A kind of synthetic method of dihydrocapsaicin

Abstract

The invention discloses a method for synthesizing dihydrocapsaicin, and the method comprises the following steps: synthesizing a first intermediate 1-isobutylcyclohexene, a second intermediate 8-methyl-6-oxonanoic acid, a third intermediate 8-methylnonanoic acid and a target product dihydrocapsaicin. The method uses cyclohexanone, isobutylmagnesium bromide and vanillin ammonium hydrochloride as raw materials, and obtains the product dihydrocapsaicin by stepwise reaction. Each reaction step adopts a conventional chemical reaction, and the reaction conditions are mild. The feasibility of the synthesis process is high, the safety and environmental protection are strong, and the product has a high yield and good purity, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic compound synthesis, in particular to a method for synthesizing dihydrocapsaicin. Background Art

[0002] Capsaicin is an amide compound, mainly found in peppers. Capsaicinoids can promote the secretion of catecholamines by the adrenal glands, and have antibacterial, anti-tumor, analgesic and anti-inflammatory effects. They can also be used as stomachic agents to promote gastric juice secretion, enhance appetite, promote blood circulation, improve the body's disease resistance, and improve digestion and other biological functions. Most capsaicinoids have physiological effects such as analgesia, anti-cancer, regulating blood lipids, antibacterial and anti-inflammatory, weight loss, anti-fatigue, analgesia, antipruritic, anti-inflammatory, antioxidant, myocardial protection, and blood pressure regulation. They can also dilate skin blood vessels and improve microcirculation. Their pungent taste can produce a series of physiological reactions and repellent effects on humans and animals. At present, capsaicinoids have been widely used in many fields such as medical treatment, beauty, biological control, food additives, and military affairs, achieving many effects.

[0003] The natural capsaicinoid compounds extracted from peppers are homologous, and they all have a common structural parent nucleus. All of them belong to the vanillylamide class of compounds, the only difference being that the R groups in the molecules are different.

[0004] The natural capsaicinoids extracted from peppers are mainly composed of capsaicin (R = -(CH 2 ) 4 CH=CHCHMe 2 , 69%), dihydrocapsaicin (R = -(CH 2 ) 6 CH 2 , 22%), nordihydrocapsaicin (R = -(CH 2 ) 3 CH=CHCHMe 2 , 7%), homodihydrocapsaicin (R = -(CH 2 ) 7 CH 2 , 1%), high capsaicin (R = -(CH 2 ) 5 CH=CHCHMe 2 , 1%), wherein the content of capsaicin and dihydrocapsaicin accounts for more than 90% of the total content of the extracted capsaicin. The natural capsaicin extracted from pepper is a mixture. It is very difficult to obtain each high-purity capsaicin compound, and it is often impossible to purify the components with low content. Therefore, to obtain each high-purity capsaicin compound, it must be synthesized by chemical method to meet the needs of people's research.

[0005] The spiciness of capsaicin or dihydrocapsaicin per gram is equivalent to 16.1×10 3 SHU is a natural capsaicin analog with a higher spiciness. Dihydrocapsaicin has a relatively high structural stability and a broad application prospect. There are many studies on its artificial synthesis. At present, the methods for synthesizing dihydrocapsaicin are mainly:

[0006] 1) The key intermediate 8-methylnonanoic acid was synthesized by Wittig reaction, and then dihydrocapsaicin was synthesized.

[0007]

[0008] In this synthetic route, expensive ethyl 6-bromohexanoate is used, and 8-methyl-6-nonenoic acid needs to be synthesized first through the Wittig reaction, and the latter is then synthesized into the key intermediate 8-methylnonanoic acid through catalytic hydrogenation. It can be seen that this process has high production costs, produces a large amount of waste triphenylphosphine oxide, is environmentally unfriendly, and the hydrogenation reaction is relatively dangerous.

[0009] 2) The key intermediate 8-methylnonanoic acid was synthesized by coupling reaction with Grignard reagent, and then dihydrocapsaicin was synthesized.

[0010]

[0011] In this synthetic route, with organo-copper-lithium reagent as catalyst, isobutyl magnesium bromide and ethyl 6-bromohexanoate can undergo coupling reaction and hydrolyze to synthesize the key intermediate 8-methylnonanoic acid. In the reaction process, an organometallic compound - organo-copper-lithium reagent is used, and the use of organo-copper-lithium reagent is demanding. The reaction system must be in a strictly anhydrous and oxygen-free environment, which is technically difficult and currently difficult to achieve industrial production. Summary of the invention

[0012] The invention solves the above-mentioned problem existing in the synthesis of dihydrocapsaicin in the prior art by providing a synthesis method of dihydrocapsaicin.

[0013] In order to solve the above technical problems, the present invention provides a method for synthesizing dihydrocapsaicin, comprising the following steps:

[0014] (1) Synthesis of the first intermediate

[0015] In an organic solvent, cyclohexanone and isobutylmagnesium bromide are used as raw materials to carry out an addition reaction, followed by hydrolysis to generate 1-isobutylcyclohexan-1-ol, and finally the pH value is adjusted to a strong acid condition, a dehydration reaction is carried out, and purification is performed to obtain 1-isobutylcyclohexene, which is the first intermediate;

[0016]

[0017] (2) Synthesis of the second intermediate

[0018] In an organic solvent, under ice bath conditions, ozone is introduced into the 1-isobutylcyclohexene prepared in step (1) for oxidation reaction to generate an ozone compound, which is then heated and cracked to generate 8-methyl-6-oxononanoic acid, which is purified to obtain a second intermediate;

[0019]

[0020] (3) Synthesis of the third intermediate

[0021] In an organic solvent, the 8-methyl-6-oxononanoic acid and hydrazine hydrate are reacted to generate a hydrazone, and then the mixture is heated under reflux to decompose the mixture under the action of a catalyst, nitrogen is released, and 8-methylnonanoic acid is purified to obtain the third intermediate;

[0022]

[0023] (4) Synthesis of dihydrocapsaicin

[0024] In an organic solvent, under ice bath conditions, reacting the 8-methylnonanoic acid synthesized in step (3) with carbonyldiimidazole to generate an active intermediate 8-methylnonanoyl imidazole, then adding vanillin amine hydrochloride, performing an exchange reaction at room temperature, and purifying to obtain the dihydrocapsaicin;

[0025]

[0026] In a preferred embodiment of the present invention, in the step (1), the pH value is 1-3.

[0027] In a preferred embodiment of the present invention, in step (1), the method of the dehydration reaction is: firstly heat and distill to remove the organic solvent, and then increase the temperature to perform steam distillation until the distilled fraction does not contain organic matter.

[0028] In a preferred embodiment of the present invention, in step (2), the process conditions of the heating cracking are: first naturally heating from ice bath conditions to room temperature, stirring for 30 to 60 minutes, then introducing oxygen, heating to 80°C and keeping warm for 1 to 3 hours.

[0029] In a preferred embodiment of the present invention, in the step (3), the catalyst comprises a strong base and a phase transfer catalyst in a molar ratio of 10 to 30:1.

[0030] In a preferred embodiment of the present invention, the strong base is at least one of strong sodium oxide or potassium hydroxide powder, and the phase transfer catalyst is at least one of 18-crown-6 or polyethylene glycol.

[0031] In a preferred embodiment of the present invention, the organic solvent is at least one of tetrahydrofuran, acetic acid, toluene or dichloromethane.

[0032] The invention has the beneficial effects of: providing a method for synthesizing dihydrocapsaicin, which uses cyclohexanone, isobutylmagnesium bromide and vanillin ammonium hydrochloride as raw materials, and obtains the product dihydrocapsaicin by step-by-step reaction; each reaction step adopts a conventional chemical reaction, the reaction conditions are mild, the feasibility of the synthesis process is high, the safety and environmental protection are strong, and the product has a high yield and good purity, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The present invention discloses a nuclear magnetic spectrum of dihydrocapsaicin prepared by the synthesis method of the present invention. DETAILED DESCRIPTION

[0034] The preferred embodiments of the present invention are described in detail below in conjunction with the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0035] See also Figure 1 , the embodiment of the present invention includes:

[0036] The invention discloses a method for synthesizing dihydrocapsaicin. The method uses cyclohexanone, isobutyl magnesium bromide and vanillin ammonium hydrochloride as raw materials, adopts conventional chemical reactions, gradually synthesizes a first intermediate 1-isobutylcyclohexene, a second intermediate 8-methyl-6-oxononanoic acid and a third intermediate 8-methylnonanoic acid, then uses the third intermediate to react with carbonyldiimidazole to generate an active transition intermediate, and finally performs an exchange reaction with vanillin amine hydrochloride at room temperature to successfully prepare dihydrocapsaicin. The synthesis route is as follows:

[0037]

[0038] In the above-mentioned synthesis method, each step adopts conventional chemical reactions, does not require harsh reaction conditions, and has no special requirements for reaction equipment. It is easy to operate, the process is safe and environmentally friendly, and is easy to industrialize.

[0039] Example 1

[0040] Synthesis of 1-isobutylcyclohexene

[0041]

[0042] Cyclohexanone (19.6 g, 0.2 mol) and 150 mL of tetrahydrofuran were added to the reaction flask, and isobutylmagnesium bromide-tetrahydrofuran solution (210 mL, 0.21 mol) was added dropwise under ice water cooling; after the addition was completed, the mixture was stirred for 1 hour, and the reaction of the raw material cyclohexanone was completed by gas phase detection, and water (250 mL) was added dropwise to quench the reaction, and 1-isobutylcyclohexan-1-ol was hydrolyzed to form 1-isobutylcyclohexan-1-ol, and then an acid (which can be an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or an organic acid such as toluenesulfonic acid, and hydrochloric acid in this embodiment) was added to the reaction system to adjust the pH value of the system to 1-1.5. The reaction system was transferred to a distillation apparatus, tetrahydrofuran in the system was removed by distillation, and the temperature was further increased for steam distillation; there was no organic matter in the fraction to be distilled out, and the distillation was stopped, and the distillate was extracted with ethyl acetate, the organic phase was combined, dried over anhydrous sodium carbonate, filtered, the filtrate was concentrated, and the residue was subjected to reduced pressure distillation to obtain 26.5 g of 1-isobutylcyclohexene, with a yield of 96%.

[0043] Example 2

[0044] Synthesis of 8-methyl-6-oxononanoic acid

[0045]

[0046] 1-isobutylcyclohexene (27.6 g, 0.2 mol) and 300 mL of acetic acid were added to the reaction flask, the ice salt was cooled to 0°C, the ozone generator was turned on, and ozone was introduced into the reaction flask for oxidation reaction to generate ozone compounds; after the reaction of the raw material 1-isobutylcyclohexene was completed, the ozone was stopped, and the temperature was naturally raised to 25°C and stirred for 1 hour; O was introduced 2 The mixture was heated to 80°C and kept for reaction for 2 hours to heat and decompose the generated ozone compound to generate 8-methyl-6-oxononanoic acid. The solvent was removed by thin film concentration to obtain an equivalent product which was directly used for the next step reaction. The purified sample was used for nuclear magnetic resonance detection, 1H NMR (400 MHz, CDCl3): 0.92 (d, 6H), 1.62m, 4H), 2.16 (m, 1H), 2.28 (td, 2H), 2.40-2.42 (m, 4H), 11.52 (brs, 1H).

[0047] Example 3

[0048] Synthesis of 8-Methylnonanoic Acid

[0049]

[0050] Add 8-methyl-6-oxononanoic acid (55.8 g, 0.3 mol), 18-crown-6 (7.9 g, 0.03 mol) and 600 mL of toluene to the reaction flask, stir well and then add powdered potassium hydroxide (59.3 g, 0.9 mol, 85%); install an oil-water separator and a reflux condenser, heat to reflux, add hydrazine hydrate (18 g, 0.45 mol, 80%) dropwise, and continue heating and reflux reaction for 4 hours after anhydrous water is generated; cool, acidify with 6 mol / L hydrochloric acid, separate the liquid at rest, dry the organic phase with sodium sulfate, concentrate, and distill the residue under reduced pressure to obtain 47 g of 8-methylnonanoic acid with a yield of 91%.

[0051] Example 4

[0052] Synthesis of Dihydrocapsaicin

[0053]

[0054] 8-Methylnonanoic acid (1.72 g, 10 mmol) and 100 mL of dichloromethane were added to the reaction flask, and carbonyldiimidazole (1.8 g, 11 mmol) / 25 mL of dichloromethane solution was added dropwise under ice-water cooling; after the addition was completed, the reaction was stirred for 1 hour, and vanillinamine hydrochloride (2.1 g, 11 mmol) was added at one time, stirred at room temperature overnight, and 50 mL of 6 mol / L hydrochloric acid was added to quench the reaction, the liquids were separated, the organic phase was dried over sodium sulfate, and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20:1-10:1) to obtain 2.95 g of dihydrocapsaicin, with a yield of 96%, and a melting point of 62-64 ° C; 1H NMR (400MHz, CDCl3): δ6.86(d,J=8.0Hz,lH),6.81(s,lH),6.76(d,J=8.2Hz,lH),5.84(s,1H),4.34(d,J=5.8H z,2H),3.87(s,3H),2.22(t,J=7.6Hz,2H),1.65(m,2H),1.50(m,1H),1.32-1.15(m,8H),0.86(t,J=6.5Hz,3H).

[0055] The synthesis method of the present invention adopts conventional chemical reactions, has mild reaction conditions, has no harsh conditions in each reaction process, has high feasibility of the synthesis process, is safe and environmentally friendly, and has a high yield and good purity of the product, and is suitable for industrial production.

[0056] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made using the contents of the present invention specification and drawings, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A method for synthesizing dihydrocapsaicin, It is characterized in that The steps include: (1) Synthesis of the first intermediate In an organic solvent, cyclohexanone and isobutylmagnesium bromide are used as raw materials to carry out an addition reaction, followed by hydrolysis to generate 1-isobutylcyclohexan-1-ol, and finally acid is added to adjust the pH value to a strong acid condition, followed by a dehydration reaction, and separation and purification to obtain 1-isobutylcyclohexene, which is the first intermediate; (2) Synthesis of the second intermediate In an organic solvent, under ice bath conditions, ozone is introduced into the 1-isobutylcyclohexene prepared in step (1) for oxidation reaction to generate an ozone compound, which is then heated and cracked to generate 8-methyl-6-oxononanoic acid, which is purified to obtain a second intermediate; (3) Synthesis of the third intermediate In an organic solvent, the 8-methyl-6-oxononanoic acid and hydrazine hydrate are reacted to generate a hydrazone, and then the mixture is heated under reflux to decompose the mixture under the action of a catalyst, nitrogen is released, and 8-methylnonanoic acid is purified to obtain the third intermediate; (4) Synthesis of dihydrocapsaicin In an organic solvent, under ice bath conditions, reacting the 8-methylnonanoic acid synthesized in step (3) with carbonyldiimidazole to generate an active intermediate 8-methylnonanoyl imidazole, then adding vanillin amine hydrochloride, performing an exchange reaction at room temperature, and purifying to obtain the dihydrocapsaicin; 2. A method for synthesizing dihydrocapsaicin according to claim 1, It is characterized in that In the step (1), the pH value is 1 to 3.

3. A method for synthesizing dihydrocapsaicin according to claim 1, It is characterized in that In the step (1), the method of the dehydration reaction is: firstly, heating and distilling to remove the organic solvent, and then heating and performing steam distillation until the distilled fraction contains no organic matter.

4. A method for synthesizing dihydrocapsaicin according to claim 1, It is characterized in that In the step (2), the process conditions for the heating cracking are: first naturally heating from ice bath conditions to room temperature, stirring for 30 to 60 minutes, then introducing oxygen, heating to 80° C. and keeping warm for 1 to 3 hours.

5. A method for synthesizing dihydrocapsaicin according to claim 1, It is characterized in that In the step (3), the catalyst comprises a strong base and a phase transfer catalyst in a molar ratio of 10 to 30:

1.

6. A method for synthesizing dihydrocapsaicin according to claim 5, It is characterized in that The strong base is at least one of sodium hydroxide or potassium hydroxide powder, and the phase transfer catalyst is at least one of 18-crown-6 or polyethylene glycol.

7. A method for synthesizing dihydrocapsaicin according to claim 1, It is characterized in that The organic solvent is at least one of tetrahydrofuran, acetic acid, toluene or dichloromethane.

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