CN113651762B - Preparation method of 1-methyl-1H-1, 2, 4-triazole-3-methyl formate - Google Patents
Preparation method of 1-methyl-1H-1, 2, 4-triazole-3-methyl formate Download PDFInfo
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- CN113651762B CN113651762B CN202111033100.0A CN202111033100A CN113651762B CN 113651762 B CN113651762 B CN 113651762B CN 202111033100 A CN202111033100 A CN 202111033100A CN 113651762 B CN113651762 B CN 113651762B
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- methyl
- triazole
- carboxylic acid
- bromo
- trimethylsilyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 42
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 21
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 16
- MWZDIEIXRBWPLG-UHFFFAOYSA-N 1-methyl-1,2,4-triazole Chemical compound CN1C=NC=N1 MWZDIEIXRBWPLG-UHFFFAOYSA-N 0.000 claims abstract description 15
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims abstract description 13
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- NKPPQSVPTZHGMA-UHFFFAOYSA-N methyl 1-methyl-1,2,4-triazole-3-carboxylate Chemical compound COC(=O)C=1N=CN(C)N=1 NKPPQSVPTZHGMA-UHFFFAOYSA-N 0.000 claims description 15
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- QAELOVNAGOMSBP-UHFFFAOYSA-N methyl 5-bromo-1-methyl-1,2,4-triazole-3-carboxylate Chemical compound COC(=O)C=1N=C(Br)N(C)N=1 QAELOVNAGOMSBP-UHFFFAOYSA-N 0.000 claims description 9
- -1 5-trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid Chemical compound 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 5
- ZYLIOXAULQKGII-UHFFFAOYSA-N 5-bromo-1-methyl-1,2,4-triazole Chemical compound CN1N=CN=C1Br ZYLIOXAULQKGII-UHFFFAOYSA-N 0.000 claims description 4
- YLECHTFIXMMMJQ-UHFFFAOYSA-N 5-bromo-1-methyl-1,2,4-triazole-3-carboxylic acid Chemical compound CN1N=C(C(O)=O)N=C1Br YLECHTFIXMMMJQ-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- LEBYPOGIEREEOF-UHFFFAOYSA-N trimethyl-(2-methyl-1,2,4-triazol-3-yl)silane Chemical compound Cn1ncnc1[Si](C)(C)C LEBYPOGIEREEOF-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000003513 alkali Substances 0.000 abstract description 4
- 238000006317 isomerization reaction Methods 0.000 abstract description 4
- 229940050176 methyl chloride Drugs 0.000 abstract description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 229910052744 lithium Inorganic materials 0.000 abstract description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 2
- 238000005956 quaternization reaction Methods 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 238000007069 methylation reaction Methods 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- QMPFMODFBNEYJH-UHFFFAOYSA-N methyl 1h-1,2,4-triazole-5-carboxylate Chemical compound COC(=O)C1=NC=NN1 QMPFMODFBNEYJH-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- DQJCHOQLCLEDLL-UHFFFAOYSA-N tricyclazole Chemical compound CC1=CC=CC2=C1N1C=NN=C1S2 DQJCHOQLCLEDLL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
The invention discloses a preparation method of 1-methyl-1H-1, 2, 4-triazole-3-methyl formate, belonging to the technical field of organic synthesis. 1,2, 4-triazole is used as a raw material, firstly nucleophilic substitution is carried out on the raw material and methyl chloride under the condition of strong alkali potassium hydroxide to obtain 1-methyl-1, 2, 4-triazole, then protection is carried out on the 5-position under the action of a lithium reagent, then 3-carboxylic acid is obtained by reacting the 3-position with carbon dioxide under the action of nonpolar strong alkali LDA, then 3-carboxylic acid methyl ester is synthesized by the raw material and thionyl chloride and methanol, and then the 5-position protection is removed to obtain 1-methyl-1H-1, 2, 4-triazole-3-methyl formate. The invention provides a novel preparation method, raw materials are easy to obtain, and the problems of N-methyl isomerization and excessive quaternization are avoided from the source.
Description
Technical Field
The invention relates to a preparation method of 1-methyl-1H-1, 2, 4-triazole-3-methyl formate, belonging to the technical field of organic synthesis.
Background
1-methyl-1H-1, 2, 4-triazole-3-carboxylic acid methyl ester, CAS:57031-66-0,1,2, 4-triazole and derivatives thereof have a substructure with stronger bioactivity, and because 1,2, 4-triazole has stronger ability to form non-covalent pi-pi conjugation, complex metal ions or form hydrogen bonds, the 1,2, 4-triazole has been attracting attention in the fields of pharmaceutical chemistry and synthesis.
For the synthesis of methyl 1-methyl-1H-1, 2, 4-triazole-3-carboxylate, methyl 1H-1,2, 4-triazole-3-carboxylate is usually used as the raw material, and then N-methylation reaction is carried out on N-H. Wherein the synthesis method of 1H-1,2, 4-triazole-3-methyl formate is more selected from diazotization deamination method [ Russian J.Bioorg.chem., [ 2013,39,53-71 ]; bioorganicheskaya Khimi ya,2013,39,61-80]. However, with the N-alkylation reaction, alkylated tautomeric byproducts may occur, possibly with tautomerism due to hydrogen proton transfer. Triazole pesticides such as tricyclazole and the like, and triazole drugs such as letrozole and the like are derivatives of 1,2, 4-triazole, and isomer byproducts of the 1,2, 4-triazole derivatives can appear in the synthesis.
N-methylation reaction is carried out by adopting 1H-1,2, 4-triazole-3-methyl formate and methyl iodide, and the yield is 52% [ Chem anandiodiv 2017,14, E1700351]. The reason for the low yield is the existence of isomer by-products. The reaction equation is as follows:
the invention adopts a brand-new synthesis method to prepare 1-methyl-1H-1, 2, 4-triazole-3-methyl formate, so as to avoid the problems of selective control of N-methylation reaction of 1,2, 4-triazole, separation and purification of isomer byproducts and the like, and selects a synthesis method which fundamentally solves the isomerization of the methyl formate, thus obtaining a high-quality product.
Disclosure of Invention
The invention discloses a preparation method of 1-methyl-1H-1, 2, 4-triazole-3-methyl formate. 1,2, 4-triazole is used as a raw material, firstly nucleophilic substitution is carried out on the raw material and methyl chloride under the condition of strong alkali potassium hydroxide to obtain 1-methyl-1, 2, 4-triazole, then protection is carried out on the 5-position under the action of a lithium reagent, then 3-carboxylic acid is obtained by reacting the 3-position with carbon dioxide under the action of nonpolar strong alkali LDA, then 3-carboxylic acid methyl ester is synthesized by the raw material and thionyl chloride and methanol, and then the 5-position protection is removed to obtain 1-methyl-1H-1, 2, 4-triazole-3-methyl formate. The invention avoids the problem of N-methyl isomerization from the source, and the obtained product has high quality.
The invention discloses a preparation method of 1-methyl-1H-1, 2, 4-triazole-3-methyl formate, which comprises the following steps:
the first step: mixing 1,2, 4-triazole, potassium hydroxide and ethanol, slowly adding methyl chloride, and heating and refluxing to obtain 1-methyl-1, 2, 4-triazole;
and a second step of: dissolving 1-methyl-1, 2, 4-triazole in tetrahydrofuran and TMEDA, cooling, adding n-butyllithium, and then adding dibromomethane to react to obtain 5-bromo-1-methyl-1H- [1,2,4] triazole; or 1-methyl-1, 2, 4-triazole is dissolved in tetrahydrofuran, LDA is added after the temperature is reduced, and then trimethylchlorosilane is added for reaction to obtain 5-trimethylsilyl-1-methyl-1H- [1,2,4] triazole;
and a third step of: mixing 5-bromo/trimethylsilyl-1-methyl-1H- [1,2,4] triazole with tetrahydrofuran, cooling, adding LDA, and introducing carbon dioxide for reaction to obtain 5-bromo/trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid;
fourth step: mixing 5-bromo/trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid with methanol, and dropwise adding thionyl chloride to react to obtain 5-bromo/(trimethylsilyl) -1-methyl-1H- [1,2,4] triazole-3-carboxylic acid methyl ester;
fifth step: mixing 5-bromo-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid methyl ester, 5% Pd/C and equivalent DBU with methanol, introducing hydrogen gas, pressurizing and removing bromine to obtain 1-methyl-1H-1, 2, 4-triazole-3-carboxylic acid methyl ester; or mixing 5-bromo-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid with acetic acid, and adding zinc powder in batches to react to obtain 1-methyl-1H-1, 2, 4-triazole-3-methyl formate; or reacting 5-trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid with tetrabutylammonium fluoride in 2-methyltetrahydrofuran to obtain 1-methyl-1H-1, 2, 4-triazole-3-methyl formate.
Further, in the first step of the technical scheme, the molar ratio of the 1,2, 4-triazole to the potassium hydroxide to the chloromethane is 1:1.4-1.5:1.0-1.5.
Further, in the second step of the technical scheme, the molar ratio of 1-methyl-1, 2, 4-triazole, TMEDA, n-butyllithium and dibromomethane is 1:0.20-0.25:1.15-1.20:1.35-2.35.
Further, in the second step of the technical scheme, the molar ratio of 1-methyl-1, 2, 4-triazole, LDA and trimethylchlorosilane is 1:1.10-1.20:1.20-1.30.
Further, in the third step of the technical scheme, the mole ratio of the 5-bromo/trimethylsilyl-1-methyl-1H- [1,2,4] triazole, LDA and carbon dioxide is 1:1.10-1.20:2.00-7.00.
Further, in the fourth step of the above technical scheme, the molar ratio of the 5-bromo/trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid to thionyl chloride is 1:1.20-1.30.
Further, in the fifth step of the above technical scheme, the molar ratio of 5-bromo-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid methyl ester to DBU is 1:1.0-1.05; the hydrogenation pressure is 0.1-0.3Mpa, and the temperature is 25-35 ℃.
Further, in the fifth step of the above technical scheme, the molar ratio of 5-bromo-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid methyl ester to zinc powder is 1:1.50-1.65; the temperature is selected from 15-35 ℃.
Further, in the fifth step of the above technical scheme, the molar ratio of 5-trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid methyl ester to TBAF is 1:1.10-1.15, the temperature is selected from 0-25 ℃.
Advantageous effects of the invention
1. The raw materials are easy to obtain. Avoiding the use of methyl iodide with strong toxicity, quick volatilization, low atomic utilization rate and high price.
2. The method fundamentally solves the problem of regiochemical selectivity in the methylation product, and avoids the problems of N-methyl isomerization and excessive quaternization.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples should be construed as merely illustrative of the present invention and not limiting the scope of the present invention. Various changes and modifications to the present invention may be made by one skilled in the art after reading the description herein, and such equivalent changes and modifications are intended to fall within the scope of the present invention as defined in the appended claims.
Example 1
To the closed reactor was added 1,2, 4-triazole (69.1 g,1.0 mol), potassium hydroxide (81.3 g,1.45 mol) and 300mL of absolute ethanol. Methyl chloride (50 g,1.01 mol) is introduced at room temperature, then the temperature is slowly raised to 75 ℃ for reaction for 6 hours, the temperature is reduced to room temperature, the materials are decompressed and concentrated to no-flow liquid, the temperature is reduced to 0 ℃, water and methylene dichloride are added for extraction, pH=7-8 is washed with water after layering, the organic phase is concentrated to no-flow liquid, and 73.2g of 1-methyl-1, 2, 4-triazole oily substance is obtained through distillation. GC purity was 99.4% in 88.1% yield.
Example 2
Under the protection of nitrogen, 1-methyl-1, 2, 4-triazole (41.5 g,0.5 mol), TMEDA (14.2 g,0.125 mol) and 300mL tetrahydrofuran are added into a reaction bottle, the temperature is reduced to minus 40 ℃, 240mL of 2.5M N-butyllithium N-hexane solution is slowly added dropwise, the temperature is raised to minus 10 ℃, the temperature is kept for 1 to 1.5 hours, then the temperature is reduced to minus 25 ℃, dibromomethane (130.4 g,0.75 mol)/tetrahydrofuran solution is added dropwise, the reaction is completed for 5 hours, then the temperature is naturally raised to 10 to 20 ℃, 2N hydrochloric acid is added for quenching, ethyl acetate extraction is carried out, saturated saline solution is used for washing, the organic phase is dried by anhydrous sodium sulfate, the filtration is carried out, the filtrate is concentrated to be not fluid, then N-heptane is added for replacement, the filtration is carried out, and the yield of 79.6 percent is obtained, namely, the 5-bromo-1-methyl-1H- [1,2,4] triazole is 64.5 g.
Example 3
Under the protection of nitrogen, 1-methyl-1, 2, 4-triazole (41.5 g,0.5 mol) and 200mL of tetrahydrofuran are added into a reaction bottle, the temperature is reduced to minus 78 ℃,1.0M LDA tetrahydrofuran solution 550mL is slowly added dropwise, trimethylchlorosilane (70.6 g,0.65 mol) tetrahydrofuran solution is added dropwise, the reaction is carried out for 2 hours after the dropwise addition is finished, then the temperature is naturally raised to 10-20 ℃, saturated ammonium chloride is added for quenching, ethyl acetate extraction, saturated saline water washing is carried out, an organic phase is dried by anhydrous sodium sulfate, filtration is carried out, filtrate is concentrated to be non-flowing liquid, then n-heptane is added for replacement, filtration is carried out, and 5-trimethylsilyl-1-methyl-1H- [1,2,4] triazole 66.8g is obtained, HPLC 98.5%, and the yield is 86.1%.
Example 4
Under the protection of nitrogen, 5-bromo-1-methyl-1H- [1,2,4] triazole (32.4 g,0.2 mol) and 100mL of tetrahydrofuran are added into a reaction bottle, the temperature is reduced to minus 78 ℃,1.0M LDA tetrahydrofuran solution 220mL is slowly added dropwise, carbon dioxide (52.8 g,1.2 mol) is slowly added, the reaction is completed for 2 hours, then natural heating is carried out to 10-20 ℃, saturated ammonium chloride is added for quenching, toluene extraction is carried out, saturated saline solution is used for washing, an organic phase is added into a sodium hydroxide aqueous solution for adjusting pH=12-13, a toluene layer is removed, a water layer is used for adjusting pH=4.0-4.5 by using 2N hydrochloric acid, dichloromethane extraction is carried out, an organic phase saturated saline solution is used for washing, organic phase sodium sulfate is dried, filtration is carried out, filtrate is concentrated to be no fluid, N-heptane is added for replacement, filtration is carried out, and the yield of 5-bromo-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid 29.9g, HP99.2% is obtained, and the yield is 72.5%.
Example 5
Under the protection of nitrogen, adding 5-trimethylsilyl-1-methyl-1H- [1,2,4] triazole (31.1 g,0.2 mol)/tetrahydrofuran into a reaction bottle, cooling to-78 ℃, slowly dropwise adding 215mL of 1.0M LDA tetrahydrofuran solution, slowly introducing carbon dioxide (61.6 g,1.4 mol), completing the reaction for 2 hours, then naturally heating to 10-20 ℃, adding saturated ammonium chloride for quenching, extracting with ethyl acetate, washing with saturated saline, drying an organic phase, filtering, concentrating the filtrate, adding MTBE for replacement, cooling, and precipitating a large amount of solid, wherein 30.2g of 5-trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid is obtained after filtering, and the yield is 75.7 percent through HPLC.
Example 6
5-bromo-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid (20.6 g,0.1 mol) and 110g of methanol are added into a reaction bottle, thionyl chloride (14.3 g,0.12 mol) is slowly added dropwise at a temperature of 20-35 ℃, the temperature is raised to 60 ℃ after the dripping, the reaction is carried out for 5 hours, the methanol is concentrated under reduced pressure, a large amount of solid is separated out by adding water, the solid is filtered, a filter cake is washed by water, and 20.3g of 5-bromo-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid methyl ester is obtained after drying, HPLC98.9%, and the yield is 92.3%.
Example 7
5-trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid (19.9 g,0.1 mol) and 100g of methanol are added into a reaction flask, thionyl chloride (14.3 g,0.12 mol) is slowly added dropwise at a temperature of 20-35 ℃, the temperature is raised to 60 ℃ after the completion of the dropwise addition, the reaction is carried out for 5 hours, the methanol is concentrated under reduced pressure and distilled off, toluene is added for replacement, then n-heptane is added, and the mixture is filtered to obtain 20.1g of methyl 5-trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylate, and HPLC (high performance liquid chromatography) 95.6% and the yield is 94.2%.
Example 8
To the reaction vessel, methyl 5-bromo-1-methyl-1H- [1,2,4] triazole-3-carboxylate (20 g,0.0908 mol), 5% Pd/C (6 g), DBU (13.8 g,0.0908 mol) and 200mL of methanol were added, nitrogen and hydrogen were replaced, followed by hydrogen and maintaining the pressure at 0.1MPa, the pressure was not lost after 16 hours of reaction, nitrogen replacement, filtration, concentration of the filtrate under reduced pressure, addition of dichloromethane and water, washing of the organic phase with saturated ammonium chloride, concentration of the organic phase to a non-fluid solution, and recrystallization of the added methanol to give methyl 1-methyl-1H-1, 2, 4-triazole-3-carboxylate 11.7g, HPLC 99.5% yield 91.3%. HNMR and HPLC peaks were consistent with standards.
Example 9
To the reaction flask, methyl 5-bromo-1-methyl-1H- [1,2,4] triazole-3-carboxylate (20 g,0.0908 mol) and 100g acetic acid were added, zinc powder (9.2 g,0.141 mol) was added in portions at 15-20deg.C, followed by heating to 50-55deg.C for 8 hours, filtration was performed, the filtrate was concentrated under reduced pressure to a non-aqueous solution, methanol was added to dissolve, insoluble matters were filtered off, concentration under reduced pressure was performed, and recrystallization was performed to obtain methyl 1-methyl-1H-1, 2, 4-triazole-3-carboxylate 10.9g, HPLC 99.1%, yield 85.1%. HNMR and HPLC peaks were consistent with standards.
Example 10
To the reaction flask, methyl 5-trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylate (20 g,0.0938 mol), tetra-n-butylammonium fluoride (24.5 g,0.1032 mol) and tetrahydrofuran were added, reacted at room temperature under nitrogen protection for 24 hours, concentrated under reduced pressure, dichloromethane and water were added, the organic phase was washed with water, the organic phase was concentrated to a non-fluid solution, methanol was added to recrystallize to give methyl 1-methyl-1H-1, 2, 4-triazole-3-carboxylate 10.8g, HPLC 99.4%, yield 81.3%. HNMR and HPLC peaks were consistent with standards.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should be covered by the protection scope of the present invention by making equivalents and modifications to the technical solution and the inventive concept thereof.
Claims (9)
1. The preparation method of the 1-methyl-1H-1, 2, 4-triazole-3-methyl formate is characterized by comprising the following steps:
the first step: mixing 1,2, 4-triazole, potassium hydroxide and ethanol, slowly adding methyl chloride, and heating and refluxing to obtain 1-methyl-1, 2, 4-triazole;
and a second step of: dissolving 1-methyl-1, 2, 4-triazole in tetrahydrofuran and TMEDA, cooling, adding n-butyllithium, and then adding dibromomethane to react to obtain 5-bromo-1-methyl-1H- [1,2,4] triazole; or 1-methyl-1, 2, 4-triazole is dissolved in tetrahydrofuran, LDA is added after the temperature is reduced, and then trimethylchlorosilane is added for reaction to obtain 5-trimethylsilyl-1-methyl-1H- [1,2,4] triazole;
and a third step of: mixing 5-bromo/trimethylsilyl-1-methyl-1H- [1,2,4] triazole with tetrahydrofuran, cooling, adding LDA, and introducing carbon dioxide for reaction to obtain 5-bromo/trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid;
fourth step: mixing 5-bromo/trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid with methanol, and dropwise adding thionyl chloride to react to obtain 5-bromo/(trimethylsilyl) -1-methyl-1H- [1,2,4] triazole-3-carboxylic acid methyl ester;
fifth step: mixing 5-bromo-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid methyl ester, 5% Pd/C and equivalent DBU with methanol, introducing hydrogen gas, pressurizing and removing bromine to obtain 1-methyl-1H-1, 2, 4-triazole-3-carboxylic acid methyl ester; or mixing 5-bromo-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid with acetic acid, and adding zinc powder in batches to react to obtain 1-methyl-1H-1, 2, 4-triazole-3-methyl formate; or reacting 5-trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid with tetrabutylammonium fluoride in 2-methyltetrahydrofuran to obtain 1-methyl-1H-1, 2, 4-triazole-3-methyl formate.
2. The method for preparing 1-methyl-1H-1, 2, 4-triazole-3-carboxylic acid methyl ester according to claim 1, wherein: in the first step, the molar ratio of 1,2, 4-triazole, potassium hydroxide and chloromethane is 1:1.4-1.5:1.0-1.5.
3. The method for preparing 1-methyl-1H-1, 2, 4-triazole-3-carboxylic acid methyl ester according to claim 1, wherein: in the second step, the molar ratio of 1-methyl-1, 2, 4-triazole, TMEDA, n-butyllithium and dibromomethane is 1:0.20-0.25:1.15-1.20:1.35-2.35.
4. The method for preparing 1-methyl-1H-1, 2, 4-triazole-3-carboxylic acid methyl ester according to claim 1, wherein: in the second step, the mole ratio of 1-methyl-1, 2, 4-triazole, LDA and trimethylchlorosilane is 1:1.10-1.20:1.20-1.30.
5. The method for preparing 1-methyl-1H-1, 2, 4-triazole-3-carboxylic acid methyl ester according to claim 1, wherein: in the third step, the mole ratio of 5-bromine/trimethylsilyl-1-methyl-1H- [1,2,4] triazole, LDA and carbon dioxide is 1:1.10-1.20:2.00-7.00.
6. The method for preparing 1-methyl-1H-1, 2, 4-triazole-3-carboxylic acid methyl ester according to claim 1, wherein: in the fourth step, the molar ratio of the 5-bromo/trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid to thionyl chloride is 1:1.20-1.30.
7. The method for preparing 1-methyl-1H-1, 2, 4-triazole-3-carboxylic acid methyl ester according to claim 1, wherein: in the fifth step, the molar ratio of 5-bromo-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid methyl ester to DBU is 1:1.0-1.05; the hydrogenation pressure is 0.1-0.3Mpa, and the temperature is 25-35 ℃.
8. The method for preparing 1-methyl-1H-1, 2, 4-triazole-3-carboxylic acid methyl ester according to claim 1, wherein: in the fifth step, the molar ratio of the 5-bromo-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid methyl ester to the zinc powder is 1:1.50-1.65; the temperature is selected from 15-35 ℃.
9. The method for preparing 1-methyl-1H-1, 2, 4-triazole-3-carboxylic acid methyl ester according to claim 1, wherein: in the fifth step, the molar ratio of the 5-trimethylsilyl-1-methyl-1H- [1,2,4] triazole-3-carboxylic acid methyl ester to TBAF is 1:1.10-1.15, the temperature is selected from 0-25 ℃.
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