CN114057748A - Preparation method of triazole pyrimidone - Google Patents
Preparation method of triazole pyrimidone Download PDFInfo
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- CN114057748A CN114057748A CN202111159896.4A CN202111159896A CN114057748A CN 114057748 A CN114057748 A CN 114057748A CN 202111159896 A CN202111159896 A CN 202111159896A CN 114057748 A CN114057748 A CN 114057748A
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- pyrimidone
- diamino
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- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 150000003852 triazoles Chemical class 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- -1 triazole pyrimidine compound Chemical class 0.000 claims abstract description 41
- PKWIYNIDEDLDCJ-UHFFFAOYSA-N guanazole Chemical compound NC1=NNC(N)=N1 PKWIYNIDEDLDCJ-UHFFFAOYSA-N 0.000 claims abstract description 29
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000605 extraction Methods 0.000 claims abstract description 18
- 238000004821 distillation Methods 0.000 claims abstract description 17
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 16
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 claims abstract description 16
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000007788 liquid Substances 0.000 claims abstract description 16
- 238000001953 recrystallisation Methods 0.000 claims abstract description 16
- 238000000926 separation method Methods 0.000 claims abstract description 16
- 238000006482 condensation reaction Methods 0.000 claims abstract description 15
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 8
- 230000002378 acidificating effect Effects 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 150000007530 organic bases Chemical class 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 21
- 230000035484 reaction time Effects 0.000 claims description 15
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 10
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 10
- 235000006408 oxalic acid Nutrition 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- ZNCPFRVNHGOPAG-UHFFFAOYSA-L sodium oxalate Chemical compound [Na+].[Na+].[O-]C(=O)C([O-])=O ZNCPFRVNHGOPAG-UHFFFAOYSA-L 0.000 claims description 2
- 229940039790 sodium oxalate Drugs 0.000 claims description 2
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 25
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 239000002895 emetic Substances 0.000 description 4
- FIKAKWIAUPDISJ-UHFFFAOYSA-L paraquat dichloride Chemical compound [Cl-].[Cl-].C1=C[N+](C)=CC=C1C1=CC=[N+](C)C=C1 FIKAKWIAUPDISJ-UHFFFAOYSA-L 0.000 description 4
- 239000000575 pesticide Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000005822 Propiconazole Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 238000004523 catalytic cracking Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of triazole pyrimidone, which comprises the following steps in sequence: (1) dicyandiamide and hydrazine hydrate are taken as raw materials, and cyclization reaction is carried out in a low-temperature acidic condition to generate 3, 5-diamino-1, 2, 4-triazole; (2) carrying out condensation reaction on the 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate under the conditions of organic base and heating to generate a triazole pyrimidine compound; (3) the triazole pyrimidine compound and bromopropane react in an inorganic base and organic solvent system, and then the triazole pyrimidine compound is obtained by distillation, extraction, liquid separation and recrystallization. The preparation method provided by the invention has the advantages that the reaction selectivity is good through a three-step method, specific reaction conditions are selected in each step, and finally, the triazole pyrimidinone with high yield and high purity can be obtained through distillation, extraction, liquid separation and recrystallization, and the preparation method is stable and mild in reaction conditions and simple to operate.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of triazole pyrimidinone.
Background
Triazole pyrimidinone (PP796), namely 2-amino-6-methyl-4-n-propyl- [1, 2, 4] -triazolo [1,5-a ] pyrimidine-5-ketone, and the structural formula is shown as follows. PP796 is an important organic synthetic and pharmaceutical intermediate, which can be used to synthesize many derived products. For example, it is an important medical and veterinary active emetic ingredient, and is also useful in the prevention of bronchospasm and in the synthesis of antiobesity drugs, etc. In addition, PP796 can also be used as an antidote for a quick-contact herbicide paraquat to remove the toxicity of paraquat on human bodies, so that people using the paraquat are protected. The emetic is an active emetic component widely added in the pesticide paraquat, can cause people and animals to vomit quickly after eating the pesticide by mistake, is used for the safety of the pesticide, and currently, the pesticide without the emetic is prohibited from entering the market in China.
Therefore, the method has wide market, large demand and high economic value.
At present, the conventional preparation method of triazole pyrimidone comprises the following steps: preparing dibromide by MMA through bromination addition, and carrying out etherification reaction with sodium methoxide to generate etherified substance; preparing dimethyl ester by catalytic cracking of etherified substances under certain conditions; condensing cyanamide and carbon disulfide under alkaline condition to prepare sodium salt of dithioic acid, and synthesizing dicyandiamide with dimethyl sulfate; dicyanate is neutralized with n-propane condensate in a solvent to prepare a methyl substituent; cyclizing the methyl substituent and hydrazine hydrate to generate n-propiconazole; carrying out an acetal reaction on n-propiconazole and benzaldehyde in xylene under the action of a catalyst to generate an aldehyde condensate, and carrying out catalytic ring closure on the aldehyde condensate and dimethyl ester in an acid-binding agent to generate a ring condensate; the cyclic compound is hydrolyzed in hydrochloric acid to remove benzaldehyde, and the triazole pyrimidone is obtained. The preparation method comprises the steps of bromination, etherification, catalytic cracking, alkaline condensation, cyclization, acetal reaction, ring-closing reaction, hydrolysis and the like, and the yield and the purity of the prepared product are lower.
Disclosure of Invention
In view of the above, the invention provides a novel preparation method of triazole pyrimidinone, and the obtained triazole pyrimidinone has high purity and yield.
In order to realize the purpose, the invention provides a preparation method of triazole pyrimidone, which comprises the following steps in sequence:
(1) dicyandiamide and hydrazine hydrate are taken as raw materials, and cyclization reaction is carried out in a low-temperature acidic condition to generate 3, 5-diamino-1, 2, 4-triazole;
(2) carrying out condensation reaction on the 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate under the conditions of organic base and heating to generate a triazole pyrimidine compound;
(3) the triazole pyrimidine compound and bromopropane react in an inorganic base and organic solvent system, and then the triazole pyrimidine compound is obtained by distillation, extraction, liquid separation and recrystallization.
The preparation method provided by the invention has the advantages that the reaction selectivity is good through a three-step method, specific reaction conditions are selected in each step, and finally, the triazole pyrimidinone with high yield and high purity can be obtained through distillation, extraction, liquid separation and recrystallization, and the preparation method is stable and mild in reaction conditions and simple to operate.
The reaction process of the preparation method of the invention is as follows:
step (1)
Step (2)
Step (3)
Preferably, the reaction temperature in the step (1) is 0-15 ℃, the acidic condition is that oxalic acid or acetic acid is added into a reaction system, the reaction time is 4-8 hours, and the molar ratio of dicyandiamide to hydrazine hydrate is 1-1.5: 1. Before the step (2) is carried out, the product obtained in the step (1) is heated for 0.5-1.5 h under 35-40 ℃, ammonia gas generated in the reaction is removed through heating, and the yield of the reaction can be 90-94.5%.
Preferably, the organic base of step (2) is ethanolamine, diethanolamine or triethanolamine. Ethanolamine substances are selected, and have good compatibility with 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate, and the ethanolamine substances are favorable for condensation reaction. The reaction temperature of the step (2) is 100-120 ℃, the reaction time is 3-6 h, the molar ratio of the 3, 5-diamino-1, 2, 4-triazole to the 3-methoxy-2-methyl methacrylate is 1: 1-1.5, and the condensation reaction of the two is facilitated by high-temperature heating. Before the step (3) is carried out, the product obtained in the step (2) is heated for 1-2 hours at 65-70 ℃ to remove the reaction product methanol, and the yield of the step (2) can reach 89.3-93.6%.
Preferably, the inorganic base in the step (3) is sodium carbonate, sodium bicarbonate, potassium carbonate, sodium oxalate or sodium hydroxide, the inorganic base is favorable for the reaction of bromopropane and amino groups on a six-membered ring, the organic solvent in the step (3) is trichloromethane, dimethylformamide or dimethyl sulfoxide, and the polar solvent is selected to be favorable for improving the reaction yield, so that the yield can reach 84.5-87.7%. The reaction temperature in the step (3) is 60-95 ℃, the reaction time is 4-8 hours, and the molar ratio of the triazole pyrimidine compound to the bromopropane to the inorganic base is 1: 1-1.5.
Preferably, ethyl acetate is adopted for distillation and extraction in the step (3), and the purity of the product obtained by extraction, liquid separation and recrystallization is higher and can reach 99%.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention. Reagents not specifically described in the present invention are commercially available.
Example 1
The preparation method of the triazole pyrimidone comprises the following steps in sequence:
(1) dicyandiamide and hydrazine hydrate in a molar ratio of 1.2:1 are taken as raw materials, oxalic acid is added into a reaction system, the reaction is carried out for 6 hours at the temperature of 1 +/-2 ℃, so that cyclization reaction is carried out to generate 3, 5-diamino-1, 2, 4-triazole, and the product is heated for 1 hour at the temperature of 37 +/-2 ℃ to remove ammonia gas;
(2) 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate with the molar ratio of 1:1.1 are subjected to condensation reaction for 4h under the reaction condition of triethanolamine and 110 +/-2 ℃ to generate a triazole pyrimidine compound, and the product is heated at 68 +/-2 ℃ for 1h to remove methanol;
(3) the triazole pyrimidone is obtained by performing distillation, extraction, liquid separation and recrystallization on ethyl acetate under the conditions that the reaction time of the triazole pyrimidone compound and bromopropane is 6 hours at the temperature of 80 +/-2 ℃ in a sodium carbonate and dimethyl sulfoxide system and the molar ratio of the triazole pyrimidone compound to the bromopropane to the sodium carbonate is 1:1.2:1.2, wherein the yield is 86.7% and the purity is 99%.
Example 2
The preparation method of the triazole pyrimidone comprises the following steps in sequence:
(1) dicyandiamide and hydrazine hydrate with the molar ratio of 1.2:1 are taken as raw materials, acetic acid is added into a reaction system, the reaction is carried out for 6 hours at the temperature of 1 +/-2 ℃, so that cyclization reaction is carried out to generate 3, 5-diamino-1, 2, 4-triazole, and the product is heated for 1 hour at the temperature of 37 +/-2 ℃ to remove ammonia gas;
(2) 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate with the molar ratio of 1:1.1 are subjected to condensation reaction for 4h under the reaction condition of triethanolamine and 110 +/-2 ℃ to generate a triazole pyrimidine compound, and the product is heated at 68 +/-2 ℃ for 1h to remove methanol;
(3) the triazole pyrimidone is obtained by performing distillation, extraction, liquid separation and recrystallization on ethyl acetate under the conditions that the reaction time of the triazole pyrimidone compound and bromopropane is 6 hours at the temperature of 80 +/-2 ℃ in a sodium carbonate and dimethyl sulfoxide system and the molar ratio of the triazole pyrimidone compound to the bromopropane to the sodium carbonate is 1:1.2:1.2, wherein the yield is 85.8% and the purity is 99%.
Example 3
The preparation method of the triazole pyrimidone comprises the following steps in sequence:
(1) dicyandiamide and hydrazine hydrate in a molar ratio of 1.2:1 are taken as raw materials, oxalic acid is added into a reaction system, the reaction is carried out for 6 hours at the temperature of 1 +/-2 ℃, so that cyclization reaction is carried out to generate 3, 5-diamino-1, 2, 4-triazole, and the product is heated for 1 hour at the temperature of 37 +/-2 ℃ to remove ammonia gas;
(2) 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate with the molar ratio of 1:1.1 are subjected to condensation reaction for 4h under the reaction condition of ethanolamine and 110 +/-2 ℃ to generate a triazole pyrimidine compound, and the product is heated at 68 +/-2 ℃ for 1h to remove methanol;
(3) the triazole pyrimidone is obtained by performing distillation, extraction, liquid separation and recrystallization on ethyl acetate under the conditions that the reaction time of the triazole pyrimidone compound and bromopropane is 6 hours at the temperature of 80 +/-2 ℃ in a sodium bicarbonate and dimethyl sulfoxide system and the molar ratio of the triazole pyrimidone compound to the bromopropane to sodium carbonate is 1:1.2:1.2, wherein the yield is 87.1% and the purity is 99%.
Example 4
The preparation method of the triazole pyrimidone comprises the following steps in sequence:
(1) dicyandiamide and hydrazine hydrate in a molar ratio of 1.2:1 are taken as raw materials, oxalic acid is added into a reaction system, the reaction is carried out for 6 hours at the temperature of 1 +/-2 ℃, so that cyclization reaction is carried out to generate 3, 5-diamino-1, 2, 4-triazole, and the product is heated for 1 hour at the temperature of 37 +/-2 ℃ to remove ammonia gas;
(2) 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate with the molar ratio of 1:1.1 are subjected to condensation reaction for 4h under the reaction condition of triethanolamine and 110 +/-2 ℃ to generate a triazole pyrimidine compound, and the product is heated at 68 +/-2 ℃ for 1h to remove methanol;
(3) the triazole pyrimidone is obtained by performing distillation, extraction, liquid separation and recrystallization on ethyl acetate under the conditions that the reaction time of the triazole pyrimidone compound and bromopropane is 6 hours at the temperature of 80 +/-2 ℃ in a sodium carbonate and dimethylformamide system and the molar ratio of the triazole pyrimidone compound to the bromopropane to the sodium carbonate is 1:1.2:1.2, wherein the yield is 87.3% and the purity is 99%.
Example 5
The preparation method of the triazole pyrimidone comprises the following steps in sequence:
(1) dicyandiamide and hydrazine hydrate in a molar ratio of 1.2:1 are taken as raw materials, hydrochloric acid is added into a reaction system, the reaction is carried out for 6 hours at the temperature of 1 +/-2 ℃, so that cyclization reaction is carried out to generate 3, 5-diamino-1, 2, 4-triazole, and the product is heated for 1 hour at the temperature of 37 +/-2 ℃ to remove ammonia gas;
(2) 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate with the molar ratio of 1:1.1 are subjected to condensation reaction for 4h under the reaction condition of triethanolamine and 110 +/-2 ℃ to generate a triazole pyrimidine compound, and the product is heated at 68 +/-2 ℃ for 1h to remove methanol;
(3) the triazole pyrimidone is obtained by performing distillation, extraction, liquid separation and recrystallization on ethyl acetate under the conditions that the reaction time of the triazole pyrimidone compound and bromopropane is 6 hours at the temperature of 80 +/-2 ℃ in a sodium carbonate and dimethyl sulfoxide system and the molar ratio of the triazole pyrimidone compound to the bromopropane to the sodium carbonate is 1:1.2:1.2, wherein the yield is 84.5% and the purity is 99%.
Example 6
The preparation method of the triazole pyrimidone comprises the following steps in sequence:
(1) dicyandiamide and hydrazine hydrate in a molar ratio of 1.2:1 are taken as raw materials, oxalic acid is added into a reaction system, the reaction is carried out for 6 hours at the temperature of 1 +/-2 ℃, so that cyclization reaction is carried out to generate 3, 5-diamino-1, 2, 4-triazole, and the product is heated for 1 hour at the temperature of 37 +/-2 ℃ to remove ammonia gas;
(2) 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate with the molar ratio of 1:1.1 are subjected to condensation reaction for 4h under the reaction condition of sodium methoxide and 110 +/-2 ℃ to generate a triazole pyrimidine compound, and the product is heated at 68 +/-2 ℃ for 1h to remove methanol;
(3) the triazole pyrimidone is obtained by performing distillation, extraction, liquid separation and recrystallization on ethyl acetate under the conditions that the reaction time of the triazole pyrimidone compound and bromopropane is 6 hours at the temperature of 80 +/-2 ℃ in a sodium carbonate and dimethyl sulfoxide system and the molar ratio of the triazole pyrimidone compound to the bromopropane to the sodium carbonate is 1:1.2:1.2, wherein the yield is 84.9% and the purity is 99%.
Example 7
The preparation method of the triazole pyrimidone comprises the following steps in sequence:
(1) dicyandiamide and hydrazine hydrate in a molar ratio of 1.2:1 are taken as raw materials, oxalic acid is added into a reaction system, the reaction system reacts for 8 hours at the temperature of 5 +/-2 ℃, so that cyclization reaction is carried out to generate 3, 5-diamino-1, 2, 4-triazole, and the product is heated for 1 hour at the temperature of 35 +/-2 ℃ to remove ammonia;
(2) 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate with the molar ratio of 1:1 are subjected to condensation reaction for 4h under the reaction condition of triethanolamine and 110 +/-2 ℃ to generate a triazole pyrimidine compound, and the product is heated for 1h at 68 +/-2 ℃ to remove methanol;
(3) the triazole pyrimidone is obtained by performing distillation, extraction, liquid separation and recrystallization on ethyl acetate under the conditions that the reaction time of the triazole pyrimidone compound and bromopropane is 6 hours at 90 +/-2 ℃ in a sodium carbonate and dimethyl sulfoxide system and the molar ratio of the triazole pyrimidone compound to the bromopropane to the sodium carbonate is 1:1.2:1.2, wherein the yield is 86.2% and the purity is 99%.
Example 8
The preparation method of the triazole pyrimidone comprises the following steps in sequence:
(1) dicyandiamide and hydrazine hydrate in a molar ratio of 1.2:1 are taken as raw materials, oxalic acid is added into a reaction system, the reaction is carried out for 6 hours at the temperature of 1 +/-2 ℃, so that cyclization reaction is carried out to generate 3, 5-diamino-1, 2, 4-triazole, and the product is heated for 1 hour at the temperature of 37 +/-2 ℃ to remove ammonia gas;
(2) 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate with the molar ratio of 1:1.1 are subjected to condensation reaction for 4h under the reaction condition of triethanolamine and 110 +/-2 ℃ to generate a triazole pyrimidine compound, and the product is heated at 68 +/-2 ℃ for 1h to remove methanol;
(3) the triazole pyrimidone is obtained by performing distillation, extraction, liquid separation and recrystallization on ethyl acetate under the conditions that the reaction time of the triazole pyrimidone compound and bromopropane is 8 hours at 90 +/-2 ℃ in a sodium carbonate and dimethyl sulfoxide system and the molar ratio of the triazole pyrimidone compound to the bromopropane to the sodium carbonate is 1:1:1.3, wherein the yield is 87.5% and the purity is 99%.
Comparative example 1
The preparation method of the triazole pyrimidone comprises the following steps in sequence:
(1) dicyandiamide and hydrazine hydrate in a molar ratio of 1.2:1 are taken as raw materials, oxalic acid is added into a reaction system, the reaction is carried out for 6 hours at the temperature of 1 +/-2 ℃, so that cyclization reaction is carried out to generate 3, 5-diamino-1, 2, 4-triazole, and the product is heated for 1 hour at the temperature of 37 +/-2 ℃ to remove ammonia gas;
(2) 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate with the molar ratio of 1:1.1 are subjected to condensation reaction for 4h under the reaction condition of sodium carbonate and 110 +/-2 ℃ to generate a triazole pyrimidine compound, and the product is heated at 68 +/-2 ℃ for 1h to remove methanol;
(3) the triazole pyrimidone is obtained by performing distillation, extraction, liquid separation and recrystallization on ethyl acetate under the conditions that triazole pyrimidine compounds and bromopropane react for 6 hours at the temperature of 80 +/-2 ℃ in a sodium carbonate and dimethyl sulfoxide system and the molar ratio of the triazole pyrimidine compounds to the bromopropane to the sodium carbonate is 1:1.2:1.2, wherein the yield is 78.7% and the purity is 95%.
Comparative example 2
The preparation method of the triazole pyrimidone comprises the following steps in sequence:
(1) dicyandiamide and hydrazine hydrate in a molar ratio of 1.2:1 are taken as raw materials, oxalic acid is added into a reaction system, the reaction is carried out for 6 hours at the temperature of 1 +/-2 ℃, so that cyclization reaction is carried out to generate 3, 5-diamino-1, 2, 4-triazole, and the product is heated for 1 hour at the temperature of 37 +/-2 ℃ to remove ammonia gas;
(2) 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate with the molar ratio of 1:1.1 are subjected to condensation reaction for 4h under the reaction condition of triethanolamine and 110 +/-2 ℃ to generate a triazole pyrimidine compound, and the product is heated at 68 +/-2 ℃ for 1h to remove methanol;
(3) the triazole pyrimidone can be obtained by carrying out distillation, extraction, liquid separation and recrystallization on ethyl acetate under the conditions that the reaction time of the triazole pyrimidone compound and bromopropane is 6 hours at the temperature of 80 +/-2 ℃ in a triethanolamine and dimethyl sulfoxide system, the molar ratio of the triazole pyrimidone compound to bromopropane to sodium carbonate is 1:1.2:1.2, the yield is 71.3%, and the purity is 97%.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. The preparation method of triazole pyrimidone is characterized by comprising the following steps in sequence:
(1) dicyandiamide and hydrazine hydrate are taken as raw materials, and cyclization reaction is carried out in a low-temperature acidic condition to generate 3, 5-diamino-1, 2, 4-triazole;
(2) carrying out condensation reaction on the 3, 5-diamino-1, 2, 4-triazole and 3-methoxy-2-methyl methacrylate under the conditions of organic base and heating to generate a triazole pyrimidine compound;
(3) the triazole pyrimidine compound and bromopropane react in an inorganic base and organic solvent system, and then the triazole pyrimidine compound is obtained by distillation, extraction, liquid separation and recrystallization.
2. The preparation method of triazole pyrimidone of claim 1, wherein the reaction temperature in the step (1) is 0-15 ℃, the acidic condition is that oxalic acid or acetic acid is added into a reaction system, the reaction time is 4-8 h, and the molar ratio of dicyandiamide to hydrazine hydrate is 1-1.5: 1.
3. The preparation method of triazole pyrimidone of claim 1, wherein the product obtained in the step (1) is heated for 0.5-1.5 h under 35-40 ℃ before the step (2) is carried out.
4. The preparation method of triazole pyrimidone of claim 1, wherein the organic base in step (2) is ethanolamine, diethanolamine or triethanolamine.
5. The preparation method of triazole pyrimidone of claim 1, wherein the reaction temperature in the step (2) is 100-120 ℃, the reaction time is 3-6 h, and the molar ratio of the 3, 5-diamino-1, 2, 4-triazole to the 3-methoxy-2-methyl methacrylate is 1: 1-1.5.
6. The preparation method of triazole pyrimidone of claim 1, wherein the product obtained in the step (2) is heated at 65-70 ℃ for 1-2 h before the step (3) is carried out.
7. The preparation method of triazole pyrimidone of claim 1, wherein the inorganic base in step (3) is sodium carbonate, sodium bicarbonate, potassium carbonate, sodium oxalate or sodium hydroxide.
8. The preparation method of triazole pyrimidone of claim 1, wherein the organic solvent in step (3) is chloroform, dimethylformamide or dimethyl sulfoxide.
9. The preparation method of triazole pyrimidone according to claim 1, wherein the reaction temperature in the step (3) is 60-95 ℃, the reaction time is 4-8 h, and the molar ratio of the triazole pyrimidine compound to the bromopropane to the inorganic base is 1: 1-1.5.
10. The preparation method of triazole pyrimidone of claim 1, wherein ethyl acetate is used for distillation and extraction in the step (3).
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