CN117003655A - Synthesis method of tranexamic acid - Google Patents

Synthesis method of tranexamic acid Download PDF

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Publication number
CN117003655A
CN117003655A CN202310948124.1A CN202310948124A CN117003655A CN 117003655 A CN117003655 A CN 117003655A CN 202310948124 A CN202310948124 A CN 202310948124A CN 117003655 A CN117003655 A CN 117003655A
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catalyst
reaction
acid
reactor
raney
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刘晓然
张少春
王喜成
牟新东
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Shanghai Suntian Technology Co ltd
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Shanghai Suntian Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/22—Preparation of carboxylic acid nitriles by reaction of ammonia with carboxylic acids with replacement of carboxyl groups by cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/303—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by hydrogenation of unsaturated carbon-to-carbon bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a method for synthesizing tranexamic acid. The method takes terephthalic acid/terephthalic acid ester as a raw material, and synthesizes tranexamic acid through the steps of hydrogenation, ammoniation dehydration, hydrolysis, hydrogenation and the like. The method for synthesizing the tranexamic acid has the advantages of low raw material cost, simple process, green route, less pollution in the reaction process, continuous operation and high efficiency.

Description

Synthesis method of tranexamic acid
Technical Field
The invention relates to the field of pharmaceutical chemistry synthesis, in particular to a synthesis method of tranexamic acid.
Background
Tranexamic acid is an antiplasmin drug and is mainly used for hemostasis in clinic. In recent years, the skin beauty field has been studied deeply, and it is proved that tranexamic acid has the functions of reducing melanin generation, anti-inflammatory, anti-allergic reaction, anti-natural skin aging and photo-aging, and can be used for treating various skin diseases such as chloasma, post-inflammatory pigmentation, urticaria, angioedema and the like, and the current demand of tranexamic acid at home and abroad is more than thousand tons.
The existing synthesis method of tranexamic acid mainly comprises the steps of preparing tranexamic acid by hydrolysis and ammoniation of p-cyanobenzyl chloride, and preparing tranexamic acid by transposition after benzene ring saturation of the tranexamic acid in a catalytic hydrogenation mode. The price of p-cyanobenzyl chloride is high (> 7 ten thousand yuan per ton), resulting in high synthesis costs. In the process of preparing the tranexamic acid by the hydrogenation of the amino toluene acid, a large amount of sulfuric acid is generally required to be added to improve the concentration of reactants, a platinum black catalyst is generally used as a catalyst, the price is high, and repeated use is required to reduce the cost. The use of a large amount of sulfuric acid in the hydrogenation step requires the addition of a large amount of barium hydroxide to remove residual sulfuric acid in the subsequent indexing step, resulting in a large amount of waste salts generated in the indexing step. The process has higher requirements on equipment, and a large amount of solid waste can be generated in the production process, so that the production cost is higher.
Therefore, the prior synthesis process of tranexamic acid has the problems of high raw material price, high catalyst cost in the hydrogenation process, more waste water and solid waste in the production process, and the like. The processes are all intermittent reactions, and the production efficiency is generally low. There is therefore still a need to develop new legal methods.
Disclosure of Invention
In order to solve the problems involved in the above methods, an object of the present invention is to provide a method for synthesizing tranexamic acid. According to the method, terephthalic acid/terephthalic acid ester is used as a raw material, and the tranexamic acid is synthesized through the steps of adding, ammoniating and dehydrating, hydrogenating, hydrolyzing, transposing and the like under the action of a catalyst. The method for synthesizing the tranexamic acid has the advantages of simple process, easy separation, continuous operation in multiple steps, high yield, reduction of three-waste emission and contribution to industrial production.
In order to achieve the above object of the present invention, the following technical solutions are specifically adopted:
the invention provides a synthesis method of tranexamic acid, which comprises the following steps represented by a reaction formula 1:
(1) Mixing terephthalic acid/terephthalic acid ester with alkali solution, dissolving, introducing into a reactor filled with a catalyst 1 for hydrogenation reaction, and acidifying the obtained product to obtain 1, 4-cyclohexanedicarboxylic acid/1, 4-cyclohexanedicarboxylic acid ester;
(2) Mixing 1, 4-cyclohexanedicarboxylic acid/1, 4-cyclohexanedicarboxylic acid ester with an ammonia source, adding the mixture into a reactor filled with a catalyst 2 for ammonification and dehydration reaction, and allowing a product to enter a storage tank to obtain 1, 4-cyclohexanedicarbonitrile;
(3) Mixing 1, 4-cyclohexanedicarbonitrile with an alkali solution, heating to perform hydrolysis reaction, acidifying after the reaction is finished, and extracting to obtain p-cyano cyclohexanecarboxylic acid;
(4) Mixing cyano-cyclohexanecarboxylic acid with a solvent, introducing the mixture into a reactor filled with a catalyst 3 for hydrogenation reaction, distilling the obtained product to remove the solvent, and rectifying to obtain tranexamic acid;
wherein R is H, C1-C6 alkyl, more preferably C1-C3 alkyl, most preferably methyl, ethyl, n-propyl or isopropyl.
In some embodiments, the catalyst 1 of step (1) is a Raney Ni, raney Co catalyst or a supported metal catalyst, the metal active component M in the supported metal catalyst is selected from one or more of Pd, ru, rh, pt, ni, co, cu, and the catalyst carrier is selected from active carbon and gamma-Al 2 O 3 、SiO 2 、Nb 2 O 5 One or more of zeolite molecular sievesSeed;
preferably, the catalyst 1 in the step (1) is Raney Ni, raney Co or a supported metal catalyst, the active component of the supported catalyst metal is one or more selected from Pd, ru, rh, ni, co, and the catalyst carrier is selected from gamma-Al 2 O 3 、SiO 2 、Nb 2 O 5 One or more of zeolite molecular sieves;
more preferably, the catalyst 1 in the step (1) is Raney Ni, raney Co or a supported metal catalyst, the active component of the supported catalyst metal is one or more selected from Pd, ru, ni, co, and the catalyst carrier is selected from gamma-Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves;
the zeolite molecular sieve is selected from one or more of H-ZSM-5, H-ZSM-35, HY and H beta.
In some embodiments, the base of step (1) is selected from one or both of sodium hydroxide, potassium hydroxide.
In some embodiments, the alkaline solution of step (1) has a mass concentration of 10% to 50% by weight, preferably 10% to 30% by weight, more preferably 15% to 30% by weight.
In some embodiments, the molar ratio of the feedstock terephthalic acid or terephthalic acid to base of step (1) is from 1:2 to 1:6, preferably from 1:2 to 1:4, more preferably from 1:2 to 1:3.
In some embodiments, the reaction temperature of step (1) is 120-250 ℃, preferably 120-220 ℃, more preferably 150-200 ℃.
In some embodiments, the reaction pressure of step (1) is 2-8MPa, preferably 2-6MPa, more preferably 3-5MPa.
Alternatively, step (1) is performed as follows: and mixing terephthalic acid/terephthalic acid ester with an alkali solution in a reaction kettle, adding a catalyst 1, replacing air in the kettle, performing hydrogenation reaction, filtering to remove the catalyst 1 after the reaction is finished, and acidifying to obtain 1, 4-cyclohexanedicarboxylic acid.
In some embodiments, when step (1) uses a reaction vessel as a reactor, the mass ratio of the feedstock to the catalyst is from 100:1 to 100:30, preferably from 100:3 to 100:20, more preferably from 100:5 to 100:15.
In some embodiments, when step (1) uses a fixed bed as the reactor, the feedstock has a mass space velocity of from 0.1 to 5 hours -1 Preferably 0.3-3h -1 More preferably 0.5 to 1.5h -1 。
In some embodiments, the reactor of step (2) is selected from a fixed bed reactor and a fluidized bed reactor.
In some embodiments, the ammonia source of step (2) is selected from one or more of ammonia gas, aqueous ammonia, urea, ammonium carbonate, ammonium bicarbonate.
In some embodiments, the molar ratio of 1, 4-cyclohexanedicarboxylic acid/1, 4-cyclohexanedicarboxylate to the ammonia source of step (2) is in the range of 1:2.0 to 1:20, preferably 1:2.0 to 1:10.0, more preferably 1:2.0 to 1:8.0.
In some embodiments, the catalyst 2 of step (2) is selected from γ -Al 2 O 3 、SiO 2 、SiO 2 -Al 2 O 3 、ZrO 2 、CeO 2 、Nb 2 O 5 One or more of zeolite molecular sieves selected from one or more of H-ZSM-5, H-ZSM-35, HY and hβ.
In some embodiments, the reaction temperature of step (2) is 250-400 ℃, preferably 280-350 ℃, more preferably 290-350 ℃.
In some embodiments, the reaction pressure of step (2) is from 0.1 to 1.0MPa, preferably from 0.1 to 0.5MPa, more preferably from 0.1 to 0.3MPa.
In some embodiments, the feedstock of step (2) has a mass space velocity of from 0.05 to 5 hours -1 Preferably 0.1-3h -1 More preferably 0.1 to 1.0h -1 。
In some embodiments, the base of step (3) is selected from one or more of sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, lithium hydroxide.
In some embodiments, the molar ratio of the base to 1, 4-cyclohexanedicarbonitrile of step (3) is in the range of 1:0.8 to 2:1, preferably 1:0.8 to 1.5:1, more preferably 1:0.9 to 1.2:1.
In some embodiments, the reaction temperature of step (3) is 50 to 200 ℃, preferably 60 to 150 ℃, more preferably 60 to 120 ℃.
In some embodiments, the catalyst 3 of step (4) is a Raney Ni, raney Co catalyst or a supported metal catalyst, wherein the metal active component M in the supported metal catalyst is selected from one or more of Pd, ru, pt, ni, co, and the catalyst support is selected from activated carbon, gamma-Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves, wherein the zeolite molecular sieves are selected from the group consisting of H-ZSM-5, H-ZSM-35, HY, H beta.
In some embodiments, the reaction solvent of step (4) is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane.
In some embodiments, the feedstock of step (4) has a mass concentration of 5 to 40wt%, preferably 10 to 30wt%, more preferably 20 to 30wt%.
In some embodiments, the reaction temperature of step (4) is from 30 to 180 ℃, preferably from 60 to 150 ℃, more preferably from 60 to 130 ℃.
In some embodiments, the reaction pressure of step (4) is from 0.5 to 6MPa, preferably from 1 to 6MPa, more preferably from 2 to 4MPa.
Preferably, step (4) is performed as follows: mixing the cyano-cyclohexanecarboxylic acid, a solvent and the catalyst 3, adding the mixture into a reaction kettle, replacing air in the kettle, introducing hydrogen, heating for hydrogenation reaction, filtering to remove the catalyst after the reaction is finished, distilling to remove the solvent, and rectifying to obtain the tranexamic acid.
In some embodiments, when step (4) uses a reaction vessel as a reactor, the mass ratio of the feedstock to the catalyst is from 100:1 to 100:30, preferably from 100:3 to 100:20, more preferably from 100:3 to 100:15.
In some embodiments, when step (4) uses a fixed bed as the reactor, the feedstock has a mass space velocity of 0.05 to 3 hours -1 Preferably 0.1-3h -1 More preferably 0.1 to 1.0h -1 。
The beneficial effects are that:
the method for synthesizing the tranexamic acid has the advantages of low raw material cost, green reaction route, continuous production in multiple steps, high efficiency and simple process operation. Compared with the traditional method, the method is easy to realize industrial production.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following description will briefly explain the drawings needed in the embodiments or the prior art, and it is obvious that the drawings in the following description are some embodiments of the present invention and that other drawings can be obtained according to these drawings without inventive effort to a person skilled in the art.
FIG. 1 is a chromatographic test result of 1, 4-cyclohexanedicarboxylic acid, which is the product obtained in step 1 of example 1;
FIG. 2 is a graph showing the results of chromatographic detection of 1, 4-cyclohexanedicarbonitrile by the product obtained in step 2 of example 1;
FIG. 3 is a mass spectrum of the product obtained in step 2 of example 1 for 1, 4-cyclohexanedicarbonitrile;
FIG. 4 shows the results of chromatographic detection of cyanocyclohexanecarboxylic acid from the product obtained in step 3 of example 1;
FIG. 5 shows the results of chromatographic detection of tranexamic acid as the product obtained in step 5 of example 1.
Detailed Description
Hereinafter, the present invention will be described in detail. Before the description, it is to be understood that the terms used in this specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description set forth herein is merely a preferred example for the purpose of illustration and is not intended to limit the scope of the invention, so that it should be understood that other equivalents or modifications may be made thereto without departing from the spirit and scope of the invention.
Step (1) in the method for synthesizing tranexamic acid according to the present invention may be carried out in a continuous reactor such as a fixed bed reactor and a fluidized bed reactor, or may be carried out in a batch reactor such as a reaction vessel. Preferably, step (1) is carried out using a continuous reactor, for example a fixed bed reactor.
The alkali in step (1) of the synthesis method according to the present invention is selected from one or both of sodium hydroxide and potassium hydroxide, and the mass concentration of the alkali solution is 10% to 50% by weight, preferably 10% to 30% by weight, more preferably 15% to 30% by weight. Although higher alkali solution concentration is helpful for hydrogenation reaction, too high alkali solution concentration can cause material viscosity to increase, easily cause problems of reaction equipment blockage, material fluidity reduction and the like, and if the alkali solution concentration is too low, the wastewater amount can be increased. When the mass concentration of the alkali solution is controlled within the above range, the reaction economy can be optimally achieved.
The molar ratio of the raw terephthalic acid or terephthalate to the base of step (1) is 1:2 to 1:6, preferably 1:2 to 1:4, more preferably 1:2 to 1:3. When the molar ratio is too high, the amount of waste water increases, and when the molar ratio is too low, the solubility in the raw material becomes poor.
The reaction temperature of step (1) is 120-250 ℃, preferably 120-220 ℃, more preferably 150-200 ℃. Too low a reaction temperature may result in a slow reaction rate, an extended time, and an excessively high reaction rate, but too high a reaction temperature may have higher requirements for heating medium, equipment safety, energy consumption, and the like.
The reaction pressure in step (1) is 2 to 8MPa, preferably 2 to 6MPa, more preferably 3 to 5MPa. Too low a reaction pressure may result in prolonged reaction time or insufficient reaction, and too high a reaction pressure may require high equipment and may result in high cost.
Alternatively, step (1) may also be carried out in a batch reactor, e.g. a reactor vessel, e.g. step (1) is carried out as follows: and mixing terephthalic acid/terephthalic acid ester with an alkali solution in a reaction kettle, adding a catalyst 1, replacing air in the kettle, performing hydrogenation reaction, filtering to remove the catalyst 1 after the reaction is finished, and acidifying to obtain 1, 4-cyclohexanedicarboxylic acid.
When the reaction kettle is used as the reactor in the step (1), the mass ratio of the raw materials to the catalyst is 100:1-100:30, preferably 100:3-100:20, and more preferably 100:5-100:15. Too low a ratio may result in prolonged reaction time or insufficient reaction, and too high a ratio may result in increased catalyst usage and increased costs.
When the fixed bed is used as the reactor in the step (1), the mass space velocity of the raw material is 0.1-5h -1 Preferably 0.3-3h -1 More preferably 0.5 to 1.5h -1 . Where the space velocity is too high, the conversion is reduced, and if the space velocity is too low, the processing capacity of the reactor is wasted. Wherein the mass airspeed calculation formula is as follows:
wherein, the mass flow unit of terephthalic acid/terephthalic ester is g/min, and the mass unit of catalyst is g.
In addition, the product obtained in the step (1) enters a storage tank after condensation and gas-liquid separation, and the pH value of the product in the storage tank is regulated to be 1-2 by hydrochloric acid with the mass percent concentration of 36% to obtain 1, 4-cyclohexanedicarboxylic acid or 1, 4-cyclohexanedicarboxylic ester.
In the step (2) of the method for synthesizing tranexamic acid, the 1, 4-cyclohexanedicarboxylic acid/1, 4-cyclohexanedicarboxylic acid ester obtained in the step (1) is mixed with an ammonia source and then added into a reactor filled with a catalyst 2 for ammonification and dehydration reaction, and the product enters a storage tank to obtain the 1, 4-cyclohexanedicarbonitrile.
Wherein the ammonia source is selected from one or more of ammonia gas, ammonia water, urea, ammonium carbonate and ammonium bicarbonate. However, ammonia or urea is preferable in view of economy and ease of operation.
The molar ratio of 1, 4-cyclohexanedicarboxylic acid/1, 4-cyclohexanedicarboxylate to the ammonia source is from 1:2.0 to 1:20, preferably from 1:2.0 to 1:10.0, more preferably from 1:2.0 to 1:8.0. Too low a ratio (i.e., insufficient ammonia source) can result in reduced reactant conversion with increased byproducts, particularly the inability of both ester groups to be completely substituted with cyano groups, resulting in excessive byproduct p-cyanocyclohexanecarboxylic acid; similarly, too high a ratio (i.e., excessive ammonia source) may cause an increase in side reactions, and the consumption of raw materials is large and the cost is high. The molar ratio of 1, 4-cyclohexanedicarboxylic acid/1, 4-cyclohexanedicarboxylic acid ester to the ammonia source is thus at least 1:2.0, but not higher than 1:20, preferably not higher than 1:10.0, more preferably not higher than 1:8.0.
In some embodiments, the reaction temperature of step (2) is 250-400 ℃, preferably 260-350 ℃, more preferably 280-340 ℃. Too low a reaction temperature can lead to slow reactions and waste of the processing capacity of the reactor; the too high temperature has high requirements on equipment, byproducts are generated, and the yield is reduced.
In some embodiments, the reaction pressure of step (2) is from 0.1 to 2.0MPa, preferably from 0.1 to 1.0MPa, more preferably from 0.1 to 0.6MPa. Too low a reaction pressure may result in a slow reaction time; the requirement on equipment is high due to the excessively high reaction pressure, and the cost becomes high.
In some embodiments, the mass space velocity of the 1, 4-cyclohexanedicarboxylic acid/1, 4-cyclohexanedicarboxylate of step (2) is in the range of from 0.05 to 5 hours -1 Preferably 0.1-3h -1 More preferably 0.1 to 1.0h -1 . The airspeed is too high, and the conversion rate is reduced; the space velocity is too low, which results in waste of the processing capacity of the reactor. Wherein the mass airspeed calculation formula is as follows:
wherein the mass flow unit of the raw material is g/min, and the mass unit of the catalyst is g.
According to the step (3) of the method for synthesizing the tranexamic acid, the 1, 4-cyclohexanedicarbonitrile obtained in the step (2) is mixed with an alkali solution, then heated for hydrolysis reaction, acidified after completion, extracted, combined with an organic phase, evaporated to dryness, and the obtained solid is dried in vacuum to obtain the p-cyano-cyclohexanecarboxylic acid.
Wherein the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide and lithium hydroxide.
The molar ratio of the base to 1, 4-cyclohexanedicarbonitrile of step (3) is from 1:0.8 to 2:1, preferably from 1:0.8 to 1.5:1, more preferably from 1:0.9 to 1.2:1. If the ratio is too low, for example below 1:1, i.e. insufficient base is used, the hydrolysis is insufficient and the reaction of the reactants is incomplete; if the ratio is too high, for example above 5:1, i.e. the alkali is excessive, the reaction by-products increase significantly.
The reaction temperature of step (3) is 50-200 ℃, preferably 60-150 ℃, more preferably 60-120 ℃. Too low a reaction temperature may result in a slow reaction rate, an extended time, and an excessively high reaction rate, but too high a reaction temperature may have higher requirements for heating medium, equipment safety, energy consumption, and the like.
According to the step (4) of the method for synthesizing the tranexamic acid, the p-cyano cyclohexanecarboxylic acid obtained in the step (3) is mixed with a solvent and then introduced into a reactor filled with a catalyst 3 for hydrogenation reaction, a product is condensed and separated from gas and liquid and then is introduced into a storage tank, and the product in the storage tank is distilled to remove the solvent and then is rectified to obtain the tranexamic acid.
Wherein the reaction solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran and 1, 4-dioxane. However, methanol is preferable in view of economy of the reaction.
The mass concentration of the raw material of step (4) is 5 to 40wt%, preferably 10 to 30wt%, more preferably 20 to 30wt%. The concentration of 1, 4-cyclohexanedicarbonitrile as a raw material is too low, for example, less than 5wt%, resulting in insufficient economy of the reaction and too low yield; if the concentration of the starting 1, 4-cyclohexanedicarbonitrile is too high, for example above 40% by weight, the reaction by-products are markedly increased.
In some embodiments, the reaction temperature of step (4) is from 30 to 180 ℃, preferably from 60 to 150 ℃, more preferably from 60 to 130 ℃. Too low a reaction temperature may result in a slow reaction rate, an extended time, and an excessively high reaction rate, but too high a reaction temperature may have higher requirements for heating medium, equipment safety, energy consumption, and the like.
In some embodiments, the reaction pressure of step (4) is from 0.5 to 6MPa, preferably from 1 to 6MPa, more preferably from 2 to 4MPa. Too low a reaction pressure may result in prolonged reaction time or insufficient reaction, and too high a reaction pressure may require high equipment and may result in high cost.
Preferably, step (4) is performed as follows: mixing the cyano-cyclohexanecarboxylic acid, a solvent and the catalyst 3, adding the mixture into a reaction kettle, replacing air in the kettle, introducing hydrogen, heating for hydrogenation reaction, filtering to remove the catalyst after the reaction is finished, distilling to remove the solvent, and rectifying to obtain the tranexamic acid.
Alternatively, step (4) may also be carried out in a batch reactor, e.g. a reactor vessel, e.g. as follows: mixing the cyano-cyclohexanecarboxylic acid, a solvent and the catalyst 3, adding the mixture into a reaction kettle, replacing air in the kettle, introducing hydrogen, heating for hydrogenation reaction, filtering to remove the catalyst after the reaction is finished, distilling to remove the solvent, and rectifying to obtain the tranexamic acid.
When the reaction kettle is used as the reactor in the step (4), the mass ratio of the raw materials to the catalyst is 100:1-100:30, preferably 100:3-100:20, and more preferably 100:3-100:15. When the fixed bed is used as the reactor in the step (4), the mass space velocity of the raw material is 0.05-3h -1 Preferably 0.1-3h -1 More preferably 0.1 to 1.0h -1 . The airspeed is too high, and the conversion rate is reduced; the space velocity is too low, which results in waste of the processing capacity of the reactor. Wherein the mass airspeed calculation formula is as follows:
wherein, the mass flow unit of the p-cyanocyclohexanecarboxylic acid is g/min, and the mass unit of the catalyst is g.
Unless otherwise indicated, all materials, reagents, methods and the like used in the examples are those conventionally used in the art.
In the following examples, deionized water, ni/gamma-Al 2 O 3 ，Ru/γ-Al 2 O 3 ，Ni/SiO 2 ，Pd/SiO 2 Ni/ZSM5 is self-made, terephthalic acid, dimethyl terephthalate, sodium hydroxide, potassium hydroxide, barium hydroxide, methanol,Ethanol and isopropanol were purchased from national pharmaceutical group chemical reagent limited; gamma-Al 2 O 3 And SiO 2 Purchased from Qingdao sea wave silica gel desiccant Co., ltd; H-ZSM-5 series molecular sieves were purchased from Tianjin southbound catalyst Co., ltd; raney Ni catalyst was purchased from Shanghai Kaiki New Material technologies Co., ltd; raney Co catalyst was purchased from Jiangsu Raney Metal technologies Co; high purity nitrogen, high purity ammonia, and high purity hydrogen were purchased from Qingdao de Haiwei technology Co.
In the method for synthesizing the tranexamic acid, terephthalic acid/terephthalate is taken as a raw material, and the tranexamic acid is synthesized through the steps of hydrogenation, ammonification and dehydration, hydrolysis, hydrogenation, transposition and the like under the action of a catalyst. The product obtained in each step was filtered through a 0.22 μm filter and analyzed by liquid chromatography. Liquid chromatography detection conditions: instrument: shimadzu LC-20A, chromatographic column: irinotecan aq C18, mobile phase: water/acetonitrile=4:1, isocratic elution, column flow 0.6ml/min, detector wavelength: 210nm, column temperature 30 ℃. The correlation calculation formula is as follows:
further, in the heterogeneous catalyst according to the present disclosure, a carrier (carrier) on which the bimetallic alloy catalyst is deposited functions to support and disperse the bimetallic alloy catalyst, thereby increasing its surface area, stabilizing the catalyst by preventing a sintering phenomenon, and reducing the price of the bimetallic alloy catalyst. The carrier itself does not have activity, but since it has the above function to affect the activity of the catalyst, even if the same composition is used, the difference in catalyst activity becomes large depending on the degree of metal catalyst loading, and therefore, the selection of the carrier needs to be regarded as very important.
The catalytic activity is affected by factors such as the composition of the metal used as the catalyst, the particle size, the kind of support, and the loading.
In this case, the reactor is not particularly limited in the present invention, and may be any one reactor selected from known batch reactors, semi-batch reactors, continuous stirred tank reactors, plug flow reactors, stationary phase reactors and fluidized bed reactors, or may be a connected mixed reactor of two or more of these reactors.
In addition, the supported catalyst according to the present invention is supported on a carrier (carrier component or carrier), and the carrier on which the metal catalyst is supported supports and disperses the metal catalyst, thereby serving to increase the surface area of the catalyst, stabilize the catalyst by preventing the sintering phenomenon, and reduce the price of the catalyst. The carrier itself is inactive but affects the catalytic activity due to the above-described function, and exhibits a large difference in catalyst activity by how much metal catalyst is supported even when the composition of the catalysts is the same, so the selection of the carrier should be regarded as very important.
The following examples are merely illustrative of embodiments of the present invention and are not intended to limit the invention in any way, and those skilled in the art will appreciate that modifications may be made without departing from the spirit and scope of the invention. Unless otherwise specified, reagents and equipment used in the following examples are commercially available products.
Example 1
1. 10g Ru/gamma-Al were packed in a fixed bed reactor 2 O 3 The catalyst (Ru load is 5 wt%) is heated to 200 ℃ under the flow rate of 50ml/min nitrogen, the back pressure of the system is 4MPa, the catalyst is switched into high-purity hydrogen, the hydrogen flow is 200ml/min, and the catalyst is preparedA mixture of terephthalic acid and 20wt% aqueous sodium hydroxide solution (molar ratio of terephthalic acid to sodium hydroxide is 1:2.2), and the mixture is stirred for 30min to dissolve completely after mixing the two) for 0.1h -1 The product is condensed and gas-liquid separated, then enters a storage tank, concentrated hydrochloric acid (the mass percentage concentration is 36 wt%) is added into the product obtained in the storage tank to regulate the pH of the system to be 1-2, a large amount of white solid is precipitated in the system, the product is filtered and dried in vacuum at 60 ℃ for 6 hours, and then the product 1, 4-cyclohexanedicarboxylic acid is obtained, and the molar yield of the step is 96%.
2. 300g of gamma-Al are introduced into a fluidized bed reactor 2 O 3 (80-120 mesh) catalyst, heating to 330 ℃ under 2L fluidization gas speed, maintaining for 1h to activate the catalyst, and after the catalyst activation is finished, heating for 0.2h -1 Dropwise adding a mixture of 1, 4-cyclohexanedicarboxylic acid and urea (the molar ratio of 1, 4-cyclohexanedicarboxylic acid to urea is 1:3) into the reactor (calculated by 1, 4-cyclohexanedicarboxylic acid), mixing the two, heating to 150 ℃ for melting, then dropwise adding, and separating the product from gas and liquid, and then entering a storage tank for storage. After the reaction is finished, adding ethanol with the mass being 2 times into the product in the storage tank for washing, evaporating the organic phase to dryness to obtain the product of the 1, 4-cyclohexanedicarbonitrile, wherein the molar yield of the step is 83%.
3. 50g of 1, 4-cyclohexanedicarbonitrile and 75g of 20wt% sodium hydroxide solution are added into a 500ml flask, the mixture is stirred and mixed, then the mixture is heated to 90 ℃, the temperature is kept for 12 hours, the temperature is reduced after the reaction is finished, the pH is adjusted to 1-2 by using concentrated hydrochloric acid, the mixture is extracted by 200ml of ethyl acetate for three times, the organic phases are combined and evaporated to dryness, and the obtained solid is dried in vacuum at 60 ℃ for 12 hours to obtain the p-cyano-cyclohexanecarboxylic acid, wherein the molar yield of the step is 71%.
4. 10g of Ni/gamma-Al was packed in a fixed bed reactor 2 O 3 The catalyst (Ni loading is 20wt%) is heated to 80 ℃ under the nitrogen flow rate of 50ml/min, the system back pressure is 2MPa, the catalyst is switched into high-purity hydrogen, the hydrogen flow rate is 200ml/min, and the methanol solution (mass percentage concentration is 20wt%) of the p-cyanocyclohexanecarboxylic acid is added for 0.1h -1 The product is condensed and gas-liquid separated and then enters a storage tank, and the obtained product is distilled to recover methanol to obtain the product tranexamic acid, wherein the molar yield of the step is 95%.
Example 2
1. 10g of Ni/gamma-Al was packed in a fixed bed reactor 2 O 3 The catalyst (Ni loading is 10 wt%) is heated to 200 ℃ under the nitrogen flow rate of 50ml/min, the system back pressure is 4MPa, the high purity hydrogen is switched to, the hydrogen flow rate is 200ml/min, the mixture of terephthalic acid and 20wt% sodium hydroxide aqueous solution (the mole ratio of terephthalic acid to sodium hydroxide is 1:2.2, and the mixture is stirred for 30min to be completely dissolved) is stirred for 0.1h -1 The product is condensed and gas-liquid separated, then enters a storage tank, concentrated hydrochloric acid (the mass percentage concentration is 36 wt%) is added into the product obtained in the storage tank to adjust the pH of the system to 1-2, a large amount of white solid is precipitated in the system, the product is filtered and dried in vacuum at 60 ℃ for 6 hours, and then the product 1, 4-cyclohexanedicarboxylic acid is obtained, and the molar yield of the step is 94%.
2. 300g of SiO was charged into a fluidized-bed reactor 2 (80-120 mesh) catalyst, heating to 330 ℃ under 2L fluidization gas speed, maintaining for 1h to activate the catalyst, and after the catalyst activation is finished, heating for 0.2h -1 Is added dropwise to the reactor at a space velocity of 1, 4-cyclohexanedicarboxylic acidThe mixture of formic acid and urea (the mol ratio of 1, 4-cyclohexanedicarboxylic acid to urea is 1:3), the mixture of the two is heated to 150 ℃ for melting and then is added dropwise, and the product is separated from gas and liquid and then enters a storage tank for storage. After the reaction is finished, adding ethanol with the mass being 2 times into the product in the storage tank for washing, evaporating the organic phase to dryness to obtain the product of the 1, 4-cyclohexanedicarbonitrile, wherein the molar yield of the step is 85%.
3. 50g of 1, 4-cyclohexanedicarbonitrile and 100g of 20wt% potassium hydroxide solution are added into a 500ml flask, stirred and mixed, heated to 90 ℃, kept for 12 hours, cooled after the reaction is finished, and subjected to pH adjustment to 1-2 by using concentrated hydrochloric acid, extracted by 200ml of ethyl acetate three times, organic phases are combined and evaporated to dryness, and the obtained solid is dried in vacuum at 60 ℃ for 12 hours to obtain the p-cyano-cyclohexanecarboxylic acid, wherein the molar yield of the step is 77%.
4. 10g Ru/gamma-Al were packed in a fixed bed reactor 2 O 3 The catalyst (Ru loading is 5 wt%) is heated to 80 ℃ under the nitrogen flow rate of 50ml/min, the system back pressure is 2MPa, the catalyst is switched into high-purity hydrogen, the hydrogen flow rate is 200ml/min, and the methanol solution (the mass percentage concentration is 20 wt%) of the p-cyanocyclohexanecarboxylic acid is added for 0.1h -1 The product is condensed and gas-liquid separated and then enters a storage tank, and the obtained product is distilled to recover methanol to obtain the product tranexamic acid, wherein the molar yield of the step is 97%.
Example 3
1. 10g Pd/SiO was charged into a fixed bed reactor 2 The catalyst (Ni loading is 10 wt%) is heated to 200 ℃ under the nitrogen flow rate of 50ml/min, the system back pressure is 4MPa,switching to high-purity hydrogen with hydrogen flow of 200ml/min, mixing terephthalic acid and 20wt% sodium hydroxide water solution (molar ratio of terephthalic acid to sodium hydroxide is 1:2.2), stirring for 30min to dissolve completely) for 0.1 hr -1 The product is condensed and gas-liquid separated, then enters a storage tank, concentrated hydrochloric acid (the mass percentage concentration is 36 wt%) is added into the product obtained in the storage tank to regulate the pH of the system to be 1-2, a large amount of white solid is precipitated in the system, the product is filtered and dried in vacuum at 60 ℃ for 6 hours, and then the product 1, 4-cyclohexanedicarboxylic acid is obtained, and the molar yield of the step is 92%.
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2. Adding 300g H-ZSM-5 (silica alumina ratio=80, 80-120 mesh) catalyst into a fluidized bed reactor, heating to 330 ℃ under the speed of 2L fluidization gas, maintaining for 1h to activate the catalyst, and after the catalyst activation is finished, performing catalyst activation for 0.2h -1 Dropwise adding a mixture of 1, 4-cyclohexanedicarboxylic acid and urea (the molar ratio of 1, 4-cyclohexanedicarboxylic acid to urea is 1:3) into the reactor (calculated by 1, 4-cyclohexanedicarboxylic acid), mixing the two, heating to 150 ℃ for melting, then dropwise adding, and separating the product from gas and liquid, and then entering a storage tank for storage. After the reaction is finished, adding ethanol with the mass being 2 times into the product in the storage tank for washing, evaporating the organic phase to dryness to obtain the product of the 1, 4-cyclohexanedicarbonitrile, wherein the molar yield of the step is 88%.
3. 50g of 1, 4-cyclohexanedicarbonitrile and 90g of 20wt% sodium hydroxide solution are added into a 500ml flask, the mixture is stirred and mixed, then the mixture is heated to 90 ℃, the temperature is kept for 12 hours, the temperature is reduced after the reaction is finished, the pH is adjusted to 1-2 by using concentrated hydrochloric acid, the mixture is extracted by 200ml of ethyl acetate for three times, the organic phases are combined and evaporated to dryness, and the obtained solid is dried in vacuum at 60 ℃ for 12 hours to obtain the p-cyano-cyclohexanecarboxylic acid, wherein the molar yield of the step is 68%.
4. 10g of Ni/HZSM5 catalyst (the loading of Ni is 20 wt%) is filled in a fixed bed reactor, the temperature is raised to 80 ℃ at the flow rate of 50ml/min of nitrogen, the back pressure of the system is 2MPa, the system is switched to high-purity hydrogen, the flow rate of the hydrogen is 200ml/min, and the methanol solution of the p-cyanocyclohexanecarboxylic acid (the concentration of the mass percent is 20 wt%) is added for 0.1h -1 The product is condensed and gas-liquid separated and then enters a storage tank, and the obtained product is distilled to recover methanol to obtain the product tranexamic acid, wherein the molar yield of the step is 94%.
Example 4
1. 10g Pd/SiO was charged into a fixed bed reactor 2 The catalyst (Pd loading is 5 wt%) is heated to 200 ℃ under the nitrogen flow rate of 50ml/min, the system back pressure is 4MPa, the high purity hydrogen is switched to, the hydrogen flow rate is 200ml/min, the mixture of terephthalic acid and 20wt% sodium hydroxide aqueous solution (the mole ratio of terephthalic acid to sodium hydroxide is 1:2.2, and the mixture is stirred for 30min to be completely dissolved) is stirred for 0.1h -1 The product is condensed and gas-liquid separated, then enters a storage tank, concentrated hydrochloric acid (the mass percentage concentration is 36 wt%) is added into the product obtained in the storage tank to regulate the pH of the system to be 1-2, a large amount of white solid is precipitated in the system, the product is filtered and dried in vacuum at 60 ℃ for 6 hours, and then the product 1, 4-cyclohexanedicarboxylic acid is obtained, and the molar yield of the step is 92%.
2. Adding 300g H-ZSM-5 (silica alumina ratio=80, 80-120 mesh) catalyst into a fluidized bed reactor, heating to 330 ℃ under the speed of 2L fluidization gas, maintaining for 1h to activate the catalyst, and after the catalyst activation is finished, performing catalyst activation for 0.2h -1 Is added dropwise to the reactor at a space velocity of 1, 4-cyclo (calculated as 1, 4-cyclohexanedicarboxylic acid)Hexadicarboxylic acid is introduced into the reactor, ammonia gas (ammonia gas flow rate: 390ml/min, molar ratio of 1, 4-cyclohexanedicarboxylic acid to ammonia gas: 1:3) is introduced, and the product is subjected to gas-liquid separation and then enters a storage tank for storage. After the reaction is finished, adding ethanol with the mass being 2 times into the product in the storage tank for washing, evaporating the organic phase to dryness to obtain the product of the 1, 4-cyclohexanedicarbonitrile, wherein the molar yield of the step is 88%.
3. 50g of 1, 4-cyclohexanedicarbonitrile and 75g of 20wt% sodium hydroxide solution are added into a 500ml flask, the mixture is stirred and mixed, then the mixture is heated to 90 ℃, the temperature is kept for 12 hours, the temperature is reduced after the reaction is finished, the pH is adjusted to 1-2 by using concentrated hydrochloric acid, the mixture is extracted by 200ml of ethyl acetate for three times, the organic phases are combined and evaporated to dryness, and the obtained solid is dried in vacuum at 60 ℃ for 12 hours to obtain the p-cyano-cyclohexanecarboxylic acid, wherein the molar yield of the step is 71%.
4. 10g Pd/SiO was charged into a fixed bed reactor 2 The catalyst (Pd load is 5 wt%) is heated to 80 ℃ under the nitrogen flow rate of 50ml/min, the system back pressure is 2MPa, the catalyst is switched into high-purity hydrogen, the hydrogen flow rate is 200ml/min, and the methanol solution (mass percentage concentration is 20 wt%) of the p-cyanocyclohexanecarboxylic acid is added for 0.1h -1 The product is condensed and gas-liquid separated and then enters a storage tank, and the obtained product is distilled to recover methanol to obtain the product tranexamic acid, wherein the molar yield of the step is 96%.
Example 5
1. 10g of Ni/H-ZSM-5 catalyst (the loading amount of Ni is 20 wt%) is filled in a fixed bed reactor, the temperature is raised to 250 ℃ at the flow rate of 50ml/min of nitrogen, the back pressure of the system is changed to 4MPa, high-purity hydrogen is switched, and the flow rate of the hydrogen is 200ml/min, a mixture of terephthalic acid and 20wt% sodium hydroxide aqueous solution (molar ratio of terephthalic acid to sodium hydroxide is 1:2.2, and the mixture is stirred for 30min to dissolve completely) is added for 0.1h -1 The product is condensed and gas-liquid separated, then enters a storage tank, concentrated hydrochloric acid (the mass percentage concentration is 36 wt%) is added into the product obtained in the storage tank to adjust the pH of the system to 1-2, a large amount of white solid is precipitated in the system, the product is filtered and dried in vacuum at 60 ℃ for 6 hours, and then the product 1, 4-cyclohexanedicarboxylic acid is obtained, and the molar yield of the step is 94%.
2. 300g of SiO was charged into a fluidized-bed reactor 2 -Al 2 O 3 The catalyst (80-120 meshes) is heated to 330 ℃ under the speed of 2L fluidization gas, and is kept for 1h to activate the catalyst, and after the catalyst activation is finished, the catalyst is heated for 0.2h -1 Dropwise adding a mixture of 1, 4-cyclohexanedicarboxylic acid and urea (the molar ratio of 1, 4-cyclohexanedicarboxylic acid to urea is 1:3) into the reactor (calculated by 1, 4-cyclohexanedicarboxylic acid), mixing the two, heating to 150 ℃ for melting, then dropwise adding, and separating the product from gas and liquid, and then entering a storage tank for storage. After the reaction is finished, adding ethanol with the mass of 2 times into the product in the storage tank for washing twice, and evaporating the organic phase to dryness to obtain the product of the 1, 4-cyclohexanedicarbonitrile, wherein the molar yield of the step is 87%.
3. 50g of 1, 4-cyclohexanedicarbonitrile and 75g of 20wt% sodium hydroxide solution are added into a 500ml flask, the mixture is stirred and mixed, then the mixture is heated to 90 ℃, the temperature is kept for 12 hours, the temperature is reduced after the reaction is finished, the pH is adjusted to 1-2 by using concentrated hydrochloric acid, the mixture is extracted by 200ml of ethyl acetate for three times, the organic phases are combined and evaporated to dryness, and the obtained solid is dried in vacuum at 60 ℃ for 12 hours to obtain the p-cyano-cyclohexanecarboxylic acid, wherein the molar yield of the step is 71%.
4. 10g of Ni/gamma-Al was packed in a fixed bed reactor 2 O 3 The catalyst (Ni loading is 20wt%) is heated to 80 ℃ under the nitrogen flow rate of 50ml/min, the system back pressure is 2MPa, the catalyst is switched into high-purity hydrogen, the hydrogen flow rate is 200ml/min, and the methanol solution (mass percentage concentration of 20wt%) of the p-cyanocyclohexanecarboxylic acid is added for 0.3h -1 The product is condensed and gas-liquid separated and then enters a storage tank, and the obtained product is distilled to recover methanol to obtain the product tranexamic acid, wherein the molar yield of the step is 90%.
Example 6
1. 60g of terephthalic acid and 150g of sodium hydroxide solution with the mass percentage concentration of 20wt% are added into a 500ml reaction kettle, after stirring and clearing, 6g of Raney Ni catalyst is added, the reaction kettle is closed, the air in the kettle is replaced by nitrogen, hydrogen is filled to 4MPa, after the reaction kettle is kept for 30min and is not leaked, the temperature is raised to 160 ℃, the reaction is started, the reaction is stopped after the hydrogen is continuously supplemented until the pressure is not continuously reduced, the reaction is cooled and decompressed, after the hydrogen in the kettle is replaced by nitrogen, the product is taken out, the catalyst is removed by filtration, after the pH value is regulated to 1-2 by concentrated hydrochloric acid, the filtration is carried out again, and the solid is dried in vacuum at 60 ℃ for 12h, thus obtaining the 1, 4-cyclohexanedicarboxylic acid.
2. 300g of SiO was charged into a fluidized-bed reactor 2 -Al 2 O 3 The catalyst (80-120 meshes) is heated to 330 ℃ under the speed of 2L fluidization gas, and is kept for 1h to activate the catalyst, and after the catalyst activation is finished, the catalyst is heated for 0.2h -1 1, 4-cyclohexanedicarboxylic acid is added dropwise into the reactor based on the space velocity of 1, 4-cyclohexanedicarboxylic acid, ammonia gas (the molar ratio of the ammonia gas to the 1, 4-cyclohexanedicarboxylic acid is 4:1) is introduced into the system, and the product passes through the gas And (5) separating the liquid and then storing the liquid in a storage tank. After the reaction is finished, adding ethanol with the mass of 2 times into the product in the storage tank for washing twice, and evaporating the organic phase to dryness to obtain the product of the 1, 4-cyclohexanedicarbonitrile, wherein the molar yield of the step is 87%.
3. 50g of 1, 4-cyclohexanedicarbonitrile and 75g of 20wt% sodium hydroxide solution are added into a 500ml flask, the mixture is stirred and mixed, then the mixture is heated to 100 ℃, the temperature is kept for 12 hours, the temperature is reduced after the reaction is finished, the pH is adjusted to 1-2 by using concentrated hydrochloric acid, the mixture is extracted by 200ml of ethyl acetate for three times, the organic phases are combined and evaporated to dryness, and the obtained solid is dried in vacuum at 60 ℃ for 12 hours to obtain the p-cyano-cyclohexanecarboxylic acid, wherein the molar yield of the step is 66%.
4. 10g of Ni/gamma-Al was packed in a fixed bed reactor 2 O 3 The catalyst (Ni loading is 20wt%) is heated to 100 ℃ under the nitrogen flow rate of 50ml/min, the system back pressure is 2MPa, the catalyst is switched into high-purity hydrogen, the hydrogen flow rate is 200ml/min, and the methanol solution (mass percentage concentration is 20wt%) of the p-cyanocyclohexanecarboxylic acid is added for 0.1h -1 The product is condensed and gas-liquid separated and then enters a storage tank, and the obtained product is distilled to recover methanol to obtain the product tranexamic acid, wherein the molar yield of the step is 94%.
Example 7
1. 10g of Ni/HZSM5 catalyst (the loading of Ni is 20 wt%) was charged in a fixed bed reactor, the temperature was raised to 200℃at a nitrogen flow rate of 50ml/min, the system back pressure was changed to 4MPa, high purity hydrogen was used, the hydrogen flow rate was 200ml/min, and a mixture of dimethyl terephthalate and 1, 4-dioxane (the mass percentage concentration was 10 wt%) was fed to the reactor at a rate of 0.1h -1 The product is condensed and gas-liquid separated, then enters a storage tank, and the solvent is distilled off to obtain a pale yellow liquid product, wherein the molar yield of the step is 93%.
2. 30g of gamma-Al are added into a fixed bed reactor 2 O 3 (20-40 mesh) catalyst, heating to 360 deg.C under nitrogen gas flow rate of 100ml/min, holding for 1 hr to activate catalyst, and after catalyst activation is completed, making reaction time be 0.1 hr -1 1, 4-cyclohexanedicarboxylic acid dimethyl ester is added into the reactor, ammonia gas (ammonia gas flow rate is 22ml/min, and the mol ratio of the ammonia gas to the 1, 4-cyclohexanedicarboxylic acid dimethyl ester is 4:1) is continuously introduced into the reactor, and the product is stored in a storage tank after gas-liquid separation. After the reaction is finished, adding 2 times of methylene dichloride into the product in a storage tank for washing twice, and evaporating the organic phase to dryness to obtain the product cyclohexanedicarbonitrile, wherein the molar yield of the step is 90%.
3. 50g of 1, 4-cyclohexanedicarbonitrile and 75g of 20wt% sodium hydroxide solution are added into a 500ml flask, the mixture is stirred and mixed, then the mixture is heated to 70 ℃, the temperature is kept for 12 hours, the temperature is reduced after the reaction is finished, the pH is adjusted to 1-2 by concentrated hydrochloric acid, the mixture is extracted by 200ml of ethyl acetate for three times, the organic phases are combined and evaporated to dryness, and the obtained solid is dried in vacuum at 60 ℃ for 12 hours to obtain the p-cyano-cyclohexanecarboxylic acid, wherein the molar yield of the step is 78%
4. 10g of Ni/gamma-Al was packed in a fixed bed reactor 2 O 3 The catalyst (the loading of Ni is 20 wt%) is heated to 120 ℃ under the nitrogen flow rate of 50ml/min, the back pressure of the system is 2MPa, the catalyst is switched into high-purity hydrogen, the hydrogen flow rate is 200ml/min,methanol solution of p-cyanocyclohexanecarboxylic acid (mass percentage concentration 20 wt%) was added at 0.3h -1 The product is condensed and gas-liquid separated and then enters a storage tank, and the obtained product is distilled to recover methanol to obtain the product tranexamic acid, wherein the molar yield of the step is 97%.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limited thereto. Although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some or all of the technical features thereof, without departing from the spirit and scope of the present invention as defined in the claims; and such modifications or substitutions are intended to be within the scope of the present invention as defined by the claims.

Claims (8)

1. A method for synthesizing tranexamic acid, which comprises the following steps represented by a reaction formula 1:
(1) Mixing terephthalic acid/terephthalic acid ester with alkali solution, dissolving, introducing into a reactor filled with a catalyst 1 for hydrogenation reaction, and acidifying the obtained product to obtain 1, 4-cyclohexanedicarboxylic acid/1, 4-cyclohexanedicarboxylic acid ester;
(2) Mixing 1, 4-cyclohexanedicarboxylic acid/1, 4-cyclohexanedicarboxylic acid ester with an ammonia source, adding the mixture into a reactor filled with a catalyst 2 for ammonification and dehydration reaction, and allowing a product to enter a storage tank to obtain 1, 4-cyclohexanedicarbonitrile;
(3) Mixing 1, 4-cyclohexanedicarbonitrile with an alkali solution, heating to perform hydrolysis reaction, acidifying after the reaction is finished, and extracting to obtain p-cyano cyclohexanecarboxylic acid;
(4) Mixing cyano-cyclohexanecarboxylic acid with a solvent, introducing the mixture into a reactor filled with a catalyst 3 for hydrogenation reaction, distilling the obtained product to remove the solvent, and rectifying to obtain tranexamic acid;
wherein R is H, C1-C6 alkyl, more preferably C1-C3 alkyl, most preferably methyl, ethyl, n-propyl or isopropyl.
2. The synthesis method according to claim 1, wherein the catalyst 1 in the step (1) is Raney Ni, raney Co or a supported metal catalyst, the metal active component M in the supported metal catalyst is one or more selected from Pd, ru, rh, pt, ni, co, cu, and the catalyst carrier is selected from activated carbon and gamma-Al 2 O 3 、SiO 2 、Nb 2 O 5 One or more of zeolite molecular sieves;
preferably, the catalyst 1 in the step (1) is Raney Ni, raney Co or a supported metal catalyst, the active component of the supported catalyst metal is one or more selected from Pd, ru, rh, ni, co, and the catalyst carrier is selected from gamma-Al 2 O 3 、SiO 2 、Nb 2 O 5 One or more of zeolite molecular sieves;
more preferably, the catalyst 1 in the step (1) is Raney Ni, raney Co or a supported metal catalyst, the supported catalyst metal active component is one or more selected from Pd, ru, ni, co, and the catalyst carrier is selected from gamma-Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves;
the zeolite molecular sieve is selected from one or more of H-ZSM-5, H-ZSM-35, HY and H beta.
3. The synthetic method according to claim 1, wherein the base of step (1) is selected from one or both of sodium hydroxide and potassium hydroxide;
preferably, the mass concentration of the alkaline solution of step (1) is 10-50 wt%, preferably 10-30wt%, more preferably 15-30wt%;
preferably, the molar ratio of terephthalic acid or terephthalic acid to base as the starting material in step (1) is from 1:2 to 1:6, preferably from 1:2 to 1:4, more preferably from 1:2 to 1:3;
Preferably, the reaction temperature of step (1) is 120-250 ℃, preferably 120-220 ℃, more preferably 150-200 ℃;
preferably, the reaction pressure of step (1) is from 2 to 8MPa, preferably from 2 to 6MPa, more preferably from 3 to 5MPa.
4. The synthetic method of claim 1, wherein optionally step (1) is performed as follows: mixing terephthalic acid/terephthalic acid ester with alkali solution in a reaction kettle, adding a catalyst 1, replacing air in the kettle, performing hydrogenation reaction, filtering to remove the catalyst 1 after the reaction is finished, and acidifying to obtain 1, 4-cyclohexanedicarboxylic acid;
preferably, when the reaction kettle is used as the reactor in the step (1), the mass ratio of the raw materials to the catalyst is 100:1-100:30, preferably 100:3-100:20, and more preferably 100:5-100:15;
preferably, when step (1) uses a fixed bed as the reactor, the feedstock has a mass space velocity of 0.1 to 5 hours -1 Preferably 0.3-3h -1 More preferably 0.5 to 1.5h -1 。
5. The synthesis process according to claim 1, wherein the reactor of step (2) is selected from the group consisting of a fixed bed reactor and a fluidized bed reactor
Preferably, the ammonia source in the step (2) is selected from one or more of ammonia gas, ammonia water, urea, ammonium carbonate and ammonium bicarbonate;
Preferably, the molar ratio of 1, 4-cyclohexanedicarboxylic acid/1, 4-cyclohexanedicarboxylic acid ester to ammonia source of step (2) is from 1:2.0 to 1:20, preferably from 1:2.0 to 1:10.0, more preferably from 1:2.0 to 1:8.0;
preferably, the catalyst 2 of step (2) is selected from gamma-Al 2 O 3 、SiO 2 、SiO 2 -Al 2 O 3 、ZrO 2 、CeO 2 、Nb 2 O 5 One or more of zeolite molecular sieves selected from one or more of H-ZSM-5, H-ZSM-35, HY and hβ;
preferably, the reaction temperature of step (2) is from 250 to 400 ℃, preferably from 280 to 350 ℃, more preferably from 290 to 350 ℃;
preferably, the reaction pressure of step (2) is from 0.1 to 1.0MPa, preferably from 0.1 to 0.5MPa, more preferably from 0.1 to 0.3MPa;
preferably, the feedstock of step (2) has a mass space velocity of from 0.05 to 5 hours -1 Preferably 0.1-3h -1 More preferably 0.1 to 1.0h -1 。
6. The synthesis method according to claim 1, wherein the base of step (3) is selected from one or more of sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, lithium hydroxide;
preferably, the molar ratio of the base to 1, 4-cyclohexanedicarbonitrile of step (3) is from 1:0.8 to 2:1, preferably from 1:0.8 to 1.5:1, more preferably from 1:0.9 to 1.2:1;
preferably, the reaction temperature of step (3) is 50-200 ℃, preferably 60-150 ℃, more preferably 60-120 ℃.
7. The synthesis method according to claim 1, wherein the catalyst 3 in the step (4) is Raney Ni, raney Co or a supported metal catalyst, wherein the metal active component M in the supported metal catalyst is selected from one or more of Pd, ru, pt, ni, co, and the catalyst carrier is selected from active carbon and gamma-Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves, wherein the zeolite molecular sieves are selected from the group consisting of H-ZSM-5, H-ZSM-35, HY, hβ;
preferably, the reaction solvent of step (4) is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane;
preferably, the mass concentration of the feedstock of step (4) is from 5 to 40wt%, preferably from 10 to 30wt%, more preferably from 20 to 30wt%;
preferably, the reaction temperature of step (4) is from 30 to 180 ℃, preferably from 60 to 150 ℃, more preferably from 60 to 130 ℃;
preferably, the reaction pressure of step (4) is from 0.5 to 6MPa, preferably from 1 to 6MPa, more preferably from 2 to 4MPa.
8. The synthesis method according to claim 1, wherein step (4) is performed as follows: mixing the cyano-cyclohexanecarboxylic acid, a solvent and a catalyst 3, adding the mixture into a reaction kettle, replacing air in the kettle, introducing hydrogen, heating for hydrogenation reaction, filtering to remove the catalyst after the reaction is finished, distilling to remove the solvent, and rectifying to obtain tranexamic acid;
Preferably, when the reaction kettle is used as the reactor in the step (4), the mass ratio of the raw materials to the catalyst is 100:1-100:30, preferably 100:3-100:20, and more preferably 100:3-100:15;
preferably, when step (4) uses a fixed bed as the reactor, the feedstock has a mass space velocity of 0.05 to 3 hours -1 Preferably 0.1-3h -1 More preferably 0.1 to 1.0h -1 。
CN202310948124.1A 2023-07-31 2023-07-31 Synthesis method of tranexamic acid Pending CN117003655A (en)

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