CN116730856B - Synthesis method of tranexamic acid - Google Patents
Synthesis method of tranexamic acid Download PDFInfo
- Publication number
- CN116730856B CN116730856B CN202310724238.8A CN202310724238A CN116730856B CN 116730856 B CN116730856 B CN 116730856B CN 202310724238 A CN202310724238 A CN 202310724238A CN 116730856 B CN116730856 B CN 116730856B
- Authority
- CN
- China
- Prior art keywords
- electrodialysis
- acid
- liquid
- tranexamic acid
- water tank
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 title claims abstract description 58
- 229960000401 tranexamic acid Drugs 0.000 title claims abstract description 56
- 238000001308 synthesis method Methods 0.000 title claims description 3
- 238000000909 electrodialysis Methods 0.000 claims abstract description 91
- 239000007788 liquid Substances 0.000 claims abstract description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000013505 freshwater Substances 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 33
- 239000000706 filtrate Substances 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 26
- 238000001914 filtration Methods 0.000 claims abstract description 17
- 238000010438 heat treatment Methods 0.000 claims abstract description 17
- 239000003513 alkali Substances 0.000 claims abstract description 16
- 229960003375 aminomethylbenzoic acid Drugs 0.000 claims abstract description 14
- QCTBMLYLENLHLA-UHFFFAOYSA-N aminomethylbenzoic acid Chemical compound NCC1=CC=C(C(O)=O)C=C1 QCTBMLYLENLHLA-UHFFFAOYSA-N 0.000 claims abstract description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000017105 transposition Effects 0.000 claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims description 21
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 20
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 claims description 12
- 239000001569 carbon dioxide Substances 0.000 claims description 10
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 10
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 claims description 9
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 6
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 239000012452 mother liquor Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000005649 metathesis reaction Methods 0.000 claims 1
- QTDXSEZXAPHVBI-UHFFFAOYSA-N 4-methylcyclohexane-1-carboxylic acid Chemical compound CC1CCC(C(O)=O)CC1 QTDXSEZXAPHVBI-UHFFFAOYSA-N 0.000 abstract description 32
- 239000012535 impurity Substances 0.000 abstract description 19
- 239000002253 acid Substances 0.000 abstract description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 27
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 239000003054 catalyst Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- GYDJEQRTZSCIOI-UHFFFAOYSA-N Tranexamic acid Chemical compound NCC1CCC(C(O)=O)CC1 GYDJEQRTZSCIOI-UHFFFAOYSA-N 0.000 description 7
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 7
- 229910021529 ammonia Inorganic materials 0.000 description 7
- ZUDYPQRUOYEARG-UHFFFAOYSA-L barium(2+);dihydroxide;octahydrate Chemical compound O.O.O.O.O.O.O.O.[OH-].[OH-].[Ba+2] ZUDYPQRUOYEARG-UHFFFAOYSA-L 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 159000000009 barium salts Chemical class 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000002910 solid waste Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000009292 Hemophilia A Diseases 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000012466 permeate Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VGKZBAMIYUHSMU-UHFFFAOYSA-N 4-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylic acid Chemical compound OC(=O)C1CCC(NC(=O)N(CCCl)N=O)CC1 VGKZBAMIYUHSMU-UHFFFAOYSA-N 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N Cyclohexanecarboxylic acid Natural products OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 201000003542 Factor VIII deficiency Diseases 0.000 description 1
- 208000031220 Hemophilia Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010019860 Hereditary angioedema Diseases 0.000 description 1
- 208000003351 Melanosis Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 206010046788 Uterine haemorrhage Diseases 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910001422 barium ion Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940099355 cyklokapron Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- 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
- C07C227/30—Preparation of optical isomers
-
- 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
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- 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
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
-
- 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
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing tranexamic acid, which comprises the following steps: (1) Adding the aminomethylbenzoic acid into water, adding concentrated sulfuric acid, heating to dissolve, filtering, carrying out hydrogenation reduction on the filtrate, and carrying out aftertreatment to obtain an aminomethylbenzoic acid hydrogenated solution; (2) Transferring the amino toluene acid hydrogenated liquid into an electrodialysis fresh water tank for electrodialysis; controlling the pH value in the fresh water tank to be 6.5-8.5 in the electrodialysis process; (3) And after electrodialysis is finished, adding alkali into electrodialysis end point liquid in a fresh water tank, and heating to perform transposition reaction to obtain the tranexamic acid. According to the invention, sulfate radicals and impurities in the hydrogenated liquid, particularly 4-methylcyclohexyl formic acid impurities, can be effectively removed through electrodialysis, and the process is smoother, more environment-friendly, higher in production efficiency and more suitable for industrial production of tranexamic acid after sulfate radicals are removed through electrodialysis.
Description
Technical Field
The invention relates to synthesis of medical chemicals, in particular to a method for synthesizing high-purity tranexamic acid.
Background
Tranexamic acid (Tranexamic acid), also known as tranexamic acid, trans-4-aminomethyl-cyclohexyl-formic acid, is an organic compound with a chemical formula of C 8H15NO2, is mainly used as a hemostatic, is also used as an adjuvant therapy for hemophilia patients with factor VIII deficiency before and after surgery as a two-wire regimen, and can also be used for hereditary angioedema, and simultaneously has a blacking and freckle removing effect about 50 times higher than that of vitamin C and about 10 times higher than that of fruit acid.
Tranexamic acid was first approved by the FDA as an injection in 1986 under the trade name Cyklokapron. Compared with other antiplasmin, the medicine has the advantage of small side effect, and is commonly used for treating functional uterine bleeding and massive hemorrhage caused by hysteromyoma. In addition, tranexamic acid is also an important synthetic block with potential bioactive compounds.
Chinese patent publication No. CN107954887B discloses a method for preparing tranexamic acid, which comprises adding tranexamic acid, water, concentrated sulfuric acid and a catalyst into a reaction vessel, stirring and heating, and then introducing hydrogen for hydrogenation reaction to obtain hydrogenation reaction liquid; and adding the hydrogenation reaction liquid and concentrated sulfuric acid into a reaction container, heating to 180-200 ℃, and carrying out conversion reaction by stirring at a constant temperature to obtain tranexamic acid. In the method, the conversion reaction is carried out under the acidic condition, the conversion effect is poor, and the proportion of trans (tranexamic acid) in the obtained product is low.
In the hydrogenation process, amino acid hydrogenation produces deaminated impurities (4-methylcyclohexyl formic acid), which are controlled in the United states pharmacopoeia by unknown impurities to a limit of less than 0.05%. The solubility of the impurity in water is poor, and tranexamic acid is recrystallized in a water system, so that the impurity is difficult to remove through later recrystallization, and most of the impurities meet pharmacopoeia requirements through repeated refining in the prior art.
The chinese patent with publication number CN100336799C discloses a main method for synthesizing amino cyclic acid at present, comprising the following steps: the amino toluene acid sulfate solution is hydrogenated and reduced to obtain amino cyclic acid (cis-trans isomerism mixed solution); adding barium carbonate into the mixed solution to remove sulfate radical; adding barium hydroxide into the filtrate for high-temperature conversion; introducing carbon dioxide and other methods into the high-temperature conversion end point liquid to enable barium salt to precipitate and remove barium ions; concentrating the filtrate for crystallization or adding solvent for crystallization to obtain tranexamic acid. The method for removing sulfate ions in the hydrogenated liquid by adding barium salt has the following defects: (1) The added barium salt is difficult to control, sulfate radical can not be removed completely when the added barium salt is less, salt can be mixed in the salt separated out when the added barium salt is more, and the product can be separated out; (2) Meanwhile, barium sulfate is very thin and difficult to centrifugally separate, and the barium sulfate is easy to permeate into filtrate; (3) a large amount of dangerous solid waste of barium sulfate is generated; (4) In the obtained crude tranexamic acid solution, the content of 4-methylcyclohexyl formic acid which is a key impurity generated in the hydrogenation process is high, the recrystallization effect is affected, and impurities in the recrystallization mother liquor cannot be directly used after being enriched.
Disclosure of Invention
The invention provides a method for synthesizing tranexamic acid, which is simple and controllable in operation, does not generate dangerous solid waste, and can control the content of 4-methylcyclohexyl formic acid in a product to be below a limit.
The technical scheme of the invention is as follows:
a method for synthesizing tranexamic acid comprises the following steps:
(1) Adding the aminomethylbenzoic acid into water, adding concentrated sulfuric acid, heating to dissolve, filtering, and carrying out hydrogenation reduction on the filtrate to obtain an aminomethylbenzoic acid hydrogenated solution;
(2) Transferring the amino toluene acid hydrogenated liquid into an electrodialysis fresh water tank for electrodialysis; controlling the pH value in the fresh water tank to be 6.5-8.5 in the electrodialysis process;
(3) After electrodialysis is finished, adding alkali into electrodialysis end point liquid in a fresh water tank, heating to perform transposition reaction, and performing aftertreatment to obtain the tranexamic acid.
The chemical reaction process of the invention is as follows:
4-methylcyclohexylformic acid impurities are produced during the aminomethylbenzoic acid hydrogenation process, which have poor solubility in water, and the aminomethylbenzoic acid is purified by recrystallization in an aqueous system, and it is difficult to remove the impurities by the subsequent recrystallization.
After hydrogenation, the sulfate radical in the aminomethylbenzoic acid hydrogenated liquid is removed by electrodialysis, the sulfate radical can be thoroughly removed, and dangerous solid wastes such as barium sulfate and the like are not generated; in addition, the pH in the fresh water tank is controlled to be 6.5-8.5 during electrodialysis, in which the 4-methylcyclohexylformic acid is in an ionic state, and can be removed by electrodialysis, while the intermediate 4-aminomethyl cyclohexylformic acid is uncharged in the pH range and remains in the fresh water tank during electrodialysis. Removing sulfate radical and 4-methyl cyclohexyl formic acid impurity by electrodialysis, adding alkali to perform high Wen Zhuaiwei reaction, obtaining high-purity tranexamic acid, and controlling the content of 4-methyl cyclohexyl formic acid in the product to be below 0.02%.
In the invention, the pH value control in the fresh water tank is critical in the electrodialysis process, when the pH value is below 6.5, the 4-methylcyclohexyl formic acid part is in a nonionic state, and the complete removal can not be realized through electrodialysis; and the 4-aminomethyl cyclohexyl formic acid is partially in an ionic state and is removed by electrodialysis, so that the product yield is reduced; when the pH value is above 8.5, the 4-aminomethyl cyclohexyl formic acid is partially in an ionic state, and is removed by electrodialysis, so that the product yield is reduced.
Preferably, the aminomethylbenzoic acid hydrogenation solution is concentrated to a concentration of 10-15% of the tranexamic acid before being transferred to the electrodialysis fresh water tank. When the concentration of the aminomethylbenzoic acid hydrogenated liquid is low, the throughput is too low, the productivity is affected, the concentration is too high, the electrodialysis efficiency is reduced, and the impurity removal speed is reduced (particularly 4-methylcyclohexyl formic acid).
Preferably, in step (2), the electrodialysis voltage is 100-200V and the current is 60-80A.
Preferably, in the step (2), electrodialysis is finished when the conductivity in the fresh water tank is not more than 500us/cm 2.
Further, electrodialysis is completed when the conductivity in the fresh water tank is not more than 100us/cm 2.
Preferably, in step (3), the base is barium hydroxide.
Preferably, the step (3) includes:
(3-1) concentrating electrodialysis end point liquid, adding alkali, and heating to perform transposition reaction;
(3-2) introducing carbon dioxide into the transposition reaction liquid, centrifuging to recover barium carbonate, and re-synthesizing the recovered barium carbonate into barium hydroxide for reuse; concentrating the filtrate, cooling and crystallizing to obtain tranexamic acid, repeating the steps for a plurality of times, and then merging the mother solution into the electrodialysis endpoint solution of the next batch to carry out transposition reaction.
Preferably, in the step (3-1), when the electrodialysis end point solution is concentrated, the concentration water yield is 60-70% of the total volume of the concentrate.
Preferably, in the step (3-2), concentration, cooling and crystallization are repeated at least twice; the water yield of the first concentration is 60-70% of the total volume of the first concentration; the water yield of the second concentration is 50-60% of the total volume of the second concentration. The concentration amount has influence on the yield and quality of the product, the concentration amount is high, and the tranexamic acid isomer is separated out; the concentration amount is low, and the yield is reduced.
Compared with the prior art, the invention has the beneficial effects that:
The conventional method for removing sulfate ions in the hydrogenated liquid by adding barium hydroxide or barium carbonate has the following disadvantages: ① The amount of the barium salt added is difficult to control, sulfate radical is added to remove completely, salt can be mixed in the salt which is added to be separated out, and the product can be separated out; ② Barium sulfate is very fine into nano-sized particles, so that the barium sulfate is difficult to centrifuge, and the barium sulfate is easy to permeate into filtrate; ③ Generating a large amount of dangerous solid waste barium sulfate; ④ The effect of removing 4-methylcyclohexyl formic acid which is a key impurity generated by the reaction is poor, and the quality and the yield of the product are affected.
(1) The invention adopts electrodialysis to remove sulfate radical, which does not have the problems, the process is simpler and more controllable, and after the pH value of the electrodialysis liquid is regulated by liquid alkali, the wastewater on the electrodialysis concentrated water side is concentrated to obtain sodium sulfate which can be recycled as a byproduct, and a large amount of dangerous solid waste is not generated.
(2) The impurities, especially 4-methylcyclohexyl formic acid, in the hydrogenated liquid can be effectively removed by electrodialysis, and the impurities are difficult to remove completely in the conventional method, and need to be removed by repeated recrystallization.
(3) The transposition reaction liquid has no 4-methylcyclohexyl formic acid impurity, the primary crystallization mother liquid has no 4-methylcyclohexyl formic acid impurity enrichment, the refining efficiency and the yield can be greatly improved by carrying out secondary crystallization after concentration, the crystallized mother liquid can be directly used in the transposition reaction, and the mother liquid after recrystallization in the conventional method has high 4-methylcyclohexyl formic acid content and cannot be directly used.
(4) After sulfate radical and 4-methylcyclohexyl formic acid are removed through electrodialysis, the process is smoother, more environment-friendly, higher in production efficiency and more suitable for industrial production.
Drawings
FIG. 1 is an HPLC plot of electrodialysis endpoint solution in example 1;
FIG. 2 is an HPLC chart of the product tranexamic acid obtained in example 1;
FIG. 3 is an HPLC chart of a solution before the shift reaction in comparative example 1;
FIG. 4 is an HPLC chart of tranexamic acid product obtained in comparative example 1.
Detailed Description
Example 1
Ammonia toluic acid (50.0 g) was added to water (1650.3 g) at room temperature, and concentrated sulfuric acid (29.8 g) was slowly added dropwise; after the addition, heating to 80-90 ℃, and stirring and dissolving completely; filtering, transferring the filtrate into a hydrogenation kettle, and adding platinum dioxide; after the replacement is finished, starting hydrogenation; and filtering to separate the catalyst and applying the catalyst after the hydrogen pressure is not reduced.
Concentrating the obtained hydrogenated liquid to obtain 1295.3g of water, transferring the concentrated liquid into an electrodialysis fresh water tank after the concentration of the tranexamic acid mixture in the concentrated liquid is about 11.9%, adding dropwise caustic soda to adjust pH=7.43, recording the liquid level of the fresh water tank, and starting electrodialysis; the voltage is 100-200V and the current is 60-80A in the electrodialysis process; simultaneously, hydrochloric acid and liquid alkali are added dropwise to control the pH value of the system to be between 6.5 and 8.5; in the electrodialysis process, the proper replenishment of pure water in the fresh water tank maintains the liquid level unchanged little, and the electrodialysis end point is regarded as when the conductivity is 460us/cm 2.
And (3) sampling and detecting an electrodialysis end point liquid, wherein the removal of 4-methylcyclohexyl formic acid is complete, and the electrodialysis end point liquid is shown in figure 1. In FIG. 1, RT 10.584min is trans-4-aminomethyl cyclohexylcarboxylic acid (tranexamic acid), RT 12.624min is tranexamic acid, and RT 14.211min is cis-4-aminomethyl cyclohexylcarboxylic acid.
Concentrating the electrodialysis end point solution to obtain 280.2g of water, adding 52.2g of barium hydroxide octahydrate, performing high-temperature conversion, maintaining the temperature at 190-220 ℃ for 13 hours, cooling to 26 ℃, introducing 7.3g of carbon dioxide into the high-temperature conversion solution, and stirring for 0.5 hour after adding; centrifuging to remove barium carbonate, concentrating the filtrate at 60-80deg.C under reduced pressure to obtain 91.5g water, cooling to 6deg.C, and centrifuging to obtain refined tranexamic acid product; continuously concentrating the filtrate at 60-80deg.C under reduced pressure to obtain about 27.8g water, cooling to 9deg.C, and centrifuging to obtain refined tranexamic acid product; combining the two refined products, and drying to obtain 35.6g, wherein the total yield is 68.5%, and the purity is 100%, as shown in FIG. 2; the mother liquor is directly applied to the next batch of transposition liquid to continue the high-temperature transposition reaction.
Comparative example 1
Ammonia toluic acid (20.0 g) was added to water (660.3 g) at room temperature, and concentrated sulfuric acid (11.9 g) was slowly added dropwise; after the addition, heating to 80-90 ℃, and stirring and dissolving completely; filtering, transferring the filtrate into a hydrogenation kettle, and adding platinum dioxide; after the replacement is finished, starting hydrogenation; after the hydrogen pressure does not drop; filtering to separate the catalyst and applying the catalyst.
Concentrating the obtained hydrogenated liquid to obtain 626.5g of water, adding barium carbonate to adjust the pH of the hydrogenated liquid to 6.3, controlling the temperature to 60-70 ℃, centrifuging to remove barium sulfate, adding 20.8g of barium hydroxide octahydrate into the filtrate to perform high rotation, and preserving the temperature to 190-220 ℃ for 15 hours; cooling to 28 ℃, introducing 2.9g of carbon dioxide into the high-rotation liquid, and stirring for 0.5h after adding; centrifuging to remove barium carbonate, and applying the barium carbonate to the hydrogenated liquid to remove sulfate ions in the hydrogenated liquid; the filtrate was sampled and sent for inspection, 4-methylcyclohexyl formic acid was almost not removed, and the total cis and trans contents were 3.04%, see fig. 3. In FIG. 3, RT 10.746min is trans 4-aminomethyl cyclohexylcarboxylic acid (tranexamic acid), RT 12.816min is tranexamic acid, RT 14.483min is cis 4-aminomethyl cyclohexylcarboxylic acid, RT 33.684min and RT 36.501min are cis and trans 4-methylcyclohexylcarboxylic acid, respectively.
Concentrating the filtrate at 60-80deg.C under reduced pressure to obtain 39.4g water, cooling to 10deg.C, and centrifuging to obtain refined tranexamic acid product; the filtrate 4-methylcyclohexyl formic acid with higher content can not be directly concentrated and crystallized for the second time, and after the impurity content is reduced by other methods, the concentrated and crystallized product of tranexamic acid is obtained; the combined drying yields 11.4g, total yield 54.8%, purity 99.66%, wherein 4-methylcyclohexylformic acid 0.09% (pharmacopoeia prescribes limits not exceeding 0.05%) as shown in FIG. 4.
Comparative example 2
Ammonia toluic acid (25.0 g) was added to water (825.9 g) at room temperature, and concentrated sulfuric acid (14.9 g) was slowly added dropwise; after the addition, heating to 80-90 ℃, and stirring and dissolving completely; filtering, transferring the filtrate into a hydrogenation kettle, and adding platinum dioxide; after the replacement is finished, starting hydrogenation; and filtering to separate the catalyst and applying the catalyst after the hydrogen pressure is not reduced.
Concentrating 725.1g of water from the obtained hydrogenated liquid, transferring the concentrated hydrogenated liquid into an electrodialysis fresh water tank after the concentration of the tranexamic acid mixture is about 18.7%, adding dropwise caustic soda to adjust pH=7.68, recording the liquid level of the fresh water tank, and starting electrodialysis; the voltage is 100-200V and the current is 60-80A in the electrodialysis process; simultaneously, hydrochloric acid and liquid alkali are added dropwise to control the pH value of the system to be between 6.5 and 8.5; in the electrodialysis process, pure water is properly supplemented in the fresh water tank to maintain the liquid level to be slightly changed, and when the electric conductivity is 900us/cm 2, the electric conductivity is slowly reduced along with the prolongation of the electrodialysis time, and the electrodialysis is stopped.
And sampling and detecting electrodialysis end point liquid, wherein the total amount of 4-methylcyclohexyl formic acid is 0.75%.
Concentrating 82.0g of water from the electrodialysis liquid, adding 26.1g of barium hydroxide octahydrate, performing high-temperature conversion, maintaining the temperature at 190-220 ℃ for 15 hours, cooling to 24 ℃, introducing 3.7g of carbon dioxide into the high-temperature conversion liquid, and stirring for 0.5 hours after adding; centrifuging to remove barium carbonate, concentrating the filtrate at 60-80deg.C under reduced pressure to obtain 32.4g water, cooling to 8deg.C, centrifuging to obtain refined tranexamic acid product, and drying to obtain 13.7g with yield of 52.8%, purity of 99.72%, wherein 4-methylcyclohexylformic acid is 0.06%.
The total content of 4-methylcyclohexyl formic acid in the filtrate is 1.52%, and concentration and crystallization cannot be continued.
Comparative example 3
Ammonia toluic acid (25.1 g) was added to water (825.6 g) at room temperature, and concentrated sulfuric acid (14.9 g) was slowly added dropwise; after the addition, heating to 80-90 ℃, and stirring and dissolving completely; filtering, transferring the filtrate into a hydrogenation kettle, and adding platinum dioxide; after the replacement is finished, starting hydrogenation; and filtering to separate the catalyst and applying the catalyst after the hydrogen pressure is not reduced.
Concentrating 632.7g of the obtained hydrogenated liquid to a concentration of about 11.1%, transferring into an electrodialysis fresh water tank, adding dropwise caustic soda to adjust pH=9.5, recording the liquid level of the fresh water tank, and starting electrodialysis; the voltage is 100-200V and the current is 60-80A in the electrodialysis process; simultaneously, hydrochloric acid and liquid alkali are added dropwise to control the pH value of the system to be 8.5-9.5; in the electrodialysis process, pure water is properly supplemented in the fresh water tank to maintain the liquid level to be little changed. Electrodialysis was stopped when the conductivity was 237us/cm 2. And (3) sampling and detecting the electrodialysis end point liquid, wherein 4-methylcyclohexyl formic acid is not detected.
Concentrating the electrodialysis solution to obtain 146.3g of water, adding 26.1g of barium hydroxide octahydrate, performing high-temperature conversion, maintaining the temperature at 190-220 ℃ for 13 hours, cooling to 25 ℃, introducing 3.7g of carbon dioxide into the high-temperature conversion solution, and stirring for 0.5 hour after adding; centrifuging to remove barium carbonate, concentrating the filtrate at 60-80deg.C under reduced pressure to obtain 50.3g water, cooling to 4deg.C, crystallizing, centrifuging to obtain refined tranexamic acid product; and (3) continuously concentrating the filtrate to obtain 17.2g of water, cooling to 4 ℃ for crystallization, and centrifuging to obtain the refined tranexamic acid product. The two refined products were dried to give 10.61g in total, with a yield of 40.8% and a purity of 99.92%, of which 4-methylcyclohexylcarboxylic acid was not detected.
The residual quantity of the tranexamic acid detected in the residual liquid is 11.82g, the total quantity in the feed liquid after electrodialysis is 22.43g, and the theoretical quantity is 26.0g, namely the electrodialysis loss is 3.57g, and the loss rate is 13.7%.
Comparative example 4
Ammonia toluic acid (25.0 g) was added to water (825.3 g) at room temperature, and concentrated sulfuric acid (14.9 g) was slowly added dropwise; after the addition, heating to 80-90 ℃, and stirring and dissolving completely; filtering, transferring the filtrate into a hydrogenation kettle, and adding platinum dioxide; after the replacement is finished, starting hydrogenation; and filtering to separate the catalyst and applying the catalyst after the hydrogen pressure is not reduced.
Concentrating the obtained hydrogenated liquid to obtain 645.2g of water, transferring the concentrated hydrogenated liquid into an electrodialysis fresh water tank after the concentration of the tranexamic acid mixture is about 11.7%, dropwise adding alkali to adjust pH=5.5, recording the liquid level of the fresh water tank, and starting electrodialysis; the voltage is 100-200V and the current is 60-80A in the electrodialysis process; simultaneously, hydrochloric acid and liquid alkali are added dropwise to control the pH value of the system to be 4.5-5.5; in the electrodialysis process, pure water is properly supplemented in the fresh water tank to maintain the liquid level to be slightly changed, and when the conductivity is smaller than 1236us/cm 2, the conductivity is slowly reduced, and the electrodialysis is stopped.
And sampling and detecting electrodialysis end point liquid, wherein the total amount of 4-methylcyclohexyl formic acid is 2.68%. After concentrating at 60-80 deg.c, 136.9g of water raffinate is added with 26.1g of barium hydroxide octahydrate for high temperature conversion. High-temperature conversion is carried out for 14 hours at the temperature of 190-220 ℃, the temperature is reduced to 22 ℃, 3.7g of carbon dioxide is introduced into the high-temperature conversion liquid, and the mixture is stirred for 0.5 hour after the addition; centrifuging to remove barium carbonate, concentrating the filtrate at 60-80deg.C under reduced pressure to obtain 47.3g water, cooling to 6deg.C, crystallizing, centrifuging to obtain refined tranexamic acid product, drying to obtain 8.42g, and collecting product with yield of 32.3% and purity of 99.89%, wherein 4-methylcyclohexyl formic acid is 0.07%.
The total content of 4-methylcyclohexyl formic acid in the filtrate is 3.9%, the residual quantity of the detected tranexamic acid in the residual liquid is 13.5g, the total quantity of the tranexamic acid in the feed liquid after electrodialysis is 21.9g, and the theoretical quantity is 26.0g, namely the loss of electrodialysis is 4.1g, and the loss rate is 15.8%.
Example 2
Ammonia toluic acid (50.3 g) was added to water (1650.5 g) at room temperature, and concentrated sulfuric acid (29.8 g) was slowly added dropwise; after the addition, heating to 80-90 ℃, and stirring and dissolving completely; filtering, transferring the filtrate into a hydrogenation kettle, and adding platinum dioxide; after the replacement is finished, starting hydrogenation; and filtering to separate the catalyst and applying the catalyst after the hydrogen pressure is not reduced.
Concentrating the obtained hydrogenated liquid to obtain 1229.8g of water, transferring the concentrated hydrogenated liquid into an electrodialysis fresh water tank after the concentration of the tranexamic acid mixture is about 10.3%, dropwise adding alkali to adjust pH=8.25, recording the liquid level of the fresh water tank, and starting electrodialysis; the voltage is 100-200V and the current is 60-80A in the electrodialysis process; simultaneously, hydrochloric acid and liquid alkali are added dropwise to control the pH value of the system to be 8.0-8.5; in the electrodialysis process, the proper replenishment of pure water in the fresh water tank maintains the liquid level unchanged little, and the electrodialysis end point is considered when the conductivity is 365us/cm 2. And (3) sampling and detecting electrodialysis end point liquid, and completely removing 4-methylcyclohexyl formic acid.
Concentrating the electrodialysis end point solution to obtain 336.9g of water, adding 52.2g of barium hydroxide octahydrate, performing high-temperature conversion, maintaining the temperature at 190-220 ℃ for 15 hours, cooling to 27 ℃, introducing 7.3g of carbon dioxide into the high-temperature conversion solution, and stirring for 0.5 hour after adding; centrifuging to remove barium carbonate, concentrating the filtrate at 60-80deg.C under reduced pressure to obtain 98.6g water, cooling to 6deg.C, and centrifuging to obtain refined tranexamic acid product; continuously concentrating the filtrate at 60-80deg.C under reduced pressure to obtain 30.2 water, cooling to 5-15deg.C, and centrifuging to obtain refined tranexamic acid product; combining the two refined products, and drying to obtain 35.9g, wherein the total yield is 69.0% and the purity is 100%; the mother liquor is directly applied to the next batch of high transfer liquor.
Example 3
Ammonia toluic acid (50.0 g) was added to water (1650.4 g) at room temperature, and concentrated sulfuric acid (29.8 g) was slowly added dropwise; after the addition, heating to 80-90 ℃, and stirring and dissolving completely; filtering, transferring the filtrate into a hydrogenation kettle, and adding platinum dioxide; after the replacement is finished, starting hydrogenation; and filtering to separate the catalyst and applying the catalyst after the hydrogen pressure is not reduced.
Concentrating the obtained hydrogenated liquid to obtain 1377.5g of water, wherein the concentration of the tranexamic acid mixture is about 14.7%, transferring the concentrated liquid into an electrodialysis fresh water tank, adding dropwise alkali to adjust pH=6.82, recording the liquid level of the fresh water tank, and starting electrodialysis; the voltage is 100-200V and the current is 60-80A in the electrodialysis process; simultaneously, hydrochloric acid and liquid alkali are added dropwise to control the pH value of the system to be between 6.5 and 7.0; in the electrodialysis process, pure water is properly supplemented in the fresh water tank to maintain the liquid level to be little changed. When the conductivity is 189us/cm 2, the electrodialysis end point is regarded as an electrodialysis end point liquid sampling detection, and the 4-methylcyclohexyl formic acid is completely removed.
Concentrating the electrodialysis end point solution to 206.5g, adding 52.2g of barium hydroxide octahydrate into the concentrated solution, performing high-temperature conversion, maintaining the temperature at 190-220 ℃ for 12 hours, cooling to 25 ℃, introducing 7.3g of carbon dioxide into the high-temperature conversion solution, and stirring for 0.5h after adding; centrifuging to remove barium carbonate, concentrating the filtrate at 60-80deg.C under reduced pressure to obtain 83.3g water, cooling to 2deg.C, and centrifuging to obtain refined tranexamic acid product; continuously concentrating the filtrate at 60-80 ℃ under reduced pressure to obtain 26.8g of water, cooling to 10 ℃, and centrifuging to obtain refined tranexamic acid; combining the two refined products, and drying to obtain 35.1g, wherein the total yield is 67.5% and the purity is 100%; the mother liquor is directly applied to the next batch of high transfer liquor.
The foregoing embodiments have described the technical solutions and advantages of the present invention in detail, and it should be understood that the foregoing embodiments are merely illustrative of the present invention and are not intended to limit the invention, and any modifications, additions, substitutions and the like that fall within the principles of the present invention should be included in the scope of the invention.
Claims (4)
1. The synthesis method of tranexamic acid is characterized by comprising the following steps:
(1) Adding the aminomethylbenzoic acid into water, adding concentrated sulfuric acid, heating to dissolve, filtering, and carrying out hydrogenation reduction on the filtrate to obtain an aminomethylbenzoic acid hydrogenated solution;
(2) Concentrating the aminomethylbenzoic acid hydrogenated liquid until the concentration of the aminomethylbenzoic acid is 10-15%, and transferring the concentrated aminomethylbenzoic acid hydrogenated liquid into an electrodialysis light water tank for electrodialysis; controlling the pH value in the fresh water tank to be 6.5-8.5 in the electrodialysis process;
(3) After electrodialysis is finished, adding alkali into electrodialysis end point liquid in a fresh water tank, heating to perform transposition reaction, and performing aftertreatment to obtain the tranexamic acid, wherein the method comprises the following steps of:
(3-1) concentrating electrodialysis end point liquid, adding alkali, and heating to perform transposition reaction; the concentration water yield is 60-70% of the total volume of the concentrate;
(3-2) introducing carbon dioxide into the transposition reaction liquid, centrifuging to recover barium carbonate, and re-synthesizing the recovered barium carbonate into barium hydroxide for reuse; concentrating the filtrate, cooling and crystallizing to obtain tranexamic acid, concentrating, cooling and crystallizing at least twice, wherein the water content of the first concentrated solution is 60-70% of the total volume of the first concentrated solution; the water yield of the second concentration is 50-60% of the total volume of the second concentration; the mother liquor is then incorporated into the electrodialysis endpoint liquor of the next batch for the metathesis reaction.
2. The method for synthesizing tranexamic acid according to claim 1, wherein the electrodialysis voltage is 100-200V and the current is 60-80A.
3. The method for synthesizing tranexamic acid according to claim 1, wherein electrodialysis is completed when the conductivity in the fresh water tank is not more than 500us/cm 2.
4. The method for synthesizing tranexamic acid according to claim 1, wherein in the step (3), the base is barium hydroxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310724238.8A CN116730856B (en) | 2023-06-19 | 2023-06-19 | Synthesis method of tranexamic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310724238.8A CN116730856B (en) | 2023-06-19 | 2023-06-19 | Synthesis method of tranexamic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116730856A CN116730856A (en) | 2023-09-12 |
| CN116730856B true CN116730856B (en) | 2024-06-07 |
Family
ID=87912989
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310724238.8A Active CN116730856B (en) | 2023-06-19 | 2023-06-19 | Synthesis method of tranexamic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116730856B (en) |
Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63115854A (en) * | 1986-11-04 | 1988-05-20 | Mitsui Toatsu Chem Inc | Production of aminoethylsulfonic acid |
| CN1218795A (en) * | 1997-11-27 | 1999-06-09 | 隆萨股份公司 | Process for preparation of aminoalcohol derivatives and their further conversion to (1R,4S)-4-((2-amino-6-chloro-5-formamido-4-pyrimidinyl) amino)-2-cyclopentenyl-1-methanol |
| CN1524847A (en) * | 2003-02-28 | 2004-09-01 | 湖南洞庭药业股份有限公司 | Producing method of of tranexamic acid |
| CN103172528A (en) * | 2011-12-23 | 2013-06-26 | 烟台万润精细化工股份有限公司 | Tranexamic acid preparation method |
| CN104710319A (en) * | 2015-01-22 | 2015-06-17 | 重庆紫光化工股份有限公司 | Green environmentally-friendly method for combined production of amino acid and analog thereof by using membrane integration technology |
| CN107954887A (en) * | 2017-11-27 | 2018-04-24 | 常州寅盛药业有限公司 | A kind of method for preparing tranexamic acid |
| CN110344077A (en) * | 2019-07-01 | 2019-10-18 | 吉林大学 | A method of by l-cysteine electrochemistry formated n-acetyl-L-cysteine |
| CN111233658A (en) * | 2020-02-27 | 2020-06-05 | 陕西嘉禾生物科技股份有限公司 | Method for extracting shikimic acid and quinic acid from folium ginkgo |
| WO2021111475A1 (en) * | 2019-12-05 | 2021-06-10 | Kawman Pharma Private Limited | Process for preparing tranexamic acid |
| CN113214103A (en) * | 2021-04-23 | 2021-08-06 | 内蒙古常盛制药有限公司 | Subsequent treatment method for enzymatic synthesis of D-p-hydroxyphenylglycine |
| CN113956173A (en) * | 2021-11-10 | 2022-01-21 | 烟台万润药业有限公司 | Preparation method of tranexamic acid |
| CN115108963A (en) * | 2021-03-19 | 2022-09-27 | 上海启讯医药科技有限公司 | Compound and preparation method and application thereof |
-
2023
- 2023-06-19 CN CN202310724238.8A patent/CN116730856B/en active Active
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63115854A (en) * | 1986-11-04 | 1988-05-20 | Mitsui Toatsu Chem Inc | Production of aminoethylsulfonic acid |
| CN1218795A (en) * | 1997-11-27 | 1999-06-09 | 隆萨股份公司 | Process for preparation of aminoalcohol derivatives and their further conversion to (1R,4S)-4-((2-amino-6-chloro-5-formamido-4-pyrimidinyl) amino)-2-cyclopentenyl-1-methanol |
| CN1524847A (en) * | 2003-02-28 | 2004-09-01 | 湖南洞庭药业股份有限公司 | Producing method of of tranexamic acid |
| CN103172528A (en) * | 2011-12-23 | 2013-06-26 | 烟台万润精细化工股份有限公司 | Tranexamic acid preparation method |
| CN104710319A (en) * | 2015-01-22 | 2015-06-17 | 重庆紫光化工股份有限公司 | Green environmentally-friendly method for combined production of amino acid and analog thereof by using membrane integration technology |
| CN107954887A (en) * | 2017-11-27 | 2018-04-24 | 常州寅盛药业有限公司 | A kind of method for preparing tranexamic acid |
| CN110344077A (en) * | 2019-07-01 | 2019-10-18 | 吉林大学 | A method of by l-cysteine electrochemistry formated n-acetyl-L-cysteine |
| WO2021111475A1 (en) * | 2019-12-05 | 2021-06-10 | Kawman Pharma Private Limited | Process for preparing tranexamic acid |
| CN111233658A (en) * | 2020-02-27 | 2020-06-05 | 陕西嘉禾生物科技股份有限公司 | Method for extracting shikimic acid and quinic acid from folium ginkgo |
| CN115108963A (en) * | 2021-03-19 | 2022-09-27 | 上海启讯医药科技有限公司 | Compound and preparation method and application thereof |
| CN113214103A (en) * | 2021-04-23 | 2021-08-06 | 内蒙古常盛制药有限公司 | Subsequent treatment method for enzymatic synthesis of D-p-hydroxyphenylglycine |
| CN113956173A (en) * | 2021-11-10 | 2022-01-21 | 烟台万润药业有限公司 | Preparation method of tranexamic acid |
Non-Patent Citations (1)
| Title |
|---|
| 吴梧桐等.《生物制药工艺学》.中国医药科技出版社,2015,第334页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116730856A (en) | 2023-09-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2787596C (en) | Process for manufacturing succinic acid | |
| CN109516479B (en) | Preparation method of battery-grade lithium hydroxide | |
| US5852211A (en) | Process for the conversion of the sodium salt of 2-keto-L-gulonic acid to the free acid | |
| CN111548323B (en) | Recovery method of aminothiazoly loximate | |
| TWI225900B (en) | Process for producing sodium persulfate | |
| JP2019131448A (en) | Method for producing lithium hydroxide | |
| US2746916A (en) | Production of lactobionic acid and its delta-lactone | |
| CN116730856B (en) | Synthesis method of tranexamic acid | |
| JP5052234B2 (en) | Method for producing succinic acid | |
| CN107835798B (en) | Process for producing succinic acid | |
| CN104355990B (en) | Method for recycling and mechanically using L- (+) -tartaric acid in D-ethyl ester production | |
| CN110563699A (en) | Post-treatment purification method of fluoro pranoprazan intermediate | |
| CN115611758A (en) | Production method of sarcosine | |
| CN111732506B (en) | Method for separating and extracting high-purity malic acid | |
| CN111662199A (en) | Refining method for recovering beta-aminopropionic acid | |
| CN112661719B (en) | Clean preparation process of aminothiazoly loximate | |
| CN104326901B (en) | Method for recycling and mechanically using L- (+) -tartaric acid in D-ethyl ester production | |
| JP2001003187A (en) | Production of sodium persulfate | |
| CN111635419B (en) | Method for treating cefdinir refined mother liquor | |
| CN110498741B (en) | Purification method of discharged sodium oxalate in alumina process | |
| US2724724A (en) | Preparation of concentrated solutions of alkylchlorophenoxyacetates | |
| CN117165961A (en) | Preparation method of electronic grade ammonium fluoride | |
| CN117447507A (en) | Method for recovering 4-BMA from 4-BMA mother liquor | |
| CN114620760A (en) | Copper sulfate recovery treatment process in production process of methyl o-formate benzenesulfonamide | |
| CN110606803A (en) | Method for recovering tartaric acid from calcium tartrate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant |