Synthesis method of 16,17-dehydrocapsaicin and its marker

Abstract

The present invention provides a method for synthesizing 16,17-dehydrocapsaicin and a marker thereof. Compound 6 and compound 7 or d3-7 are used as raw materials, and a target compound can be efficiently chemically synthesized only through an amidation reaction. The structural formula of compound 6 is #imgabs0#, the structural formula of compound 7 is #imgabs1#, and the structural formula of compound d3-7 is #imgabs2#. The present invention also provides a method for synthesizing 16,17-dehydrocapsaicin. 6-n-heptenoic acid and alkyl alcohol ROH are used as starting materials. The target molecule is efficiently synthesized through esterification reaction, olefin metathesis reaction, Wittig reaction, ester hydrolysis, and amidation reaction in sequence. The entire synthetic route is reasonably designed, the raw materials are simple and readily available, the operation is simple, the operability is strong, the purification is easy, and the obtained product has high purity. The synthesized target molecule provides a test sample for in vivo pharmacokinetics research of capsaicin and metabolite bioactivity research, and has important application value.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a method for synthesizing 16,17-dehydrocapsaicin and a marker thereof. Background Art

[0002] Capsaicin, also known as trans-8-methyl-N-vanillyl-6-nonenamide, also known as capsaicin, is the most important pungent component of chili peppers and is widely used in pepper sprays and crop protection agents. As an active pharmaceutical ingredient, capsaicin is often used in topical preparations to relieve pain. Furthermore, capsaicin has been found to possess antioxidant, anticancer, and anti-inflammatory properties, and is currently in Phase III clinical trials as a treatment for arthritis, postoperative pain, acute and chronic neuropathy, and musculoskeletal pain.

[0003] In the body, drugs are typically biotransformed through Phase I and Phase II metabolic pathways. Since Phase I reactions primarily involve oxidation, reduction, and hydrolysis, the resulting metabolites may possess pharmacological activity, thus requiring further safety evaluation. Phase I metabolism of capsaicin in vivo is primarily mediated by P450 enzymes. Phase I metabolic processes primarily occur at alkyl chains, aromatic rings, and amides, generating capsaicin hydroxylation, demethylation, and dehydrogenation metabolites. Macrocyclic metabolites (M1), ω-(16-hydroxycapsaicin, M2), ω-1 (17-hydroxycapsaicin, M3) alcohols, and terminal dehydrodiene (16,17-dehydrocapsaicin, M4) account for 80% of the total metabolite production. Furthermore, there is evidence that 16,17-dehydrocapsaicin produces a strong spicy sensation, suggesting that it may exert pharmacological properties similar to capsaicin through TRPV1-mediated regulation. Further studies on the pharmacokinetics of capsaicin in vivo and the pharmacological activities of its major metabolites will undoubtedly contribute to a more comprehensive understanding of capsaicin's diverse effects in the body. However, the above research is currently greatly limited due to the lack of sufficient capsaicin metabolite standards and effective chemical synthesis methods. Summary of the Invention

[0004] In view of this, the present invention provides a method for synthesizing 16,17-dehydrocapsaicin and a marker thereof.

[0005] Specifically, the synthesis method of 16,17-dehydrocapsaicin provided by the present invention comprises the following steps: using compound 6 and compound 7 as raw materials to undergo amidation reaction to synthesize 16,17-dehydrocapsaicin, wherein the structural formula of compound 6 is The structural formula of compound 7 is The structural formula of 16,17-dehydrocapsaicin is

[0006] Based on the above synthesis method, it includes: under the action of diisopropylethylamine and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, the compound 6 and the compound 7 undergo an amidation reaction at 0°C to 30°C to synthesize 16,17-dehydrocapsaicin. The amidation reaction route is:

[0007]

[0008] Preferably, the molar ratio of compound 6, diisopropylethylamine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate and compound 7 is 1:(2.5-3.0):(1-1.5):(1-1.5).

[0009] Specifically, the steps for synthesizing 16,17-dehydrocapsaicin include: first, in an N,N-dimethylformamide solution, uniformly stirring the compound 6, diisopropylethylamine and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate at 0°C to 30°C for 20 to 45 minutes; then, adding compound 7 in batches, and returning the mixture to room temperature for reaction to synthesize 16,17-dehydrocapsaicin.

[0010] Based on the above, the method includes: after the amidation reaction occurs to synthesize 16,17-dehydrocapsaicin, firstly quenching the amidation reaction with a hydrochloric acid aqueous solution, then extracting with ethyl acetate to obtain an organic phase, washing the organic phase with water and brine, and drying with sodium sulfate; then concentrating under reduced pressure to obtain a crude product; and purifying the crude product by column chromatography to obtain pure 16,17-dehydrocapsaicin.

[0011] Based on the above synthesis method, the synthesis method of compound 6 includes: using compound 5 as a raw material to undergo ester hydrolysis reaction to synthesize compound 6, wherein the structural formula of compound 5 is And the group R is methyl or ethyl. The reaction route of this step is:

[0012]

[0013] Based on the above synthesis method, the synthesis method of compound 6 includes: in the presence of lithium hydroxide, compound 5 undergoes an ester hydrolysis reaction at room temperature to synthesize compound 6. Preferably, the molar ratio of compound 5 to lithium hydroxide monohydrate is 1:(2.0-3.0).

[0014] The synthesis method of compound 6 specifically includes: in a tetrahydrofuran aqueous solution, the compound 5 and lithium hydroxide monohydrate are stirred at room temperature to react until the reaction of the compound 5 is complete, thereby synthesizing the compound 6; then, the tetrahydrofuran is removed by vacuum concentration, and then the mixture is extracted with ethyl acetate under an acidic environment. The organic phase is dried with sodium sulfate and then concentrated in a vacuum to obtain pure compound 6.

[0015] Based on the above synthesis method, the synthesis method of compound 5 includes: using compound 4 and triphenylphosphine methyl bromide as raw materials to perform Wittig reaction to synthesize compound 5, wherein the structural formula of compound 4 is

[0016] Based on the above synthesis method, the synthesis method of compound 5 includes: in a nitrogen atmosphere and under the action of potassium tert-butoxide, compound 4 and triphenylphosphine bromomethane undergo Wittig reaction at 0°C to 30°C to synthesize compound 5. The reaction route of this step is: Preferably, the molar ratio of compound 4, triphenylphosphine methyl bromide and potassium tert-butoxide is 1:(2.0-3.0):(2.5-3.0).

[0017] The synthesis method of the compound 5 specifically comprises: reacting the compound 4, triphenylphosphine methyl bromide and potassium tert-butoxide at 0°C to 30°C in a nitrogen atmosphere and tetrahydrofuran solvent to synthesize the compound 5; then concentrating by reduced pressure distillation and purifying by column chromatography to obtain pure compound 5.

[0018] Based on the above synthesis method, the synthesis method of compound 4 includes: using compound 2 and compound 3 as raw materials to undergo olefin metathesis reaction to synthesize compound 4, wherein the structural formula of compound 2 is The structural formula of compound 3 is

[0019] Based on the above synthesis method, the synthesis method of compound 4 includes: in a nitrogen atmosphere and under the action of Grubbs second-generation catalyst, compound 2 and compound 3 undergo olefin metathesis reaction at 25°C to 60°C to synthesize compound 4. The reaction route of this step is: Preferably, the molar ratio of the compound 2, the Grubbs second-generation catalyst and the compound 3 is 1: (0.01-0.05): (2.0-4.0).

[0020] The synthesis method of compound 4 specifically includes: in a nitrogen atmosphere and under the action of Grubbs second-generation catalyst, the compound 2 and compound 3 are refluxed at 40°C to 50°C until the compound 2 is completely reacted to synthesize the compound 4; then, pure compound 4 is obtained by vacuum concentration and column chromatography purification.

[0021] Based on the above synthesis method, the synthesis method of the compound 2 includes: using 6-n-heptenoic acid and alkyl alcohol ROH as raw materials to carry out an esterification reaction to synthesize the compound 2.

[0022] Based on the above synthesis method, the synthesis method of compound 2 includes: under the action of thionyl chloride, 6-n-heptenoic acid and methanol or ethanol undergo esterification reaction at 0°C to 70°C to synthesize compound 2. The reaction route of this step is: Preferably, the molar ratio of 6-n-heptenoic acid, alkyl alcohol (methanol or ethanol) and thionyl chloride is 1: (500-1000): (1.2-2.0).

[0023] The synthesis method of the compound 2 specifically includes: first mixing 6-n-heptenoic acid, alkyl alcohol ROH and thionyl chloride at -5°C to 5°C, then reacting at 40°C to 60°C to completely synthesize the compound 2; then purifying by vacuum concentration or other methods to obtain pure compound 2.

[0024] The present invention also provides a method for synthesizing 16,17-dehydrocapsaicin, comprising the steps of:

[0025] Esterification reaction: Under the action of thionyl chloride, 6-n-heptenoic acid and methanol or ethanol undergo esterification reaction at 0℃~70℃ to synthesize compound 2, the structural formula of which is and the group R is a methyl group or an ethyl group;

[0026] Olefin metathesis reaction: In a nitrogen atmosphere and under the action of Grubbs second-generation catalyst, the compound 2 and compound 3 undergo olefin metathesis reaction at 25°C to 60°C to synthesize compound 4, wherein the structural formula of the compound 3 is The structural formula of compound 4 is

[0027] Wittig reaction: Compound 4 and triphenylphosphine methyl bromide undergo Wittig reaction at 0°C to 30°C in a nitrogen atmosphere under the action of potassium tert-butoxide to synthesize compound 5, the structural formula of which is

[0028] Ester hydrolysis reaction: Under the action of lithium hydroxide, the compound 5 undergoes ester hydrolysis at room temperature.

[0029] The compound 6 is synthesized by decomposition reaction. The structural formula of the compound 6 is

[0030] Amidation reaction: Under the action of diisopropylethylamine and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, the compound 6 and the compound 7 undergo an amidation reaction at 0°C to 30°C to synthesize 16,17-dehydrocapsaicin, wherein the structural formula of the compound 7 is

[0031] The present invention also provides a method for synthesizing a 16,17-dehydrocapsaicin marker, comprising: using compound 6 and compound d3-7 as raw materials to undergo amidation reaction to obtain a target compound: d3-16,17-dehydrocapsaicin, wherein the structural formula of the compound d3-7 is The structural formula of d3-16,17-dehydrocapsaicin is

[0032] The synthesis method based on the above-mentioned marker includes: under the action of diisopropylethylamine and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, the compound 6 and compound d3-7 undergo an amidation reaction at 0°C to 30°C to synthesize the isotope marker of 16,17-dehydrocapsaicin: d3-16,17-dehydrocapsaicin.

[0033] Among them, preferably, the molar ratio of compound 6, diisopropylethylamine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate and compound d3-7 is 1:(2.5~3.0):(1~1.5):(1~1.5).

[0034] Based on the above, the method comprises the following steps: after the amidation reaction occurs to synthesize d3-16,17-dehydrocapsaicin, quenching the amidation reaction with a hydrochloric acid aqueous solution, extracting with ethyl acetate to obtain an organic phase, washing the organic phase with water and brine, and drying with sodium sulfate; then concentrating under reduced pressure to obtain a crude product; and purifying the crude product by column chromatography to obtain pure d3-16,17-dehydrocapsaicin.

[0035] Therefore, the above-mentioned synthesis method provided by the present invention can achieve efficient chemical synthesis of 16,17-dehydrocapsaicin or its isotope label by only amidation reaction using compound 6 and compound 7 or d3-7 as raw materials. The operation is simple and the operability is strong. The synthesized 16,17-dehydrocapsaicin or its isotope label provides a test sample for the in vivo pharmacokinetics study of capsaicin and the biological activity study of metabolites, and has important application value.

[0036] In addition, the above-mentioned synthesis method provided by the present invention can also start from 6-n-heptenoic acid and efficiently achieve the synthesis of the target molecule through esterification reaction, olefin metathesis reaction, Wittig reaction, ester hydrolysis, and amidation reaction. The entire synthesis route is reasonably designed, the raw materials are simple and easy to obtain, the operation is simple, the operability is strong, the purification is easy, and the purity of the obtained product is high, with a purity of more than 95%, which meets the purity requirements of capsaicin metabolite standards, provides test samples for the in vivo pharmacokinetics study of capsaicin and the biological activity study of metabolites, and has important application value. DETAILED DESCRIPTION

[0037] The technical solution of the present invention is further described in detail below through specific implementation methods.

[0038] Example 1

[0039] This embodiment provides a method for synthesizing 16,17-dehydrocapsaicin, and its synthetic route is:

[0040]

[0041] The specific synthesis method of 16,17-dehydrocapsaicin is as follows: 6.4g of diisopropylethylamine (DIPEA) and 9.1g of benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) were added to 60mL of N,N-dimethylformamide (DMF) solution containing 3.3g of compound 6 at 0°C. The reaction system was stirred at 0°C for 30 minutes, and then 4.5g of compound 7 was added in batches to react at room temperature. The reaction was quenched with 0.5M aqueous hydrochloric acid solution, and the organic phase was separated by extraction with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 4.8g of 16,17-dehydrocapsaicin 8 with a yield of 80% and a purity of 99.0%.

[0042] Among them, 16,17-dehydrocapsaicin 1 H NMR (400MHz, CDCl3) δ6.86(d,J=8.0Hz,1H),6.80(d,J=1.9Hz,1H),6.76(dd,J=8.0,2.0Hz,1H),6.15–6.10(m,1H),5.72(br s,2H),5.66–5.58(m,1H),4.86(s,2H),4.35(d,J=5.6Hz,2H),3.87(s,3H),2.21(t,J= 7.6Hz,2H),2.15–2.09(m,2H),1.82(s,3H),1.73–1.64(m,2H),1.48–1.41(m,2H)ppm.

[0043] 16,17-dehydrocapsaicin 13 C NMR (151MHz, CDCl3) δ172.81,146.84,145.27,142.16,133.34,130.47,130.29,120 .94,114.60,114.50,110.81,56.06,43.68,36.79,32.55,29.18,25.46,18.79ppm.

[0044] Example 2

[0045] This embodiment provides a method for synthesizing 16,17-dehydrocapsaicin, which starts from compound 5-1 and sequentially synthesizes the target compound through ester hydrolysis reaction and amidation reaction. The main difference between this embodiment and the synthesis method provided in Example 1 is that compound 6 in this embodiment is obtained from compound 5-1 through ester hydrolysis reaction. The specific synthesis method of compound 6 is as follows: 0.84g of lithium hydroxide monohydrate is added to 10mL of tetrahydrofuran / water (volume ratio 2:1) solution containing 1.80g of compound 5-1, and the reaction system is stirred at room temperature for 2 hours. After compound 5 is completely consumed, the reaction mixture is concentrated in vacuo to remove tetrahydrofuran. The pH value of the mixture is adjusted to 2 with 0.5M hydrochloric acid, and then extracted with ethyl acetate. The organic phase is dried with sodium sulfate and concentrated in vacuo to obtain 1.5g of compound 6 with a yield of 92%; wherein the 1 H NMR (400MHz,CDCl3)δ6.17-6.12(m,1H),5.67-5.60(m,1H),4.87(s,2H),2.37(t,J=7.4Hz,2H),2.19-2.10(m,2H),1.83(s,3H),1.70-1.63(m,2H),1.51-1.43(m,2H)ppm. The reaction route of this step is

[0046] Example 3

[0047] This embodiment provides a method for synthesizing 16,17-dehydrocapsaicin, which starts from compound 4-1 and sequentially undergoes Wittig reaction, ester hydrolysis reaction and amidation reaction to synthesize the target compound. The main difference between this embodiment and the synthesis method provided in Example 2 is that in this embodiment, compound 5-1 is prepared by reacting compound 4-1 with triphenylphosphine methyl bromide (Ph3P + The specific synthesis method of compound 5-1 is as follows: under nitrogen atmosphere, 9.40g Ph3P + MeBr and 50mL tetrahydrofuran (THF). 2.80g of potassium tert-butoxide (t-BuOK) was added in portions at 0°C. The reaction system was stirred at this temperature for 30 minutes before adding 1.80g of compound 4-1. Subsequently, the reaction mixture was naturally warmed to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain 1.30g of compound 5-1 with a yield of 72%; wherein the 1H NMR (400 MHz, CDCl3) δ 6.14 (dd, J = 15.7, 1.6 Hz, 1H, H-7), 5.63 (dt, J = 15.7, 8.0 Hz, 1H, H-6), 4.86 (s, 2H), 3.67 (s, 3H), 2.32 (t, J = 7.5 Hz, 2H), 2.16-2.10 (m, 2H), 1.82 (s, 3H), 1.65 (dt, J = 15.1, 7.5 Hz, 2H), 1.48-1.40 (m, 2H) ppm. The reaction route of this step is

[0048] Example 4

[0049] This embodiment provides a method for synthesizing 16,17-dehydrocapsaicin, which starts from compound 2-1 and sequentially synthesizes the target compound through olefin metathesis reaction, Wittig reaction, ester hydrolysis reaction and amidation reaction. The main difference between the synthesis method provided in this embodiment and that provided in Example 3 is that compound 4-1 in this embodiment is synthesized by olefin metathesis reaction of compound 2-1 and compound 3. The specific synthesis method of compound 4-1 is as follows: under a nitrogen atmosphere, 2.80g of compound 2-1 and 0.42g of Grubbs second-generation catalyst (Grubbs catalyst II) are added to a dry three-necked flask, and then 40mL of anhydrous dichloromethane solution containing 4.20g of compound 3 is added by syringe. The reaction system is refluxed under a continuous nitrogen flow (to remove by-product ethylene) for 12 hours at a temperature of 45°C. After compound 2 is completely consumed, the reaction mixture is concentrated in vacuo, and the crude product is purified by column chromatography to obtain 2.60g of compound 4-1 with a yield of 73%; the yield of compound 4-1 is 73%. 1 H NMR (400 MHz, CDCl3) δ 6.79 (dt, J = 15.9, 8.0 Hz, 1H, H-6), 6.08 (dd, J = 15.9, 1.5 Hz, 1H, H-7), 3.68 (s, 3H), 2.34 (t, J = 7.3 Hz, 2H), 2.29-2.21 (m, 5H), 1.71-1.63 (m, 2H), 1.54-1.48 (m, 2H) ppm. The reaction route of this step is

[0050] Example 5

[0051] The present embodiment provides a method for synthesizing 16,17-dehydrocapsaicin, which starts from 6-n-heptenoic acid and sequentially undergoes esterification reaction, olefin metathesis reaction, Wittig reaction, ester hydrolysis reaction and amidation reaction to synthesize the target compound. The main difference between the synthesis method provided in this embodiment and that provided in Example 4 is that compound 2-1 in this embodiment is synthesized by esterification reaction of 6-n-heptenoic acid and methanol. The specific synthesis method of compound 2-1 is as follows: 2.50g of 6-n-heptenoic acid (compound 1) is added to 40ml of methanol, 2.80g of thionyl chloride is added dropwise at 0°C, and then the reaction system is heated and refluxed for 2 hours. After the reaction is complete, the mixture is allowed to cool naturally to room temperature and concentrated under reduced pressure to obtain 2.60g of compound 2-1 with a yield of 92%; the yield of compound 2-1 is 92%. 1 H NMR (400MHz,CDCl3)δ5.84-5.74(m,1H),5.04-4.93(m,2H),3.67(s,3H),2.32(t,J=7.5Hz,2H),2.10-2.04(m,2H),1.68-1.61(m,2H),1.46-1.38(m,2H)ppm. The reaction route of this step is

[0052] Example 6

[0053] This embodiment provides a method for synthesizing 16,17-dehydrocapsaicin, and its synthetic route is:

[0054]

[0055] The synthesis method provided in this example is basically the same as that provided in Example 5, with the main difference being that: in this example, the raw material used in the esterification reaction to synthesize compound 2-2 was ethanol instead of methanol, and 2.86 g of compound 2-2 was synthesized at 10° C. with a yield of 93%; 2.34 g of compound 2-2 and 3.15 g of compound 3 were subjected to olefin metathesis reaction at 50° C. to synthesize 2.14 g of compound 4-2 with a yield of 72%; 2.00 g of compound 4-2 and 9.60 g of Ph3P + MeBr was reacted with 2.80 g of potassium tert-butoxide to produce 1.38 g of compound 5-2 at 20° C. with a yield of 71%.

[0056] Example 7

[0057] This embodiment provides a method for synthesizing a 16,17-dehydrocapsaicin marker, which is substantially the same as the synthesis method provided in any one of Examples 1 to 7, with the main difference being that the method for synthesizing the 16,17-dehydrocapsaicin marker in this embodiment is as follows: 6.4 g of DIPEA and 9.1 g of HBTU were added to 60 mL of a DMF solution containing 3.3 g of compound 6 at 0°C. The reaction system was stirred at 0°C for 30 minutes, followed by the addition of 4.5 g of compound d3-7 in batches to react at room temperature. The reaction was quenched with 0.5 M aqueous hydrochloric acid solution, extracted with ethyl acetate, and the organic phase was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 4.9 g of d3-16,17-dehydrocapsaicin d3-8 with a yield of 81% and a purity of 98.6%. The synthetic route for this step is:

[0058]

[0059] d3-16,17-dehydrocapsaicin 1 H NMR (400MHz, CDCl3) δ6.86(d,J=8.0Hz,1H),6.80(d,J=1.9Hz,1H),6.76(dd,J=8.0,2.0Hz,1H),6.15–6.10(m,1H),5.72(br s,2H),5.66–5.58(m,1H),4.86(s,2H),4.35(d,J=5.6Hz,2H),2.21(t,J=7.6Hz ,2H),2.15–2.09(m,2H),1.82(s,3H),1.73–1.64(m,2H),1.48–1.41(m,2H)ppm.

[0060] Example 8

[0061] This example provides a method for synthesizing a 16,17-dehydrocapsaicin marker, which is substantially the same as the method provided in Example 7, with the main difference being that, in this example, the reaction temperature for synthesizing the 16,17-dehydrocapsaicin marker is 20° C., 2.5 g of compound 6, 5.0 g of DIPEA, 7.0 g of HBTU, and 3.65 g of compound d3-7 are used, with a yield of 80% and a purity of 97.9%.

[0062] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to preferred embodiments, ordinary technicians in the field should understand that the specific implementation methods of the present invention can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solutions of the present invention. They should all be included in the scope of the technical solutions claimed for protection by the present invention.

Claims

1. A method for synthesizing 16,17-dehydrocapsaicin, comprising the steps of: Esterification reaction: 6-n-heptenoic acid and methanol or ethanol are used as raw materials to undergo esterification reaction to synthesize compound 2, the structural formula of which is and the group R is a methyl group or an ethyl group; Olefin metathesis reaction: Compound 4 is synthesized by olefin metathesis reaction using compound 2 and compound 3 as raw materials, wherein: The structural formula of compound 3 is The structural formula of compound 4 is Wittig reaction: Compound 5 is synthesized by Wittig reaction using compound 4 and triphenylphosphine methyl bromide as raw materials. The structural formula of compound 5 is Ester hydrolysis reaction: Compound 6 is synthesized by ester hydrolysis reaction using compound 5 as raw material. The structural formula of compound 6 is Amidation reaction: Compound 6 and compound 7 are used as raw materials to undergo an amidation reaction in the presence of diisopropylethylamine and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate to synthesize 16,17-dehydrocapsaicin, wherein the structural formula of compound 7 is The structural formula of 16,17-dehydrocapsaicin is 2. The synthesis method according to claim 1, characterized in that it comprises the following steps of synthesizing 16,17-dehydrocapsaicin by amidation reaction of compound 6 and compound 7 at 0°C to 30°C under the action of diisopropylethylamine and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, wherein: The molar ratio of the compound 6, diisopropylethylamine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate and the compound 7 is 1:(2.5-3.0):(1-1.5):(1-1.5).

3. The synthesis method according to claim 2, characterized in that it includes, after the amidation reaction to synthesize 16,17-dehydrocapsaicin occurs, first quenching the amidation reaction with aqueous hydrochloric acid, then extracting with ethyl acetate to obtain an organic phase, washing the organic phase with water and brine, and drying over sodium sulfate; then concentrating under reduced pressure to obtain a crude product; and purifying the crude product by column chromatography to obtain pure 16,17-dehydrocapsaicin.

4. The synthesis method according to any one of claims 1 to 3, characterized in that the synthesis method of compound 6 comprises: Under the action of lithium hydroxide, the compound 5 undergoes an ester hydrolysis reaction at room temperature to synthesize the compound 6.

5. The synthesis method according to any one of claims 1 to 3, characterized in that the synthesis method of compound 5 comprises: In a nitrogen atmosphere and under the action of potassium tert-butoxide, the compound 4 and triphenylphosphine methyl bromide undergo Wittig reaction at 0° C. to 30° C. to synthesize the compound 5.

6. The synthesis method according to any one of claims 1 to 3, characterized in that the synthesis method of compound 4 comprises: Under nitrogen atmosphere and the action of Grubbs second-generation catalyst, the compound 2 and the compound 3 undergo olefin metathesis reaction at 25° C. to 60° C. to synthesize the compound 4.

7. The synthesis method according to claim 6, characterized in that the synthesis method of compound 2 comprises: Under the action of thionyl chloride, 6-n-heptenoic acid and alkyl alcohol ROH undergo esterification reaction at 0°C to 70°C to synthesize the compound 2.

8. A method for synthesizing 16,17-dehydrocapsaicin, comprising the steps of: Esterification reaction: Under the action of thionyl chloride, 6-heptenoic acid and methanol or ethanol undergo esterification reaction at 0℃~70℃ to synthesize compound 2, wherein, The molar ratio of 6-n-heptenoic acid, methanol or ethanol, and thionyl chloride is 1: (500-1000): (1.2-2.0), and the structural formula of the compound 2 is and the group R is a methyl group or an ethyl group; Olefin metathesis reaction: In a nitrogen atmosphere and under the action of Grubbs second-generation catalyst, the compound 2 and compound 3 undergo olefin metathesis reaction at 25°C to 60°C to synthesize compound 4, wherein the molar ratio of the compound 2, Grubbs second-generation catalyst and compound 3 is 1: (0.01-0.05): (2.0-4.0), and the structural formula of the compound 3 is The structural formula of compound 4 is Wittig reaction: In a nitrogen atmosphere and under the action of potassium tert-butoxide, the compound 4 and triphenylphosphine methyl bromide undergo Wittig reaction at 0°C to 30°C to synthesize compound 5, wherein the molar ratio of the compound 4, triphenylphosphine methyl bromide and potassium tert-butoxide is 1: (2.0-3.0): (2.5-3.0), and the structural formula of the compound 5 is Ester hydrolysis reaction: Under the action of lithium hydroxide, the compound 5 undergoes ester hydrolysis reaction at room temperature to synthesize compound 6, wherein the molar ratio of the compound 5 to lithium hydroxide monohydrate is 1: (2.0-3.0), and the structural formula of the compound 6 is Amidation reaction: Under the action of diisopropylethylamine and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, the compound 6 and the compound 7 undergo an amidation reaction at 0°C to 30°C to synthesize 16,17-dehydrocapsaicin, wherein the molar ratio of the compound 6, diisopropylethylamine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate and the compound 7 is 1:(2.5-3.0):(1-1.5):(1-1.5), and the structural formula of the compound 7 is 9. The synthesis method according to claim 8, characterized in that the amidation reaction step further comprises, after the amidation reaction occurs to synthesize 16,17-dehydrocapsaicin, quenching the amidation reaction with aqueous hydrochloric acid, extracting with ethyl acetate to obtain an organic phase, washing the organic phase with water and brine, and drying over sodium sulfate; then concentrating under reduced pressure to obtain a crude product; and purifying the crude product by column chromatography to obtain pure 16,17-dehydrocapsaicin.

10. A method for synthesizing a 16,17-dehydrocapsaicin marker, comprising the steps of: Esterification reaction: 6-n-heptenoic acid and methanol or ethanol are used as raw materials to undergo esterification reaction to synthesize compound 2, the structural formula of which is and the group R is a methyl group or an ethyl group; Olefin metathesis reaction: Compound 4 is synthesized by olefin metathesis reaction using compound 2 and compound 3 as raw materials, wherein: The structural formula of compound 3 is The structural formula of compound 4 is Wittig reaction: Compound 5 is synthesized by Wittig reaction using compound 4 and triphenylphosphine methyl bromide as raw materials. The structural formula of compound 5 is Ester hydrolysis reaction: Compound 6 is synthesized by ester hydrolysis reaction using compound 5 as raw material. The structural formula of compound 6 is Amidation reaction: Compound 6 and compound d3-7 are used as raw materials, and amidation reaction is carried out under the action of diisopropylethylamine and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate to produce the target compound: d3-16,17-dehydrocapsaicin, wherein the structural formula of compound d3-7 is The structural formula of d3-16,17-dehydrocapsaicin is 11. The synthesis method according to claim 10 is characterized in that it includes undergoing an amidation reaction between the compound 6 and the compound d3-7 at 0°C to 30°C in the presence of diisopropylethylamine and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate to synthesize d3-16,17-dehydrocapsaicin, and the molar ratio of the compound 6, diisopropylethylamine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate and the compound d3-7 is 1:(2.5-3.0):(1-1.5):(1-1.5).

12. The synthesis method according to claim 11, characterized in that it further comprises, after the amidation reaction occurs to synthesize d3-16,17-dehydrocapsaicin, quenching the amidation reaction with aqueous hydrochloric acid, extracting with ethyl acetate to obtain an organic phase, washing the organic phase with water and brine, and drying over sodium sulfate; then concentrating under reduced pressure to obtain a crude product; and purifying the crude product by column chromatography to obtain pure d3-16,17-dehydrocapsaicin.

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