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CN111057015B - 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide compounds - Google Patents

2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide compounds Download PDF

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CN111057015B
CN111057015B CN202010004490.8A CN202010004490A CN111057015B CN 111057015 B CN111057015 B CN 111057015B CN 202010004490 A CN202010004490 A CN 202010004490A CN 111057015 B CN111057015 B CN 111057015B
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triazol
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acetic acid
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CN111057015A (en
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孟繁浩
李世龙
梁经纬
李晚秋
戴傲伦
王琳
孙琦
赵楠
张廷剑
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CHINA MEDICAL UNIVERSITY
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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Abstract

本发明属于医药技术领域，尤其涉及2‑（4‑苯基‑1H‑1,2,3‑三唑‑1‑基）乙酸及乙酰肼类化合物及其制备方法和应用。所述2‑（4‑苯基‑1H‑1,2,3‑三唑‑1‑基）乙酸及乙酰肼类化合物，其通式如I、II所示：

Figure DEST_PATH_IMAGE001
。本发明制备的化合物在体外激酶实验中显现出了良好的结果，表明具有良好的抗肿瘤活性，同时为药物设计提供新思路。本发明所提供的通式Ⅰ、通式Ⅱ所示的2‑（4‑苯基‑1H‑1,2,3‑三唑‑1‑基）乙酸及乙酰肼类新化合物的制备方法简单可行，收率较好，适合工业化生产。

Figure 202010004490

The invention belongs to the technical field of medicine, and in particular relates to 2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetic acid and acetylhydrazide compounds and a preparation method and application thereof. Described 2-(4-phenyl-1H-1,2,3-triazole-1-yl) acetic acid and acetyl hydrazide compound, its general formula is as shown in I, II:

Figure DEST_PATH_IMAGE001
. The compounds prepared by the invention show good results in the in vitro kinase experiment, indicating that they have good anti-tumor activity, and at the same time provide new ideas for drug design. The preparation method of 2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetic acid and acetyl hydrazide class new compounds shown in general formula I and general formula II provided by the present invention is simple and feasible , the yield is good, suitable for industrial production.

Figure 202010004490

Description

2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide compounds
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide compounds, and a preparation method and application thereof.
Background
Malignant tumor is a serious disease which is difficult to treat at present, seriously harms human health, has an increasing incidence rate year by year, and attracts more and more attention of people. The existing antitumor drugs on the market have defects in side effects, selectivity and drug resistance, and the search for more efficient, low-side-effect, broad-spectrum and cheap antitumor drugs is increasingly a hot point of research.
The acyl hydrazine and triazole fragments are key anti-tumor fragments, the inventor conducts ADME screening on anti-tumor drugs on the market, and designs a series of compounds by adopting fragment growth and molecular docking modes, so as to obtain the drugs with good anti-tumor activity, and simultaneously provide a new idea for drug design.
Disclosure of Invention
In view of the above problems, the present invention aims to provide a compound of 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide and a preparation method thereof, wherein the compound has good antitumor activity and can be used for preparing antitumor drugs.
In order to achieve the purpose, the invention adopts the following technical scheme.
The general structural formula of the 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide compound is shown as I, II:
Figure BDA0002354733100000011
wherein:
each R1 is independently H, F, Cl, Br, hydroxyl, methyl, methoxy, nitro;
each R2 is independently H, amino, acetylamino, benzoylamino;
each R3 is independently H, F, Cl, Br, hydroxyl, methyl, methoxy, amino, nitro;
each R4 is independently H, ethyl.
The novel compounds represented by the general formula I and the general formula II comprise 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid, acethydrazide compounds, derivatives, trans isomers and pharmaceutically acceptable salts, hydrates or solvates thereof.
Further, the 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide compound or pharmaceutically acceptable salt, trans isomer, hydrate or solvate thereof is selected from any one of the following compounds.
(E) -N' - (4-chlorobenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-01);
(E) -N' - (3-chlorobenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-02);
(E) -N' - (4-hydroxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-03);
(E) -N' - (2-hydroxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-04);
(E) -N' - (2-nitrobenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-05);
(E) -N' - (5-chloro-2-hydroxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-06);
(E) -N' - (3, 5-dibromo-2-hydroxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-07);
(E) -N' - (5-bromo-2-hydroxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-08);
(E) -N' - (2, 4-dimethoxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-09);
(E) -N' - (3, 4-dimethoxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-10);
(E) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) -N' - (3,4, 5-trimethoxybenzylidene) acetohydrazide (L-11);
(E) -2- (4- (3-acetamidophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (4-chlorobenzylidene) acethydrazide (YX-01);
(E) -2- (4- (3-acetamidophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (3-chlorobenzylidene) acetohydrazide (YX-02);
(E) -2- (4- (3-acetamidophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (4-hydroxybenzylidene) acethydrazide (YX-03);
(E) -2- (4- (3-acetamidophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (2-hydroxybenzylidene) acetohydrazide (YX-04);
(E) -2- (4- (3-acetamidophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (2-nitrobenzylidene) acethydrazide (YX-05);
(E) -2- (4- (3-acetamidophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (5-chloro-2-hydroxybenzylidene) acetohydrazide (YX-06);
(E) -2- (4- (3-acetamidophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (3, 5-dibromo-2-hydroxybenzylidene) acethydrazide (YX-07);
(E) -2- (4- (3-acetamidophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (3, 5-dibromo-2-hydroxybenzylidene) acethydrazide (YX-08);
(E) -2- (4- (3-acetamidophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (2, 4-dimethoxybenzylidene) acetohydrazide (YX-09);
(E) -2- (4- (3-acetamidophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (3, 4-dimethoxybenzylidene) acetohydrazide (YX-10);
(E) -2- (4- (3-acetamidophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (3,4, 5-trimethoxybenzylidene) acetohydrazide (YX-11).
Further, the 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide compound is selected from any one of the following compounds of the general formula II or pharmaceutically acceptable salts, trans isomers, hydrates or solvates thereof.
2- (4- (3-benzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-01);
2- (4- (3- (4-bromobenzoylamino) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-02);
2- (4- (3- (3-chlorobenzoylamino) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-03);
2- (4- (3- (2-nitrobenzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-04);
2- (4- (3- (4-hydroxybenzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-05);
2- (4- (3- (5-bromo-2-hydroxybenzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-06);
2- (4- (3- (3, 4-dimethoxybenzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-07);
2- (4- (3- (2-fluorobenzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-08);
2- (4- (3- (3-fluorobenzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-09);
these compounds are not meant to be limiting in any way.
A preparation method of 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide compounds comprises the following steps.
Preparation of a compound of formula I: using azido-substituted 2-bromoethyl acetate as a starting material, carrying out Husige cycloaddition reaction on phenylacetylene and derivatives thereof in the presence of copper sulfate pentahydrate and vitamin C to generate an intermediate 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) ethyl acetate and derivatives thereof, hydrolyzing to obtain an important intermediate 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and corresponding derivatives thereof, then condensing the product with (E) -benzylidene hydrazine prepared from benzaldehyde derivatives and hydrazine hydrate by using triethylamine as an acid binding agent to generate a target compound shown in a general formula I, wherein the synthetic route is shown in figure 1.
Preparation of the target compound of formula II: a benzoic acid derivative is taken as an initial raw material, chlorinated by thionyl chloride, then subjected to acylation reaction with m-aminophenylacetylene, subjected to Husige cycloaddition reaction with ethyl azidoacetate in the presence of copper sulfate pentahydrate and vitamin C, and further hydrolyzed to obtain a target compound shown in a general formula II, wherein the synthetic route is shown in figure 2.
A pharmaceutical composition is characterized by comprising the 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide compound, pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier.
The 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide compounds, pharmaceutically acceptable salts, hydrates or solvates thereof or pharmaceutical compositions are applied to preparation of antitumor drugs.
Compared with the prior art, the invention has the following beneficial effects.
The 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide compounds prepared by the invention show good results in-vitro kinase experiments, show that the compounds have good antitumor activity, and provide a new idea for drug design. The preparation method of the novel compounds of 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide shown in the general formulas I and II is simple and feasible, has high yield and is suitable for industrial production.
Drawings
FIG. 1 is a synthetic route of 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide compounds shown in a general formula I.
FIG. 2 is a synthetic route of 2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acetic acid and acethydrazide compounds shown in the general formula II.
Detailed Description
The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are provided to illustrate the present invention, but these examples are only for illustrating the present invention and the present invention is not limited to these.
Example Synthesis of 12- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acetic acid.
Figure BDA0002354733100000041
59.88mmol of 2-bromoethyl acetate is dissolved in 40mL of dichloromethane in a reaction bottle, 77.84mmol of sodium azide (2) is dissolved in 10mL of water and slowly poured into the reaction bottle for mixing, the mixture reacts at 40 ℃ for 12 hours under the catalysis of sodium iodide, after the reaction is finished, the mixture is cooled to room temperature, an aqueous layer is removed, an organic layer is dried, and the solvent is evaporated under reduced pressure to obtain 2- (2-azidoethoxy) ethane-1-onium (3) which is colorless and transparent liquid with the yield of 95%.
63.02mmol of phenylacetylene is dissolved in a reaction bottle by 25mL of absolute ethyl alcohol, 1.25mmol of anhydrous copper sulfate and a small amount of vitamin C are dissolved in 4mL of water, the mixture is heated and shaken for 2min, the aqueous solution is poured into the reaction bottle, 57.29mmol of 2- (2-azido ethoxy) ethane-1-onium obtained in the previous step is added to react for 4H at 60 ℃, the solvent is removed by reduced pressure distillation, 50mL of water is added, 15-20mL of ethyl acetate is used for extraction for 3 times, the organic layer is dried and the solvent is removed by reduced pressure distillation, and light white solid ethyl 2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acetate (5) is obtained, and the yield is 73 percent.
43.24mmol of ethyl 2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acetate (5) was added to an aqueous alkali solution prepared from 172.97mmol of NaOH, and the mixture was reacted at 40 ℃ for 5 hours, cooled to room temperature, adjusted to Ph ═ 2 with hydrochloric acid, and a white solid was precipitated, filtered by suction, and dried to obtain 2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acetic acid with a yield of 96.7%.
Example 2 synthesis of (E) -benzylidenehydrazine derivative was performed.
Figure BDA0002354733100000051
And (2) putting 37.69mmol of benzaldehyde into a reaction bottle, slowly dropwise adding 226.15mmol of 80% hydrazine hydrate while stirring to generate a light yellow solid, reacting at normal temperature for 30min after dropwise adding, adding 20mL of saturated sodium chloride aqueous solution, performing suction filtration, and washing a filter cake twice with 15mL of saturated sodium chloride aqueous solution to obtain the (E) -benzylidene hydrazine product with the yield of 83.9%.
Other derivatives were prepared in the same manner as the corresponding benzaldehyde derivatives.
Example 3 was carried out.
The compound shown in the general formula I is synthesized by the following technical scheme.
Figure BDA0002354733100000052
The specific scheme is as follows.
(1) Preparation of (E) -N' - (4-chlorobenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-01).
2.46mmol of 2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acetic acid and HOBt (2.71mmol) were dissolved in dry, anhydrous DMF (8mL), EDCI (2.46mmol) was added at 0 ℃ and stirred for half an hour, then (E) - (4-chlorobenzylidene) (2.71mmol) and Et were added 3 And (3) reacting N (6.15mmol) at room temperature for 6 hours, pouring the obtained product into water to separate out a large amount of white solid after the reaction is finished, performing suction filtration to obtain a crude product, dissolving the crude product into 15mL of methanol, performing reflux stirring to dissolve the solid, performing suction filtration, cooling the filtrate to separate out yellow crystals, performing suction filtration again to obtain a filter cake, namely the product (E) -N' - (4-chlorobenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) acethydrazide which is a white solid and has the yield of 66.72%. 1 H NMR(600MHz,DMSO-d6)δ11.94(s,1H,–N–H),8.56(s,1H,–N–CH＝),8.07(s,1H,–N＝CH–),7.87(d,J＝7.1Hz,2H,Ar–H),7.80(d,J＝8.5Hz,2H,Ar–H),7.52(d,J＝8.5Hz,2H,Ar–H),7.47(t,J＝7.7Hz,2H,Ar–H),7.35(t,J＝7.4Hz,1H,Ar–H),5.76(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ167.94,162.68,147.15,146.62,143.75,135.07,133.29,131.27,129.41,129.21,128.29,125.59,123.64,51.16。
(2) (E) -N' - (3-chlorobenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-02) was prepared in the same manner as (L-01).
White solid, yield 63.45%. 1 H NMR(600MHz,DMSO-d6)δ11.99(s,1H,–N–H),8.55(s,1H,–N–CH＝),8.05(s,1H,–N＝CH–),7.87(m,3H,Ar–H),7.73–7.69(t,1H,Ar–H),7.51–7.44(m,5H,Ar–H),7.34(t,J＝7.4Hz,1H,Ar–H),5.77(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ168.25,146.58,143.25,136.71,134.19,131.15,130.14,129.41,128.27,126.63,126.44,125.58,123.63,51.26。
(3) (E) -N' - (4-hydroxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-03) by the same method as (L-01).
White solid, yield 58.23%. 1 H NMR(600MHz,DMSO-d6)δ11.68(s,1H,–N–H),9.94(s,1H,–O–H),8.56(s,1H,–N–CH＝),7.98(s,1H,–N＝CH–),7.89(d,2H,Ar–H),7.60(d,J＝7.4Hz,2H,Ar–H),7.49–7.34(m,3H,Ar–H),6.85(d,J＝6.7Hz,2H,Ar–H),5.71(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ167.41,159.94,146.60,145.33,131.30,129.40,129.29,128.27,125.59,125.34,123.67,116.18,51.13。
(4) (E) -N' - (2-hydroxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-04) was prepared in the same manner as (L-01).
White solid, yield 63.45%. 1 H NMR(600MHz,DMSO-d6)δ11.78(s,1H,–N–H),10.04(s,1H,–O–H),8.55(s,1H,–N–CH＝),8.38(s,1H,–N＝CH–),7.90–7.85(m,3H,Ar–H),7.80(d,J＝6.3Hz,1H,Ar–H),7.46(m,3H,Ar–H),7.35(d,J＝7.5Hz,1H,Ar–H),7.29–7.24(t,J＝7.8Hz,1H,Ar–H),5.73(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ167.53,156.95,146.59,142.22,131.88,131.30,129.41,128.28,126.74,125.59,123.66,120.51,119.89,116.64,51.15。
(5) (E) -N' - (2-nitrobenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-05) by the same method as (L-01).
Light yellow solid, yield 53.14%. 1 H NMR(600MHz,DMSO-d6)δ12.15(s,1H,–N–H),8.56(s,1H,–N–CH＝),8.47(s,1H,–N＝CH–),7.88(d,J＝6.5Hz,2H,Ar–H),7.81(t,J＝7.6Hz,1H,Ar–H),7.69(t,J＝7.8Hz,1H,Ar–H),7.49–7.45(m,3H,Ar–H),7.35(t,J＝7.3Hz,2H,Ar–H),5.77(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ168.20,148.57,146.88,146.67,140.65,134.08,131.22,129.41,129.02,128.45,125.65,125.05,123.64,123.22,53.06。
(6) (E) -N' - (5-chloro-2-hydroxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-06) was prepared in the same manner as (L-01).
White solid, yield 48.59%. 1 H NMR(600MHz,DMSO-d6)δ11.86(s,1H,–N–H),10.37(s,1H,–O–H),8.54(s,1H,–N–CH＝),8.32(s,1H,–N＝CH–),7.87(d,J＝7.4Hz,2H,Ar–H),7.83(d,J＝2.6Hz,1H,Ar–H),7.46(m,3H,Ar–H),7.35(d,J＝7.5Hz,1H,Ar–H),7.29(d,J＝8.8Hz,1H,Ar–H),5.77(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ167.89,162.65,155.69,146.56,140.20,131.29,129.42,128.28,125.57,125.44,123.80,123.64,122.37,118.42,51.27。
(7) (E) -N' - (3, 5-dibromo-2-hydroxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-07) was prepared in the same manner as (L-01).
Light yellow solid, yield 55.47%. 1 H NMR(600MHz,DMSO-d6)δ12.58(s,1H,–O–H),12.02(s,1H,–N–H),8.62(s,1H,–N＝CH–),8.52(s,1H,–N–CH＝),8.41(s,1H,Ar–H),8.29(s,1H,Ar–H),7.47(m,3H,Ar–H),7.35(d,J＝1.9Hz,2H,Ar–H),5.81(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ167.85,163.01,147.88,146.81,141.75,136.12,132.68,131.11,129.42,128.39,125.65,125.60,123.49,121.34,51.38。
(8) (E) -N' - (5-bromo-2-hydroxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide (L-08) was prepared in the same manner as (L-01).
White solid, yield 58.55%. 1 H NMR(600MHz,DMSO-d6)δ11.85(s,1H,–N–H),10.39(s,1H,–O–H),8.54(s,1H,–N–CH＝),8.30(s,1H,–N＝CH–),7.95(s,1H,Ar–H),7.87(m,2H,Ar–H),7.46(m,3H,Ar–H),7.41(d,J＝8.7Hz,1H,Ar–H),7.35(d,J＝7.4Hz,1H,Ar–H),5.77(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ167.18,155.49,145.94,139.60,133.45,130.68,128.76,127.62,125.36,124.96,122.96,122.31,118.26,110.76,50.62。
(9) (E) -N' - (2, 4-dimethoxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide ((L-09) was prepared in the same manner as (L-01).
Pale yellow solid, yield 49.52%. 1 H NMR(600MHz,DMSO-d6)δ11.79(s,1H,–N–H),8.64(s,1H,–N＝CH–),8.57(s,1H,–N–CH＝),7.99(s,1H,Ar–H),7.87(d,J＝7.6Hz,2H,Ar–H),7.49(d,J＝1.3Hz,1H,Ar–H),7.46(d,J＝7.7Hz,1H,Ar–H),7.40–7.37(m,2H,Ar–H),7.35(t,J＝7.4Hz,1H,Ar–H),5.76(s,2H,CH 2 ),3.82(s,6H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ163.22,160.00,157.87,155.31,148.89,146.34,133.50,129.89,127.55,122.84,122.15,117.82,114.60,106.41,99.36,98.13,56.55,55.73,55.37。
(10) (E) -N' - (3, 4-dimethoxybenzylidene) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acethydrazide ((L-10) was prepared in the same manner as (L-01).
White solid, yield 67.14%. 1 H NMR(600MHz,DMSO-d6)δ11.80(s,1H,–N–H),8.65(s,1H,–N＝CH–),8.58(s,1H,–N–CH＝),8.00(s,1H,Ar–H),7.88(d,J＝7.1Hz,2H,Ar–H),7.47(m,3H,Ar–H),7.41(d,J＝1.7Hz,1H,Ar–H),7.36(d,J＝7.4Hz,1H,Ar–H),5.77(s,2H,CH 2 ),3.83(s,6H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ167.62,151.23,149.56,146.62,145.09,131.30,129.41,128.28,127.07,125.59,123.64,122.06,111.95,109.08,56.05,51.24。
(11) (E) -2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) -N' - (3,4, 5-trimethoxybenzylidene) acethydrazide ((L-11) was prepared in the same manner as (L-01).
White solid, yield 65.31%. 1 H NMR(600MHz,DMSO-d6)δ11.91(s,1H,–N–H),8.66(s,1H,–N＝CH–),8.57(s,1H,–N–CH＝),7.87(d,J＝7.2Hz,2H,Ar–H),7.47(m,2H,Ar–H),7.35(t,J＝7.2Hz,1H,Ar–H),7.22(s,2H,Ar–H),5.77(s,2H,CH 2 ),3.74(s,6H,CH 3 ),3.71(s,3H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ167.86,161.68,153.65,146.62,144.83,140.72,139.71,131.29,129.74,129.42,128.29,125.58,123.64,106.10,104.86,102.78,100.00,60.65,56.43,51.29。
(12) (E) -2- (4- (3-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (4-chlorobenzylidene) acethydrazide (YX-01) was prepared in the same manner as (L-01).
White solid, yield 61.24%. 1 H NMR(600MHz,DMSO-d6)δ11.96(s,1H,–N–H),10.07(s,1H,–N–H),8.50(s,1H,–N–CH＝),8.16(s,1H,Ar–H),8.07(s,1H,–N＝CH–),7.81(d,J＝8.5Hz,2H,Ar–H),7.58(d,J＝7.4Hz,1H,Ar–H),7.53(d,J＝8.5Hz,2H,Ar–H),7.49(d,J＝7.4Hz,1H,Ar–H),7.38(t,J＝7.9Hz,1H,Ar–H),5.77(s,2H,CH 2 ),2.08(s,3H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ168.91,168.13,161.12,146.56,143.38,140.38,136.25,134.19,131.64,131.34,130.24,129.79,128.34,127.40,123.65,120.43,115.99,51.26,24.55。
(13) (E) -2- (4- (3-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (3-chlorobenzylidene) acetohydrazide (YX-02) was prepared in the same manner as (L-01).
White solid, yield 57.21%. 1 H NMR(600MHz,DMSO-d6)δ12.01(s,1H,–N–H),10.09(s,1H,–N–H),8.51(s,1H,–N–CH＝),8.17(s,1H,Ar–H),8.07(s,1H,–N＝CH–),7.94(s,1H,Ar–H),7.89(s,1H,Ar–H),7.86(d,J＝7.6Hz,1H,Ar–H),7.59(d,J＝7.6Hz,1H,Ar–H),7.56(d,J＝7.7Hz,1H,Ar–H),7.37(m,2H,Ar–H),5.80(s,2H,CH 2 ),2.09(s,3H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ168.91,167.45,159.94,148.69,146.52,145.29,140.37,131.68,129.80,129.52,129.28,125.31,123.68,120.42,118.85,116.18,115.97,51.14,24.55。
(14) (E) -2- (4- (3-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (4-hydroxybenzylidene) acethydrazide (YX-03) was prepared in the same manner as (L-01).
White solid, yield 52.11%. 1 H NMR(600MHz,DMSO-d6)δ11.70(s,1H,–N–H),10.07(s,1H,–O–H),10.00(s,1H,–N–H),8.50(s,1H,–N–CH＝),8.16(s,1H,Ar–H),7.97(s,1H,–N＝CH–),7.60(d,J＝8.7Hz,2H,Ar–H),7.56(d,J＝8.7Hz,1H,Ar–H),7.49(d,J＝7.6Hz,1H,Ar–H),7.37(t,J＝7.9Hz,1H,Ar–H),6.85(d,J＝8.7Hz,2H,Ar–H),5.71(s,2H,CH 2 ),2.08(s,3H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ168.91,167.45,159.94,148.69,146.52,145.29,140.37,131.68,129.80,129.52,129.28,125.31,123.68,120.42,118.85,116.18,115.97,51.14,24.55。
(15) (E) -2- (4- (3-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (2-hydroxybenzylidene) acethydrazide (YX-04) was prepared in the same manner as (L-01).
White solid, yield 53.24%. 1 H NMR(600MHz,DMSO-d6)δ11.81(s,1H,–N–H),10.07(s,2H,–N–H,–O–H),8.50(s,1H,–N–CH＝),8.39(s,1H,–N＝CH–),8.16(s,1H,Ar–H),7.58(d,J＝5.5Hz,1H,Ar–H),7.49(d,J＝7.4Hz,1H,Ar–H),7.38(t,J＝7.9Hz,1H,Ar–H),7.27(t,J＝7.0Hz,1H,Ar–H),6.92(m,2H,Ar–H),6.88(t,J＝7.5Hz,1H,Ar–H),5.72(s,2H,CH 2 ),2.08(s,3H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ168.91,167.57,162.48,156.95,148.23,146.53,142.15,140.38,131.89,129.80,126.69,123.67,120.49,119.89,116.84,116.63,115.97,51.18,24.55。
(16) (E) -2- (4- (3-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (2-nitrobenzylidene) acethydrazide (YX-05) was prepared in the same manner as (L-01).
Light yellow solid, yield 45.21%. 1 H NMR(600MHz,DMSO-d6)δ12.17(s,1H,–N–H),10.07(s,1H,–N–H),8.51(s,1H,–N–CH＝),8.47(s,1H,–N＝CH–),8.17(s,1H,Ar–H),7.82(t,J＝7.5Hz,1H,Ar–H),7.69(t,J＝7.3Hz,1H,Ar–H),7.59(m,2H,Ar–H),7.50(d,J＝7.4Hz,1H,Ar–H),7.40–7.35(m,2H,Ar–H),5.77(s,2H,CH 2 ),2.08(s,3H,CH 3 )。
. 13 C NMR(150MHz,DMSO-d6)δ167.85,167.18,147.49,145.54,139.60,139.32,133.04,130.16,128.74,127.94,127.51,124.01,122.59,121.48,119.37,117.81,114.92,50.13,23.49。
(17) (E) -2- (4- (3-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (5-chloro-2-hydroxybenzylidene) acethydrazide (YX-06) was prepared in the same manner as (L-01).
White solid, yield 58.29%. 1 H NMR(600MHz,DMSO-d6)δ11.88(s,1H,–N–H),10.44(s,1H,–O–H),10.06(s,1H,–N–H),8.48(s,1H,–N–CH＝),8.32(s,1H,–N＝CH–),8.15(s,1H,Ar–H),7.58(d,J＝7.5Hz,1H,Ar–H),7.49(d,J＝7.3Hz,1H,Ar–H),7.37(t,J＝7.8Hz,1H,Ar–H),7.09(s,1H,Ar–H),7.01(d,J＝8.8Hz,1H,Ar–H),6.94(d,J＝8.8Hz,1H,Ar–H),5.78(s,2H,CH 2 ),2.08(s,3H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ168.90,167.90,161.33,140.37,133.21,131.27,129.79,129.09,128.27,127.15,123.78,123.63,122.37,120.46,118.99,117.87,115.97,51.27,24.54。
(18) (E) -2- (4- (3-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (3, 5-dibromo-2-hydroxybenzylidene) acethydrazide (YX-07) was prepared in the same manner as (L-01).
White solid, yield 62.31%. 1 H NMR(600MHz,DMSO-d6)δ12.63(s,1H,–N–H),12.23(s,1H,–O–H),12.04(s,1H,–N–H),8.56(s,1H,–N–CH＝),8.46(s,1H,–N＝CH–),8.42(s,1H,Ar–H),8.31(s,1H,Ar–H),7.94(s,1H,Ar–H),7.58(d,J＝8.0Hz,1H,Ar–H),7.50(d,J＝7.2Hz,1H,Ar–H),7.37(s,1H,Ar–H),5.81(s,2H,CH 2 ),2.08(s,3H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ168.89,163.02,154.00,152.70,147.84,146.75,140.38,136.31,132.67,131.49,129.79,123.51,121.35,120.50,116.07,111.77,111.01,51.35,24.54。
(19) (E) -2- (4- (3-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (5-bromo-2-hydroxybenzylidene) acetohydrazide (YX-08) was prepared in the same manner as (L-01).
White solid, yield 57.64%. 1 H NMR(600MHz,DMSO-d6)δ11.85(s,1H,–N–H),10.39(s,1H,–O–H),10.04(s,1H,–N–H),8.47(s,1H,–N–CH＝),8.30(s,1H,–N＝CH–),8.14(s,1H,Ar–H),7.95(s,1H,Ar–H),7.57(d,J＝4.9Hz,1H,Ar–H),7.48(d,J＝7.8Hz,1H,Ar–H),7.43–7.34(m,3H,Ar–H),5.77(s,2H,CH 2 ),2.07(s,3H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ168.89,167.90,162.78,156.11,146.49,140.37,140.10,134.11,131.68,129.80,128.32,123.63,122.92,120.42,118.87,115.96,111.39,51.27,24.55。
(20) (E) -2- (4- (3-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (2, 4-dimethoxybenzylidene) acethydrazide (YX-09) was prepared in the same manner as in (L-01).
Light yellow solid, yield 59.36%. 1 H NMR(600MHz,DMSO-d6)δ10.05(s,1H,–N–H),8.83(s,1H,–N–CH＝),8.42(s,1H,–N＝CH–),8.16(s,1H,Ar–H),7.91(d,J＝8.6Hz,1H,Ar–H),7.55(d,J＝8.0Hz,1H,Ar–H),7.48(d,J＝7.7Hz,1H,Ar–H),7.36(t,J＝7.9Hz,1H,Ar–H),6.66(s,1H,Ar–H),6.64(d,J＝8.6Hz,1H,Ar–H),5.47(s,2H,CH 2 ),3.88(s,3H,CH 3 ),3.84(s,3H,CH 3 ),2.07(s,3H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ167.81,163.92,162.77,159.54,154.92,145.34,139.28,130.64,128.69,127.10,122.60,119.32,117.71,114.85,114.09,105.94,97.63,55.26,54.92,50.05,23.47。
(21) (E) -2- (4- (3-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (3, 4-dimethoxybenzylidene) acethydrazide (YX-10) was prepared in the same manner as (L-01).
White solid, yield 54.32%. 1 H NMR(600MHz,DMSO-d6)δ11.80(s,1H,–N–H),10.08(s,1H,–N–H),8.52(s,1H,–N–CH＝),8.17(s,1H,Ar–H),8.00(s,1H,–N＝CH–),7.59(d,J＝7.7Hz,1H,Ar–H),7.50(d,J＝7.3Hz,1H,Ar–H),7.41(s,1H,Ar–H),7.38(t,J＝7.9Hz,1H,Ar–H),7.23(d,J＝6.7Hz,1H,Ar–H),7.02(d,J＝8.2Hz,1H,Ar–H),5.77(s,2H,CH 2 ),3.83(s,3H,CH 3 ),3.81(s,3H,CH 3 ),2.08(s,3H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ167.86,166.61,150.12,148.46,145.50,143.99,139.32,130.62,128.74,125.98,122.60,121.01,119.37,117.79,114.91,110.82,107.89,54.95,54.90,50.20,23.48。
(22) (E) -2- (4- (3-acetylaminophenyl) -1H-1,2, 3-triazol-1-yl) -N' - (3,4, 5-trimethoxybenzylidene) acetohydrazide (YX-11) was prepared in the same manner as (L-01).
An off-white solid in 58.21% yield. 1 H NMR(600MHz,DMSO-d6)δ11.90(s,1H,–N–H),10.05(s,1H,–N–H),8.51(s,1H,–N–CH＝),8.16(s,1H,Ar–H),7.99(s,1H,–N＝CH–),7.58(d,J＝8.0Hz,1H,Ar–H),7.49(d,J＝7.7Hz,1H,Ar–H),7.37(t,J＝7.9Hz,1H,Ar–H),7.08(s,2H,Ar–H),5.78(s,2H,CH 2 ),3.85(d,9H,CH 3 ),2.08(s,3H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ168.89,167.87,162.76,161.67,153.66,146.58,144.82,140.38,139.71,131.68,129.77,123.63,120.42,118.88,116.03,106.09,104.84,60.58,56.46,36.23,31.22,24.51。
Example 4 preparation of N- (3-ethynylphenyl) benzamide and its derivatives.
Figure BDA0002354733100000111
Dissolving 24.57mmol of benzoic acid or a derivative thereof in 15mL of acetonitrile in a reaction bottle, slowly dripping 29.48mmol of thionyl chloride into the reaction bottle, reacting at 60 ℃ for 3 hours under the catalysis of DMF, cooling to room temperature after the reaction is finished, distilling off the organic solvent under reduced pressure, taking out unreacted thionyl chloride with 10-15mL of dichloromethane in a rotating manner, dissolving the thionyl chloride with a small amount of dichloromethane, cooling in a cold well, slowly dripping m-aminophenylacetylene diluted by a small amount of dichloromethane, adding triethylamine in an amount which is the same as the amount of the dichloromethane, adding water after the reaction is finished, extracting the dichloromethane, drying the organic layer, and distilling off the solvent under reduced pressure to obtain the N- (3-ethynylphenyl) benzamide or derivative product.
Example 52 preparation of (2-azidoethoxy) ethan-1-ium.
Figure BDA0002354733100000112
59.88mmol of 2-ethyl bromoacetate is taken and dissolved in a reaction bottle by 40mL of dichloromethane, 77.84mmol of sodium azide is dissolved in 10mL of water and slowly poured into the reaction bottle for mixing, the mixture reacts for 12h at 40 ℃ under the catalysis of sodium iodide, after the reaction is finished, the mixture is cooled to room temperature, an aqueous layer is removed, an organic layer is dried and then the solvent is evaporated under reduced pressure, and 2- (2-azidoethoxy) ethane-1-onium is obtained as colorless and transparent liquid with the yield of 95%.
Example 6 was carried out.
The compound shown in the general formula II is synthesized by the following technical scheme.
Figure BDA0002354733100000113
(1) Preparation of 2- (4- (3-benzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-01).
Dissolving 18.08mmol of N- (3-ethynylphenyl) benzamide in 15mL of absolute ethanol, dissolving 1.25mmol of anhydrous copper sulfate and a small amount of vitamin C in 4mL of water, heating and shaking for 2min, pouring the aqueous solution into a reaction bottle, adding 17.32mmol of 2- (2-azidoethoxy) ethane-1-onium, reacting at 60 ℃ for 4H, evaporating the solvent under reduced pressure, adding 50mL of water, extracting with 15-20mL of ethyl acetate for 3 times, drying the organic layer, evaporating the solvent under reduced pressure to obtain the ethyl 2- (4- (3-benzoylamino) phenyl) -1H-1,2, 3-triazol-1-yl) acetate with the yield of 85.3%.
And (3) adding an alkaline water solution prepared from NaOH into the product obtained in the previous step, reacting at 40 ℃ for 5H, cooling to room temperature, adjusting the pH value to 2 with hydrochloric acid, separating out a solid, performing suction filtration, and drying to obtain the 2- (4- (3-benzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid with the yield of 96.7%.
White solid, yield 73.58%. 1 H NMR(600MHz,DMSO-d6)δ13.48(s,1H,O-H),10.37(s,1H,N-H),8.45(d,J＝63.4Hz,2H,Ar-H,N-CH＝),8.00(s,2H,Ar-H),7.60(t,J＝71.1Hz,6H Ar-H),5.40(d,J＝50.5Hz,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ169.08,166.09,146.69,140.24,135.32,132.09,131.55,129.71,128.86,128.17,123.26,121.10,120.30,117.54,51.39。
(2) The 2- (4- (3- (4-bromobenzoylamino) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-02) was prepared in the same manner as (N-01).
Off-white solid, yield 61.54%. 1 H NMR(600MHz,DMSO-d6)δ10.46(s,1H,O-H),8.56(s,1H,N-H),8.37(s,1H,N-CH＝),8.01–7.91(m,3H,Ar-H),7.77(d,J＝8.4Hz,3H,Ar-H),7.58(d,J＝7.5Hz,1H,Ar-H),7.45(t,J＝7.8Hz,1H,Ar-H),5.47(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ166.66,164.02,145.69,138.99,133.27,130.83,130.33,129.25,128.74,124.85,122.25,120.20,119.33,116.47,60.98。
(3) The 2- (4- (3- (3-chlorobenzoylamino) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-03) was prepared in the same manner as (N-01).
Light yellow solid, yield 58.21%. 1 H NMR(600MHz,DMSO-d6)δ10.53(s,1H,O-H),8.56(s,1H,N-H),8.38(t,J＝1.7Hz,1H,N-CH＝),8.09(t,J＝1.8Hz,1H,Ar-H),8.04–7.97(m,1H,Ar-H),7.87–7.79(m,1H,Ar-H),7.68(ddd,J＝8.0,2.0,1.0Hz,1H,Ar-H),7.64–7.54(m,2H,Ar-H),7.46(t,J＝7.9Hz,1H,Ar-H),5.37(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ169.03,164.59,146.67,139.98,137.23,133.70,131.92,131.52,130.86,129.76,127.96,127.03,123.31,121.35,120.40,117.60,51.17。
(4) Preparation of 2- (4- (3- (2-nitrobenzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-04) was carried out in the same manner as (N-01).
White solid, yield 51.23%. 1 H NMR(600MHz,DMSO-d6)δ10.80(s,1H,O-H),8.54(s,1H,N-H),8.27(s,1H,N-CH＝),8.16(d,J＝8.1Hz,1H,Ar-H),7.89(t,J＝7.5Hz,1H,Ar-H),7.79(ddd,J＝15.5,8.1,3.8Hz,2H,Ar-H),7.66–7.55(m,2H,Ar-H),7.45(t,J＝7.9Hz,1H,Ar-H),5.34(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ169.03,164.71,146.99,146.55,139.91,134.57,133.08,131.70,131.49,129.97,129.82,124.74,123.38,121.39,119.66,116.75,51.16。
(5)2- (4- (3- (4-hydroxybenzamido) phenyl) -1H-1,2, 3-triazole-1-yl) acetic acid (N-05) is prepared by the same method as (N-01).
White solid, yield 55.26%. 1 H NMR(600MHz,DMSO-d6)δ10.11(s,2H,O-H),8.51(s,1H,N-H),8.34(s,1H,N-CH＝),7.84(dd,J＝52.7,8.0Hz,4H,Ar-H),7.53(d,J＝7.4Hz,1H,Ar-H),7.41(t,J＝7.8Hz,1H,Ar-H),6.89(d,J＝8.3Hz,2H,Ar-H),5.34(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ169.06,165.67,161.14,146.80,140.54,131.41,130.23,129.63,125.72,123.22,120.72,120.26,117.48,115.42,51.22。
(6) Preparation of 2- (4- (3- (5-bromo-2-hydroxybenzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-06) was carried out in the same manner as (N-01).
Pale yellow solid, yield 79.54%. 1 H NMR(600MHz,DMSO-d6)δ11.99(s,1H,O-H),10.57(s,1H,O-H),8.58(s,1H,N-H),8.28(s,1H,N-CH＝),8.15(d,J＝2.5Hz,1H,Ar-H),7.71(dd,J＝8.1,1.1Hz,1H,Ar-H),7.66(dd,J＝8.8,2.6Hz,1H,Ar-H),7.63(s,1H,Ar-H),7.60(d,J＝2.5Hz,1H,Ar-H),7.58(d,J＝2.6Hz,1H,Ar-H),7.46(t,J＝7.9Hz,1H,Ar-H),7.08(d,J＝8.8Hz,1H,Ar-H),5.36(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ168.98,165.41,157.79,146.51,139.13,136.29,131.85,131.65,129.90,123.44,121.65,120.72,120.63,120.06,117.85,110.61,51.18。
(7)2- (4- (3- (3, 4-dimethoxybenzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-07) was prepared in the same manner as (N-01).
White solid, yield 57.65%. 1 H NMR(600MHz,DMSO-d6)δ10.34(s,1H,O-H),8.56(s,1H,N-H),8.37(s,1H,N-CH＝),7.85(dd,J＝8.1,1.1Hz,1H,Ar-H),7.72(dd,J＝8.4,2.0Hz,1H,Ar-H),7.65(d,J＝2.0Hz,1H,Ar-H),7.56(d,J＝7.8Hz,1H,Ar-H),7.43(t,J＝7.9Hz,1H,Ar-H),7.10(d,J＝8.5Hz,1H,Ar-H),5.37(s,2H,CH 2 ),3.88(s,3H,CH 3 ),3.85(s,3H,CH 3 )。
13 C NMR(150MHz,DMSO-d6)δ169.03,165.43,152.11,148.71,146.75,140.41,131.38,129.63,127.24,123.29,121.70,120.85,120.50,117.69,111.58,111.35,56.14,51.17。
(8) Preparation of 2- (4- (3- (2-fluorobenzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-08) was carried out in the same manner as (N-01).
White solid, yield 51.20%. 1 H NMR(600MHz,DMSO-d6)δ13.48(s,1H,O-H),10.54(s,1H,N-H),8.54(s,1H,N-CH＝),8.33(s,1H,Ar-H),7.76–7.67(m,2H,Ar-H),7.64–7.55(m,2H,Ar-H),7.44(t,J＝7.9Hz,1H,Ar-H),7.35(dt,J＝7.5,5.2Hz,2H,Ar-H),5.35(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ169.06,163.39,160.63,158.16,146.62,139.92,133.06,131.65,130.41,129.90,125.02,123.34,121.31,119.74,116.89,116.54,51.17。
(9) Preparation of 2- (4- (3- (3-fluorobenzamido) phenyl) -1H-1,2, 3-triazol-1-yl) acetic acid (N-09) was carried out in the same manner as (N-01).
White solid, yield 55.37%. 1 H NMR(600MHz,DMSO-d6)δ13.50(s,1H,O-H),10.50(s,1H,N-H),8.56(s,1H,N-CH＝),8.38(s,1H,Ar-H),7.89(d,J＝7.9Hz,1H,Ar-H),7.87–7.83(m,1H,Ar-H),7.82(dd,J＝8.1,1.1Hz,1H,Ar-H),7.64–7.57(m,2H,Ar-H),7.50–7.43(m,2H,Ar-H),5.36(s,2H,CH 2 )。
13 C NMR(150MHz,DMSO-d6)δ168.05,145.59,138.92,130.46,130.03,129.97,128.72,123.38,122.26,120.25,119.30,116.49,114.05,113.90,50.15。
Example 7 in vitro kinase activity assay was performed.
The screening method comprises the following steps: cell-free assay for c-Met kinase activity.
The inhibitory activity of the inhibitors on c-Met compounds was determined using an ADP-Glo assay. The reaction buffer was passed through 50mM HEPES, pH 7.5, 10mM MgCl 2 0.1mg/mL BSA, 2mM DTT and 1% DMSO. Reaction buffer (50mM HEPES, pH 7.5, 10mM MgCl) was used 2 、0.1mg/mL BSA，2mMDTT, 1% DMSO) the recombinant c-Met kinase was diluted to 2.2 μ g/mL and ATP (10mM) was diluted to 250 μ M with reaction buffer, and the test compound and positive drug (GSK1363089) were formulated as four concentration gradient solutions (6 × 10) -2 M，6×10 -4 M，6×10 -6 M，6×10 -8 M), the reaction was started by adding 2 μ LATP solution, 1 μ L drug solution and 2 μ L enzyme solution in order to 96 wells. The assay was performed at 37 ℃ for 1h and incubated at room temperature for 40 min before adding 5. mu.LADP-Glo reagent. 10 μ L of kinase detection reagent was added and incubated at room temperature for 30 minutes, and then the luminescence value was measured using the chemiluminescence module of a full-wavelength multifunctional microplate reader.
TABLE 1 c-Met kinase Activity List
Figure BDA0002354733100000141
Figure BDA0002354733100000151
Note: in the upper panel-indicates no inhibitory activity.

Claims (3)

1.一种2-（4-苯基-1H-1,2,3-三唑-1-基）乙酸或乙酰肼类化合物或其药学上可接受的盐，所述化合物选自下述任一种：1. A 2-(4-phenyl-1H-1,2,3-triazol-1-yl) acetic acid or acetyl hydrazide compound or a pharmaceutically acceptable salt thereof, the compound is selected from any of the following: A sort of: （E）-N' - （3-氯亚苄基）-2-（4-苯基 - 1H-1,2,3-三唑-1-基）乙酰肼；( E ) -N' -(3-chlorobenzylidene)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetohydrazide; （E）-N' - （4-羟基亚苄基）-2-（4-苯基 - 1H-1,2,3-三唑-1-基）乙酰肼；( E ) -N' -(4-hydroxybenzylidene)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetohydrazide; （E）-N' - （2-硝基亚苄基）-2-（4-苯基 - 1H-1,2,3-三唑-1-基）乙酰肼；( E ) -N' -(2-nitrobenzylidene)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetohydrazide; （E）-N' - （5-氯-2-羟基亚苄基）-2-（4-苯基 - 1H-1,2,3-三唑-1-基）乙酰肼；( E ) -N' -(5-chloro-2-hydroxybenzylidene)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetohydrazide; （E）-N' - （3,5-二溴-2-羟基亚苄基）-2-（4-苯基 - 1H-1,2,3-三唑-1-基）乙酰肼；( E ) -N' -(3,5-dibromo-2-hydroxybenzylidene)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetohydrazide; （E）-N' - （5-溴-2-羟基亚苄基）-2-（4-苯基 - 1H-1,2,3-三唑-1-基）乙酰肼；( E ) -N' -(5-bromo-2-hydroxybenzylidene)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetohydrazide; （E）-N' - （3,4-二甲氧基亚苄基）-2-（4-苯基 - 1H-1,2,3-三唑-1-基）乙酰肼；( E ) -N' -(3,4-dimethoxybenzylidene)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetohydrazide; （E）-2-（4-苯基 - 1H-1,2,3-三唑-1-基）-N' - （3,4,5- 三甲氧基亚苄基）乙酰肼；( E )-2-(4-phenyl-1H-1,2,3-triazol-1-yl) -N' -(3,4,5-trimethoxybenzylidene)acetylhydrazide; （E）-2-（4-（3-乙酰氨基苯基）-1H-1,2,3-三唑-1-基）-N' - （4-氯亚苄基）乙酰肼；( E )-2-(4-(3-acetamidophenyl)-1H-1,2,3-triazol-1-yl) -N' -(4-chlorobenzylidene)acetylhydrazide; （E）-2-（4-（3-乙酰氨基苯基）-1H-1,2,3-三唑-1-基）-N' - （3-氯亚苄基）乙酰肼；( E )-2-(4-(3-acetamidophenyl)-1H-1,2,3-triazol-1-yl) -N' -(3-chlorobenzylidene)acetylhydrazide; （E）-2-（4-（3-乙酰氨基苯基）-1H-1,2,3-三唑-1-基）-N' - （4-羟基亚苄基）乙酰肼；( E )-2-(4-(3-acetamidophenyl)-1H-1,2,3-triazol-1-yl) -N' -(4-hydroxybenzylidene)acetylhydrazide; （E）-2-（4-（3-乙酰氨基苯基）-1H-1,2,3-三唑-1-基）-N' - （2-羟基亚苄基）乙酰肼；( E )-2-(4-(3-acetamidophenyl)-1H-1,2,3-triazol-1-yl) -N' -(2-hydroxybenzylidene)acetylhydrazide; （E）-2-（4-（3-乙酰氨基苯基）-1H-1,2,3-三唑-1-基）-N' - （2-硝基亚苄基）乙酰肼；( E )-2-(4-(3-acetamidophenyl)-1H-1,2,3-triazol-1-yl) -N' -(2-nitrobenzylidene)acetylhydrazide; （E）-2-（4-（3-乙酰氨基苯基）-1H-1,2,3-三唑-1-基）-N' - （5-氯-2-羟基亚苄基）乙酰肼；( E )-2-(4-(3-Acetylaminophenyl)-1H-1,2,3-triazol-1-yl) -N' -(5-chloro-2-hydroxybenzylidene)acetyl Hydrazine; （E）-2-（4-（3-乙酰氨基苯基）-1H-1,2,3-三唑-1-基）-N' - （3,5-二溴-2-羟基亚苄基）乙酰肼；( E )-2-(4-(3-acetamidophenyl)-1H-1,2,3-triazol-1-yl) -N' -(3,5-dibromo-2-hydroxybenzylidene) base) acetyl hydrazide; （E）-2-（4-（3-乙酰氨基苯基）-1H-1,2,3-三唑-1-基）-N' - （3,4-二甲氧基亚苄基）乙酰肼；( E )-2-(4-(3-acetamidophenyl)-1H-1,2,3-triazol-1-yl) -N' -(3,4-dimethoxybenzylidene) Acetylhydrazine; （E）-2-（4-（3-乙酰氨基苯基）-1H-1,2,3-三唑-1-基）-N' - （3,4,5-三甲氧基亚苄基）乙酰肼；( E )-2-(4-(3-acetamidophenyl)-1H-1,2,3-triazol-1-yl) -N' -(3,4,5-trimethoxybenzylidene ) acetyl hydrazide; 2-（4-（3-（4-溴苯甲酰胺基）苯基）-1H-1,2,3-三唑-1-基）乙酸；2-(4-(3-(4-Bromobenzamido)phenyl)-1H-1,2,3-triazol-1-yl)acetic acid; 2-（4-（3-（3-氯苯甲酰胺基）苯基）-1H-1,2,3-三唑-1-基）乙酸；2-(4-(3-(3-Chlorobenzamido)phenyl)-1H-1,2,3-triazol-1-yl)acetic acid; 2-（4-（3-（4-羟基苯甲酰胺基）苯基）-1H-1,2,3-三唑-1-基）乙酸；2-(4-(3-(4-Hydroxybenzamido)phenyl)-1H-1,2,3-triazol-1-yl)acetic acid; 2-（4-（3-（5-溴-2-羟基苯甲酰胺基）苯基）-1H-1,2,3-三唑-1-基）乙酸。2-(4-(3-(5-Bromo-2-hydroxybenzamido)phenyl)-1H-1,2,3-triazol-1-yl)acetic acid. 2.一种药物组合物，其特征在于，该药物组合物包括权利要求1所述的2-（4-苯基-1H-1,2,3-三唑-1-基）乙酸或乙酰肼类化合物或其药学上可接受的盐，及药学上可接受的载体。2. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises the 2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetic acid or acetylhydrazide of claim 1 compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 3.权利要求1所述的2-（4-苯基-1H-1,2,3-三唑-1-基）乙酸或乙酰肼类化合物或其药学上可接受的盐或如权利要求2所述的药物组合物在制备抗肿瘤药物中的应用。3. The 2-(4-phenyl-1H-1,2,3-triazol-1-yl) acetic acid or acetylhydrazide compound of claim 1 or a pharmaceutically acceptable salt thereof or as claimed in claim 2 The application of the pharmaceutical composition in the preparation of antitumor drugs.
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