CN115636781A - Synthesis method of 2, 4-dimethyl-5-aminopyridine - Google Patents
Synthesis method of 2, 4-dimethyl-5-aminopyridine Download PDFInfo
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- SHSQTJRJQHPJRQ-UHFFFAOYSA-N 4,6-dimethylpyridin-3-amine Chemical compound CC1=CC(C)=C(N)C=N1 SHSQTJRJQHPJRQ-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000001308 synthesis method Methods 0.000 title description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 40
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims abstract description 28
- BZIDYPIJVCEUIB-UHFFFAOYSA-N 4,6-dimethylpyridine-3-carbonitrile Chemical compound CC1=CC(C)=C(C#N)C=N1 BZIDYPIJVCEUIB-UHFFFAOYSA-N 0.000 claims abstract description 26
- OCYMJCILWYHKAU-UHFFFAOYSA-N 4,6-dimethyl-2-oxo-1h-pyridine-3-carbonitrile Chemical compound CC1=CC(C)=C(C#N)C(O)=N1 OCYMJCILWYHKAU-UHFFFAOYSA-N 0.000 claims abstract description 24
- RETJKTAVEQPNMH-UHFFFAOYSA-N 2-chloro-4,6-dimethylpyridine-3-carbonitrile Chemical compound CC1=CC(C)=C(C#N)C(Cl)=N1 RETJKTAVEQPNMH-UHFFFAOYSA-N 0.000 claims abstract description 23
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 23
- 230000008569 process Effects 0.000 claims abstract description 22
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 16
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000005708 Sodium hypochlorite Substances 0.000 claims abstract description 10
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims abstract description 10
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 238000006731 degradation reaction Methods 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- 239000007864 aqueous solution Substances 0.000 claims description 30
- 239000002244 precipitate Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 18
- 239000011541 reaction mixture Substances 0.000 claims description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 239000003638 chemical reducing agent Substances 0.000 claims description 12
- 239000005457 ice water Substances 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 9
- 239000012320 chlorinating reagent Substances 0.000 claims description 9
- 230000003472 neutralizing effect Effects 0.000 claims description 9
- 238000000967 suction filtration Methods 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 7
- 239000001099 ammonium carbonate Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims description 4
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000002386 leaching Methods 0.000 claims description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000006872 improvement Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- 238000010438 heat treatment Methods 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- GMAJNANLBOHCAU-UHFFFAOYSA-N 2,4-dimethyl-5-nitropyridine Chemical compound CC1=CC(C)=C([N+]([O-])=O)C=N1 GMAJNANLBOHCAU-UHFFFAOYSA-N 0.000 description 3
- DVBWVOJRHMVPTR-UHFFFAOYSA-N 4,6-dimethylpyridine-3-carboxamide Chemical compound CC1=CC(C)=C(C(N)=O)C=N1 DVBWVOJRHMVPTR-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000018 receptor agonist Substances 0.000 description 3
- 229940044601 receptor agonist Drugs 0.000 description 3
- 239000008399 tap water Substances 0.000 description 3
- 235000020679 tap water Nutrition 0.000 description 3
- JYYNAJVZFGKDEQ-UHFFFAOYSA-N 2,4-Dimethylpyridine Chemical compound CC1=CC=NC(C)=C1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GBBSAMQTQCPOBF-UHFFFAOYSA-N 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane Chemical compound CB1OB(C)OB(C)O1 GBBSAMQTQCPOBF-UHFFFAOYSA-N 0.000 description 1
- MOQKFCFVTVIJJS-UHFFFAOYSA-N 2,4-dimethyl-3-nitropyridine Chemical compound CC1=CC=NC(C)=C1[N+]([O-])=O MOQKFCFVTVIJJS-UHFFFAOYSA-N 0.000 description 1
- BNRMNJDPIILASR-UHFFFAOYSA-N 2-(furan-2-yl)-7h-purine Chemical class C1=COC(C=2N=C3N=CNC3=CN=2)=C1 BNRMNJDPIILASR-UHFFFAOYSA-N 0.000 description 1
- HWZUMEVIIGNXGM-UHFFFAOYSA-N 2-chloro-4-methyl-5-nitropyridine Chemical compound CC1=CC(Cl)=NC=C1[N+]([O-])=O HWZUMEVIIGNXGM-UHFFFAOYSA-N 0.000 description 1
- 102000009346 Adenosine receptors Human genes 0.000 description 1
- 108050000203 Adenosine receptors Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
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Abstract
The invention discloses a method for synthesizing 2, 4-dimethyl-5-aminopyridine, which is characterized by comprising the following steps: (1) Reacting acetylacetone with cyanoacetamide to obtain 3-cyano-4, 6-dimethyl-2-hydroxypyridine; (2) Reacting 3-cyano-4, 6-dimethyl-2-hydroxypyridine with a chlorinated reagent to obtain 2-chloro-3-cyano-4, 6-dimethylpyridine; (3) Reacting 2-chloro-3-cyano-4, 6-dimethylpyridine with a reducing reagent to obtain 4, 6-dimethyl-3-cyanopyridine; (4) Reacting 4, 6-dimethyl-3-cyanopyridine with sulfuric acid to obtain 4, 6-dimethyl-3-formamide pyridine; (5) The 4, 6-dimethyl-3-formamide pyridine and sodium hypobromite or sodium hypochlorite are subjected to Hofmann degradation reaction to obtain the product, and the method has the advantages of easily obtained raw materials, low price, mild reaction conditions, safety, effective improvement of process yield and suitability for industrial mass production.
Description
Technical Field
The invention relates to the field of synthesis of medicine and pesticide intermediates, in particular to a synthesis method of 2, 4-dimethyl-5-aminopyridine.
Background
G protein-coupled adenosine receptors play an important role in the regulation of a wide range of physiological functions. In particular, A3 receptor agonists have been identified for the treatment of cardiac ischemia and accordingly, a number of compounds have been evaluated for selective A3 receptor agonist activity. N6-substituted purinyl furan nuclear amide 1 (structural formula shown below) was selected as the A3 receptor agonist to be evaluated. And 2, 4-dimethyl-5-aminopyridine is an important intermediate for synthesizing the same.
The existing 2, 4-dimethyl-5-aminopyridine synthesis methods comprise two methods, the first technology is to use 2, 4-dimethylpyridine as a starting material, obtain a mixture of 2, 4-dimethyl-5-nitropyridine and 2, 4-dimethyl-3-nitropyridine by mixed acid nitration, only obtain about 5% of 2, 4-dimethyl-5-nitropyridine after separation and purification (a synthesis scheme is shown in the figure below), and then obtain the 2, 4-dimethyl-5-aminopyridine by catalytic hydrogenation reduction of nitro, wherein the total yield is less than 5%, so that the process has no great application value in large-scale production.
Another process uses trimethylcyclotriboroxane and 2-chloro-5-nitro-4-methylpyridine as starting materials to produce 2, 4-dimethyl-5-nitropyridine under the catalysis of tetrakis (triphenylphosphine) palladium, and then the nitro group is reduced by catalytic hydrogenation to obtain 2, 4-dimethyl-5-aminopyridine (see a synthesis scheme shown in a figure below). This process is very limited in practical application.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a synthetic method of 2, 4-dimethyl-5-aminopyridine, which has the advantages of easily obtained raw materials, low price, mild reaction conditions, safety, effective improvement of process yield and suitability for industrial mass production.
The technical scheme adopted by the invention for solving the technical problems is as follows: a method for synthesizing 2, 4-dimethyl-5-aminopyridine comprises the following steps:
(1) Reacting acetylacetone with cyanoacetamide to obtain 3-cyano-4, 6-dimethyl-2-hydroxypyridine (compound 2);
(2) Reacting 3-cyano-4, 6-dimethyl-2-hydroxypyridine with a chlorinating agent to obtain 2-chloro-3-cyano-4, 6-dimethylpyridine (compound 3);
(3) Reacting 2-chloro-3-cyano-4, 6-dimethylpyridine with a reducing agent to obtain 4, 6-dimethyl-3-cyanopyridine (compound 4);
(4) Reacting 4, 6-dimethyl-3-cyanopyridine with sulfuric acid to obtain 4, 6-dimethyl-3-formamide pyridine (compound 5);
(5) 4, 6-dimethyl-3-formamide pyridine and sodium hypobromite or sodium hypochlorite are subjected to Hofmann degradation reaction to obtain 2, 4-dimethyl-5-aminopyridine (compound 6).
Further, the specific process of the step (1) is as follows: adding acetylacetone into an alkaline aqueous solution, slowly adding cyanoacetamide at a temperature of T1, controlling the temperature to be not higher than T2, stirring at normal temperature until the reaction is completed, forming a precipitate, then filtering, leaching with water, and drying to obtain 3-cyano-4, 6-dimethyl-2-hydroxypyridine (compound 2), wherein the temperature of T1 is controlled to be not less than 0 ℃ and not more than 40 ℃, and the temperature of T2 is controlled to be not less than 10 ℃ and not more than 50 ℃.
Further, the mass ratio of acetylacetone to cyanoacetamide is 1: (1-2), wherein the alkaline aqueous solution is potassium carbonate aqueous solution, sodium carbonate aqueous solution, ammonium carbonate aqueous solution, sodium bicarbonate aqueous solution, ammonium bicarbonate aqueous solution, sodium hydroxide aqueous solution or potassium hydroxide aqueous solution.
Further, the specific process of the step (2) is as follows: stirring 3-cyano-4, 6-dimethyl-2-hydroxypyridine and a chlorinating agent at a reaction temperature T3 until the reaction is completely carried out, cooling the reaction liquid to room temperature, then slowly pouring into ice water, keeping the temperature not higher than T4, stirring for reaction for 1h to form a precipitate, filtering, drying, and then recrystallizing by using n-heptane to obtain the 2-chloro-3-cyano-4, 6-dimethylpyridine (compound 3), wherein the control temperature of T3 is more than or equal to 60 ℃ and less than or equal to 250 ℃, and the control temperature of T4 is more than or equal to 10 ℃ and less than or equal to 40 ℃.
Further, the mass ratio of the 3-cyano-4, 6-dimethyl-2-hydroxypyridine to the chlorinating agent is 1: (1-10), wherein the chlorination reagent is thionyl chloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, triphosgene, chlorine gas, sulfuryl chloride or phenylphosphoryl dichloride.
Further, the specific process of the step (3) is as follows: stirring 2-chloro-3-cyano-4, 6-dimethylpyridine and a reducing agent at a temperature of T5 until the reaction is completed, cooling the mixture to T6, then neutralizing the mixture with concentrated ammonia water, extracting the mixture with dichloromethane, collecting an organic phase, drying with anhydrous sodium sulfate, desolventizing, and recrystallizing with methanol to obtain 4, 6-dimethyl-3-cyanopyridine (compound 4), wherein the control temperature of T5 is between 0 ℃ and T5 and less than or equal to 150 ℃, and the control temperature of T6 is between-10 ℃ and less than or equal to T6 and less than or equal to 40 ℃.
Further, the mass ratio of the 2-chloro-3-cyano-4, 6-dimethylpyridine to the reducing agent is 1: (1-5), wherein the reducing agent comprises sodium borohydride, potassium borohydride, zinc powder, iron powder or hydrogen.
Further, the specific process of the step (4) is as follows: stirring 4, 6-dimethyl-3-cyanopyridine and sulfuric acid at a temperature of T7 until complete reaction; after the reaction is completed, cooling the reaction mixture to room temperature, pouring the reaction mixture into ice water, neutralizing the solution with ammonia water to form a precipitate, performing suction filtration to collect the precipitate, washing the precipitate with water, and drying to obtain the 4, 6-dimethyl-3-formamide pyridine (the compound 5), wherein the control temperature of T7 is more than or equal to 80 ℃ and less than or equal to 180 ℃.
Further, the mass ratio of the 4, 6-dimethyl-3-cyanopyridine to the sulfuric acid is 1: (1-10).
Further, the specific process of the step (5) is as follows: stirring 4, 6-dimethyl-3-formamide pyridine and sodium hypobromite or sodium hypochlorite to react for 1 hour at the temperature of T8, then reacting for 1 hour at the temperature of T9, cooling the reaction mixture to room temperature and extracting with ethyl acetate, collecting an organic layer, washing with saturated NaCl, drying with anhydrous sodium sulfate, and desolventizing to obtain the 2, 4-dimethyl-5-aminopyridine (compound 6), wherein the control temperature of T8 is more than or equal to minus 10 ℃ and less than or equal to T8 and less than or equal to 50 ℃, and the control temperature of T9 is more than or equal to 50 ℃ and less than or equal to T9 and less than or equal to 110 ℃.
Further, the amount ratio of said 4, 6-dimethyl-3-carboxamide pyridine to said sodium hypobromite or said 4, 6-dimethyl-3-carboxamide pyridine to said sodium hypochlorite is 1: (1-4).
Compared with the prior art, the invention has the advantages that: the invention relates to a synthesis method of 2, 4-dimethyl-5-aminopyridine, which adopts low-cost acetylacetone and cyanoacetamide as initial raw materials, obtains 3-cyano-4, 6-dimethyl-2-hydroxypyridine through cyclization, and then obtains the 2, 4-dimethyl-5-aminopyridine through five steps of chlorination, reduction, cyano hydrolysis, bromine removal, hofmann degradation and the like. The method has the advantages of simple selected process route, mild and safe reaction conditions, wide raw material source, effective improvement of process yield (total yield of 51%), suitability for large-scale industrial production and wide application prospect.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of 2, 4-dimethyl-5-aminopyridine synthesized in example 1 of the present invention.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
A method for synthesizing 2, 4-dimethyl-5-aminopyridine comprises the following steps:
(1) Reacting acetylacetone with cyanoacetamide to obtain 3-cyano-4, 6-dimethyl-2-hydroxypyridine (compound 2);
(2) Reacting 3-cyano-4, 6-dimethyl-2-hydroxypyridine with a chlorinating agent to obtain 2-chloro-3-cyano-4, 6-dimethylpyridine (compound 3);
(3) Reacting 2-chloro-3-cyano-4, 6-dimethylpyridine with a reducing agent to obtain 4, 6-dimethyl-3-cyanopyridine (compound 4);
(4) Reacting 4, 6-dimethyl-3-cyanopyridine with sulfuric acid to obtain 4, 6-dimethyl-3-formamide pyridine (a compound 5);
(5) The 4, 6-dimethyl-3-formamide pyridine and sodium hypobromite or sodium hypochlorite are subjected to Hofmann degradation reaction to obtain 2, 4-dimethyl-5-aminopyridine (compound 6), and the synthetic route is shown as follows:
the specific process of the step (1) is as follows: adding acetylacetone into an alkaline aqueous solution, slowly adding cyanoacetamide at a temperature of T1, controlling the temperature to be not higher than T2, stirring at normal temperature until the reaction is completed, forming a precipitate, then, filtering, leaching with water, and drying to obtain 3-cyano-4, 6-dimethyl-2-hydroxypyridine (compound 2), wherein the temperature of T1 is controlled to be not less than 0 ℃ and not more than 40 ℃, the temperature of T2 is controlled to be not less than 10 ℃ and not more than 50 ℃, and the mass ratio of acetylacetone to cyanoacetamide is 1: (1-2), the alkaline aqueous solution is potassium carbonate aqueous solution, sodium carbonate aqueous solution, ammonium carbonate aqueous solution, sodium bicarbonate aqueous solution, ammonium bicarbonate aqueous solution, sodium hydroxide aqueous solution or potassium hydroxide aqueous solution.
The specific process of the step (2) is as follows: stirring 3-cyano-4, 6-dimethyl-2-hydroxypyridine and a chlorinating agent at a reaction temperature T3 until the reaction is completely carried out, cooling the reaction liquid to room temperature, then slowly pouring into ice water, keeping the temperature not higher than T4, stirring for reaction for 1h to form a precipitate, filtering, drying, and then recrystallizing by using n-heptane to obtain the 2-chloro-3-cyano-4, 6-dimethylpyridine (compound 3), wherein the control temperature of T3 is more than or equal to 60 ℃ and less than or equal to T3 and less than or equal to 250 ℃, the control temperature of T4 is more than or equal to 10 ℃ and less than or equal to T4 and less than or equal to 40 ℃, and the mass ratio of the 3-cyano-4, 6-dimethyl-2-hydroxypyridine to the chlorinating agent is 1: (1-10), the chlorinating agent is thionyl chloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, triphosgene, chlorine gas, sulfuryl chloride or phenylphosphoryl dichloride.
The specific process of the step (3) is as follows: stirring 2-chloro-3-cyano-4, 6-dimethylpyridine and a reducing agent at a temperature of T5 until the reaction is completed, cooling the mixture to T6, then neutralizing the mixture with concentrated ammonia water, extracting the mixture with dichloromethane, collecting an organic phase, drying with anhydrous sodium sulfate, desolvating, and recrystallizing with methanol to obtain 4, 6-dimethyl-3-cyanopyridine (compound 4), wherein the temperature of T5 is controlled to be 0 ℃ to 150 ℃ inclusive, the temperature of T6 is controlled to be-10 ℃ to 40 ℃ inclusive, and the mass ratio of the 2-chloro-3-cyano-4, 6-dimethylpyridine to the reducing agent is 1: (1-5), the reducing agent comprises sodium borohydride, potassium borohydride, zinc powder, iron powder or hydrogen.
The specific process of the step (4) is as follows: stirring 4, 6-dimethyl-3-cyanopyridine and sulfuric acid at a temperature of T7 until complete reaction; after the reaction is completed, cooling the reaction mixture to room temperature, pouring the reaction mixture into ice water, neutralizing the solution with ammonia water to form a precipitate, performing suction filtration to collect the precipitate, washing the precipitate with water, and drying to obtain the 4, 6-dimethyl-3-formamide pyridine (the compound 5), wherein the control temperature of T7 is more than or equal to 80 ℃ and less than or equal to 180 ℃, and the mass ratio of the 4, 6-dimethyl-3-cyanopyridine to the sulfuric acid is 1: (1-10).
The specific process of the step (5) is as follows: stirring 4, 6-dimethyl-3-formamide pyridine and sodium hypobromite or sodium hypochlorite for reaction for 1 hour at the temperature of T8, then reacting for 1 hour at the temperature of T9, cooling the reaction mixture to room temperature and extracting with ethyl acetate, collecting an organic layer, washing with saturated NaCl, drying with anhydrous sodium sulfate, and desolventizing to obtain 2, 4-dimethyl-5-aminopyridine (compound 6), wherein the control temperature of T8 is-10 ℃ to T8 ℃ to 50 ℃, the control temperature of T9 is 50 ℃ to 110 ℃, and the weight ratio of 4, 6-dimethyl-3-formamide pyridine to sodium hypobromite or 4, 6-dimethyl-3-formamide pyridine to sodium hypochlorite is 1: (1-4).
Example 1
A method for synthesizing 2, 4-dimethyl-5-aminopyridine comprises the following steps:
1. synthesis of 3-cyano-4, 6-dimethyl-2-hydroxypyridine
Adding 50L of tap water into a 100L reaction kettle, adding 5.5kg of potassium carbonate under stirring, adding 4kg of acetylacetone after full dissolution, then adding 3.4kg of cyanoacetamide in batches, keeping the temperature not higher than 40 ℃, after the addition is finished, stirring the mixture at room temperature for 24 hours, and generating a large amount of white solid precipitate; the mixture was then filtered, and the filter cake was washed with water and dried to give an off-white solid 5.3kg with a yield of 90%.
2. Synthesis of 2-chloro-3-cyano-4, 6-dimethylpyridine
A3L reaction flask was charged with 1.5L of phosphorus oxychloride and 750g of 3-cyano-4, 6-dimethyl-2-hydroxypyridine, stirred, the mixture was slowly heated to reflux (about 108 ℃ C.), the reaction mixture became clear, stirred and reacted for 1.5 hours, then poured into 6kg of ice water, stirred and reacted for 1 hour, during which time the temperature was kept below 30 ℃ C., a precipitate was formed, collected by suction filtration, washed with water, dried, and recrystallized from n-heptane to give 780g of a white solid with a yield of 93%.
3. Synthesis of 4, 6-dimethyl-3-cyanopyridine
Adding 4L of water and 2L of concentrated hydrochloric acid into a 10L reaction bottle, adding 350g of 2-chloro-3-cyano-4, 6-lutidine under stirring, heating to 60 ℃, then slowly adding 200g of zinc powder, controlling the temperature to be not higher than 80 ℃, after the zinc powder is added, continuing to keep the temperature of the mixture (60-70 ℃) for reaction for 2 hours, after the reaction is completed, cooling the mixture to 5 ℃, and then neutralizing with concentrated ammonia water; finally, the mixture was extracted with dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate, desolventized, and recrystallized from methanol to give 230g of off-white solid in 83% yield.
4. Synthesis of 4, 6-dimethylnicotinamide
Into a 250mL reaction flask, 100mL of concentrated sulfuric acid was added, 70g of 4, 6-dimethyl-3-cyanopyridine was added with stirring, then, the temperature was raised to 120 ℃ to react for 2 hours, and the reaction mixture was cooled to room temperature and poured into ice water. The solution was neutralized with ammonia to form a precipitate, which was collected by suction filtration and washed with water. Drying to obtain 75g of gray solid with the yield of 94%.
5. Synthesis of 2, 4-dimethyl-5-aminopyridine
Adding 100mL of water into a 250mL reaction bottle, stirring, and adding 10g of sodium hydroxide; cooling to 0 ℃, dropping 15g of bromine into the sodium hydroxide aqueous solution, stirring for 15 minutes at 0 ℃, then adding 11g of 4, 6-dimethyl-3-formamide pyridine at one time, stirring for 1 hour at 0 ℃, heating to 80 ℃, and continuing to react for 1 hour. Then, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. The collected organic layer was washed with saturated NaCl, dried over anhydrous sodium sulfate, and desolventized to give 7g of a yellowish solid in a yield of 78%, and the NMR spectrum was as shown in FIG. 1.
Example 2
1. Synthesis of 3-cyano-4, 6-dimethyl-2-hydroxypyridine
Adding 5L of tap water into a 10L reaction kettle, adding 165g of sodium hydroxide under stirring, adding 400g of acetylacetone after full dissolution, then adding 340g of cyanoacetamide in batches, keeping the temperature not higher than 40 ℃, and after the addition is finished, stirring the mixture at room temperature for reaction for 24 hours, wherein a large amount of white solid precipitates; the mixture was then filtered, and the filter cake was washed with water and dried to give 515g of off-white solid in 87% yield.
2. Synthesis of 2-chloro-3-cyano-4, 6-dimethylpyridine
Adding 2L 1, 4-dioxane into a 5L reaction bottle, adding 2100g of phosphorus pentachloride and 750g of 3-cyano-4, 6-dimethyl-2-hydroxypyridine under stirring, slowly heating the mixture to 100 ℃, after the reaction mixture becomes clear, stirring for reacting for 1.5 hours, then pouring the mixture into 7kg of ice water, stirring for reacting for 1 hour, keeping the temperature below 30 ℃ during the reaction period to form a precipitate, performing suction filtration to collect the precipitate, washing with water, drying, and recrystallizing with n-heptane to obtain 757g of white solid with the yield of 90%.
3. Synthesis of 4, 6-dimethyl-3-cyanopyridine
Adding 4L of water and 2L of concentrated hydrochloric acid into a 10L reaction bottle, adding 350g of 2-chloro-3-cyano-4, 6-dimethylpyridine while stirring, heating to 60 ℃, then slowly adding 274g of zinc powder, controlling the temperature to be not higher than 80 ℃, after the zinc powder is added, continuously keeping the temperature of the mixture (60-70 ℃) for reaction for 2 hours, after the reaction is completed, cooling the mixture to 5 ℃, and then neutralizing the mixture with concentrated ammonia water; finally, the mixture was extracted with dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate, desolventized, and recrystallized from methanol to give 223g of off-white solid in 80% yield.
4. Synthesis of 4, 6-dimethylnicotinamide
To a 250mL reaction flask, 100mL of concentrated sulfuric acid was added, 70g of 4, 6-dimethyl-3-cyanopyridine was added with stirring, then, the temperature was raised to 105 ℃ to react for 2 hours, and the reaction mixture was cooled to room temperature and poured into ice water. The solution was neutralized with ammonia to form a precipitate, which was collected by suction filtration and washed with water. Oven dried to give 72g of grey solid, 91% yield.
5. Synthesis of 2, 4-dimethyl-5-aminopyridine
Adding 200mL of water into a 500mL reaction bottle, stirring, and adding 20g of sodium hydroxide; cooling to 0 ℃, dropping 30g of bromine into the sodium hydroxide aqueous solution, stirring for 15 minutes at 0 ℃, then adding 22g of 4, 6-dimethyl-3-formamide pyridine at one time, stirring for 1 hour at 0 ℃, heating to 90 ℃, and continuing to react for 1 hour. Then, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. The collected organic layer was washed with saturated NaCl, dried over anhydrous sodium sulfate, and desolventized to give 13.5g of an earth-yellow solid in 75% yield.
Example 3
1. Synthesis of 3-cyano-4, 6-dimethyl-2-hydroxypyridine
Adding 5L of tap water into a 10L reaction kettle, adding 320g of ammonium bicarbonate under stirring, adding 400g of acetylacetone after full dissolution, then adding 340g of cyanoacetamide in batches, keeping the temperature not higher than 40 ℃, and stirring the mixture at room temperature for 24 hours after the addition is finished, wherein a large amount of white solid precipitates; the mixture was then filtered, and the filter cake was washed with water and dried to give 492g of an off-white solid in 83% yield.
2. Synthesis of 2-chloro-3-cyano-4, 6-dimethylpyridine
A3L reaction flask was charged with 1.5L of thionyl chloride and 750g of 3-cyano-4, 6-dimethyl-2-hydroxypyridine, stirred, the mixture was slowly heated to reflux (about 82 ℃ C.), the reaction mixture became clear, stirred and reacted for 1.5 hours, then poured into 6kg of ice water, stirred and reacted for 1 hour, during which time the temperature was kept below 30 ℃ C., a precipitate was formed, collected by suction filtration and washed with water, dried, and recrystallized from n-heptane to give 715g of a white solid in a yield of 85%.
3. Synthesis of 4, 6-dimethyl-3-cyanopyridine
Adding 2L of water and 1L of concentrated hydrochloric acid into a 5L reaction bottle, adding 170g of 2-chloro-3-cyano-4, 6-dimethylpyridine under stirring, heating to 60 ℃, then slowly adding 67g of zinc powder, controlling the temperature to be not higher than 80 ℃, after the zinc powder is added, continuing to keep the temperature of the mixture (60-70 ℃) for reacting for 2 hours, after the reaction is completed, cooling the mixture to 5 ℃, and then neutralizing with concentrated ammonia water; finally, the mixture was extracted with dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate, desolventized, and recrystallized from methanol to give 104g of off-white solid in 77% yield.
4. Synthesis of 4, 6-dimethylnicotinamide
Into a 250mL reaction flask, 100mL of concentrated sulfuric acid was added, 70g of 4, 6-dimethyl-3-cyanopyridine was added with stirring, then, the temperature was raised to 90 ℃ to react for 2 hours, and the reaction mixture was cooled to room temperature and poured into ice water. The solution was neutralized with ammonia to form a precipitate, which was collected by suction filtration and washed with water. Drying to obtain 70g of gray solid with the yield of 88%.
5. Synthesis of 2, 4-dimethyl-5-aminopyridine
Adding 200mL of water into a 500mL reaction bottle, stirring, and adding 20g of sodium hydroxide; cooling to 0 ℃, dropping 30g of bromine into the sodium hydroxide aqueous solution, stirring for 15 minutes at 0 ℃, then adding 22g of 4, 6-dimethyl-3-formamide pyridine at one time, stirring for 1 hour at 0 ℃, heating to 100 ℃, and continuing to react for 1 hour. Then, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. The collected organic layer was washed with saturated NaCl, dried over anhydrous sodium sulfate, and desolventized to obtain an yellowish solid 12.5g in a yield of 70%.
The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Those skilled in the art should also realize that changes, modifications, additions and substitutions can be made without departing from the true spirit and scope of the invention.
Claims (11)
1. A method for synthesizing 2, 4-dimethyl-5-aminopyridine is characterized by comprising the following steps:
(1) Reacting acetylacetone with cyanoacetamide to obtain 3-cyano-4, 6-dimethyl-2-hydroxypyridine;
(2) Reacting 3-cyano-4, 6-dimethyl-2-hydroxypyridine with a chlorinated reagent to obtain 2-chloro-3-cyano-4, 6-dimethylpyridine;
(3) Reacting 2-chloro-3-cyano-4, 6-dimethylpyridine with a reducing agent to obtain 4, 6-dimethyl-3-cyanopyridine (compound 4);
(4) Reacting 4, 6-dimethyl-3-cyanopyridine with sulfuric acid to obtain 4, 6-dimethyl-3-formamide pyridine;
(5) Carrying out Hoffman degradation reaction on 4, 6-dimethyl-3-formamide pyridine and sodium hypobromite or sodium hypochlorite to obtain the 2, 4-dimethyl-5-aminopyridine.
2. The method for synthesizing 2, 4-dimethyl-5-aminopyridine according to claim 1, characterized in that the specific process of step (1) is as follows: adding acetylacetone into an alkaline aqueous solution, slowly adding cyanoacetamide at a temperature of T1, controlling the temperature to be not higher than T2, stirring at normal temperature until the reaction is completed, forming a precipitate, then filtering, leaching with water, and drying to obtain the 3-cyano-4, 6-dimethyl-2-hydroxypyridine, wherein the temperature of T1 is controlled to be not less than 0 ℃ and not more than 40 ℃, and the temperature of T2 is controlled to be not less than 10 ℃ and not more than 50 ℃.
3. The method for synthesizing 2, 4-dimethyl-5-aminopyridine according to claim 1, wherein: the mass ratio of the acetylacetone to the cyanoacetamide is 1: (1-2), wherein the alkaline aqueous solution is potassium carbonate aqueous solution, sodium carbonate aqueous solution, ammonium carbonate aqueous solution, sodium bicarbonate aqueous solution, ammonium bicarbonate aqueous solution, sodium hydroxide aqueous solution or potassium hydroxide aqueous solution.
4. The method for synthesizing 2, 4-dimethyl-5-aminopyridine according to claim 1, wherein: the specific process of the step (2) is as follows: stirring 3-cyano-4, 6-dimethyl-2-hydroxypyridine and a chlorinating agent at a reaction temperature T3 until the reaction is completely carried out, cooling the reaction liquid to room temperature, then slowly pouring into ice water, keeping the temperature not higher than T4, stirring for reaction for 1h to form a precipitate, filtering, drying, and then recrystallizing by using n-heptane to obtain the 2-chloro-3-cyano-4, 6-dimethylpyridine, wherein the control temperature of T3 is more than or equal to 60 ℃ and less than or equal to 250 ℃, and the control temperature of T4 is more than or equal to 10 ℃ and less than or equal to 40 ℃.
5. The method for synthesizing 2, 4-dimethyl-5-aminopyridine according to claim 4, wherein: the mass ratio of the 3-cyano-4, 6-dimethyl-2-hydroxypyridine to the chlorinating agent is 1: (1-10), wherein the chlorination reagent is thionyl chloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, triphosgene, chlorine, sulfuryl chloride or phenyl phosphoryl dichloride.
6. The method for synthesizing 2, 4-dimethyl-5-aminopyridine according to claim 4, wherein: the specific process of the step (3) is as follows: stirring 2-chloro-3-cyano-4, 6-dimethylpyridine and a reducing agent at the temperature of T5 until the mixture completely reacts, cooling the mixture to T6, then neutralizing the mixture with concentrated ammonia water, extracting the mixture with dichloromethane, collecting an organic phase, drying with anhydrous sodium sulfate, desolventizing, and recrystallizing with methanol to obtain the 4, 6-dimethyl-3-cyanopyridine, wherein the control temperature of T5 is more than or equal to 0 ℃ and less than or equal to 150 ℃, and the control temperature of T6 is more than or equal to-10 ℃ and less than or equal to 40 ℃.
7. The method for synthesizing 2, 4-dimethyl-5-aminopyridine according to claim 6, wherein: the mass ratio of the 2-chloro-3-cyano-4, 6-dimethylpyridine to the reducing agent is 1: (1-5), wherein the reducing agent comprises sodium borohydride, potassium borohydride, zinc powder, iron powder or hydrogen.
8. The method for synthesizing 2, 4-dimethyl-5-aminopyridine according to claim 1, characterized in that the specific process of the step (4) is as follows: stirring 4, 6-dimethyl-3-cyanopyridine and sulfuric acid at a temperature of T7 until complete reaction; after the reaction is completed, cooling the reaction mixture to room temperature, pouring the reaction mixture into ice water, neutralizing the solution with ammonia water to form a precipitate, performing suction filtration to collect the precipitate, washing the precipitate with water, and drying to obtain the 4, 6-dimethyl-3-formamide pyridine, wherein the control temperature of T7 is more than or equal to 80 ℃ and less than or equal to 180 ℃.
9. The method for synthesizing 2, 4-dimethyl-5-aminopyridine according to claim 8, wherein: the mass ratio of the 4, 6-dimethyl-3-cyanopyridine to the sulfuric acid is 1: (1-10).
10. The method for synthesizing 2, 4-dimethyl-5-aminopyridine according to claim 1, wherein the specific process of step (5) is as follows: stirring 4, 6-dimethyl-3-formamide pyridine and sodium hypobromite or sodium hypochlorite to react for 1 hour at the temperature of T8, then reacting for 1 hour at the temperature of T9, cooling the reaction mixture to room temperature and extracting with ethyl acetate, collecting an organic layer, washing with saturated NaCl, drying with anhydrous sodium sulfate, and desolventizing to obtain the 2, 4-dimethyl-5-aminopyridine, wherein the control temperature of T8 is more than or equal to minus 10 ℃ and less than or equal to T8 and less than or equal to 50 ℃, and the control temperature of T9 is more than or equal to 50 ℃ and less than or equal to T9 and less than or equal to 110 ℃.
11. The method for synthesizing 2, 4-dimethyl-5-aminopyridine according to claim 10, wherein:
the ratio of the 4, 6-dimethyl-3-formamide pyridine to the sodium hypobromite or the 4, 6-dimethyl-3-formamide pyridine to the sodium hypochlorite is 1: (1-4).
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| US4631081A (en) * | 1982-09-29 | 1986-12-23 | Ici Australia Limited | Herbicidal cyclohexane-1,3-dione derivatives |
| CN111943884A (en) * | 2019-05-14 | 2020-11-17 | 上海玲骰生物科技有限公司 | Preparation method of medical intermediate 2-chloro-3-aminopyridine |
| CN113929622A (en) * | 2021-11-22 | 2022-01-14 | 山西永津集团有限公司 | Synthetic method of 2,5, 6-trichloro-cyanic acid |
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| US4631081A (en) * | 1982-09-29 | 1986-12-23 | Ici Australia Limited | Herbicidal cyclohexane-1,3-dione derivatives |
| CN111943884A (en) * | 2019-05-14 | 2020-11-17 | 上海玲骰生物科技有限公司 | Preparation method of medical intermediate 2-chloro-3-aminopyridine |
| CN113929622A (en) * | 2021-11-22 | 2022-01-14 | 山西永津集团有限公司 | Synthetic method of 2,5, 6-trichloro-cyanic acid |
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