阅读说明：本技术 一种3-三氟甲基取代吡唑衍生物及其合成方法与应用 (3-trifluoromethyl substituted pyrazole derivative and synthesis method and application thereof ) 是由 竺传乐 曾浩 江焕峰 于 2019-09-20 设计创作，主要内容包括：本发明属于医药材料合成技术领域,具体涉及一种3-三氟甲基取代吡唑衍生物及其合成方法。该衍生物将醛、磺酰肼、2-溴-3,3,3-三氟丙烯、碱与有机溶剂Ⅰ混合反应或者将腙、2-溴-3,3,3-三氟丙烯、碱与有机溶剂Ⅰ混合反应即得。该方法高效,反应对官能团适应性好,对底物适应性广,产物收率高；其原料廉价易得,可放大至十克级或更大规模生产,且操作简单、安全,反应条件温和。所得产物包括构建COX-2抑制剂Colecoxib和Mavacoxib、肺癌抑制剂SC-560、麻疹病毒抑制剂AS-136的关键中间体,在农药、医药及材料领域中具有广泛用途,具有良好的工业应用前景。(The invention belongs to the technical field of medical material synthesis, and particularly relates to a 3-trifluoromethyl substituted pyrazole derivative and a synthesis method thereof. The derivative is prepared by mixing aldehyde, sulfonyl hydrazide, 2-bromo-3, 3, 3-trifluoropropene, alkali and an organic solvent I for reaction or mixing hydrazone, 2-bromo-3, 3, 3-trifluoropropene, alkali and the organic solvent I for reaction. The method is efficient, the reaction has good adaptability to functional groups, the adaptability to substrates is wide, and the product yield is high; the raw materials are cheap and easy to obtain, the scale can be enlarged to a level of ten grams or larger, the operation is simple and safe, and the reaction condition is mild. The obtained product comprises key intermediates for constructing COX-2 inhibitors Colecoxib and Mavacoxib, lung cancer inhibitors SC-560 and measles virus inhibitors AS-136, has wide application in the fields of pesticides, medicines and materials, and has good industrial application prospect.)

1. A3-trifluoromethyl-substituted pyrazole derivative is characterized in that the structural formula is as follows:

wherein R is phenyl, 2-naphthyl, 1-naphthyl, 9-anthryl, 1-pyrenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, p-methylthiophenyl, p-morpholinophenyl, p-hydroxyphenyl, p-alkynylphenyl, p-carbomethoxyphenyl, p-trifluoromethylphenyl, p-cyanophenyl, p-nitrophenyl, 3-carbazolyl, p-methylsulfonylphenyl, p-acetamidophenyl, p-phenylphenyl, m-phenylphenyl, o-phenylphenyl, p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, p-bromophenyl, m-bromophenyl, o-bromophenyl, p-iodophenyl, m-iodophenyl, o-iodophenyl, vinyl, cyclohexenyl, 2-furyl, 3-furyl, p-chlorophenyl, p-methylphenyl, m-nitrophenyl, p-methoxyphenyl, 2-thienyl, 3-thienyl, 2-benzothienyl, 3-pyridyl, 4-quinoline, cyclohexyl, tert-butyl or n-butyl.

2. The method for synthesizing a 3-trifluoromethyl-substituted pyrazole derivative according to claim 1, which comprises the following two methods:

the method comprises the following steps: mixing aldehyde, a sulfonyl hydrazide compound, 2-bromo-3, 3, 3-trifluoropropene, alkali and an organic solvent I to obtain a reactant I, then reacting, and carrying out product extraction and post-treatment on the obtained product to obtain the 3-trifluoromethyl substituted pyrazole derivative;

the second method comprises the following steps: mixing hydrazone, 2-bromo-3, 3, 3-trifluoropropene, alkali and an organic solvent I to obtain a reactant II, then reacting, and extracting and processing the obtained product to obtain the 3-trifluoromethyl substituted pyrazole derivative.

3. The method for synthesizing a 3-trifluoromethyl-substituted pyrazole derivative according to claim 2, wherein:

in the first process, the aldehyde is

The sulfonyl hydrazide compound in the first method is p-toluenesulfonyl hydrazide, benzenesulfonyl hydrazide, p-nitrobenzenesulfonyl hydrazide, p-trifluoromethylbenzenesulfonyl hydrazide or 2,4, 6-trimethylbenzenesulfonyl hydrazide.

4. The method for synthesizing a 3-trifluoromethyl-substituted pyrazole derivative according to claim 2, wherein:

in the second method, the hydrazone isWherein R is¹Is p-toluenesulfonyl, benzenesulfonyl, p-nitrobenzenesulfonyl, p-trifluoromethylbenzenesulfonyl or 2,4, 6-trimethylbenzenesulfonyl.

5. The method for synthesizing a 3-trifluoromethyl-substituted pyrazole derivative according to claim 2, wherein:

in the reactant I in the first method, the molar ratio of aldehyde to sulfonyl hydrazide compound is 1: 1-1: 3;

in the reactant I in the first method, the molar ratio of aldehyde to 2-bromo-3, 3, 3-trifluoropropene is 1: 1-1: 10;

in the reactant I in the first method, the molar ratio of aldehyde to alkali is 1: 1-1: 5;

in the reactant II in the second method, the molar ratio of hydrazone to 2-bromo-3, 3, 3-trifluoropropene is 1: 1-1: 10;

in the reactant II in the second method, the molar ratio of hydrazone to alkali is 1: 1-1: 5.

6. The method for synthesizing a 3-trifluoromethyl-substituted pyrazole derivative according to claim 5, wherein:

in the reactant I in the first method, the molar ratio of aldehyde to sulfonyl hydrazide compound is 1: 1.2;

in the reactant I in the first method, the molar ratio of aldehyde to 2-bromo-3, 3, 3-trifluoropropene is 1: 2;

in the reactant II in the second method, the molar ratio of hydrazone to 2-bromo-3, 3, 3-trifluoropropene is 1: 2.

7. The method for synthesizing a 3-trifluoromethyl-substituted pyrazole derivative according to claim 2, wherein:

in the first method and the second method, the alkali is one or more than two of cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, triethylamine, triethylenediamine and 1, 8-diazabicycloundecen-7-ene;

in the first method and the second method, the organic solvent I is one or more than two of N, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane, toluene, acetone, N-methylpyrrolidone, tetrahydrofuran, ethanol, methanol and acetonitrile.

8. The method for synthesizing a 3-trifluoromethyl-substituted pyrazole derivative according to claim 2, wherein: the reaction temperature in the first method and the second method is 20-80 ℃, the reaction time is 1-24 h, and the reaction is carried out in the air or nitrogen atmosphere.

9. The method for synthesizing a 3-trifluoromethyl-substituted pyrazole derivative according to claim 2, wherein:

the product is extracted and processed in the first method and the second method, namely the product is cooled to room temperature, water and an organic solvent II are added to extract a reaction solution, an organic layer is decompressed and rotary evaporated to remove the solvent, a crude product is obtained, and the 3-trifluoromethyl substituted pyrazole derivative is obtained through column chromatography or recrystallization purification;

the organic solvent II is ethyl acetate, dichloromethane or diethyl ether;

the column chromatography purification is to mix petroleum ether and ethyl acetate according to the volume ratio of 2: 1-500: 1, and then carry out column chromatography purification on the eluent;

the recrystallization purification comprises the steps of mixing petroleum ether and ethyl acetate according to the volume ratio of 5: 1-100: 1, and then heating for recrystallization.

10. Use of 3-trifluoromethyl-substituted pyrazole derivatives according to claim 1, characterized in that: the 3-trifluoromethyl substituted pyrazole derivative is used for pesticides or medical materials.

Technical Field

The invention belongs to the technical field of medical material synthesis, and particularly relates to a 3-trifluoromethyl substituted pyrazole derivative, and a synthesis method and application thereof.

Background

The 3-trifluoromethyl substituted pyrazole derivatives have important application values in the fields of materials and medicines, such as COX-2 inhibitors Colecoxib and MavacoxibThe lung cancer inhibitor SC-560, the arterial thrombotic disease therapeutic drug DPC-602, the measles virus inhibitor AS-136A, the anticoagulant Razaxaban, the pesticide DP-23, and the like all contained a 3-trifluoromethyl-substituted pyrazole backbone structure (FIG. 1) (Eur. J. org. chem.2017, 6566). The traditional synthesis method of the compound mainly utilizes dehydration condensation cyclization reaction of hydrazine compounds and 1, 3-dicarbonyl compounds or acetylenic ketone compounds, but the strategy is often accompanied by generation of regioselective isomers (5-trifluoromethyl substituted pyrazole) (T.Norris, R.Colon-Cruz, D.H.B.Ripin, Org.Biomol. chem.2005,3,1844; A.Shavnya, S.M.Sakya, M.L.Munich, B.Rast, K.L.DeMello, B.H.Jaynes, Tetrahedron Lett.2005,46,6887; S.P.Singh, V.Ku, R.Aggarwal, J.Elguero, J.Heterococcus. chem.2006,43, 1; P.S.Huhries, J.M.T.T, Tegarwaal, J.Elguero, J.F.E.F.F.F.J.F.F.F.T.C.J.F.F.J.F.F.F.J.F.F.F.F.J.F.F.F.F.J.F.F.F.J.F.F.F.J.F.F.J.C.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A. Tetrahedron, K.J.J.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.S.P.S.S.S.S.S.S.P.S.P.P.S.P.P.P.P.P.S.F.F.F.S.F.F.F.F.F.F..S.villanova, m.murgu i a, j.org.chem.2008,73,3523; h.dai, y. -q.li, d.du, x.qin, x.zhang, h. -b.yu, j. -x.fang, j.agric.food chem.2008,56,10805; x.yang, s.shui, x.chen, h.he, f.wu, j.fluorine chem.2010,131, 426; v.m.muzalviskiy, a.yu.rulev, a.r.romanov, e.v.kondrashov, i.a.usahakov, v.a.chertkov, v.g.nanjdenko, j.org.chem.2017,82,7200); furthermore, the regioselectivity of 2,2, 2-trifluorodiazoethane with alkynes [3+2 ]]Cyclization reactions were also of interest for the synthesis of this class of compounds (Angew. chem. int. Ed.2013,52,6255; Angew. chem. int. Ed.2017,56,8823) (FIG. 2). However, the highly reactive gaseous 2,2, 2-trifluorodiazoethane is explosive and requires in situ generation and utilization of excess transition metal or flow chemistry strategies to drive the reaction to occur, which is not conducive to scale-up synthesis. Therefore, the development of a general synthetic method of the high-selectivity 3-trifluoromethyl substituted pyrazole derivative from simple raw materials is still a difficult problem to be solved.

Disclosure of Invention

To solve the disadvantages and shortcomings of the prior art, the present invention has a primary object to provide a 3-trifluoromethyl substituted pyrazole derivative.

Another object of the present invention is to provide a method for synthesizing the 3-trifluoromethyl-substituted pyrazole derivative.

Still another object of the present invention is to provide use of the above 3-trifluoromethyl-substituted pyrazole derivative.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

a3-trifluoromethyl substituted pyrazole derivative has a structural formula as follows:

wherein R is phenyl, 2-naphthyl, 1-naphthyl, 9-anthryl, 1-pyrenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, p-methylthiophenyl, p-morpholinophenyl, p-hydroxyphenyl, p-alkynylphenyl, p-carbomethoxyphenyl, p-trifluoromethylphenyl, p-cyanophenyl, p-nitrophenyl, 3-carbazolyl, p-methylsulfonylphenyl, p-acetamidophenyl, p-phenylphenyl, m-phenylphenyl, o-phenylphenyl, p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, p-bromophenyl, m-bromophenyl, o-bromophenyl, p-iodophenyl, m-iodophenyl, o-iodophenyl, vinyl, cyclohexenyl, 2-furyl, 3-furyl, p-chlorophenyl, p-methylphenyl, m-nitrophenyl, p-methoxyphenyl, 2-thienyl, 3-thienyl, 2-benzothienyl, 3-pyridyl, 4-quinoline, cyclohexyl, tert-butyl or n-butyl.

The invention further provides a synthesis method of the 3-trifluoromethyl substituted pyrazole derivative, which comprises the following two methods:

the method comprises the following steps: mixing aldehyde, a sulfonyl hydrazide compound, 2-bromo-3, 3, 3-trifluoropropene, alkali and an organic solvent I to obtain a reactant I, then reacting, and carrying out product extraction and post-treatment on the obtained product to obtain the 3-trifluoromethyl substituted pyrazole derivative;

the second method comprises the following steps: mixing hydrazone, 2-bromo-3, 3, 3-trifluoropropene, alkali and an organic solvent I to obtain a reactant II, then reacting, and extracting and processing the obtained product to obtain the 3-trifluoromethyl substituted pyrazole derivative.

Preferably, the aldehyde in the first process is

Preferably, the sulfonyl hydrazide compound in the first method is p-toluenesulfonyl hydrazide, benzenesulfonyl hydrazide, p-nitrobenzenesulfonyl hydrazide, p-trifluoromethyl benzenesulfonyl hydrazide or 2,4, 6-trimethyl benzenesulfonyl hydrazide.

Preferably, in the reactant I in the first method, the molar ratio of the aldehyde to the sulfonyl hydrazide compound is 1:1 to 1: 3.

More preferably, in the reactant I in the first method, the molar ratio of the aldehyde to the sulfonyl hydrazide compound is 1: 1.2.

Preferably, in the reactant I in the first method, the molar ratio of the aldehyde to the 2-bromo-3, 3, 3-trifluoropropene is 1: 1-1: 10.

More preferably, in the reactant I in the first method, the molar ratio of the aldehyde to the 2-bromo-3, 3, 3-trifluoropropene is 1: 2.

Preferably, in the reactant I in the first method, the molar ratio of the aldehyde to the base is 1: 1-1: 5.

Preferably, the hydrazone in the second method isWherein R is¹Is p-toluenesulfonyl, benzenesulfonyl, p-nitrobenzenesulfonyl, p-trifluoromethylbenzenesulfonyl or 2,4, 6-trimethylbenzenesulfonyl.

Preferably, the base used in the first and second methods is one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, triethylamine, triethylenediamine and 1, 8-diazabicycloundecen-7-ene.

Preferably, the organic solvent I in the first method and the second method is one or more than two of N, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane, toluene, acetone, N-methylpyrrolidone, tetrahydrofuran, ethanol, methanol and acetonitrile.

Preferably, in the reactant II of the second method, the molar ratio of the hydrazone to the 2-bromo-3, 3, 3-trifluoropropene is 1:1 to 1: 10.

More preferably, in the reactant II of the second method, the molar ratio of the hydrazone to the 2-bromo-3, 3, 3-trifluoropropene is 1: 2.

Preferably, in the reactant II of the second method, the molar ratio of the hydrazone to the alkali is 1:1 to 1: 5.

Preferably, the reaction temperature in the first method and the second method is 20-80 ℃, the reaction time is 1-24 h, and the reaction is carried out in the air or nitrogen atmosphere.

Preferably, the post-extraction treatment of the product in the first and second methods comprises cooling the product to room temperature, adding water and an organic solvent II, extracting the reaction solution, performing reduced pressure rotary evaporation on the organic layer to remove the solvent to obtain a crude product, and purifying by column chromatography or recrystallization to obtain the 3-trifluoromethyl substituted pyrazole derivative.

More preferably, the organic solvent II is ethyl acetate, dichloromethane or diethyl ether.

More preferably, the column chromatography purification is to mix petroleum ether and ethyl acetate according to a volume ratio of 2: 1-500: 1, and then perform column chromatography purification on the eluent.

More preferably, the recrystallization purification is to mix petroleum ether and ethyl acetate according to the volume ratio of 5: 1-100: 1, and then heat recrystallization is carried out.

The invention further provides application of the 3-trifluoromethyl substituted pyrazole derivative in the field of pesticides or medical materials.

The reaction equation involved in the method of the invention:

the first method comprises the following steps:

the second method comprises the following steps:

compared with the prior art, the invention has the following advantages and beneficial effects:

(1) the synthesis method is efficient and has good selectivity; the used raw materials are cheap and easy to obtain; no catalyst is needed; no metal is required; the reaction has good adaptability to functional groups, wide adaptability to substrates and high product yield;

(2) the synthetic method can be amplified to a ten-gram level or larger scale for production, is simple and safe to operate, has mild reaction conditions, and has good industrial application prospect;

(3) the product obtained by the invention has wide application in the fields of pesticide, medicine and material.

Drawings

FIG. 1 is a structural diagram of some pharmaceutically active compounds containing 3-trifluoromethyl substituted pyrazole building blocks.

FIG. 2 is a reaction scheme for constructing 3-trifluoromethyl substituted pyrazole derivatives in the prior art.

FIG. 3 is a hydrogen spectrum of the product obtained in examples 1 to 9;

FIG. 4 is a carbon spectrum of the product obtained in examples 1 to 9;

FIG. 5 shows fluorine spectra of the products obtained in examples 1 to 9.

Detailed Description

The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto. For process parameters not specifically noted, reference may be made to conventional techniques.

The same 3-trifluoromethyl-substituted pyrazole derivatives were prepared in the following examples 1 to 9. The structural formula of the product is as follows:

the hydrogen spectrum, the carbon spectrum and the fluorine spectrum of the obtained product are respectively shown in FIG. 3, FIG. 4 and FIG. 5; the structural characterization data are as follows:

Yellow solid,mp:112-113℃；

¹H NMR(400MHz,CDCl₃)δ13.25(brs,1H),7.50-7.52(m,2H),7.33-7.39(m,3H),6.60(s,1H)；

¹³C NMR(100MHz,CDCl₃)δ145.3,143.4(q,²J_F-C＝38.0Hz),129.4,129.2,127.8,125.5,121.1(q,¹J_F-C＝267.2Hz),100.8；

¹⁹F NMR(376MHz,CDCl₃)δ-62.0(s,3F)；

IR(KBr):3127,2881,1592,1498,1437,1271,1158cm^-1；

HRMS(ESI,m/z):[M+H]⁺Calcd.for C₁₀H₇F₃N₂+H,213.0634；found,213.0635