Trifluoromethyl pyrazole derivative and applications thereof

A technology of trifluoromethylpyrazole and fluoromethylpyrazole, which is applied in the field of new trifluoromethylpyrazole derivatives and applications, can solve dependence, the range of synthetic substrates and the lack of wide application, and triazene There are few problems in the application of intermediates, etc., to achieve the effect of environmental protection operation and simple and convenient operation

Pending Publication Date: 2019-12-31
INST OF MEDICINAL PLANT DEV CHINESE ACADEMY OF MEDICAL SCI +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing 3-trifluoromethylpyrazole synthetic method has limitations, its synthetic process always depends on the use of stoichiometric catalyst or pretreatment starting material, and the scope of synthetic substrate and application are not extensive
Although CF 3 CHN 2 Terminal N electrophilicity and CF 3 CHN 2 Preparation and storage have made breakthroughs, but based on CF 3 CHN 2 Terminal N electrophilicity, formation of triazene intermediates via Lewis base activation in organic synthesis and medicinal chemistry is poorly studied

Method used

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  • Trifluoromethyl pyrazole derivative and applications thereof
  • Trifluoromethyl pyrazole derivative and applications thereof
  • Trifluoromethyl pyrazole derivative and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: Synthesis of 5-phenyl-3-trifluoromethyl-1H-pyrazole

[0046]

[0047] In the presence of DBU (0.06mmol, 0.2eq) as Lewis base, 1,4-dioxane (0.4mL) was added as solvent, phenylacetylene (0.3mmol, 1.0eq) and CF 3 CHN 2(1.2mmol, 4.0 equivalents, 1.5mol / L toluene) was reacted at 80°C for 12h, and the solvent was evaporated off after the reaction to obtain a light yellow solid 5-phenyl-3-trifluoromethyl-1H-pyrazole, the yield 97%.

[0048] 1H NMR (600MHz, CDCl3): δ=11.34(s,1H), 7.58–7.57(m,2H), 7.49–7.46(m,2H), 7.44–7.42(m,1H), 6.78(s,1H) ppm.13C NMR (151MHz, CDCl3): δ=145.5, 144.4 (q, JC-F=36.2Hz), 1230.0, 129.8, 128.45, 126.1, 121.6 (q, JC-F=238.7Hz), 101.7ppm.HRMS (ESI): calcd for C10H8N2F3[M +H]+: 213.0634, found 213.0631

[0049] 1H-NMR spectrum and 13C-NMR spectrum as figure 1 , 2 As shown, it was detected by a nuclear magnetic resonance spectrometer (Bruker VNMRS600).

Embodiment 2

[0050] Example 2: Synthesis of 3-(3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridine

[0051]

[0052] In the presence of DBU (0.06mmol, 0.2eq) as Lewis base, 1,4-dioxane (0.4mL) was added as solvent, 3-alkynyl-pyridine (0.3mmol, 1.0eq) and CF 3 CHN 2 (1.2mmol, 4.0 equivalents, 1.5mol / L toluene) was reacted at 80°C for 16h, and after the reaction was completed, the solvent was evaporated to obtain a light yellow solid 3-(3-(trifluoromethyl)-1H-pyrazole-5- Base) pyridine, yield 96%.

[0053] 1H NMR (600MHz, MeOD): δ = 8.95 (d, J = 1.2Hz, 1H), 8.58–8.57 (m, 1H), 8.19 (d, J = 7.9Hz, 1H), 7.55 (dd, J = 7.9 ,4.9Hz,1H),7.13(s,1H)ppm.13C NMR(151MHz,MeOD):δ=150.4,147.4,145.1,142.7(q,JC-F=32.6 Hz),135.3,126.8,125.8,122.8 (q, JC-F=267.2Hz), 103.0ppm.1HRMS(ESI): calcd for C9H5N3F3[M-H]-:212.0441, found212.0438.

[0054] 1H-NMR spectrum and 13C-NMR spectrum as image 3 , 4 shown.

Embodiment 3

[0055] Example 3: Synthesis of ethyl 5-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylate

[0056]

[0057] In the presence of DBU (0.06mmol, 0.2eq) as Lewis base, 1,4-dioxane (0.4mL) was added as solvent, ethyl phenylpropiolate (0.3mmol, 1.0eq) and CF 3 CHN 2 (1.2mmol, 4.0 equivalents, 1.5mol / L toluene) was reacted at 80°C for 20h, and the solvent was evaporated off after the reaction to obtain a white solid 5-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylate Acetate ethyl ester, yield 82%.

[0058] 1H NMR (600MHz, CDCl3): δ=11.34(s, 1H), 7.53(dd, J=5.2, 3.1Hz, 2H), 7.48–7.43(m, 3H), 4.25(q, J=7.1Hz, 2H ), 1.24(t,J=7.1Hz,3H)ppm.

[0059] 13C NMR (151MHz, CDCl3): δ=162.0, 148.9, 143.7 (q, JC-F=37.8Hz), 130.8, 129.5, 129.1, 127.6, 121.0 (q, JC-F=268.8Hz), 109.94, 61.59, 14.18.ppm.1HRMS(ESI):calcd for C13H12O2N2F3[M+H]+:285.0845, found 285.0842.

[0060] 1H-NMR spectrum and 13C-NMR spectrum as Figure 5 , 6 shown.

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Abstract

The invention discloses a trifluoromethyl pyrazole derivative and applications thereof. The trifluoromethyl pyrazole derivative is obtained by utilizing intermolecular trifluorodiazoethane-alkyne cycloaddition reaction catalyzed by Lewis base, can be used for the cycloaddition reaction with terminal/internal alkyne; and a new approach for the synthesis of 3-trifluoromethyl pyrazole is provided. Apreparation method has the characteristics of environmental protection and simple operation, and is suitable for application and large-scale production. The invention also provides applications in preventing and treating cancers, immune system diseases, cardiovascular diseases or infectious diseases.

Description

technical field [0001] The invention belongs to the field of chemical synthesis and pharmaceutical intermediate synthesis, in particular to a novel trifluoromethylpyrazole derivative and its application. Background technique [0002] Pyrazoles are the core skeleton of many bioactive molecules and have a wide range of applications in the fields of chemistry and biology. Pyrazole derivatives are one of the most active compounds with a wide range of chemical, biological and pharmaceutical properties. 3-Trifluoromethylpyrazole is one of the typical compounds of pyrazole derivatives and widely exists in many important biologically active molecules. A conventional method for the synthesis of 3-trifluoromethylpyrazoles involves the condensation of hydrazine hydrate with fluoroalkyl 1,3-dicarbonyl compounds. However, the obvious limitations of these methods are the need to pre-treat the starting material and poor regioselectivity. Although these methods have made progress, they c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/12C07D401/04C07D231/14C07D495/04A61P35/00A61P37/02A61P7/02A61P9/00A61P31/00A61P31/18A61P9/12A61P33/06
CPCA61P7/02A61P9/00A61P9/12A61P31/00A61P31/18A61P33/06A61P35/00A61P37/02C07D231/12C07D231/14C07D401/04C07D495/04
Inventor 王磊孙晓波孙桂波杨振戴子茹
Owner INST OF MEDICINAL PLANT DEV CHINESE ACADEMY OF MEDICAL SCI
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