CN108558822B - Synthesis method of N- ((5-bromothiophene-2-yl) sulfonyl) -2, 4-dichlorobenzamide - Google Patents

Synthesis method of N- ((5-bromothiophene-2-yl) sulfonyl) -2, 4-dichlorobenzamide Download PDF

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CN108558822B
CN108558822B CN201810558279.3A CN201810558279A CN108558822B CN 108558822 B CN108558822 B CN 108558822B CN 201810558279 A CN201810558279 A CN 201810558279A CN 108558822 B CN108558822 B CN 108558822B
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dichlorobenzamide
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房月
吴振
杨锦明
王庆东
杨子健
纪顺俊
汪顺义
赵玉军
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Yancheng Jinming Pharmaceutical Co ltd
Yancheng Teachers University
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention relates to a method for synthesizing N- ((5-bromothiophene-2-yl) sulfonyl) -2, 4-dichlorobenzamide, belonging to the technical field of organic synthesis. The method comprises the following steps: (1) weighing the raw materials according to a ratio, adding 2, 4-dichlorobenzoic acid and 2-bromothiophene sulfonyl azide into a reactor, sequentially adding a small amount of acetonitrile solvent, a cobalt catalyst and a trace amount of tert-butyl isonitrile into the reactor, and stirring and reacting for 2-6 h at the temperature of 60-90 ℃; (2) and after the reaction is finished, carrying out rotary evaporation and concentration on the reaction product, loading the sample, and separating by utilizing column chromatography to obtain a target product III. The target product can be prepared by a one-step method, the synthesis method is simple, the reaction time is short, an inert atmosphere is not needed, the energy consumption is low, the one-way yield of the target product can reach 76%, and the conversion rate of raw materials is high. In addition, the method has low requirements on reaction equipment, the cobalt catalyst raw material is cheap and easy to obtain, and the industrial cost is low.

Description

Synthesis method of N- ((5-bromothiophene-2-yl) sulfonyl) -2, 4-dichlorobenzamide
Technical Field
The invention belongs to the technical field of organic synthesis, relates to synthesis of an antitumor reagent LY573636, and more particularly relates to a synthesis method of N- ((5-bromothiophene-2-yl) sulfonyl) -2, 4-dichlorobenzamide.
Background
LY573636 is a class of antitumor agents widely used in the treatment of colon, lung, breast, ovarian and prostate cancers. It has attracted attention from many chemists, pharmacologists and biologists over the past few decades.
The synthesis method of LY573636 has few reports and is relatively single. Yates. m.h., et al, investigated the preparation of LY 573636. Na from carboxylic acids and amides, published in org. processes res.dev.,2009,13,255-262, which showed that the desired product was obtained in 89% yield and that a kilogram scale of production was possible. However, the reaction conditions are complex: triethylamine is used as alkali, DMAP is used as coupling catalyst, and additives such as isopropyl acetate are added, and N is needed2And (4) protecting. In addition, the method has the characteristics of long synthetic route, multi-step reaction, long time, non-conformity with atom economy and the like, and the synthetic method needs to add various alkalis and additives and has higher production cost.
Disclosure of Invention
In order to overcome the problems in the prior art, the invention aims to provide a novel method for synthesizing N- ((5-bromothiophene-2-yl) sulfonyl) -2, 4-dichlorobenzamide.
In order to achieve the above object, the present invention provides a method for synthesizing N- ((5-bromothien-2-yl) sulfonyl) -2, 4-dichlorobenzamide, wherein the synthetic route of the method is shown as the following formula:
Figure BDA0001682176270000011
the method for synthesizing N- ((5-bromothien-2-yl) sulfonyl) -2, 4-dichlorobenzamide, which comprises the following steps:
(1) weighing the raw materials according to the proportion, adding a compound I and a compound II into a reactor, sequentially adding a small amount of acetonitrile solvent, cobalt catalyst and trace tert-butyl isonitrile into the reactor, and stirring and reacting for 2-6 h at the temperature of 60-90 ℃;
(2) after the reaction is finished, carrying out rotary evaporation and concentration on the reaction product, loading the reaction product, and separating by utilizing column chromatography to obtain a target product III, N- ((5-bromothiophene-2-yl) sulfonyl) -2, 4-dichlorobenzamide;
the compound I is 2, 4-dichlorobenzoic acid, and the structural formula is shown as the following formula II:
Figure BDA0001682176270000021
the compound II is 2-bromothiophene sulfonyl azide, and the structural formula is shown as the following formula III:
Figure BDA0001682176270000022
the structural formula of the target product III is shown as the following formula IV:
Figure BDA0001682176270000023
further, the molar ratio of the compound i to the compound ii in the above technical scheme is 1: 1.2-1: 1.5.
furthermore, the molar ratio of compound i to compound ii in the above technical scheme is preferably 1: 1.5.
further, the cobalt catalyst in the above technical scheme is octa-carbon based cobaltic oxide.
Further, the molar volume ratio of the compound i to the solvent acetonitrile in the above technical scheme is preferably 1 mmol: 8 mL.
Further, the molar volume ratio of the compound i to the tert-butyl isonitrile in the above technical scheme is preferably 1 mmol: 200 μ L.
Further, the molar ratio of the compound i to the octacarbonyl cobaltic oxide in the above technical scheme is preferably 1: 0.05.
further, the reaction temperature in step (1) of the above technical solution is preferably 80 ℃.
Further, the reaction time in step (1) of the above technical scheme is preferably 4 h.
Further, the specific selection of the stationary phase and the mobile phase in the column chromatography separation in the step (2) of the technical scheme is as follows: the stationary phase is 200-300 mesh silica gel powder, and the mobile phase is ethyl acetate: petroleum ether is 1: 4.
compared with the prior art, the synthesis method of the N- ((5-bromothiophene-2-yl) sulfonyl) -2, 4-dichlorobenzamide has the following beneficial effects:
(1) according to the invention, the target product N- ((5-bromothiophene-2-yl) sulfonyl) -2, 4-dichlorobenzamide can be prepared in one step only by introducing an acetonitrile solvent, a cobalt catalyst and a trace amount of tert-butyl isonitrile into a reaction system, the one-way yield of the target product can reach 76%, the conversion rate of raw materials is high, and the defects of complicated synthetic steps, long process and low product yield of the substance in the prior art are overcome;
(2) the synthesis method has the advantages of simple process, short reaction time, no need of long-time reaction in an inert atmosphere, low energy consumption, low requirement on reaction equipment, low cost and easy obtainment of cobalt catalyst raw materials, and thus, the synthesis method has low industrialization cost;
(3) the method has the advantages of simple post-treatment process and convenient operation, the target product can be separated only by column chromatography, the purity of the separated target product is high, and in addition, the method selects acetonitrile as a solvent, so the method is green and environment-friendly.
Drawings
FIG. 1 is a nuclear magnetic spectrum of a target product prepared in example 1 of the present invention;
FIG. 2 is an IR spectrum of a target product prepared in example 1 of the present invention;
FIG. 3 is a high resolution mass spectrum of the target product prepared in example 1 of the present invention.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to the accompanying drawings. The embodiment is implemented on the premise of the technical scheme of the invention, and a detailed implementation mode and a specific operation process are given, but the protection scope of the invention is not limited to the following embodiment.
Various modifications to the precise description of the invention will be readily apparent to those skilled in the art from the information contained herein without departing from the spirit and scope of the appended claims. It is to be understood that the scope of the invention is not limited to the procedures, properties, or components defined, as these embodiments, as well as others described, are intended to be merely illustrative of particular aspects of the invention. Indeed, various modifications of the embodiments of the invention which are obvious to those skilled in the art or related fields are intended to be covered by the scope of the appended claims.
For a better understanding of the invention, and not as a limitation on the scope thereof, all numbers expressing quantities, percentages, and other numerical values used in this application are to be understood as being modified in all instances by the term "about". Accordingly, unless expressly indicated otherwise, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Example 1
The method for synthesizing N- ((5-bromothien-2-yl) sulfonyl) -2, 4-dichlorobenzamide of this example comprises the following steps:
0.5mmol (0.0955g) of 2, 5-dichlorobenzoic acid, 0.75mmol (0.2011g) of 2-bromothiophene sulfonyl azide and 0.025mmol (0.0086g) of octacarbonyl cobaltic acid are respectively weighed and added into a 25mL reaction tube; then, sequentially adding 4mL of acetonitrile solvent and 100 microliters of tert-butyl isonitrile measured by a micro-syringe into the reactor, and stirring the whole reaction system at 80 ℃ for reaction for 4 hours; after the reaction is finished, performing rotary evaporation concentration, loading, and performing column chromatography separation (under the column chromatography separation conditions, the stationary phase is silica gel powder of 200-300 meshes, the mobile phase is ethyl acetate and petroleum ether is 1: 4, 0.1583g of the target product is obtained, the target product is a white solid, and the yield is 76%.
Example 2
The method for synthesizing N- ((5-bromothien-2-yl) sulfonyl) -2, 4-dichlorobenzamide of this example comprises the following steps:
3mmol (0.5730g) of 2, 5-dichlorobenzoic acid, 4.5mmol (1.2065g) of 2-bromothiophene sulfonyl azide and 0.15mmol (0.0516g) of octacarbonyl cobaltic acid are weighed into a 50mL round-bottom flask respectively; then, adding 24mL of acetonitrile solvent and 600 microliters of tert-butyl isonitrile measured by a micro syringe into the round-bottom flask in sequence, and stirring the whole reaction system at 80 ℃ for reaction for 4 hours; after the reaction is finished, performing rotary evaporation concentration, loading, and performing column chromatography separation (under the column chromatography separation conditions, the stationary phase is silica gel powder of 200-300 meshes, the mobile phase is ethyl acetate and petroleum ether is 1: 4, 0.8163g of the target product is obtained, the target product is a white solid, and the yield is 65%.
Example 3
The method for synthesizing N- ((5-bromothien-2-yl) sulfonyl) -2, 4-dichlorobenzamide of this example comprises the following steps:
respectively weighing 6mmol (1.1460g) of 2, 5-dichlorobenzoic acid, 9mmol (2.4129g) of 2-bromothiophene sulfonyl azide and 0.3mmol (0.1032g) of octacarbonyl cobaltic acid into a 100mL round-bottom flask, then sequentially adding 48mL of acetonitrile solvent and 1.2mL of tert-butyl isonitrile measured by a microsyringe into the round-bottom flask, and stirring the whole reaction system at 80 ℃ for reaction for 4 hours; after the reaction is finished, performing rotary evaporation concentration, and performing sample loading and column chromatography separation (under the column chromatography separation conditions, the stationary phase is silica gel powder of 200-300 meshes, the mobile phase is ethyl acetate and petroleum ether is 1: 4, 1.4943g of the target product is obtained, the target product is a white solid, and the yield is 60%.
The target products prepared in example 1 were each subjected to nuclear magnetic resonance (400MHz,1the method is characterized by means of H NMR (nuclear magnetic resonance), infrared (FTIR), High Resolution Mass Spectrum (HRMS) and the like, and the test results are respectively shown in the attached drawings 1, 2 and 3.
As can be seen from fig. 1:
the test results for the target product are as follows:1H NMR(400MHz,DMSO-d6)7.73(dd,J＝9.3,2.9Hz,2H),7.58(d,J＝8.3Hz,1H),7.52(dd,J＝8.3,1.9Hz,1H),7.43(d,J＝4.1Hz,1H).13C NMR(75MHz,DMSO-d6)164.4,139.9,136.3,135.1,132.3,131.4,131.3,130.7,129.6,127.6,121.2, wherein:
1H NMR(400MHz,DMSO-d6)7.73, multiplet, two hydrogens attached to the chloromethyl group on the phenyl ring; 7.58, doublet, which is ascribed to one hydrogen on the methine group linked to the methylene group linked to the carbonyl group on the phenyl ring; 7.52, doublet, one hydrogen on the methine group attached to the bromomethyl group on the thiophene ring; 7.43, doublet, one hydrogen of methine attached to sulfonyl group on thiophene ring.13C NMR(75MHz,DMSO-d6)164.4,139.9,136.3,135.1,132.3,131.4,131.3,130.7,129.6,127.6,121.2, wherein: 164.4 carbon on carbon group, the remaining ten carbons are six carbons on benzene ring and four carbons on thiophene ring, respectively.
As can be seen from the infrared spectrum of fig. 2, the target characteristic peaks of the target product are as follows:
IR: 3311, stretching vibration peak attributed to N-H bond; 3097cm-1Stretching vibration peak attributed to unsaturated C-H; 1687cm-1A stretching vibration peak attributed to carbon radicals; 1353cm-1Characteristic absorption peaks ascribed to sulfones; 812cm-1The gamma absorption peak is attributed to asymmetric trisubstituted on a benzene ring; 755cm-1Characteristic absorption peaks ascribed to C-Cl bonds; 671cm-1Characteristic absorption peaks ascribed to C-Br bonds.
As can be seen from fig. 3, the high-quality (HRMS) test data for the target product is as follows:
HRMS(ESI)m/z:calcd.for C11H8BrCl2NO3S2[M+H]+413.8428, found: 413.8449. Wherein the theoretical value is 413.8428, and the measured value is 413.8449, which meets the requirement.
From the results of the nuclear magnetic, infrared and mass spectrometry tests, it can be determined that the target compound prepared in this example is N- ((5-bromothien-2-yl) sulfonyl) -2, 4-dichlorobenzamide.

Claims (6)

  1. A method for synthesizing N- ((5-bromothien-2-yl) sulfonyl) -2, 4-dichlorobenzamide, characterized in that: the method comprises the following steps:
    (1) weighing the raw materials according to a ratio, adding a compound I and a compound II into a reactor, sequentially adding an acetonitrile solvent, a cobalt catalyst and tert-butyl isonitrile into the reactor, and stirring and reacting for 2-6 h at the temperature of 60-90 ℃; the cobalt catalyst is cobaltic octacarbonyl; the molar volume ratio of the compound I to the solvent acetonitrile is 1 mmol: 8 mL; the molar volume ratio of the compound I to the tert-butyl isonitrile is 1 mmol: 200 mu L; the molar ratio of the compound I to the octacarbonylcobaltic oxide is 1: 0.05;
    (2) after the reaction is finished, carrying out rotary evaporation and concentration on the reaction product, loading the reaction product, and separating by utilizing column chromatography to obtain a target product III, N- ((5-bromothiophene-2-yl) sulfonyl) -2, 4-dichlorobenzamide;
    the compound I is 2, 4-dichlorobenzoic acid, and the structural formula is shown as the following formula II:
    Figure FDA0002619280050000011
    the compound II is 2-bromothiophene sulfonyl azide, and the structural formula is shown as the following formula III:
    Figure FDA0002619280050000012
    the structural formula of the target product III is shown as the following formula IV:
    Figure FDA0002619280050000013
  2. 2. the method of synthesizing N- ((5-bromothien-2-yl) sulfonyl) -2, 4-dichlorobenzamide according to claim 1 wherein: the molar ratio of the compound I to the compound II is 1: 1.2-1: 1.5.
  3. 3. the method of synthesizing N- ((5-bromothien-2-yl) sulfonyl) -2, 4-dichlorobenzamide according to claim 2 characterized in that: the molar ratio of the compound I to the compound II is 1: 1.5.
  4. 4. the method of synthesizing N- ((5-bromothien-2-yl) sulfonyl) -2, 4-dichlorobenzamide according to claim 1 wherein: the reaction temperature in step (1) was 80 ℃.
  5. 5. The method of synthesizing N- ((5-bromothien-2-yl) sulfonyl) -2, 4-dichlorobenzamide according to claim 1 wherein: the reaction time in the step (1) is 4 h.
  6. 6. The method of synthesizing N- ((5-bromothien-2-yl) sulfonyl) -2, 4-dichlorobenzamide according to claim 1 wherein: the specific selection of the stationary phase and the mobile phase in the column chromatography separation in the step (2) is as follows: the stationary phase is 200-300 mesh silica gel powder, and the mobile phase is ethyl acetate: petroleum ether is 1: 4.
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