Continuous flow production process of hydroxycarbazole

Abstract

The invention belongs to the technical field of production, separation and purification of hydroxyl carbazole, and provides a continuous flow production process of hydroxyl carbazole, which specifically comprises the following steps: (1) mixing raw materials of o-halogenated aniline, benzenediol, an organic solvent and an acid catalyst, and pumping into a first reactor for reaction; (2) sequentially performing extraction, reduced pressure distillation, recrystallization and drying treatment on the reaction liquid at the outlet of the first-stage reactor to obtain a reaction product photoreaction intermediate; (3) continuously pumping a mixed solution of the photoreaction intermediate prepared in the step (2), a photoreaction catalyst and a second solvent into a second-stage photoreactor, and carrying out photochemical reaction under the irradiation of a UV-LED light source; and (4) sequentially carrying out neutralization, reduced pressure distillation and recrystallization on the reaction liquid at the outlet of the second-stage photoreactor to obtain a hydroxyl carbazole product. By adopting the technical scheme provided by the invention, various hydroxycarbazole with high yield and high purity can be prepared, and the production period is shortened.

Description

Technical Field

[0001] The invention belongs to the technical field of production, separation and purification of hydroxycarbazole, and in particular relates to a continuous flow production process of hydroxycarbazole. Background Art

[0002] Hydroxycarbazole has attracted much attention due to its special rigid fused ring structure and has broad application prospects. This compound is easy to carry out structural chemical modification. Not only can various functional groups be conveniently introduced into the carbazole ring, but the hydroxyl group itself can also undergo group conversion or connect other functional groups to form a larger molecular conjugated system. The carbazole derivatives obtained by this modification can be used to prepare organic electroluminescent materials and hole transport materials. In addition, hydroxycarbazole is also a biologically active alkaloid that can effectively inhibit the growth of pathogenic microorganisms. Therefore, it can be used as an active group for antifungal and antitumor effects in drug synthesis. At present, hydroxycarbazole and its derivatives are widely used in organic optoelectronic materials, bioimaging, dyes, sensor detection, pesticides, medicines and other fields. For example, 4-hydroxycarbazole, as a key intermediate of the antihypertensive drug carvedilol, plays an important role in the drug synthesis process.

[0003] At present, the synthesis method of hydroxycarbazole is mainly a thermochemical synthesis method, that is, it is prepared by multi-step reaction under high temperature and high pressure intermittent or semi-intermittent conditions. Patent WO2007077111A1 reports a method for preparing hydroxycarbazole by multi-step reaction under the catalysis of precious metals such as palladium. However, the above thermochemical synthesis method has harsh reaction conditions, high cost of catalytic reagents, and difficult reaction operation, resulting in high production costs, scarce and expensive raw materials, and a series of problems such as high by-product generation and low yield; and the subsequent product separation process is also difficult to scale up, resulting in a significant increase in production costs, which seriously restricts its industrial development.

[0004] The photochemical reaction method is more environmentally friendly and is currently used as a new way to produce hydroxycarbazole. However, the existing methods are all intermittent reactions, resulting in low photon transfer efficiency and high light source energy consumption, which leads to low reaction yield, long reaction time and serious side reactions. In addition, in the prior art, hydroxycarbazole is prepared by the photochemical reaction method. Although 1-hydroxycarbazole, 2-hydroxycarbazole or 3-hydroxycarbazole with a certain yield can be prepared by different raw materials, 4-hydroxycarbazole has the same preparation route as 2-hydroxycarbazole. In the existing preparation process, the products obtained are all 2-hydroxycarbazole as the main product, and the yield of 4-hydroxycarbazole is extremely low, which brings great difficulty to the production and separation of 4-hydroxycarbazole.

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

[0006] The invention aims at the shortcomings of the existing preparation method of hydroxycarbazole and develops a continuous flow production process of hydroxycarbazole. The production process has mild reaction conditions, readily available raw materials, a simple separation and purification process, high reaction yield, high selectivity and low production cost, and can realize the preparation and effective separation of 1-hydroxycarbazole, 2-hydroxycarbazole, 3-hydroxycarbazole and 4-hydroxycarbazole.

[0007] To achieve the above object, 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) The raw materials o-halogenated aniline, hydroquinone, organic solvent and acid catalyst are mixed and continuously pumped into the first-stage reactor for reaction;

[0010] (2) subjecting the reaction liquid at the outlet of the first-stage reactor to extraction, vacuum distillation, recrystallization, and drying treatments to obtain a photoreaction intermediate as a reaction product;

[0011] (3) continuously pumping a solution of the photoreaction intermediate obtained in step (2) mixed with a photoreaction catalyst and a second solvent into a second-stage photoreactor to carry out a photochemical reaction under irradiation with a UV-LED light source;

[0012] (4) subjecting the reaction liquid at the outlet of the second-stage photoreactor to the following steps, including neutralization, vacuum distillation, and recrystallization, to obtain a hydroxycarbazole product;

[0013] Wherein, the o-halogenated aniline is selected from at least one of 2-chloroaniline, 2-bromoaniline, 2-fluoroaniline and 2-iodoaniline, the catechol 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, 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 the art, the maximum emission wavelength of a light source is referred to as the central emission wavelength.

[0015] The present invention is further configured that the photoreaction intermediate product of the reaction in step (1) includes at least one of 2-hydroxy-2′-halogen-diphenylamine, 3-hydroxy-2′-halogen-diphenylamine and 4-hydroxy-2′-halogen-diphenylamine; and the hydroxycarbazole product finally obtained 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-halogenated aniline is 1:(0.5-2.0), and more preferably 1:(0.6-1.4); the molar ratio of the acid catalyst to the raw material hydroquinone is 0.05-0.5; and more preferably 0.05-0.2.

[0019] In step (1), the raw materials continuously conveyed are two feeds, one feed is a solution of a mixture of hydroquinone, an acid catalyst and an organic solvent, in which the concentration of hydroquinone is 25-40wt% and the concentration of the acid catalyst is 3-10wt%; the other feed is a mixed solution of o-halogenated aniline and an organic solvent, in which the concentration of o-halogenated aniline is 35-50wt%; the flow rate of the two feeds is 0.5-1.5 mL / min, and after the two feeds 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 a T-shaped, butterfly-shaped or branch-shaped microchannel reactor, and the channel size of the first-stage reactor is 0.5-2.0 mm.

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

[0022] The present invention is further configured 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°C, preferably 0-25°C.

[0023] The present invention is further configured to recrystallize the residual liquid containing the photoreaction intermediate after the reduced pressure distillation, the solvent used for recrystallization is selected from at least one of water, methanol, ethanol, acetonitrile or acetone, the acid solution used for adjusting the pH is selected from at least one of formic acid, acetic acid, propionic acid, hydrochloric acid, phosphoric acid or sulfuric acid, and the alkaline solution used for adjusting 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 temperature of the recrystallization is controlled in stages: the temperature is raised from 20-25°C to 40-50°C at a rate of 10-20°C / min, the temperature is kept constant for 5-20 minutes, and the pH is adjusted to 7.5-11; then the temperature is continued to be raised to 80-90°C at a rate of 10-20°C / min, the temperature is kept constant for 10-20 minutes, and the pH is adjusted to 3-6.5; finally, the temperature is lowered to 20-25°C at a rate of 5-15°C / min, the temperature is kept constant for 10-20 minutes, and the mixture is filtered at a constant temperature.

[0025] The present invention is further configured to separate an extract and a raffinate containing a photoreaction intermediate after extraction treatment, wherein the raffinate is subjected to reduced pressure distillation to separate an organic solvent, the remaining raffinate containing the photoreaction intermediate is cooled and then recrystallized, and the separated organic solvent is returned to the raw material feed end for recycling; the separated extract is subjected to reduced pressure distillation to separate an extractant and an acid catalyst, which are then recycled.

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

[0027] The present invention is further configured that, in step (3), the photoreaction catalyst 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 to 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 a T-shaped, butterfly-shaped or branch-shaped plate-type microchannel reactor, and the channel size of the second-stage photoreactor is 0.5-2.0 mm.

[0031] The present invention is further configured such that the photochemical reaction conditions are: room temperature, and a 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 that, in step (3), the UV-LED light source is a plurality of small LED lamps integrated with a plate-type light source, and is equipped with air cooling; the LED lamp emission wavelength peak width is 10-30 nanometers, and the radiation power is 1-200 mW / cm 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 that in step (3), the continuously conveyed raw materials are two feeds, one feed is a solution containing a photoreaction intermediate, and the concentration of the photoreaction intermediate is 3-10wt%; the other feed is a solution containing a photoreaction catalyst, and the concentration of the photoreaction catalyst is 1.0-6.0wt%; the flow rate of the two feeds is the same, which is 1.0-2.0 mL / min. After the two feeds are mixed, they enter the second-stage photoreactor for reaction.

[0035] The present invention is further configured that, in step (4), the reaction liquid at the outlet is neutralized to a pH of 6.5-7.5 with an acid solution, and then vacuum distillation is performed, and the high-temperature kettle liquid remaining after the solvent is separated is recrystallized;

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

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

[0038] The high-temperature kettle liquid after vacuum distillation is first heated to 190-210°C at a heating rate of 10-20°C / min, kept at a constant temperature for 5-15 minutes, and filtered at a constant temperature; then cooled to 140-160°C at a cooling rate of 5-15°C / min, kept at a constant temperature for 10-20 minutes, and filtered at a constant temperature; then cooled to 90-110°C at a cooling rate of 5-15°C / min, kept at a constant temperature for 10-20 minutes, and filtered at a constant temperature; finally cooled to room temperature at a cooling rate of 5-15°C / min, filtered at a constant temperature, and the final product is obtained; or,

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

[0040] The high-temperature kettle liquid after the reduced pressure distillation is first heated to 190-210°C at a heating rate of 10-20°C / min, kept at a constant temperature for 5-15 minutes, and filtered at a constant temperature; then cooled to 140-160°C at a cooling rate of 5-15°C / min, kept at a constant temperature for 10-20 minutes, and filtered at a constant temperature; finally cooled to room temperature at a cooling rate of 5-15°C / min, filtered at a constant temperature, and the final product is obtained.

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

[0042] The present invention is further configured such that the acid solution is a hydrochloric acid solution or a 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) The present invention adopts a continuous flow synthesis and separation process method, using hydroquinone and o-halogenated aniline as raw materials to synthesize hydroxycarbazole through a two-step continuous flow reactor. The hydroquinone conversion rate is greater than 99.5%, the intermediate yield is greater than 94%, the intermediate purity is greater than 99.5%, the total yield of hydroxycarbazole is greater than 85%, and the purity of the hydroxycarbazole product is greater than 99%.

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

[0046] (3) The present invention realizes the two-step synthesis of hydroxycarbazole, which has low raw material cost, few synthesis steps, simple continuous synthesis and separation process flow, and can further improve production capacity by adopting a parallel amplification strategy, and can even be directly applied to industrial production; the circulation of solvent and catalyst is achieved by vacuum distillation, and photons, as a traceless "reagent", are green and environmentally friendly, thereby improving the economic benefits of hydroxycarbazole. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The present invention is a process flow chart of the continuous flow production process of hydroxycarbazole.

[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 This is the photochemical continuous synthesis route of 2-hydroxycarbazole and 4-hydroxycarbazole in the examples. DETAILED DESCRIPTION

[0051] The present invention is described in detail and completely with specific embodiments and in conjunction with the accompanying drawings. It should be understood that the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of the present invention.

[0052] In the technical solution of the present invention, room temperature refers to 20-30°C.

[0053] References Figure 1 The process flow and Figure 2 The synthetic route shown in the figure, the continuous flow production process of hydroxycarbazole of the present invention specifically comprises the following steps:

[0054] (1) mixing the raw materials o-halogenated aniline and hydroquinone, an organic solvent and an acid catalyst, and continuously pumping them into a first-stage reactor for reaction;

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

[0056] (3) mixing the photoreaction intermediate obtained in step (2) with a photoreaction catalyst and a second solvent, and continuously pumping the mixture into a second-stage photoreactor to carry out a photochemical reaction under irradiation with a UV-LED light source;

[0057] (4) neutralizing, distilling under reduced pressure, and recrystallizing the reaction liquid at the outlet of the second-stage photoreactor to obtain a hydroxycarbazole product;

[0058] Wherein, the o-halogenated aniline is selected from at least one of 2-chloroaniline, 2-bromoaniline, 2-fluoroaniline and 2-iodoaniline; the catechol 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, 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 difference in raw materials, the photoreaction intermediate product of the reaction in step (1) includes at least one of 2-hydroxy-2′-halogen-diphenylamine, 3-hydroxy-2′-halogen-diphenylamine and 4-hydroxy-2′-halogen-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-halogenated aniline 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 consisting 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 a T-shaped, butterfly-shaped or branch-shaped microchannel reactor, and the channel size of the first-stage reactor is 0.5-2.0 mm; the reaction temperature of the first-stage reaction is 90-200° C., and the reaction time is 30-90 minutes.

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

[0067] In one embodiment of the present invention, in step (1), the continuously conveyed raw materials are two feeds, one feed is a mixed solution of hydroquinone, an acid catalyst and an organic solvent, in which the concentration of hydroquinone is 25-40wt% and the concentration of the acid catalyst is 3-10wt%; the other feed is a mixed solution of o-halogenated aniline and an organic solvent, in which the concentration of o-halogenated aniline is 35-50wt%; the flow rate of the two feeds is the same, which is 0.5-1.5 mL / min; after the two feeds 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 water; the extraction temperature is 0-60°C, preferably 0-25°C, and more preferably 0-10°C.

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

[0070] In one embodiment of the present invention, in step (2), firstly, the extract containing the extractant and the acid catalyst and the raffinate containing the solvent and the reaction product after extraction are separated; then, the extract is subjected to vacuum distillation to separate the extractant and the acid catalyst, and the raffinate is subjected to vacuum distillation to separate the organic solvent, and the remaining kettle liquid containing the reaction product is recrystallized; the recrystallization comprises the following process:

[0071] Raise the temperature from 20-25 ℃ to 40-50 ℃ at 10-20 ℃ / min, keep the temperature constant for 5-20 minutes, adjust the pH to 7.5-11, then continue to raise the temperature to 80-90 ℃ at 10-20 ℃ / min, keep the temperature constant for 10-20 minutes, adjust the pH to 3-6.5; finally, lower the temperature to 20-25 ℃ at 5-15 ℃ / min, keep the temperature constant for 10-20 minutes, and filter at the 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 temperature rise stage, an alkaline solution is used to adjust the pH to 8-10; in the second temperature rise stage, an acid solution is used to adjust the pH to 3.5-5.0.

[0074] In one embodiment of the present invention, the residual liquid containing the photoreaction intermediate after the reduced pressure 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 for adjusting the pH is selected from at least one of formic acid, acetic acid, propionic acid, hydrochloric acid, phosphoric acid or sulfuric acid, and the alkaline solution used for adjusting 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 hydrochloric acid solution and / or phosphoric acid solution, with a mass fraction of 1-10%, and the alkaline solution is sodium hydroxide and / or potassium hydroxide solution, with a mass fraction of 5-15%; the drying temperature is 50-120°C, and the drying time is 1.5~5.0h; the drying temperature is preferably 60-70°C.

[0076] In one embodiment of the present invention, in step (3), the photoreaction catalyst 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 photoreaction catalyst is a mixed photoreaction catalyst consisting 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 photoreaction catalyst is a mixed photoreaction catalyst 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 to the intermediate raw material is (1.5-4.5:1); preferably (2.4-3.2):1, such as 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 of dimethyl sulfoxide and organic nitrile; 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 a T-shaped, butterfly-shaped or branch-shaped microchannel reactor, and the channel size of the second-stage photoreactor is 0.5-2.0 mm; the photochemical reaction conditions are: room temperature, residence time is 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 plurality of small LED lamps integrated with a plate-type light source, and is equipped with air cooling; the LED lamp has an emission wavelength peak width of 10-30 nanometers and a radiation power of 1-200 mW / cm 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 continuously conveyed raw materials are two feeds, one feed is a solution containing a photoreaction intermediate, and the concentration of the photoreaction intermediate is 3-10wt%; the other feed is a solution containing a photoreaction catalyst, and the concentration of the photoreaction catalyst is 1.0-6.0wt%; the flow rate of the two feeds is the same, which is 1.0-2.0 mL / min; the two feeds are mixed in a microchannel mixer and then enter the second-stage photoreactor for reaction.

[0086] In one embodiment of the present invention, in step (4), an acid solution is used to neutralize to a pH of 6.5 to 7.5, and then vacuum distillation is performed to separate the solvent, and the remaining kettle liquid is recrystallized under reduced pressure conditions, wherein the pressure condition is -0.1 MPa to -0.05 MPa, preferably -0.1 MPa to -0.075 MPa;

[0087] The recrystallization stage control comprises the following process:

[0088] The high-temperature kettle liquid after vacuum distillation is first heated to 190-210°C at a heating rate of 10-20°C / min, kept at a constant temperature for 5-15 minutes, and filtered at a constant temperature; then cooled to 140-160°C at a cooling rate of 5-15°C / min, kept at a constant temperature for 10-20 minutes, and filtered at a constant temperature; then cooled to 90-110°C at a cooling rate of 5-15°C / min, kept at a constant temperature for 10-20 minutes, and filtered at a constant temperature; finally cooled to room temperature at a cooling rate of 5-15°C / min, filtered at a constant temperature, and the final product is obtained; or,

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

[0090] The high-temperature kettle liquid after the reduced pressure distillation is first heated to 190-210°C at a heating rate of 10-20°C / min, kept at a constant temperature for 5-15 minutes, and filtered at a constant temperature; then cooled to 140-160°C at a cooling rate of 5-15°C / min, kept at a constant temperature for 10-20 minutes, and filtered at a constant temperature; finally cooled to room temperature at a cooling rate of 5-15°C / min, filtered at a constant temperature, and the final product is obtained.

[0091] The acid solution is hydrochloric acid solution or sulfuric acid solution, 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 the photochemical reaction.

[0093] The technology of the invention is described in detail below in conjunction with specific embodiments.

[0094] Example 1

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

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

[0097] The solvent of 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 a mixture of benzenesulfonic acid and phosphoric acid in a mass ratio of 4:1, and 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, calculated by mass percentage, includes two feeds, a mixed solution of 37.1% hydroquinone + 6.7% acid catalyst and a 45.2% o-bromoaniline solution. The feed flow rate is 1 mL / min. After the two feeds are mixed in the mixer, they enter the first stage reactor for reaction. The reaction temperature is 140°C and the residence time is 60 minutes.

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

[0100] The outlet material of the first-stage reactor in step (1) is extracted with a 10% ethanol aqueous solution as an extractant at a temperature of 5°C to obtain an extract and a raffinate containing the photoreaction intermediate; wherein the raffinate is subjected to reduced pressure distillation to separate the organic solvent, and the remaining kettle liquid is cooled and recrystallized, and water is selected as the solvent for recrystallization. The recrystallization process is as follows: after adding 25 mL of water to the kettle liquid, the temperature is increased from 25°C to 45°C at 10°C / min, and the temperature is kept constant for 15 minutes, and a 10% potassium hydroxide solution is added to pH = 9.5; the temperature is continued to be increased to 85°C at 15°C / min, and the temperature is kept constant for 10 minutes, and a 5% hydrochloric acid solution is added to pH = 4; finally, the temperature is reduced to 25°C at 15°C / min, and the temperature is kept constant for 20 minutes, and the mixture is filtered at the constant temperature. Finally, the recrystallized product was dried in an oven at 60 °C for 2 h to obtain 4-hydroxy-2′-bromo-diphenylamine intermediate, which was characterized by H NMR and MS. Its molecular formula was C 12 H 10 BrNO, its structural formula is as follows:

[0101] ;

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

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

[0104] The two feeds for the second stage reaction are: 5% intermediate solution and 3.6% photoreaction catalyst solution, respectively, in terms of 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 photoreaction catalyst is a mixture of triethylamine and potassium hydroxide in a mass ratio of 0.4:1. The flow rate of both feeds is 1.5 mL / min. The second stage photoreactor uses a butterfly 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 radiation power is 20 mW / cm 2 The two feeds are mixed in a mixer and transported to the second-stage photoreactor for photochemical reaction at a reaction temperature of 25°C and a residence time of 300 seconds.

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

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

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

[0108] Example 2

[0109] This embodiment provides a production process of 2-hydroxycarbazole and 4-hydroxycarbazole. The reaction principle of this embodiment is as follows: Figure 4 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 program in step (4) is different. The details are as follows:

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

[0111] .

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

[0113] After testing, 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 purities of 2-hydroxycarbazole and 4-hydroxycarbazole were 99.2% and 99.1%, respectively.

[0114] Example 3

[0115] This embodiment provides a production process of 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] After testing, 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 purities of 2-hydroxycarbazole and 4-hydroxycarbazole were 99.2% and 99.3%, respectively.

[0117] Comparative Example 1

[0118] Batch Synthesis of 2-Hydroxycarbazole and 4-Hydroxycarbazole

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

[0120] Step (1) adopts intermittent synthesis, and the specific steps are as follows: 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 respectively. In a 50 mL beaker, add 15.62 g of o-chloroaniline and 25 g of solvent, and stir evenly with a glass rod. Slowly heat the three-necked flask to 110 °C in an oil bath, and turn on the magnetic stirring at the same time. Then slowly add the o-chloroaniline solution to the three-necked flask through a constant pressure dropping funnel, and control the dropping time to 45 minutes. After the dropwise addition is completed, adjust the oil bath temperature to slowly rise to 160 °C and react for 9 hours. After the reaction is completed, turn off the magnetic stirring and oil bath temperature control, and naturally cool to room temperature in a fume hood.

[0121] Step (3) was synthesized by batch synthesis, and the specific steps were as follows: In a 50 mL three-necked glass flask, a vacuum pump was used to evacuate and fill with argon three times. 10 g of solvent, 256.54 mg of the second-stage catalyst and 252.62 mg of 3-hydroxy-2'-chlorodiphenylamine were added in sequence, and the reaction was maintained in an oxygen-free environment by an argon balloon, and the reaction was stirred for 5 h.

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

[0123] After testing, 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%; the purity of the photoreaction intermediate obtained in step (2) was 99.7%; in step (3), the conversion rate of the photoreaction intermediate was 56.5%, 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 process method using intermittent reaction has more by-products and significantly reduced the yield, thereby increasing the difficulty of purification.

[0124] Comparative Example 2

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

[0126] After testing, 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%, and the total yield of 2-hydroxycarbazole and 4-hydroxycarbazole was 15.75%, of which the yield of 4-hydroxycarbazole was 6.5%. 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 synthetic 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 / cm 2 , the reaction temperature was 30 °C and the residence time was 10 min.

[0129] After testing, 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%, and the total yield of 2-hydroxycarbazole and 4-hydroxycarbazole was 3.38%, of which the yield of 4-hydroxycarbazole was 1.2%. The purities of 2-hydroxycarbazole and 4-hydroxycarbazole obtained in step (4) were 95.0% and 94.3%, respectively.

[0130] Comparative Example 4

[0131] The synthetic 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: heating from 25°C to 45°C at 10°C / min, keeping the temperature constant for 15 minutes, adding potassium hydroxide solution until the pH value is 11.2; heating to 85°C at 15°C / min, keeping the temperature constant for 10 minutes, adding hydrochloric acid solution until the pH value is 3; finally cooling to 25°C at 15°C / min, keeping the temperature constant for 20 minutes, and filtering at the constant temperature;

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

[0134] After testing, 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%, and 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] After testing, in step (3), the conversion rate of the photoreaction intermediate was 52.5%, the yield of 2-hydroxycarbazole was 7.8%, and no 4-hydroxycarbazole was detected.

[0138] Comparative Example 6

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

[0140] After testing, in step (1), the conversion rate of resorcinol was 90.6%, and the yield of the photoreaction intermediate was 73.0%; in step (3), the conversion rate of the 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 synthetic 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: heating from 25°C to 45°C at 10°C / min, keeping the temperature constant for 5 minutes, adding a 10% potassium hydroxide solution to a pH of 9.5; heating to 70°C at 10°C / min, keeping the temperature constant for 5 minutes, adding a 10% hydrochloric acid solution to a pH of 4; finally cooling to 25°C at 20°C / min, keeping the temperature constant for 20 minutes, and filtering at the constant temperature;

[0144] The photoreaction catalyst in step (3) is potassium tert-butoxide.

[0145] After testing, in step (2), the purity of the photoreaction intermediate obtained was 94.7%; in step (3), the conversion rate of the intermediate was 97.8%, and 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 synthetic 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%, wherein the yield of 4-hydroxycarbazole was 21.5%.

[0149] Comparative Example 9

[0150] The synthetic 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] According to the test, in step (3), the conversion rate of the photoreaction intermediate was 60.8%, and the sum of the yields of 2-hydroxycarbazole and 4-hydroxycarbazole was 17.6%.

[0152] In summary, according to the results of the embodiments and comparative examples of the present invention, it can be seen that by adopting the continuous synthesis method of the present invention in combination with a microchannel reactor and appropriate process conditions, 4-hydroxycarbazole with a high yield and high purity can be successfully obtained; 1-hydroxycarbazole, 2-hydroxycarbazole or 3-hydroxycarbazole can also be prepared by this method.

[0153] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not limitations on the implementation methods of the present invention. For ordinary technicians in the relevant field, other different forms of changes or modifications can be made based on the above description. It is impossible to list all the implementation methods here. All obvious changes or modifications derived from the technical solution 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: The steps include: (1) The raw materials o-halogenated aniline, hydroquinone, organic solvent and acid catalyst are mixed and continuously pumped into the first-stage reactor for reaction; (2) subjecting the reaction liquid at the outlet of the first-stage reactor to extraction, vacuum distillation, recrystallization, and drying treatments to obtain a photoreaction intermediate as a reaction product; (3) continuously pumping a solution of the photoreaction intermediate obtained in step (2) mixed with a photoreaction catalyst and a second solvent into a second-stage photoreactor to carry out a photochemical reaction under irradiation with a UV-LED light source; (4) subjecting the reaction liquid at the outlet of the second-stage photoreactor to the following steps, including neutralization, vacuum distillation, and recrystallization, to obtain a hydroxycarbazole product; The o-halogenated aniline is selected from at least one of 2-chloroaniline, 2-bromoaniline, 2-fluoroaniline and 2-iodoaniline, the catechol 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, and the channel size of the microchannel reactor is 0.15mm-3.0mm, wherein in step (1), the reaction temperature of the first-stage reaction is 90-200°C, and the residence time is 30-90 minutes; in step (3), the maximum emission wavelength range of the UV-LED light source is 270nm-320nm, and the conditions of the photochemical reaction are: room temperature, and the residence time is 100-1200 seconds.

2. A 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 the raw material hydroquinone to o-halogenated aniline is 1:(0.5-2.0); and the molar ratio of the acid catalyst to the raw material hydroquinone is 0.05-0.

5.

3. A continuous flow production process for hydroxycarbazole according to claim 1, characterized in that: In step (1), the raw materials continuously conveyed are two feeds, one feed is a solution of a mixture of hydroquinone, an acid catalyst and an organic solvent, in which the concentration of hydroquinone is 25-40wt% and the concentration of the acid catalyst is 3-10wt%; the other feed is a mixed solution of o-halogenated aniline and an organic solvent, in which the concentration of o-halogenated aniline is 35-50wt%; the flow rate of the two feeds is 0.5-1.5mL / min, and after the two feeds are mixed, they are pumped into the first-stage reactor for reaction.

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

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

6. The continuous flow production process of 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°C, preferably 0-25°C; Recrystallize the residual liquid containing the photoreaction intermediate after the reduced pressure distillation, wherein the solvent used for the recrystallization is selected from at least one of water, methanol, ethanol, acetonitrile or acetone, the acid solution used for adjusting the pH is selected from at least one of formic acid, acetic acid, propionic acid, hydrochloric acid, phosphoric acid or sulfuric acid, and the alkaline solution used for adjusting 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 raised from 20-25°C to 40-50°C at a rate of 10-20°C / min, the temperature is kept constant for 5-20 minutes, and the pH value is adjusted to 7.5-11; then the temperature is further raised to 80-90°C at a rate of 10-20°C / min, the temperature is kept constant for 10-20 minutes, and the pH value is adjusted to 3-6.5; finally, the temperature is lowered to 20-25°C at a rate of 5-15°C / min, the temperature is kept constant for 10-20 minutes, and the mixture is filtered at a constant temperature; The drying temperature is 50-120°C, preferably 60-70°C.

7. The continuous flow production process of hydroxycarbazole according to claim 1, characterized in that: In step (3), the photoreaction catalyst is selected from one or more of methylamine, ethylamine, diethylamine, triethylamine, aniline, diisopropylamine, sodium hydroxide and potassium hydroxide; The second solvent for the photoreaction is selected from one or more of acetonitrile, malononitrile, ethyl acetate, dimethyl sulfoxide, toluene, and cyclohexane; The molar ratio of the photoreaction catalyst to the intermediate raw material is (1.5-4.5:1).

8. The continuous flow production process of 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 plurality of small LED lamps integrated with a plate-type light source, the LED lamp emission wavelength peak width is 10-30nm, and the radiation power is 1-200 mW / cm 2 ; The photochemical reaction conditions are: room temperature, reaction residence time is 150-600 seconds.

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

10. The continuous flow production process of hydroxycarbazole according to claim 1, characterized in that: In step (4), the reaction liquid at the outlet is neutralized to a pH of 6.5-7.5 with an acid solution, and then vacuum distillation is performed to recrystallize the high-temperature kettle liquid remaining after the solvent is separated; The recrystallization is carried out in stages under reduced pressure conditions, the pressure condition is -0.1 to -0.05 MPa, and the specific stage-by-stage control process is as follows: The high-temperature kettle liquid after vacuum distillation is first heated to 190-210°C at a heating rate of 10-20°C / min, kept at a constant temperature for 5-15 minutes, and filtered at a constant temperature; then cooled to 140-160°C at a cooling rate of 5-15°C / min, kept at a constant temperature for 10-20 minutes, and filtered at a constant temperature; then cooled to 90-110°C at a cooling rate of 5-15°C / min, kept at a constant temperature for 10-20 minutes, and filtered at a constant temperature; finally cooled to room temperature at a cooling rate of 5-15°C / min, filtered at a constant temperature, and the final product is obtained; or, The specific segmented control process of recrystallization is as follows: The high-temperature kettle liquid after the reduced pressure distillation is first heated to 190-210°C at a heating rate of 10-20°C / min, kept at a constant temperature for 5-15 minutes, and filtered at a constant temperature; then cooled to 140-160°C at a cooling rate of 5-15°C / min, kept at a constant temperature for 10-20 minutes, and filtered at a constant temperature; finally cooled to room temperature at a cooling rate of 5-15°C / min, filtered at a constant temperature, and the final product is obtained.

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