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Preparation method of 5-aryl-3-trifluoromethyl-1H-pyrazole compound

A technology for trifluoromethyl compounds, which is applied in the field of pyrazole compounds and its preparation, can solve the problems of long reaction time, many steps, cumbersome operations, etc., and achieve high atom utilization, mild reaction conditions, and good substrate universality Effect

Inactive Publication Date: 2013-03-20
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] However, these synthetic methods have many steps, cumbersome operation, low yield, high reaction temperature, long reaction time, and poor universality to substrates, which undoubtedly limit their application range.

Method used

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  • Preparation method of 5-aryl-3-trifluoromethyl-1H-pyrazole compound
  • Preparation method of 5-aryl-3-trifluoromethyl-1H-pyrazole compound
  • Preparation method of 5-aryl-3-trifluoromethyl-1H-pyrazole compound

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0014] Example 1: Preparation of 5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazole

[0015]

[0016] Weigh Ag into a dry 50mL Schlenk reaction flask 2 O (0.46g, 2.0mmol), KOAc (0.20g, 2.0mmol), DABCO (0.011g, 0.1mmol), replace argon 3 times, add 4.0mL dry dichloromethane to the system, 2-(4- Methylphenyl) acetylene (0.12g, 1.0mmol), placed at room temperature and stirred for 2h, then introduced CF generated on site into the system 3 CHN 2 Gas (0.68g, 5.0mmol CF 3 CH 2 NH 2 Dissolve HCl in 20ml of water, add dropwise 0.41g, 6.0mmol NaNO 2 Solution prepared), ventilated for about 3h, ventilated, placed at room temperature and stirred for 20h. The reaction was complete as detected by TLC. Add 20 mL of ethyl acetate and 20 mL of water to the system, separate the layers, extract the aqueous phase with ethyl acetate (20 mL x 2), combine the organic phases and wash twice with water (40 mL), anhydrous MgSO 4 Drying, column chromatography (eluent: petroleum ether / ethyl acetate...

example 2

[0017] Example 2: Preparation of 5-(2-methoxyphenyl)-3-trifluoromethyl-1H-pyrazole

[0018]

[0019] A method similar to Experiment 1, using silver acetate as a catalyst, potassium carbonate as a base, 2-methoxyphenyl-1-acetylene, silver acetate, potassium carbonate, DABCO and 2,2,2-trifluoromethyldiazo The molar proportion of ethane is 1 / 3 / 3 / 1 / 10, reacts 24h at 50 ℃, synthesizes 5-(2-methoxyphenyl)-3-trifluoromethyl-1H-pyrazole, receives The rate is 72%. 1 H NMR (400MHz, CDCl 3 )δ4.01(s,3H),6.87(s,1H),7.05-7.10(m,2H),7.37(t,J=8.0Hz,1H),7.65(d,J=7.6Hz,1H), 11.82(s,1H); 13 C NMR (100MHz, CDCl 3 )δ156.0,143.0(q,J C-F =38.0Hz),142.1,130.2,128.0,121.6,121.5(q,J C-F =266.7Hz),116.3,111.7,100.9,55.8; 19 F NMR (376MHz, CDCl 3 )δ-62.11(s,3F).

example 3

[0020] Example 3: Preparation of 5-(3-methoxyphenyl)-3-trifluoromethyl-1H-pyrazole

[0021]

[0022] A method similar to Experiment 1, using silver oxide as a catalyst, potassium acetate as a base, chloroform as a solvent, 3-methoxyphenyl-1-acetylene, silver oxide, potassium acetate, DABCO and 2,2,2- The molar ratio of trifluoromethyldiazoethane is 1 / 2 / 2 / 0.1 / 5, reacted for 20h at 0°C to synthesize 5-(3-methoxyphenyl)-3-trifluoromethane Base-1H-pyrazole, yield 92%. 1 H NMR(400MHz,DMSO-d6)δ3.82(s,3H),6.95(d,J=7.2Hz,1H),7.18(s,1H),7.34-7.41(m,2H),7.44(s, 1H),14.08(s,1H); 13 C NMR (100MHz, DMSO-d6) δ159.8, 144.0, 142.2 (q, J C-F =40.0Hz),130.2,129.4,121.8(q,J C-F =265.8Hz),117.8,114.6,111.0,101.1,55.2; 19 F NMR (376 MHz, DMSO-d6) δ-60.70 (s, 3F).

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Abstract

The invention relates to a preparation method of a 5-aryl-3-trifluoromethyl-1H-pyrazole compound. The preparation method comprises the steps of: adding a catalyst, alkali and DABCO(1,4-diazabicyclo[2,2,2]octane) into a drying reactor, continuously adding 2-aryl-1-acetylene and 2,2,2-trifluoromethyl diazoethane into an organic solvent for completely reacting for 3-24h at the temperature of 0-50 DEG C, and washing, extracting and separating to obtain the 5-aryl-3-trifluoromethyl-1H-pyrazole compound, wherein the molar ratio of the 2-aryl-1-acetylene to the catalyst to the alkali to the DABCO to the 2,2,2-trifluoromethyl diazoethane is 1:(1-3):(1-3):(0.1-1):(2-10). The preparation method provided by the invention is simple, convenient and efficient for synthesizing trifluoromethyl pyrazole compounds and has the advantages of simplicity of operation, mild reaction condition, high yield, good substrate universality and high atom utilization rate.

Description

technical field [0001] The invention relates to a class of pyrazole compounds and a preparation method, in particular to a preparation method of a class of 5-aryl-3-trifluoromethyl-1H-pyrazole compounds. Background technique [0002] Trifluoromethyl-substituted pyrazole is an important structural unit of various molecules with physiological activity, so it has important application value in the pharmaceutical field. For example, Ryanodine receptor catalyst DP-23 (G.PPLahm et al., Bioorg.Med.Chem.Lett.2005,15,4898-4906); MV virus inhibitor 16677 (A.Sun et al., Bioorg .Med.Chem.Lett.2007,17,5199-5203); NSAID Celebrex (A.H.Schoenthal et al., Expert Opin.Investig.Drugs 2008,17,197-208). The reported common method for the synthesis of trifluoromethyl-substituted pyrazoles is to utilize the condensation reaction of trifluoromethyl β-diketone with hydrazine and its derivatives (S.Guillou et al., Tetrahedron 2011,67,8451- 8457; Santos Fustero, et al., Chem. Rev. 2011, 111, 6984–70...

Claims

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Application Information

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IPC IPC(8): C07D231/12
Inventor 马军安李峰聂晶
Owner TIANJIN UNIV
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