CN111454170A - Acetanilide compound and preparation method and application thereof - Google Patents
Acetanilide compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN111454170A CN111454170A CN202010296780.4A CN202010296780A CN111454170A CN 111454170 A CN111454170 A CN 111454170A CN 202010296780 A CN202010296780 A CN 202010296780A CN 111454170 A CN111454170 A CN 111454170A
- Authority
- CN
- China
- Prior art keywords
- compound
- acetanilide
- acid
- mmol
- acetanilide compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention relates to an acetanilide compound and a preparation method and application thereof, belonging to the technical field of organic synthesis, and the invention provides an acetanilide compound with antitumor activity, a preparation method and application thereof, which effectively solve the preparation problem of the acetanilide compound with antitumor activity.
Description
Technical Field
The invention relates to an acetanilide compound and a preparation method and application thereof, belonging to the technical field of organic synthesis.
Background
Acetanilide compounds are nitrogen-containing heterocyclic compounds with biological and pharmaceutical activities, and are important structural skeletons of certain natural products and medicines, the acetanilide compounds are structural units of a plurality of natural products and medicine synthesis, and most importantly, a plurality of heterocyclic compounds have biological activities, such as local anesthetic otacaine (octacaine), Etidocaine (Etidocaine) amide local anesthetic, analgesic Phenacetin (Phenacetin), β 1 receptor blocker Acebutolol (Acebutol), and anilide antipyretic analgesic Bucetin (Bucetin).
The development of a new green and environment-friendly synthesis process becomes a new interest of modern drug synthesis researchers. In recent years, methods for synthesizing acetanilide-containing compounds have been reported, and these conventional methods require complicated conditions, i.e., complicated synthesis steps, addition of a noble metal catalyst, requirement of environmentally unfriendly raw materials, long reaction time, and the like.
The invention provides a novel method for synthesizing acetanilide compounds, and synthesizes 12 acetanilide novel compounds which are not reported in documents. The method has the advantages of environmental protection, simplicity, high efficiency, mild conditions, high yield and the like; the synthesis of the compound selects a cheap and easily available 1, 4-dioxane compound which is not reported as an acylation reagent, and has original innovativeness and high application value.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides an acetanilide compound and a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the technical scheme that: an acetanilide compound, the structure of which is shown in a general formula I:
wherein R is selected from hydrogen and C1～C4A hydrocarbon group of1～C4Alkoxy, halogen, hydroxy, aryl, ester, nitro or 3, 5-dimethyl.
As a preferred embodiment of the acetanilide compound of the present invention, the compound C1～C4The hydrocarbon group of (A) is-CH3or-C (CH)3)3。
As a preferred embodiment of the acetanilide compound of the present invention, the compound C1～C4Alkoxy of is-OCH3。
As a preferred embodiment of the acetanilide compound of the invention, the ester group is-COOCH2CH3。
In a preferred embodiment of the acetanilide compound of the present invention, the acetanilide compound has a structure of:
in a second aspect, the present invention provides a method for preparing the acetanilide compound, which comprises the following steps:
adding the compound 1 and 1, 4-dioxane into a reactor, adding an oxidant and acid, and stirring for reaction to obtain the acetanilide compound.
As a preferred embodiment of the process for producing an acetanilide compound of the present invention, the molar ratio of the compound 1 to 1, 4-dioxane is 1: (10-20), wherein the molar ratio of the compound 1 to the oxidant is 1: (0.5-2), wherein the molar ratio of the compound 1 to the acid is 1: (0.1 to 1).
Preferably, the molar ratio of compound 1 to 1, 4-dioxane is 1: 10.
as a preferable embodiment of the preparation method of the acetanilide compound, the reaction temperature is 80-160 ℃, and the reaction time is 1-24 hours.
In a preferred embodiment of the method for producing an acetanilide compound of the present invention, the oxidizing agent is at least one of hydrogen peroxide, peracetic acid, di-t-butyl peroxide, t-butyl hydroperoxide, 2,6, 6-tetramethylpiperidine oxide, and ammonium persulfate, and the acid is at least one of m-chloroperoxybenzoic acid, trifluoromethanesulfonic acid, hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid, and acetic acid.
As a preferable embodiment of the method for producing the acetanilide compound of the present invention, the reaction solution is cooled to room temperature after the completion of the reaction, the reaction solution is diluted, filtered, and the solvent is removed by rotary evaporation under reduced pressure to obtain a crude product, which is purified by column chromatography to obtain the acetanilide compound.
Preferably, the reactor is a schlenk tube (schlenk tube) and the reaction is carried out under air conditions.
Preferably, the eluent used for column chromatography purification is petroleum ether: dichloromethane: the volume ratio of the ethyl acetate is (0.5-50): (0-20): 1.
In a third aspect, the invention provides an application of the acetanilide compound in preparing an antitumor drug.
Preferably, the anti-tumor drug is a drug for resisting human promyelocytic acute leukemia cell H L60 and human cervical cancer Hela cell.
Compared with the prior art, the acetanilide compound with the anti-tumor activity, the preparation method and the application thereof have the beneficial effects that the acetanilide compound with the anti-tumor activity, and the preparation method and the application thereof are provided, so that the problem of preparing the acetanilide compound with the anti-tumor activity is effectively solved.
Drawings
FIG. 1 is a hydrogen spectrum of product 2a obtained in example 1.
FIG. 2 is a carbon spectrum of the product 2a obtained in example 1.
FIG. 3 is a hydrogen spectrum of the product 2b obtained in example 2.
FIG. 4 is a carbon spectrum of the product 2b obtained in example 2.
FIG. 5 is a hydrogen spectrum of the product 2c obtained in example 3.
FIG. 6 is a carbon spectrum of the product 2c obtained in example 3.
FIG. 7 is a hydrogen spectrum of product 2d obtained in example 4.
FIG. 8 is a carbon spectrum of the product 2d obtained in example 4.
FIG. 9 is a hydrogen spectrum of product 2e obtained in example 5.
FIG. 10 is a carbon spectrum of the product 2e obtained in example 5.
FIG. 11 is a hydrogen spectrum of the product 2f obtained in example 6.
FIG. 12 is a carbon spectrum of the product 2f obtained in example 6.
FIG. 13 is a hydrogen spectrum of 2g of the product obtained in example 7.
FIG. 14 is a chart showing a carbon spectrum of 2g of the product obtained in example 7.
FIG. 15 is a hydrogen spectrum of the product obtained in example 8 for 2 h.
FIG. 16 is a carbon spectrum of the product obtained in example 8 for 2 h.
FIG. 17 is a hydrogen spectrum of product 2i obtained in example 9.
FIG. 18 is a carbon spectrum of product 2i obtained in example 9.
FIG. 19 is a hydrogen spectrum of product 2j obtained in example 10.
FIG. 20 is a carbon spectrum of product 2j obtained in example 10.
FIG. 21 is a hydrogen spectrum of product 2k obtained in example 11.
FIG. 22 is a carbon spectrum of product 2k obtained in example 11.
FIG. 23 is a hydrogen spectrum of 2l, a product obtained in example 12.
FIG. 24 is a carbon spectrum of 2l, a product obtained in example 12.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1
Adding 0.5 mmol of aniline, 5 mmol of 1, 4-dioxane, 0.25 mmol of di-tert-butyl peroxide and 0.05 mmol of trifluoroacetic acid into a reactor, stirring and reacting at 80 ℃ for 16 hours, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, decompressing and carrying out rotary evaporation to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain the 2- (2-hydroxyether) -N-phenylacetamide compound 2 a.
The hydrogen spectrum and the carbon spectrum of the obtained product 2a are respectively shown in fig. 1 and fig. 2, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)8.83(s,1H),7.59(d,J＝8.0Hz,2H),7.31(t,J＝7.8Hz,2H),7.11(t,J＝7.4Hz,1H),4.10(s,2H),3.87–3.83(m,2H),3.72–3.69(m,2H)；
13C NMR(101MHz,CDCl3)168.23,137.30,128.98,124.55,119.95,73.17,70.54,61.48；
HRMS(ESI):Calcd.for C10H14NO3[M+H]+:196.0968；found:196.0961。
from the above data it is concluded that the structure of the resulting product 2a is shown below:
example 2
Adding 0.5 mmol of 4-methylaniline, 10 mmol of 1, 4-dioxane, 1 mmol of hydrogen peroxide and 0.05 mmol of m-chloroperoxybenzoic acid into a reactor, stirring and reacting at 100 ℃ for 16 hours, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, decompressing and carrying out rotary evaporation to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain the 2- (2-hydroxyether) -N- (p-tolyl) acetamide compound 2 b.
The hydrogen spectrum and the carbon spectrum of the obtained product 2b are respectively shown in fig. 3 and 4, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)8.67(s,1H),7.38(d,J＝8.3Hz,2H),7.03(d,J＝8.2Hz,2H),4.02(s,2H),3.79–3.73(m,2H),3.64–3.60(m,2H),2.23(s,3H)；
13C NMR(101MHz,CDCl3)168.04,134.73,134.16,129.46,119.98,73.16,70.55,61.48,20.87；
HRMS(ESI):Calcd.for C11H16NO3[M+H]+:210.1125；found:210.1113。
the structure of the resulting product 2b is deduced from the above data as shown in the following formula:
example 3
Adding 0.5 mmol of 3-methoxyaniline, 10 mmol of 1, 4-dioxane, 0.5 mmol of peroxyacetic acid and 0.5 mmol of trifluoromethanesulfonic acid into a reactor, stirring at 160 ℃ for reaction for 16 hours, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain the 2- (2-hydroxyethoxy) -N- (3-methoxyphenyl) acetamide compound 2 c.
The hydrogen spectrum and the carbon spectrum of the obtained product 2c are respectively shown in fig. 5 and 6, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)8.78(s,1H),7.33(s,1H),7.20(t,J＝8.1Hz,1H),7.08(d,J＝7.9Hz,1H),6.67(d,J＝8.2Hz,1H),4.10(s,2H),3.88–3.83(m,2H),3.79(s,3H),3.73–3.70(m,2H).
13C NMR(101MHz,CDCl3)168.19,160.12,138.52,129.67,112.13,110.29,105.71,73.18,70.56,61.51,55.32.
HRMS(ESI):Calcd.for C11H16NO4[M+H]+:226.1074；found:226.1063。
the structure of the resulting product 2c is deduced from the above data as shown in the following formula:
example 4
Adding 0.5 mmol of 4-tert-butyl aniline and 8 mmol of 1, 4-dioxane, 0.25 mmol of di-tert-butyl peroxide and 0.5 mmol of hydrochloric acid into a reactor, stirring and reacting at 120 ℃ for 24 hours, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, decompressing and distilling to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain the N- (4- (tert-butyl) phenyl) -2- (2-hydroxyethoxy) acetamide compound 2 d.
The hydrogen spectrum and the carbon spectrum of the obtained product 2d are respectively shown in fig. 7 and 8, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)8.73(s,1H),7.50(d,J＝8.4Hz,2H),7.33(d,J＝8.4Hz,2H),4.10(s,2H),3.88–3.81(m,2H),3.84(d,J＝4.3Hz,1H),3.74–3.69(m,2H),1.30(s,9H).
13C NMR(101MHz,CDCl3)168.03,147.53,134.64,125.79,119.74,73.15,70.57,61.52,34.38,31.36.
HRMS(ESI):Calcd.for C14H22NO3[M+H]+:252.1594；found:252.1599。
the structure of the resulting product 2d was deduced from the above data to be shown in the following formula:
example 5
Adding 0.5 mmol of 2-hydroxyaniline, 5 mmol of 1, 4-dioxane, 0.5 mmol of tert-butyl hydroperoxide and 0.25 mmol of p-toluenesulfonic acid into a reactor, stirring and reacting for 5 hours at 150 ℃, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, decompressing and distilling to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain the 2- (2-hydroxyethoxy) -N- (2-hydroxypropyl) acetamide compound 2 e.
The hydrogen spectrum and the carbon spectrum of the obtained product 2e are respectively shown in fig. 9 and fig. 10, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)9.11(s,1H),7.20(d,J＝7.8Hz,1H),7.10(dd,J＝11.1,4.3Hz,1H),6.99(d,J＝8.1Hz,1H),6.84(t,J＝7.6Hz,1H),4.14(s,2H),3.88–3.81(m,2H),3.73–3.70(m,2H).
13C NMR(101MHz,CDCl3)169.79,127.19,124.94,122.51,120.44,73.26,70.08,61.46.
HRMS(ESI):Calcd.for C10H14NO4[M+H]+:212.0917；found:212.0906。
the structure of the resulting product 2e is deduced from the above data as shown in the following formula:
example 6
Adding 0.5 mmol of 4-fluoroaniline, 10 mmol of 1, 4-dioxane, 0.25 mmol of 2,2,6, 6-tetramethylpiperidine oxide and 0.5 mmol of acetic acid into a reactor, stirring and reacting at 80 ℃ for 20 hours, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product, and carrying out column chromatography purification on the crude product to obtain the N- (4-fluorophenyl) -2- (2-hydroxyethoxy) acetamide compound 2 f.
The hydrogen spectrum and the carbon spectrum of the obtained product 2f are respectively shown in fig. 11 and 12, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)8.91(s,1H),7.56(dd,J＝8.8,4.8Hz,2H),7.01(t,J＝8.6Hz,1H),4.12(s,2H),3.86(d,J＝4.3Hz,2H),3.73(d,J＝4.5Hz,2H)..
13C NMR(101MHz,CDCl3)168.25,159.49(d,J＝243.6Hz),133.37(d,J＝2.7Hz),121.68(d,J＝7.9Hz),115.59(d,J＝22.6Hz),73.17,70.45,61.47.
19F NMR(376MHz,CDCl3)-117.75.
HRMS(ESI):Calcd.for C10H13FNO3[M+H]+:214.0874；found:214.0880。
the structure of the resulting product 2f is deduced from the above data as shown in the following formula:
example 7
Adding 0.5 mmol of 4-chloroaniline, 5 mmol of 1, 4-dioxane, 1 mmol of di-tert-butyl peroxide and 0.5 mmol of m-chloroperoxybenzoic acid into a reactor, stirring and reacting at 80 ℃ for 24 hours, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain 2g of N- (4-chlorophenyl) -2- (2-hydroxyethoxy) acetamide compound.
The hydrogen spectrum and the carbon spectrum of the obtained product 2g are respectively shown in fig. 13 and 14, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)8.99(s,1H),7.54(d,J＝8.5Hz,2H),7.25(d,J＝8.5Hz,2H),4.09(d,J＝4.0Hz,2H),3.83(d,,J＝3.6Hz,2H),3.69(d,J＝3.6Hz,2H),2.93(s,1H).
13C NMR(101MHz,CDCl3)168.50,135.92,129.50,128.96,121.20,73.18,70.44,61.40.
HRMS(ESI):Calcd.for C10H13ClNO3[M+H]+:230.0579；found:230.0566。
from the above data it is concluded that the structure of 2g of the product obtained is shown below:
example 8
Adding 0.5 mmol of 3-bromoaniline and 5 mmol of 1, 4-dioxane, 0.5 mmol of di-tert-butyl peroxide and 0.05 mmol of trifluoroacetic acid into a reactor, stirring and reacting for 4 hours at 150 ℃, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, decompressing and rotary evaporating to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain the N- (3-bromophenyl) -2- (2-hydroxyethoxy) acetamide compound for 2 hours.
The hydrogen spectrum and the carbon spectrum of the obtained product 2h are respectively shown in fig. 15 and 16, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)8.91(s,1H),7.82(t,J＝1.8Hz,1H),7.54(d,J＝8.0Hz,1H),7.24(d,J＝8.1Hz,1H),7.17(t,J＝8.0Hz,1H),4.12(s,2H),3.91–3.85(m,2H),3.76–3.71(m,2H).
13C NMR(101MHz,CDCl3)168.34,138.66,130.28,127.45,122.71,118.33,73.16,70.48,61.53.
HRMS(ESI):Calcd.for C10H13BrNO3[M+H]+:274.0073；found:274.0068。
the structure of the resulting product 2h is deduced from the above data as shown in the following formula:
example 9
Adding 0.5 mmol of 4-phenylaniline, 6 mmol of 1, 4-dioxane, 0.25 mmol of ammonium persulfate and 0.5 mmol of trifluoromethanesulfonic acid into a reactor, stirring at 110 ℃ for 18 hours for reaction, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, decompressing and distilling to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain the N- ([1,1' -biphenyl ] -4-yl) -2- (2-hydroxyethyoxy) acetamide compound 2 i.
The hydrogen spectrum and the carbon spectrum of the obtained product 2i are respectively shown in fig. 17 and fig. 18, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)8.79(s,1H),7.68(d,J＝8.5Hz,2H),7.57(d,J＝6.7Hz,4H),7.43(t,J＝7.6Hz,2H),7.33(t,J＝7.4Hz,1H),4.16(s,2H),3.90(t,J＝4.7Hz,2H),3.80–3.75(t,J＝4.7Hz,2H).
13C NMR(101MHz,CDCl3)167.98,140.53,137.39,136.64,128.78,127.64,127.13,126.86,120.11,73.14,70.62,61.65,29.70.
HRMS(ESI):Calcd.for C16H18NO3[M+H]+:272.1281；found:272.1282。
the structure of the resulting product 2i is deduced from the above data as shown in the following formula:
example 10
Adding 0.5 mmol of 2-nitroaniline, 10 mmol of 1, 4-dioxane, 0.5 mmol of hydrogen peroxide and 0.5 mmol of p-toluenesulfonic acid into a reactor, stirring and reacting at 100 ℃ for 12 hours, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, decompressing and carrying out rotary evaporation to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain the 2- (2-hydroxyethoxy) -N- (2-nitrophenyl) acetamide compound 2 j.
The hydrogen spectrum and the carbon spectrum of the obtained product 2j are respectively shown in fig. 19 and fig. 20, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)9.11(s,1H),7.20(d,J＝7.8Hz,1H),7.10(t,J＝7.7Hz,1H),6.99(d,J＝8.1Hz,1H),6.84(t,J＝7.6Hz,1H),4.14(s,2H),3.88–3.82(m,2H),3.73–3.70(m,2H).
13C NMR(101MHz,CDCl3)169.79,127.19,124.94,122.51,120.44,73.26,70.08,61.46.
HRMS(ESI):Calcd.for C10H13N2O5[M+H]+:241.0819；found:241.0815。
the structure of the resulting product 2j is deduced from the above data as shown in the following formula:
example 11
Adding 0.5 mmol of 3-Ethyl formate aniline and 10 mmol of 1, 4-dioxane, 0.5 mmol of di-tert-butyl peroxide and 0.5 mmol of acetic acid into a reactor, stirring and reacting at 120 ℃ for 16 hours, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, decompressing and distilling to remove the solvent to obtain a crude product, and purifying the crude product by column chromatography to obtain the Ethyl3- (2- (2-hydroxyethoxy) acetamido) benzoate compound 2 k.
The hydrogen spectrum and the carbon spectrum of the obtained product 2k are respectively shown in fig. 21 and 22, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)9.04(s,1H),8.05(s,1H),8.01(d,J＝8.2Hz,1H),7.77(d,J＝7.7Hz,1H),7.38(t,J＝7.9Hz,1H),4.36(q,J＝7.1Hz,2H),4.14(s,2H),3.97–3.86(m,2H),3.77–3.73(m,2H),1.38(t,J＝7.1Hz,3H).
13C NMR(101MHz,CDCl3)168.46,166.38,137.61,131.14,129.10,125.42,124.30,120.68,73.21,70.53,61.49,61.21,14.29.
HRMS(ESI):Calcd.for C13H18NO5[M+H]+:268.1179；found:268.1183。
the structure of the resulting product 2k is deduced from the above data as shown in the following formula:
example 12
Adding 0.5 mmol of 3, 5-dimethylaniline, 5 mmol of 1, 4-dioxane, 0.5 mmol of di-tert-butyl peroxide and 0.05 mmol of trifluoroacetic acid into a reactor, stirring at 120 ℃ for reaction for 6 hours, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, carrying out reduced pressure rotary evaporation to remove the solvent to obtain a crude product, and carrying out column chromatography purification on the crude product to obtain 2l of the N- (3,5-dimethyl phenyl) -2- (2-hydroxyethoxy) acetamide compound.
The hydrogen spectrum and the carbon spectrum of the obtained product 2l are respectively shown in fig. 23 and 24, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3)8.59(s,1H),7.22(s,2H),6.77(s,1H),4.10(s,2H),3.87–3.84(m,2H),3.73–3.70(m,2H),2.29(s,6H).
13C NMR(101MHz,CDCl3)167.89,138.71,137.08,126.30,117.63,73.12,70.61,61.56,21.36.
HRMS(ESI):Calcd.for C12H18NO3[M+H]+:224.1281；found:224.1288。
from the above data it is concluded that the structure of the resulting product 2l is shown below:
examples of effects
The antitumor activity of 2 a-2 l of the novel compounds obtained in examples 1-12 was tested by formulating each compound to 100. mu.g.m L-1The positive control drug 5-fluorouracil (5-fluorouricil, 5-FU) is prepared into 100 mu g.m L-1The inhibition of each compound on human leukemia cells K562, human promyelocytic acute leukemia cells H L60 and human cervical cancer Hela cells was tested by the tetramethylazozolium (MTT) method using methanol and DMSO solvents as blank controls, respectively, as follows:
(1) the cell culture solution is prepared by collecting a bag of RPMI-1640 culture medium powder (net content of 10.4g) and pouring into a clean beaker, dissolving with 900m L ultra-pure water, and adding 100mg m L-1Streptomycin 1m L, penicillin 0.5m L and NaHCO32g, after magnetic stirring, using a Zeiss filter sterilized by high pressure in an ultra-clean bench to filter and sterilize by a filter membrane of 0.22 mu m, directly storing the filtrate in a glass bottle (450m L/bottle) sterilized by damp heat, before using the culture medium, taking the frozen serum, inactivating the serum at 56 ℃ for 30min, adding the inactivated serum into the prepared RPMI-1640 culture solution (adding 50m L serum into 450m L culture medium), shaking up gently, covering, sealing by tinfoil paper, and storing in a refrigerator of 4 ℃.
Preparation of MTT solution 50mg of MTT powder was dissolved in 10m L of PBS solution, filtered through a 0.22 μm filter and stored in a refrigerator at 4 ℃.
(2) Antitumor activity experiment comprises respectively centrifuging K562, H L60 and Hela cells in logarithmic growth phase at 4 deg.C and 3000rpm for 3min, removing supernatant, adding fresh RPMI-1640 culture medium, and diluting to 1 × 105Cell suspension/ml 200. mu. L per well was seeded in 96-well plates at 37 ℃ with 5% CO2After culturing for 1h in the cell culture box, each well is respectively added with 2 mu L sample solution, each sample is provided with 3 parallel wells, two groups of blank controls with three wells are additionally arranged, after adding the samples and culturing for 24 h.24h under the same conditions, the cells are observed under an optical microscope to determine whether the samples have cytotoxic activity preliminarily, photographing is carried out if necessary, and 5 mg.m L is added into each well-120 mu L of MTT solution, culturing for 4h, centrifuging 96-well plate (4 deg.C, 2000rpm, 20min), adding 150 mu L DMSO to each well, shaking sufficiently to dissolve the purple precipitate completely, measuring optical density OD at 570nm on a microplate reader, averaging each group of samples, and determining inhibition (inhibition, IR)% (OD)Blank space-ODSample (I))/ODBlank space× 100% formula calculation.
The results of testing the proliferation activity of the acetanilide compounds on K562, H L60 and Hela cells by the MTT method are shown in Table 1.
TABLE 1
As can be seen from Table 1, the compound prepared by the scheme of the invention has certain inhibition effect on K562, H L60 and He L a cells, wherein the inhibition effect of the compound 2K on the K562, H L60 and He L a cells is equivalent to that of 5-FU.
In conclusion, the acetanilide compound provided by the invention has an inhibiting effect on tumors, and the preparation scheme of the scheme is environment-friendly and good in economic benefit, and has a good production and application prospect.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. An acetanilide compound, which is characterized in that the structure of the acetanilide compound is shown as a general formula I:
wherein R is selected from hydrogen and C1～C4A hydrocarbon group of1～C4Alkoxy, halogen, hydroxy, aryl, ester, nitro or 3, 5-dimethyl.
2. The acetanilide compound of claim 1 wherein C is1～C4The hydrocarbon group of (A) is-CH3or-C (CH)3)3。
3. The acetanilide compound of claim 1 wherein C is1～C4Alkoxy of is-OCH3。
4. The acetanilide compound of claim 1 wherein the ester group is-COOCH2CH3。
5. The acetanilide compound of claim 1, wherein the acetanilide compound has the structure:
6. a process for the preparation of an acetanilide compound according to any one of claims 1 to 5 comprising the steps of:
adding the compound 1 and 1, 4-dioxane into a reactor, adding an oxidant and acid, and stirring for reaction to obtain the acetanilide compound.
7. The process for preparing an acetanilide compound according to claim 6, wherein the molar ratio of compound 1 to 1, 4-dioxane is 1: (10-20), wherein the molar ratio of the compound 1 to the oxidant is 1: (0.5-2), wherein the molar ratio of the compound 1 to the acid is 1: (0.1 to 1).
8. The method for preparing acetanilide compounds according to claim 6, wherein the reaction temperature is 80 to 160 ℃ and the reaction time is 1 to 24 hours.
9. The method for producing an acetanilide compound according to claim 6, wherein the oxidizing agent is at least one of hydrogen peroxide, peracetic acid, di-t-butyl peroxide, t-butyl hydroperoxide, 2,6, 6-tetramethylpiperidine oxide, and ammonium persulfate, and the acid is at least one of m-chloroperoxybenzoic acid, trifluoromethanesulfonic acid, hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid, and acetic acid.
10. Use of the acetanilide compound according to any one of claims 1 to 5 in the preparation of an antitumor medicament.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010296780.4A CN111454170B (en) | 2020-04-15 | 2020-04-15 | Acetanilide compound and preparation method and application thereof |
| PCT/CN2020/096245 WO2021208223A1 (en) | 2020-04-15 | 2020-06-16 | Acetanilide compound, preparation method for same, and applications thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010296780.4A CN111454170B (en) | 2020-04-15 | 2020-04-15 | Acetanilide compound and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111454170A true CN111454170A (en) | 2020-07-28 |
| CN111454170B CN111454170B (en) | 2021-08-31 |
Family
ID=71676482
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010296780.4A Active CN111454170B (en) | 2020-04-15 | 2020-04-15 | Acetanilide compound and preparation method and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN111454170B (en) |
| WO (1) | WO2021208223A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5032617A (en) * | 1985-05-03 | 1991-07-16 | Sri International | Substituted benzamide radiosensitizers |
| CN103588660A (en) * | 2013-11-18 | 2014-02-19 | 中国医学科学院生物医学工程研究所 | Novel acyl aniline compound and application thereof |
| CN110746370A (en) * | 2018-07-23 | 2020-02-04 | 新发药业有限公司 | Preparation method of 4- (4-aminophenyl) morpholine-3-one |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5840324B2 (en) * | 2013-04-15 | 2016-01-06 | 株式会社レナサイエンス | New uses of PAI-1 inhibitors |
-
2020
- 2020-04-15 CN CN202010296780.4A patent/CN111454170B/en active Active
- 2020-06-16 WO PCT/CN2020/096245 patent/WO2021208223A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5032617A (en) * | 1985-05-03 | 1991-07-16 | Sri International | Substituted benzamide radiosensitizers |
| CN103588660A (en) * | 2013-11-18 | 2014-02-19 | 中国医学科学院生物医学工程研究所 | Novel acyl aniline compound and application thereof |
| CN110746370A (en) * | 2018-07-23 | 2020-02-04 | 新发药业有限公司 | Preparation method of 4- (4-aminophenyl) morpholine-3-one |
Non-Patent Citations (2)
| Title |
|---|
| BROWN J. M. ET AL: "Structure-activity relationships for tumor radiosensitization by analogs of nicotinamide and benzamide", 《INTERNATIONAL JOURNAL OF RADIATION BIOLOGY》 * |
| STN CAPLUS: "《STN CAPLUS REG.数据库检索结果》", 31 December 2017 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021208223A1 (en) | 2021-10-21 |
| CN111454170B (en) | 2021-08-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6511083B2 (en) | Crystal of pyrrole derivative | |
| EA022756B1 (en) | Crystalline forms of eltrombopag and use thereof | |
| BR112016011700B1 (en) | PROCESS FOR POMALIDOMIDE SYNTHESES | |
| CN109651333B (en) | 2-indol-3-yl-quinoline compound with anti-tumor activity and preparation method and application thereof | |
| JP2016014029A (en) | Novel form of multicyclic compound | |
| CN106831524B (en) | A kind of chiral pyrrolidine ketone acetamide derivative and its preparation method and application | |
| TW202140423A (en) | Process for the preparation of (r)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)-cyclopropyl) benzoic acid or a salt thereof | |
| CN111454170A (en) | Acetanilide compound and preparation method and application thereof | |
| RU2679636C1 (en) | New method of the n,n'-bis[2-(1h-imidazol-4-yl)ethyl]malonamide obtaining | |
| CN108440626B (en) | Crystal form of cytarabine 5' -O-L-valine ester hydrochloride and preparation method thereof | |
| JP2007262040A (en) | Method for producing 3-substituted amino ring-formed amine derivative | |
| CN101277959A (en) | Process for preparing zolpidem hemitartrate and tartrate polymorphs | |
| CN102351775B (en) | Preparation method of levo-5-hydroxytryptophan | |
| KR20190024900A (en) | Crystalline forms of 9-aminomethyl substituted tetracycline compounds and methods for their preparation | |
| KR100933172B1 (en) | Improved preparation of atorvastatin calcium salt | |
| CN108440376B (en) | Preparation method of ropinirole hydrochloride | |
| CN111792999B (en) | Dinaphthylamine compounds, and preparation method and application thereof | |
| CN116621817B (en) | Entecavir fumarate crystal form, preparation method, pharmaceutical composition and application thereof | |
| CN1556701A (en) | Tetrapeptide derivative crystals | |
| CN110922354B (en) | Chemical resolution preparation method of 1-R-3-haloperidol-4-carboxylic acid and product thereof | |
| CN117069695B (en) | Potassium ion competitive acid retarder solid free form and preparation method thereof | |
| US20230133435A1 (en) | Cocrystals derivatives of apixaban | |
| CN115160234B (en) | Aryl acetate-containing 1,4, 5-trisubstituted imidazole compound, preparation method and application | |
| KR20140054800A (en) | Methods of preparing a 1-deoxy-1-(2-hydroxyethyl amino)-d-glucitol and miglitol | |
| CN108129479B (en) | 5, 6-dihydrobenzo [ f ] indolo [2,3-b ] quinoline compound and synthetic method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |