CN110105261A - A method of continuous, rapid synthesis and purification epiphysin using microreactor - Google Patents

Abstract

The present invention relates to a kind of using microreactor continuous, rapid synthesis and the method for purifying epiphysin, this method dissolves 5- methoxytryptamine first with methylene chloride, again it is delivered in microreactor simultaneously with acetic anhydride and is reacted, reaction resulting material enters in liquid distributing device after mixing with the aqueous sodium carbonate that pumping comes to be extracted, gained lower layer organic phase is after vacuum distillation and recrystallization, as high-purity epiphysin.This method is mixed using methylene chloride promotion reactant and the separation of product and impurity, synthesis and the separating-purifying continuous quickly progress in microreactor, simpler efficient.

Description

A method for continuously and rapidly synthesizing and purifying melatonin using a microreactor

technical field

The invention relates to the technical field of medical synthesis, in particular to a method for continuously and rapidly synthesizing and purifying melatonin using a microreactor.

Background technique

Melatonin (chemical name N-acetyl-5-methoxytryptamine) is an indole hormone secreted by the pineal gland of the human brain. Its main function is to maintain the circadian rhythm of human physiology, which is beneficial to sleep and can enhance Human immune function, inhibit the growth of tumor cells. Melatonin also has an inhibitory effect on the central nervous system. It is a more effective peroxide radical scavenger than vitamin E. It can regulate human growth and development, reproductive function and many organs.

Microreactor, also known as microchannel reactor, is a new type of reaction equipment. Microreactors typically contain fluid flow channels with equivalent diameters on the order of micrometers to millimeters in which chemical reactions take place. With the development of technology, more and more attention has been paid to microreactors. Compared with conventional reactors, microreactors have the following advantages:

1) The reaction time can be precisely controlled. The reactant undergoes a chemical reaction during the continuous flow in the microreactor, and the reaction time can be accurately controlled by controlling the residence time of the material;

2) Materials can be mixed instantaneously in precise proportions. The precise ratio of reaction materials can be accurately controlled by controlling the reaction parameters of the microreactor;

3) The experimental results are easy to scale up. Continuous flow is the most notable feature of microreactor technology, and a large number of target products can be prepared through continuous flow;

4) High safety performance. Some reactions that used to be explosive under normal conditions can be safely carried out in microreactors.

Although the microreactor has many advantages, its product synthesis and separation and purification cannot be carried out at the same time. Generally, it is necessary to synthesize the product in the microreactor and collect it, and then send the collected product to other equipment or subsequent processes. Carry out purification operation. The synthesis and purification of existing microreactor products are separated, the whole process is not coherent, there may be pauses in the middle, and the overall production efficiency is low.

There have been many reports on the synthesis process of melatonin. Yang Jianwu et al. (Yang Jianwu, Cao Huilan. Synthesis and characterization of melatonin [J]. Chemical Research, 2003, 14 (4): 42-44.) reported a 5-methoxytryptamine as raw material, acetic anhydride Acylating reagent reacts the method for synthesizing N-acetyl-5-methoxytryptamine, and this method has problems such as acylation time is long (more than three hours), reaction speed is slower, energy consumption is big, cost is high, and is not suitable for Industrial production. Miryam Femandez-Suarez et al. (The development of integrated microfluidic chemistry platforms for lead optimization in the phar maceutical industry, Fourth international conference on Nanochannels, Microchannels and Minichannels, Miryam Femandez-Suarez, et al., Page 1-6) disclosed a The method for preparing melatonin with a microreactor, although the reaction time is reduced to 12s by using a microreactor, the synthesis and separation are still operated separately, and continuous production has not been realized.

The inventor team (CN106622070A) disclosed a method for continuously preparing melatonin using a microreactor earlier. On this basis, after a large number of long-term experiments and summaries, in line with the purpose of continuing to optimize the function of the microreactor, further development A method for continuous synthesis and isolation of melatonin using microreactor as a carrier was developed. The method not only simplifies the operation, but also realizes uninterrupted production, can efficiently separate and purify the melatonin while synthesizing it, and has a high degree of industrialization and automation.

Contents of the invention

The purpose of the present invention is to overcome the disadvantages of long reaction time, low efficiency, separate synthesis and purification, cumbersome and complicated post-treatment of the product, etc. existing in the existing melatonin synthesis method, and to provide a continuous and rapid synthesis and purification of melatonin using a microreactor. The method for melanin, the method comprises the following steps:

(a) 5-methoxytryptamine is dissolved in dichloromethane to obtain 5-methoxytryptamine-dichloromethane solution; a certain concentration of sodium carbonate aqueous solution is prepared; The oxytryptamine-dichloromethane solution and acetic anhydride are transported into the micro-reactor according to a certain ratio, and at the same time, the prepared sodium carbonate aqueous solution is transported to the outlet of the micro-reactor to mix it with the reacted material, and the resulting mixed material enters the separation Separate the liquid in the liquid device, transport the lower organic phase to the vacuum distillation device for distillation, and recrystallize the liquid obtained from the distillation.

Further, the concentration of the 5-methoxytryptamine-dichloromethane solution is 0.025-0.1 g/mL. Choosing dichloromethane as a solvent is mainly to make use of its inmiscibility with water to facilitate subsequent separation and purification; if ethanol is selected, the subsequent separation operation will be difficult to carry out effectively; if THF is selected, it will cause swelling and deformation of the pipeline and destroy micro-reactions aisle.

Further, the mass fraction of the sodium carbonate aqueous solution is 10%-30%.

Further, the mass ratio of each material required for the reaction is 5-methoxytryptamine: acetic anhydride: sodium carbonate solution = 1:2-10:20-50. Acetic anhydride should be in excess, so its ratio is higher than that of 5-methoxytryptamine-dichloromethane solution; for cost saving, sodium carbonate solution should be in excess (approximately equivalent to the flow sum of the other two materials), so as to quench the excess acetic anhydride, and extract the acetic acid generated by the reaction into the inorganic phase, which is beneficial to the separation of reaction by-products and unreacted acetic anhydride from the product.

Further, the microreactor is made of PTFE, and the length of the microtube is 80-120cm.

Further, during the reaction, the microreactor is placed in a water bath at 20°C, and ultrasonic vibration is performed at the same time, the residence time of the mixed material in the microreactor is 10-90s, and the flow rate is 1.18-47.1mL/h.

Further, the vacuum degree of vacuum distillation is 0.09MPa, the temperature is 40°C, and the recrystallization temperature is -10°C.

Compared with the prior art, the beneficial effects of the present invention are mainly reflected in the following aspects: (1) utilize dichloromethane to dissolve the raw material 5-methoxytryptamine to make a reaction solution, so that it can be better combined with another The reaction solution acetic anhydride is fully mixed and reacted, and the toxicity of dichloromethane is relatively small, which is also beneficial to the separation and purification of the product and impurities; (2) the residence time of the material in the microreactor is short, the reaction is fully and completely, and the reacted material is in the microreactor. The outlet is directly mixed with sodium carbonate aqueous solution for extraction, the whole process is more coherent, and the organic liquid phase obtained after extraction is subjected to vacuum distillation and crystallization to obtain high-purity melatonin products; (3) Synthesis and separation and purification of existing microreactor products It cannot be carried out at the same time. Generally, it is necessary to synthesize the product in the microreactor and collect it, and then carry out the next purification operation on the collected product. The synthesis and purification of the product are separated, the whole process is not coherent, and the production efficiency is low. Low. The present invention successfully solves the above-mentioned problems.

Description of drawings

Figure 1 is a schematic diagram of the synthesis device of the present invention.

Detailed ways

In order to enable those skilled in the art to fully understand the technical solutions and beneficial effects of the present invention, further description will be given below in conjunction with specific examples.

The device used in the present invention is shown in Figure 1, and this microreactor inlet is connected with reaction solution A and reaction solution B respectively by two parallel pipelines, and its outlet is connected with solution C by branch pipeline, all The reaction solution is accurately metered and delivered by a micro delivery pump. The outlet material is mixed with solution C and transported to a liquid separator (separating funnel) for liquid separation, and the lower organic phase is distilled under reduced pressure and recrystallized to obtain a high-purity product. The microreactor is made of PTFE, and the length of the microtube is 100cm.

Example 1

Dissolve 0.3 g of 5-methoxytryptamine in 6 mL of dichloromethane to obtain a 5-methoxytryptamine-dichloromethane solution with a concentration of 0.050 g/mL. Dissolve 1 g of sodium carbonate in 9 mL of water to obtain a 10% aqueous solution of sodium carbonate.

The microreactor was placed in a water bath at 20 °C while ultrasonic oscillation was turned on. The 5-methoxytryptamine-dichloromethane solution and acetic anhydride are simultaneously pumped into the microreactor through the inlet pipeline, and the sodium carbonate aqueous solution is immediately pumped to the outlet of the microreactor to mix with the outlet materials. The flow rate of 5-methoxytryptamine-dichloromethane solution is 37.7mL/h, the flow rate of acetic anhydride is 9.4mL/h, the flow rate of sodium carbonate aqueous solution is 40mL/h, and the material residence time is about 45s.

The material coming out from the microreactor is mixed with the aqueous sodium carbonate solution and enters the separatory funnel, and the lower dichloromethane layer is removed for distillation under reduced pressure (vacuum degree 0.09MPa, water bath temperature 40°C, all solvents are evaporated to dryness). The liquid obtained by distillation was recrystallized at -10°C to obtain 0.30 g of solid. Calculation shows that the product yield is 80.61%. Tests such as NMR have shown that the solid is indeed melatonin.

Example 2

Dissolve 0.3 g of 5-methoxytryptamine in 4 mL of dichloromethane to obtain a 5-methoxytryptamine-dichloromethane solution with a concentration of 0.075 g/mL. Dissolve 1 g of sodium carbonate in 10 mL of water to obtain a 10% aqueous solution of sodium carbonate.

The microreactor was placed in a water bath at 20 °C while ultrasonic oscillation was turned on. The 5-methoxytryptamine-dichloromethane solution and acetic anhydride are simultaneously pumped into the microreactor through the inlet pipeline, and the sodium carbonate aqueous solution is immediately pumped to the outlet of the microreactor to mix with the outlet materials. The flow rate of 5-methoxytryptamine-dichloromethane solution is 1.06mL/h, the flow rate of acetic anhydride is 0.12mL/h, the flow rate of sodium carbonate aqueous solution is 5mL/h, and the material residence time is about 45s.

The material coming out from the microreactor is mixed with the aqueous sodium carbonate solution and enters the separatory funnel, and the lower dichloromethane layer is removed for distillation under reduced pressure (vacuum degree 0.09MPa, water bath temperature 40°C, all solvents are evaporated to dryness). The liquid obtained by distillation was recrystallized at -10°C to obtain 0.28 g of solid. Calculation shows that the product yield is 73.7%.

Claims (7)

1. A method for continuously and rapidly synthesizing and purifying melatonin utilizing microreactor, is characterized in that, comprises the following steps: (a) dissolving 5-methoxytryptamine in dichloromethane to obtain a 5-methoxytryptamine-dichloromethane solution; preparing a certain concentration of sodium carbonate aqueous solution; (b) 5-methoxytryptamine-dichloromethane solution and acetic anhydride are transported into the microreactor according to a certain ratio through the micropipes connected in parallel, and the sodium carbonate aqueous solution prepared is delivered to the microreactor outlet at the same time, so that Mix with the reacted material, the obtained mixed material enters the liquid separation device for liquid separation, transports the lower organic phase to the vacuum distillation device for distillation, and recrystallizes the liquid obtained from the distillation. 2. The method according to claim 1, characterized in that: the concentration of the 5-methoxytryptamine-dichloromethane solution is 0.025-0.1 g/mL. 3. the method for claim 1 is characterized in that: the massfraction of described sodium carbonate aqueous solution is 10%-30%. 4. The method according to claim 1, characterized in that: the mass ratio of each material required for the reaction is 5-methoxytryptamine: acetic anhydride: sodium carbonate solution=1:2-10:20-50. 5. The method according to claim 1, characterized in that: the microreactor is made of PTFE, and the length of the microtube is 80-120cm. 6. The method as claimed in claim 1, characterized in that: during the reaction, the microreactor is placed in a 20°C water bath, and ultrasonic vibration is processed simultaneously, the residence time of the mixed material in the microreactor is 10-90s, and the flow rate is 1.18- 47.1mL/h. 7. The method according to claim 1, characterized in that: the vacuum degree of vacuum distillation is 0.09MPa, the temperature is 40°C, and the recrystallization temperature is -10°C.