CN113307778A - Preparation method of 3-trifluoromethyl substituted 1,2, 4-triazole compound - Google Patents

Preparation method of 3-trifluoromethyl substituted 1,2, 4-triazole compound Download PDF

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CN113307778A
CN113307778A CN202110644663.7A CN202110644663A CN113307778A CN 113307778 A CN113307778 A CN 113307778A CN 202110644663 A CN202110644663 A CN 202110644663A CN 113307778 A CN113307778 A CN 113307778A
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substituted
trifluoromethyl
triazole compound
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王慧
陈铮凯
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Hangzhou Vocational and Technical College
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    • 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

Abstract

The invention discloses a preparation method of a 3-trifluoromethyl substituted 1,2, 4-triazole compound, which comprises the following steps: molybdenum hexacarbonyl, cuprous acetate, triethylamine,

Description

Preparation method of 3-trifluoromethyl substituted 1,2, 4-triazole compound
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a 3-trifluoromethyl substituted 1,2, 4-triazole compound.
Background
The 1,2, 4-triazole compound is an extremely important five-membered nitrogen-containing heterocyclic ring and widely exists in molecular frameworks with biological and pharmaceutical activities (chem. Rev.2010,110, 1809-1827). Many drugs contain 1,2, 4-triazole molecular structures, such as deferasirox, maraviroc, sitagliptin, and the like. Polysubstituted 1,2, 4-triazole molecules are also frequently used in ligand chemistry. Trifluoromethyl can significantly improve the physicochemical properties of the parent molecule, such as electronegativity, bioavailability, metabolic stability, lipophilicity, etc. (j.med.chem.2015,58, 8315-. Therefore, the construction of the trifluoromethyl substituted 1,2, 4-triazole compound has important theoretical research significance and practical application value.
Figure BDA0003108657450000011
The traditional method for synthesizing trifluoromethyl substituted 1,2, 4-triazole in the literature reports at present mainly comprises the cyclization reaction of trifluoroacetyl hydrazine and amidine compounds and the hydrazinolysis of trifluoromethyl substituted 1,2, 4-oxazolinone. And the copper-catalyzed multi-component reaction taking diazonium salt, trifluorodiazoethane and nitrile as raw materials constructs trifluoromethyl-substituted 1,2, 4-triazole. Meanwhile, the compound can be synthesized by adopting cyclization reaction of trifluoroethylimidoyl chloride, aldehyde hydrazone and hydrazide.
Most developed synthetic methods obtain fully substituted 1,2, 4-triazole, and the reports on the synthetic method of 3, 4-disubstituted 1,2, 4-triazole are not extensive. Therefore, a method for simply and efficiently synthesizing 3-trifluoromethyl substituted 1,2, 4-triazole by taking cheap and easily-obtained functionalized isonitrile and trifluoroethylimidoyl chloride as starting raw materials and performing cycloaddition reaction co-catalyzed by molybdenum and copper is developed.
Disclosure of Invention
The invention provides a preparation method of a 3-trifluoromethyl substituted 1,2, 4-triazole compound, which has the advantages of simple reaction steps, cheap and easily obtained starting raw materials, high reaction efficiency and convenient operation and application; the method can be easily expanded to gram level, and provides possibility for subsequent scale production and application.
A preparation method of 3-trifluoromethyl substituted 1,2, 4-triazole compound comprises the following steps: molybdenum hexacarbonyl, cuprous acetate, triethylamine,
Figure BDA0003108657450000021
Adding a molecular sieve, trifluoroethylimidoyl chloride and functionalized isonitrile (NIITP) into an organic solvent, reacting for 18-30 hours at 70-90 ℃, and after the reaction is completed, performing post-treatment to obtain the 3-trifluoromethyl-substituted 1,2, 4-triazole compound;
the structure of the trifluoroethylimidoyl chloride is shown as a formula (II):
Figure BDA0003108657450000022
the functionalized isonitrile has a structure shown in a formula (III):
Ph3P＝N-NC (III)
the structure of the 3-trifluoromethyl substituted 1,2, 4-triazole compound is shown as the formula (I):
Figure BDA0003108657450000023
in the formulas (I) to (III), R is phenethyl or substituted or unsubstituted aryl;
in R, the substituent on the aryl is selected from C1～C4Alkyl radical, C1～C4Alkoxy, halogen or trifluoromethyl.
The substitution position of the aryl on R can be ortho, para or meta.
The reaction formula is as follows:
Figure BDA0003108657450000031
in the reaction, molybdenum hexacarbonyl and functionalized isonitrile form a metal complex, the reaction may first undergo copper-promoted [3+2] cycloaddition reaction of the functionalized isonitrile to trifluoroethylimidoyl chloride to form a five-membered ring intermediate, and then triphenylphosphine oxide is removed under the action of water in a system to generate a final 3-trifluoromethyl-substituted 1,2, 4-triazole compound.
In the present invention, the optional post-processing procedure includes: filtering, mixing the sample with silica gel, and finally performing column chromatography purification to obtain the corresponding 3-trifluoromethyl-substituted 1,2, 4-triazole compound, wherein the column chromatography purification is a technical means commonly used in the field.
Preferably, R is a phenethyl group, a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is selected from methyl, methoxy, fluoro or chloro, in which case the aromatic amine and the trifluoroethylimidoyl chloride are readily available and the reaction yield is high.
The functionalized isonitrile is active and is used in excess relative to the amount of p-trifluoroethylimidoyl chloride, preferably, the molar amount of trifluoroethylimidoyl chloride: functionalized isonitriles: molybdenum hexacarbonyl: cuprous acetate: triethylamine is 1: 1-2: 0.02-0.08: 0.2-0.8: 1-3; as a further preference, the molar amount of trifluoroethylimidoyl chloride: functionalized isonitriles: molybdenum hexacarbonyl: cuprous acetate: triethylamine 1:1.5:0.05:0.5: 2.
In the present invention, the organic solvent capable of sufficiently dissolving the raw material can cause the reaction, but the difference in reaction efficiency is large, and the aprotic solvent is preferably an aprotic solvent which can effectively promote the reaction; preferably, the organic solvent is acetonitrile, DMF or THF; further preferably, the organic solvent is THF, in which case the various starting materials can be converted into the product with high conversion.
The amount of the organic solvent can be used for better dissolving the raw materials, and the amount of the organic solvent used for 1mmol of trifluoroethylimidoyl chloride is about 5-10 mL.
Preferably, the metal activator is molybdenum hexacarbonyl, which has better properties for activating the functionalized isonitrile.
Preferably, the catalyst is cuprous acetate, which is relatively inexpensive, and the reaction efficiency is high when cuprous acetate is used as the catalyst.
Preferably, the base is triethylamine, the triethylamine is relatively cheap, and the reaction efficiency is higher when the triethylamine is used as an accelerator.
Further preferably, the 3-trifluoromethyl substituted 1,2, 4-triazole compound is one of compounds shown in formula (I-1) to formula (I-5):
Figure BDA0003108657450000041
in the preparation method, the aromatic amine, the functionalized isonitrile, the molybdenum hexacarbonyl, the cuprous acetate and the triethylamine are generally commercially available products and can be conveniently obtained from the market, and the trifluoroethyliminecarbonyl chloride can be quickly synthesized from the corresponding aromatic amine, triphenylphosphine, carbon tetrachloride and trifluoroacetic acid.
Compared with the prior art, the invention has the beneficial effects that: the preparation method has mild reaction conditions, easy operation and simple and convenient post-treatment; the reaction starting raw materials are cheap and easy to obtain, the designability of a reaction substrate is strong, the tolerance range of a substrate functional group is wide, the reaction efficiency is high, 4-substituted 1,2, 4-triazole compounds with trifluoromethyl can be designed and synthesized according to actual needs, and the practicability is strong.
Detailed Description
The invention is further described with reference to specific examples.
Adding molybdenum hexacarbonyl, cuprous acetate, triethylamine, trifluoroethylimidoyl chloride (II), functionalized isonitrile (III) and 2mL of organic solvent into a 35mL Schlenk tube according to the raw material ratio of Table 1, uniformly mixing and stirring, reacting for 18-30 hours according to the reaction conditions of Table 2, filtering, mixing a sample with silica gel, and purifying by column chromatography to obtain a corresponding 3-trifluoromethyl-substituted 1,2, 4-triazole compound (I), wherein the reaction process is shown as the following formula:
Figure BDA0003108657450000051
TABLE 1 raw material addition amounts of examples 1 to 15
Figure BDA0003108657450000052
TABLE 2
Figure BDA0003108657450000053
Figure BDA0003108657450000061
In tables 1 and 2, T is the reaction temperature, T is the reaction time, Ph is phenyl, Me is methyl, Et is ethyl, T-Bu is T-butyl, OMe is methoxy, SMe is methylthio, NO2Is nitro, THF is tetrahydrofuran.
Structure confirmation data of the compounds prepared in examples 1 to 5:
nuclear magnetic resonance of 3-trifluoromethyl-substituted 1,2, 4-triazole compound (I-1) prepared in example 1 ((iii))1H NMR、13C NMR and19f NMR) the data were:
Figure BDA0003108657450000062
1H NMR(400MHz,CDCl3)δ8.31(s,1H),7.34(d,J＝8.1Hz,2H),7.23(d, J＝8.3Hz,2H),2.45(s,3H).
13C{1H}NMR(101MHz,CDCl3)δ146.4,144.6(C-F,q,2J(C-F)＝39.1Hz), 141.2,130.5,129.7,125.6,118.2(C-F,q,1J(C-F)＝271.2Hz),21.2(C-F,q, 1J(C-F)＝9.8Hz).
19F NMR(377MHz,CDCl3)δ-60.6.
HRMS(ESI):[M+H]+calcd.for C10H9F3N3 228.0743,found 228.0744.
nuclear magnetic resonance of 3-trifluoromethyl-substituted 1,2, 4-triazole compound (I-2) prepared in example 2 (ii)1H NMR、13C NMR and19f NMR) the data were:
Figure BDA0003108657450000063
1H NMR(400MHz,CDCl3)δ8.34(s,1H),7.56(d,J＝8.6Hz,2H),7.30(d, J＝8.5Hz,2H),1.38(s,9H).
13C{1H}NMR(101MHz,CDCl3)δ154.3,146.4(C-F,q,2J(C-F)＝35.6Hz), 129.6,126.9,125.4,118.2(C-F,q,1J(C-F)＝271.2Hz),35.0,31.2.
19F NMR(377MHz,CDCl3)δ-60.6.
M.p.130.4-131.8℃
HRMS(ESI):[M+H]+calcd.for C13H15F3N3 270.1213,found 270.1219.
nuclear magnetic resonance of 3-trifluoromethyl-substituted 1,2, 4-triazole compound (I-3) prepared in example 3 (ii)1H NMR、13C NMR and19f NMR) the data were:
Figure BDA0003108657450000071
1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.43–7.37(m,2H),7.31–7.24 (m,2H).
13C{1H}NMR(101MHz,CDCl3)δ163.6(C-F,d,3J(C-F)＝252.7Hz),146.3, 144.7(C-F,q,2J(C-F)＝39.5Hz),128.1(C-F,d,2J(C-F)＝9.2Hz),118.1(C-F,q, 1J(C-F)＝271.2Hz),117.2(C-F,d,1J(C-F)＝23.4Hz),117.2.
19F NMR(377MHz,CDCl3)δ-60.6,-108.3.
M.p.91.6-93.8℃
HRMS(ESI):[M+H]+calcd.for C9H6F4N3 232.0492,found 232.0499.
nuclear magnetic resonance of 3-trifluoromethyl-substituted 1,2, 4-triazole compound (I-4) prepared in example 4 (ii)1H NMR、13C NMR and19f NMR) the data were:
Figure BDA0003108657450000072
1H NMR(400MHz,CDCl3)δ8.41(s,1H),8.10(d,J＝8.3Hz,1H),8.00(d, J＝8.0Hz,1H),7.66–7.55(m,3H),7.53(d,J＝7.2Hz,1H),7.17(d,J＝8.3 Hz,1H).
13C{1H}NMR(101MHz,CDCl3)δ147.1,145.6(C-F,q,2J(C-F)＝39.5Hz), 134.0,131.6,129.5,128.6,128.6,128.3,127.6,125.4,124.9,120.9,118.1(C-F, q,1J(C-F)＝271.6Hz).
19F NMR(377MHz,CDCl3)δ-61.4.
M.p.132.4-134.6℃
HRMS(ESI):[M+H]+calcd.for C13H9F3N3 264.0743,found 264.0748.
nuclear magnetic resonance of 3-trifluoromethyl-substituted 1,2, 4-triazole compound (I-5) prepared in example 5 (ii)1H NMR、13C NMR and19f NMR) the data were:
Figure BDA0003108657450000081
1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.36–7.27(m,3H),7.06(d,J＝ 6.3Hz,2H),4.36(t,J＝7.1Hz,2H),3.10(t,J＝7.1Hz,2H).
13C{1H}NMR(101MHz,CDCl3)δ146.0(C-F,q,2J(C-F)＝41.5Hz),135.6, 129.2,128.6,127.7,118.6(C-F,q,1J(C-F)＝270.1Hz),47.4,36.8.
19F NMR(377MHz,CDCl3)δ-61.9.
HRMS(ESI):[M+H]+calcd.for C11H11F3N3 242.0900,found 242.0905。

Claims (5)

1. a preparation method of a 3-trifluoromethyl substituted 1,2, 4-triazole compound is characterized by comprising the following steps: molybdenum hexacarbonyl, cuprous acetate, triethylamine,
Figure FDA0003108657440000013
Adding a molecular sieve, trifluoroethylimidoyl chloride and functionalized isonitrile into an organic solvent, reacting at 70-90 ℃ for 18-30 hours, and after the reaction is completed, performing post-treatment to obtain the 3-trifluoromethyl substituted 1,2, 4-triazole compound;
the structure of the trifluoroethylimidoyl chloride is shown as a formula (II):
Figure FDA0003108657440000011
the functionalized isonitrile has a structure shown in a formula (III):
Ph3P＝N-NC (III)
the structure of the 3-trifluoromethyl substituted 1,2, 4-triazole compound is shown as the formula (I):
Figure FDA0003108657440000012
in the formulas (I) to (III), R is phenethyl or substituted or unsubstituted aryl;
in R, the substituent on the aryl is selected from C1～C4Alkyl radical, C1～C4Alkoxy, halogen or trifluoromethyl.
2. The method for preparing 3-trifluoromethyl substituted 1,2, 4-triazole compound according to claim 1, wherein R is phenethyl, substituted or unsubstituted phenyl;
the substituent on the phenyl is selected from methyl, methoxy, fluorine or chlorine.
3. The method for preparing 3-trifluoromethyl-substituted 1,2, 4-triazole compound according to claim 1, wherein the molar ratio of trifluoroethylimidoyl chloride: functionalized isonitriles: molybdenum hexacarbonyl: cuprous acetate: triethylamine is 1: 1-2: 0.02-0.08: 0.2-0.8: 1-3.
4. The method for preparing 3-trifluoromethyl substituted 1,2, 4-triazole compound according to claim 1, wherein the organic solvent is tetrahydrofuran.
5. The preparation method of the 3-trifluoromethyl-substituted 1,2, 4-triazole compound according to claim 1, wherein the 3-trifluoromethyl-substituted 1,2, 4-triazole compound is one of compounds shown in formula (I-1) to formula (I-5):
Figure FDA0003108657440000021
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113880781A (en) * 2021-09-24 2022-01-04 浙江理工大学 Method for synthesizing 3-trifluoromethyl substituted 1,2, 4-triazole compound by taking glucose as carbon source
CN113929924A (en) * 2021-11-30 2022-01-14 常州大学 Isopolymolybdic acid metal organic framework material for preparing polylactic acid and preparation method
CN114195726A (en) * 2021-12-06 2022-03-18 浙江理工大学 Preparation method of 1,2, 4-triazolyl substituted arylamine compound
CN115286578A (en) * 2022-08-30 2022-11-04 浙江理工大学 Preparation method of pyrazole compound containing trifluoromethyl

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113880781A (en) * 2021-09-24 2022-01-04 浙江理工大学 Method for synthesizing 3-trifluoromethyl substituted 1,2, 4-triazole compound by taking glucose as carbon source
CN113880781B (en) * 2021-09-24 2023-08-18 浙江理工大学 Method for synthesizing 3-trifluoromethyl substituted 1,2, 4-triazole compound by taking glucose as carbon source
CN113929924A (en) * 2021-11-30 2022-01-14 常州大学 Isopolymolybdic acid metal organic framework material for preparing polylactic acid and preparation method
CN113929924B (en) * 2021-11-30 2022-04-22 常州大学 Isopolymolybdic acid metal organic framework material for preparing polylactic acid and preparation method
CN114195726A (en) * 2021-12-06 2022-03-18 浙江理工大学 Preparation method of 1,2, 4-triazolyl substituted arylamine compound
CN114195726B (en) * 2021-12-06 2023-08-18 浙江理工大学 Preparation method of 1,2, 4-triazole substituted arylamine compound
CN115286578A (en) * 2022-08-30 2022-11-04 浙江理工大学 Preparation method of pyrazole compound containing trifluoromethyl
CN115286578B (en) * 2022-08-30 2023-10-03 浙江理工大学 Preparation method of trifluoromethyl-containing pyrazole compound

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