CN114524771A - Preparation method of 6-hydroxy-2,4,5-triaminopyrimidine sulfate - Google Patents
Preparation method of 6-hydroxy-2,4,5-triaminopyrimidine sulfate Download PDFInfo
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- CN114524771A CN114524771A CN202011316595.3A CN202011316595A CN114524771A CN 114524771 A CN114524771 A CN 114524771A CN 202011316595 A CN202011316595 A CN 202011316595A CN 114524771 A CN114524771 A CN 114524771A
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- NHIKDNWKXUBYHV-UHFFFAOYSA-N 2,3-dihydro-1h-isoindole-5-carbonitrile Chemical compound N#CC1=CC=C2CNCC2=C1 NHIKDNWKXUBYHV-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 60
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 46
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 24
- ZZTURJAZCMUWEP-UHFFFAOYSA-N diaminomethylideneazanium;hydrogen sulfate Chemical compound NC(N)=N.OS(O)(=O)=O ZZTURJAZCMUWEP-UHFFFAOYSA-N 0.000 claims abstract description 23
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 15
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 43
- 239000012065 filter cake Substances 0.000 claims description 30
- 238000007363 ring formation reaction Methods 0.000 claims description 29
- 238000005984 hydrogenation reaction Methods 0.000 claims description 28
- 235000010288 sodium nitrite Nutrition 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 238000001914 filtration Methods 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 27
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 22
- 238000007034 nitrosation reaction Methods 0.000 claims description 17
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 12
- 239000013078 crystal Substances 0.000 claims description 11
- 229910052759 nickel Inorganic materials 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 230000020477 pH reduction Effects 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 229920002472 Starch Polymers 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 239000008237 rinsing water Substances 0.000 claims description 9
- 235000019698 starch Nutrition 0.000 claims description 9
- 239000008107 starch Substances 0.000 claims description 9
- 238000012360 testing method Methods 0.000 claims description 9
- 238000006722 reduction reaction Methods 0.000 claims description 7
- -1 sodium alkoxide Chemical class 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 230000009935 nitrosation Effects 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 239000002994 raw material Substances 0.000 claims 1
- 239000002351 wastewater Substances 0.000 abstract description 16
- 239000000460 chlorine Substances 0.000 abstract description 15
- 229910052801 chlorine Inorganic materials 0.000 abstract description 15
- NDEMNVPZDAFUKN-UHFFFAOYSA-N guanidine;nitric acid Chemical compound NC(N)=N.O[N+]([O-])=O.O[N+]([O-])=O NDEMNVPZDAFUKN-UHFFFAOYSA-N 0.000 abstract description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 13
- 229960000789 guanidine hydrochloride Drugs 0.000 abstract description 13
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 abstract description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract description 8
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 abstract description 8
- 239000011780 sodium chloride Substances 0.000 abstract description 4
- 235000010344 sodium nitrate Nutrition 0.000 abstract description 4
- 239000004317 sodium nitrate Substances 0.000 abstract description 4
- 238000011161 development Methods 0.000 abstract description 3
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 8
- 238000003825 pressing Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 3
- SWELIMKTDYHAOY-UHFFFAOYSA-N 2,4-diamino-6-hydroxypyrimidine Chemical compound NC1=CC(=O)N=C(N)N1 SWELIMKTDYHAOY-UHFFFAOYSA-N 0.000 description 2
- 229960004150 aciclovir Drugs 0.000 description 2
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 230000003602 anti-herpes Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- SYEYEGBZVSWYPK-UHFFFAOYSA-N 2,5,6-triamino-4-hydroxypyrimidine Chemical compound NC1=NC(N)=C(N)C(O)=N1 SYEYEGBZVSWYPK-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- RSKNEEODWFLVFF-UHFFFAOYSA-N sulfuric acid;2,5,6-triamino-1h-pyrimidin-4-one Chemical compound OS(O)(=O)=O.NC1=NC(=O)C(N)=C(N)N1 RSKNEEODWFLVFF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
In order to solve the problems in the traditional preparation method of 6-hydroxy-2,4,5-triaminopyrimidine sulfate, the invention provides a new method for 6-hydroxy-2,4,5-triaminopyrimidine sulfate, which adopts guanidine sulfate to replace the traditional guanidine nitrate or guanidine hydrochloride, cyclizing with methyl cyanoacetate, nitrosating, catalytic hydrogenating, acidifying with sulfuric acid to obtain 6-hydroxy-2,4,5-triaminopyrimidine sulfate, avoiding generating sodium nitrate or sodium chloride, reducing total nitrogen or chlorine in subsequent wastewater, protecting environment, meanwhile, the reaction safety risk brought by guanidine nitrate or the product quality risk brought by guanidine hydrochloride can be avoided, and the sustainable development is facilitated.
Description
Technical Field
The invention belongs to the technical field of medicines and chemical engineering, and particularly relates to a preparation method of 6-hydroxy-2,4,5-triaminopyrimidine sulfate.
Background
Chemical name: 6-Hydroxy-2,4,5-triaminopyrimidine sulfate, having the English name of 6-Hydroxy-2,4,5-triaminopyrimidine sulfehydate, and having the structural formula (I) shown below.
It is an important intermediate of a series of high-efficiency and low-toxicity anti-herpes drugs such as acyclovir, famciclovir and the like.
Because acyclovir is an anti-herpes medicine with high efficiency and low toxicity, has wide market prospect, arouses wide attention of various medicine fields, and a plurality of reports about preparation methods of 6-hydroxy-2,4,5-triaminopyrimidine sulfate exist at present.
The preparation process of the 6-hydroxy-2,4,5-triaminopyrimidine sulfate is roughly divided into the following steps:
(1) by ring closure
Methyl cyanoacetate and guanidine nitrate or guanidine hydrochloride are cyclized in methanol solution under the catalytic action of sodium methoxide to generate 6-hydroxy-2, 4-diaminopyrimidine.
(2) Nitrosation
Nitrosation of the 5-position of the 6-hydroxy-2, 4-diaminopyrimidine ring is carried out with sodium nitrite/acid reagent.
(3) Catalytic hydrogenation
Reduction of nitroso groups to amino groups
(4) Acidifying to form salts
Acidifying with sulfuric acid to obtain 6-hydroxy-2,4,5-triaminopyrimidine sulfuric acid.
The cyclization in the 6-hydroxy-2,4,5-triaminopyrimidine sulfate is a very important step, and the step has very important significance in environmental protection and safety risk. In history, the research on the cyclization is mainly to perform the cyclization through guanidine nitrate or guanidine hydrochloride, because guanidine nitrate contains nitrate and guanidine hydrochloride contains halogen salt, a large amount of sodium nitrate or sodium chloride can be generated in the cyclization reaction process and brought into nitrosation reaction, a large amount of high-nitrogen or high-chlorine wastewater can be generated, great pressure is brought to environment-friendly treatment, meanwhile, guanidine nitrate belongs to explosive products due to the fact that the guanidine nitrate has a nitro group, the safety risk is high, the stability of guanidine hydrochloride is poor, the guanidine hydrochloride is easy to absorb moisture, the product quality risk is easy to cause, the product yield is reduced, and the production cost is improved.
Through the analysis, the guanidine sulfate is cyclized, so that sodium nitrate or sodium chloride can be prevented from being generated, total nitrogen or total chlorine in subsequent wastewater is reduced, the environment is protected, the safety risk caused by guanidine nitrate or the product quality risk caused by guanidine hydrochloride can be avoided, the product yield risk is reduced, and sustainable development is facilitated.
Disclosure of Invention
In view of the above-mentioned deficiencies, the present invention provides a novel process for the preparation of 6-hydroxy-2,4,5-triaminopyrimidine sulfate.
The technical scheme of the invention is as follows:
a process for preparing 6-hydroxy-2,4,5-triaminopyrimidine sulfate includes such steps as cyclization, nitrosation, catalytic hydrogenation, acidifying with sulfuric acid to obtain 6-hydroxy-2,4,5-triaminopyrimidine sulfate, and reacting on methyl cyanoacetate to obtain guanidine sulfate.
Further, the preparation method specifically comprises the following steps:
(1) adding guanidine sulfate into methanol, adding organic strong base sodium alkoxide, heating for dissociating for 1-2 hours, slowly dripping methyl cyanoacetate into the solution after dissociating is finished, and performing reflux cyclization reaction for 3-4 hours to obtain cyclization reaction liquid;
(2) distilling the cyclization reaction solution obtained in the step (1) to recover methanol, adding water, heating to 75-85 ℃, stirring to dissolve, cooling to 20-30 ℃, dropwise adding sulfuric acid, and adjusting the pH value to 1-2;
(3) slowly dripping the prepared sodium nitrite solution into the reaction system in the step (2) for nitrosation reaction to obtain a nitrite solution;
(4) filtering the nitrite solution in the step (3) to obtain nitrite wastewater and a nitrite filter cake. Compared with the traditional method that a great amount of high-nitrogen or high-chlorine wastewater is generated in the process of guanidine nitrate or guanidine hydrochloride cyclization reaction, the total nitrogen content and the total chlorine content in nitrite wastewater obtained by the method are greatly reduced. Rinsing the filter cake with water, and then adding the filter cake into a hydrogenation kettle to carry out hydrogenation reduction reaction to generate triamino solution;
(5) and (3) reacting the triamino solution obtained in the step (4) with dilute sulfuric acid to generate 6-hydroxy-2,4,5-triaminopyrimidine sulfate.
Further, in the step (1), the organic strong alkali sodium alkoxide is one or a mixture of sodium methoxide, sodium ethoxide and sodium tert-butoxide; the molar ratio of the guanidine sulfate to the organic strong base sodium alkoxide is 1: 4-4.4, wherein the molar ratio of the guanidine sulfate to the methyl cyanoacetate is 1: 2-2.2.
Further, the free temperature in the step (1) is 60-70 ℃;
further, the mass percentage concentration of the sulfuric acid adopted in the step (2) is 50-70%, and the molar ratio of the sulfuric acid to the guanidine sulfate is 1.1-1.3: 1
Further, the mass percentage concentration of the sodium nitrite solution in the step (3) is 30-50%, and the molar ratio of the sodium nitrite to the guanidine sulfate added in the step (1) is 2-2.4: 1.
Further, the nitrosation reaction temperature in the step (3) is 10-20 ℃, and the starch KI test paper turns blue by using the nitrite solution as a judgment standard of the reaction end point.
Further, the filter cake in the step (4) is rinsed by water, and the pH value of the rinsing water is detected to be 6-7.
Further, the hydrogenation reduction reaction in the step (4) is to add the rinsed nitrite filter cake into a hydrogenation kettle, add water, start stirring, add alkali liquor, and adjust the pH value to 13-14; then adding active nickel, starting stirring, replacing with nitrogen, filling hydrogen into a hydrogenation kettle, and carrying out hydrogenation reduction reaction to obtain a triamino substance solution; preferably, the alkali liquor is sodium hydroxide solution or potassium hydroxide solution, the dosage of the active nickel is 1-2% of the theoretical nitrite mass, and the hydrogenation reaction conditions are as follows: the temperature is 70-80 ℃, the pressure is 0.4-0.6MPa, and the reaction time is 1-2 hours.
Further, the step (5) is specifically operated as: and (3) filtering and separating the triamino substance solution obtained in the step (4), dropwise adding dilute sulfuric acid into the filtrate for acidification, adjusting the pH to 1, filtering and drying to obtain 6-hydroxy-2,4,5-triaminopyrimidine sulfate crystals, wherein the mass percentage concentration of the dilute sulfuric acid is 50-70%.
The invention has the beneficial effects that:
the invention provides a novel method for preparing 6-hydroxy-2,4,5-triaminopyrimidine sulfate, which adopts guanidine sulfate to replace the traditional guanidine nitrate or guanidine hydrochloride to perform cyclization with methyl cyanoacetate, avoids generating sodium nitrate or sodium chloride, reduces the total nitrogen or total chlorine in subsequent wastewater, is beneficial to environmental protection, can simultaneously avoid the reaction safety risk brought by guanidine nitrate or the product quality risk brought by guanidine hydrochloride and reduce the product yield risk, and the prepared 6-hydroxy-2,4,5-triaminopyrimidine sulfate has the crystal yield higher than 90 percent and the purity higher than 98 percent, and is beneficial to sustainable development.
Detailed Description
Example 1
(1) 40g of guanidine sulfate was added to 100g of methanol, 41g of solid sodium methoxide was added thereto, and the mixture was stirred and heated to 60 ℃ to dissociate the guanidine sulfate for 1 hour. Then, 37g of methyl cyanoacetate is slowly added into the reaction solution dropwise, and the reflux cyclization reaction is finished for 3 hours to obtain a cyclization reaction solution.
(2) Distilling the cyclization reaction solution obtained in the step (1) to recover a solvent methanol, adding 150g of water, stirring, heating to 80 ℃, dissolving, cooling to 20 ℃, dropwise adding 90g of sulfuric acid with the mass percentage concentration of 50%, acidifying, and adjusting the pH to 1 for later use.
(3) And (3) dissolving 27g of sodium nitrite in 40.5g of water to prepare a sodium nitrite solution with the mass percentage concentration of 40%, slowly dropwise adding the sodium nitrite solution into the step (2) for reaction, wherein the reaction temperature is 20 ℃, and the reaction end point is a nitrite solution to enable the starch KI test paper to turn blue, so as to obtain the nitrite solution.
(4) And (4) filtering after the nitrosation reaction in the step (3) is finished to obtain nitrite wastewater and a nitrite filter cake, wherein the nitrite filter pressing water contains total nitrogen 2680 and total chlorine 529. Rinsing the nitrite filter cake with water until the pH value of rinsing water is 7, directly adding the nitrite filter cake into a hydrogenation kettle without drying, then adding 800g of water, starting stirring, adjusting the pH value to 13 with 30% by mass of sodium hydroxide solution, then adding 0.6g of active nickel, replacing with nitrogen, filling hydrogen into the hydrogenation kettle to control the pressure to be 0.4Mpa, heating to 70 ℃, and finishing the reaction after 2 hours to obtain the triammonium solution.
(5) And (3) filtering and separating the triamino solution obtained in the step (4), dropwise adding 50 mass percent sulfuric acid into the filtrate to adjust the pH value to 1, continuously stirring for 30min for acidification, filtering and drying to obtain 81.9g of light yellow 6-hydroxy-2,4,5-triaminopyrimidine sulfate crystals with the purity of 98.6%.
Example 2
(1) 40g of guanidine sulfate is added into 100g of methanol, then 51.5g of solid sodium ethoxide is added, and the mixture is stirred and heated to 60 ℃ to be dissociated for 1 hour. Then, 36g of methyl cyanoacetate was slowly added dropwise to the reaction solution, and the reaction was terminated by refluxing for 3 hours to obtain a cyclization reaction solution.
(2) Distilling the cyclization reaction solution obtained in the step (1) to recover a solvent methanol, adding 150g of water, stirring, heating to 80 ℃, dissolving, cooling to 20 ℃, dropwise adding 90g of sulfuric acid with the mass percentage concentration of 50%, acidifying, and adjusting the pH to 1 for later use.
(3) And (3) dissolving 27g of sodium nitrite in 40.5g of water to prepare a sodium nitrite solution with the mass percentage concentration of 40%, slowly dropwise adding the sodium nitrite solution into the step (2) for reaction, wherein the reaction temperature is 10 ℃, and the reaction end point is a nitrite solution to enable the starch KI test paper to turn blue, so as to obtain the nitrite solution.
(4) And (3) filtering after the nitrosation reaction is finished to obtain nitrite wastewater and a nitrite filter cake, wherein nitrite filter pressing water total nitrogen is 2590, total chlorine is 537, the nitrite filter cake is rinsed by water until the pH of rinsing water is 7, the nitrite filter cake is directly added into a hydrogenation kettle without being dried, then 800g of water is added, stirring is started, the pH is adjusted to 13 by 30% sodium hydroxide solution in percentage by mass, then 0.6g of active nickel is added, after replacement by nitrogen, hydrogen is filled into the hydrogenation kettle to control the pressure to be 0.4MPa, the temperature is increased to 80 ℃, and the reaction is finished after 1 hour, so that the triammonium solution is obtained.
(5) And (3) filtering and separating the triamino solution obtained in the step (4), dropwise adding 50 mass percent sulfuric acid into the filtrate to adjust the pH value to 1, continuously stirring for 30min for acidification, filtering and drying to obtain yellowish 6-hydroxy-2,4,5-triaminopyrimidine sulfate crystals 81.1g with the purity of 98.4%.
Example 3
(1) 40g of guanidine sulfate is added into 100g of methanol, 73g of solid sodium tert-butoxide is added, and the mixture is stirred and heated to 60 ℃ to be dissociated for 1 hour. Then, 36g of methyl cyanoacetate was slowly added dropwise to the reaction solution, and the reaction was terminated by refluxing for 3 hours to obtain a cyclization reaction solution.
(2) Distilling the cyclization reaction solution obtained in the step (1) to recover a solvent methanol, adding 150g of water, stirring, heating to 80 ℃, dissolving, cooling to 10 ℃, dropwise adding 90g of sulfuric acid with the mass percentage concentration of 50%, acidifying, and adjusting the pH to 2 for later use.
(3) And (3) dissolving 27g of sodium nitrite in 40.5g of water to prepare a sodium nitrite solution with the mass percentage concentration of 40%, slowly dropwise adding the sodium nitrite solution into the step (2) for reaction, wherein the reaction temperature is 20 ℃, and the reaction end point is a nitrite solution to enable the starch KI test paper to turn blue, so as to obtain the nitrite solution.
(4) And (3) filtering after the nitrosation reaction is finished to obtain nitrite wastewater and a nitrite filter cake, wherein the nitrite filter pressing water contains 2720 total nitrogen, wherein the total chlorine is 552, the nitrite filter cake is rinsed by water until the pH value of the rinsing water is 7, the nitrite filter cake is directly added into a hydrogenation kettle without being dried, then 800g of water is added, stirring is started, the pH value is adjusted to 13 by using 30% sodium hydroxide solution in percentage by mass, then 0.6g of active nickel is added, after replacement by nitrogen, hydrogen is filled into the hydrogenation kettle to control the pressure to be 0.6MPa, the temperature is raised to 70 ℃, and the reaction is finished after 2 hours, so that the triammonium solution is obtained.
(5) And (3) filtering and separating the triamino solution obtained in the step (4), dripping sulfuric acid with the mass percentage concentration of 70% into the filtrate to adjust the pH value to 1, continuing stirring for 30min for acidification, filtering and drying to obtain light yellow 6-hydroxy-2,4,5-triaminopyrimidine sulfate crystals of 82.3g with the purity of 98.7%.
Comparative example 1
(1) 45g of guanidine nitrate was added to 100g of methanol, 41g of solid sodium methoxide was added thereto, and the mixture was stirred and heated to 60 ℃ to dissociate the guanidine nitrate for 1 hour. Then, 36g of methyl cyanoacetate was slowly added dropwise to the reaction solution, and the reaction was terminated by refluxing for 3 hours to obtain a cyclization reaction solution.
(2) Distilling the cyclization reaction solution obtained in the step (1) to recover a solvent methanol, adding 150g of water, stirring, heating to 80 ℃, dissolving, cooling to 20 ℃, dropwise adding 90g of sulfuric acid with the mass percentage concentration of 50%, acidifying, and adjusting the pH to 1 for later use.
(3) And (3) dissolving 27g of sodium nitrite in 40.5g of water to prepare a sodium nitrite solution with the mass percentage concentration of 40%, slowly dropwise adding the sodium nitrite solution into the step (2) for reaction, wherein the reaction temperature is 20 ℃, and the reaction end point is a nitrite solution to enable the starch KI test paper to turn blue, so as to obtain the nitrite solution.
(4) And (3) filtering after the nitrosation reaction is finished in the step (3) to obtain nitrite wastewater and a nitrite filter cake, wherein the nitrite filter pressing water contains total nitrogen 31240, the total chlorine is 559, the nitrite filter cake is rinsed by water until the pH of the rinsing water is 7, the nitrite filter cake is directly added into a hydrogenation kettle without being dried, then 800g of water is added, stirring is started, the pH is adjusted to 13 by using 30% sodium hydroxide solution in percentage by mass, then 0.6g of active nickel is added, after replacement by nitrogen, hydrogen is filled into the hydrogenation kettle to control the pressure to be 0.4MPa, the temperature is raised to 70 ℃, and the reaction is finished after 2 hours, so that the triammonium solution is obtained.
(5) And (3) filtering and separating the triamino solution obtained in the step (4), dropwise adding 50 mass percent sulfuric acid into the filtrate to adjust the pH value to 1, continuously stirring for 30min for acidification, filtering and drying to obtain 81.5g of light yellow 6-hydroxy-2,4,5-triaminopyrimidine sulfate crystals with the purity of 98.3%.
Comparative example 2
(1) Guanidine hydrochloride 35.5g was added to 100g of methanol, followed by solid sodium methoxide 41g, and the mixture was stirred and warmed to 60 ℃ to dissociate for 1 hour. Then, 36g of methyl cyanoacetate was slowly added dropwise to the reaction solution, and the reaction was terminated by refluxing for 3 hours to obtain a cyclization reaction solution.
(2) Distilling the cyclization reaction solution obtained in the step (1) to recover a solvent methanol, adding 150g of water, stirring, heating to 80 ℃, dissolving, cooling to 20 ℃, dropwise adding 90g of sulfuric acid with the mass percentage concentration of 50%, acidifying, and adjusting the pH to 1 for later use.
(3) And (3) dissolving 27g of sodium nitrite in 40.5g of water to prepare a sodium nitrite solution with the mass percentage concentration of 40%, slowly dropwise adding the sodium nitrite solution into the step (2) for reaction, wherein the reaction temperature is 20 ℃, and the reaction end point is a nitrite solution to enable the starch KI test paper to turn blue, so as to obtain the nitrite solution.
(4) And (3) filtering after the nitrosation reaction is finished in the step (3) to obtain nitrite wastewater and a nitrite filter cake, wherein the nitrite filter pressing water contains total nitrogen 2630 and total chlorine 34580, the nitrite filter cake is rinsed by water until the pH value of the rinsing water is 7, the nitrite filter cake is directly added into a hydrogenation kettle without being dried, then 800g of water is added, stirring is started, the pH value is adjusted to 13 by using a 30% sodium hydroxide solution in percentage by mass, then 0.6g of active nickel is added, after replacement by nitrogen, hydrogen is filled into the hydrogenation kettle to control the pressure to be 0.4MPa, the temperature is raised to 70 ℃, and the reaction is finished after 2 hours, so that the triammonium solution is obtained.
(5) And (3) filtering and separating the triamino solution obtained in the step (4), dropwise adding 50 mass percent sulfuric acid into the filtrate to adjust the pH value to 1, continuously stirring for 30min for acidification, filtering and drying to obtain yellowish 6-hydroxy-2,4,5-triaminopyrimidine sulfate crystals of 77.9g with the purity of 98.1%.
Comparative example 3
(1) 40g of guanidine sulfate was added to 100g of methanol, and then 35g of solid sodium methoxide was added thereto, and the mixture was stirred and heated to 50 ℃ to dissociate the guanidine sulfate for 1 hour. Then, 36g of methyl cyanoacetate was slowly added dropwise to the reaction solution, and the reaction was terminated by refluxing for 3 hours to obtain a cyclization reaction solution.
(2) Distilling the cyclization reaction solution obtained in the step (1) to recover a solvent methanol, adding 150g of water, stirring, heating to 80 ℃, dissolving, cooling to 20 ℃, dropwise adding 90g of sulfuric acid with the mass percentage concentration of 50%, acidifying, and adjusting the pH to 1 for later use.
(3) And (3) dissolving 27g of sodium nitrite in 40.5g of water to prepare a sodium nitrite solution with the mass percentage concentration of 40%, slowly dropwise adding the sodium nitrite solution into the step (2) for reaction, wherein the reaction temperature is 20 ℃, and the reaction end point is a nitrite solution to enable the starch KI test paper to turn blue, so as to obtain the nitrite solution.
(4) And (3) filtering after the nitrosation reaction is finished in the step (3) to obtain nitrite wastewater and a nitrite filter cake, wherein the nitrite filter pressing water total nitrogen 3895 is used, the total chlorine is 591, the nitrite filter cake is rinsed by water until the pH of rinsing water is 4, the nitrite filter cake is directly added into a hydrogenation kettle without being dried, then 800g of water is added, stirring is started, the pH is adjusted to 13 by using a sodium hydroxide solution with the mass percentage concentration of 30%, then 0.6g of active nickel is added, after replacement by nitrogen, hydrogen is filled into the hydrogenation kettle to control the pressure to be 0.4MPa, the temperature is raised to 70 ℃, and the reaction is finished after 2 hours, so that the triammonium solution is obtained.
(5) And (3) filtering and separating the triamino solution obtained in the step (4), dropwise adding 50 mass percent sulfuric acid into the filtrate to adjust the pH value to 1, continuously stirring for 30min for acidification, filtering and drying to obtain 51g of light yellow 6-hydroxy-2,4,5-triaminopyrimidine sulfate crystals with the purity of 90.2%.
Comparative example 4
(1) 40g of guanidine sulfate was added to 100g of methanol, 50g of solid sodium methoxide was added thereto, and the mixture was stirred and heated to 50 ℃ to dissociate the guanidine sulfate for 1 hour. Then, 36g of methyl cyanoacetate was slowly added dropwise to the reaction solution, and the reaction was terminated by refluxing for 3 hours to obtain a cyclization reaction solution.
(2) Distilling the cyclization reaction solution obtained in the step (1) to recover a solvent methanol, adding 150g of water, stirring, heating to 80 ℃, dissolving, cooling to 20 ℃, dropwise adding 80g of sulfuric acid with the mass percentage concentration of 50%, acidifying, and adjusting the pH to 1 for later use.
(3) Dissolving 22g of sodium nitrite in 40.5g of water to prepare a sodium nitrite solution with the mass percentage concentration of 40%, slowly dropwise adding the sodium nitrite solution into the step (2) for reaction, wherein the reaction temperature is 20 ℃, and the reaction end point is that the nitrite solution turns blue on the starch KI test paper to obtain the nitrite solution
(4) And (3) filtering after the nitrosation reaction is finished in the step (3) to obtain nitrite wastewater and a nitrite filter cake, wherein the nitrite filter pressing water contains total nitrogen 4765, total chlorine is 535, the nitrite filter cake is rinsed by water until the pH of rinsing water is 7, the nitrite filter cake is directly added into a hydrogenation kettle without being dried, then 800g of water is added, stirring is started, the pH is adjusted to 13 by using a sodium hydroxide solution with the mass percentage concentration of 30%, then 0.6g of active nickel is added, after replacement by nitrogen, hydrogen is filled into the hydrogenation kettle to control the pressure to be 0.4MPa, the temperature is raised to 70 ℃, and the reaction is finished after 2 hours, so that the triammonium solution is obtained.
(5) And (3) filtering and separating the triamino solution obtained in the step (4), dripping sulfuric acid with the mass percentage concentration of 30% into the filtrate to adjust the pH value to 1, continuing stirring for 30min for acidification, filtering and drying to obtain 60.6g of light yellow 6-hydroxy-2,4,5-triaminopyrimidine sulfate crystals with the purity of 89.3%.
Compared with the traditional method for cyclizing guanidine nitrate or guanidine hydrochloride and methyl cyanoacetate, the method disclosed by the invention can effectively reduce the total nitrogen or total chlorine in the subsequent wastewater; and moreover, the method can reduce the total nitrogen or chlorine in the wastewater and simultaneously obtain excellent 6-hydroxy-2,4,5-triaminopyrimidine sulfate crystal yield and purity without any operation parameters.
The above is only a preferred embodiment of the present invention, and it should be noted that the above preferred embodiment should not be considered as limiting the present invention, and the protection scope of the present invention should be subject to the scope defined by the claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and such modifications and adaptations are intended to be within the scope of the invention.
Claims (10)
1. A preparation method of 6-hydroxy-2,4,5-triaminopyrimidine sulfate is characterized in that guanidine sulfate and methyl cyanoacetate are used as raw materials, and the 6-hydroxy-2,4,5-triaminopyrimidine sulfate is prepared through cyclization, nitrosation, catalytic hydrogenation and acidification and salt formation by sulfuric acid.
2. The process for the preparation of 6-hydroxy-2,4,5-triaminopyrimidine sulfate according to claim 1, characterized in that it comprises in particular the steps of:
(1) adding guanidine sulfate into methanol, adding organic strong base sodium alkoxide, heating to dissociate for 1-2 hours, after dissociating, slowly dropwise adding methyl cyanoacetate into the solution, and performing reflux cyclization reaction for 3-4 hours to obtain a cyclization reaction solution;
(2) distilling the cyclization reaction solution obtained in the step (1) to recover methanol, adding water, heating to 75-85 ℃, stirring to dissolve, cooling to 20-30 ℃, dropwise adding sulfuric acid, and adjusting the pH value to 1-2;
(3) slowly dripping the prepared sodium nitrite solution into the reaction system in the step (2) for nitrosation reaction to obtain a nitrite solution;
(4) filtering the nitrite solution obtained in the step (3), rinsing a filter cake with water, and then adding the filter cake into a hydrogenation kettle to perform hydrogenation reduction reaction to generate a triammonium solution;
(5) and (3) reacting the triamino solution obtained in the step (4) with dilute sulfuric acid to generate 6-hydroxy-2,4,5-triaminopyrimidine sulfate.
3. The method for preparing 6-hydroxy-2,4,5-triaminopyrimidine sulfate according to claim 2, wherein in step (1), the strong organic alkali sodium alkoxide is one or more of sodium methoxide, sodium ethoxide and sodium tert-butoxide; the molar ratio of the guanidine sulfate to the organic strong base sodium alkoxide is 1: 4-4.4; the molar ratio of the guanidine sulfate to the methyl cyanoacetate is 1: 2-2.2.
4. The process for preparing 6-hydroxy-2,4,5-triaminopyrimidine sulfate according to claim 2, wherein the free temperature in step (1) is 60 to 70 ℃.
5. The method for preparing 6-hydroxy-2,4,5-triaminopyrimidine sulfate according to claim 2, wherein the concentration of sulfuric acid used in step (2) is 50 to 70% by mass, and the molar ratio of sulfuric acid to guanidine sulfate in step (2) is 2.3 to 2.6: 1.
6. the method for preparing 6-hydroxy-2,4,5-triaminopyrimidine sulfate according to claim 2, wherein the concentration of the sodium nitrite solution in step (3) is 30 to 50% by mass, and the molar ratio of sodium nitrite to guanidine sulfate added in step (1) is 2 to 2.4: 1.
7. The preparation method of 6-hydroxy-2,4,5-triaminopyrimidine sulfate according to claim 2, characterized in that the nitrosation reaction temperature in step (3) is 10-20 ℃, and starch KI test paper is turned blue by using a nitrosation solution as a judgment standard of a reaction end point.
8. The preparation method of 6-hydroxy-2,4,5-triaminopyrimidine sulfate according to claim 2, characterized in that the filter cake in the step (4) is rinsed with water, and the pH of the rinsing water is detected to be 6-7.
9. The preparation method of 6-hydroxy-2,4,5-triaminopyrimidine sulfate according to claim 2, characterized in that the hydrogenation reduction reaction in step (4) is to add the rinsed nitrite filter cake into a hydrogenation kettle, add water, start stirring, add alkali liquor, and adjust the pH value to 13-14; then adding active nickel, starting stirring, replacing with nitrogen, filling hydrogen into the hydrogenation kettle, and carrying out hydrogenation reduction reaction to obtain a triamino substance solution; preferably, the alkali liquor is a sodium hydroxide solution or a potassium hydroxide solution, the amount of the active nickel is 1-2% of the theoretical nitrite mass, and the hydrogenation reaction conditions are as follows: the temperature is 70-80 ℃, the pressure is 0.4-0.6MPa, and the reaction time is 1-2 hours.
10. A process for the preparation of 6-hydroxy-2,4,5-triaminopyrimidine sulfate according to claim 2, characterized in that step (5) is specifically operated as: and (5) filtering and separating the triamino substance solution obtained in the step (4), dropwise adding dilute sulfuric acid into the filtrate for acidification, filtering and drying to obtain 6-hydroxy-2,4,5-triaminopyrimidine sulfate crystals, wherein the mass percentage concentration of the dilute sulfuric acid is 50-70%.
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| CN115650922A (en) * | 2022-11-04 | 2023-01-31 | 南通市常海食品添加剂有限公司 | Method for preparing 2,4,5-triamino-6-hydroxypyrimidine sulfate through microchannel reaction |
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