released from the pheromone formulation was then calculated under the same conditions as in Example 1. The results are shown in Figure 2. Furthermore, the amount released 77 days after installation was 0.81 mg / day / unit.

[0127] Discussion 1: The test results for DEET, which is the same amide compound as the pheromone substance of MFLB (Comparative Examples 3, 4, and 5), are discussed below (see Figure 2). Comparative Example 3's pheromone preparation is equipped with a container made of biodegradable polymer, Comparative Example 4's pheromone preparation is equipped with a container made of HDPE, and Comparative Example 5's pheromone preparation is equipped with a container made of EVA. In Comparative Example 5 where EVA was used as the container, it was stably released at about 1.0 mg / day. However, in Comparative Example 4 where HDPE was used as the container, almost no release was observed. On the other hand, in Comparative Example 3 where a biodegradable polymer was used as the container, an excessive release rate of up to 8.0 mg / day or more was reached about 10 days after the start of the experiment. From the above results, it was found that in the pheromone formulations of Comparative Examples 3, 4, and 5, the release rate of the pheromone substance was different in the order of HDPE container < EVA container << biodegradable polymer container. Also, considering the original filling amounts of the pheromone substances in Comparative Examples 3, 4, and 5, the excessive release rate of the pheromone formulation in Comparative Example 3 suggests that the life of the pheromone formulation is short.

[0128] Discussion 2: Regarding the test results of the pheromone substance of MFLB (Example 1 and Comparative Examples 1 and 2), the following discussion is presented (see Figure 1). The pheromone formulation of Example 1 has a container made of a biodegradable polymer, the pheromone formulation of Comparative Example 1 has a container made of HDPE, and the pheromone formulation of Comparative Example 2 has a container made of EVA. In both Comparative Example 1 where HDPE was used as the container and Comparative Example 2 where EVA was used as the container, almost no release of the pheromone substance was observed. On the other hand, in Example 1 where a biodegradable polymer was used as the container, a release amount comparable to that of Comparative Example 5 above was obtained, and sufficient release amounts were present even beyond 2 months and even beyond 3 months. From the above results, it was found that in the pheromone formulations of Example 1 and Comparative Examples 1 and 2, the release rate of the pheromone substance was different in the order of HDPE container = EVA container < biodegradable polymer container. Also, these results indicate that the release of the pheromone substance of MFLB is difficult without a specific polymer.

[0129] Investigation 3: From Investigations 1 and 2 above, it was found that the pheromone substance of MFLB and DEET belong to the same amide compound, but even for the same amide compound, different release characteristics are shown depending on the type of container of the pheromone preparation. Therefore, in the case of amide compounds, it is difficult to estimate the release rate of one amide compound from that of another amide compound, and it is considered that the release amount strongly depends on the type of polymer of the container.

[0130] Investigation 4: By using the polymer containers described in Examples 1 to 3, a release amount comparable to that of Comparative Example 5 was obtained, and a sufficient release amount was still present even after more than two months (see Figure 1). Therefore, from the results that sufficient release amounts were obtained for the pheromone preparations of Examples 1 to 3 even after more than two months and even after more than three months (see Figure 1), it was demonstrated that the pheromone preparations of Examples 1 to 3 are sustained-release.

[0131] <Communication disruption test of MFLB> The following experiment was carried out using three sugarcane fields in Brazil where MFLB occurs as test plots respectively. In these three test plots, 250 slow-release pheromone preparations manufactured according to the method described in Example 2 were installed per hectare in Field 1 (Example 4), 1000 slow-release pheromone preparations described in Example 2 were installed per hectare in Field 2 (Example 5), and an untreated field without installing the preparation was set as Field 3 (Comparative Example 6 ). The slow-release pheromone preparations were placed at equal intervals in the fields on February 22, 2022. From February 23 to March 11, 2022, four traps equipped with a commercially available MFLB attractant (Migdo, manufactured by Fuji Flavor Co., Ltd.) were installed in each test plot, and the number of adult insects trapped in each trap was counted. The number of adult insects trapped in the traps in each test plot is shown in Table 1 below.

[0132]

Table 1

[0133] In Comparative Example 6 (untreated field), field 3 attracted 11.45 animals per day, while in Example 4 (250 plants / ha), field 1 attracted only 2.80 animals, and in Example 5 (1000 plants / ha), field 2 attracted an even smaller number, only 0.57 animals. These results demonstrate that a sustained-release pheromone formulation containing at least (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide as the pheromone substance for MFLB has a communication disruption effect on MFLB.

Claims

1. A sustained-release pheromone formulation targeting Migdolus fryanus, comprising at least an isomer mixture (2RS,2'RS)-2-methyl-N-(2'-methylbutyl)butanamide and a biodegradable polymer container for housing the isomer mixture.

2. The sustained-release pheromone formulation according to claim 1, wherein the biodegradable polymer is selected from aliphatic polyesters, aromatically modified aliphatic polyesters, and combinations thereof.

3. The sustained-release pheromone formulation according to claim 1, wherein the biodegradable polymer is a blend of one selected from polybutylene succinate and polybutylene adipate succinate and a polycaproton, and the blend ratio (mass ratio) is 100:0 to 45:

55.

4. A method for controlling Migdolus fryanus, comprising at least the step of installing a sustained-release pheromone preparation according to any one of claims 1 to 3 in a field at a set density of 1 to 50,000 units / ha, and releasing the isomer mixture in the sustained-release pheromone preparation into the field at a release rate of 0.05 g to 3 g / day / ha.

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