A method for synthesizing the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate

Abstract

A method for synthesizing the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate. The present invention uses 3-butyn-1-alcohol as a starting material, and obtains a target fragment A through hydroxyl protection, Grignard reaction, reduction and acetylation; the protected 3-butyn-1-alcohol is subjected to bromination reaction, cross-coupling reaction of alkynyl bromide and Grignard reagent, reduction, deprotection and halogenation to obtain a target fragment B; the Grignard reagents of target fragments A and B undergo a Grignard reagent coupling reaction under the catalysis of Li2CuCl4 to obtain a key intermediate. Finally, the target product, tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate, is obtained through deprotection and acetylation. The raw materials of the present invention are cheap and easily available, all reaction conditions are mild, it is easy to scale up, there is little pollution to the environment, and promotion has good economic and social value.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis and relates to a method for synthesizing the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate. Background Art

[0002] The South American tomato leafminer, Tuta absoluta (Meyrick), is native to Peru in western South America. It belongs to the order Lepidoptera, family Gelechiidae. It primarily harms Solanaceae crops, including tomatoes and potatoes. First discovered in Yili, Xinjiang, my country in 2017 (Journal of Biosafety, 2019, 28, 200), it had invaded over 80 countries and regions by 2017, including seven of the top ten tomato-growing nations: India, Turkey, Egypt, and Italy. Its tomato acreage accounted for over half of the global tomato planting area (J. Pestic. Sci., 2011, 84, 403). The tomato leafminer has a strong ability to adapt to its environment. An adult female tomato leafminer lays 250-300 eggs in her lifetime, with 10 to 12 generations each year. Tomato leafminer larvae obtain nutrients by gnawing on the stems, leaves, flowers, and fruits of plants. This damage continues to occur at all stages of tomato growth. In severe cases, it can lead to a yield loss of 80% to 100% (An.Soc.Entomol.Brasil.,1995,24,587.).

[0003] The tomato leafminer sex pheromone has biological activity that attracts male moths (An. Soc. Entomol. Brasil 1994, 23, 271.) and is widely used for population monitoring, trapping, and mating disruption of this pest. Its high bioactivity, strong specificity, and its safety to natural enemies, human health, and the environment make it a promising green pest control method.

[0004] The tomato leafminer sex pheromone was first isolated by Attygalle, AB, et al., who identified its major component (90%) as (3E,8Z,11Z)-3,8,11-tetradecatriene acetate (Bioorg. Med. Chem. Lett., 1996, 4, 305-314). The minor component was identified by Griepink, FC, et al. as (3E,8Z)-3,8-tetradecadiene acetate (Tetrahedron Lett., 1996, 37, 411). Although the tomato leafminer sex pheromone exhibits significant biological activity, the insect only synthesizes and secretes very small amounts of the pheromone. Therefore, obtaining large quantities of the pheromone requires chemical synthesis. However, the high cost of synthesizing olefinic compounds is a major limitation to the industrial production and large-scale use of tomato leafminer sex pheromone in agricultural control. Therefore, research on the synthesis of tomato leafminer sex pheromone has important theoretical and practical significance.

[0005] It has been reported that a 9:1 ratio of the primary and secondary components of the tomato leafminer sex pheromone has been used for early detection and later luring and killing of the tomato leafminer, demonstrating excellent results. This suggests that the secondary pheromone component, (3E,8Z)-3,8-tetradecadienyl acetate, plays a significant role in controlling the tomato leafminer. Currently, there are two synthetic strategies for (3E,8Z)-3,8-tetradecadienyl acetate: 1) The C5+C5+C4 strategy (see Route 1 below): At -78°C, THP(MOM)-protected 4-pentyn-1-ol is treated with n-BuLi and then alkylated with 1-bromopentane. The alkyl halide is then reduced, deprotected, and brominated (iodinated) to yield a halogenated alkane, which then undergoes a coupling reaction with THP-protected 3-butyn-1-ol lithium salt in THF-HMPA. (3E,8Z)-3,8-tetradecadienyl acetate is synthesized through further reduction, deprotection, and acetylation (a) Tetrahedron Lett., 1996, 37, 411; b) Synthesis, 2015, 47, 961-968). 2) Based on the C6+C6+C2 strategy (see Route 2 in the following formula for details): 1,6-Hexanediol is selectively monoacylated in the presence of a resin catalyst and then oxidized to the aldehyde via a modified Stahl method. The aldehyde is condensed with malonic acid to yield (E)-3-enoic acid. The acid is hydrolyzed in a NaOH solution and then refluxed in methanol with concentrated sulfuric acid as a catalyst to yield the corresponding ester. The ester is also oxidized using the modified Stahl method to yield the key aldehyde. Then, at -78°C, hexyltriphenylphosphonium bromide was treated with KN[Si(Me)3]2 to react with aldehyde to prepare dienoic acid, which was then reduced and acetylated to obtain (3E,8Z)-3,8-tetradecadienyl acetate (a) Tetrahedron Lett., 2022, 107: 153928. b) Tao Yunhai, Dong Kewu, Zhu Quan, et al. Synthesis method and intermediates of sex pheromone components of tomato leafminer [P]. China: CN115417769A, 2022-12-02).

[0006] Route 1: C5+C5+C4 strategy

[0007]

[0008] Route 2: C6+C2+C6 strategy

[0009]

[0010] Existing synthesis methods all involve reactions involving strong bases at -78°C, which have problems such as harsh reaction conditions, high equipment requirements, and expensive equipment prices. In addition, Route 1 also involves the use of precious metal Pd catalysts and the carcinogen HMPA, which increases the synthesis cost and poses a threat to human health, making it unfavorable for industrial production. Summary of the Invention

[0011] The present invention uses a cheap commercial reagent 3-butyn-1 alcohol as a raw material and adopts a Grignard reagent instead of n-BuLi to participate in the reaction, thereby avoiding the flammable and explosive safety hazards caused by the use of strong bases such as butyl lithium or KN[Si(Me)3]2. The reaction conditions are mild, which is conducive to large-scale industrial production.

[0012] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0013] A method for synthesizing the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate comprises the following steps: using 3-butyn-1-ol as a starting material, obtaining a target fragment A having a structure shown in Formula 1 through steps such as hydroxyl protection, Grignard reaction, reduction, and acetylation; subjecting the protected 3-butyn-1-ol to bromination reaction, cross-coupling reaction of alkynyl bromide and Grignard reagent, reduction, deprotection, and halogenation to obtain a target fragment B having a structure shown in Formula 2; subjecting the target fragments A and B to a Grignard reagent coupling reaction under the catalysis of Li2CuCl4 to obtain a key intermediate having a structure shown in Formula 3; and finally obtaining the target product, tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate I, through deprotection and acetylation.

[0014] Formula 1: Formula 2:

[0015] Formula 3: I:

[0016] In Formula 1 and Formula 3, R can be, but is not limited to, R=t-Bu, Bn, TMS, THP; in Formula 2, X is Cl, Br, or I.

[0017] 1. Preferably, the method for preparing the compound having the structure shown in Formula 1 (i.e., target fragment A) comprises the following steps:

[0018] (1) When R in Formula 1 is R1=t-Bu, the preparation method of the compound having the structure shown in Formula 4 comprises the following steps:

[0019] 3-Butyn-1-ol is catalyzed by an acid and a resin to protect the alcoholic hydroxyl group, thereby obtaining a compound having a structure shown in Formula 4; the resin is an ion exchange resin;

[0020] When R in Formula 1 is R2=Bn, the preparation method of the compound having the structure shown in Formula 4 comprises the following steps:

[0021] 3-Butyn-1-ol reacts with a benzyl halide in the presence of a base and TBAB to obtain a compound having a structure shown in Formula 4;

[0022] Formula 4:

[0023] (2) treating the compound having the structure shown in Formula 4 with a Grignard reagent and performing a Grignard reaction with an aldehyde to obtain a compound having the structure shown in Formula 5;

[0024] Formula 5:

[0025] (3) reducing the compound having the structure shown in Formula 5 to obtain a compound having the structure shown in Formula 6;

[0026] Formula 6:

[0027] (4) Acetylation of the compound having the structure shown in Formula 6 to obtain a compound having the structure shown in Formula 1;

[0028] In Formula 5, Formula 6, and Formula 1, the type of R is the same as that in Formula 4.

[0029] 2. Preferably, the method for preparing the compound having the structure shown in Formula 2 (i.e., target fragment B) comprises the following steps:

[0030] (1) a compound having a structure shown in Formula 4 is subjected to a bromination reaction with N-bromosuccinimide catalyzed by silver nitrate to obtain a compound having a structure shown in Formula 7;

[0031] Formula 7:

[0032] (2) A compound having a structure as shown in Formula 7 undergoes a cross-coupling reaction with a Grignard reagent under the action of a copper catalyst and a ligand to obtain a compound having a structure as shown in Formula 8; the ligand is preferably N-methylpyrrolidone, triphenylphosphine or triethyl phosphate;

[0033] Formula 8:

[0034] (3) reducing the compound having the structure shown in Formula 8 with catalytic hydrogen to obtain a compound having the structure shown in Formula 9; the catalyst for the reduction reaction is preferably a Lindlar catalyst or a P-2Ni catalyst;

[0035] Formula 9:

[0036] (4) When R in Formula 9 is R1=t-Bu, the preparation method of the compound having the structure shown in Formula 10 comprises the following steps:

[0037] The compound having the structure shown in Formula 9 is deprotected under acid catalysis to obtain a compound having the structure shown in Formula 10; the acid is preferably concentrated sulfuric acid, trifluoroacetic acid or hydrobromic acid, more preferably concentrated sulfuric acid;

[0038] When R in Formula 9 is R2=Bn, the preparation method of the compound having the structure shown in Formula 10 comprises the following steps:

[0039] The compound having the structure shown in Formula 9 is subjected to the action of trimethylsilyl chloride and sodium iodide to remove the benzyl group to obtain a compound having the structure shown in Formula 10;

[0040] Formula 10:

[0041] (5) The compound having the structure shown in Formula 10 is subjected to an Appel reaction with triphenylphosphine and a carbon tetrahalide to obtain a compound having the structure shown in Formula 2. The carbon tetrahalide is preferably carbon tetrabromide or carbon tetrachloride;

[0042] In Formula 7, Formula 8, and Formula 9, the type of R is the same as that in Formula 4.

[0043] 3. Preferably, the method for preparing the compound having the structure shown in Formula 3 comprises the following steps:

[0044] A compound having a structure shown in Formula 1 and a compound having a structure shown in Formula 2 are subjected to a Grignard reagent coupling reaction to obtain a compound having a structure shown in Formula 3; the catalyst used in the Grignard reagent coupling reaction is preferably Li2CuCl4, the molar ratio of the compound having a structure shown in Formula 1 to the catalyst is preferably 1:0.03~0.05, and the temperature of the Grignard reagent coupling reaction is preferably -20°C~0°C.

[0045] 4. Preferably, the preparation method of the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate comprises the following steps:

[0046] (1) removing the protecting group of the compound having the structure shown in Formula 3 under the catalysis of an acid to obtain a compound having the structure shown in Formula 11;

[0047] Formula 11:

[0048] (2) A compound having the structure shown in formula 11 is acetylated to obtain the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate I.

[0049] In the present invention, the alcoholic hydroxyl protecting group is preferably benzyl or tert-butyl. When tert-butyl is used as the protecting group, the deprotection yield is higher, so tert-butyl is most preferably used as the protecting group. In the tert-butyl protection step, the resin is preferably an ion exchange resin, more preferably Amberlyst 15 ion exchange resin. When the tert-butyl group is removed, the acid catalyst is preferably concentrated sulfuric acid, trifluoroacetic acid or hydrobromic acid. When the catalyst is concentrated sulfuric acid, the yield is the highest, so the acid catalyst is more preferably concentrated sulfuric acid. In the present invention, the catalyst used in the Grignard reagent coupling reaction is Li2CuCl4, and the molar ratio of the compound having the structure shown in Formula 1 to the catalyst is preferably 1:0.03 to 0.05, more preferably 1:0.03, and the temperature of the Grignard reagent coupling reaction is preferably -20°C to 0°C.

[0050] The technical solution of the present invention achieves the following beneficial technical effects:

[0051] The present invention uses 3-butyn-1-ol as a raw material and obtains two target fragments A and B through a convergent synthesis strategy. The two target fragments A and B undergo a Grignard reagent coupling reaction catalyzed by Li2CuCl4 to obtain a key intermediate, which is then reduced and acetylated to obtain the target product (3E,8Z)-3,8-tetradecadienyl acetate.

[0052] The method of the present invention is used to synthesize the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate, which does not involve the use of expensive metal catalysts and reagents, and does not involve a low-temperature (-78°C) reaction involving a strong base. The reaction conditions are mild, the requirements for equipment are low, and the method is not likely to endanger the health of workers, which is conducive to large-scale production. DETAILED DESCRIPTION

[0053]

[0054] Route 3

[0055] The following is a detailed description of the preparation method of (3E,8Z)-3,8-tetradecadienyl acetate in combination with the above three routes.

[0056] The present invention provides a compound having a structure represented by Formula 4 by protecting the alcoholic hydroxyl group of 3-butyn-1-ol under the catalysis of an acid and a resin. The acid is preferably concentrated sulfuric acid; the resin catalyst is preferably an ion exchange resin, and in a specific embodiment of the present invention, the ion exchange resin is preferably Amberlyst 15; the reaction solvent is preferably dichloromethane; the amounts of the acid, resin catalyst, and solvent are not particularly limited, as long as they allow the reaction to proceed smoothly; and the reaction temperature is preferably 0 to 20°C.

[0057] After the hydroxyl protection reaction is completed, the pH of the reaction solution is preferably adjusted to neutral with an aqueous sodium carbonate solution, then filtered to remove the resin catalyst, the aqueous phase is extracted with dichloromethane, the organic phase is washed with water, the organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Finally, vacuum distillation is performed to obtain a colorless, transparent liquid, i.e., the compound 4-(tert-butoxy)-1-butyne having the structure shown in Formula 4.

[0058] After obtaining the compound having the structure shown in Formula 4, it is treated with a Grignard reagent (denoted as Grignard reagent 1) and subjected to a Grignard reaction with an aldehyde to obtain a compound having the structure shown in Formula 5. In the present invention, the Grignard reagent is preferably ethylmagnesium bromide or butylmagnesium bromide; the preparation of the Grignard reagent 1 is preferably carried out under nitrogen or argon protection; the solvent used in the Grignard reagent 1 is preferably tetrahydrofuran, and the amount of tetrahydrofuran is not particularly required, as long as it allows the reaction to proceed smoothly; in a specific embodiment of the present invention, the preparation of the Grignard reagent 1 is preferably carried out under nitrogen protection. Magnesium chips and anhydrous tetrahydrofuran are added to a three-necked flask, stirred vigorously, and heated to 55-66°C. Then, an initiator is added to the reaction solution. After successful initiation, a mixture of the initiator and n-butyl bromide is added dropwise using a dropping funnel. After the addition is complete, stirring is continued for 10-30 minutes. The temperature is lowered to 10-30°C, and the remaining n-butyl bromide is continued to be added dropwise. After the addition is complete, the reaction is continued at this temperature for 1-2 hours, and the mixture is stored under nitrogen for standby use. The molar amount of magnesium chips used in the Grignard reagent 1 is greater than the total molar amount of the initiator and bromobutane; the initiator in the preparation of the Grignard reagent 1 is preferably 1,2-dibromoethane, iodine, an alkyl Grignard reagent or DIBAL-H, and there is no special requirement for the amount of the initiator, as long as the reaction can be initiated smoothly; the aldehyde is preferably paraformaldehyde; the molar ratio of the compound having the structure shown in Formula 4, the Grignard reagent 1 and the aldehyde is preferably 1:1.5 to 2:2; in the present invention, the temperature of the Grignard reaction is preferably 30 to 50°C; the time of the Grignard reaction is preferably 6 to 24 hours, more preferably 8 to 12 hours.

[0059] After the Grignard reaction is completed, the reaction solution is preferably poured into ice water, then filtered, the residual product in the solid is washed with ethyl acetate, and then the organic phase is washed with water, the organic phases are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. Finally, the crude product is purified by silica gel column chromatography to obtain a light yellow transparent liquid, i.e., a compound 5-(tert-butoxy)-2-pentyn-1-ol having a structure shown in Formula 5. The eluent for the silica gel column chromatography purification is preferably a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 10:1 to 4:1.

[0060] After obtaining the compound having the structure shown in Formula 5, it is reduced to obtain a compound having the structure shown in Formula 6. In the present invention, the catalyst for the reduction reaction is LiAlH4; the reduction reaction solvent is preferably tetrahydrofuran. In the present invention, there is no special requirement for the amount of tetrahydrofuran used, as long as it can allow the reduction reaction to proceed smoothly. In a specific embodiment of the present invention, LiAlH4 is preferably mixed with two-thirds volume of tetrahydrofuran solvent and stirred for 10 minutes, and then the compound having the structure shown in Formula 5 is dissolved in one-third volume of anhydrous tetrahydrofuran and added dropwise to the above mixture; the reduction reaction temperature is preferably room temperature; and the reaction time is preferably 2 to 6 hours.

[0061] After the reduction reaction is completed, the reaction is preferably placed in an ice bath, ethyl acetate is slowly added dropwise to the reaction solution until no bubbles are generated, and then water is added dropwise. The mixture is then filtered, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Finally, it is separated and purified by silica gel column chromatography to obtain a colorless transparent liquid, i.e., compound (E)-5-(tert-butoxy)-2-pentene-1-ol having a structure shown in Formula 6. The eluent for the silica gel column chromatography purification is preferably a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to ethyl acetate is preferably 10:1 to 4:1.

[0062] After obtaining the compound having the structure shown in Formula 6, it is acetylated (denoted as acetylation reaction 1) to obtain the compound having the structure shown in Formula 1. In the present invention, the acetylation agent is preferably acetic anhydride; the catalyst for the acetylation reaction is preferably DMAP; the acetylation reaction solvent is preferably dichloromethane, and the present invention has no special requirements for the amount of dichloromethane used, as long as it can smoothly proceed with the acetylation reaction; in the present invention, the molar ratio of the compound having the structure shown in Formula 6, the acetylation agent, and DMAP is preferably 1:1.2:0.1; the temperature of the acetylation reaction is preferably 10 to 30°C; and the acetylation reaction time is preferably 1 to 5 hours.

[0063] After the acetylation reaction is completed, the reaction mixture is preferably extracted with dichloromethane and water, the organic phase is dried and concentrated to obtain a crude product, and finally separated and purified by silica gel column chromatography to obtain a colorless transparent liquid, namely, the compound (E)-5-(tert-butoxy)-2-pentene-1-acetate having the structure represented by Formula 1. The eluent for the silica gel column chromatography purification is preferably a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 10:1 to 4:1.

[0064] The obtained compound having the structure represented by Formula 4 undergoes a bromination reaction with N-bromosuccinimide under the catalysis of silver nitrate to obtain a compound having the structure represented by Formula 7. In the present invention, the molar ratio of the compound having the structure represented by Formula 4 to silver nitrate is preferably 1:0.05; the molar ratio of the compound having the structure represented by Formula 4 to N-bromosuccinimide is preferably 1:1.2; the solvent for the bromination reaction is preferably acetone, and the present invention has no special requirements for the amount of acetone used, as long as it can smoothly proceed with the bromination reaction; the temperature of the bromination reaction is preferably room temperature, and the reaction time is preferably 1 to 3 hours.

[0065] After bromination reaction is completed, the reaction solution is preferably concentrated under reduced pressure, petroleum ether is added to the remaining mixture to make pulp, filtered, the product in the solid is cleaned with petroleum ether, the organic phase is washed with water, the organic phase is combined, and a crude product is obtained by drying over anhydrous sodium sulfate and concentrating under reduced pressure. Finally, it is separated and purified by silica gel column chromatography to obtain a light yellow transparent liquid, i.e., the compound 1-bromo-4-(tert-butoxy)-1-butyne with the structure shown in Formula 7. The eluent of the silica gel column chromatography purification is preferably a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether and ethyl acetate is preferably 20: 1.

[0066] The obtained compound having the structure shown in Formula 7 undergoes a cross-coupling reaction with a Grignard reagent (denoted as Grignard reagent 2) under the action of a Cu catalyst and a ligand to obtain a compound having the structure shown in Formula 8. In the present invention, the ligand is preferably N-methylpyrrolidone, triphenylphosphine or triethyl phosphate; the Cu catalyst is preferably a CuCl2 catalyst; the Grignard reagent 2 is preferably amylmagnesium bromide; in the present invention, the molar ratio of the compound having the structure shown in Formula 7, the catalyst and the ligand is preferably 1:0.03:0.04~0.1; the molar ratio of the compound having the structure shown in Formula 7 to the Grignard reagent 2 is preferably 1:1.2~1.5; in a specific embodiment of the present invention, the temperature when the Grignard reagent 2 is added dropwise is preferably -20~0°C, the dropwise addition time of the Grignard reagent 2 is preferably 40min, and the reaction time after the dropwise addition is completed is preferably 0.5~1h. In the present invention, the preparation method of the Grignard reagent 2, including the amount of reactants, reaction temperature, time, etc., is preferably the same as the preparation method of the Grignard reagent 1, and will not be repeated here.

[0067] After the reaction is completed, the reaction solution is preferably poured into a hydrochloric acid solution, the aqueous phase is extracted with petroleum ether, the organic phase is washed with water, the organic phases are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. Finally, the product is separated and purified by silica gel column chromatography to obtain a light yellow transparent liquid, i.e., 1-(tert-butoxy)-3-nonyne, a compound having a structure shown in Formula 8. The eluent for the silica gel column chromatography separation and purification is preferably a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to ethyl acetate is preferably 20:1.

[0068] After obtaining the compound having the structure shown in Formula 8, it is catalytically reduced to obtain a compound having the structure shown in Formula 9. The reaction environment of the reduction reaction is a hydrogen atmosphere; the catalyst is preferably a Lindlar catalyst or a P-2Ni catalyst, more preferably a P-2Ni catalyst; the molar ratio of sodium borohydride to nickel acetate tetrahydrate in the P-2Ni catalyst is preferably 1 to 1.5:1; the molar ratio of the compound having the structure shown in Formula 8, the catalyst, and ethylenediamine is preferably 1:0.25:0.5; the temperature of the reduction reaction is preferably room temperature; and the reduction reaction time is preferably 3 to 8 hours.

[0069] After the reduction reaction is completed, the reaction solution is preferably filtered through diatomaceous earth, the product remaining in the solid is washed with petroleum ether, the organic phase is washed with water, the organic phases are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. Finally, the product is separated and purified by silica gel column chromatography to obtain a colorless transparent liquid, i.e., compound (Z)-1-(tert-butoxy)-3-nonene having a structure shown in Formula 9. The eluent for the silica gel column chromatography separation and purification is preferably a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to ethyl acetate is preferably 20:1.

[0070] After obtaining the compound having the structure shown in Formula 9, the protecting group is removed under the catalysis of an acid to obtain a compound having the structure shown in Formula 10 (recorded as deprotection reaction one). The acid is preferably concentrated sulfuric acid, trifluoroacetic acid or hydrobromic acid, more preferably concentrated sulfuric acid. The deprotection reaction solvent is preferably methanol or dichloromethane, more preferably methanol; the amount of the acid catalyst in the deprotection reaction is preferably 10 to 50% of the molar amount of the compound having the structure shown in Formula 9, more preferably 30 to 50%; the deprotection reaction temperature is preferably 15 to 65°C, more preferably the deprotection reaction is carried out under reflux conditions; the deprotection reaction time is preferably 6 to 24 hours, more preferably 8 to 10 hours.

[0071] After the deprotection reaction is completed, the reaction solution is preferably neutralized with an alkaline solution, preferably one of sodium bicarbonate, sodium carbonate, or sodium hydroxide solution. The aqueous phase is then extracted with dichloromethane, and the organic phase is washed three times with water. The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Finally, vacuum distillation using an oil pump is performed to obtain a colorless, transparent liquid, i.e., compound (Z)-3-nonen-1-ol having the structure shown in Formula 10.

[0072] After obtaining the compound having the structure represented by Formula 10, an Appel reaction is performed with triphenylphosphine and a carbon tetrahalide to obtain a compound having the structure represented by Formula 2. The carbon tetrahalide is preferably carbon tetrabromide or carbon tetrachloride. In the present invention, the solvent used in the Appel reaction is preferably dichloromethane; there are no specific requirements for the amount of solvent used, as long as it ensures the smooth progress of the Appel reaction. In specific embodiments of the present invention, the Appel reaction temperature is preferably 0-10°C, and the Appel reaction time is preferably 0.5-3 hours.

[0073] After the Appel reaction is completed, the reaction solution is preferably subjected to vacuum distillation, followed by addition of petroleum ether for slurrying and filtration. The residual product in the solid is washed with petroleum ether, and the organic phases are combined, dried over sodium sulfate, and concentrated to obtain a crude product. Finally, vacuum distillation using an oil pump is performed to obtain a colorless, transparent liquid, i.e., the compound (Z)-3-nonene-1-bromide having the structure shown in Formula 2. The vacuum distillation temperature is preferably 100-130°C.

[0074] The obtained compound having the structure shown in Formula 1 and the Grignard reagent of the compound having the structure shown in Formula 2 (denoted as Grignard reagent 3) are subjected to a Grignard reagent coupling reaction to obtain a compound having the structure shown in Formula 3. The catalyst used in the Grignard reagent coupling reaction is Li2CuCl4, and the molar ratio of the compound having the structure shown in Formula 1 to the catalyst is preferably 1:0.03-0.05; in a specific embodiment of the present invention, the temperature of the Grignard reagent coupling reaction is -20°C to 0°C; and the reaction time is preferably 0.5-1h. In the present invention, the preparation method of the Grignard reagent 3, including the amount of reactants, reaction temperature, time, etc., is preferably consistent with the preparation method of the Grignard reagent 1, and will not be repeated here.

[0075] After the Grignard reagent coupling reaction is completed, the reaction solution is poured into ice water and filtered through celite. The aqueous phase is then extracted with petroleum ether. The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Finally, the product is separated and purified by silica gel column chromatography to obtain a colorless transparent liquid, i.e., the compound (3E,8Z)-1-(tert-butoxy)-3,8-tetradecadiene having the structure shown in Formula 3. The eluent for the silica gel column chromatography separation and purification is preferably a mixture of petroleum ether and ethyl acetate, with the volume ratio of petroleum ether to ethyl acetate preferably being 99:1.

[0076] After obtaining the compound having the structure shown in Formula 3, the protecting group is removed under acid catalysis (referred to as deprotection reaction 2) to obtain a compound having the structure shown in Formula 11, namely (3E,8Z)-3,8-tetradecadien-1-ol. In the present invention, the amount of reactants used in the deprotection reaction 2, as well as the reaction temperature, time, and post-treatment method are preferably the same as those in the deprotection reaction 1, and will not be repeated here.

[0077] After obtaining the compound having the structure represented by Formula 11, acetylation (referred to as acetylation reaction II) is performed to obtain the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate I. In the present invention, the amounts of reactants used in acetylation reaction II, as well as the reaction temperature, time, and post-treatment methods, are preferably the same as those in acetylation reaction I and are not further described here.

[0078] The following will be combined with the embodiments of the present invention, taking the case where R in Route 3 is R1=t-Bu as an example, to clearly and in detail describe the technical solution of the present invention.

[0079] Example 1

[0080] (1) Synthesis of 4-(tert-butoxy)-1-butyne (Formula 4):

[0081] Under an ice bath, 3-butyn-1-ol (50g, 715mmol), 500ml of dichloromethane, 3ml of concentrated sulfuric acid, and 2g of Amberlyst 15 were added to a 1L three-necked flask. Isobutylene was then added to the reaction mixture, and the reaction was allowed to proceed for 6-8 hours. The reaction was monitored by gas chromatography. After completion of the reaction, the pH of the reaction mixture was adjusted to neutral with aqueous sodium carbonate solution. The mixture was extracted with dichloromethane (150ml x 3) and water (70ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the fraction with a top temperature of 60-70°C was collected by vacuum distillation to obtain 4-(tert-butoxy)-1-butyne as a colorless, transparent liquid (74.9g, 94.7% yield). 1 HNMR (400MHz, CDCl3) δ3.47(t,J=7.3Hz,2H),2.39(td,J=7.3,2.6Hz,2H),1.95(t,J=2.7Hz,1H),1.19(s,9H). 13 C NMR (101MHz, CDCl3) δ81.73,73.18,68.98,60.27,27.48,20.80.

[0082] (2) Synthesis of 5-(tert-butoxy)-2-pentyn-1-ol (Formula 5):

[0083] Under nitrogen, add magnesium turnings (5g, 208mmol) and 230ml of anhydrous tetrahydrofuran to a clean, dry 500ml three-necked flask equipped with a magnetic rod. Stir vigorously and raise the temperature to 60°C. Add the initiator 1,2-dibromoethane (3g, 16mmol) to the reaction solution. After successful initiation, add a mixture of 1,2-dibromoethane (3g, 16mmol) and n-butyl bromide (3g, 22mmol) dropwise using a dropping funnel. Continue stirring for 15 minutes. Cool to 20°C and add the remaining n-butyl bromide (19g, 138mmol) dropwise. After addition is complete, continue the reaction at 20°C for 30 minutes to obtain butylmagnesium bromide Grignard reagent. Store under nitrogen for later use.

[0084] Under a nitrogen atmosphere, add 4-(tert-butoxy)-1-butyne (4.6 g, 36.5 mmol) and 110 ml of anhydrous tetrahydrofuran to a 250 ml three-necked flask. Place the flask in an ice bath and add the prepared butylmagnesium bromide Grignard reagent (54.8 mmol, 1.5 eq) with a syringe. After addition, raise the temperature to 40°C and stir for 2 hours. Then, cool to room temperature and add paraformaldehyde (2.2 g, 73 mmol). Allow to react at 40°C for 8 hours. Monitor the reaction by thin-layer chromatography. After completion, quench the reaction mixture by pouring it into 200 ml of ice water. Filter the reaction mixture through celite and extract with ethyl acetate (300 ml x 3) and water (100 ml x 3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Finally, the product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to obtain the product 5-(tert-butoxy)-2-pentyn-1-ol as a light yellow transparent liquid, 3.98 g, with a yield of 70%. 1 H NMR (400MHz, CDCl3) δ4.21(t,J=2.2Hz,2H),3.45(t,J=7.3Hz,2H),2.41(tt,J=7.3,2.2Hz,2H),2.20(s,1H),1.18(s,9H). 13 C NMR (101MHz, CDCl3) δ83.33,79.36,73.42,60.39,51.14,27.47,21.08.

[0085] (3) Synthesis of (E)-5-(tert-butoxy)-2-penten-1-ol (Formula 6):

[0086] Under an ice bath, lithium aluminum hydride (4 g, 105 mmol) and 200 ml of anhydrous tetrahydrofuran were added to a 500 ml three-necked flask and stirred for 10 minutes. 5-(tert-Butoxy)-2-pentyn-1-ol (11 g, 58 mmol) was then dissolved in 100 ml of anhydrous tetrahydrofuran and added dropwise to the mixture. The mixture was allowed to react at room temperature for 4 hours, monitored by gas chromatography. After the reaction was complete, the reaction mixture was placed under an ice bath. Ethyl acetate was slowly added dropwise until bubbles ceased. 200 ml of water was then added dropwise. The mixture was filtered and extracted with ethyl acetate (200 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product (E)-5-(tert-Butoxy)-2-penten-1-ol was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to obtain 9.6 g of (E)-5-(tert-Butoxy)-2-penten-1-ol as a colorless, transparent liquid in an 86.1% yield. 1 H NMR (400MHz, CDCl3) δ5.69(ddt,J=3.4,2.3,1.1Hz,2H),4.11–4.02(m,2H),3.37(t,J=7.0Hz,2H),2.31–2.22(m,2H),1.81(s,1H),1.17(s,9H). 13 C NMR (101MHz, CDCl3) δ130.66,129.66,72.84,63.63,61.17,33.56,27.53.

[0087] (4) Synthesis of (E)-5-(tert-butoxy)-2-pentene-1-acetate (Formula 1):

[0088] Under ice, to a 250ml three-necked flask were added (E)-5-(tert-butoxy)-2-penten-1-ol (7.9g, 41mmol), 80ml of dichloromethane, and DMAP (0.5g, 4mmol) in sequence. Acetic anhydride (6.3g, 62mmol) was then added dropwise with stirring. The mixture was allowed to react at room temperature for 3 hours, and the reaction was monitored by thin-layer chromatography. After completion of the reaction, the mixture was extracted with dichloromethane (150ml x 3) and water (70ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain (E)-5-(tert-butoxy)-2-penten-1-acetate as a colorless, transparent liquid (9g), with a yield of 90%. 1H NMR(400MHz, CDCl3) δ5.78(dtt,J=15.8,6.6,1.2Hz,1H),5.62(dtt,J=15.4,6.4,1.4Hz,1H),4.50( dd,J=6.3,1.2Hz,2H),3.37(t,J=7.0Hz,2H),2.27(qd,J=6.9,1.3Hz,2H),2.04(s,3H),1.17(s,9H). 13 C NMR (101MHz, CDCl3) δ170.82,133.01,125.40,72.76,65.16,60.91,33.60,27.52,21.00.

[0089] (5) Synthesis of 1-bromo-4-(tert-butoxy)-1-butyne (Formula 7):

[0090] At room temperature, 4-(tert-butoxy)-1-butyne (20 g, 158.7 mmol), 260 ml of acetone, and silver nitrate (1.4 g, 8.2 mmol) were added to a 500 ml three-necked flask. NBS (34 g, 191 mmol) was then added with stirring and allowed to react for 1.5 h. After the reaction, the mixture was concentrated under reduced pressure, slurried with petroleum ether, filtered through silica gel, and extracted with petroleum ether (300 ml x 3) and water (100 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain 1-bromo-4-(tert-butoxy)-1-butyne as a light yellow, transparent liquid (26.4 g, 81% yield). 1 H NMR (400MHz, CDCl3) δ3.45 (t, J = 7.3Hz, 2H), 2.40 (t, J = 7.3Hz, 2H), 1.18 (s, 9H). 13 C NMR (101MHz, CDCl3) δ77.61,73.32,60.05,38.75,27.48,22.01.

[0091] (6) Synthesis of 1-(tert-butoxy)-3-nonyne (Formula 8):

[0092] Under a nitrogen atmosphere, magnesium turnings (5g, 208mmol) and 230ml of anhydrous tetrahydrofuran were added to a clean, dry three-necked flask in sequence. The temperature was raised to 60°C. The initiator, 1,2-dibromoethane (3g, 21mmol), was added to the mixture. After successful initiation, a mixture of 1,2-dibromoethane (3g, 16mmol) and 1-bromopentane (3.3g, 22mmol) was added dropwise. Finally, the temperature was lowered to 20°C and the remaining 1-bromopentane (20.8g, 138mmol) was added dropwise. After the addition was complete, the mixture was stirred at 20°C for 30 minutes to obtain the pentylmagnesium bromide Grignard reagent. The mixture was stored under nitrogen and set aside.

[0093] Under nitrogen, CuCl2 (188 mg, 1.4 mmol), 38 ml of anhydrous tetrahydrofuran, 1-bromo-4-(tert-butoxy)-1-butyne (10 g, 48.7 mmol), and N-methylpyrrolidone (188 mg, 1.9 mmol) were added sequentially to a 250 ml three-necked flask. The reaction mixture was placed in an ice bath and stirred until the CuCl2 was completely dissolved. The prepared amylmagnesium bromide Grignard reagent (58.44 mmol, 1.2 eq) was then added dropwise to the mixture over 40 min. The reaction was allowed to proceed for 30 min after the addition was complete. The reaction solution was poured into a 1 M HCl solution and extracted with petroleum ether (200 ml x 3) and water (100 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain 1-(tert-butoxy)-3-nonyne as a light yellow transparent liquid, 6.9 g, with a yield of 72%. 1 H NMR (400MHz, CDCl3) δ3.43(t,J=7.5Hz,2H),2.35(tt,J=7.5,2.4Hz,2H),2.13(tt,J=7.2,2. 4Hz,2H),1.47(dq,J=9.4,6.7Hz,2H),1.40–1.24(m,4H),1.19(s,9H),0.89(t,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ81.23,76.98,73.03,60.98,31.06,28.74,27.52,22.22,21.13,18.72,13.98.

[0094] (7) Synthesis of (Z)-1-(tert-butoxy)-3-nonene (Formula 9):

[0095] Under a hydrogen atmosphere, nickel acetate tetrahydrate (4.4 g, 17.7 mmol) and 90 ml of ethanol were added to a 250 ml three-necked flask in sequence. The mixture was stirred thoroughly, followed by sodium borohydride (0.7 g, 17.7 mmol) and stirring at room temperature for 30 min. After 30 min, ethylenediamine (2.4 g, 35.4 mmol) was added to the flask. 1-(tert-Butoxy)-3-nonyne (14 g, 71.4 mmol) was dissolved in 65 ml of ethanol and added dropwise to the reaction mixture using a dropping funnel. The mixture was allowed to react at room temperature for 3-4 h. The reaction was complete when hydrogen consumption ceased. The reaction mixture was filtered and extracted with petroleum ether (150 ml x 3) and water (100 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain (Z)-1-(tert-butoxy)-3-nonene as a colorless transparent liquid, 13.1 g, with a yield of 93%. 1 H NMR (400MHz, CDCl3) δ5.52–5.40(m,1H),5.40–5.32(m,1H),3.32(t,J=7.4Hz,2H),2.26(qd, J=7.2,1.3Hz,2H),2.12–1.98(m,2H),1.39–1.22(m,6H),1.19(s,9H),0.89(t,J=6.7Hz,3H). 13 C NMR (101MHz, CDCl3) δ131.79,125.70,72.62,61.45,31.51,29.36,28.97,27.55,27.32,22.56,14.05.

[0096] (8) Synthesis of (Z)-3-nonen-1-ol (Formula 10):

[0097] To a 150ml three-necked flask, (Z)-1-(tert-butoxy)-3-nonene (13.9g, 70.2mmol) and 35ml of methanol were added sequentially. Concentrated sulfuric acid (3.5g, 35.1mmol, 50mol%) was then dissolved in 35ml of methanol and added dropwise to the mixture. The temperature was raised to reflux for 8h and the reaction was monitored by thin-layer chromatography. Upon completion of the reaction, the pH of the reaction mixture was adjusted to neutral with saturated sodium bicarbonate solution. The organic phase was extracted with ethyl acetate (150ml x 3) and then with water (100ml x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, the product (Z)-3-nonen-1-ol) was obtained as a colorless, transparent liquid (9.0g) with a yield of 90%. 1H NMR (400MHz, CDCl3) δ5.65–5.45(m,1H),5.45–5.30(m,1H),3.63(t,J=6.5Hz,2H),2.32(qd,J=6. 7,1.5Hz,2H),2.05(qd,J=7.2,1.6Hz,2H),1.63(s,1H),1.43–1.20(m,6H),0.88(t,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ133.52,124.94,62.33,31.49,30.79,29.36,27.32,22.54,14.03.

[0098] (9) Synthesis of (Z)-3-nonene-1-bromide (Formula 2):

[0099] Under ice, (Z)-3-nonen-1-ol (7.6 g, 53.5 mmol) and 70 ml of dichloromethane were added to a 250 ml three-necked flask. Triphenylphosphine (16.8 g, 64.2 mmol) was added while stirring. Finally, carbon tetrabromide (21.3 g, 64.2 mmol) was dissolved in 70 ml of dichloromethane and added dropwise to the reaction mixture. The reaction mixture was allowed to react for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, 150 ml of petroleum ether was added, the mixture was slurried, and the mixture was filtered. Finally, the mixture was extracted with petroleum ether (150 ml x 3) and water (50 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product was distilled under reduced pressure by oil pump, and the fraction at a top temperature of 100°C was collected to obtain (Z)-3-nonen-1-bromide as a colorless, transparent liquid, 10.7 g, with a yield of 97%. 1 H NMR (400MHz, CDCl3) δ5.87–5.19(m,2H),3.36(t,J=7.2Hz,2H),2.62(qd,J=7.2,1.5Hz,2H) ,2.03(qd,J=7.2,1.5Hz,2H),1.45–1.33(m,2H),1.33–1.22(m,4H),0.89(t,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ133.23,125.73,32.59,31.48,30.86,29.20,27.39,22.54,14.05.

[0100] (10) Synthesis of (3E,8Z)-1-(tert-butoxy)-3,8-tetradecadiene (Formula 3):

[0101] Under nitrogen, magnesium turnings (0.6 g, 25 mmol) and 25 ml of anhydrous tetrahydrofuran were added to a 250 ml three-necked flask in sequence. The temperature was raised to 60°C. The initiator, 1,2-dibromoethane (0.4 g, 2.1 mmol), was added and stirred for 5-10 minutes. A significant temperature rise accompanied by bubbling indicated successful initiation. A mixed solution of 1,2-dibromoethane (0.3 g, 1.6 mmol) and (Z)-3-nonene-1-bromide (0.3 g, 1.5 mmol) was then added dropwise. After addition, the mixture was stirred at 60°C for 10 minutes. The reaction mixture was cooled to 20°C and the remaining (Z)-3-nonene-1-bromide (2.9 g, 14.1 mmol) was added dropwise. Stirring was continued at this temperature for 30 minutes after addition. The mixture was stored under nitrogen and set aside.

[0102] To a 250ml three-necked flask, add copper chloride (43mg, 5mol%) and lithium chloride (27mg, 10mol%) and dry under reduced pressure at 100°C for 30 minutes. Add 10ml of anhydrous tetrahydrofuran under ice-salt bath, stir for 30 minutes, then add (E)-5-(tert-butoxy)-2-pentene-1-acetate (1.3g, 6.5mmol) and stir for 30 minutes. Begin the dropwise addition of the prepared Grignard reagent, and allow the reaction to continue for 30 minutes. Pour the reaction solution into 10ml of ice water, filter through celite, and extract with petroleum ether (30ml x 3) and water (10ml x 3). The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. Finally, the product (3E,8Z)-1-(tert-butoxy)-3,8-tetradecadiene) is isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1) to obtain 1.5g of (3E,8Z)-1-(tert-butoxy)-3,8-tetradecadiene as a colorless, transparent liquid in an 88% yield. 1 H NMR (400MHz, CDCl3) δ5.64–5.20(m,4H),3.33(t,J=7.3Hz,2H),2.28–2.14(m, 2H),2.09–1.90(m,6H),1.41–1.23(m,8H),1.18(s,9H),0.88(t,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ131.99,130.18,129.52,126.85,72.60,61.79,34.09,32.22,31.54,29.55,29.44,27.57,27.21,26.67,22.58,14.07.

[0103] (11) Synthesis of (3E,8Z)-3,8-tetradecadien-1-ol (Formula 11):

[0104] To a 250ml three-necked flask, (3E,8Z)-1-(tert-butoxy)-3,8-tetradecadiene (200mg, 0.75mmol) and 3ml of methanol were added sequentially. Concentrated sulfuric acid (37mg, 0.38mmol) was then dissolved in 2ml of methanol and added dropwise to the mixture. After the addition was complete, the mixture was heated to reflux and allowed to react for 8h. The reaction was monitored by thin-layer chromatography. Upon completion of the reaction, the pH of the reaction mixture was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (50ml x 3) and water (20ml x 3), respectively. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain (3E,8Z)-3,8-tetradecadien-1-ol as a colorless, transparent liquid (150mg, 95% yield). 1 H NMR(400MHz, CDCl3)δ5.55(dt,J=13.4,6.6Hz,1H),5.46–5.26(m,3H),3.62(t,J=6.3Hz,2H),2 .26(q,J=6.6Hz,2H),2.15–1.90(m,6H),1.57(s,1H),1.41–1.23(m,8H),0.88(t,J=6.8Hz,3H). 13 CNMR (101MHz, CDCl3) δ133.99,130.32,129.34,126.01,62.05,36.00,32.23,31.52,29.50,29.42,27.20,26.69,22.57,14.06.

[0105] (12) Synthesis of the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate (Ⅰ):

[0106] To a 100ml round-bottom flask were added (3E,8Z)-3,8-tetradecadien-1-ol (200mg, 0.95mmol), 5ml of dichloromethane, and DMAP (5mg, 10mol%). Acetic anhydride (146mg, 1.43mmol) was then added dropwise in an ice bath and allowed to react at room temperature for 3h. After completion of the reaction, the mixture was extracted with petroleum ether (50ml x 3) and water (20ml x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Finally, the product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to obtain (3E,8Z)-3,8-tetradecadien-1-ol as a colorless, transparent liquid (220mg, 93% yield). 1HNMR (400MHz, CDCl3) δ5.58–5.45(m,1H),5.45–5.28(m,3H),4.06(t,J=6.9Hz,2H),2. 31(qd,J=6.8,1.3Hz,2H),2.11–1.92(m,9H),1.49–1.22(m,8H),0.87(t,J=6.9Hz,3H). 13 CNMR (101MHz, CDCl3) δ171.09,133.27,130.29,129.37,125.29,64.12,32.15,31.96,31.52,29.44,29.43,27.20,26.63,22.57,20.96,14.06.

[0107] Example 2

[0108] (1) Synthesis of 4-(tert-butoxy)-1-butyne (Formula 4):

[0109] Under an ice bath, 3-butyn-1-ol (20 g, 286 mmol), 200 ml of dichloromethane, and 2 ml of concentrated sulfuric acid were added sequentially to a 1 L three-necked flask. Isobutylene was then introduced into the reaction mixture, and the reaction was allowed to proceed for 6-8 hours. Gas chromatography was used to monitor the reaction. A small amount of residual starting material remained. The pH of the reaction mixture was adjusted to neutral with aqueous sodium carbonate solution. The mixture was extracted with dichloromethane (150 ml x 3) and water (70 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. Finally, the fraction with a top temperature of 60-70°C was collected by vacuum distillation to yield 4-(tert-butoxy)-1-butyne as a colorless, transparent liquid (28.4 g, 78.9% yield).

[0110] (2) Synthesis of 5-(tert-butoxy)-2-pentyn-1-ol (Formula 5):

[0111] The preparation method of butylmagnesium bromide Grignard reagent (amount of reactants, reaction temperature and time, etc.) is the same as that in Example 1 and will not be repeated here.

[0112] Under a nitrogen atmosphere, add 4-(tert-butoxy)-1-butyne (4.6 g, 36.5 mmol) and 110 ml of anhydrous tetrahydrofuran to a 250 ml three-necked flask. Place the flask in an ice bath and add the prepared butylmagnesium bromide Grignard reagent (54.8 mmol, 1.5 eq) with a syringe. After addition, raise the temperature to 30°C and stir for 2 hours. Then, cool to room temperature and add paraformaldehyde (2.2 g, 73 mmol). Allow to react at 30°C for 8 hours. Monitor the reaction by thin-layer chromatography. After completion, quench the reaction mixture by pouring it into 200 ml of ice water. Filter the reaction mixture through celite and extract with ethyl acetate (300 ml x 3) and water (100 ml x 3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Finally, the product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to obtain the product 5-(tert-butoxy)-2-pentyn-1-ol as a light yellow transparent liquid, 3.4 g, with a yield of 60%.

[0113] (3) Synthesis of (E)-5-(tert-butoxy)-2-penten-1-ol (Formula 6):

[0114] Under an ice bath, lithium aluminum hydride (4 g, 105 mmol) and 200 ml of anhydrous tetrahydrofuran were added to a 500 ml three-necked flask and stirred for 10 minutes. 5-(tert-Butoxy)-2-pentyn-1-ol (11 g, 58 mmol) was then dissolved in 100 ml of anhydrous tetrahydrofuran and added dropwise to the mixture. The mixture was allowed to react at room temperature for 4 hours, monitored by gas chromatography. After the reaction was complete, the reaction mixture was placed under an ice bath. Ethyl acetate was slowly added dropwise until bubbles ceased. 200 ml of water was then added dropwise. The mixture was filtered and extracted with ethyl acetate (200 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product (E)-5-(tert-Butoxy)-2-penten-1-ol was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to obtain 9.6 g of (E)-5-(tert-Butoxy)-2-penten-1-ol as a colorless, transparent liquid in an 86.1% yield.

[0115] (4) Synthesis of (E)-5-(tert-butoxy)-2-pentene-1-acetate (Formula 1):

[0116] Under ice, to a 250ml three-necked flask were added (E)-5-(tert-butoxy)-2-penten-1-ol (7.9g, 41mmol), 80ml of dichloromethane, and DMAP (0.5g, 4mmol) in sequence. Acetic anhydride (6.3g, 62mmol) was then added dropwise with stirring. The mixture was allowed to react at room temperature for 3 hours, and the reaction was monitored by thin-layer chromatography. After completion of the reaction, the mixture was extracted with dichloromethane (150ml x 3) and water (70ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain (E)-5-(tert-butoxy)-2-penten-1-acetate as a colorless, transparent liquid (9g), with a yield of 90%.

[0117] (5) Synthesis of 1-bromo-4-(tert-butoxy)-1-butyne (Formula 7):

[0118] At room temperature, 4-(tert-butoxy)-1-butyne (20 g, 158.7 mmol), 260 ml of acetone, and silver nitrate (1.4 g, 8.2 mmol) were added to a 500 ml three-necked flask. NBS (34 g, 191 mmol) was then added with stirring and allowed to react for 1.5 h. After the reaction, the mixture was concentrated under reduced pressure, slurried with petroleum ether, filtered through silica gel, and extracted with petroleum ether (300 ml x 3) and water (100 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain 1-bromo-4-(tert-butoxy)-1-butyne as a light yellow, transparent liquid (26.4 g, 81% yield).

[0119] (6) Synthesis of 1-(tert-butoxy)-3-nonyne (Formula 8):

[0120] The preparation method of amylmagnesium bromide Grignard reagent (amount of reactants, reaction temperature and time, etc.) is the same as that in Example 1 and will not be repeated here.

[0121] Under a nitrogen atmosphere, CuCl2 (40 mg, 0.3 mmol), 38 ml of anhydrous tetrahydrofuran, 1-bromo-4-(tert-butoxy)-1-butyne (2.3 g, 11.2 mmol), and triphenylphosphine (262 mg, 1 mmol) were added sequentially to a 250 ml three-necked flask. The reaction mixture was placed in an ice bath and stirred until the CuCl2 was completely dissolved. The prepared amylmagnesium bromide Grignard reagent (13.44 mmol, 1.2 eq) was then added dropwise to the mixture over 40 min, and the reaction was allowed to proceed for 30 min. The reaction solution was poured into dilute hydrochloric acid and extracted with petroleum ether (100 ml x 3) and water (50 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product, 1-(tert-butoxy)-3-nonyne, was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain 1.5 g of 1-(tert-butoxy)-3-nonyne as a light yellow, transparent liquid in a yield of 68.2%.

[0122] (7) Synthesis of (Z)-1-(tert-butoxy)-3-nonene (Formula 9):

[0123] Under a hydrogen atmosphere, nickel acetate tetrahydrate (4.4 g, 17.7 mmol) and 90 ml of ethanol were added to a 250 ml three-necked flask in sequence. The mixture was stirred thoroughly, followed by sodium borohydride (0.7 g, 17.7 mmol) and stirring at room temperature for 30 min. After 30 min, ethylenediamine (2.4 g, 35.4 mmol) was added to the flask. 1-(tert-Butoxy)-3-nonyne (14 g, 71.4 mmol) was dissolved in 65 ml of ethanol and added dropwise to the reaction mixture using a dropping funnel. The mixture was allowed to react at room temperature for 3-4 h. The reaction was complete when hydrogen consumption ceased. The reaction mixture was filtered and extracted with petroleum ether (150 ml x 3) and water (100 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain the product (Z)-1-(tert-butoxy)-3-nonene as a colorless transparent liquid, 13.1 g, with a yield of 93%.

[0124] (8) Synthesis of (Z)-3-nonen-1-ol (Formula 10):

[0125] To a 150ml three-necked flask, (Z)-1-(tert-butoxy)-3-nonene (0.4g, 1.4mmol) and 1ml of methanol were added sequentially. Concentrated sulfuric acid (52mg, 0.4mmol, 30mol%) was then dissolved in 35ml of methanol and added dropwise to the mixture. The temperature was raised to reflux for 16h and the reaction was monitored by thin-layer chromatography. After the reaction, the pH of the reaction mixture was adjusted to neutral with saturated sodium bicarbonate solution. The organic phase was extracted with ethyl acetate (30ml x 3) and then with water (15ml x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, the product (Z)-3-nonen-1-ol was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain 0.25g of (Z)-3-nonen-1-ol as a colorless, transparent liquid in an 88% yield.

[0126] (9) Synthesis of (Z)-3-nonene-1-bromide (Formula 2):

[0127] Under ice, (Z)-3-nonen-1-ol (7.6 g, 53.5 mmol) and 70 ml of dichloromethane were added to a 250 ml three-necked flask. Triphenylphosphine (16.8 g, 64.2 mmol) was added while stirring. Finally, carbon tetrabromide (21.3 g, 64.2 mmol) was dissolved in 70 ml of dichloromethane and added dropwise to the reaction mixture. The reaction mixture was allowed to react for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, 150 ml of petroleum ether was added, the mixture was slurried, and the mixture was filtered. Finally, the mixture was extracted with petroleum ether (150 ml x 3) and water (50 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product was distilled under reduced pressure by oil pump, and the fraction at a top temperature of 100°C was collected to obtain (Z)-3-nonen-1-bromide as a colorless, transparent liquid, 10.7 g, with a yield of 97%.

[0128] (10) Synthesis of (3E,8Z)-1-(tert-butoxy)-3,8-tetradecadiene (Formula 3):

[0129] Under nitrogen, magnesium turnings (0.6 g, 25 mmol) and 25 ml of anhydrous tetrahydrofuran were added to a 250 ml three-necked flask in sequence. The temperature was raised to 60°C. The initiator, 1,2-dibromoethane (0.4 g, 2.1 mmol), was added and stirred for 5-10 minutes. A significant temperature rise accompanied by bubbling indicated successful initiation. A mixed solution of 1,2-dibromoethane (0.3 g, 1.6 mmol) and (Z)-3-nonene-1-bromide (0.3 g, 1.5 mmol) was then added dropwise. After addition, the mixture was stirred at 60°C for 10 minutes. The reaction mixture was cooled to 20°C and the remaining (Z)-3-nonene-1-bromide (2.9 g, 14.1 mmol) was added dropwise. Stirring was continued at this temperature for 30 minutes after addition. The mixture was stored under nitrogen and set aside.

[0130] To a 250ml three-necked flask, add copper chloride (43mg, 5mol%) and lithium chloride (27mg, 10mol%) and dry under reduced pressure at 100°C for 30 minutes. Add 10ml of anhydrous tetrahydrofuran under ice-salt bath, stir for 30 minutes, then add (E)-5-(tert-butoxy)-2-pentene-1-acetate (1.3g, 6.5mmol) and stir for 30 minutes. Begin the dropwise addition of the prepared Grignard reagent, and allow the reaction to continue for 30 minutes. Pour the reaction solution into 10ml of ice water, filter through celite, and extract with petroleum ether (30ml x 3) and water (10ml x 3). The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. Finally, the product (3E,8Z)-1-(tert-butoxy)-3,8-tetradecadiene) is isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1) to obtain 1.5g of (3E,8Z)-1-(tert-butoxy)-3,8-tetradecadiene as a colorless, transparent liquid in an 88% yield.

[0131] (11) Synthesis of (3E,8Z)-3,8-tetradecadien-1-ol (Formula 11):

[0132] To a 250ml three-necked flask, (3E,8Z)-1-(tert-butoxy)-3,8-tetradecadiene (200mg, 0.75mmol) and 3ml of methanol were added sequentially. Concentrated sulfuric acid (37mg, 0.38mmol) was then dissolved in 2ml of methanol and added dropwise to the mixture. After the addition was complete, the mixture was heated to reflux and allowed to react for 8h. The reaction was monitored by thin-layer chromatography. Upon completion of the reaction, the pH of the reaction mixture was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (50ml x 3) and water (20ml x 3), respectively. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain (3E,8Z)-3,8-tetradecadien-1-ol as a colorless, transparent liquid (150mg, 95% yield).

[0133] (12) Synthesis of the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate (Ⅰ):

[0134] To a 100ml round-bottom flask were added (3E,8Z)-3,8-tetradecadien-1-ol (200mg, 0.95mmol), 5ml of dichloromethane, and DMAP (5mg, 10mol%). Acetic anhydride (146mg, 1.43mmol) was then added dropwise in an ice bath and allowed to react at room temperature for 3h. After completion of the reaction, the mixture was extracted with petroleum ether (50ml x 3) and water (20ml x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Finally, the product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to obtain (3E,8Z)-3,8-tetradecadien-1-ol as a colorless, transparent liquid (220mg, 93% yield).

[0135] The results of the examples show that the present invention synthesizes (3E,8Z)-3,8-tetradecadienyl acetate, a minor component of the tomato leafminer sex pheromone, starting from the commercially available reagent 3-butyn-1-ol. The total yield, calculated using the longest reaction route (10 steps), is 22.7%. Overall, the method of the present invention for synthesizing (3E,8Z)-3,8-tetradecadienyl acetate, avoids the use of expensive metal catalysts and reagents, and does not involve a low-temperature (-78°C) reaction involving a strong base. The reaction conditions are mild, making it suitable for large-scale production.

[0136] The above description is only a preferred specific embodiment of the present invention, and the protection scope of the present invention is not limited thereto. All equivalent technical solutions also fall within the protection scope of the present invention.

Claims

1. A method for synthesizing the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate, characterized in that: The following steps are included: (1) Using 3-butyn-1-ol as the starting material, the target fragment A having the structure shown in Formula 1 is obtained through hydroxyl protection, Grignard reaction, reduction, and acetylation; (2) the protected 3-butyn-1-ol is subjected to bromination reaction to obtain alkynyl bromide, the alkynyl bromide is subjected to cross-coupling reaction with a Grignard reagent, reduced, deprotected and halogenated to obtain the target fragment B having the structure shown in Formula 2; (3) The target fragments A and B undergo a Grignard reagent coupling reaction under the catalysis of Li2CuCl4 to obtain a key intermediate having the structure shown in Formula 3; (4) Finally, the target product, tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate I, was obtained by deprotection and acetylation; Formula 1: Formula 2: Formula 3: I The alcoholic hydroxyl protecting group R in Formula 1 and Formula 3 is t-Bu, Bn; in Formula 2, X is Cl, Br or I; The method for preparing the compound having the structure shown in Formula 1 comprises the following steps: (1.1) When R in Formula 1 is R1=t-Bu, the method for preparing the compound having the structure shown in Formula 4 comprises the following steps: 3-Butyn-1-ol is catalyzed by acid and resin to protect the alcoholic hydroxyl group to obtain a compound having the structure shown in Formula 4; When R in Formula 1 is R2=Bn, the preparation method of the compound having the structure shown in Formula 4 comprises the following steps: 3-Butyn-1-ol reacts with a benzyl halide in the presence of a base and TBAB to obtain a compound having a structure shown in Formula 4; Formula 4: (2.1) The compound having the structure shown in Formula 4 is treated with a Grignard reagent and reacts with an aldehyde to obtain a compound having the structure shown in Formula 5; Formula 5: (3.1) The compound having the structure shown in Formula 5 is reduced to obtain a compound having the structure shown in Formula 6; Formula 6 (4.1) A compound having the structure shown in Formula 6 is acetylated to obtain a compound having the structure shown in Formula 1; In Formula 5, Formula 6, and Formula 1, the type of R is the same as that in Formula 4; The method for preparing the compound having the structure shown in Formula 2 comprises the following steps: (1.2) The compound having the structure of Formula 4 is subjected to a bromination reaction with N-bromosuccinimide catalyzed by silver nitrate to obtain a compound having the structure of Formula 7; Formula 7: (2.2) The compound having the structure shown in Formula 7 undergoes a cross-coupling reaction with a Grignard reagent in the presence of a copper catalyst and a ligand to obtain a compound having the structure shown in Formula 8; Formula 8: (3.2) The compound having the structure shown in Formula 8 is reduced by catalytic hydrogen to obtain the compound having the structure shown in Formula 9; Formula 9: (4.2) When R in Formula 9 is R1=t-Bu, the method for preparing the compound having the structure shown in Formula 10 comprises the following steps: The compound having the structure shown in Formula 9 is subjected to acid catalysis to remove the tert-butyl group to obtain a compound having the structure shown in Formula 10; When R in Formula 9 is R2=Bn, the preparation method of the compound having the structure shown in Formula 10 comprises the following steps: The compound having the structure shown in Formula 9 is subjected to the action of trimethylsilyl chloride and sodium iodide to remove the benzyl group to obtain a compound having the structure shown in Formula 10; Formula 10; (5.2) The compound having the structure shown in Formula 10 undergoes an Appel reaction with triphenylphosphine and carbon tetrahalide to obtain a compound having the structure shown in Formula 2; In Formula 7, Formula 8, and Formula 9, the type of R is the same as that in Formula 4.

2. The method for synthesizing the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate according to claim 1, characterized in that: The method comprises the following steps: (1) removing the tert-butyl group from the compound having the structure shown in Formula 3 under acid catalysis to obtain a compound having the structure shown in Formula 11; Formula 11: (2) A compound having the structure shown in formula 11 is acetylated to obtain the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate I.

3. The method for synthesizing the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate according to claim 1, characterized in that: In step (1.1), the resin is Amberlyst 15 ion exchange resin.

4. The method for synthesizing the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate according to claim 1, characterized in that: In step (2.1), the Grignard reagent is ethylmagnesium bromide or butylmagnesium bromide; and the reaction temperature is 30-50°C.

5. The method for synthesizing the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate according to claim 1, characterized in that: In step (2.2), the ligand is N-methylpyrrolidone, triphenylphosphine or triethyl phosphate.

6. The method for synthesizing the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate according to claim 1, characterized in that: In step (3.2), the catalyst is a P-2Ni catalyst or a Lindlar catalyst.

7. The method for synthesizing the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate according to claim 1, characterized in that: In step (4.2), the acid is concentrated sulfuric acid, trifluoroacetic acid or hydrobromic acid.

8. The method for synthesizing the tomato leafminer sex pheromone (3E,8Z)-3,8-tetradecadienyl acetate according to claim 1, characterized in that: The molar ratio of the compound having the structure shown in Formula 1 to the catalyst is 1:0.03-0.05; and the temperature of the Grignard reagent coupling reaction is -20-0°C.

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