A photochemical micro-reaction system and method for synthesizing aslidol

Abstract

The present invention relates to a photochemical micro-reaction system and method for synthesizing aslido, the method comprising: continuously flowing α-terpinene and oxygen dissolved with a photosensitizer through a photochemical microreactor, reacting under illumination conditions, and obtaining aslido; wherein the photochemical microreactor comprises a transparent microchannel, an inner diameter of 0.5-5.0 mm, and an aspect ratio of 2000-200000:1; the illumination conditions include: an illumination power of 400-1000 W, a wavelength of 400-450 nm; and a reaction pressure of 5-20 bar. Compared with the prior art, the present invention has the advantages of easy construction of reaction equipment, short reaction time, solvent-free, green, high yield and large output of product aslido, stable operation of the reaction system, and a single set of equipment combined with a supporting process can realize the solvent-free and green continuous flow synthesis of kilogram-level to ten kilogram-level aslido, and the cost of synthesizing aslido per unit mass is much lower than the cost required by the traditional plant extraction method, and the commercial application prospect is broad.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and relates to a photochemical microreaction system and method for synthesizing astridol, and in particular to a photochemical microreaction system and method for producing kilogram-level astridol under solvent-free conditions. Background Art

[0002] Astridol (structure shown in Eq.1) is an important active pharmaceutical ingredient (API) commonly used as an anti-tumor drug, plant metabolite and anti-kala-azar drug. The traditional source of astridol is extracted from organisms, which involves quite tedious and dangerous processing steps. However, it is safer and more efficient to synthesize astridol using singlet oxygen through photochemical oxidation of α-terpinene (structure shown in Eq.2). The process only involves substrate (α-terpinene), light source, oxygen and photosensitizer, and visible light photons as a "traceless reagent" can make the entire synthesis process be regarded as a biological-like green synthesis route.

[0003]

[0004] In the process of light propagating from the wall to the center of the reactor, the light intensity decreases exponentially along the light propagation distance. This attenuation effect makes the light intensity distribution in the traditional autoclave photoreactor extremely uneven, and usually requires a longer residence time and a higher photosensitizer concentration to obtain a high yield. The use of continuous flow technology can improve the yield while reducing the residence time. For example, Arnab Chaudhuri et al. (Chemical Engineering Journal 400 (2020) 125875) compared the difference between the use of continuous flow and autoclave processes to synthesize Aslidol. Under the same conditions of substrate α-terpinene concentration of 0.1 mol / L and photosensitizer Bengal red concentration of 1 mol.%, the continuous flow process was used to shorten the reaction time from 1h 6min of the autoclave process to 50s, and the yield was increased from 50% of the autoclave process to 70%.

[0005] At present, the continuous flow process for synthesizing astridol often uses solvents and the concentration of reactants is low. Oksana Shvydkiv et al. (Catalysis Today 308 (2018) 102–118) synthesized astridol in a continuous flow falling film reactor, using isopropanol as solvent. Although 89% reaction selectivity was obtained, the concentration of substrate α-terpinene was only 0.025-0.1 mol / L, and the concentration of photosensitizer was 0.5-10 mol%. Dario Cambié et al. (Angew. Chem. Int. Ed. 2019, 58, 14374–14378) synthesized astridol using a microreactor based on a fluorescent solar concentrator, using ethanol as solvent, and obtained an 85% yield under the conditions of substrate α-terpinene concentration of 0.4 mol / L and photosensitizer Bengal red concentration of 1 mol.%. Although the substrate concentration has increased, the use of solvents still brings considerable waste, which limits the scale-up of production and is not conducive to green production principles. Summary of the invention

[0006] The purpose of the present invention is to provide a photochemical microreaction system and method for synthesizing astridol, which is used to solve the problems of the existing astridol synthesis reaction, such as long residence time and high amount of photosensitizer, and can achieve kilogram-level production of astridol under solvent-free conditions.

[0007] The purpose of the present invention can be achieved by the following technical solutions:

[0008] A method for synthesizing Aslidol, comprising:

[0009] α-terpinene dissolved with photosensitizer and oxygen are continuously passed through a photochemical microreactor to react under light conditions to obtain Astridol;

[0010] The photochemical microreactor comprises a transparent microchannel with an inner diameter of 0.5 to 5.0 mm and an aspect ratio of 2000 to 200000:1; the illumination conditions include: an LED light source input power of 400 to 1000 W and a wavelength of 400 to 450 nm; and a reaction pressure of 5 to 20 bar.

[0011] α-Terpinene dissolved with photosensitizer (m-TPP) is transported by a high-pressure horizontal flow pump under solvent-free conditions, oxygen is transported by an oxygen bottle, and both gas and liquid phases are fed into the PFA microchannel at the same time, and a narrow peak monochromatic light source is used to initiate the photooxidation process.

[0012] Furthermore, the photosensitizer is meso-tetraphenylporphyrin (m-TPP).

[0013] Furthermore, the concentration of the photosensitizer in α-terpinene is 0.011-0.050 mol%, and the concentration of α-terpinene is 7-10 mol / L.

[0014] Furthermore, the flow rate of α-terpinene containing photosensitizer into the photochemical microreactor is 0.2-10 mL / min; the flow rate of oxygen into the photochemical microreactor is 4.55-100 mL / min, measured at a pressure of 6.08 bar.

[0015] Furthermore, the transparent microchannel is made of PFA, FEP, glass or quartz.

[0016] A photochemical micro-reaction system for the above-mentioned synthesis method comprises a mixer, a photochemical micro-reactor, a pressure regulating valve connected in sequence, an oxygen storage tank connected to the mixer, and a fluid pump for conveying α-terpinene dissolved with a photosensitizer.

[0017] Furthermore, the photochemical microreactor comprises a housing and a transparent microchannel arranged in the housing.

[0018] Furthermore, the transparent microchannel is arranged in a rounded rectangular shape.

[0019] Furthermore, the transparent microchannel is arranged in a box, and a light source is also arranged in the box.

[0020] Furthermore, a reflector is provided on the inner wall of the box.

[0021] Furthermore, a heat dissipation fan is also provided in the box.

[0022] A high-power box-type optical microreactor and process for producing kilograms of astridol under solvent-free conditions, using a high-power narrow-peak monochromatic light source and singlet oxygen to photooxidize α-terpinene. Under the condition of a residence time of minutes, the selectivity and production capacity of astridol are greater than 90% and kilograms to ten kilograms / day, respectively. In addition, the microscale characteristic dimensions of the microchannels, microtubes / capillaries used are extremely beneficial for improving mass transfer and photon transfer to obtain kilograms of astridol production capacity. With the further increase of raw material flux and the further enlargement of microchannels, the production capacity of astridol can even be increased to more than ten kilograms / day (10-100kg / day). A single set of equipment combined with a supporting process can realize the solvent-free, green continuous flow synthesis of kilograms to ten kilograms of astridol. The cost of synthesizing astridol per unit mass is much lower than the cost required by traditional plant extraction methods, and has broad commercial application prospects.

[0023] Compared with the prior art, the present invention has the following characteristics:

[0024] 1) Compared with photochemical kettle reactors, the sub-millimeter characteristic size of continuous flow optical microreactors is very beneficial to solving the attenuation effect, which greatly improves the uniformity of light intensity distribution in the reactor. The [4+2] cycloaddition reaction for the synthesis of astridol is very complicated, and often leads to the generation of a large number of by-products due to the self-oxidation of α-terpinene. The use of optical microreactors with shorter residence times combined with narrow peak LED light sources can improve the reaction selectivity of astridol. When using low-power and wide-wavelength LED light sources, the production capacity of astridol is often limited to milligrams and grams, and the use of solvents not only increases the generation of waste, but also limits the scale-up potential of these photoreactors to a certain extent. However, by using solvent-free reaction media and optical microreactors with high-power, narrow-wavelength LED light sources, the daily production capacity of astridol, a valuable active pharmaceutical ingredient, can reach more than kilograms.

[0025] 2) The photomicroreactor device of the present invention is superior to the commonly used photoreactor for singlet oxygen photooxidation in the following aspects: the residence time of the photomicroreactor is less than 1 minute, the selectivity of the aslido reaction is close to 94%, and the production capacity is close to 3.5 kg / day. Under given operating conditions, the space-time yield and photochemical space-time yield are 9.3 kg / (L·h) and 34.7 mol / (kW·Day), respectively, and these excellent reaction results are carried out in the above-mentioned photomicroreactor under the condition of solvent-free medium, which greatly promotes the development of green sustainable chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is a structural schematic diagram of a photochemical micro-reaction system in the present invention;

[0027] Description of the markings in the figure:

[0028] 1- fluid pump, 2- oxygen storage tank, 3- mixer, 4- transparent microchannel, 5- light source, 6- pressure regulating valve, 7- sample bottle. DETAILED DESCRIPTION

[0029] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0030] like Figure 1 A photochemical micro-reaction system shown includes a mixer 3, a photochemical micro-reactor, a pressure regulating valve 6 connected in sequence, and an oxygen storage tank 2 connected to the mixer 3 and a fluid pump 1 for conveying α-terpinene dissolved with a photosensitizer.

[0031] Among them, the photochemical microreactor includes a transparent microchannel 4 with an inner diameter of 0.5 to 5.0 mm, an aspect ratio of 2000 to 200000:1, a length of preferably 10 to 100 m, and an internal volume of preferably 1.96 to 19.6 mL; the material is PFA, FEP, glass or quartz; preferably, the transparent microchannel 4 is a rounded rectangle wrapped around a 3D printed support structure.

[0032] In some specific embodiments, the transparent microchannel 4 is disposed in a box, a light source 5 is also disposed in the box, and a reflector is also disposed on the inner wall of the box.

[0033] In some preferred embodiments, the distance between the transparent microchannel 4 and the light source is kept as short as possible to increase the light flux of the reaction medium. In a preferred embodiment, the distance between the transparent microchannel 4 and the light source is 2.5-3.5 cm.

[0034] In some preferred embodiments, the light source used is a monochromatic, high-brightness, narrow-wavelength LED, the number of which is preferably 200 to 500, the input power is 400 to 1000 W, and the maximum emission wavelength range is between 400 and 450 nm.

[0035] In some specific embodiments, in order to remove the heat generated by the high-power light source, a plurality of cooling fans are installed on the top of the transparent microchannel 4, and the air supply volume is preferably 1.5-50m 3 / min.

[0036] In addition, a power pack is provided in the photochemical microreactor to supply power to the fan, the light source and the auxiliary devices; an automatic shutdown timer and a manual circuit breaker are installed to ensure safety; and the power of the light source can be adjusted by a power regulator.

[0037] A method for synthesizing Aslidol, comprising:

[0038] α-terpinene dissolved with photosensitizer tetraphenylporphyrin and oxygen are continuously passed through the photochemical microreactor to react under light conditions to obtain aslidol, and the product is collected in a glass sample bottle 7 connected to the transparent microchannel 4 through the outlet thereof;

[0039] Among them, the lighting conditions include: the LED light source input power is 400-1000W, the wavelength is 400-450nm; the emission spectrum of the light source and the absorption spectrum of the photosensitizer show good overlap, which plays a vital role in the effective generation of singlet oxygen and improving the selectivity of aspartame.

[0040] The reaction pressure is 5 to 20 bar, which is beneficial to increase the solubility of singlet oxygen in the reaction system to accelerate the mass transfer rate and keep the temperature at room temperature;

[0041] The concentration of the photosensitizer in α-terpinene is 0.011-0.050 mol%, and the concentration of α-terpinene is 7-10 mol / L; the flow rate of α-terpinene containing the photosensitizer into the photochemical microreactor is 0.2-10 mL / min; the flow rate of oxygen into the photochemical microreactor is 4.55-100 mL / min, measured at a pressure of 6.08 bar.

[0042] The present invention relates to a high-power box-type photochemical microreactor for producing kilogram-level astrid under solvent-free conditions, which shows a great contribution to the development of green sustainable pharmaceutical industry. The high-power box-type photochemical microreactor system is mainly composed of a narrow-peak purple LED light source with a total power of more than 100W, a microchannel or micro / thin tube (with an inner diameter of 0.2-20mm) with a stable support structure made by 3D printing, a back pressure valve (i.e., a pressure regulating valve 6), a reflector, a cooling fan and a box. Corresponding process features: the substrate α-terpinene and the raw gas oxygen dissolved in the solvent-free photosensitizer are respectively transported into the photochemical microreactor system by a metering fluid conveying device such as a horizontal flow pump (i.e., a fluid pump 1) and a gas mass flowmeter through a mixer; the photosensitizer sensitizes oxygen under light conditions to produce singlet oxygen, and then undergoes an oxidation reaction with α-terpinene to produce astrid.

[0043] The present invention has the advantages of easy construction of reaction equipment, short reaction time, solvent-free, green, high yield and large output of the product astridol, stable operation of the reaction system, etc. A single set of equipment combined with a supporting process can achieve solvent-free, green continuous flow synthesis of kilograms to ten kilograms of astridol. The unit mass of astridol synthesis cost is much lower than the cost required by the traditional plant extraction method, and has broad commercial application prospects.

[0044] The following embodiments are implemented based on the above technical solution of the present invention, and provide detailed implementation methods and specific operation processes, but the protection scope of the present invention is not limited to the following embodiments.

[0045] Embodiment 1:

[0046] like Figure 1 A photochemical micro-reaction system shown includes a mixer 3, a photochemical micro-reactor, a pressure regulating valve 6 connected in sequence, and an oxygen storage tank 2 connected to the mixer 3 and a fluid pump 1 for conveying α-terpinene dissolved with a photosensitizer.

[0047] The photochemical microreactor includes a box, a transparent microchannel 4 and a light source 5 arranged in the box, and a reflector arranged on the inner wall of the box. The transparent microchannel 4 has an inner diameter of 1.0 mm, a length of 20 m, an internal volume of 15.71 mL, and is made of PFA. The light source 5 is an LED lamp with an input power of 600 W and an emission wavelength of 415 to 420 nm.

[0048] A method for synthesizing Aslidol, comprising:

[0049] α-terpinene (wherein the concentration of α-terpinene is 8.97 mol / L and the concentration of the photosensitizer in α-terpinene is 0.0167 mol%) and oxygen are continuously passed through the photochemical microreactor to react under light conditions to obtain aslidol, and the product is collected in a glass sample bottle connected to the outlet of the transparent microchannel 4;

[0050] The reaction pressure is 6.08 bar, which is controlled by a 100 psi back pressure valve; the flow rate of α-terpinene dissolved with photosensitizer into the photochemical microreactor is 0.4-2.0 mL / min; the flow rate of oxygen into the photochemical microreactor is 11.76-30.76 mL / min, and the residence time of α-terpinene dissolved with photosensitizer in the photochemical microreactor is 0.28-1.29 min.

[0051] The concentrations of α-terpinene and astilbene were measured by gas chromatography (GC FID, Agilent 7890B, HP-5 column) and used to determine the yield, selectivity, productivity and other key parameters.

[0052] Table 1 shows the changes in the results of α-terpinene photooxidation with residence time. When the residence time is 0.48 min, the selectivity and productivity can reach 94.1% and 3.51 kg / day. In addition, although the yield will be reduced by reducing the residence time, the selectivity and productivity will be further improved. When using a higher feed flow rate and a longer microchannel volume, the productivity of Aslido will reach 5-10 kg / day.

[0053] Table 1

[0054]

[0055] Embodiment 2:

[0056] Compared with Example 1, the only difference is:

[0057] The transparent microchannel 4 has a length of 10 m, an internal volume of 7.85 mL, an LED lamp power of 240 to 600 W, a photosensitizer concentration in α-terpinene of 0.017 mol%, a flow rate of α-terpinene containing photosensitizer passing into the photochemical microreactor of 1.0 mL / min, a flow rate of oxygen passing into the photochemical microreactor of 15.4 mL / min, and a residence time of α-terpinene containing photosensitizer in the photochemical microreactor of 0.48 min;

[0058] The rest is the same as in Example 1.

[0059] Table 2 shows the changes in the photooxidation results of α-terpinene with the light source power. As the input power of the LED light source decreases, the production capacity and space-time yield decrease simultaneously, but the aspartame selectivity increases.

[0060] Table 2

[0061]

[0062] Embodiment 3:

[0063] Compared with Example 1, the only difference is:

[0064] The amount of m-TPP is 0.011-0.028 mol%, the flow rate of α-terpinene dissolved with photosensitizer into the photochemical microreactor is 0.2 mL / min, and oxygen is delivered from the oxygen bottle at a flow rate of 4.41 mL / min. Under the above conditions, the residence time is 1.70 min;

[0065] The rest is the same as in Example 1.

[0066] Table 3

[0067]

[0068] Table 3 shows the changes in the results of α-terpinene photooxidation with the amount of m-TPP. With the increase in the amount of m-TPP, the yield, selectivity and space-time yield of astilbene in the α-terpinene photooxidation reaction under solvent-free conditions are improved.

[0069] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for synthesizing Aslido, characterized in that: include: α-terpinene dissolved with photosensitizer and oxygen are continuously passed through a photochemical microreactor to react under light conditions to obtain aslidol; The photochemical microreactor comprises a transparent microchannel (4) with an inner diameter of 1 mm and an aspect ratio of 10,000 to 20,000:1; the illumination conditions include: an LED light source input power of 240 to 600 W and a wavelength of 415 to 420 nm; a reaction pressure of 6.08 bar; The photosensitizer is tetraphenylporphyrin; The concentration of the photosensitizer in α-terpinene is 0.0167-0.017 mol%; The flow rate of α-terpinene containing photosensitizer into the photochemical microreactor is 0.4-1 mL / min; the flow rate of oxygen into the photochemical microreactor is 8.82-15.435 mL / min, measured at a pressure of 6.08 bar.

2. The method for synthesizing Aslido according to claim 1, characterized in that The material of the transparent microchannel (4) is PFA, FEP, glass or quartz.

3. The method for synthesizing Aslido according to claim 1 or 2, characterized in that: The photochemical micro-reaction system used comprises a mixer (3), a photochemical micro-reactor, a pressure regulating valve (6) connected in sequence, an oxygen storage tank (2) connected to the mixer (3), and a fluid pump (1) for conveying α-terpinene dissolved with a photosensitizer.

4. The method for synthesizing Aslido according to claim 3, characterized in that: The photochemical microreactor comprises a box body, and a transparent microchannel (4) and a light source arranged in the box body.

5. The method for synthesizing Aslido according to claim 4, characterized in that: The transparent microchannel (4) is arranged in a winding manner in the shape of a rounded rectangle.

6. The method for synthesizing Aslido according to claim 4, characterized in that: The inner wall of the box is also provided with a reflector.

7. The method for synthesizing Aslido according to claim 4, characterized in that: A heat dissipation fan is also arranged in the box body.

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