CN117776944A - Synthesis method of tranexamic acid - Google Patents

Synthesis method of tranexamic acid Download PDF

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Publication number
CN117776944A
CN117776944A CN202311621161.8A CN202311621161A CN117776944A CN 117776944 A CN117776944 A CN 117776944A CN 202311621161 A CN202311621161 A CN 202311621161A CN 117776944 A CN117776944 A CN 117776944A
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catalyst
reaction
compound
reactor
supported metal
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刘晓然
蒋士峰
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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Abstract

The invention relates to a method for synthesizing tranexamic acid. According to the method, 4-cyano-cyclohexanecormaldehyde is used as a raw material, and tranexamic acid is synthesized through steps of oxidation/oxidation esterification, 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 is shown in the following reaction formula 1, wherein p-cyanoborobenzyl is mainly used as a raw material, tranexamic acid is prepared by hydrolysis and ammoniation, and tranexamic acid is prepared by saturated benzene rings through catalytic hydrogenation. 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, repeated use is required to reduce the cost, and the catalytic effect is not ideal. The use of large amounts of sulfuric acid in the hydrogenation step requires the addition of large amounts of barium hydroxide to remove residual sulfuric acid, resulting in a large amount of waste salts generated in the metathesis step. The process route 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 increased.
In summary, the existing synthesis process of tranexamic acid has the problems of high raw material price, high catalyst cost in the hydrogenation process, more wastewater and solid waste in the production process, high comprehensive cost and the like. In addition, each step in the reaction formula 1 is a batch reaction, 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 in the prior art, the invention aims to provide a method for synthesizing tranexamic acid. The method takes 4-cyano cyclohexane formaldehyde as a raw material, and synthesizes the tranexamic acid through the steps of oxidization/oxidization esterification, hydrogenation 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 discharge and contribution to industrial production.
In order to achieve the above object of the present invention, according to one aspect of the present invention, there is provided a method for synthesizing tranexamic acid represented by the following reaction formula 2, comprising the steps of:
(1) Mixing the compound I (4-cyanocyclohexane formaldehyde) with a solvent, respectively introducing the mixture and air into a reactor filled with a catalyst 1 for oxidation reaction, distilling a product to remove the solvent to obtain a compound II, and introducing the obtained product into a storage tank;
(2) Adding the compound II into a reactor filled with a catalyst 2 to carry out hydrogenation reaction to obtain a compound III;
(3) Mixing the compound III with an alkali solution, heating for reaction, and regulating pH after the reaction is finished to obtain a compound IV (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 in step (1) is a supported metal catalyst, the metal active component M in the supported metal catalyst is selected from one or more of Pd, ru, pt, au, and the catalyst support is selected from γ -Al 2 O 3 、SiO 2 、TiO 2 、ZnO、MgO、CeO 2 One or more of hydrotalcite;
preferably, the catalyst 1 in the step (1) is a supported metal catalyst, the metal active component in the supported metal catalyst is selected from one or more of Pd, au and Pt, and the catalyst carrier is selected from gamma-Al 2 O 3 、ZnO、MgO、CeO 2 One or more of hydrotalcite;
more preferably, the catalyst 1 of step (1) is a supported metal catalyst,the metal active component in the supported metal catalyst is one or more selected from Pd and Au, and the catalyst carrier is selected from ZnO, mgO, ceO 2 One or more of hydrotalcite.
In some embodiments, the supported metal catalyst in step (1) comprises from 0.1% to 30%, preferably from 0.2% to 20%, more preferably from 0.5% to 10% active component based on the total weight of the catalyst; the carrier is 70% to 99.9%, preferably 80% to 99.8%, more preferably 90% to 99.5%.
In some embodiments, the solvent of step (1) is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol.
In some embodiments, the molar ratio of compound I to air of step (1) is from 1:5 to 1:30.
In some embodiments, the reaction temperature of step (1) is 40-150 ℃ and the reaction pressure is 0.1-5MPa.
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 catalyst 2 of step (2) 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;
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 supported metal catalyst in step (2) comprises from 0.1% to 50%, preferably from 0.2% to 40%, more preferably from 0.5% to 30% active component based on the total weight of the catalyst; the carrier is 50% to 99.9%, preferably 60% to 99.8%, more preferably 70% to 99.5%.
In some embodiments, the reaction temperature of step (2) is 50-250 ℃, preferably 60-200 ℃, more preferably 80-150 ℃.
In some embodiments, the reaction pressure of step (2) is from 1 to 8MPa, preferably from 1 to 6MPa, more preferably from 2 to 5MPa.
In some embodiments, the solvent of step (2) is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol.
In some embodiments, when step (2) is performed in a batch reactor, the mass ratio of catalyst 1 to compound II is from 1:100 to 30:100, preferably from 3:100 to 20:100, more preferably from 5:100 to 15:100.
In some embodiments, when step (2) is performed in a continuous reactor, the mass space velocity of compound II is from 0.1 to 5 hours -1 Preferably 0.1-3h -1 More preferably 0.1 to 1.0h -1 。
In some embodiments, when step (2) is performed in a continuous reactor, the molar ratio of compound II to hydrogen is from 1:5 to 1:50, preferably from 1:5 to 1:30, more preferably from 1:5 to 1:10.
In some embodiments, the base in step (3) comprises one or more of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, strontium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, strontium carbonate.
In some embodiments, the mass ratio of base to compound III in step (3) is 1:1 to 5:1, preferably 1:1 to 3:1, more preferably 1:1 to 2:1.
In some embodiments, the reaction temperature of step (3) is 60 to 200 ℃, preferably 80 to 160 ℃, more preferably 90 to 150 ℃.
In some embodiments, the compound I described in step (1) can be synthesized by the following method:
(i) Mixing a compound V (1, 3-butadiene), a compound VI (acrylonitrile) and a polymerization inhibitor to perform Diels-Alder reaction to synthesize a compound VII (4-cyano-1-cyclohexene);
(ii) The compound VII is subjected to carbonylation reaction in the presence of Rh-based catalyst 3 to synthesize compound I (4-cyanocyclohexane formaldehyde).
In some embodiments, the molar ratio of compound V to compound VI in step (i) is from 1:10 to 10:1. In some embodiments, the reaction temperature in step (i) is from 80 to 250 ℃, preferably from 100 to 200 ℃, more preferably from 110 to 170 ℃.
In some embodiments, catalyst 3 in step (ii) is a Rh catalyst precursor and an organophosphine ligand.
In some embodiments, the molar ratio of compound VI to Rh catalyst precursor and organophosphine ligand in step (ii) is from 100 to 100000:1:1 to 10, preferably from 500 to 10000:1:2 to 6, more preferably from 300 to 5000:1:3 to 4.
In some embodiments, the Rh catalyst precursor in step (ii) is one of rhodium dicarbonyl acetylacetonate, rhodium monochlorodicarbonyl dimer, rhodium bis (norbornadiene) tetrafluoroborate, or rhodium bis (1, 5-cyclooctadiene) chloride, and the organophosphine ligand is one of tris (2, 4, 6-trimethylphenyl) phosphine, tri-o-tolylphosphine, or triphenylphosphine.
In some embodiments, the reaction temperature in step (ii) is 50 to 180 ℃, preferably 60 to 150 ℃, more preferably 70 to 120 ℃.
In some embodiments, H in step (ii) 2 The ratio of the pressure to the CO was 1:1.
In some embodiments, the reaction pressure in step (ii) is from 1 to 10MPa, preferably from 1 to 8MPa, more preferably from 2 to 6MPa.
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 shows the results of chromatographic detection of tranexamic acid as the product obtained in example 7.
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.
In a first aspect, the present application provides a method for synthesizing tranexamic acid, the method comprising the steps of:
(1) Mixing the compound I (4-cyanocyclohexane formaldehyde) with a solvent, respectively introducing the mixture and air into a reactor filled with a catalyst 1 for oxidation reaction, distilling a product to remove the solvent to obtain a compound II, and introducing the obtained product into a storage tank;
(2) Adding the compound II into a reactor filled with a catalyst 2 to carry out hydrogenation reaction to obtain a compound III;
(3) Mixing the compound III with an alkali solution, heating for reaction, and regulating pH after the reaction is finished to obtain a compound IV (tranexamic acid);
wherein R is H, C1-C6 alkyl, more preferably C1-C3 alkyl, most preferably methyl, ethyl, n-propyl or isopropyl.
Step (1) may be carried out in a continuous reactor such as a fixed bed reactor or 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 batch reactor, e.g. a reactor vessel.
The solvent in the step (1) is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, isobutanol and tertiary butanol.
The molar ratio of the compound I in the step (1) to air is 1:5-1:30. Too high a molar ratio will increase the system pressure and too low a molar ratio will result in a low conversion of compound I and incomplete oxidation reactions.
The reaction temperature in the step (1) is 40-150 ℃, and the reaction pressure is 0.1-5MPa. 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. 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.
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 flow unit of the compound I is g/min, and the mass unit of the catalyst is g.
Step (2) may be performed in a continuous reactor such as a fixed bed reactor or a fluidized bed reactor, or may be performed in a batch reactor such as a reaction vessel. Preferably, step (2) is carried out using a continuous reactor, for example a fixed bed reactor.
The reaction temperature of step (2) is 50-250 ℃, preferably 60-200 ℃, more preferably 80-150 ℃. 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 (2) is 1 to 8MPa, preferably 1 to 6MPa, more preferably 2 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.
When step (2) is carried out in a batch reactor, the mass ratio of catalyst 1 to compound II is from 1:100 to 30:100, preferably from 3:100 to 20:100, more preferably from 5:100 to 15:100. 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 step (2) is carried out in a continuous reactor, the mass space velocity of the compound II is from 0.1 to 5 hours -1 Preferably 0.1-3h -1 More preferably 0.1 to 1.0h -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 rate unit of the compound II is g/min, and the mass unit of the catalyst is g.
The alkali in the step (3) is selected from one or more of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, strontium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, magnesium carbonate and strontium carbonate.
The ratio of base to compound III of step (3) is from 1:1 to 5:1, preferably from 1:1 to 3:1, more preferably from 1:1 to 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 from 90 to 200 ℃, preferably from 90 to 180 ℃, more preferably from 90 to 150 ℃. 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 combination with the first aspect, the compound I may be prepared by the following steps:
(i) Mixing a compound V (1, 3-butadiene), a compound VI (acrylonitrile) and a polymerization inhibitor, and then heating to 80-250 ℃ to perform Diels-Alder reaction for 0.5-3 h to prepare a compound VII (4-cyano-1-cyclohexene);
(ii) Compound VII was carbonylated in the presence of Rh-based catalyst 3 to synthesize Compound I (4-cyanocyclohexane Formaldehyde.)
The molar ratio of the compound V to the compound VI in the step (i) is 1:10-10:1. Too low a molar ratio results in serious waste of acrylonitrile, and too high a molar ratio results in increased by-products, mainly by-products of 1, 3-butadiene dimerization product vinylcyclohexene and heavy components.
The reaction temperature in step (i) is 80-250 ℃, preferably 100-200 ℃, more preferably 120-180 ℃. 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 temperature in step (ii) is 50 to 180 ℃, preferably 60 to 150 ℃, more preferably 70 to 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.
H in said step (ii) 2 The ratio of the pressure to the CO was 1:1.
The reaction pressure in step (ii) is 1 to 10MPa, preferably 1 to 8MPa, more preferably 2 to 6MPa. 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.
Unless otherwise indicated, all materials, reagents, methods and the like used in the examples are those conventionally used in the art.
In the examples below, deionized water, pd/hydrotalcite, pd/MgO, au/hydrotalcite, ni/gamma-Al 2 O 3 The Rh catalyst precursor, the organic phosphine ligand and other catalysts are self-made, butadiene, acrylonitrile, sodium hydroxide, potassium hydroxide, barium hydroxide, methanol, ethanol and isopropanol purchased from national pharmaceutical chemicals Co., ltd; 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, air, high purity carbon monoxide, high purity hydrogen were purchased from Qingdao de Hai Wenyujin.
In the method for synthesizing the tranexamic acid, 4-cyano cyclohexane formaldehyde is taken as a raw material, and the tranexamic acid is synthesized through the steps of oxidization/oxidization esterification, hydrogenation and the like under the action of a catalyst. The product obtained after the post-treatment was filtered through a 0.22 μm filter membrane and analyzed and detected 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:
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.
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.
Examples
Preparation of Compound I (4-cyanocyclohexane Formaldehyde)
Example 1
Synthesis of 4-cyano-1-cyclohexene:
100g of acrylonitrile and 0.2g of p-tert-butylcatechol are added into a 500mL stainless steel high-pressure reaction kettle, the air in the kettle is replaced by nitrogen after the reaction kettle is closed, 50g of 1, 3-butadiene is added through a steel bottle, a needle valve is closed, the temperature is heated to 140 ℃ for reaction after heating, the needle valve is used for sampling until the residual amount of the butadiene is less than 0.2%, the total reaction is carried out for 3 hours, unreacted acrylonitrile is removed at 50 ℃ on a rotary evaporator, the vinyl cyclohexene of a butadiene dimerization product is removed at 80 ℃, then the heavy components of the reaction are transferred into a 200mL round bottom flask, the distillation column is decompressed and rectified at 160 ℃, the size of the distillation column is 25mm (ID) multiplied by 40cm (L), the filler is 5mm multiplied by 10mm glass filaments, and 71.6g of 4-cyano-1-cyclohexene can be obtained through rectification, and the yield is 72.3% (based on butadiene). The main by-product of the reaction is vinyl cyclohexene, a 1, 3-butadiene dimerization product, and a heavy component.
Synthesis of 4-cyanocyclohexane-formaldehyde:
50g of 4-cyano-1-cyclohexene, 0.08g of rhodium dicarbonyl acetylacetonate and 0.25g of triphenylphosphine were introduced into a 100mL reactor, and the mixture was treated with N 2 Introducing 2MPa H after replacement deoxidation 2 And 2MPa CO, stirring and reacting for 6 hours at 80 ℃, cooling to room temperature, slowly emptying, and filtering to obtain 59.5g 4-cyanocyclohexane formaldehyde, wherein the yield is 93.0%.
Example 2
Synthesis of 4-cyano-1-cyclohexene:
100g of acrylonitrile and 0.2g of p-tert-butylcatechol are added into a 500mL stainless steel high-pressure reaction kettle, the air in the kettle is replaced by nitrogen after the reaction kettle is closed, 100g of 1, 3-butadiene is added through a steel bottle, a needle valve is closed, the temperature is heated to 160 ℃ for reaction after heating, the residual amount of the butadiene is less than 0.2 percent through the needle valve, the total reaction is carried out for 3 hours, unreacted acrylonitrile is removed at 50 ℃ on a rotary evaporator, the vinyl cyclohexene of a butadiene dimerization product is removed at 80 ℃, then the heavy components of the reaction are transferred into a 300mL round bottom flask, the distillation column is decompressed and rectified at 160 ℃, the size of the distillation column is 25mm (ID) multiplied by 40cm (L), the filler is 5mm multiplied by 10mm glass filaments, and 152.6g of 4-cyano-1-cyclohexene can be obtained through rectification, and the yield is 77.0 percent (based on butadiene). The main by-product of the reaction is vinyl cyclohexene, a 1, 3-butadiene dimerization product, and a heavy component.
Synthesis of 4-cyanocyclohexane-formaldehyde:
50g of 4-cyano-1-cyclohexene, 0.024g of rhodium dicarbonyl acetylacetonate and 0.1g of triphenylphosphine were introduced into a 10mL reaction vessel, and the mixture was treated with N 2 Introducing 2MPa H after replacement deoxidation 2 And 2MPa CO, stirring at 80deg.CThe mixture is stirred for 8 hours, cooled to room temperature, slowly emptied and filtered to obtain 62.1g of 4-cyanocyclohexane formaldehyde with the yield of 97.0 percent.
Example 3
Synthesis of 4-cyano-1-cyclohexene:
100g of acrylonitrile and 0.2g of p-tert-butylcatechol are added into a 250mL stainless steel high-pressure reaction kettle, the air in the kettle is replaced by nitrogen after the reaction kettle is closed, 100g of 1, 3-butadiene is added through a steel bottle, a needle valve is closed, the temperature is heated to 180 ℃ for reaction after heating, the needle valve is closed to sample until the residual amount of the butadiene is less than 0.2%, the total reaction is carried out for 3 hours, unreacted acrylonitrile is removed at 50 ℃ on a rotary evaporator, the vinyl cyclohexene of a butadiene dimerization product is removed at 80 ℃, then the heavy components of the reaction are transferred into a 300mL round bottom flask, the distillation column is decompressed and rectified at 160 ℃, the size of the distillation column is 25mm (ID) multiplied by 40cm (L), the filler is 5mm multiplied by 10mm glass filaments, and 150.0g of 4-cyano-1-cyclohexene can be obtained through rectification, and the yield is 75.7% (based on butadiene). The main by-product of the reaction is vinyl cyclohexene, a 1, 3-butadiene dimerization product, and a heavy component.
Synthesis of 4-cyanocyclohexane-formaldehyde:
into a 300mL reaction vessel were charged 100g of 4-cyano-1-cyclohexene, 0.005g of rhodium dicarbonyl acetylacetonate and 0.02g of triphenylphosphine, using N 2 Introducing 2MPa H after replacement deoxidation 2 And 2MPa CO, stirring and reacting for 24 hours at 100 ℃, cooling to room temperature, slowly emptying, and filtering to obtain 121.0g 4-cyanocyclohexane formaldehyde, wherein the yield is 94.5%.
Example 4
Synthesis of 4-cyano-1-cyclohexene:
100g of acrylonitrile and 0.2g of p-tert-butylcatechol are added into a 250mL stainless steel high-pressure reaction kettle, the air in the kettle is replaced by nitrogen after the reaction kettle is closed, 100g of 1, 3-butadiene is added through a steel bottle, a needle valve is closed, the temperature is heated to 200 ℃ for reaction after heating, the needle valve is closed to sample until the residual amount of the butadiene is less than 0.2%, the total reaction is carried out for 3 hours, unreacted acrylonitrile is removed at 50 ℃ on a rotary evaporator, the vinyl cyclohexene of a butadiene dimerization product is removed at 80 ℃, then the heavy components of the reaction are transferred into a 300mL round bottom flask, the distillation column is decompressed and rectified at 160 ℃, the size of the distillation column is 25mm (ID) multiplied by 40cm (L), the filler is 5mm multiplied by 10mm glass filaments, and 147.0g of 4-cyano-1-cyclohexene can be obtained through rectification, and the yield is 74.2% (based on butadiene). The main by-product of the reaction is vinyl cyclohexene, a 1, 3-butadiene dimerization product, and a heavy component.
Synthesis of 4-cyanocyclohexane-formaldehyde:
110g of 4-cyano-1-cyclohexene, 0.08g of rhodium dicarbonyl acetylacetonate and 0.25g of triphenylphosphine were introduced into a 300mL reactor, and the mixture was treated with N 2 Introducing 1MPa H after replacement deoxidation 2 And 1MPa CO, stirring and reacting for 10 hours at 90 ℃, cooling to room temperature, slowly emptying, and filtering to obtain 131.0g 4-cyanocyclohexane formaldehyde, wherein the yield is 93.0%.
Example 5
Synthesis of 4-cyano-1-cyclohexene:
the reaction was carried out in the same manner as in example 2 except that 1, 3-butadiene was added in 5 batches, and after each batch was reacted to pressure equilibrium, the temperature was lowered and cooled to room temperature, and 20g of 1, 3-butadiene was continuously fed. The reaction mixture was distilled to obtain 175.6g of 4-cyano-1-cyclohexene in a yield of 88.6% (based on butadiene).
Synthesis of 4-cyanocyclohexane-formaldehyde:
130g of 4-cyano-1-cyclohexene, 0.12g of rhodium chlorodicarbonyl dimer and 0.25g of triphenylphosphine were introduced into a 300mL reactor, with N 2 Introducing 1MPa H after replacement deoxidation 2 And 1MPa CO, stirring and reacting for 20h at 90 ℃, cooling to room temperature, slowly emptying, and filtering to obtain 156.0g 4-cyanocyclohexane formaldehyde with the yield of 93.7%.
Example 6
Synthesis of 4-cyano-1-cyclohexene:
the reaction was carried out in the same manner as in example 2 except that 1, 3-butadiene was added to the acrylonitrile liquid heated to 160℃at a rate of 0.5ml/min by a plunger pump until the weight of butadiene added reached 100g, and after the addition was completed, the reaction was continued until the pressure in the reaction vessel was no longer changed to stop the reaction. The reaction mixture was distilled to obtain 179.5g of 4-cyano-1-cyclohexene in a yield of 90.6% (based on butadiene).
Synthesis of 4-cyanocyclohexane-formaldehyde:
110g of 4-cyano-1-cyclohexene, 0.15g of bis (1, 5-cyclooctadiene rhodium chloride) and 0.25g of triphenylphosphine were introduced into a 300mL reactor, with N 2 Introducing 2MPa H after replacement deoxidation 2 And 2MPa CO, stirring and reacting for 20h at 90 ℃, cooling to room temperature, slowly emptying, and filtering to obtain 135.9g 4-cyanocyclohexane formaldehyde, wherein the yield is 96.5%.
Preparation of Compound IV (tranexamic acid)
Example 7
Synthesis of 4-cyanocyclohexane carboxylic acid (ester):
60g of 4-cyanocyclohexane formaldehyde, 120g of methanol and 6g of Pd/hydrotalcite catalyst (Pd load is 5 wt%) are added into a 500ml reaction kettle, the reaction kettle is closed, air is filled to 2MPa, after the reaction kettle is kept for 30min and is not leaked, the temperature is raised to 80 ℃ to start the reaction, the reaction is stopped after the air is continuously supplemented until the pressure is not continuously reduced any more in the reaction process, the temperature is reduced, the pressure is relieved, the product is taken out, the catalyst is removed by filtration, and the organic phase is evaporated to dryness to obtain the product 4-cyanocyclohexane methyl formate, wherein the molar yield of the step is 95%.
Synthesis of 4- (aminomethyl) cyclohexane carboxylic acid (ester):
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 flow rate of 50ml/min nitrogen, the back pressure of the system is 3MPa, the system is switched into high-purity hydrogen, the flow rate of the hydrogen is 200ml/min, and the methanol solution (the mass percentage concentration is 30wt%) of the methyl 4-cyanocyclohexanecarboxylate is added for 0.1h -1 The reaction product is condensed and gas-liquid separated, and then enters a storage tank, the obtained product is distilled to recover methanol, and then is rectified to obtain 4- (aminomethyl) methyl cyclohexane formate (boiling point 240.7 ℃), and the molar yield of the step is 83%.
Synthesis of tranexamic acid:
50g of methyl 4- (aminomethyl) cyclohexane formate and 250g of sodium hydroxide solution with the mass percentage concentration of 20wt% are added into a 500ml flask, the mixture is stirred and mixed, then the mixture is heated to 120 ℃ and kept for 12 hours, the temperature is reduced after the reaction is finished, the pH value is adjusted to 1-2 by concentrated hydrochloric acid, then the mixture is evaporated to dryness, the obtained solid is added with deionized water which is 0.5 times of the solid to pulp for 30 minutes, the obtained solid is filtered and dried in vacuum at 60 ℃ for 12 hours to obtain tranexamic acid, and the molar yield of the step is 87%. FIG. 1 shows the results of chromatographic detection of tranexamic acid as the product obtained in this example.
Example 8
Synthesis of 4-cyanocyclohexane carboxylic acid (ester):
60g of 4-cyanocyclohexane formaldehyde, 120g of methanol and 6g of Pd/MgO catalyst (the Pd load is 5 wt%) are added into a 500ml reaction kettle, the reaction kettle is closed, air is filled to 3MPa, the reaction kettle is heated to 80 ℃ to start reaction after the reaction kettle is kept for 30min, the reaction is stopped after the air is continuously supplemented until the pressure is not continuously reduced, the reaction is stopped after the temperature is reduced, the pressure is relieved, the product is taken out, the catalyst is removed by filtration, and the organic phase is evaporated to dryness to obtain the product 4-cyanocyclohexane methyl formate, wherein the molar yield of the step is 96%.
Synthesis of 4- (aminomethyl) cyclohexane carboxylic acid (ester):
10g Raney Ni catalyst (particle shape, 20-40 mesh) was charged in a fixed bed reactor, the temperature was raised to 100℃at a nitrogen flow rate of 50ml/min, the system back pressure was changed to 3MPa, high purity hydrogen was used, the hydrogen flow rate was 200ml/min, and a methanol solution of methyl 4-cyanocyclohexanecarboxylate (concentration by mass: 30 wt%) was fed to the reactor at a rate of 0.1h -1 The reaction product is condensed and gas-liquid separated, and then enters a storage tank, the obtained product is distilled to recover methanol, and then is rectified to obtain 4- (aminomethyl) methyl cyclohexane formate (boiling point 240.7 ℃), and the molar yield of the step is 85%.
Synthesis of tranexamic acid:
50g of methyl 4- (aminomethyl) cyclohexane formate and 250g of potassium hydroxide solution with the mass percentage concentration of 20wt% are added into a 500ml flask, stirred and mixed, heated to 120 ℃, kept for 12 hours, cooled after the reaction is finished, and adjusted to pH 1-2 by concentrated hydrochloric acid, then evaporated to dryness, the obtained solid is added with deionized water with the concentration of 0.5 times, pulped for 30 minutes, the obtained solid is filtered, and vacuum-dried for 12 hours at 60 ℃ to obtain tranexamic acid, and the molar yield of the step is 85%.
Example 9
Synthesis of 4-cyanocyclohexane carboxylic acid (ester):
60g of 4-cyanocyclohexane formaldehyde, 120g of methanol and 6g of Au/MgO catalyst (the loading amount of Au is 5 wt%) are added into a 500ml reaction kettle, the reaction kettle is closed, air is filled to 2MPa, the reaction kettle is heated to 80 ℃ to start reaction after the reaction kettle is kept for 30min, the reaction is stopped after the air is continuously supplemented until the pressure is not continuously reduced any more, the reaction is cooled and decompressed, the product is taken out, the catalyst is removed by filtration, and the organic phase is evaporated to dryness to obtain the product 4-cyanocyclohexane methyl formate, wherein the molar yield of the step is 92%.
Synthesis of 4- (aminomethyl) cyclohexane carboxylic acid (ester):
Pd/gamma-Al packing in fixed bed reactor 2 O 3 The catalyst (Pd load is 5 wt%) is heated to 100 ℃ under the flow rate of 50ml/min nitrogen, the back pressure of the system is 3MPa, the catalyst is switched into high-purity hydrogen, the hydrogen flow rate is 200ml/min, and the methanol solution (the mass percentage concentration is 30 wt%) of the methyl 4-cyanocyclohexanecarboxylate is added for 0.1h -1 The reaction product is condensed and gas-liquid separated, and then enters a storage tank, the obtained product is distilled to recover methanol, and then is rectified to obtain 4- (aminomethyl) methyl cyclohexane formate (boiling point 240.7 ℃), and the molar yield of the step is 91%.
Synthesis of tranexamic acid:
50g of methyl 4- (aminomethyl) cyclohexane formate and 250g of barium hydroxide solution with the mass percentage concentration of 5wt% are added into a 500ml flask, stirred and mixed, heated to 120 ℃ and kept for 12 hours, cooled after the reaction is finished, pH value is adjusted to 1-2 by concentrated hydrochloric acid, then evaporated to dryness, the obtained solid is added with 0.5 times deionized water to pulp for 30 minutes, the obtained solid is filtered and dried in vacuum at 60 ℃ for 12 hours to obtain tranexamic acid, and the molar yield of the step is 80%.
Example 10
Synthesis of 4-cyanocyclohexane carboxylic acid (ester):
60g of 4-cyanocyclohexane formaldehyde, 120g of methanol and 6g of Au/hydrotalcite catalyst (the loading amount of Au is 5 wt%) are added into a 500ml reaction kettle, the reaction kettle is closed, air is filled to 2MPa, the reaction kettle is heated to 80 ℃ to start reaction after the reaction kettle is kept for 30min, the reaction is stopped after the air is continuously supplemented until the pressure is not continuously reduced any more, the reaction is stopped after the temperature is reduced and the pressure is relieved, the product is taken out, the catalyst is removed by filtration, and the organic phase is evaporated to dryness to obtain the product 4-cyanocyclohexane methyl formate, wherein the molar yield of the step is 94%.
Synthesis of 4- (aminomethyl) cyclohexane carboxylic acid (ester):
a Raney Co catalyst (granular, 20-40 mesh) was packed in a fixed bed reactor, the temperature was raised to 100℃at a nitrogen flow rate of 50ml/min, the system back pressure was changed to 3MPa, high purity hydrogen was used, the hydrogen flow rate was 200ml/min, and a methanol solution of methyl 4-cyanocyclohexanecarboxylate (concentration by mass: 30 wt%) was fed for 0.1h -1 The reaction product is condensed and gas-liquid separated, and then enters a storage tank, the obtained product is distilled to recover methanol, and then is rectified to obtain 4- (aminomethyl) methyl cyclohexane formate (boiling point 240.7 ℃), and the molar yield of the step is 85%.
Synthesis of tranexamic acid:
50g of methyl 4- (aminomethyl) cyclohexane formate and 250g of calcium hydroxide solution with the mass percentage concentration of 5wt% are added into a 500ml flask, the mixture is stirred and mixed, then the mixture is heated to 120 ℃ and kept for 12 hours, the temperature is reduced after the reaction is finished, the pH value is adjusted to 1-2 by concentrated hydrochloric acid, then the mixture is evaporated to dryness, the obtained solid is added with deionized water which is 0.5 times of the solid to pulp for 30 minutes, the obtained solid is filtered and dried in vacuum at 60 ℃ for 12 hours to obtain tranexamic acid, and the molar yield of the step is 83%.
Example 11
Synthesis of 4-cyanocyclohexane carboxylic acid (ester):
60g of 4-cyanocyclohexane formaldehyde, 120g of methanol and 6g of Au/CeO are added into a 500ml reaction kettle 2 The catalyst (the loading amount of Au is 5 wt%) is sealed, the reaction kettle is filled with air to 3MPa, after the reaction kettle is kept for 30min and is not leaked, the temperature is raised to 100 ℃ to start the reaction, the reaction is stopped after the air is continuously supplemented until the pressure is not continuously reduced in the reaction process, the temperature is reduced, the pressure is relieved, the product is taken out, the catalyst is removed by filtration, and the organic phase is evaporated to dryness to obtain the product methyl 4-cyanocyclohexanecarboxylate, wherein the molar yield of the step is 94%.
Synthesis of 4- (aminomethyl) cyclohexane carboxylic acid (ester):
in a fixed bedThe reactor was filled with Raney Ni catalyst (particle shape, 20-40 mesh), heated to 120deg.C at a nitrogen flow rate of 50ml/min, the system back pressure was changed to 4MPa, and high purity hydrogen was used at a hydrogen flow rate of 200ml/min, and a methanol solution (mass percentage concentration: 30 wt%) of methyl 4-cyanocyclohexanecarboxylate was added at a rate of 0.1h -1 The reaction product is condensed and gas-liquid separated, and then enters a storage tank, the obtained product is distilled to recover methanol, and then is rectified to obtain 4- (aminomethyl) methyl cyclohexane formate (boiling point 240.7 ℃), and the molar yield of the step is 89%.
Synthesis of tranexamic acid:
50g of methyl 4- (aminomethyl) cyclohexane formate and 250g of magnesium hydroxide solution with the mass percentage concentration of 5wt% are added into a 500ml flask, the mixture is stirred and mixed, then the mixture is heated to 120 ℃ and kept for 12 hours, the temperature is reduced after the reaction is finished, the pH value is adjusted to 1-2 by concentrated hydrochloric acid, then the mixture is evaporated to dryness, the obtained solid is added with deionized water which is 0.5 times of the solid to pulp for 30 minutes, the obtained solid is filtered and dried in vacuum at 60 ℃ for 12 hours to obtain tranexamic acid, and the molar yield of the step is 80%.
Example 12
Synthesis of 4-cyanocyclohexane carboxylic acid (ester):
10g of Pd/hydrotalcite catalyst (Pd loading amount is 5 wt%) was charged in a fixed bed reactor, the temperature was raised to 80℃at an air flow rate of 50ml/min, the system was back-pressure to 2MPa, the air flow rate was 200ml/min, and a methanol solution of 4-cyanocyclohexane formaldehyde (mass percentage concentration: 30 wt%) was fed for 1.0h -1 The mixture is pumped into a reactor for reaction, the product is condensed and separated from gas and liquid, and then enters a storage tank, and the organic phase is evaporated to dryness to obtain the product methyl 4-cyanocyclohexanecarboxylate, wherein the molar yield of the step is 94%.
Synthesis of 4- (aminomethyl) cyclohexane carboxylic acid (ester):
60g of methyl 4-cyanocyclohexanecarboxylate, 120g of methanol and 6g of Raney Ni are added into a 500ml reaction kettle, the reaction kettle is closed, after the air in the reaction kettle is replaced by nitrogen, the pressure is kept for 30min to be 4MPa, the temperature is raised to 120 ℃ to start the reaction, the hydrogen is continuously supplemented to the target amount in the reaction process, the temperature is reduced, the pressure is relieved, after the hydrogen in the reaction kettle is replaced by nitrogen, the product is taken out, the catalyst is removed by filtration, the methanol is removed by distillation of an organic phase, the methyl 4- (aminomethyl) cyclohexanecarboxylate (boiling point 240.7 ℃) is obtained after the product is rectified, and the molar yield of the step is 92%.
Synthesis of tranexamic acid:
50g of methyl 4- (aminomethyl) cyclohexane formate and 250g of sodium hydroxide solution with the mass percentage concentration of 20wt% are added into a 500ml flask, the mixture is stirred and mixed, then the mixture is heated to 140 ℃, the temperature is kept for 12 hours, the temperature is reduced after the reaction is finished, the pH value is adjusted to 1-2 by concentrated hydrochloric acid, then the mixture is evaporated to dryness, the obtained solid is added with 0.5 times deionized water to pulp for 30 minutes, the obtained solid is filtered, and vacuum-dried for 12 hours at 60 ℃ to obtain tranexamic acid, and the molar yield of the step is 89%.
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 (10)

1. A method for synthesizing tranexamic acid represented by the following reaction formula 1, comprising the steps of:
(1) Mixing a compound I (4-cyanocyclohexane formaldehyde) with a solvent, respectively introducing the mixture and air into a reactor filled with a catalyst 1 for oxidation reaction, introducing the obtained product into a storage tank, and distilling the product to remove the solvent to obtain a compound II;
(2) Adding the compound II into a reactor filled with a catalyst 2 to carry out hydrogenation reaction to obtain a compound III;
(3) Mixing the compound III with an alkali solution, heating for reaction, and regulating pH after the reaction is finished to obtain a compound IV (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 process according to claim 1, wherein the catalyst 1 in step (1) is a supported metal catalyst, the metal active component M in the supported metal catalyst is selected from one or more of Pd, ru, pt, au, and the catalyst carrier is selected from γ -Al 2 O 3 、SiO 2 、TiO 2 、ZnO、MgO、CeO 2 One or more of hydrotalcite;
preferably, the catalyst 1 in the step (1) is a supported metal catalyst, the metal active component in the supported metal catalyst is selected from one or more of Pd, au and Pt, and the catalyst carrier is selected from gamma-Al 2 O 3 、ZnO、MgO、CeO 2 One or more of hydrotalcite;
more preferably, the catalyst 1 in the step (1) is a supported metal catalyst, the metal active component in the supported metal catalyst is selected from one or more of Pd and Au, and the catalyst carrier is selected from ZnO, mgO, ceO 2 One or more of hydrotalcite;
preferably, for the supported metal catalyst in step (1), the active component comprises from 0.1% to 30%, preferably from 0.2% to 20%, more preferably from 0.5% to 10% based on the total weight of the catalyst; the carrier is 70% to 99.9%, preferably 80% to 99.8%, more preferably 90% to 99.5%.
3. The synthetic method according to claim 1, wherein the solvent of step (1) is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol;
preferably, the molar ratio of the compound I to air of step (1) is from 1:5 to 1:30;
preferably, the reaction temperature of step (1) is 40-150 ℃, and the reaction pressure is 0.1-5MPa;
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 。
4. The synthesis process according to claim 1, wherein the catalyst 2 of step (2) 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 supported catalyst carrier is selected from activated carbon, gamma-Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves selected from one or more of H-ZSM-5, H-ZSM-35, HY and hβ;
preferably, for the supported metal catalyst in step (2), the active component comprises from 0.1% to 50%, preferably from 0.2% to 40%, more preferably from 0.5% to 30% based on the total weight of the catalyst; the carrier is 50% to 99.9%, preferably 60% to 99.8%, more preferably 70% to 99.5%.
5. The synthesis according to claim 1, wherein the reaction temperature of step (2) is 50-250 ℃, preferably 60-200 ℃, more preferably 80-150 ℃;
preferably, the reaction pressure of step (2) is from 1 to 8MPa, preferably from 1 to 6MPa, more preferably from 2 to 5MPa;
preferably, the solvent of step (2) is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol;
preferably, when step (2) is carried out in a batch reactor, the mass ratio of catalyst 1 to compound II is from 1:100 to 30:100, preferably from 3:100 to 20:100, more preferably from 5:100 to 15:100;
preferably, when stepWhen step (2) is carried out in a continuous reactor, the mass space velocity of the compound II is 0.1 to 5h -1 Preferably 0.1-3h -1 More preferably 0.1 to 1.0h -1 ；
Preferably, when step (2) is carried out in a continuous reactor, the molar ratio of compound II to hydrogen is from 1:5 to 1:50, preferably from 1:5 to 1:30, more preferably from 1:5 to 1:10.
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 base to compound III of step (3) is from 1:1 to 5:1, preferably from 1:1 to 3:1, more preferably from 1:1 to 2:1;
preferably, the reaction temperature of step (3) is from 90 to 200 ℃, preferably from 90 to 180 ℃, more preferably from 90 to 150 ℃.
7. The synthetic method according to claim 1, wherein the compound I in step (1) is synthesized by:
(i) Mixing a compound V (1, 3-butadiene), a compound VI (acrylonitrile) and a polymerization inhibitor to perform Diels-Alder reaction to synthesize a compound VII (4-cyano-1-cyclohexene);
(ii) The compound VII is subjected to carbonylation reaction in the presence of a catalyst to synthesize a compound I (4-cyano cyclohexane formaldehyde).
8. The synthetic method of claim 7 wherein the molar ratio of compound V to compound VI in step (i) is 1:10 to 10:1;
preferably, the reaction temperature in step (i) is from 80 to 250 ℃, preferably from 100 to 200 ℃, more preferably from 120 to 180 ℃.
9. The synthetic method of claim 7 wherein the catalyst in step (ii) is a Rh catalyst precursor and an organophosphine ligand;
preferably, the molar ratio of compound VI to Rh catalyst precursor and organophosphine ligand in step (ii) is from 100 to 100000:1:1 to 10, preferably from 500 to 10000:1:2 to 6, more preferably from 300 to 5000:1:3 to 4;
preferably, the Rh catalyst precursor in step (ii) is one of rhodium dicarbonyl acetylacetonate, rhodium monochlorodicarbonyl dimer, rhodium bis (norbornadiene) tetrafluoroborate or rhodium bis (1, 5-cyclooctadiene) chloride, and the organophosphine ligand is one of tris (2, 4, 6-trimethylphenyl) phosphine, tri-o-tolylphosphine or triphenylphosphine.
10. The synthetic method according to claim 7, characterized in that the reaction temperature in step (ii) is 50-180 ℃, preferably 60-150 ℃, more preferably 70-120 ℃;
preferably, H in step (ii) 2 And CO at a pressure ratio of 1:1;
preferably, the reaction pressure in step (ii) is from 1 to 10MPa, preferably from 1 to 8MPa, more preferably from 2 to 6MPa.
CN202311621161.8A 2023-11-30 2023-11-30 Synthesis method of tranexamic acid Pending CN117776944A (en)

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