CN116003276A - Method for synthesizing capsaicin by utilizing micro-reaction chip - Google Patents

Abstract

The invention relates to a method for synthesizing capsaicin by using a micro-reaction chip, using vanillin and nonanoic acid as raw materials, organic bases as acid-binding agents, and reacting in the micro-reaction chip to generate capsaicin. The micro-reaction chip is similar to A single-channel micro-reaction chip with a Tesla valve structure or a multi-channel micro-reaction chip similar to a Tesla valve structure. Compared with the prior art, the present invention has the advantages of rapidity, high efficiency, safety, and low amplification effect. At the same time, the micro-reaction system is well sealed, which can effectively prevent capsaicin from volatilizing, avoiding operator contact and causing bodily harm.

Description

A kind of method utilizing microreaction chip to synthesize capsaicin

technical field

The invention relates to the field of fine chemical industry, in particular to a method for synthesizing nonanoylvanillamine (capsaicin) using a micro-reaction chip similar to a Tesla valve with high flow performance.

Background technique

N-vanillinyl-n-nonylamide (nonylic acid vanillylamide) (English name: Nonylic acid Vanillylamide) has the strongest spicy taste and very strong irritation in capsaicin, which can be extracted from natural pepper Or synthesized by chemical methods. Because synthetic capsaicin has an absolute advantage over natural capsaicin in terms of price and spiciness, it is widely adopted and praised by users at home and abroad. Its structure is as follows:

Physical and chemical properties: white or off-white solid; mp: 56-58°C; at 25°C, the solubility in water is 27ppm. The acute toxicity data of this product: the rat oral LD50 is 5110mg/Kg.

From the chemical structure, capsaicin can be regarded as an amide compound formed by fatty acid and vanillyl amine. Therefore, its chemical synthesis and biosynthesis have striking similarities. The initial synthesis of capsaicin was to confirm the chemical structure of natural capsaicin. Ernst Spth et al. used isobutyl zinc and 1,6-monoethyl adipate monoacyl chloride as raw materials to obtain 8-methanol through a series of chemical synthesis. Base-6-nonenoic acid, and then through acid chlorination (that is, to replace the fatty acid and coenzyme A (COA) in the biosynthesis discovered by biochemistry to form the activated form of fatty acid-COA), and then react with vanillylamine to obtain capsaicin. This method has become a classic method for the synthesis of capsaicin, and the following synthetic methods only differ in the synthesis or source of the raw material fatty acid and vanillylamine. Hideshi Fujiwake et al. synthesized vanillylamine using catechol as a raw material, and then synthesized a series of capsaicinoid compounds by enzymatic methods, creating a biomimetic synthesis of capsaicin.

Capsaicinoid-like substances (Capsaicinoid-like Substances), that is, the structure of capsiate (Capsiate) substances are esters formed by vanillyl alcohol and corresponding capsaicin fatty acids. A group of people headed by Tatsuo Watanabe in Japan first used fatty acids to undergo acid chlorination. After reacting with vanillyl alcohol, synthesized capsaicin ester compounds and derivatives thereof, and studied the stability of such substances in different solvents; A series of similar compounds including capsaicinoid have a yield of 64% to 86%.

Due to the strong irritant of capsaicin, the volatilization of the reaction solution during the batch synthesis process can easily cause discomfort to the operators, and conventional protective equipment cannot provide protection. Improving the overall sealing and automation rate of the equipment will increase the investment in production equipment by 2 to 3 times , the cost increase will greatly offset the project profit, and the economic benefit of the project is low.

Contents of the invention

The purpose of the present invention is exactly to provide a kind of fast, efficient, low-cost in order to overcome the defective that above-mentioned prior art exists, the method that utilizes micro-reaction chip to synthesize capsaicin that is easy to industrial amplification.

The object of the present invention can be achieved through the following technical solutions: a method utilizing micro-reaction chip to synthesize capsaicin, using vanillin and nonanoic acid as raw materials, and organic base as acid-binding agent, characterized in that, in the micro-reaction chip The reaction produces capsaicin.

Further, the micro-reaction chip is a single-channel micro-reaction chip similar to a Tesla valve structure or a multi-channel micro-reaction chip similar to a Tesla valve structure.

Further, the single-channel micro-reaction chip contains one or more microstructures similar to Tesla valves in series;

The multi-channel micro-reaction chip is internally composed of two or more single-channel micro-reaction chips connected in parallel.

Further, the material of the micro-reaction chip is one of glass, stainless steel, ABS plastic, PLA plastic, PMMA, ceramics, and resin.

Further, the micro-reaction chip is integrally formed by 3D printing or laser engraving, or is divided into upper and lower parts and then fixed and formed.

Further, the micro-reaction chip includes a surface layer and a main body, wherein there are two upper and lower heat conduction channels between the surface layer and the main body, and the width and length of the heat conduction channels are the same as the internal chip size of the micro-reaction chip.

Further, the method includes the following steps:

S1, raw material mixing section

Dissolving and mixing the vanillin and the acid-binding agent in a solvent is material A, wherein the amount of the solvent is 3-5 times the total mass of the vanillin and the acid-binding agent;

Dissolving nonanoyl chloride in a solvent is material B, wherein the amount of solvent is 3-5 times the mass of nonanoyl chloride;

The temperature of the raw material mixing section is 0-30°C, and the system pressure is 0.2-0.8Mpa;

The molar ratio of the raw material feed material is n (vanillyl amine): n (nonanoyl chloride): n (acid-binding agent)=1.0:1.0～1.5:1.1～1.8;

S2, reaction section

Material A and material B are pre-mixed (pre-mixed in the preheating chip, the structure of the preheating chip is the same as that of the micro-reaction chip, and the pre-heating temperature is 20-30 ℃), then enter the micro-reaction chip, and the temperature is raised for reaction, and the reaction temperature is controlled At 20-60°C, the residence time is 30-180s.

S3, cooling section

The reaction product flows into the cooling chip to cool to 20-30°C, and the cooled material and washing water (that is, pure water, the amount of washing water is 0-1.0 equivalent of the total volume of the material) enters another group of cooling chips for mixing and washing. Then it flows into the liquid separation equipment for continuous liquid separation, and the organic phase is continuously distilled to obtain the crude product, which is further recrystallized online to obtain a high-purity product. The structure of the cooling chip is the same as that of the micro reaction chip.

Further, the acid-binding agent is one of triethylamine, ammonia water, liquid caustic soda, sodium carbonate solution, and potassium carbonate solution.

Further, the solvent is one of benzene, toluene, o-xylene, m-xylene, and xylene mixed solvents.

Compared with the prior art, the present invention has the following beneficial effects:

1. the present invention utilizes the micro-reaction chip of class Tesla valve structure to prepare nonanoyl vanillyl amine (capsaicin), and the method is: take vanillin and n-nonanoyl chloride as raw material, and benzene is a solvent, and the material is made of The pump pumps the materials into the micro-mixer and mixes them respectively, and then enters the micro-reaction chip. The present invention adopts a micro-reaction chip similar to the Tesla valve structure. When the fluid passes through the Tesla valve in the forward direction, the fluid will flow in each The circuit port is divided into two paths, and then the two paths of fluid will converge at the next intersection and accelerate. Conversely, if the fluid flows into the Tesla valve in the reverse direction, the fluid will also be divided into two paths at the first intersection and converge again at the second intersection. The difference is that this time, the flow direction of the two fluids is Contradictory, so great resistance is formed, so the Tesla valve can only pass through in the forward direction, and it is difficult to reverse the reverse flow. Since the Tesla valve structure can accelerate the forward flow of fluid, it can effectively reduce internal pressure and reduce the overall pressure of the reaction system. The reaction chip is connected with a back pressure valve to control the pressure of the system. The pressure range is 0.2MPa~0.8MPa. The positive flow promotion and internal shunt mixing shorten the reaction time to less than 180s. The reaction solution is continuously washed and concentrated on-line to obtain the crude product. If further purification is required, recrystallization solvent can be added after concentration, continuous filtration on-line, and freeze-drying. The whole process of material volume is controllable, the equipment is well sealed, and it is not easy to volatilize, which greatly reduces the harm to operators caused by volatilization of capsaicin.

2. The purpose of the present invention is to provide a kind of fast, efficient, safe, equipment comprehensive cost is low, be easy to the new method of industrial scale-up production nonanoylvanillamine (capsaicin), the reaction chip that adopts is to contain class Tesla valve microchip Structural reaction chip, the reaction chip can adopt a single-channel reaction chip with multiple Tesla valve-like microstructures connected in series according to parameters such as flow rate and flux, or a multi-channel reaction chip with multiple single-channel reaction chips connected in parallel.

3. The size of the Tesla valve-like microstructure in the reaction chip of the present invention can be adjusted according to actual needs, and the reaction chip module is easy to clean and has a long service life.

Description of drawings

Figure 1 shows the microstructure of a single Tesla-like valve;

2 is a cross-sectional view of a single-channel micro-reaction chip connected in series with a plurality of Tesla-like valve microstructures;

3 is a cross-sectional view of a multi-channel micro-reaction chip formed in parallel after a plurality of Tesla-like valve microstructures are connected in series;

Fig. 4 is a frontal cross-sectional view of the side of the micro-reaction chip;

Fig. 5 is a schematic diagram of fluid flow inside the Tesla valve microstructure.

Detailed ways

The present invention will be described in detail below in conjunction with the accompanying drawings and specific embodiments.

Utilize the micro-reaction chip of class Tesla valve to synthesize nonanoylvanillamine (capsaicin) flow process as follows:

S1, raw material mixing section

Dissolving and mixing the vanillin and the acid-binding agent in a solvent is material A, and the amount of the solvent is 3-5 times the total mass of the vanillin and the acid-binding agent;

Dissolving nonanoyl chloride in a solvent is material B, wherein the amount of solvent is 3-5 times of the total mass of nonanoyl chloride material;

The temperature of the raw material mixing section is 0-30°C, and the system pressure is 0.2-0.8Mpa;

The molar ratio of the raw material feed material is n (vanillyl amine): n (nonanoyl chloride): n (acid-binding agent)=1.0:1.0～1.5:1.1～1.8;

S2, reaction section

Material A and material B are pumped into the preheating chip through the three-way pipe for pre-mixing (the structure of the preheating chip is the same as that of the micro-reaction chip, and the preheating temperature is 20-30°C), and then enter the micro-reaction chip, and the temperature rises to react. It is controlled at 20-60°C, and the residence time is 30-180s.

S3, cooling section

The reaction product flows into the cooling chip to cool to 20-30°C, and the cooled material and washing water (that is, pure water, the amount of washing water is 0-1.0 equivalent of the total volume of the material) enters another group of cooling chips for mixing and washing. Then it flows into the liquid separation equipment for continuous liquid separation, and the organic phase is continuously distilled to obtain the crude product, which is further recrystallized online to obtain a high-purity product. The structure of the cooling chip is the same as that of the micro reaction chip.

Adopt above-mentioned microstructure reaction chip, the specific example that nonanoyl vanilla amine (capsaicin) is synthetic is as follows:

Example 1

The system pressure is controlled at 0.2MPa, the acid binding agent is triethylamine, the molar ratio of vanillyl amine, n-nonanoyl chloride and triethylamine is 1.0:1.2:1.25, the solvent is toluene, vanillyl amine/triethylamine/toluene solution and n- Nonanoyl chloride/toluene solution, two streams of materials are pumped into the preheating chip at the same time, the temperature of the preheating section is 25 ° C, enter the micro reaction chip for reaction, the reaction temperature is 45 ° C, the residence time is 120s, after the reaction is completed, it enters the cooling chip, the cooling temperature At 25°C, after cooling, the reaction liquid and the washing water with a quarter volume of the reaction liquid are simultaneously pumped into the mixing chip for mixing and washing, then flow into the liquid separation equipment for continuous liquid separation, and the organic phase is continuously concentrated to obtain the crude product of capsaicin, capsaicin Yield 89.4%, purity 96.3%.

In this embodiment, the fabrication of the micro-reaction chip is as follows: the high-temperature-resistant glass is used as a material, and it is integrally processed by laser engraving to prepare a single-channel micro-reaction chip as shown in Figure 1. The micro-reaction chip is composed of 8 special The Tesla-like valve microstructures are connected in series (as shown in Figure 2). The dimensions of a single Tesla-like valve are: 3cm in length, 2cm in width, and 2cm in height. The direct connection channel L of the microstructure is 1cm in length. The external dimensions of the single-channel micro-reaction chip are: length 35cm, width 3.4cm, height 3.4cm. The flow of fluid in the micro-reaction chip is shown in Figure 5.

The preheating chip, the micro-reaction chip and the cooling chip have the same structure and are soaked in different temperature solvents respectively.

Example 2

The system pressure is controlled at 0.5MPa, the acid-binding agent is 20% sodium carbonate solution, the molar ratio of vanillyl amine, n-nonanoyl chloride and sodium carbonate is 1.0:1.15:1.1, and the solvent is m-xylene, vanillyl amine/sodium carbonate solution/m- Xylene solution and nonanoyl chloride/m-xylene solution, the two materials are pumped into the preheating chip at the same time. After entering the cooling chip, the cooling temperature is 20°C. After cooling, the reaction solution directly flows into the liquid separation equipment for continuous liquid separation, and the organic phase is continuously concentrated to obtain the crude product of capsaicin. The yield of capsaicin is 93.2%, and the purity is 95.8%.

In this embodiment, the production of the micro-reaction chip is as follows: use stainless steel as the material, adopt the machining slotting method, process a module with 10 Tesla-like valve structures connected in series on one side of the stainless steel plate, and use screws to connect the two The processed and symmetrical steel plate is fixed into a single-channel micro-reaction chip containing 10 Tesla-like valve structures connected in series. The size of a single Tesla-like valve is: length 3cm, width 2cm, height 2cm, micro The direct connection channel of the structure is 1cm long. The external dimensions of the single-channel reaction chip are: 35cm in length, 3cm in width, and 3cm in height. The micro-reaction chip made of stainless steel has high compressive strength and relatively thin wall thickness, which is more conducive to heat transfer.

The preheating chip, the micro-reaction chip and the cooling chip have the same structure and are soaked in different temperature solvents respectively.

Example 3

The system pressure is controlled at 0.6MPa, the acid-binding agent is triethylamine, the molar ratio of vanillin, n-nonanoyl chloride and triethylamine is 1.0:1.2:1.25, and the solvent is m-xylene, vanillin/triethylamine/m-xylene Xylene solution and n-nonanoyl chloride/m-xylene solution, the two materials are pumped into the preheating chip at the same time. After entering the cooling chip, the cooling temperature is 20°C. After cooling, the reaction solution and the washing water with a quarter volume of the reaction solution are simultaneously pumped into the mixing chip for mixing and washing, and flow into the liquid separation device for continuous liquid separation, and the organic phase is continuously concentrated to obtain Crude product of capsaicin, the yield of capsaicin is 96.8%, and the purity is 95.9%.

The structures of the preheating chip, the reaction chip and the cooling chip used in this embodiment are the same as those in Embodiment 1. Example 4

The system pressure is controlled at 0.5MPa, the acid binding agent is 35% potassium carbonate solution, the molar ratio of vanillyl amine, n-nonanoyl chloride and potassium carbonate is 1.0:1.2:1.1, the solvent is toluene, vanillyl amine/potassium carbonate/toluene solution and n-nonanoyl chloride Acyl chloride/toluene solution, two streams of materials are pumped into the preheating chip at the same time, the temperature of the preheating section is 30 ° C, enters the micro reaction chip for reaction, the reaction temperature is 45 ° C, the residence time is 150s, after the reaction is completed, it enters the cooling chip, the cooling temperature is 25 ℃, after cooling, the reaction solution directly flows into the liquid separation equipment for continuous liquid separation, and the organic phase is continuously concentrated to obtain the crude product of capsaicin, with a capsaicin yield of 92.4% and a purity of 95.3%.

In the present embodiment, the making of the micro-reaction chip is as follows:

Using PMMA as the material, it is processed by 3D printing, and the single-channel micro-reaction chip is prepared as shown in Figure 1. The inside of the reaction chip is composed of 8 Tesla-like valve microstructures connected in series. The size of a single Tesla-like valve is : 3cm in length, 2cm in width, and 2cm in height, and the length of the direct connection channel of the microstructure is 1cm. The external dimensions of the single-channel reaction chip are: length 35cm, width 3.4cm, height 3.4cm. The processing difficulty of PMMA material is low, and the use of 3D printing mode is conducive to large-scale preparation, and the overall cost is low.

The preheating chip, the reaction chip, and the cooling chip have the same structure and are soaked in different temperature solvents respectively.

Example 5

The system pressure is controlled at 0.2MPa, the acid-binding agent is 20% liquid caustic soda, the molar ratio of vanillyl amine, n-nonanoyl chloride and liquid caustic soda is 1.0:1.2:1.2, and the solvent is o-xylene, vanillic amine/liquid caustic soda/ortho di Toluene solution and n-nonanoyl chloride/o-xylene solution, the two materials are pumped into the preheating chip at the same time, the temperature of the preheating section is 20°C, and enter the micro-reaction chip for reaction, the reaction temperature is 45°C, the residence time is 120s, after the reaction is completed, enter Cool the chip at a cooling temperature of 25°C. After cooling, the reaction solution directly flows into the liquid separation device for continuous liquid separation, and the organic phase is continuously concentrated to obtain crude capsaicin. The yield of capsaicin is 87.4%, and the purity is 96.7%.

In this embodiment, the production of the micro-reaction chip is as follows: ABS plastic is used as the material and processed by 3D printing to prepare a multi-channel micro-reaction chip as shown in Figure 3-4. The micro-reaction chip is internally composed of three single The channel micro-reaction chips are connected in parallel, and each single-channel micro-reaction chip is composed of six Tesla-like valve microstructures connected in series. Fig. 4 is the front section view of the side of the micro-reaction chip. The micro-reaction chip includes a surface layer 2 and a main body 1, wherein there are two heat conduction channels 3 up and down between the surface layer 2 and the main body 1, and the width and length of the heat conduction channel 3 are the same as the internal chip size of the micro-reaction chip. Similarly, the material enters and exits from the chip inlet and outlet 4 .

The preheating chip, the micro-reaction chip and the cooling chip have the same structure and are soaked in different temperature solvents respectively.

Example 6

The system pressure is controlled at 0.3MPa, the acid binding agent is triethylamine, the molar ratio of vanillyl amine, n-nonanoyl chloride and triethylamine is 1.0:1.2:1.25, the solvent is toluene, vanillyl amine/triethylamine/toluene solution and n- Nonanoyl chloride/toluene solution, two streams of materials are pumped into the preheating chip at the same time, the temperature of the preheating section is 25 ° C, enter the micro reaction chip for reaction, the reaction temperature is 60 ° C, the residence time is 120s, after the reaction is completed, it enters the cooling chip, the cooling temperature At 25°C, after cooling, the reaction liquid and the washing water with a quarter volume of the reaction liquid are simultaneously pumped into the mixing chip for mixing and washing, then flow into the liquid separation equipment for continuous liquid separation, and the organic phase is continuously concentrated to obtain the crude product of capsaicin, capsaicin Yield 94.4%, purity 95.3%.

The structures of the preheating chip, the reaction chip and the cooling chip used in this embodiment are the same as those in Embodiment 1.

Claims (10)

1. a kind of method utilizing micro-reaction chip to synthesize capsaicin, take vanillin and nonanoic acid as raw material, and organic base is an acid-binding agent, it is characterized in that, reacts and generates capsaicin in micro-reaction chip. 2. a kind of method utilizing micro-reaction chip to synthesize capsaicin according to claim 1, is characterized in that, described micro-reaction chip is the single channel micro-reaction chip of similar Tesla valve structure or similar Tesla valve Structured multi-channel microreaction chip. 3. a kind of method utilizing micro-reaction chip to synthesize capsaicin according to claim 2, is characterized in that, described single channel micro-reaction chip is that inside contains one or more similar microstructures of Tesla valves in series; The multi-channel micro-reaction chip is internally composed of two or more single-channel micro-reaction chips connected in parallel. 4. a kind of method utilizing micro-reaction chip to synthesize capsaicin according to claim 2, is characterized in that, the material of described micro-reaction chip is glass, stainless steel, ABS plastics, PLA plastics, PMMA, pottery, resin A sort of. 5. a kind of method utilizing micro-reaction chip to synthesize capsaicin according to claim 2, is characterized in that, described micro-reaction chip is processed by 3D printing integral molding processing or laser engraving integral molding processing or is divided into upper and lower two pieces and processes respectively Post-fix molding. 6. a kind of method utilizing micro-reaction chip to synthesize capsaicin according to claim 1 or 2, is characterized in that, described micro-reaction chip comprises surface layer and main body, wherein between surface layer and main body there are two heat conduction passages up and down, The width and length of the heat conduction channel are the same as the internal chip size of the micro-reaction chip. 7. a kind of method utilizing micro-reaction chip to synthesize capsaicin according to claim 1, is characterized in that, described method comprises the following steps: S1, raw material mixing section Dissolving and mixing vanillin and acid-binding agent in a solvent is material A; dissolving nonanoyl chloride in a solvent is material B; S2, reaction section Material A and material B are pre-mixed and then enter the micro-reaction chip to heat up and react; S3, cooling section The reaction product flows into the cooling chip for cooling, and the cooled material and washing water enter another group of cooling chips for mixing and washing, and then carry out continuous liquid separation and distillation to obtain the product. 8. a kind of method utilizing micro-reaction chip to synthesize capsaicin according to claim 7, is characterized in that the temperature of raw material mixing section is 0～30 ℃, and system pressure is 0.2～0.8Mpa; The molar ratio of the raw material feed material is n (vanillyl amine): n (nonanoyl chloride): n (acid-binding agent)=1.0:1.0～1.5:1.1～1.8; The temperature of the reaction section is controlled at 20-60°C, and the residence time is 30-180s. 9. a kind of method utilizing micro-reaction chip to synthesize capsaicin according to claim 1 is characterized in that described acid-binding agent is one of triethylamine, ammoniacal liquor, liquid caustic soda, sodium carbonate solution, potassium carbonate solution kind. 10. a kind of method utilizing micro-reaction chip to synthesize capsaicin according to claim 1 is characterized in that described solvent is the one in benzene, toluene, o-xylene, m-xylene, xylene mixed solvent.

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