CN110559958B - Device for continuously preparing 2, 6-dihydroxy benzaldehyde and application thereof - Google Patents
Device for continuously preparing 2, 6-dihydroxy benzaldehyde and application thereof Download PDFInfo
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Abstract
The invention provides a device for continuously preparing 2, 6-dihydroxy benzaldehyde and application thereof. The device comprises a first continuous reaction unit for hydroxyl protection reaction, a second continuous reaction unit for lithiation hydroformylation and a third continuous reaction unit for deprotection reaction which are sequentially connected in series, wherein the third continuous reaction unit comprises: and the first columnar continuous reactor is connected with the second continuous reaction unit and is used for performing deprotection treatment on the lithiated aldehyde-based product and simultaneously performing liquid separation to obtain an organic phase and a water phase containing 2, 6-dihydroxy benzaldehyde. When the device is applied to the preparation of the 2, 6-dihydroxy benzaldehyde, the reaction time is shortened, and intermediate purification treatment is not needed, so that compared with a batch process, the device can greatly save the equipment cost and the post-treatment cost, greatly improve the production efficiency, and be more beneficial to the industrial scale-up production of the 2, 6-dihydroxy benzaldehyde.
Description
Technical Field
The invention relates to the field of preparation of 2, 6-dihydroxy benzaldehyde, and particularly relates to a device for continuously preparing 2, 6-dihydroxy benzaldehyde and application thereof.
Background
2, 6-dihydroxy benzaldehyde is a very important organic synthesis intermediate. Can be used in the fields of electric insulating materials, ion exchange resins, dyes and the like, and can also be applied to the aspect of medicine, for example, the compound is an important segment of a new drug voxelotor for Sickle Cell Disease (SCD). Its synthesis can have multiple routes.
For example, 1, 3-dimethoxybenzene is used as a raw material, and 2, 6-dihydroxy benzaldehyde is obtained through two steps of lithiation, aldehyde group adding and demethylation reaction. The raw materials of the method are easy to obtain, the reaction condition is mild, the total yield of the two steps is about 70%, but the demethylation uses Lewis acid, the treatment after the reaction is more complicated, and the three wastes are larger.
In another example, resorcinol is used as the starting material, and only one step is needed, so that the route is simpler and the cost of the raw material is extremely low. However, the reaction selectivity is poor, a large amount of by-product 2, 4-dihydroxybenzaldehyde (2, 6-dihydroxybenzaldehyde: 2, 4-dihydroxybenzaldehyde ═ 41: 24) is easily produced, and the purification of the product is difficult.
And resorcinol is taken as a raw material to obtain the 2, 6-dihydroxy benzaldehyde through three steps, wherein in the first step, resorcinol reacts with ethyl vinyl ether to ensure that hydroxyl is protected by Ethyl Vinyl Ether (EVE), in the second step, aldehyde group is formed on 1-position of resorcinol through lithiation, in the third step, EVE protecting group is removed under an acidic condition to obtain the 2, 6-dihydroxy benzaldehyde, the raw material of the route is easy to obtain and cheap, the reaction conditions of the three steps are mild, the production cost is low, and the total yield of the three steps is 65.6%.
However, in the preparation of 2, 6-dihydroxybenzaldehyde by the three-step method, in which Tetrahydrofuran (THF) is used as a solvent in the first step, resorcinol and ethyl vinyl ether require at least 16 hours at room temperature to complete the reaction, and the reaction efficiency is decreased once the temperature is increased. After the production scale is enlarged, the production efficiency is low, the production capacity is low, and the energy consumption and the production cost are increased. And after the reaction, the post-treatment steps of quenching, washing, concentrating, dewatering and the like are needed, so that the production efficiency is further reduced. And the second step is that the EVE-protected resorcinol reacts with butyl lithium at the temperature of-10-0 ℃ for 30-40 min. And (2) continuing to react for 1-2 hours at the temperature of-10 to-5 ℃ after adding Dimethylformamide (DMF), wherein the step is a low-temperature reaction, but the reaction temperature is difficult to further reduce because more materials participate in the batch reaction and the heat transmission is difficult. And (3) after the reaction is finished, quenching by using hydrochloric acid, adjusting the pH value of the system to 0.7-0.8, reacting at room temperature, wherein the reaction also needs 16 hours, and the reaction efficiency is reduced once the temperature is increased. And after the reaction is finished, washing the reaction product by using saturated saline solution, concentrating and replacing the reaction product by an acetonitrile system after washing the reaction product by using water, and finally crystallizing the reaction product in acetonitrile to obtain the 2, 6-dihydroxy benzaldehyde product.
Therefore, the reaction time of the three-step reaction is long, and the post-treatment process of each step is more. If the traditional batch process is used for large-scale production, the length of equipment chain, a large amount of occupied reaction kettles, low production efficiency, high equipment occupancy rate and high production cost are inevitably caused.
Disclosure of Invention
The invention mainly aims to provide a device for continuously preparing 2, 6-dihydroxy benzaldehyde and application thereof, and aims to solve the problems of low production efficiency and high cost of a 2, 6-dihydroxy benzaldehyde preparation process in the prior art.
In order to accomplish the above object, according to one aspect of the present invention, there is provided an apparatus for continuously preparing 2, 6-dihydroxybenzaldehyde, comprising a first continuous reaction unit for hydroxyl protection reaction, a second continuous reaction unit for lithiation hydroformylation, and a third continuous reaction unit for deprotection reaction, which are connected in series in this order, the third continuous reaction unit comprising: and the first columnar continuous reactor is connected with the second continuous reaction unit and is used for performing deprotection treatment on the lithiated hydroformylation product and simultaneously performing liquid separation to obtain an organic phase and a water phase containing 2, 6-dihydroxy benzaldehyde.
Further, the first column continuous reactor is provided with a first stirrer so as to stir the materials in the first column continuous reactor during the deprotection treatment and liquid separation.
Further, the third continuous reaction unit may further include: the first cylindrical continuous reactor is provided with a deprotection agent inlet and a lithiation hydroformylation product inlet, the deprotection agent supply device is connected with the deprotection agent inlet, the lithiation hydroformylation product inlet is connected with the second continuous reaction unit, the deprotection agent inlet is preferably arranged at the upper part of the first cylindrical continuous reactor, and the lithiation hydroformylation product inlet is preferably arranged at the lower part of the first cylindrical continuous reactor.
Further, the above apparatus further comprises a continuous washing unit comprising a second cylindrical continuous reactor connected to the first cylindrical continuous reactor for washing the organic phase with a washing liquid, preferably the second cylindrical continuous reactor is provided with a second stirrer for stirring the contents of the second cylindrical continuous reactor during the washing process; preferably the continuous wash unit further comprises: a scrubbing liquid supply apparatus, the second cylindrical continuous reactor having a scrubbing liquid inlet and an organic phase inlet, the scrubbing liquid supply apparatus being connected to the scrubbing liquid inlet, preferably the scrubbing liquid inlet being disposed in an upper portion of the second cylindrical continuous reactor, preferably the organic phase inlet being disposed in a lower portion of the second cylindrical continuous reactor; preferably the organic solvent supply means, the second cylindrical continuous reactor further has an organic solvent inlet connected to the organic solvent supply means, preferably the organic solvent inlet is disposed below the organic phase inlet.
Further, the third continuous reaction unit further comprises a buffer tank, and the buffer tank is connected and arranged between the first columnar continuous reactor and the organic phase inlet.
Further, the second continuous reaction unit includes: the second coil type continuous reactor is provided with a hydroxyl protection reaction product inlet, a lithiation reagent inlet and a lithiation product outlet, the hydroxyl protection reaction product inlet is connected with the first continuous reaction unit, and preferably, the second coil type continuous reactor is provided with a second heat exchange jacket; a lithiation reagent supply device connected to the lithiation reagent inlet; the third coil type continuous reactor is provided with a lithiation product inlet, an aldehydization reagent inlet and a lithiation aldehydization product outlet, the lithiation product inlet is connected with the lithiation product outlet, the lithiation aldehydization product outlet is connected with the third continuous reaction unit, and preferably, the third coil type continuous reactor is provided with a third heat exchange jacket; and the supply equipment of the hydroformylation reagent is connected with the inlet of the hydroformylation reagent.
Further, the first continuous reaction unit includes: the first coil type continuous reactor is provided with a reaction material inlet and a hydroxyl protection reaction product outlet, the hydroxyl protection reaction product outlet is connected with the second continuous reaction unit, and preferably the first coil type continuous reactor is provided with a first heat exchange jacket; the resorcinol solution supply equipment is connected with the reaction material inlet; and the ethyl vinyl ether solution supply equipment is connected with the reaction material inlet.
Further, a sampling valve is arranged on a connecting pipeline among the first continuous reaction unit, the second continuous reaction unit and the third continuous reaction unit.
According to another aspect of the present invention, there is provided a use of the apparatus for continuously producing 2, 6-dihydroxybenzaldehyde according to any one of the above in the continuous production of 2, 6-dihydroxybenzaldehyde.
Further, the above applications include: carrying out hydroxyl protection reaction on resorcinol and ethyl vinyl ether in a first continuous reaction unit to obtain a hydroxyl protection product system, preferably adding resorcinol and ethyl vinyl ether into the first continuous reaction unit in a solution mode, and preferably controlling the temperature of the hydroxyl protection reaction to be 30-45 ℃, and more preferably 30-35 ℃; sequentially carrying out lithiation and hydroformylation reaction on the hydroxyl protection product system in a second continuous reaction unit under the action of a lithiation reagent and an hydroformylation reagent to obtain a lithiation and hydroformylation product system, wherein the lithiation reagent is preferably butyl lithium, the hydroformylation reagent is dimethylformamide, and the temperature of the lithiation and hydroformylation reaction is preferably-30 to 25 ℃, and more preferably-20 to-15 ℃ or 5 to 25 ℃; carrying out hydroxyl protecting group removal treatment on a lithiated aldehyde-based product system in a first cylindrical continuous reactor by using a deprotection agent to obtain an organic phase containing 2, 6-dihydroxybenzaldehyde, preferably selecting the deprotection agent as strong inorganic acid, further preferably selecting the deprotection agent as dilute hydrochloric acid, dilute sulfuric acid or dilute nitric acid, and preferably selecting the temperature for hydroxyl protecting group removal treatment to be 30-45 ℃; and washing the organic phase in a second cylindrical continuous reactor by using a detergent and an optional organic solvent to obtain the washed organic phase, wherein the detergent is preferably saline water or sodium bicarbonate aqueous solution, and the organic solvent is preferably any one of methyl tert-butyl ether, ethyl acetate and 2-methyltetrahydrofuran.
Furthermore, the retention time of the resorcinol and the ethyl vinyl ether in the first continuous reaction unit is 20-180 min, and the retention time of the deprotection agent and the lithiation aldehyde group product in the first cylindrical continuous reactor is preferably 20-180 min.
By applying the technical scheme of the invention, when the device is adopted to prepare the 2, 6-dihydroxybenzaldehyde, the reaction time of hydroxyl protection reaction and deprotection in the synthetic route can be greatly shortened. And the continuous reaction units are directly connected, the product system obtained by each continuous reaction unit can enter the next continuous reaction unit without post-treatment, and the reaction of each step is carried out simultaneously after the device is operated, so that the overall production efficiency is improved. In conclusion, when the device is applied to the preparation of the 2, 6-dihydroxybenzaldehyde, the reaction time is shortened, and the intermediate purification treatment is not needed, so that compared with the batch process, the device cost and the post-treatment cost can be greatly saved, the production efficiency is greatly improved, and the industrial scale-up production of the 2, 6-dihydroxybenzaldehyde is more facilitated.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
FIG. 1 is a schematic view showing the structure of an apparatus for continuously producing 2, 6-dihydroxybenzaldehyde according to a preferred embodiment of the present invention.
Wherein the figures include the following reference numerals:
10. a first continuous reaction unit; 11. a resorcinol solution supply device; 12. ethyl vinyl ether solution; 13. a first coil continuous reactor;
20. a second continuous reaction unit; 21. a lithiation reagent supply apparatus; 22. a second coil continuous reactor; 23. an hydroformylation reagent supply apparatus; 24. a third coiled continuous reactor;
30. a third continuous reaction unit; 31. a deprotecting agent supply apparatus; 32. a first cylindrical continuous reactor; 33. a buffer tank;
40. a continuous washing unit; 41. a washing liquid supply device; 42. a second cylindrical continuous reactor; 43. an organic solvent supply device.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail below with reference to the embodiments with reference to the attached drawings.
As analyzed by the background art of the application, the preparation process of the 2, 6-dihydroxy benzaldehyde in the prior art has low production efficiency and high cost, and in order to solve the problem, the application provides a device for continuously preparing the 2, 6-dihydroxy benzaldehyde and application thereof.
In an exemplary embodiment of the present application, there is provided an apparatus for continuously preparing 2, 6-dihydroxybenzaldehyde, as shown in fig. 1, the apparatus comprises a first continuous reaction unit 10 for hydroxyl protection reaction, a second continuous reaction unit 20 for lithiation hydroformylation, and a third continuous reaction unit 30 for deprotection reaction, which are connected in series, wherein the third continuous reaction unit 30 comprises a first cylindrical continuous reactor 32, and the first cylindrical continuous reactor 32 is connected with the second continuous reaction unit 20 for performing a deprotection treatment on the lithiation hydroformylation product and simultaneously performing liquid separation to obtain an organic phase containing 2, 6-dihydroxybenzaldehyde and an aqueous phase.
When the device is used for preparing the 2, 6-dihydroxybenzaldehyde, the reaction time of hydroxyl protection reaction and deprotection in the synthetic route can be greatly shortened. And the continuous reaction units are directly connected, the product system obtained by each continuous reaction unit can enter the next continuous reaction unit without post-treatment, and the reaction of each step is carried out simultaneously after the device is operated, so that the overall production efficiency is improved. In conclusion, when the device is applied to the preparation of the 2, 6-dihydroxybenzaldehyde, the reaction time is shortened, and the intermediate purification treatment is not needed, so that compared with the batch process, the device cost and the post-treatment cost can be greatly saved, the production efficiency is greatly improved, and the industrial scale-up production of the 2, 6-dihydroxybenzaldehyde is more facilitated.
In one embodiment, in order to accelerate the reaction process, it is preferable that the first column continuous reactor 32 is provided with a first stirrer to stir the contents of the first column continuous reactor 32 during the deprotection treatment and liquid separation.
In order to improve the controllability of the reaction process of the third continuous reaction unit 30, it is preferable that, as shown in fig. 1, the third continuous reaction unit 30 further includes a deprotecting agent supply device 31, the first cylindrical continuous reactor 32 has a deprotecting agent inlet and a lithiated aldehyde-based product inlet, the deprotecting agent supply device 31 is connected to the deprotecting agent inlet, and the lithiated aldehyde-based product inlet is connected to the second continuous reaction unit 20. The deprotection agent is supplied to the first columnar continuous reactor 32 by the deprotection agent supply device 31, and the reaction process can be controlled by adjusting the supply speed, so that the conversion rate of materials is improved. In addition, in order to improve the deprotection treatment efficiency and the separation efficiency of the organic phase and the aqueous phase, it is preferable that the inlet for the deprotecting agent is provided at the upper part of the first cylindrical continuous reactor 32, and it is preferable that the inlet for the lithiated aldehyde-based product is provided at the lower part of the first cylindrical continuous reactor 32. The positions of the deprotection agent inlet and the lithiation hydroformylation product inlet are arranged, so that the deprotection agent and the lithiation hydroformylation product are in countercurrent contact, and in the contact process, the cylindrical continuous reactor is favorable for separating a water phase from an organic phase due to the action of gravity, and the product treatment efficiency is improved.
In order to further improve the efficiency and purity of the product treatment, it is preferred that the apparatus further comprises a continuous washing unit 40, as shown in fig. 1, the continuous washing unit 40 comprising a second cylindrical continuous reactor 42, the second cylindrical continuous reactor 42 being connected to the first cylindrical continuous reactor 32 for washing the organic phase with a washing liquid. The organic phase is washed by the second cylindrical continuous reactor 42, which also facilitates the separation of the organic phase from the aqueous phase. In order to increase the washing rate, it is preferable that the second cylindrical continuous reactor 42 is provided with a second stirrer to stir the contents of the second cylindrical continuous reactor 42 during the washing.
In addition, in order to improve the effect of product washing and the controllability of efficiency, it is preferable that the above-mentioned continuous washing unit 40 further includes a washing liquid supply means 41, as shown in fig. 1, and the second cylindrical continuous reactor 42 has a washing liquid inlet and an organic phase inlet, and the washing liquid supply means is connected to the washing liquid inlet. The washing liquid is supplied into the second column-shaped continuous reactor 42 by the washing liquid supply means 41, and the washing rate and the washing effect are controlled by adjusting the supply speed. It is further preferred that the scrubbing liquid inlet is disposed in the upper portion of the second cylindrical continuous reactor 42 and that the organic phase inlet is disposed in the lower portion of the second cylindrical continuous reactor 42. The washing liquid inlet and the organic phase inlet are arranged at positions which are favorable for countercurrent contact of the washing liquid and the organic phase, so that the washing efficiency is improved, and meanwhile, the columnar continuous reactor is favorable for separation of the organic phase and the water phase, namely, the washing and separation integrated treatment is integrated, so that the treatment efficiency of the product is improved.
Preferably, the continuous washing unit 40 further comprises an organic solvent supply device 43, and the second cylindrical continuous reactor 42 further has an organic solvent inlet connected to the organic solvent supply device, preferably, the organic solvent inlet is disposed below the organic phase inlet. The solubility of 2, 6-dihydroxybenzaldehyde in the organic phase is increased by using an organic solvent to reduce the loss of 2, 6-dihydroxybenzaldehyde.
After the chemical reaction is completed, the obtained product system is stable in the organic phase after being subjected to liquid separation by the first cylindrical continuous reactor 32, and in order to improve the washing production efficiency, it is preferable that, as shown in fig. 1, the third continuous reaction unit 30 further includes a buffer tank 33, and the buffer tank 33 is connected and disposed between the first cylindrical continuous reactor 32 and the inlet of the organic phase. By providing the buffer tank 33, the organic phase can be washed again when accumulated to a certain amount, thereby improving the utilization rate and washing amount of the washing liquid.
In one embodiment of the present application, as shown in fig. 1, the second serialization reaction unit 20 includes a second coil type continuous reactor 22, a lithiation reagent supply apparatus 21, a third coil type continuous reactor 24, and an aldehydization reagent supply apparatus 23, the second coil type continuous reactor 22 has a hydroxyl group-protecting reaction product inlet, a lithiation reagent inlet, and a lithiation product outlet, and the hydroxyl group-protecting reaction product inlet is connected to the first serialization reaction unit 10; the lithiation reagent supply device 21 is connected with the lithiation reagent inlet; the third coil type continuous reactor 24 is provided with a lithiation product inlet, an aldehydization reagent inlet and a lithiation aldehydization product outlet, the lithiation product inlet is connected with the lithiation product outlet, and the lithiation aldehydization product outlet is connected with the third continuous reaction unit 30; the aldehydic reagent supply 23 is connected to the aldehydic reagent inlet. By using the second continuous reaction unit 20, the lithiation reagent and the hydroxyl protection reaction product are subjected to lithiation reaction in the second coil type continuous reactor 22, and the lithiation product after lithiation directly enters the third coil type continuous reactor 24 to be subjected to hydroformylation, so that lithiation and hydroformylation are separately and continuously performed, and the utilization rate of the material is higher. In addition, the second coiled continuous reactor 22 is preferably provided with a second heat exchange jacket, the third coiled continuous reactor 24 is preferably provided with a third heat exchange jacket, and the heat exchange jackets are used for controlling the temperature of the second coiled continuous reactor 22 and the temperature of the third coiled continuous reactor 24, so that the heat exchange jackets are simple in structure, and the heat exchange is uniform.
In another embodiment of the present application, as shown in fig. 1, the first continuous reaction unit 10 comprises a first coiled continuous reactor 13, a resorcinol solution supply device 11 and an ethyl vinyl ether solution supply device 12, the first coiled continuous reactor 13 has a reaction material inlet and a hydroxyl protecting reaction product outlet, the hydroxyl protecting reaction product outlet is connected with a second continuous reaction unit 20, and the first coiled continuous reactor 13 is preferably provided with a first heat exchange jacket; the resorcinol solution supply device 11 is connected with the reaction material inlet; an ethyl vinyl ether solution supply 12 is connected to the reactant inlet. Resorcinol and ethyl vinyl ether advance in the interior limit reaction of first coil pipe formula continuous reactor 13 simultaneously, because the coil pipe cross-sectional area is less for material wherein is heated comparatively evenly, and the contact effect of material has obtained improving, consequently makes the material of same weight, reaction time in the device of this application has shortened for the reaction time in the current batch reaction device.
In order to control the product quality of each reaction unit, it is preferable that a sampling valve is provided in a connection line between the first continuous reaction unit 10, the second continuous reaction unit 20, and the third continuous reaction unit 30. The products of the first continuous reaction unit 10, the second continuous reaction unit 20 and the third continuous reaction unit 30 are detected through sampling valves, and the material flow rate and the reaction temperature are adjusted in time as necessary according to the detection result, so that the conversion rate of the raw materials and the product quality are ensured.
In another exemplary embodiment of the present application, there is provided a use of the apparatus for continuously producing 2, 6-dihydroxybenzaldehyde according to any one of the above in the continuous production of 2, 6-dihydroxybenzaldehyde.
When the device is used for preparing the 2, 6-dihydroxybenzaldehyde, the reaction time of hydroxyl protection reaction and deprotection in the synthetic route can be greatly shortened. And the continuous reaction units are directly connected, the product system obtained by each continuous reaction unit can enter the next continuous reaction unit without post-treatment, and the reaction of each step is carried out simultaneously after the device is operated, so that the overall production efficiency is improved. In conclusion, when the device is applied to the preparation of the 2, 6-dihydroxybenzaldehyde, the reaction time is shortened, and the intermediate purification treatment is not needed, so that compared with the batch process, the device cost can be greatly saved, the production efficiency is greatly improved, and the industrial scale-up production of the 2, 6-dihydroxybenzaldehyde is more facilitated.
In one embodiment, the application comprises: carrying out hydroxyl protection reaction on resorcinol and ethyl vinyl ether in a first continuous reaction unit 10 to obtain a hydroxyl protection product system; sequentially carrying out lithiation and hydroformylation reactions on the hydroxyl protection product system under the action of a lithiation reagent and an hydroformylation reagent in the second continuous reaction unit 20 to obtain a lithiation and hydroformylation product system; carrying out hydroxyl protecting group removal treatment on the lithiated aldehyde alkylation product system in a first cylindrical continuous reactor 32 by using a deprotection agent to obtain an organic phase containing 2, 6-dihydroxybenzaldehyde; the organic phase is washed in a second cylindrical continuous reactor 42 with a detergent and optionally an organic solvent to obtain a washed organic phase. The application of the method converts the existing batch into a continuous process by a three-step method, and the next step can be directly carried out without post-treatment among the steps, so that the production efficiency is improved. The resorcinol and the ethyl vinyl ether can be added into the first continuous reaction unit 10 in a solution manner as in the prior art, for example, a polar solvent such as tetrahydrofuran is used for dissolving to form a corresponding solution. Preferably, the lithiation reagent is butyl lithium, and the hydroformylation reagent is dimethylformamide so as to ensure the stability of the reaction. The deprotecting agent is preferably an inorganic strong acid, and more preferably a dilute hydrochloric acid, a dilute sulfuric acid, or a dilute nitric acid. In addition, the washing process may use water as a detergent, and it is preferable that the detergent is a salt solution or an aqueous solution of sodium bicarbonate in order to improve washing efficiency. The organic solvent is selected from 2, 6-dihydroxy benzaldehyde with good solubility and easy volatilization during concentration, and preferably is one of methyl tert-butyl ether, ethyl acetate and 2-methyl tetrahydrofuran
The continuous reaction enables heat generated by materials participating in the reaction in unit time to be easily conducted out, so that the reaction temperature of each reaction is further expanded, and in order to improve the reaction speed of the hydroxyl protection reaction and reduce the occurrence of side reactions, the temperature of the hydroxyl protection reaction is preferably 30-45 ℃, and more preferably 30-35 ℃. The temperature of the lithiation hydroformylation reaction is preferably-30 to 25 ℃, the temperature of the lithiation hydroformylation reaction is more preferably-20 to-15 ℃ in order to improve the yield of a target product in the lithiation hydroformylation reaction, and the temperature of the lithiation hydroformylation reaction is preferably 5 to 25 ℃ in order to reduce the utilization of heat energy and reduce the cost. In order to increase the rate of the hydroxyl-protecting group-removing treatment, the temperature of the hydroxyl-protecting group-removing treatment is preferably 30 to 45 ℃.
In one embodiment of the present invention, based on the characteristics of the first continuous reaction unit 10, the reaction time of resorcinol and ethyl vinyl ether is shortened, and in order to improve the production efficiency, the retention time of resorcinol and ethyl vinyl ether in the first continuous reaction unit 10 is preferably 20-180 min; based on the characteristics of the first cylindrical continuous reactor 32, the reaction time of deprotection is shortened, and in order to improve the production efficiency, the retention time of the deprotection agent and the lithiation aldehyde alkylation product in the first cylindrical continuous reactor 32 is preferably 20-180 min.
The advantageous effects of the present application will be further described below with reference to examples and comparative examples.
The preparation of 2, 6-dihydroxybenzaldehyde was carried out according to the above route with the apparatus shown in FIG. 1, wherein the molar ratio of resorcinol to ethyl vinyl ether was 1: 3, the molar ratio of resorcinol to butyl lithium is 1: 1.4, the molar ratio of resorcinol to dimethylformamide is 1: 3.5H in Resorcinol and Dilute hydrochloric acid+In a molar ratio of 1: 4.
the tetrahydrofuran solution of resorcinol and the tetrahydrofuran solution of ethyl vinyl ether are continuously fed into a first coil type continuous reactor 13, and the temperature T of the first coil type continuous reactor 13 is controlled by a first heat exchange jacket1To carry out hydroxyl protecting reaction with retention time t1To obtain a hydroxyl protection product system; the hydroxyl-protected product system and butyl lithium are continuously fed into a second coil continuous reactor 22, and the temperature T of the second coil continuous reactor 22 is controlled by a second heat exchange jacket2To carry out lithiation reaction with retention time t2The obtained lithiation product system and dimethylformamide continuously enter a third coil type continuous reactor 24, and the temperature T of the third coil type continuous reactor 24 is controlled by a third heat exchange jacket3To carry out an aldolization reaction with a residence time t3(ii) a The obtained lithiation aldehyde-based product system enters from the lower part of the first cylindrical continuous reactor 32, dilute hydrochloric acid enters from the upper part of the first cylindrical continuous reactor 32, and the two are in countercurrent contact in the first cylindrical continuous reactor 32 to carry out deprotection reaction, so that an organic phase and a water phase containing 2, 6-dihydroxy benzaldehyde are obtained and layered, wherein the temperature of the deprotection reaction is T4Residence time of t4Organic containing 2, 6-dihydroxybenzaldehydeThe upper phase and the lower phase; the organic phase enters from the lower part of the second cylindrical continuous reactor 42, the methyl tert-butyl ether enters from the lower part of the second cylindrical continuous reactor 42 and the inlet is positioned below the inlet of the organic phase, the salt water enters from the upper part of the second cylindrical continuous reactor 42, and the three are washed in the second cylindrical continuous reactor 42 in a countercurrent contact manner, wherein the volume ratio of the organic phase, the methyl tert-butyl ether and the salt water is 5:2:2 (calculated by the mass of the resorcinol, such as 1g of the resorcinol, 5mL of the organic phase, 2mL of the methyl tert-butyl ether and 2mL of the salt water), the organic phase and the water phase which are separated after washing are obtained, and the residence time is t5The organic phase is above and the aqueous phase below and the organic phase contains 2, 6-dihydroxybenzaldehyde. And concentrating and replacing the washed organic phase with an acetonitrile system, and finally crystallizing in acetonitrile to obtain the product 2, 6-dihydroxy benzaldehyde.
The content of resorcinol in the tetrahydrofuran solution of resorcinol is 30%, the content of ethyl vinyl ether in the tetrahydrofuran solution of ethyl vinyl ether is 80 wt%, the concentration of butyl lithium is 2.0M, the concentration of dilute hydrochloric acid is 3M, and the concentration of salt water is 20 wt%. The flow rate was adjusted by the respective supply means in each example to control the residence time in each continuous reactor, specifically, the process parameters such as temperature, residence time, etc. and the yield of each reactor in each example are shown in table 1.
TABLE 1
The same materials as those in the previous embodiment are used in the batch reaction device shown in Table 2 to prepare 2, 6-dihydroxybenzaldehyde, wherein the temperature of the hydroxyl protection reaction is 20-25 ℃, the temperature of the lithiation hydroformylation reaction is-10-0 ℃, and the temperature of the deprotection reaction is 20-25 ℃.
TABLE 2
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
when the device is used for preparing the 2, 6-dihydroxybenzaldehyde, the reaction time of hydroxyl protection reaction and deprotection in the synthetic route can be greatly shortened. And the continuous reaction units are directly connected, the product system obtained by each continuous reaction unit can enter the next continuous reaction unit without post-treatment, and the reaction of each step is carried out simultaneously after the device is operated, so that the overall production efficiency is improved. In conclusion, when the device is applied to the preparation of the 2, 6-dihydroxybenzaldehyde, the reaction time is shortened, and the intermediate purification treatment is not needed, so that compared with the batch process, the device cost can be greatly saved, the production efficiency is greatly improved, and the industrial scale-up production of the 2, 6-dihydroxybenzaldehyde is more facilitated.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (28)
1. An apparatus for continuously preparing 2, 6-dihydroxybenzaldehyde, characterized in that it comprises a first continuous reaction unit (10) for hydroxyl protection reaction, a second continuous reaction unit (20) for lithiation hydroformylation, and a third continuous reaction unit (30) for deprotection reaction, which are connected in series in this order, said third continuous reaction unit (30) comprising:
a first columnar continuous reactor (32) which is connected with the second continuous reaction unit (20) and is used for performing deprotection treatment on the lithiated hydroformylation product and simultaneously performing liquid separation to obtain an organic phase and an aqueous phase containing 2, 6-dihydroxy benzaldehyde,
the first cylindrical continuous reactor (32) is provided with a first stirrer to stir the materials in the first cylindrical continuous reactor (32) during deprotection treatment and liquid separation,
the third continuous reaction unit (30) further comprises:
a deprotecting agent supply device (31), wherein the first cylindrical continuous reactor (32) is provided with a deprotecting agent inlet and a lithiated hydroformylation product inlet, the deprotecting agent supply device (31) is connected with the deprotecting agent inlet, the lithiated hydroformylation product inlet is connected with the second continuous reaction unit (20), the deprotecting agent inlet is arranged at the upper part of the first cylindrical continuous reactor (32), and the lithiated hydroformylation product inlet is arranged at the lower part of the first cylindrical continuous reactor (32),
the apparatus further comprises a continuous washing unit (40), the continuous washing unit (40) comprising a second cylindrical continuous reactor (42), the second cylindrical continuous reactor (42) being connected to the first cylindrical continuous reactor (32) for washing the organic phase with a washing liquid.
2. The apparatus according to claim 1, wherein the second cylindrical continuous reactor (42) is configured with a second agitator to agitate the material within the second cylindrical continuous reactor (42) during the washing process.
3. The device according to claim 1, wherein the continuous washing unit (40) further comprises:
a scrubbing liquid supply (41), the second cylindrical continuous reactor (42) having a scrubbing liquid inlet and an organic phase inlet, the scrubbing liquid supply (41) being connected to the scrubbing liquid inlet.
4. The apparatus according to claim 3, wherein the scrubbing liquid inlet is disposed at an upper portion of the second cylindrical continuous reactor (42).
5. The apparatus according to claim 3, wherein the organic phase inlet is arranged in the lower part of the second cylindrical continuous reactor (42).
6. The device according to claim 3, wherein the continuous washing unit (40) further comprises: an organic solvent supply device (43), the second cylindrical continuous reactor (42) further having an organic solvent inlet connected to the organic solvent supply device.
7. The apparatus according to claim 6, wherein the organic solvent inlet is disposed below the organic phase inlet.
8. The apparatus according to claim 3, wherein the third continuous reaction unit (30) further comprises a buffer tank (33), the buffer tank (33) being connectively disposed between the first cylindrical continuous reactor (32) and the organic phase inlet.
9. The apparatus according to claim 1, characterized in that said second continuous reaction unit (20) comprises:
a second coil type continuous reactor (22) having a hydroxyl group protection reaction product inlet, a lithiation reagent inlet and a lithiation product outlet, the hydroxyl group protection reaction product inlet being connected to the first continuous reaction unit (10);
a lithiation reagent supply device (21) connected to the lithiation reagent inlet;
a third coil type continuous reactor (24) which is provided with a lithiation product inlet, an aldehydization reagent inlet and a lithiation aldehydization product outlet, wherein the lithiation product inlet is connected with the lithiation product outlet, and the lithiation aldehydization product outlet is connected with the third continuous reaction unit (30);
an aldehydic reagent supply device (23) connected to the aldehydic reagent inlet.
10. The apparatus according to claim 9, wherein the second coil continuous reactor (22) is provided with a second heat exchange jacket.
11. The apparatus according to claim 9, characterized in that the third coiled continuous reactor (24) is provided with a third heat exchange jacket.
12. The apparatus according to claim 1, characterized in that said first continuous reaction unit (10) comprises:
a first coil type continuous reactor (13) having a reaction material inlet and a hydroxyl group-protected reaction product outlet, the hydroxyl group-protected reaction product outlet being connected to the second continuous reaction unit (20);
a resorcinol solution supply device (11) connected to the reaction material inlet;
and the ethyl vinyl ether solution supply device (12) is connected with the reaction material inlet.
13. The apparatus according to claim 12, characterized in that the first coiled continuous reactor (13) is provided with a first heat exchange jacket.
14. The apparatus according to claim 1, wherein sampling valves are provided on connecting lines between the first continuous reaction unit (10), the second continuous reaction unit (20) and the third continuous reaction unit (30).
15. Use of the apparatus for continuously producing 2, 6-dihydroxybenzaldehyde according to any one of claims 1 to 14 for continuously producing 2, 6-dihydroxybenzaldehyde.
16. The application according to claim 15, wherein the application comprises:
carrying out hydroxyl protection reaction on resorcinol and ethyl vinyl ether in the first continuous reaction unit (10) to obtain a hydroxyl protection product system, wherein the temperature of the hydroxyl protection reaction is 30-45 ℃;
sequentially carrying out lithiation and hydroformylation reaction on the hydroxyl protection product system in a second continuous reaction unit (20) under the action of a lithiation reagent and an hydroformylation reagent to obtain a lithiation and hydroformylation product system, wherein the hydroformylation reagent is dimethylformamide, and the temperature of the lithiation and hydroformylation reaction is-30-25 ℃;
carrying out hydroxyl protecting group removal treatment on the lithiated aldehyde alkylation product system in a first cylindrical continuous reactor (32) by using a deprotection agent to obtain an organic phase containing the 2, 6-dihydroxybenzaldehyde, wherein the temperature of the hydroxyl protecting group removal treatment is 30-45 ℃;
washing the organic phase in a second cylindrical continuous reactor (42) with a detergent to obtain a washed organic phase.
17. The application according to claim 15, wherein the application comprises:
carrying out hydroxyl protection reaction on resorcinol and ethyl vinyl ether in the first continuous reaction unit (10) to obtain a hydroxyl protection product system, wherein the temperature of the hydroxyl protection reaction is 30-45 ℃;
sequentially carrying out lithiation and hydroformylation reaction on the hydroxyl protection product system in a second continuous reaction unit (20) under the action of a lithiation reagent and an hydroformylation reagent to obtain a lithiation and hydroformylation product system, wherein the hydroformylation reagent is dimethylformamide, and the temperature of the lithiation and hydroformylation reaction is-30-25 ℃;
carrying out hydroxyl protecting group removal treatment on the lithiated aldehyde alkylation product system in a first cylindrical continuous reactor (32) by using a deprotection agent to obtain an organic phase containing the 2, 6-dihydroxybenzaldehyde, wherein the temperature of the hydroxyl protecting group removal treatment is 30-45 ℃;
the organic phase is washed in a second cylindrical continuous reactor (42) with a detergent and an organic solvent to obtain a washed organic phase.
18. Use according to claim 16 or 17, wherein said resorcinol and ethyl vinyl ether are both added to said first continuous reaction unit (10) in solution.
19. The use according to claim 16 or 17, wherein the temperature of the hydroxyl protection reaction is 30 to 35 ℃.
20. Use according to claim 16 or 17, wherein the lithiating agent is butyl lithium.
21. The use according to claim 16 or 17, wherein the temperature of the lithiation hydroformylation reaction is-20 to-15 ℃.
22. The use according to claim 16 or 17, wherein the temperature of the lithiation hydroformylation reaction is 5 to 25 ℃.
23. Use according to claim 16 or 17, wherein the deprotecting agent is a strong inorganic acid.
24. Use according to claim 23, wherein the deprotecting agent is dilute hydrochloric acid, dilute sulfuric acid or dilute nitric acid.
25. Use according to claim 16 or 17, wherein the detergent is a saline solution or an aqueous sodium bicarbonate solution.
26. The use according to claim 17, wherein the organic solvent is any one of methyl tert-butyl ether, ethyl acetate, and 2-methyltetrahydrofuran.
27. Use according to claim 16 or 17, wherein the retention time of the resorcinol and the ethyl vinyl ether in the first continuous reaction unit (10) is 20 to 180 min.
28. Use according to claim 16 or 17, wherein the retention time of the deprotecting agent and the lithiated hydroformylation product in the first cylindrical continuous reactor (32) is 20 to 180 min.
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