A method for synthesizing cis, cis, cis-3,6,9-heptadecatriene

Abstract

The invention provides a kind of cis, cis, cis-3,6,9-heptatriene synthesis method, including (1) under the action of butyl lithium, n-octanal and (1-propanol) triphenylphosphine bromide react to generate cis-3-undecenol; (2) cis-3-undecenol and Dess-Martin oxidant / N, N-dimethylcyclohexylamine generate cis-unsaturated olefinic aldehyde; (3) under the action of bis(trimethylsilyl) sodium amide, the cis-unsaturated olefinic aldehyde obtained by step (2) reacts with (cis-3-hexenyl) triphenylphosphine iodide to generate cis, cis, cis-3,6,9-heptatriene. The present invention uses n-octanal as raw material, and through three-step reaction, cis, cis, cis-3,6,9-heptatriene can be obtained. The synthesis method provided by the present invention has few reaction steps, high yield, good stereoselectivity, and is conducive to industrial production.

Description

Technical Field

[0001] The invention belongs to the field of insect pheromone synthesis, and specifically relates to a method for synthesizing cis, cis, cis-3,6,9-heptadecatriene. Background Art

[0002] Pheromones are a general term for trace chemical substances that play a role in chemical communication between organisms. They are compounds used by insects to indicate various information such as aggregation, foraging, mating, and alertness. They are the chemical molecular language of insect communication. Using insects' own semiochemical substances to control the harm of pests or to interfere with and prevent pests from causing harm is an efficient, non-toxic, and pollution-free technology with broad application prospects. At present, the application of pheromones has approached 1% of the global pesticide market, and the growth trend is significant.

[0003] The activity of insect pheromones is closely related to the structure of their chemical components. The chemical structures of pheromone components can be mainly divided into Type I and Type II. Type I is a C 10 -C 18 Alcohol, aldehyde, acetate compounds, this type of pheromone exists in most moth insects; Type II is C 17 -C 23 Unsaturated hydrocarbons and their corresponding epoxy derivatives are widely distributed in geometrids, moths and noctuids. Among them, cis, cis, cis-3,6,9-heptadecatriene is an important component of the pheromone of the Sophora japonica geometrid.

[0004] Chemical synthesis is the main source of a large number of pheromones and an important basis for the industrialization of pheromone control. 18 -C 23The research on the synthesis of unsaturated hydrocarbons mainly uses α-linolenic acid derivatives as raw materials, and uses cis-triene in the α-linolenic acid structure to synthesize through lithium aluminum hydride reduction, halogenation or sulfonation, and Grignard reaction, but this method cannot synthesize cis, cis, cis-3,6,9-heptadecatriene. At present, there are few studies on the synthesis method of cis, cis, cis-3,6,9-heptadecatriene. Millar et al. (1987) used 1-nonyne and 1-toluenesulfonyloxy-2,5-octanediyne as raw materials, and prepared cis, cis, cis-3,6,9-heptadecatriene through the method of Grignard reagent ethylmagnesium bromide catalytic coupling and borohydride reduction. However, the raw materials used in this method are not easy to prepare, the synthesis conditions are harsh, and it is not easy to mass produce. Liu Tianlin et al. (1991) used propargyl alcohol as a raw material to synthesize 2-pentynol with ethyl bromide under the catalysis of lithium amide, and then brominated it with phosphorus tribromide to obtain a bromide, which was then coupled with a di-Grignard reagent of propargyl alcohol to generate 2,5-octanediyne-1-ol, and then brominated. The bromide was coupled with a Grignard reagent of 1-nonyne to obtain 3,6,9-heptadecatriyne, and finally catalyzed by Lindlar catalyst to prepare cis, cis, cis-3,6,9-heptadecatriene. The Grignard intermediates used in this method are difficult to prepare and difficult to preserve. At the same time, the method has a long synthesis step and is not easy to scale up for production.

[0005] The existing synthesis technology cannot provide sufficient pheromones to meet the needs of subsequent activity testing, resulting in stagnation in the research and development of finished Sophora japonica looper pheromones. Therefore, developing an efficient method for preparing cis, cis, cis-3,6,9-heptadecatriene is an important research topic in this technical field. Summary of the invention

[0006] In order to solve the shortcomings of the prior art, the present invention provides a method for synthesizing cis, cis, cis-3,6,9-heptadecatriene, using n-octanal as a raw material and preparing cis, cis, cis-3,6,9-heptadecatriene through three-step reactions.

[0007] Specifically, the synthesis method comprises the following steps:

[0008] (1) Under the action of butyl lithium, n-octanal reacts with (1-propanol)triphenylphosphonium bromide to generate cis-3-undecenol;

[0009] (2) cis-3-undecenyl alcohol reacts with Dess-Martin oxidant / N,N-dimethylcyclohexylamine to generate cis-unsaturated enal;

[0010] (3) Under the action of sodium bis(trimethylsilyl)amide, the cis-unsaturated aldehyde obtained in step (2) reacts with (cis-3-hexenyl)triphenylphosphine iodide to generate cis,cis,cis-3,6,9-heptadecatriene.

[0011] Wherein, the solvent used in step (1) is tetrahydrofuran;

[0012] The molar ratio of n-octanal, (1-propanol)triphenylphosphonium bromide and butyl lithium is 0.84:1:1.

[0013] The solvent used in step (2) is dichloromethane;

[0014] The molar ratio of cis-3-undecenol, Dess-Martin periodinane and N,N-dimethylcyclohexylamine is 1:1.1:1.1.

[0015] The solvent used in step (3) is tetrahydrofuran;

[0016] The molar ratio of cis-unsaturated aldehyde, (cis-3-hexenyl)triphenylphosphine iodide and sodium bis(trimethylsilyl)amide is 1:1.2:1.2.

[0017] Specifically,

[0018] In the step (1), N 2 Under a CO atmosphere, (1-propanol)triphenylphosphonium bromide and a tetrahydrofuran solution of butyl lithium were mixed at -25°C, stirred at room temperature for 30 min, cooled to -25°C again, and then a tetrahydrofuran solution of n-octanal was added and reacted for 4 h.

[0019] In the step (2), N,N-dimethylcyclohexylamine is added to a dichloromethane solution of Dess-Martin periodinane at 0° C., stirred for 20 min, and then cis-3-undecenol is added and reacted for 60 min.

[0020] In the step (3), in N 2 Under the atmosphere, a tetrahydrofuran solution of (cis-3-hexenyl) triphenylphosphine iodide and sodium bis(trimethylsilyl)amide are mixed at -78°C, stirred at room temperature for 30 minutes, and then cooled to -78°C again, and a tetrahydrofuran solution of cis-unsaturated aldehyde is added to react for 4 hours. The steps (1) and (3) also include a purification step. Specifically, after reacting for 4 hours, methanol is added to terminate the reaction, and then ether and water are added for liquid extraction. The organic phase is retained, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a product. More specifically, the reduced pressure concentration can be carried out by rotary evaporation to evaporate the organic solvent.

[0021] After the step (2) was reacted for 60 minutes, the oxidant was removed by vacuum filtration, and the solvent was removed by rotary evaporation.

[0022] Beneficial effects of the present invention:

[0023] (1) The present invention provides a simple synthesis method of cis, cis, cis-3,6,9-heptadecatriene, which uses cheap n-octanal as a raw material and can prepare cis, cis, cis-3,6,9-heptadecatriene through only three steps of reaction.

[0024] (2) Cis-β,γ-unsaturated aldehydes are very important synthetic intermediates in organic synthesis. Since such compounds have high reactivity and are structurally unstable, double bonds are easily isomerized or migrated, resulting in low yield and many side reactions (Islam A, et al, Journal Chemical Ecology, 2007, 33(9):1763-73). The present invention uses a combination of Dess-Martin and N,N-dimethylcyclohexylamine in the process of synthesizing cis-β,γ-unsaturated aldehydes, thereby avoiding the generation of trans-β,γ-unsaturated aldehydes, ensuring that the final products are all cis-configuration, and facilitating mass production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is a synthetic route of cis, cis, cis-3,6,9-heptadecatriene;

[0026] Figure 2 Comparison of the NMR images of cis, cis, cis-3,6,9-heptadecatriene and cis, cis, trans-3,6,9-heptadecatriene. DETAILED DESCRIPTION

[0027] The present invention is further illustrated and described below in conjunction with embodiments, but the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the present invention and embodiments, all other inventions and embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0028] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0029] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0030] (1-Propanol)triphenylphosphine bromide and (cis-3-hexenyl)triphenylphosphine iodide were prepared by methods well known in the art, such as the method disclosed in Seongjin Kim et al, "The first total synthesis of iPF 4α-VI and its deuterated analog" [J]. Tetrahedron Letters, 2002, 43 (15): 2801-2805.

[0031] Example 1 Synthesis of cis-3-undecenyl alcohol

[0032] In N 2 Under the atmosphere, 32.00g (0.08mol) (1-propanol) triphenylphosphonium bromide was dissolved in 100ml tetrahydrofuran (THF), 32ml (0.08mol) butyl lithium (2.5M tetrahydrofuran solution) was added at -25°C, and then stirred at room temperature for 30min; cooled to -25°C again, and 12ml of 5.6M octanal THF solution was slowly added. After reacting for 4h, 5ml methanol was added to terminate the reaction, 50ml ether and 20ml water were added for liquid extraction, and the organic phase was collected, dried over anhydrous sodium sulfate, the organic solvent was removed by rotary evaporation, and purified by silica gel column chromatography to obtain 9.75g cis-3-undecenol with a purity of 96% and a yield of 86%.

[0033] The NMR data of the obtained product: 1 H NMR (500 MHz, CDCl 3 )δ:0.88[3H,m],1.22-1.35[10H,m],1.95-2.12[2H,m],2.23-2.37[2H,m],3.59-3.67[2H,m],5.32-5.44[1H,m],5.50-5.61[1H,m].

[0034] The mass spectrum data of the obtained product: GC-MS (70eV, EI): 170, the chemical formula is C 11 H 22 O.

[0035] Example 2 Synthesis of cis, cis, cis-3,6,9-heptadecatriene

[0036] At 0°C, 4.20 g (0.033 mol) of N,N-dimethylcyclohexylamine was added to 20 ml of a 1.65 M solution of Dess-Martin periodinane (13.99 g, 0.033 mol), stirred for 20 min, then 5.10 g (0.03 mol) of cis-3-undecenol prepared in Example 1 was slowly added and reacted for 60 min. The oxidant was removed by vacuum filtration, and the solvent was removed by rotary evaporation to obtain the oxidation product, cis-unsaturated aldehyde, which could be carried out in the next step without purification.

[0037] In N 2Under the atmosphere, 16.99g (0.036mol) (cis-3-hexenyl) triphenylphosphine iodide was dissolved in 50ml tetrahydrofuran (THF), and 36ml (0.036mol) sodium bis(trimethylsilyl)amide (1M tetrahydrofuran solution) was added at -78°C, and then stirred at room temperature for 30min; cooled to -78°C again, and 5ml of 6.0M THF solution of the above oxidation product was slowly added. After reacting for 4h, 5ml of methanol was added to terminate the reaction, and 20ml of ether and 10ml of water were added for liquid extraction, and the organic phase was collected, dried over anhydrous sodium sulfate, the organic solvent was evaporated by rotary evaporation, and purified by silica gel column chromatography to obtain 5.65g of cis, cis, cis-3,6,9-heptadecatriene, with a two-step yield of 76% and a purity of 97%.

[0038] The NMR data of the obtained product:

[0039] Cis, cis, cis-3,6,9-heptadecatriene: 1 H NMR (500 MHz, CDCl 3 )δ:0.87[3H,m],0.99[3H,m],1.32[10H,m],2.06[4H,m],2.81[4H,m],5.34[6H,m].

[0040] The mass spectrum data of the obtained product: GC-MS (70eV, EI): 248, the chemical formula is C 17 H 30 .

[0041] Test Example 1 Synthesis of 3,6,9-heptadecatriene

[0042] At 0°C, 5.10 g (0.03 mol) of cis-3-undecenol prepared in Example 1 was slowly added to 20 ml of a 1.65 M solution of Dess-Martin periodinane (13.99 g, 0.033 mol). After reacting for 60 min, the oxidant was removed by vacuum filtration, and the solvent was removed by rotary evaporation to obtain an oxidation product, which could be carried out in the next step without purification.

[0043] In N 2Under the atmosphere, 16.99g (0.036mol) (cis-3-hexenyl) triphenylphosphine iodide was dissolved in 50ml tetrahydrofuran (THF), and 36ml (0.036mol) sodium bis(trimethylsilyl)amide (1M tetrahydrofuran solution) was added at -78°C, and then stirred at room temperature for 30min; cooled to -78°C again, and 5ml of 6.0M THF solution of the above oxidation product was slowly added. After 4h of reaction, 5ml of methanol was added to terminate the reaction, and 20ml of ether and 10ml of water were added for liquid extraction, and the organic phase was collected, dried over anhydrous sodium sulfate, the organic solvent was evaporated by rotary evaporation, and silica gel column chromatography was performed to obtain 5.36g 3,6,9-heptadecatriene, with a two-step yield of 72%, wherein the content ratio of cis, cis, cis-3,6,9-heptadecatriene and cis, cis, trans-3,6,9-heptadecatriene was about 1:4.

[0044] The NMR data of the obtained product:

[0045] Cis, cis, cis-3,6,9-heptadecatriene: 1 H NMR (500 MHz, CDCl 3 )δ:0.87[3H,m],0.99[3H,m],1.32[10H,m],2.06[4H,m],2.81[4H,m],5.34[6H,m].

[0046] The mass spectrum data of the obtained product: GC-MS (70eV, EI): 248, the chemical formula is C 17 H 30 .

[0047] Cis, cis, trans-3,6,9-heptadecatriene: 1 H NMR (500 MHz, CDCl 3 )δ:0.87[3H,m],1.00[3H,m],1.26[12H,m],1.38[2H,m],2.09[2H,m],2.20[2H,m],5.40[1 H,m],5.70[1H,m],5.96[1H,m],6.09[1H,m],6.16[1H,dd,J=15Hz],6.38[1H,dd,J=15Hz].

[0048] The mass spectrum data of the obtained product: GC-MS (70eV, EI): 248, the chemical formula is C 17 H 30 .

Claims

1. A method for synthesizing cis, cis, cis-3,6,9-heptadecatriene, characterized in that: The steps include: (1) Under the action of butyl lithium, n-octanal reacts with (1-propanol)triphenylphosphonium bromide to generate cis-3-undecenyl alcohol; (2) cis-3-undecenyl alcohol reacts with Dess-Martin oxidant / N,N-dimethylcyclohexylamine to generate cis-unsaturated enal; (3) Under the action of sodium bis(trimethylsilyl)amide, the cis-unsaturated enal obtained in step (2) reacts with (cis-3-hexenyl)triphenylphosphonium iodide to generate cis,cis,cis-3,6,9-heptadecatriene.

2. The synthesis method according to claim 1, characterized in that The solvent used in step (1) is tetrahydrofuran; and / or the molar ratio of n-octanal, (1-propanol)triphenylphosphine bromide and butyl lithium is 0.84:1:1; 3. The synthesis method according to claim 2, characterized in that In the step (1), under a N2 atmosphere, (1-propanol)triphenylphosphonium bromide and a tetrahydrofuran solution of butyl lithium are mixed at -25°C, stirred at room temperature for 30 minutes, cooled to -25°C again, and then a tetrahydrofuran solution of n-octanal is added and reacted for 4 hours.

4. The synthesis method according to claim 1, characterized in that The solvent used in step (2) is dichloromethane; and / or the molar ratio of cis-3-undecenol, Dess-Martin periodinane and N,N-dimethylcyclohexylamine is 1:1.1:1.

1.

5. The synthesis method according to claim 1 or 4, characterized in that: In the step (2), N,N-dimethylcyclohexylamine is added to a dichloromethane solution of Dess-Martin periodinane at 0° C., stirred for 20 min, and then cis-3-undecenol is added and reacted for 60 min.

6. The synthesis method according to claim 5, characterized in that After the step (2) was reacted for 60 minutes, the oxidant was removed by vacuum filtration, and the solvent was removed by rotary evaporation.

7. The synthesis method according to claim 1, characterized in that The solvent used in step (3) is tetrahydrofuran; and / or the molar ratio of the cis-unsaturated aldehyde, (cis-3-hexenyl)triphenylphosphine iodide and sodium bis(trimethylsilyl)amide is 1:1.2:1.

2.

8. The synthesis method according to claim 7, characterized in that In the step (3), under a N2 atmosphere, a tetrahydrofuran solution of (cis-3-hexenyl)triphenylphosphine iodide and sodium bis(trimethylsilyl)amide are mixed at -78°C, stirred at room temperature for 30 minutes, cooled to -78°C again, and a tetrahydrofuran solution of cis-unsaturated aldehyde is added to react for 4 hours.

9. The synthesis method according to claim 3 or 8, characterized in that: The steps (1) and (3) also include a purification step: after reacting for 4 hours, methanol is added to terminate the reaction, and then ether and water are added for liquid extraction, the organic phase is retained, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the target product.

10. The synthesis method according to claim 9, characterized in that The reduced pressure concentration is carried out by rotary evaporation to evaporate the organic solvent.

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