A continuous flow process for the production of hydroxycarbazoles

Abstract

The present application belongs to the technical field of hydroxycarbazole production separation and purification, and provides a continuous flow production process of hydroxycarbazole, specifically comprising the following steps: (1) mixing raw materials o-halogenated aniline, hydroquinone, an organic solvent and an acid catalyst, and then pumping into a first reactor for reaction; (2) sequentially subjecting the reaction liquid at the outlet of the first-stage reactor to extraction, vacuum distillation, recrystallization and drying treatment to obtain a reaction product photoreaction intermediate; (3) continuously pumping the photoreaction intermediate prepared in step (2) into a second-stage photoreactor together with a solution of a photoreaction catalyst and a second solvent, and performing a photochemical reaction under the irradiation of a UV-LED light source; and (4) sequentially subjecting the reaction liquid at the outlet of the second-stage photoreactor to neutralization, vacuum distillation and recrystallization to obtain a hydroxycarbazole product. The technical scheme of the present application can realize the preparation of a plurality of hydroxycarbazoles with high yield and high purity, and shorten the production cycle.

Description

Technical Field

[0001] This invention belongs to the field of hydroxycarbazole production, separation and purification technology, and specifically relates to a continuous flow production process for hydroxycarbazole. Background Technology

[0002] Hydroxycarbazole has attracted much attention due to its unique rigid fused-ring structure and has broad application prospects. This compound is easily modified through structural chemistry, allowing for the convenient introduction of various functional groups onto the carbazole ring. Furthermore, the hydroxyl group itself can undergo group transformation or connect to other functional groups, thus forming a larger molecular conjugated system. Carbazole derivatives obtained through such modification can be used to prepare organic electroluminescent materials and hole transport materials. In addition, hydroxycarbazole is also a bioactive alkaloid that can effectively inhibit the growth of pathogenic microorganisms. Therefore, it can be used as an active group in drug synthesis for antifungal and antitumor purposes. Currently, hydroxycarbazole and its derivatives are widely used in organic optoelectronic materials, bioimaging, dyes, sensing and detection, pesticides, and pharmaceuticals. For example, 4-hydroxycarbazole, as a key intermediate in the antihypertensive drug carvedilol, plays an important role in drug synthesis.

[0003] Currently, the main method for synthesizing hydroxycarbazole is thermochemical synthesis, which involves multiple steps of reaction under high temperature and high pressure in a batch or semi-batch manner. Patent WO2007077111A1 reports a method for preparing hydroxycarbazole through multiple steps under the catalysis of noble metals such as palladium. However, this thermochemical synthesis method suffers from stringent reaction conditions, high cost of catalysts, and complex reaction operations, resulting in high production costs, scarce and expensive raw materials, numerous byproducts, and low yields. Furthermore, the subsequent product separation process is difficult to scale up, significantly increasing production costs and severely hindering its industrialization.

[0004] Photochemical reactions are currently being used as a new route for the production of hydroxycarbazole due to their greener and more environmentally friendly nature. However, existing methods are all batch reactions, resulting in low photon transmission efficiency, high energy consumption of the light source, low reaction yield, long reaction time, and serious side reactions. Furthermore, while existing photochemical reaction methods for the preparation of hydroxycarbazole can produce 1-hydroxycarbazole, 2-hydroxycarbazole, or 3-hydroxycarbazole in certain quantities depending on the raw materials, 4-hydroxycarbazole, because its preparation route is the same as that of 2-hydroxycarbazole, consistently yields 2-hydroxycarbazole as the main product, with extremely low yields of 4-hydroxycarbazole. This poses a significant challenge to the production and separation of 4-hydroxycarbazole.

[0005] Therefore, a new process for the production of hydroxycarbazole is still needed, which is applicable to the preparation and separation of 1-hydroxycarbazole, 2-hydroxycarbazole, 3-hydroxycarbazole and 4-hydroxycarbazole. Summary of the Invention

[0006] This invention addresses the shortcomings of existing methods for preparing hydroxycarbazole by developing a continuous flow production process for hydroxycarbazole. This process features mild reaction conditions, readily available raw materials, simple separation and purification processes, high reaction yield, high selectivity, and low production costs. It can achieve the preparation and effective separation of 1-hydroxycarbazole, 2-hydroxycarbazole, 3-hydroxycarbazole, and 4-hydroxycarbazole.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows:

[0008] In a first aspect, the present invention provides a continuous flow production process for hydroxycarbazole, comprising the following steps:

[0009] (1) After mixing the raw materials o-halogenated aniline, hydroquinone, organic solvent and acid catalyst, the mixture is continuously pumped into the first-stage reactor for reaction;

[0010] (2) The reaction liquid at the outlet of the first stage reactor is subjected to extraction, vacuum distillation, recrystallization and drying in sequence to obtain the photoreaction intermediate of the reaction product;

[0011] (3) The solution of the photoreaction intermediate obtained in step (2) mixed with the photoreaction catalyst and the second solvent is continuously pumped into the second-stage photoreactor and photochemical reaction is carried out under UV-LED light source irradiation.

[0012] (4) The reaction liquid at the outlet of the second-stage photoreactor is subjected to neutralization, vacuum distillation and recrystallization in sequence to obtain the hydroxycarbazole product;

[0013] Wherein, the o-haloaniline is selected from at least one of 2-chloroaniline, 2-bromoaniline, 2-fluoroaniline and 2-iodoaniline, the hydroquinone is selected from at least one of catechol, resorcinol and hydroquinone, and the acid catalyst is selected from at least one of non-oxidizing acids; both the first-stage reactor and the second-stage photoreactor are microchannel reactors, the channel size of the microchannel reactor is 0.15mm-3.0mm, and the maximum emission wavelength range of the UV-LED light source is 270-320nm.

[0014] In this field, the maximum emission wavelength of a light source is the center emission wavelength.

[0015] The present invention is further configured such that the photoreaction intermediate of the product of step (1) includes at least one of 2-hydroxy-2′-halo-diphenylamine, 3-hydroxy-2′-halo-diphenylamine and 4-hydroxy-2′-halo-diphenylamine; and the finally obtained hydroxycarbazole product includes at least one of 1-hydroxycarbazole, 2-hydroxycarbazole, 3-hydroxycarbazole or 4-hydroxycarbazole.

[0016] The present invention is further configured such that, in step (1), the organic solvent is selected from one or more of benzene, toluene, xylene, ethyl acetate, ethyl propionate, dioxane, cyclohexane, and dimethyl sulfoxide.

[0017] The present invention is further configured such that, in step (1), the acid catalyst is selected from at least one of dilute sulfuric acid, phosphoric acid, acetic acid, benzenesulfonic acid or p-toluenesulfonic acid.

[0018] The present invention is further configured such that, in step (1), the molar ratio of the raw material hydroquinone to o-haloaniline is 1:(0.5-2.0), more preferably 1:(0.6-1.4); the molar ratio of the acid catalyst to the raw material hydroquinone is 0.05-0.5; more preferably 0.05-0.2.

[0019] In step (1), the raw materials continuously conveyed are two feed streams. One feed stream is a solution of hydroquinone, acid catalyst and organic solvent mixed together. The concentration of hydroquinone in the mixed solution is 25-40 wt%, and the concentration of acid catalyst is 3-10 wt%. The other feed stream is a solution of o-haloaniline and organic solvent mixed together. The concentration of o-haloaniline is 35-50 wt%. The flow rate of the two feed streams is 0.5-1.5 mL / min. After the two feed streams are mixed, they are pumped into the first-stage reactor for reaction.

[0020] The present invention is further configured such that, in step (1), the first-stage reactor is selected as a T-shaped, butterfly-shaped or branch-shaped microchannel reactor, and the channel size of the first-stage reactor is 0.5~2.0mm.

[0021] The present invention is further configured such that the reaction temperature of the first-stage reaction is 90-200℃ and the reaction time is 30-90 minutes; preferably, the reaction temperature of the first-stage reaction is 120-180℃ and the reaction time is 40-70 minutes.

[0022] The present invention is further configured such that, in step (2), the extractant used for extraction is selected from one or more of water, methanol, ethanol, acetonitrile, ethyl acetate, ethyl propionate, triethylamine and ammonia; the extraction temperature is 0-60 ℃, preferably 0-25 ℃.

[0023] The present invention is further configured to recrystallize the residual liquid containing the photoreaction intermediate after vacuum distillation. The solvent used for recrystallization is selected from at least one of water, methanol, ethanol, acetonitrile or acetone. The acid solution used to adjust the pH is selected from at least one of formic acid, acetic acid, propionic acid, hydrochloric acid, phosphoric acid or sulfuric acid. The alkaline solution used to adjust the pH is selected from at least one of sodium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine, calcium hydroxide, potassium hydroxide, sodium hydroxide or sodium carbonate.

[0024] The recrystallization temperature is controlled in stages: the temperature is increased from 20-25℃ to 40-50℃ at a rate of 10-20℃ / min, held constant for 5-20 minutes, and adjusted to pH=7.5-11; then the temperature is increased to 80-90℃ at a rate of 10-20℃ / min, held constant for 10-20 minutes, and adjusted to pH=3-6.5; finally, the temperature is decreased to 20-25℃ at a rate of 5-15℃ / min, held constant for 10-20 minutes, and filtered under constant temperature.

[0025] The present invention is further configured such that, after extraction treatment, an extract and a raffinate containing photoreaction intermediates are separated, wherein the raffinate is separated into an organic solvent by vacuum distillation, and the remaining raffinate containing photoreaction intermediates is cooled and recrystallized, and the separated organic solvent is returned to the feed end for recycling; part of the separated extract is separated into an extractant and an acid catalyst by vacuum distillation and recycled.

[0026] The present invention is further configured such that, in step (2), the drying temperature is 50-120 ℃, preferably 60-70 ℃.

[0027] The present invention is further configured such that, in step (3), the photocatalyst is selected from one or more of methylamine, ethylamine, diethylamine, triethylamine, aniline, diisopropylamine, sodium hydroxide and potassium hydroxide;

[0028] The second solvent used for the photoreaction is selected from one or more of acetonitrile, malononitrile, ethyl acetate, dimethyl sulfoxide, toluene, and cyclohexane.

[0029] The present invention is further configured such that, in step (3), the molar ratio of the photoreaction catalyst and the intermediate raw material is (1.5-4.5:1); preferably (2.4-3.2):1.

[0030] The present invention is further configured such that, in step (3), the second-stage photoreactor is selected as a T-shaped, butterfly-shaped or branch-shaped plate microchannel reactor, and the channel size of the second-stage photoreactor is 0.5~2.0mm.

[0031] The present invention further specifies that the photochemical reaction conditions are: room temperature and reaction residence time of 100-1200 seconds; the reaction residence time is preferably 150-600 seconds, and more preferably 200-360 seconds.

[0032] The present invention is further configured such that, in step (3), the UV-LED light source is a panel light source integrating several small LED lamps and equipped with air cooling; the peak width of the LED lamp emission wavelength is 10-30 nanometers, and the radiation power is 1-200 mW / cm². 2 .

[0033] The present invention is further configured such that, in step (3), the maximum emission wavelength of the LED light source is 280-300 nm.

[0034] The present invention is further configured such that, in step (3), the raw materials continuously conveyed are two feed streams, one feed stream is a solution containing a photoreaction intermediate with a concentration of 3~10wt%; the other feed stream is a solution containing a photoreaction catalyst with a concentration of 1.0~6.0wt%; the two feed streams have the same flow rate of 1.0~2.0 mL / min, and after the two feed streams are mixed, they enter the second-stage photoreactor for reaction.

[0035] The present invention is further configured such that, in step (4), the reaction liquid at the outlet is neutralized to pH=6.5-7.5 by acid solution, and then vacuum distillation is performed to recrystallize the remaining high-temperature reactor liquid after the solvent is separated.

[0036] The recrystallization is carried out in stages under reduced pressure conditions, ranging from -0.1 to -0.05 MPa.

[0037] The specific segmented control process is as follows:

[0038] The high-temperature distillate from vacuum distillation is first heated to 190-210℃ at a rate of 10-20℃ / min, held at that temperature for 5-15 minutes, and then filtered under vacuum at the same temperature. Next, it is cooled to 140-160℃ at a rate of 5-15℃ / min, held at that temperature for 10-20 minutes, and then filtered under vacuum at the same temperature. Then, it is cooled to 90-110℃ at a rate of 5-15℃ / min, held at that temperature for 10-20 minutes, and then filtered under vacuum at the same temperature. Finally, it is cooled to room temperature at a rate of 5-15℃ / min, and then filtered under vacuum at the same temperature to obtain the final product; or...

[0039] The specific segmented control process of recrystallization is as follows:

[0040] The high-temperature distillate from vacuum distillation is first heated to 190-210℃ at a heating rate of 10-20℃ / min, held at that temperature for 5-15 minutes, and then filtered under vacuum at that temperature. Next, it is cooled to 140-160℃ at a cooling rate of 5-15℃ / min, held at that temperature for 10-20 minutes, and then filtered under vacuum at that temperature. Finally, it is cooled to room temperature at a cooling rate of 5-15℃ / min, and then filtered under vacuum at that temperature to obtain the final product.

[0041] The present invention is further configured such that, in step (4), the solvent separated by vacuum distillation is recycled as a solvent for photochemical reaction.

[0042] The present invention is further configured such that the acid solution is selected as hydrochloric acid solution or sulfuric acid solution, and the mass fraction of the acid solution is 5-15%.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] (1) This invention employs a continuous flow synthesis and separation process to synthesize hydroxycarbazole using hydroquinone and o-haloaniline as raw materials through a two-step continuous flow reactor. The hydroquinone conversion rate is >99.5%, the intermediate yield is >94%, the intermediate purity is ≥99.5%, the total yield of hydroxycarbazole is >85%, and the purity of the hydroxycarbazole product is >99%.

[0045] (2) The continuous flow synthesis and separation process of the present invention can be used to obtain high yield of 4-hydroxycarbazole.

[0046] (3) This invention realizes the two-step synthesis of hydroxycarbazole, with low raw material cost, fewer synthesis steps, and simple continuous synthesis and separation process. The parallel scale-up strategy can further improve the production capacity and can even be directly applied to industrial production. The solvent and catalyst are recycled through vacuum distillation. Photons, as a traceless "reagent", have the characteristics of being green and environmentally friendly, which improves the economic benefits of hydroxycarbazole. Attached Figure Description

[0047] Figure 1 This is a process flow diagram of the continuous flow production process of hydroxycarbazole according to the present invention.

[0048] Figure 2 This is a photochemical continuous synthesis route for hydroxycarbazole.

[0049] Figure 3 This is the photochemical continuous synthesis route of 3-hydroxycarbazole in Example 1.

[0050] Figure 4 The photochemical continuous synthesis route for 2-hydroxycarbazole and 4-hydroxycarbazole in the examples is shown. Detailed Implementation

[0051] The present invention will now be described in detail with reference to specific embodiments and accompanying drawings. It should be understood that the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of the present invention.

[0052] In the technical solution of this invention, room temperature refers to 20~30℃.

[0053] For reference Figure 1 The process flow shown is as follows: Figure 2 The synthetic route shown, and the continuous flow production process of hydroxycarbazole described in this invention, specifically include the following steps:

[0054] (1) After mixing the raw materials o-halogenated aniline and hydroquinone, as well as the organic solvent and acid catalyst, the mixture is continuously pumped into the first-stage reactor for reaction;

[0055] (2) The reaction liquid at the outlet of the first-stage reactor is subjected to extraction, vacuum distillation, recrystallization and drying in sequence to obtain the photoreaction intermediate of the reaction product;

[0056] (3) The photoreaction intermediate obtained in step (2) is mixed with the photoreaction catalyst and the second solvent and then continuously pumped into the second-stage photoreactor and subjected to photochemical reaction under UV-LED light source irradiation.

[0057] (4) The reaction liquid at the outlet of the second-stage photoreactor is subjected to neutralization, vacuum distillation and recrystallization in sequence to obtain the hydroxycarbazole product;

[0058] Wherein, the o-haloaniline is selected from at least one of 2-chloroaniline, 2-bromoaniline, 2-fluoroaniline, and 2-iodoaniline; the hydroquinone is selected from at least one of catechol, resorcinol, and hydroquinone; the acid catalyst is selected from at least one of non-oxidizing acids; both the first-stage reactor and the second-stage photoreactor are microchannel reactors, the channel size of the microchannel reactor is 0.15mm-3.0mm, and the maximum emission wavelength range of the UV-LED light source is 270-320nm.

[0059] In the technical solution of the present invention, due to the different raw materials, the photoreaction intermediate of the product of step (1) includes at least one of 2-hydroxy-2′-halo-diphenylamine, 3-hydroxy-2′-halo-diphenylamine and 4-hydroxy-2′-halo-diphenylamine; the hydroxycarbazole finally obtained includes at least one of 1-hydroxycarbazole, 2-hydroxycarbazole, 3-hydroxycarbazole or 4-hydroxycarbazole.

[0060] In one embodiment of the present invention, in step (1), the molar ratio of the raw material hydroquinone to o-haloaniline is 1:(0.5-2.0), more preferably 1:(0.6-1.4); the molar ratio of the acid catalyst to the raw material hydroquinone is 0.05-0.5, more preferably 0.05-0.2.

[0061] In one embodiment of the present invention, in step (1), the organic solvent is selected from one or more of benzene, toluene, xylene, ethyl acetate, ethyl propionate, dioxane, cyclohexane, and dimethyl sulfoxide.

[0062] In one embodiment of the present invention, in step (1), the acid catalyst is selected from at least one of dilute sulfuric acid, phosphoric acid, acetic acid, benzenesulfonic acid or p-toluenesulfonic acid.

[0063] In one embodiment of the present invention, in step (1), the acid catalyst is a mixed acid catalyst composed of one selected from benzenesulfonic acid and p-toluenesulfonic acid and one selected from dilute sulfuric acid, phosphoric acid and acetic acid.

[0064] In one embodiment of the present invention, in step (1), the acid catalyst is a mixed acid catalyst composed of benzenesulfonic acid and phosphoric acid, and the molar ratio of benzenesulfonic acid to phosphoric acid is 1.5-4.0:1; more preferably 2.5:1.

[0065] In one embodiment of the present invention, in step (1), the first-stage reactor is selected as a T-type, butterfly-type or branch-type microchannel reactor, and the channel size of the first-stage reactor is 0.5~2.0mm; the reaction temperature of the first-stage reaction is 90-200℃, and the reaction time is 30-90 minutes.

[0066] Preferably, the reaction temperature of the first-stage reaction is 120-180°C, for example, 130°C, 140°C, 150°C or 160°C; the reaction time is preferably 40-70 minutes.

[0067] In one embodiment of the present invention, in step (1), the raw materials continuously fed are two feed streams. One feed stream is a solution of hydroquinone, acid catalyst and organic solvent mixed together. The concentration of hydroquinone in the mixed solution is 25-40 wt%, and the concentration of acid catalyst is 3-10 wt%. The other feed stream is a mixed solution of o-haloaniline and organic solvent. The concentration of o-haloaniline is 35-50 wt%. The flow rates of the two feed streams are the same, which is 0.5-1.5 mL / min. After the two feed streams are mixed, they are pumped into the microchannel reactor for reaction.

[0068] In one embodiment of the present invention, in step (2), the extractant used for extraction is selected from one or more of water, methanol, ethanol, acetonitrile, ethyl acetate, ethyl propionate, triethylamine and ammonia; the extraction temperature is 0-60 ℃, preferably 0-25 ℃, and more preferably 0-10 ℃.

[0069] In one embodiment of the present invention, in step (2), the extractant used for extraction is a 5-15% aqueous ethanol solution.

[0070] In one embodiment of the present invention, in step (2), the extract containing the extractant and acid catalyst and the raffinate containing the solvent and reaction products are first separated; then the extractant and acid catalyst are separated from the extract by vacuum distillation, the organic solvent is separated from the raffinate by vacuum distillation, and the remaining reactor liquid containing the reaction products is recrystallized; the recrystallization includes the following process:

[0071] Increase the temperature from 20-25℃ to 40-50℃ at a rate of 10-20℃ / min, hold the temperature for 5-20 minutes, adjust the pH to 7.5-11, then continue to increase the temperature to 80-90℃ at a rate of 10-20℃ / min, hold the temperature for 10-20 minutes, and adjust the pH to 3-6.5. Finally, decrease the temperature to 20-25℃ at a rate of 5-15℃ / min, hold the temperature for 10-20 minutes, and filter under constant temperature.

[0072] In one embodiment of the present invention, the extractant, acid catalyst and solvent separated in step (2) are recycled.

[0073] In one embodiment of the present invention, after the initial heating stage, the pH is adjusted to 8-10 using an alkaline solution; and in the second heating stage, the pH is adjusted to 3.5-5.0 using an acidic solution.

[0074] In one embodiment of the present invention, the residual liquid containing the photoreaction intermediate after vacuum distillation is recrystallized. The solvent used for recrystallization is selected from at least one of water, methanol, ethanol, acetonitrile or acetone. The acid solution used to adjust the pH is selected from at least one of formic acid, acetic acid, propionic acid, hydrochloric acid, phosphoric acid or sulfuric acid. The alkaline solution used to adjust the pH is selected from at least one of sodium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine, calcium hydroxide, potassium hydroxide, sodium hydroxide or sodium carbonate.

[0075] In one embodiment of the present invention, in step (2), during the recrystallization process, the acid solution used to adjust the pH is selected as hydrochloric acid solution and / or phosphoric acid solution, with a mass fraction of 1-10%, and the alkaline solution is selected as sodium hydroxide and / or potassium hydroxide solution, with a mass fraction of 5-15%; the drying temperature is 50-120 ℃, and the drying time is 1.5-5.0 h; the drying temperature is preferably 60-70 ℃.

[0076] In one embodiment of the present invention, in step (3), the photocatalyst is selected from one or more of methylamine, ethylamine, diethylamine, triethylamine, aniline, diisopropylamine, sodium hydroxide and potassium hydroxide;

[0077] The second solvent used for the photoreaction is selected from one or more of acetonitrile, malononitrile, ethyl acetate, dimethyl sulfoxide, toluene, and cyclohexane.

[0078] In one embodiment of the present invention, the photocatalyst is a mixed photocatalyst composed of one of methylamine, ethylamine, diethylamine, triethylamine, aniline and diisopropylamine and one of sodium hydroxide and potassium hydroxide.

[0079] In one embodiment of the present invention, the photocatalyst is a mixed photocatalyst composed of triethylamine and potassium hydroxide, and the molar ratio of triethylamine to potassium hydroxide is (0.1-0.4):1.

[0080] In one embodiment of the present invention, in step (3), the molar ratio of the photoreaction catalyst and the intermediate raw material is (1.5-4.5:1); preferably (2.4-3.2):1, for example 2.5:1, 2.7:1, 2.9:1 or 3:1.

[0081] In one embodiment of the present invention, the solvent used for the photoreaction is a mixed solvent composed of dimethyl sulfoxide and organic nitriles; preferably, the solvent used for the photoreaction is a mixed solvent of dimethyl sulfoxide and acetonitrile, and the mass ratio of the two is (0.1-0.5):1.

[0082] In one embodiment of the present invention, in step (3), the second-stage photoreactor is selected as a T-shaped, butterfly-shaped or branch-shaped microchannel reactor, and the channel size of the second-stage photoreactor is 0.5~2.0mm; the photochemical reaction conditions are: room temperature, residence time of 100-1200 seconds; preferably 150-600 seconds, and more preferably 200-360 seconds.

[0083] In one embodiment of the present invention, in step (3), the UV-LED light source is a panel light source integrating several small LED lamps and equipped with air cooling; the peak width of the emitted wavelength of the LED lamp is 10-30 nanometers, and the radiation power is 1-200 mW / cm². 2 Preferably, the maximum emission wavelength of the LED light source is 280-300 nm.

[0084] In one embodiment of the present invention, the material of the second-stage photoreactor is selected from quartz, inorganic glass or organic glass, and the ultraviolet light transmittance is ≥85%.

[0085] In one embodiment of the present invention, in step (3), the raw materials continuously fed are two feed streams. One feed stream is a solution containing a photoreaction intermediate with a concentration of 3-10 wt%; the other feed stream is a solution containing a photoreaction catalyst with a concentration of 1.0-6.0 wt%. The two feed streams have the same flow rate of 1.0-2.0 mL / min. After the two feed streams are mixed by a microchannel mixer, they enter the second-stage photoreactor for reaction.

[0086] In one embodiment of the present invention, in step (4), the solution is neutralized to pH 6.5 to 7.5, and then vacuum distillation is performed to separate the solvent. The remaining liquid is recrystallized under vacuum conditions, wherein the pressure conditions are -0.1 MPa to -0.05 MPa, preferably -0.1 MPa to -0.075 MPa.

[0087] The recrystallization segment control includes the following process:

[0088] The high-temperature distillate from vacuum distillation is first heated to 190-210°C at a rate of 10-20°C / min, held at this temperature for 5-15 minutes, and then filtered under vacuum at the same temperature. Next, it is cooled to 140-160°C at a rate of 5-15°C / min, held at this temperature for 10-20 minutes, and then filtered under vacuum at the same temperature. Then, it is cooled to 90-110°C at a rate of 5-15°C / min, held at this temperature for 10-20 minutes, and then filtered under vacuum at the same temperature. Finally, it is cooled to room temperature at a rate of 5-15°C / min, and then filtered under vacuum at the same temperature to obtain the final product. Alternatively,

[0089] The specific segmented control process of recrystallization is as follows:

[0090] The high-temperature distillate from vacuum distillation is first heated to 190-210℃ at a heating rate of 10-20℃ / min, held at that temperature for 5-15 minutes, and then filtered under vacuum at that temperature. Next, it is cooled to 140-160℃ at a cooling rate of 5-15℃ / min, held at that temperature for 10-20 minutes, and then filtered under vacuum at that temperature. Finally, it is cooled to room temperature at a cooling rate of 5-15℃ / min, and then filtered under vacuum at that temperature to obtain the final product.

[0091] The acid solution is selected from hydrochloric acid or sulfuric acid, and the mass fraction of the acid solution is 5-15%.

[0092] In one embodiment of the present invention, the solvent separated in step (4) is recycled as a solvent for photochemical reaction.

[0093] The invention will now be described in detail with reference to specific embodiments.

[0094] Example 1

[0095] This embodiment provides a production process for 3-hydroxycarbazole, and its synthetic route is as follows: Figure 3 As shown, the specific process flow includes the following:

[0096] (1) First-order reaction: continuous preparation of photoreaction intermediates

[0097] The solvent for the first-stage reaction is a mixed solvent composed of dioxane and p-xylene in a mass ratio of 0.5:1. The acid catalyst is composed of benzenesulfonic acid and phosphoric acid in a mass ratio of 4:1. The first-stage reactor is a T-type microchannel reactor with a channel size of 1.0 mm.

[0098] The feed for the first-stage reaction, by mass percentage, consists of two streams: a mixed solution of 37.1% hydroquinone and 6.7% acid catalyst, and a solution of 45.2% o-bromoaniline. The feed flow rate for both streams is 1 mL / min. After being mixed by a mixer, the two streams enter the first-stage reactor for reaction at a temperature of 140°C and a residence time of 60 minutes.

[0099] (2) Separation and purification of photoreaction intermediates:

[0100] The effluent from the first-stage reactor in step (1) was extracted with a 10% ethanol aqueous solution as the extractant at a temperature of 5 °C to obtain an extract and a raffinate containing photoreaction intermediates. The raffinate was then separated from the organic solvent by vacuum distillation. The remaining liquid was cooled and recrystallized using water as the recrystallization solvent. The recrystallization process was as follows: 25 mL of water was added to the liquid, and the temperature was increased from 25 °C to 45 °C at a rate of 10 °C / min. The temperature was held for 15 minutes, and a 10% potassium hydroxide solution was added until the pH reached 9.5. The temperature was then increased to 85 °C at a rate of 15 °C / min and held for 10 minutes. A 5% hydrochloric acid solution was added until the pH reached 4. Finally, the temperature was decreased to 25 °C at a rate of 15 °C / min and held for 20 minutes. The mixture was then filtered under vacuum at the same temperature. Finally, the recrystallized product was dried in an oven at 60 °C for 2 h to obtain the 4-hydroxy-2′-bromo-diphenylamine intermediate, which was characterized by 1H NMR and mass spectrometry, and its molecular formula was C2. 12 H 10 BrNO, its structural formula is shown below:

[0101] ;

[0102] The extract is separated into extractant and catalyst by vacuum distillation. The organic solvent separated from the raffinate, as well as the extractant and acid catalyst separated from the extract, are recycled.

[0103] (3) Second-order reaction: Photochemical continuous synthesis of hydroxycarbazole:

[0104] The second-stage reaction consists of two feed streams: 5% intermediate solution and 3.6% photocatalyst solution (by mass percentage). The solvent for the second-stage reaction is a mixture of acetonitrile and dimethyl sulfoxide in a mass ratio of 0.3:1, and the photocatalyst is a mixture of triethylamine and potassium hydroxide in a mass ratio of 0.4:1. Both feed streams have a flow rate of 1.5 mL / min. The second-stage photoreactor is a butterfly-shaped microchannel reactor with a channel size of 1.0 mm. The maximum emission wavelength of the UV-LED light source is 280 nm, and the radiant power is 20 mW / cm². 2 The two feed streams are mixed by a mixer and then conveyed to the second-stage photoreactor for photochemical reaction at a temperature of 25 °C and a residence time of 300 seconds.

[0105] (4) Separation and purification of hydroxycarbazole:

[0106] The material from the outlet of the second-stage photoreactor in step (3) was neutralized to pH 6.5-7.5 with a 5% hydrochloric acid solution and then subjected to vacuum distillation. The separated solvent was recycled, and the remaining liquid was recrystallized at a pressure of -0.095 MPa. The recrystallization temperature control program was as follows: a heating rate of 15 °C / min in the temperature range of 140 °C to 200 °C, with a holding time of 10 minutes at 200 °C, followed by vacuum filtration; a cooling rate of 5 °C / min in the temperature range of 200 °C to 150 °C, with a holding time of 10 minutes at 150 °C, followed by vacuum filtration; and a cooling rate of 10 °C / min in the temperature range of 150 °C to 25 °C. The final product was 3-hydroxycarbazole.

[0107] According to the liquid chromatography-mass spectrometry, in step (1), the conversion rate of the raw material hydroquinone was 98.5%, the yield of the photoreaction intermediate was 94.7%, and the purity of the photoreaction intermediate obtained in step (2) was 99.1%; in step (3), the conversion rate of the photoreaction intermediate was 97.6%, the yield of the product 3-hydroxycarbazole was 90.8%, and in step (4), the purity of 3-hydroxycarbazole was 98.4%.

[0108] Example 2

[0109] This embodiment provides a production process for 2-hydroxycarbazole and 4-hydroxycarbazole. The reaction principle of this embodiment is as follows: Figure 4 As shown. The synthesis process of this embodiment is basically the same as that of Example 1, except that the hydroquinone raw material in step (1) is resorcinol, and the recrystallization temperature control procedure in step (4) is different. Specifically, as follows:

[0110] The hydroquinone raw material in step (1) is resorcinol; the structural formula of the obtained photoreaction intermediate is:

[0111] .

[0112] The recrystallization temperature control procedure in step (4) is as follows: the heating rate is 15 °C / min in the temperature range of 140 °C to 200 °C, and the temperature is held at 200 °C for 10 minutes, followed by constant temperature filtration; the cooling rate is 5 °C / min in the temperature range of 200 °C to 150 °C, and the temperature is held at 150 °C for 10 minutes, followed by constant temperature filtration; the cooling rate is 5 °C / min in the temperature range of 150 °C to 100 °C, and the temperature is held at 100 °C for 10-20 minutes, followed by constant temperature filtration; the cooling rate is 10 °C / min in the temperature range of 100 °C to 25 °C.

[0113] According to the test results, in step (1), the conversion rate of resorcinol was 99.9% and the yield of the photoreaction intermediate was 94.7%; the purity of the photoreaction intermediate obtained in step (2) was 99.7%; in step (3), the conversion rate of the photoreaction intermediate was 99.1% and the sum of the yields of 2-hydroxycarbazole and 4-hydroxycarbazole was 90.6%, of which the yield of 4-hydroxycarbazole was 40.1%; in step (4), the purity of 2-hydroxycarbazole and 4-hydroxycarbazole was 99.2% and 99.1%, respectively.

[0114] Example 3

[0115] This embodiment provides a production process for 2-hydroxycarbazole and 4-hydroxycarbazole. The synthesis process of this embodiment is basically the same as that of Example 2, except that the halogenated aniline raw material in step (1) is o-chloroaniline.

[0116] According to the test results, in step (1), the conversion rate of resorcinol was 99.7% and the yield of the photoreaction intermediate was 94.0%; the purity of the photoreaction intermediate obtained in step (2) was 99.6%; in step (3), the conversion rate of the photoreaction intermediate was 98.8% and the sum of the yields of 2-hydroxycarbazole and 4-hydroxycarbazole was 90.5%, of which the yield of 4-hydroxycarbazole was 40.0%; in step (4), the purity of 2-hydroxycarbazole and 4-hydroxycarbazole was 99.2% and 99.3%, respectively.

[0117] Comparative Example 1

[0118] Intermittent synthesis of 2-hydroxycarbazole and 4-hydroxycarbazole

[0119] The synthesis process of this comparative example is basically the same as that of Example 3, except that:

[0120] Step (1) employs a batch synthesis, with the following specific steps: In a 100 mL three-necked flask, add 13.35 g of resorcinol, 20 g of solvent, and 1.96 g of the first-stage catalyst. In a 50 mL beaker, add 15.62 g of o-chloroaniline and 25 g of solvent, and stir thoroughly with a glass rod. Slowly heat the three-necked flask to 110 °C in an oil bath while simultaneously turning on the magnetic stirrer. Then, slowly add the o-chloroaniline solution dropwise to the three-necked flask using a constant-pressure dropping funnel, controlling the addition time at 45 minutes. After the addition is complete, adjust the oil bath temperature and slowly raise it to 160 °C, reacting for 9 hours. After the reaction is complete, turn off the magnetic stirrer and oil bath temperature control, and allow the mixture to cool naturally to room temperature in a fume hood.

[0121] Step (3) employs a batch synthesis, the specific steps of which are as follows: In a 50 mL three-necked glass flask, a vacuum pump is used to evacuate the flask and purge it with argon gas three times. 10 g of solvent, 256.54 mg of secondary catalyst, and 252.62 mg of 3-hydroxy-2'-chlorodiphenylamine are added sequentially. The reaction is maintained in an oxygen-free environment by using an argon balloon, and the reaction is stirred for 5 h.

[0122] The separation and purification processes in steps (2) and (4) are the same.

[0123] According to the test results, in this comparative example, in step (1), the conversion rate of resorcinol was 91.4%, and the yield of the photoreaction intermediate was 81.9%; in step (2), the purity of the photoreaction intermediate was 99.7%; in step (3), the conversion rate of the photoreaction intermediate was 56.5%, and the sum of the yields of 2-hydroxycarbazole and 4-hydroxycarbazole was 21.2%, of which the yield of 4-hydroxycarbazole was 5.2%; in step (4), the purities of 2-hydroxycarbazole and 4-hydroxycarbazole were 92% and 90.8%, respectively. It can be seen that the batch reaction process results in more byproducts and a significantly lower yield, thereby increasing the difficulty of purification.

[0124] Comparative Example 2

[0125] The synthesis process of this comparative example is basically the same as that of Example 3, except that no catalyst is added in steps (1) and (3), and the residence time of the photoreaction in step (3) is extended to 10 minutes.

[0126] According to the test, in step (1), the conversion rate of resorcinol was 0.51% and the yield of the photoreaction intermediate was 0.5%; in step (3), the conversion rate of the intermediate was 15.8%, the total yield of 2-hydroxycarbazole and 4-hydroxycarbazole was 15.75%, of which the yield of 4-hydroxycarbazole was 6.5%; and the purities of 2-hydroxycarbazole and 4-hydroxycarbazole obtained in step (4) were 99.4% and 99.3%, respectively.

[0127] Comparative Example 3

[0128] The synthesis process of this comparative example is basically the same as that of Example 3, except that: no catalyst is added in step (3), the maximum emission wavelength of the UV-LED light source is 360 nm, and the radiation power is 100 mW / cm². 2 The reaction temperature was 30 ℃ and the residence time was 10 minutes.

[0129] According to the test, in step (1), the conversion rate of resorcinol was 99.7% and the yield of the photoreaction intermediate was 94.7%; the purity of the photoreaction intermediate obtained in step (2) was 99.6%; in step (3), the conversion rate of the intermediate was 16.0%, the total yield of 2-hydroxycarbazole and 4-hydroxycarbazole was 3.38%, of which the yield of 4-hydroxycarbazole was 1.2%; and the purity of 2-hydroxycarbazole and 4-hydroxycarbazole obtained in step (4) was 95.0% and 94.3%, respectively.

[0130] Comparative Example 4

[0131] The synthesis process of this comparative example is basically the same as that of Example 3, except that:

[0132] In step (2), the recrystallization step is as follows: the temperature is increased from 25 ℃ to 45 ℃ at 10 ℃ / min, and the temperature is kept constant for 15 minutes. Potassium hydroxide solution is added until the pH is 11.2; the temperature is increased to 85 ℃ at 15 ℃ / min, and the temperature is kept constant for 10 minutes. Hydrochloric acid solution is added until the pH is 3; finally, the temperature is decreased to 25 ℃ at 15 ℃ / min, and the temperature is kept constant for 20 minutes. The solution is then filtered under vacuum at the constant temperature.

[0133] In step (3), the channel size of the microchannel reactor is 1 cm, and the photoreaction residence time is 120 minutes.

[0134] The purity of the intermediate obtained in step (2) was 90.6%; in step (3), the conversion rate of the photoreaction intermediate was 98.7%, the total yield of 2-hydroxycarbazole and 4-hydroxycarbazole was 45.6%, of which the yield of 4-hydroxycarbazole was 10.1%.

[0135] Comparative Example 5

[0136] The synthesis process of this comparative example is basically the same as that of comparative example 1, except that the light source for the photoreaction in step (3) is a 250 W high-pressure mercury lamp.

[0137] The results showed that in step (3), the conversion rate of the photoreaction intermediate was 52.5%, the yield of 2-hydroxycarbazole was 7.8%, and 4-hydroxycarbazole was not detected.

[0138] Comparative Example 6

[0139] The synthesis process of this comparative example is basically the same as that of comparative example 1, except that: in step (1), the acid catalyst is phosphoric acid, and in step (3), the photocatalyst is potassium phosphate trihydrate.

[0140] According to the test, in step (1), the conversion rate of resorcinol was 90.6% and the yield of photoreaction intermediate was 73.0%; in step (3), the conversion rate of photoreaction intermediate was 54.1% and the sum of the yields of 2-hydroxycarbazole and 4-hydroxycarbazole was 11.2%, of which the yield of 4-hydroxycarbazole was 3.4%.

[0141] Comparative Example 7

[0142] The synthesis process of this comparative example is basically the same as that of Example 3, except that:

[0143] In step (2), the recrystallization step is as follows: the temperature is increased from 25 ℃ to 45 ℃ at 10 ℃ / min, and the temperature is kept constant for 5 minutes. A 10% potassium hydroxide solution is added until the pH is 9.5. The temperature is then increased to 70 ℃ at 10 ℃ / min and kept constant for 5 minutes. A 10% hydrochloric acid solution is added until the pH is 4. Finally, the temperature is decreased to 25 ℃ at 20 ℃ / min and kept constant for 20 minutes. The solution is then filtered under vacuum at the constant temperature.

[0144] In step (3), the photocatalyst is potassium tert-butoxide.

[0145] The purity of the photoreaction intermediate obtained in step (2) was 94.7%; in step (3), the conversion rate of the intermediate was 97.8%, the sum of the yields of 2-hydroxycarbazole and 4-hydroxycarbazole was 68.3%, of which the yield of 4-hydroxycarbazole was 25.6%.

[0146] Comparative Example 8

[0147] The synthesis process of this comparative example is basically the same as that of Example 3, except that the solvent used in step (3) is methanol.

[0148] According to the test, in step (3), the conversion rate of the photoreaction intermediate was 87.4%, and the sum of the yields of 2-hydroxycarbazole and 4-hydroxycarbazole was 52.3%, of which the yield of 4-hydroxycarbazole was 21.5%.

[0149] Comparative Example 9

[0150] The synthesis process of this comparative example is basically the same as that of Example 3, except that the solvent used in step (3) is 1,4-dioxane.

[0151] The conversion rate of the photoreaction intermediate in step (3) was 60.8%, and the sum of the yields of 2-hydroxycarbazole and 4-hydroxycarbazole was 17.6%.

[0152] In summary, based on the various embodiments and comparative results of the present invention, it can be seen that by using the continuous synthesis method of the present invention in conjunction with a microchannel reactor and suitable process conditions, 4-hydroxycarbazole with high yield and high purity can be successfully obtained; 1-hydroxycarbazole, 2-hydroxycarbazole or 3-hydroxycarbazole can also be obtained by using this method.

[0153] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is impossible to exhaustively list all the implementation methods here. All obvious variations or modifications derived from the technical solutions of the present invention are still within the scope of protection of this patent.

Claims

1. A continuous flow production process for hydroxycarbazole, characterized in that, Includes the following steps: (1) After mixing the raw materials o-halogenated aniline, hydroquinone, organic solvent and acid catalyst, the mixture is continuously pumped into the first-stage reactor for reaction; (2) The reaction liquid at the outlet of the first stage reactor is subjected to extraction, vacuum distillation, recrystallization and drying in sequence to obtain the photoreaction intermediate of the reaction product; (3) The solution of the photoreaction intermediate obtained in step (2) mixed with the photoreaction catalyst and the second solvent is continuously pumped into the second-stage photoreactor and photochemical reaction is carried out under UV-LED light source irradiation. (4) The reaction liquid at the outlet of the second-stage photoreactor is subjected to neutralization, vacuum distillation and recrystallization in sequence to obtain the hydroxycarbazole product; The o-haloaniline is selected from at least one of 2-chloroaniline, 2-bromoaniline, 2-fluoroaniline and 2-iodoaniline; the hydroquinone is selected from at least one of catechol, resorcinol and hydroquinone; and the acid catalyst is selected from at least one of non-oxidizing acids. The first-stage reactor and the second-stage photoreactor are both microchannel reactors with a channel size of 0.15 mm to 3.0 mm. In step (1), the reaction temperature of the first-stage reaction is 90-200 ℃ and the residence time is 30-90 minutes. In step (3), the maximum emission wavelength range of the UV-LED light source is 270 nm to 320 nm, and the photochemical reaction conditions are: room temperature and residence time of 100-1200 seconds. In step (3), the photocatalyst is a mixed photocatalyst composed of one of methylamine, ethylamine, diethylamine, triethylamine, aniline and diisopropylamine and one of sodium hydroxide and potassium hydroxide; the second solvent used for the photoreaction is selected from one or more of acetonitrile, malononitrile, ethyl acetate, dimethyl sulfoxide, toluene and cyclohexane.

2. The continuous flow production process for hydroxycarbazole according to claim 1, characterized in that, In step (1), the organic solvent is selected from one or more of benzene, toluene, xylene, ethyl acetate, ethyl propionate, dioxane, cyclohexane, and dimethyl sulfoxide; the acid catalyst is selected from at least one of dilute sulfuric acid, phosphoric acid, acetic acid, benzenesulfonic acid, or p-toluenesulfonic acid; the molar ratio of hydroquinone to o-haloaniline is 1:(0.5-2.0); and the molar ratio of acid catalyst to hydroquinone is 0.05-0.

5.

3. The continuous flow production process for hydroxycarbazole according to claim 1, characterized in that, In step (1), the raw materials continuously conveyed are two feed streams. One feed stream is a solution of hydroquinone, acid catalyst and organic solvent mixed together. The concentration of hydroquinone in the mixed solution is 25-40 wt%, and the concentration of acid catalyst is 3-10 wt%. The other feed stream is a solution of o-haloaniline and organic solvent mixed together. The concentration of o-haloaniline is 35-50 wt%. The flow rate of the two feed streams is 0.5-1.5 mL / min. After the two feed streams are mixed, they are pumped into the first-stage reactor for reaction.

4. The continuous flow production process for hydroxycarbazole according to claim 1, characterized in that, In step (1), the first-stage reactor is a T-type, butterfly-type or branch-type microchannel reactor; the reaction temperature of the first-stage reaction is 120-180℃ and the reaction time is 40-70 minutes.

5. The continuous flow production process for hydroxycarbazole according to claim 1, characterized in that, The photoreaction intermediate includes at least one of 2-hydroxy-2′-halo-diphenylamine, 3-hydroxy-2′-halo-diphenylamine, and 4-hydroxy-2′-halo-diphenylamine; the final hydroxycarbazole product includes at least one of 1-hydroxycarbazole, 2-hydroxycarbazole, 3-hydroxycarbazole, or 4-hydroxycarbazole.

6. The continuous flow production process for hydroxycarbazole according to claim 1, characterized in that, In step (2), the extractant used for extraction is selected from one or more of water, methanol, ethanol, acetonitrile, ethyl acetate, ethyl propionate, triethylamine and ammonia water, and the extraction temperature is 0-60 ℃; The residual liquid containing the photoreaction intermediate after vacuum distillation is recrystallized. The solvent used for recrystallization is selected from at least one of water, methanol, ethanol, acetonitrile or acetone. The acid solution used to adjust the pH is selected from at least one of formic acid, acetic acid, propionic acid, hydrochloric acid, phosphoric acid or sulfuric acid. The alkaline solution used to adjust the pH is selected from at least one of sodium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine, calcium hydroxide, potassium hydroxide, sodium hydroxide or sodium carbonate. The recrystallization temperature is controlled in stages: the temperature is increased from 20-25℃ to 40-50℃ at a rate of 10-20℃ / min, held at the temperature for 5-20 minutes, and adjusted to pH=7.5-11; then the temperature is increased to 80-90℃ at a rate of 10-20℃ / min, held at the temperature for 10-20 minutes, and adjusted to pH=3-6.5; finally, the temperature is decreased to 20-25℃ at a rate of 5-15℃ / min, held at the temperature for 10-20 minutes, and filtered under constant temperature. The drying temperature is 50-120 ℃.

7. A continuous flow production process for hydroxycarbazole according to claim 6, characterized in that, In step (2), the extraction temperature is 0-25 ℃.

8. A continuous flow production process for hydroxycarbazole according to claim 6, characterized in that, In step (2), the drying temperature is 60-70 ℃.

9. The continuous flow production process for hydroxycarbazole according to claim 1, characterized in that, In step (3), the molar ratio of the photoreaction catalyst to the intermediate raw material is (1.5-4.5:1).

10. A continuous flow production process for hydroxycarbazole according to claim 1, characterized in that, In step (3), the second-stage photoreactor is a T-shaped, butterfly-shaped, or branch-shaped microchannel reactor; the UV-LED light source is a panel light source integrating several small LED lamps, with an LED lamp emission wavelength peak width of 10-30nm and a radiation power of 1-200 mW / cm². 2 The photochemical reaction conditions are: room temperature and a reaction residence time of 150-600 seconds.

11. A continuous flow production process for hydroxycarbazole according to claim 1, characterized in that, In step (3), the raw materials continuously fed are two feed streams. One feed stream is a solution containing a photoreaction intermediate with a concentration of 3-10 wt%; the other feed stream is a solution containing a photoreaction catalyst with a concentration of 1.0-6.0 wt%. The two feed streams have the same flow rate of 1.0-2.0 mL / min. After the two feed streams are mixed, they enter the second-stage photoreactor for reaction.

12. The continuous flow production process for hydroxycarbazole according to claim 1, characterized in that, In step (4), the reaction solution at the outlet is neutralized to pH 6.5-7.5 with an acid solution, and then vacuum distillation is performed. The remaining high-temperature reactor liquid after the solvent is separated is recrystallized. The recrystallization is carried out in stages under reduced pressure conditions, with the pressure range being -0.1 to -0.05 MPa. The specific staged control process is as follows: The high-temperature distillate from vacuum distillation is first heated to 190-210℃ at a rate of 10-20℃ / min, held at that temperature for 5-15 minutes, and then filtered under vacuum at the same temperature. Next, it is cooled to 140-160℃ at a rate of 5-15℃ / min, held at that temperature for 10-20 minutes, and then filtered under vacuum at the same temperature. Then, it is cooled to 90-110℃ at a rate of 5-15℃ / min, held at that temperature for 10-20 minutes, and then filtered under vacuum at the same temperature. Finally, it is cooled to room temperature at a rate of 5-15℃ / min, and then filtered under vacuum at the same temperature to obtain the final product; or... The specific segmented control process of recrystallization is as follows: The high-temperature distillate from vacuum distillation is first heated to 190-210℃ at a heating rate of 10-20℃ / min, held at that temperature for 5-15 minutes, and then filtered under vacuum at that temperature. Next, it is cooled to 140-160℃ at a cooling rate of 5-15℃ / min, held at that temperature for 10-20 minutes, and then filtered under vacuum at that temperature. Finally, it is cooled to room temperature at a cooling rate of 5-15℃ / min, and then filtered under vacuum at that temperature to obtain the final product.

Images