CN111196783A - 2,4, 6-substituted pyrimidine derivatives containing acyl urea structure, and preparation method and application thereof - Google Patents

2,4, 6-substituted pyrimidine derivatives containing acyl urea structure, and preparation method and application thereof Download PDF

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CN111196783A
CN111196783A CN202010060878.XA CN202010060878A CN111196783A CN 111196783 A CN111196783 A CN 111196783A CN 202010060878 A CN202010060878 A CN 202010060878A CN 111196783 A CN111196783 A CN 111196783A
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ethylphenyl
carbamoyl
acetamide
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CN111196783B (en
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张秋荣
刘宏民
张佩
刘秀娟
王涛
刘丽敏
栗娜
李二冬
张洋
汪正捷
陈秀英
郑甲信
周蕊
赵培荣
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Zhengzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom

Abstract

The invention belongs to the field of medicinal chemistry, and discloses a 2,4, 6-substituted pyrimidine derivative with an anti-tumor activity and containing an acylurea structure, and a preparation method and application thereof. The compounds of the present invention have the structure of formula i, wherein: r is chlorine atom, anilino, substituted anilino and substituted phenol. The evaluation of in vitro antitumor activity finds that the series of compounds have obvious inhibiting and killing effects on various tumor cells, are further optimized and developed into new drugs, and can be used as active ingredients for clinical prevention and cancer treatment.

Description

2,4, 6-substituted pyrimidine derivatives containing acyl urea structure, and preparation method and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, relates to pyrimidine derivatives, and particularly relates to 2,4, 6-substituted pyrimidine derivatives containing an acylurea structure and having antitumor activity, and a preparation method and application thereof.
Background
According to the American cancer society, more than 800 million people die of cancer in 2010 in the world, accounting for 21.6 percent of death caused by diseases, and the cancer replaces cardiovascular diseases and becomes the disease with the largest death number in the world. Therefore, research and development of highly effective antitumor drugs are urgently needed. The pyrimidine compounds are important six-membered heterocyclic compounds, have low-toxicity, high-efficiency and broad-spectrum action modes, and are always a very important field in new drug molecular design, synthesis and biological activity research. The reports of combining the pyrimidine and the acyl urea compounds are few, so that the research on the 2,4, 6-substituted pyrimidine derivatives of the acyl urea fragments has very important research value and is beneficial to the development of the independent property right medicaments in China.
Disclosure of Invention
In order to develop and utilize the existing clinical medicine resources, the invention aims to provide 2,4, 6-substituted pyrimidine derivatives containing acyl urea fragments, thereby opening up a new way for searching new anti-tumor active compounds; the invention also aims to provide a preparation method and application thereof in antitumor drugs.
The structural general formula of the 4-substituted 2,4, 6-substituted pyrimidine derivative containing the acyl urea fragment is as follows:
Figure BDA0002374425730000011
in the general formula I: r is a chlorine atom, an anilino group, a 2-chloroanilino group, a 3-chloroanilino group, a 4-chloroanilino group, a 2-fluoroanilino group, a 3-fluoroanilino group, a 4-fluoroanilino group, a 2-methylanilino group, a 3-methylanilino group, a 4-methylanilino group, a 3,4, 5-trimethoxyanilino group, a 3-chloro-4-fluoroanilino group, a 3, 4-dichloroanilino group, a 2-ethoxyanilino group, a 3-ethylanilino group, a 4-ethoxyanilino group, a 2-methoxyanilino group, a 3-methoxyanilino group, a 4-methoxyanilino group, a phenol group, a 2-chlorophenol group, a 3-fluorophenol group, a 4-bromophenol group, a 4-nitrophenol group, a 3-nitrophenol group, a 4-ethylphenol group, a phenol group, 4-methoxyethylphenol group, 3,4, 5-trimethoxyphenol group, 3-methylphenylphenol group, 4-methoxyphenol group, 4-ethoxyphenol group, 2, 6-dimethylphenol group.
The following compounds are preferred: 4g of 2- ((4-chloro-6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- (4-ethylphenyl) carbamoyl) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- (phenylamino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-chlorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-chlorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((2-fluorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
5g N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-fluorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-methylphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-methylphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3,4, 5-trimethoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
5l of N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-chloro-4-fluorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-chloro-4-chlorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-ethylphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-ethoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-methoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-methoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
2- ((4- (3-fluorophenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (4-bromophenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (3-nitrophenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
6g 2- ((4- (4-ethylphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (3-methylphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (4-methylphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (4-methoxyphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (4-ethoxyphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (2, 6-dimethylphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide.
The preparation method of the 2,4, 6-substituted pyrimidine derivative containing the acyl urea fragment comprises the following synthetic steps: a. oxalyl chloride, chloroacetyl and 4-ethylaniline are subjected to substitution reaction in a 1, 2-dichloroethane solution to generate a compound 1 a; b. reacting the compound 2 with the compound 1a in water and a potassium hydroxide aqueous solution to generate a compound 3 a; c, reacting the pyrimidine derivative 3a of the acyl urea-containing substrate segment with hydroxyl at the 4-position with phosphorus oxychloride to generate 4g of pyrimidine derivative containing acyl urea-containing segment with chlorine at the 4-position; 4g of quinazoline derivative containing ureido segment and 4 th chlorine atom reacts with aniline compound in DMF solution to generate pyrimidine derivative 5a-5s containing acyl ureido segment; e.4 position is chlorine atom containing quinazoline derivative 4g and phenol compound in acetonitrile and triethylamine reaction to generate acyl ureido segment containing pyrimidine derivative 6a-6o.
The synthetic route is as follows:
Figure BDA0002374425730000041
the aniline compound in the step (d) is as follows: aniline, 2-chloroaniline, 3-chloroaniline, 4-chloroaniline, 2-fluoroaniline, 3-fluoroaniline, 4-fluoroaniline, 2-methylaniline, 3-methylaniline, 4-methylaniline, 3,4, 5-trimethoxyaniline, 3-chloro-4-fluoroaniline, 3, 4-dichloroaniline, 2-ethoxyaniline, 3-ethylaniline, 4-ethoxyaniline, 2-methoxyaniline, 3-methoxyaniline, 4-methoxyaniline;
the phenol compound of step (e) is: phenol, 2-chlorophenol, 3-fluorophenol, 4-bromophenol, 4-nitrophenol, 3-nitrophenol, 4-ethylphenol, 4-methoxyethylphenol, 3,4, 5-trimethoxyphenol, 3-methylphenol, 4-methoxyphenol, 4-ethoxyphenol, 2, 6-dimethylphenol.
Through in vitro antitumor activity evaluation, the 2,4, 6-substituted pyrimidine derivative containing the acyl urea segment has good inhibition effect on human gastric cancer cells (MGC-803), human colon cancer cells (SW620), human prostate cancer cells (PC-3) and human lung cancer cells (A549). IC of some of the compounds50The value is less than 10 (mu mol/L), and is superior to the activity of the clinically used antitumor drug 5-fluorouracil by being used as a contrast. Therefore, the 2,4, 6-substituted pyrimidine derivatives containing the acyl urea fragment provided by the invention open up a new way for developing novel antitumor drugs and combined drugs of the drugs.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. These examples are intended to be illustrative of the invention only and are not intended to limit the scope of the invention as claimed.
Characterization of the synthesized compounds the instrument used: NMR spectra were measured using a Bruker DPX-400 model superconducting nuclear magnetic resonance apparatus, Sweden, with TMS as an internal standard; high resolution mass spectra were determined using a Waters-Micromass Q-Tof mass spectrometer.
Example 12- ((4-chloro-6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- (4-ethylphenyl) carbamoyl) acetamide (4g)
Under the ice-bath condition, chloroacetyl (2.00g, 0.21mmol) is dissolved in 50ml of 1, 2-dichloroethane solution, oxalyl chloride (3.62ml,0.42mmol) is slowly added, the temperature is raised to 90 ℃, and the reaction is carried out for 4 h; transferring to an ice bath, slowly adding 4-ethylaniline (0.21mmol), detecting by TLC to finish the reaction, performing suction filtration, and drying to obtain a compound 1a (2-chloro-N- (4-ethylphenyl) carbamoyl) acetamide);
at room temperature, 6-trifluoromethyl-4-hydroxy-2-mercaptopyrimidine (2.00g,10.20mmol) is dissolved in 50ml of an aqueous solution of potassium hydroxide (1.14g,20.40mmol), the temperature is raised to 90 ℃, then 1g (2.45,10.20mmol) of acetone solution (10ml) is added dropwise to the reaction solution, reflux reaction is carried out for 0.5h after the dropwise addition is finished, the reaction solution is cooled to room temperature and filtered, and a filter cake is washed with water and acetone respectively for three times (3 x 10ml) to obtain 3g of 2- ((4-hydroxy-6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- (4-ethylphenyl) carbamoyl) acetamide which is a white pure compound product.
Under the ice bath condition, 8ml of phosphorus oxychloride is slowly dripped into the synthesized 1, 4-dioxane solution of 2- ((4-hydroxy-6- (trifluoromethyl) pyrimidine-2-yl) sulfenyl) -N- (4-ethylphenyl) carbamoyl) acetamide, the temperature is slowly increased to 90 ℃ in a gradient manner, the reaction is continued for 4h, then the reaction is stopped, the reaction liquid is cooled to the room temperature, then the reaction liquid is slowly dripped into the vigorously stirred crushed ice water mixture, the reaction system is maintained at 0 ℃, the stirring is continued for 10min after the dripping is finished, the suction filtration is carried out, the water is washed for three times, the drying is carried out at the room temperature, and the column chromatography (V) is carried out on a stir-fried samplePetroleum ether：VEthyl acetate5: 1) the eluent was concentrated to give 4g of product.
White solid powder, yield 71.2%;1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.25(s,1H),8.02(s,1H),7.88(d,J＝7.8Hz,1H),7.25–7.18(m,2H),7.07(t,J＝7.0Hz,1H),4.24(d,J＝10.9Hz,2H),2.51(d,J＝1.8Hz,2H),1.10(t,J＝7.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ172.37,169.89,162.74,155.60,155.24,150.32,138.27,137.39,128.76,128.63,124.38,121.00,120.03,118.26,116.67,114.29,35.62,21.01.Calcd for C16H17lF3N4O3[M+H3O]+:437.0662found:437.2000.
example 2N- ((4-ethylphenyl) carbamoyl) -2- ((4- (phenylamino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5a)
The synthesized 2- ((4-chloro-6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- (4-ethylphenyl) carbamoyl) acetamide (200mg,0.48mmol) and aniline (8)7.20. mu.l, 0.96mmol) was added to 4ml of N, N-dimethylformamide, the temperature was raised to 90 ℃ and the reaction was carried out for 1h, TLC (V)Petroleum ether:VEthyl acetate3: 1). And after the reaction is completed, extracting with water and ethyl acetate, stir-frying the sample, and separating by column chromatography to obtain the pure product N- ((4-ethylphenyl) carbamoyl) -2- ((4- (phenylamino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide.
White solid powder, yield 73.2%;1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),10.20(s,2H),7.59(d,J＝7.8Hz,2H),7.38(dd,J＝15.8,8.1Hz,4H),7.18–7.07(m,3H),6.85(s,1H),4.13(s,2H),2.55(dd,J＝15.2,7.7Hz,2H),1.15(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.98,169.87,162.42,160.23,154.53,154.28,150.47,148.57,139.12,128.92,128.11,124.63,119.73,35.18,27.49,15.62.Calcd for C22H20F3N5NaO2S[M+H]+：476.1368,found:476.1369.
example 3N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((2-chlorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5b)
The procedure is as in example 2, substituting aniline with 2-chloroaniline.
White solid powder, yield 75.3%;1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.39(s,1H),10.18(d,J＝22.8Hz,1H),7.72(dd,J＝5.7,2.3Hz,1H),7.60–7.55(m,1H),7.37(d,J＝8.8Hz,3H),7.14(dd,J＝8.8,2.1Hz,3H),6.86(s,1H),4.13(s,2H),2.55–2.51(m,2H),1.13(d,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ173.26,170.98,170.37,160.06,159.98,150.45,139.75,139.20,135.04,133.17,130.56,130.52,128.10,123.37,119.74,118.70,117.52,46.13,27.48,15.57.Calcd for C22H20ClF3N5O2S[M+H]+：510.0978,found:510.0977.
example 4N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-chlorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5c)
The procedure is as in example 2, except that 3-chloroaniline was used instead of aniline.
White solid powder, yield 77.1%;1H NMR(400MHz,DMSO-d6)δ10.97(d,J＝49.8Hz,1H),10.40(s,1H),10.22(s,1H),7.75(d,J＝12.5Hz,1H),7.59(d,J＝8.2Hz,1H),7.44–7.33(m,3H),7.15(dd,J＝8.0,3.1Hz,3H),6.88(s,1H),4.15(d,J＝4.5Hz,2H),2.55(dd,J＝15.2,7.7Hz,2H),1.17(t,J＝22.3,14.7Hz,3H).13C NMR(101MHz,DMSO-d6)δ171.22,170.35,160.09,150.45,139.81,139.12,135.13,133.16,130.56,128.10,123.36,119.72,118.76,118.20,35.03,27.49,15.61.Calcd for C22H19ClF3N5O2S[M+H]+：510.0978,found:510.0974.
example 5N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-chlorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5d)
The procedure is as in example 2, except that 4-chloroaniline was used instead of aniline.
White solid powder, yield 70.9%;1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),10.33(s,1H),10.19(s,1H),7.63(t,J＝8.0Hz,2H),7.45–7.37(m,4H),7.15(d,J＝8.3Hz,2H),6.85(s,1H),4.15(s,2H),2.55(dd,J＝15.1,7.6Hz,2H),1.15(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ171.05,170.18,160.06,159.68,150.46,139.14,137.22,135.11,128.80,128.73,128.09,121.83,120.67,119.74,32.70,19.95,15.27.Calcd for C22H19ClF3N5NaO2S[M+Na]+：532.0798,found:532.0809.
example 6N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((2-fluorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5e)
The preparation method was the same as in example 2, except that aniline was replaced with 2-fluoroaniline.
White solid powder, yield 65.2%;1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),10.20(s,1H),10.01(s,1H),7.83(s,1H),7.41(d,J＝8.4Hz,2H),7.32–7.25(m,1H),7.25–7.19(m,2H),7.16(d,J＝8.3Hz,2H),6.99(s,1H),4.07(s,2H),2.57–2.52(m,2H),1.16(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.91,170.16,160.92,159.96,150.43,139.10,135.17,128.08,126.29,125.19,124.42,122.72,121.85,119.71,119.12,115.87,115.68,35.09,27.49,15.56.Calcd for C22H20N5O2S[M+H]+：494.1274,found:494.1275.
example 7N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-fluorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5f)
The preparation method was the same as in example 2, except that 3-fluoroaniline was used instead of aniline.
White solid powder, yield 64.9%;1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),10.42(s,2H),8.31(d,J＝1.6Hz,1H),7.58(dt,J＝19.0,6.0Hz,2H),7.42(s,2H),7.15(d,J＝8.4Hz,2H),6.90(d,J＝6.2Hz,2H),4.15(s,2H),2.55(d,J＝7.5Hz,2H),1.15(t,J＝7.6Hz,3H).13CNMR(101MHz,DMSO-d6)δ171.00,170.33,162.90,159.57,150.69,140.19,138.72,134.89,130.16,127.96,119.79,114.84,110.26,106.18,35.03,27.10,15.84.Calcd forC22H19F4N5NaO2S Calcd for C22H20N5O2S[M+H]+：494.1274,found:494.1277.
example 8N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-fluorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5g)
The preparation was carried out in the same manner as in example 2, except that 4-fluoroaniline was used instead of aniline.
White solid powder, yield 65.3%;1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),10.24(s,1H),10.20(s,1H),7.61(d,J＝7.9Hz,2H),7.40(d,J＝8.4Hz,2H),7.24–7.12(m,4H),6.82(s,1H),4.12(s,2H),2.55(dd,J＝15.2,7.6Hz,2H),1.15(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.98,170.23,150.46,139.13,137.98,135.11,134.72,134.51,128.10,124.12,122.51,121.94,119.73,115.66,115.43,34.77,27.10,15.60.Calcd forC22H19F4N5NaO2S[M+Na]+：516.1093,found:516.1047.
example 9N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((2-methylphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5h)
The procedure is as in example 2, substituting aniline with 2-methylaniline.
White solid powder, yield 66.7%;1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.22(s,1H),10.15(s,1H),7.49(d,J＝7.2Hz,1H),7.40(d,J＝8.4Hz,2H),7.33(s,1H),7.26(t,J＝7.8Hz,1H),7.15(d,J＝8.4Hz,2H),6.93(d,J＝7.5Hz,1H),6.84(s,1H),4.13(s,2H),2.55(dd,J＝15.1,7.6Hz,2H),2.30(s,3H),1.15(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.92,170.80,167.13,164.87,159.69,145.94,138.93,138.25,138.03,136.79,131.84,128.28,126.95,124.50,124.47,120.77,35.02,27.49,21.04,15.61.Calcd forC23H22F3N5NaO2S[M+Na]+：512.1344,found:512.1362.
example 10N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-methylphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5i)
The procedure is as in example 2, substituting aniline with 3-methylaniline.
White solid powder, yield 57.4%;1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),10.24(s,1H),9.68(s,1H),7.41(t,J＝9.3Hz,3H),7.26(d,J＝7.2Hz,1H),7.21(d,J＝6.7Hz,1H),7.16(d,J＝8.4Hz,4H),3.99(s,2H),2.56(q,J＝7.6Hz,2H),2.20(s,3H),1.16(t,J＝7.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.82,170.69,170.33,161.38,150.57,150.42,139.06,135.50,135.21,130.65,128.11,126.26,123.76,121.92,119.66,119.21,34.97,27.50,17.72,15.59.Calcd for C23H22F3N5NaO2S[M+Na]+：512.1344,found:512.1362.
example 11N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-methylphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5j)
The procedure is as in example 2, except that 4-methylaniline is used instead of aniline.
White solid powder, yield 61.2%;1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),10.21(s,1H),10.12(s,1H),7.46(d,J＝5.2Hz,2H),7.41(d,J＝8.4Hz,2H),7.16(t,J＝7.8Hz,4H),6.81(s,1H),4.13(s,2H),2.55(q,J＝7.6Hz,2H),1.15(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.95,170.26,159.98,150.47,139.09,135.55,135.18,132.77,129.32,128.09,121.88,120.54,119.67,119.16,35.20,27.49,20.44,15.60.Calcd forC23H22F3N5NaO2S[M+Na]+：512.1344,found:512.1367.
example 12N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3,4, 5-trimethoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5k)
The procedure is as in example 2, except that 3,4, 5-trimethoxyaniline is used instead of aniline.
White solid powder, yield 65.3%;1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),10.24(s,1H),10.18(s,1H),7.41(d,J＝8.4Hz,2H),7.15(d,J＝8.4Hz,2H),7.00(s,2H),6.82(s,1H),4.13(s,2H),2.56(q,J＝7.6Hz,2H),1.16(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.78,170.63,152.86,150.42,139.10,135.14,134.14,128.08,121.85,119.69,119.12,60.09,55.76,34.95,27.49,15.59.Calcd for C25H26F3N5NaO5S[M+Na]+：588.1504,found:588.1533.
example 13N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-chloro-4-fluorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5l)
The preparation method was the same as in example 2 except that 3-chloro-4-fluoroaniline was used instead of aniline.
White solid powder, yield 55.4%;1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),10.37(s,1H),10.21(s,1H),7.82(dd,J＝6.7,2.2Hz,1H),7.62–7.56(m,1H),7.39(d,J＝8.6Hz,3H),7.15(d,J＝8.3Hz,2H),6.83(s,1H),4.13(s,2H),2.55(dd,J＝15.3,7.7Hz,2H),1.14(d,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.98,170.31,160.06,159.83,154.70,152.25,150.67,150.43,139.12,135.44,135.11,128.09,120.58,119.72,119.44,117.15,116.93,35.04,27.49,15.60.Calcd for C22H19lF4N5O2S[M+H]+：528.0884；found:528.0885.
example 14N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-chloro-4-chlorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5m)
The procedure is as in example 2, except that 3-chloro-4-chloroaniline was used instead of aniline.
White solid powder, yield 56.3%;1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),10.45(s,1H),10.19(s,1H),7.89(d,J＝1.9Hz,1H),7.62(dd,J＝6.3,3.3Hz,2H),7.39(d,J＝8.4Hz,2H),7.15(d,J＝8.4Hz,2H),6.86(s,1H),4.15(s,2H),2.55(q,J＝7.6Hz,2H),1.15(dd,J＝9.8,5.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ171.05,170.27,160.00,150.44,139.13,138.46,135.10,131.09,130.76,128.10,121.51,120.34,119.73,35.09,27.49,15.61.Calcd for C22H19l2F3N5O2S[M+H]+：544.0589,found:544.0588.
example 15N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((2-ethoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5N)
The procedure is as in example 2, substituting aniline for 2-ethoxyaniline.
White solid powder, yield 75.3%;1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),10.23(s,1H),9.50(s,1H),7.73(s,1H),7.41(d,J＝8.4Hz,2H),7.15(d,J＝8.4Hz,3H),7.07(d,J＝8.0Hz,1H),7.02(t,J＝3.4Hz,1H),6.95(t,J＝8.1Hz,1H),4.11(d,J＝7.0Hz,2H),2.56(q,J＝7.6Hz,2H),1.38(dd,J＝13.9,7.0Hz,2H),1.30(d,J＝6.7Hz,3H),1.14(d,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.56,170.38,160.10,150.44,147.59,139.09,135.17,128.10,127.11,123.99,120.25,119.69,116.18,112.69,112.00,63.81,27.50,15.61,14.58,14.47.Calcd forC24H253N5O3S[M+H]+：520.1630,found:520.1630.
example 16N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-ethylphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5o)
The procedure is as in example 2, substituting aniline with 3-ethylaniline.
White solid powder, yield 70.3%;1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),10.22(s,1H),10.17(s,1H),7.49(s,1H),7.40(d,J＝8.4Hz,2H),7.35(s,1H),7.28(t,J＝7.8Hz,1H),7.15(d,J＝8.4Hz,2H),6.96(d,J＝7.5Hz,1H),6.83(s,1H),4.12(s,2H),2.57(dd,J＝17.5,7.6Hz,4H),1.18–1.12(m,6H).13C NMR(101MHz,DMSO-d6)δ170.82,170.42,154.52,150.44,144.49,139.11,138.23,137.57,135.14,128.82,128.11,125.84,124.50,123.23,119.70,118.68,112.40,34.98,28.10,27.49,15.62,15.39.Calcd for C24H24F3N5NaO2S[M+Na]+：526.1501,found:526.1528.
example 17N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-ethoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5p)
The procedure is as in example 2, substituting aniline with 4-ethoxyaniline.
White solid powder, yield 69.7%;1H NMR(400MHz,DMSO-d6)δ1H NMR(400MHz,DMSO)δ10.89(s,1H),10.23(s,1H),10.07(s,1H),7.47(s,2H),7.41(d,J＝8.4Hz,3H),7.15(d,J＝8.4Hz,2H),6.91(d,J＝8.8Hz,3H),6.78(s,1H),4.12(s,2H),3.98–3.92(m,2H),2.55(q,J＝7.6Hz,2H),1.33–1.29(m,3H),1.16(d,J＝7.6Hz,3H).
13C NMR(101MHz,DMSO-d6)δ170.94,170.26,150.50,149.87,142.11,139.12,135.17,128.09,121.91,119.68,115.25,114.99,114.54,63.26,27.50,15.61,14.84,14.61.Calcd for C24H25F3N5O3S[M+H]+：520.1630,found:520.1632.
example 18N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((2-methoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5q)
The procedure is as in example 2, substituting aniline for 2-methoxyaniline.
White solid powder, yield 68.3%;1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),10.22(s,1H),9.60(s,1H),7.80(s,1H),7.41(d,J＝8.4Hz,2H),7.15(d,J＝8.4Hz,3H),7.08(d,J＝7.9Hz,2H),6.96(t,J＝7.6Hz,1H),4.06(s,2H),3.83(s,3H),2.56(q,J＝7.6Hz,2H),1.15(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.58,170.35,150.44,139.09,135.17,128.11,125.84,124.37,121.53,120.24,119.70,117.45,113.14,111.65,55.63,35.04,27.49,15.62.Calcd for C23H22F3N5NaO3S[M+Na]+：528.1293,found:528.1325.
EXAMPLE 19N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-methoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5r)
The procedure is as in example 2, substituting aniline with 3-methoxyaniline.
White solid powder, yield 65.3%;1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),10.22(s,1H),9.60(s,1H),7.79(s,1H),7.41(d,J＝8.4Hz,2H),7.15(d,J＝8.4Hz,4H),7.09(s,1H),6.96(t,J＝7.6Hz,1H),4.07(s,2H),3.83(s,3H),2.58–2.53(m,2H),1.14(d,J＝7.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.62,170.35,150.44,139.09,135.17,128.10,124.50,121.95,120.24,119.70,111.65,70.51,69.75,69.64,55.62,35.04,27.49,15.61.Calcdfor C23H23F3N5O3S[M+H]+：506.1474,found:506.1475.
example 20N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-methoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (5s)
The procedure is as in example 2, except that 4-methoxyaniline is used instead of aniline.
White solid powder, yield 55.3%;1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.23(s,1H),10.06(s,1H),7.48(s,2H),7.40(d,J＝8.5Hz,2H),7.15(d,J＝8.5Hz,2H),6.93(d,J＝8.9Hz,2H),6.77(s,1H),4.10(s,2H),3.72(s,3H),2.55(q,J＝7.6Hz,2H),1.15(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.92,170.26,150.49,142.25,139.12,135.15,134.05,128.11,121.90,119.70,119.18,116.73,114.91,114.45,114.06,55.24,35.15,27.49,15.62.Calcd for C23H23F3N5O3S[M+H]+：506.1474,found:506.1475.
example 21N- ((4-ethylphenyl) carbamoyl) -2- ((4-phenoxy-6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide (6a)
The synthesized 2- ((4-chloro-6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- (4-ethylphenyl) carbamoyl) acetamide (200mg,0.48mmol) and phenol (89.88mg,0.96mmol) were added to 4ml acetonitrile with triethylamine (1.44mmol), warmed to 80 ℃ and TLC (V)Petroleum ether:VEthyl acetate5: 1) and (6) detecting. And (3) after the reaction is completed, extracting with water and ethyl acetate, stir-frying, separating by column chromatography, and drying to obtain the compound N- ((4-ethylphenyl) carbamoyl) -2- ((4-phenoxy-6- (trifluoromethyl) pyrimidine-2-yl) thio) acetamide.
White solid powder, yield 73.2%;1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),10.20(s,1H),7.48(dd,J＝8.6,6.7Hz,5H),7.36(d,J＝7.3Hz,1H),7.32(dd,J＝6.6,5.5Hz,2H),7.24(d,J＝8.4Hz,2H),4.05(s,2H),2.64(q,J＝7.6Hz,2H),1.23(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.41,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,124.04,106.94,40.52,32.75,20.86.Calcd for C21H19F3N4O3S[M-H]-：475.3175,found:475.3175.
example 222- ((4- (2-chlorophenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide (6b)
The procedure is as in example 21, but 2-chlorophenol is used instead of phenol.
White solid powder, yield 73.8%;1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),10.13(s,1H),7.60(s,1H),7.50(dd,J＝7.9,1.4Hz,1H),7.43(d,J＝8.3Hz,3H),7.40–7.36(m,1H),7.33(dd,J＝10.6,4.5Hz,1H),7.18(d,J＝8.4Hz,2H),3.92(s,2H),2.57(q,J＝7.6Hz,2H),1.17(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.61,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,123.98,106.94,40.52,32.75,20.86.Calcd for C22H18ClF3N4NaO3S[M+Na]+：533.0683,found:533.0683.
example 232- ((4- (3-fluorophenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide (6c)
The procedure is as in example 21, substituting 3-fluorophenol for phenol.
White solid powder, yield 87.2%;1H NMR(400MHz,DMSO-d6)δ10.73(d,J＝14.1Hz,1H),10.12(s,1H),7.45(d,J＝2.0Hz,1H),7.43(d,J＝2.6Hz,1H),7.40(s,1H),7.35(d,J＝8.4Hz,1H),7.26–7.22(m,1H),7.17(s,1H),7.15(s,1H),7.13(d,J＝1.9Hz,1H),7.11(d,J＝2.3Hz,1H),3.99(s,2H),2.57(dd,J＝12.9,5.3Hz,2H),1.16(t,J＝4.1Hz,3H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.43,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,123.73,106.94,40.52,32.75,20.86.Calcd for C22H18F4N4NaO3S[M+Na]+：527.1341,found:527.1339.
example 242- ((4- (4-bromophenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide (6d)
The procedure is as in example 21, substituting 4-bromophenol for phenol.
White solid powder, yield 75.8%;1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),10.18(s,1H),7.81(d,J＝8.4Hz,1H),7.65(d,J＝8.7Hz,2H),7.48(d,J＝10.2Hz,2H),7.29(d,J＝8.7Hz,2H),7.21(d,J＝8.4Hz,2H),4.06(s,2H),2.61(d,J＝7.7Hz,3H),1.23–1.20(m,3H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.36,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,124.09,106.94,40.52,32.75,20.86.Calcd for C22H18BrF3N4NaO3S[M+Na]+：577.0133,found:577.0132.
example 252- ((4- (4-Nitrophenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide (6e)
The procedure is as in example 21, except that 4-nitrophenol is used instead of phenol.
Pale yellow solid powder, yield 79.5%;1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),10.17(s,1H),8.41–8.36(m,2H),7.69–7.64(m,3H),7.51(d,J＝8.4Hz,2H),7.28(d,J＝8.5Hz,2H),4.06(s,2H),2.69(dd,J＝7.5,4.5Hz,2H),1.28(dd,J＝7.6,6.1Hz,4H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.38,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,123.75,106.94,40.52,32.75,20.86.Calcd forC22H18F3N5NaO5S[M+Na]+：544.0878,found:544.0876.
example 262- ((4- (3-Nitrophenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide (6f)
The procedure is as in example 21, except that 3-nitrophenol is used instead of phenol.
Pale yellow solid powder, yield 81.1%;1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),10.03(s,1H),8.21(d,J＝2.1Hz,1H),8.14(d,J＝8.2Hz,1H),7.78–7.72(m,1H),7.66(t,J＝8.2Hz,1H),7.55(s,1H),7.39(d,J＝8.3Hz,2H),7.17(d,J＝8.3Hz,2H),3.93(s,2H),2.57(q,J＝7.6Hz,2H),1.17(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.38,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,123.73,106.94,40.52,32.75,20.86.Calcd for C22H19F3N5O5S[M+H]+：522.1059,found:522.1060.
example 272- ((4- (4-ethylphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide (6g)
The procedure is as in example 21, except that 4-ethylphenol is used instead of phenol.
White solid powder, yield 83.8%;1H NMR(400MHz,DMSO-d6)δ10.74(d,J＝9.9Hz,1H),10.16(s,1H),7.43(d,J＝8.4Hz,2H),7.37–7.33(m,1H),7.23(d,J＝8.6Hz,2H),7.19–7.11(m,4H),3.99(s,2H),2.63–2.55(m,4H),1.16(ddd,J＝7.6,4.5,2.8Hz,6H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.32,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,123.78,106.94,40.52,32.75,20.86.Calcd for C24H23F3N4NaO3S[M+Na]+：527.1341,found:527.1339.
example 282- ((4- (4-methoxyethylphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide (6h)
The procedure is as in example 21, except that 4-methoxyethylphenol is used instead of phenol.
White solid powder, yield 81.9%;1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),10.16(s,1H),7.43(d,J＝8.5Hz,2H),7.36(s,1H),7.26(d,J＝8.6Hz,2H),7.21–7.12(m,4H),4.00(s,2H),3.58–3.50(m,2H),3.23(s,3H),2.81(t,J＝6.8Hz,2H),2.57(q,J＝7.6Hz,2H),1.16(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.45,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,123.81,106.94,40.52,32.75,20.86.Calcd for C25H26F3N4O4S[M+H]+：507.1314,found:507.1313.
example 292- ((4- (3,4, 5-Trimethoxyphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide (6i)
The same procedure as in example 21 was used to prepare a mixture of 3,4, 5-trimethoxyphenol and phenol.
White solid powder, yield 78.4%;1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),10.17(s,1H),9.21(s,2H),7.40(d,J＝8.4Hz,2H),7.29(s,1H),7.16(d,J＝8.4Hz,2H),4.07(s,2H),3.71(s,3H),3.55(s,6H),2.56(d,J＝7.6Hz,2H),1.16(t,J＝7.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.61,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,123.67,106.94,40.52,32.75,20.86.Calcd forC25H25F3N4NaO6S[M+Na]+：589.1345,found:589.1343.
example 302- ((4- (3-Methylphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide (6j)
The procedure is as in example 21, except that 3-methylphenol is used instead of phenol.
White solid powder, yield 86.2%;1H NMR(400MHz,DMSO-d6)δ10.79(d,J＝13.4Hz,1H),10.19(s,1H),7.48(d,J＝8.4Hz,2H),7.43(s,1H),7.35(t,J＝7.8Hz,1H),7.23(d,J＝8.4Hz,2H),7.15(d,J＝7.6Hz,1H),7.13–7.07(m,2H),4.06(s,2H),2.65–2.60(m,2H),2.35(s,3H),1.22(d,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.36,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,123.59,106.94,40.52,32.75,20.86.C23H21F3N4NaO3S[M+Na]+：513.1184,found:513.1182.
example 312- ((4- (4-Methylphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide (6k)
The procedure is as in example 21, except that 4-methylphenol is used instead of phenol.
White solid powder, yield 89.1%;1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),10.14(s,1H),7.43(d,J＝8.5Hz,2H),7.36(s,1H),7.18(t,J＝7.7Hz,4H),7.10(d,J＝8.5Hz,2H),3.98(s,2H),2.60–2.54(m,2H),2.29(s,3H),1.18–1.15(m,3H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.41,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,124.04,106.94,40.52,32.75,20.86.C23H22F3N4O3S[M+H]+：491.1365,found:491.1365.
example 322- ((4- (4-Methoxyphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide (6l)
The procedure is as in example 21, except that 4-methoxyphenol is used instead of phenol.
White solid powder, yield 81.9%;1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),10.15(s,1H),7.43(d,J＝8.4Hz,2H),7.33(s,1H),7.19–7.13(m,4H),6.97–6.91(m,2H),3.99(s,2H),3.75(s,3H),2.56(dd,J＝15.3,7.7Hz,2H),1.15(d,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.38,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,123.86,106.94,40.52,32.75,20.86.C23H22F3N4O4S[M+H]+：507.1314,found:507.1313.
example 332- ((4- (4-Ethoxyphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide (6m)
The procedure is as in example 21, except that 4-ethoxyphenol is used instead of phenol.
White solid powder, yield 71.6%;1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),10.14(s,1H),7.42(d,J＝8.5Hz,2H),7.33(s,1H),7.19–7.12(m,4H),6.94–6.90(m,2H),3.99(s,2H),2.55(dd,J＝9.7,5.5Hz,2H),2.52–2.49(dd,2H),1.31(t,J＝7.1Hz,3H),1.18(t,3H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.72,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,123.86,106.94,40.52,32.75,20.86.C23H22F3N4O4S[M+H]+：521.1470,found:521.1472.
example 342- ((4- (2, 6-dimethylphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide (6N)
The procedure is as in example 21, substituting 2, 6-dimethylphenol for phenol.
White solid powder, yield 65.9%;1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),10.35(s,1H),7.96(d,J＝8.4Hz,1H),7.67–7.63(m,2H),7.38(d,J＝8.4Hz,2H),7.25(s,3H),4.06(s,2H),2.80–2.75(m,2H),2.20(s,6H),1.39–1.35(m,3H).13C NMR(101MHz,DMSO-d6)δ176.94,174.94,174.71,160.97,160.55,156.54,155.57,144.35,140.42,135.00,133.39,131.49,126.59,124.94,123.83,106.94,40.52,32.75,20.86.C24H23F3N4NaO3S[M+Na]+：527.1341,found:527.1343.
examples of the applications
In vitro antitumor activity test: four cell lines, MGC-803 (human gastric cancer cell), PC-3 (human prostate cancer cell), SW620 (human colon cancer cell), and A549 (human lung cancer cell), were used in the MTT method.
Log phase cells were collected, cell suspension concentration was adjusted, 100 μ l was added per well, and cell density was adjusted by plating (marginal wells filled with PBS). Volume percent 5% CO2Incubate at 37 ℃ for 24h until the cell monolayer is spread to the bottom of the well (96-well plate), add the drug synthesized by the invention with a concentration gradient, generally set at 9 concentrations, 200. mu.l per well, and set at 3 multiple wells. Volume percent 5% CO2Incubation was carried out at 37 ℃ for 72h, observed under an inverted microscope, and 20. mu.l of MTT solution (5mg/ml, i.e., 0.5% MTT) was added to each well and incubation was continued for 4 h. Terminating the culture, carefully removing the culture solution in the wells, adding 150. mu.l of dimethyl sulfoxide into each well, and placing on a shaker for 10min at low speed to fully dissolve the crystals. The absorbance of each well was measured at OD 490nm in an ELISA detector. SPSS software is used for counting experimental results and calculating IC50The results are as follows (μmol/L) values:
TABLE 1 in vitro antitumor Activity test Table
Figure BDA0002374425730000181

Claims (5)

1.2, 4, 6-substituted pyrimidine derivatives containing acyl urea structure, characterized by having the structure described in general formula I:
Figure FDA0002374425720000011
r is a chlorine atom, an anilino group, a 2-chloroanilino group, a 3-chloroanilino group, a 4-chloroanilino group, a 2-fluoroanilino group, a 3-fluoroanilino group, a 4-fluoroanilino group, a 2-methylanilino group, a 3-methylanilino group, a 4-methylanilino group, a 3,4, 5-trimethoxyanilino group, a 3-chloro-4-fluoroanilino group, a 3, 4-dichloroanilino group, a 2-ethoxyanilino group, a 3-ethylanilino group, a 4-ethoxyanilino group, a 2-methoxyanilino group, a 3-methoxyanilino group, a 4-methoxyanilino group, a phenol group, a 2-chlorophenol group, a 3-fluorophenol group, a 4-bromophenol group, a 4-nitrophenol group, a 3-nitrophenol group, a 4-ethylphenol group, a phenol group, 4-methoxyethylphenol group, 3,4, 5-trimethoxyphenol group, 3-methylphenylphenol group, 4-methoxyphenol group, 4-ethoxyphenol group, or 2, 6-dimethylphenol group.
2. The acyl urea structure-containing 2,4, 6-substituted pyrimidine derivative according to claim 1, wherein: the compound is one of the following compounds:
4g of 2- ((4-chloro-6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- (4-ethylphenyl) carbamoyl) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- (phenylamino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-chlorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-chlorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((2-fluorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
5g N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-fluorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-methylphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-methylphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3,4, 5-trimethoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
5l of N- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-chloro-4-fluorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-chloro-4-chlorophenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-ethylphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-ethoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((3-methoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
n- ((4-ethylphenyl) carbamoyl) -2- ((4- ((4-methoxyphenyl) amino) -6- (trifluoromethyl) pyrimidin-2-yl) thio) acetamide;
2- ((4- (3-fluorophenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (4-bromophenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (3-nitrophenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
6g 2- ((4- (4-ethylphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (3-methylphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (4-methylphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (4-methoxyphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (4-ethoxyphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide;
2- ((4- (2, 6-dimethylphenoxy) -6- (trifluoromethyl) pyrimidin-2-yl) thio) -N- ((4-ethylphenyl) carbamoyl) acetamide.
3. The method for preparing the 2,4, 6-substituted pyrimidine derivatives containing an acylurea structure according to claim 1, is achieved by the following synthetic steps:
Figure FDA0002374425720000031
a. oxalyl chloride, chloroacetyl and 4-ethylaniline are subjected to substitution reaction in a 1, 2-dichloroethane solution to generate a compound 1 a; b. reacting the compound 2 with the compound 1a in water and a potassium hydroxide aqueous solution to generate a compound 3 a; c. reacting the compound 3a with phosphorus oxychloride to generate 4g of a compound; d. reacting 4g of the compound with aniline compounds in a DMF solution to generate pyrimidine derivatives 5a-5s containing acylureido segments; d. reacting 4g of the compound with a phenol compound in acetonitrile and triethylamine to generate pyrimidine derivatives 6a-6o containing acyl ureido segments;
the aniline compound in the step (d) is as follows: aniline, 2-chloroaniline, 3-chloroaniline, 4-chloroaniline, 2-fluoroaniline, 3-fluoroaniline, 4-fluoroaniline, 2-methylaniline, 3-methylaniline, 4-methylaniline, 3,4, 5-trimethoxyaniline, 3-chloro-4-fluoroaniline, 3, 4-dichloroaniline, 2-ethoxyaniline, 3-ethylaniline, 4-ethoxyaniline, 2-methoxyaniline, 3-methoxyaniline, or 4-methoxyaniline;
the phenol compound in the step (e) is: phenol, 2-chlorophenol, 3-fluorophenol, 4-bromophenol, 4-nitrophenol, 3-nitrophenol, 4-ethylphenol, 4-methoxyethylphenol, 3,4, 5-trimethoxyphenol, 3-methylphenol, 4-methoxyphenol, 4-ethoxyphenol, or 2, 6-dimethylphenol.
4. Use of 2,4, 6-substituted pyrimidine derivatives containing an acylurea moiety according to any of claims 1-2 as active ingredients in the preparation of medicaments for the preparation of antitumor drugs.
5. Use of the 2,4, 6-substituted pyrimidine derivatives containing an acylurea moiety according to claim 4 in the manufacture of a medicament, wherein: can be used as active ingredient for preparing medicine for resisting human gastric cancer cell, human colon cancer cell, human prostate cancer cell or human lung cancer cell.
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