CN111018752A - Para-cyclopropanyl substituted benzene sulfonyl aniline and preparation method thereof - Google Patents
Para-cyclopropanyl substituted benzene sulfonyl aniline and preparation method thereof Download PDFInfo
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- CN111018752A CN111018752A CN201911359931.XA CN201911359931A CN111018752A CN 111018752 A CN111018752 A CN 111018752A CN 201911359931 A CN201911359931 A CN 201911359931A CN 111018752 A CN111018752 A CN 111018752A
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- C07—ORGANIC CHEMISTRY
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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- C07—ORGANIC CHEMISTRY
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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Abstract
The invention discloses para-cyclopropanyl substituted benzenesulfonyl aniline and a preparation method thereof, wherein the preparation method comprises the following steps: dissolving p-bromobenzenesulfonic acid and aniline in pyridine, then adding a condensing agent EDC-HCl, and reacting for 2-3 h at the temperature of 50-80 ℃ to obtain p-bromobenzenesulfonanilide; dissolving p-bromophenylsulfonanilide in dioxane solution, adding cyclopropyl boric acid, sodium carbonate and water solution Pd (dppf) Cl2The mixed system reacts for 8-10h at 110 ℃ in the nitrogen atmosphere, and the p-cyclopropane benzene sulfonyl aniline is prepared by post-treatment.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to para-cyclopropane phenyl sulfonanilide and a preparation method thereof.
Background
Sulfonamide compounds have very diverse pharmacological activities, such as stronger antihypertensive, antiarrhythmic, antithrombotic activities, etc., and many drug molecules and natural products contain sulfonamide structures or fragments, so the sulfonamide derivatives are important drug intermediates. However, the synthesis of the cyclopropane sulfanilamide compound is only reported in documents, and the introduction of the cyclopropane substituent reported in the documents is relatively complicated and difficult, most of the cyclopropane substituents are prepared by closing a ring through a terminal alkene, and the cyclopropane sulfanilamide compound has the defects of difficult preparation, long step, expensive raw materials, difficult operation, low yield and the like. Particularly, the types and the synthesis methods of the p-cyclopropylbenzenesulfonyl aniline have not been reported in the literature. The synthetic route disclosed by the invention is simple and short, and only two steps of reactions are needed; the preparation method has strong operability and high yield, and is an excellent method suitable for mass preparation. The present disclosure has significant research and utility values as such compounds are valuable pharmaceutical intermediates.
Disclosure of Invention
The invention aims to provide the p-cyclopropane benzene sulfonyl aniline and the preparation method thereof, the prepared p-cyclopropane benzene sulfonyl aniline has potential pharmaceutical activity, the reaction is easy to operate, the product is easy to purify, and the method is suitable for batch preparation.
In order to achieve the purpose, the invention adopts the following technical scheme:
para-cyclopropyl substituted benzene sulfonyl aniline with the structural formula
The preparation method of the novel compound p-cyclopropyl substituted benzenesulfonyl aniline comprises the following steps:
(1) dissolving p-bromobenzenesulfonic acid and aniline in pyridine, then adding a condensing agent EDC-HCl, and reacting for 2-3 h at the temperature of 50-80 ℃ to obtain p-bromobenzenesulfonanilide;
(2) dissolving p-bromophenylsulfonanilide in dioxane solution, adding cyclopropyl boric acid, sodium carbonate, Pd (dppf) Cl2Reacting the mixed system for 8-10h at 110 ℃ in a nitrogen atmosphere, and performing post-treatment to obtain p-cyclopropylphenyl sulfonyl aniline;
the specific reaction equation is as follows:
furthermore, the molar ratio of the aniline, the p-bromobenzenesulfonic acid and the condensing agent EDC-HCl in the step (1) is 1:1: 1.5-1: 1.2: 2.
Further, in the step (2), p-bromobenzenesulfonylaniline and cyclopropylboric acid, sodium carbonate, Pd (dppf) Cl2The molar ratio of (1: 1:2: 0.05) to (1: 1:5: 0.1).
The invention has the beneficial effects that: the p-cyclopropyl substituted benzene sulfonyl aniline is an important drug intermediate and has potential pharmacological activity. The preparation method provided by the invention is easy to operate, high in product yield and suitable for batch preparation, so that the preparation method of the p-cyclopropane benzene sulfonyl aniline has important application value.
Detailed Description
The present invention will be further described with reference to the following examples. It is to be understood that the following examples are illustrative only and are not intended to limit the scope of the invention, which is to be given numerous insubstantial modifications and adaptations by those skilled in the art based on the teachings set forth above.
Example 1
The preparation of the para-cyclopropane substituted benzenesulfonanilides of this example was as follows:
(1) synthesis of p-bromophenylsulfonanilide
Adding 4.74g (0.02 mol) of p-bromobenzenesulfonic acid into a 100mL single-neck bottle, adding 100mL of pyridine, stirring to dissolve, adding 1.86g (0.02 mol) of aniline, slowly adding 5.73g (0.03 mol) of condensing agent EDC-HCl into the reaction liquid in batches, heating to 50 ℃ to react for 2 hours, removing pyridine by rotary evaporation, pouring residual water into a separating funnel, adding a proper amount of ethyl acetate into the separating funnel to extract for 3 times, washing an ethyl acetate layer with dilute hydrochloric acid for 1 time, combining organic layers, drying the organic layer by anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 5.3g of white solid with the yield of 85%;
MS：m/z: [M+1]: 311.9，313.9。
1H NMR (400 MHz, DMSO-d6)：7.88-7.89（m, 4H）, 7.20 (m, 2H), 6.81（m,1H）, 6.63(d, 2H) , 5.3（br, 1H）。
elemental analysis C12H10BrNO2C, 46.17, H, 3.23, Br, 25.60, N, 4.49, O, 10.25 and S, 10.27.
Measured C, 65.70, H, 5.77, Br, 33.65, N, 6.13, S, 13.50.
(2) Synthesis of para-cyclopropanyl substituted benzene sulfonyl aniline
3.12g (0.01 mol) of p-bromobenzenesulfonanilide was weighed, 15mL of dioxane and 5mL of water were added, and after stirring and dissolution, 0.86g (0.01 mol) of cyclopropylboronic acid, 2.12g (0.02 mol) of sodium carbonate and Pd (dppf) Cl were weighed20.37g (0.0005 mol) was added to the reaction system, which was then purged with nitrogen 3 times, and the reaction temperature was set at 110 ℃ for 8 hours. After the reaction is finished, evaporating the solvent under reduced pressure, adding a proper amount of water and ethyl acetate into the residue, extracting for 3 times, drying the extract liquor by using anhydrous sodium sulfate, removing the solvent by using a rotary evaporator, and purifying the obtained residue by using a column to obtain 2.43g of a white body with the yield of 89%;
MS：m/z: [M+1]: 274。
1H NMR (400 MHz, DMSO-d6)：7.78（m, 2H）, 7.58（d, 2H）, 7.20 (m, 3H),6.81（m, 1H）, 6.63 (d, 2H) , 4.5（br, 1H）, 1.55（m, 1H）, 1.24（m, 2H）, 0.99（m,2H）。
elemental analysis C15H15NO2Theoretical S values (in%) are C, 65.91, H,5.53, N, 5.12 and S, 11.73.
Measured values of C, 65.70, H, 5.74, N, 5.13, S, 11.72.
Example 2
The preparation of the para-cyclopropane substituted benzenesulfonanilides of this example was as follows:
(1) synthesis of p-bromophenylsulfonanilide
Adding 4.74g (0.02 mol) of p-bromobenzenesulfonic acid into a 100mL single-neck bottle, adding 100mL of pyridine, stirring to dissolve, adding 2.04g (0.022 mol) of aniline, slowly adding 5.73g (0.03 mol) of condensing agent EDC-HCl into the reaction liquid in batches, heating to 50 ℃ to react for 2 hours, removing pyridine by rotary evaporation, pouring residual water into a separating funnel, adding a proper amount of ethyl acetate into the separating funnel to extract for 3 times, washing an ethyl acetate layer with diluted hydrochloric acid for 1 time, combining organic layers, drying the organic layer by anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 5.49g of white solid with the yield of 88%;
(2) synthesis of para-cyclopropanyl substituted benzene sulfonyl aniline
3.12g (0.01 mol) of p-bromobenzenesulfonanilide was weighed, 15mL of dioxane and 5mL of water were added, and after stirring and dissolution, 0.86g (0.01 mol) of cyclopropylboronic acid, 2.12g (0.03 mol) of sodium carbonate, and Pd (dppf) Cl were weighed20.37g (0.0005 mol) was added to the reaction system, which was then purged with nitrogen 3 times, and the reaction temperature was set at 110 ℃ for 8 hours. After the reaction, the solvent was evaporated under reduced pressure, and then the residue was extracted with an appropriate amount of water and ethyl acetate for 3 times, and after the extract was dried with anhydrous sodium sulfate, the solvent was removed by a rotary evaporator, and the residue was purified by column chromatography to obtain 2.46g of a white substance with a yield of 90%.
Example 3
The preparation of the para-cyclopropane substituted benzenesulfonanilides of this example was as follows:
(1) synthesis of p-bromophenylsulfonanilide
Adding 4.74g (0.02 mol) of p-bromobenzenesulfonic acid into a 100mL single-neck bottle, adding 100mL of pyridine, stirring to dissolve, adding 2.23g (0.024 mol) of aniline, slowly adding 5.73g (0.03 mol) of condensation agent EDC-HCl into the reaction liquid in batches, heating to 50 ℃ to react for 2 hours, removing pyridine by rotary evaporation, pouring residual water into a separating funnel, adding a proper amount of ethyl acetate into the separating funnel to extract for 3 times, washing an ethyl acetate layer with dilute hydrochloric acid for 1 time, combining organic layers, drying the organic layer by anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 5.55g of white solid with the yield of 89%;
(2) synthesis of para-cyclopropanyl substituted benzene sulfonyl aniline
3.12g (0.01 mol) of p-bromobenzenesulfonanilide was weighed, 15mL of dioxane and 5mL of water were added, and after stirring and dissolving, 0.86g (0.01 mol) of cyclopropylboronic acid and 2.12g (0.0 mol) of sodium carbonate were weighed4mol），Pd（dppf）Cl20.58g (0.0008 mol) was added to the reaction system, which was then purged with nitrogen 3 times, and the reaction temperature was set at 110 ℃ for 9 hours. After the reaction, the solvent was evaporated under reduced pressure, and then the residue was extracted with an appropriate amount of water and ethyl acetate for 3 times, and after the extract was dried with anhydrous sodium sulfate, the solvent was removed by a rotary evaporator, and the residue was purified by column chromatography to obtain 2.48g of a white substance with a yield of 91%.
Example 4
The preparation of the para-cyclopropane substituted benzenesulfonanilides of this example was as follows:
(1) synthesis of p-bromophenylsulfonanilide
Adding 4.74g (0.02 mol) of p-bromobenzenesulfonic acid into a 100mL single-neck bottle, adding 100mL of pyridine, stirring to dissolve, adding 2.23g (0.024 mol) of aniline, slowly adding 6.9g (0.036 mol) of condensation agent EDC-HCl into the reaction liquid in batches, heating to 50 ℃ to react for 2 hours, removing pyridine by rotary evaporation, pouring residual water into a separating funnel, adding a proper amount of ethyl acetate into the separating funnel to extract for 3 times, washing an ethyl acetate layer with diluted hydrochloric acid for 1 time, combining organic layers, drying the organic layer by anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 5.74g of white solid with the yield of 92%;
(2) synthesis of para-cyclopropanyl substituted benzene sulfonyl aniline
3.12g (0.01 mol) of p-bromobenzenesulfonanilide was weighed, 15mL of dioxane and 5mL of water were added, and after stirring and dissolution, 0.86g (0.01 mol) of cyclopropylboronic acid, 2.12g (0.04 mol) of sodium carbonate and Pd (dppf) Cl were weighed21.16g (0.001 mol) was added to the reaction system, which was then replaced with nitrogen 3 times, and the reaction temperature was set at 110 ℃ for 10 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and then, an appropriate amount of water and ethyl acetate were added to the residue to extract 3 times, and after the extract was dried with anhydrous sodium sulfate, the solvent was removed by a rotary evaporator, and the obtained residue was purified by column chromatography to obtain 2.53g of a white substance with a yield of 93%.
Example 5
The preparation of the para-cyclopropane substituted benzenesulfonanilides of this example was as follows:
(1) synthesis of p-bromophenylsulfonanilide
A100 mL single-neck bottle is taken, 4.74g (0.02 mol) of p-bromobenzenesulfonic acid is added, 100mL of pyridine is added, stirring is carried out for dissolution, 2.23g (0.024 mol) of aniline is added, 5.73g (0.04 mol) of condensation agent EDC-HCl is slowly added in batches to the reaction liquid, then the mixture is heated to 50 ℃ for reaction for 2 hours, pyridine is removed by rotary evaporation, residual water is added into a separating funnel, a proper amount of ethyl acetate is added for extraction for 3 times, an ethyl acetate layer is washed with diluted hydrochloric acid for 1 time, organic layers are combined, the solvent is removed under reduced pressure after the organic layer is dried by anhydrous sodium sulfate, 5.99g of white solid is obtained, and the yield is 96%.
(2) Synthesis of para-cyclopropanyl substituted benzene sulfonyl aniline
3.12g (0.01 mol) of p-bromobenzenesulfonanilide was weighed, 15mL of dioxane and 5mL of water were added, and after stirring and dissolution, 0.86g (0.01 mol) of cyclopropylboronic acid, 2.12g (0.05 mol) of sodium carbonate and Pd (dppf) Cl were weighed21.16g (0.001 mol) was added to the reaction system, which was then replaced with nitrogen 3 times, and the reaction temperature was set at 110 ℃ for 10 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and then, an appropriate amount of water and ethyl acetate were added to the residue to extract 3 times, and after the extract was dried with anhydrous sodium sulfate, the solvent was removed by a rotary evaporator, and the obtained residue was purified by column chromatography to obtain 2.6g of a white substance with a yield of 95%.
The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (4)
1. A para-cyclopropanyl substituted benzenesulphonanilide characterised in that: the structural formula of the para-cyclopropane benzene sulfonyl aniline is shown in the specification
2. The process for producing a p-cyclopropylalkyl-substituted benzenesulfonanilide according to claim 1, which comprises the steps of:
(1) dissolving p-bromobenzenesulfonic acid and aniline in pyridine, adding EDC-HCl, and reacting for 2-3 h at 50-80 ℃ to obtain p-bromobenzenesulfonanilide;
(2) dissolving p-bromophenylsulfonanilide in dioxane solution, adding cyclopropyl boric acid, sodium carbonate, Pd (dppf) Cl2Reacting the mixed system for 8-10h at 110 ℃ in the nitrogen atmosphere, and performing post-treatment to obtain the p-cyclopropylphenyl sulfonyl aniline;
the specific reaction equation is as follows:
3. the process for producing a p-cyclopropylalkyl-substituted benzenesulfonanilide according to claim 2, wherein: the molar ratio of the aniline, the p-bromobenzenesulfonic acid and the EDC-HCl in the step (1) is 1:1: 1.5-1: 1.2: 2.
4. The process for producing a p-cyclopropylalkyl-substituted benzenesulfonanilide according to claim 2, wherein: in the step (2), the p-bromobenzenesulfonylaniline, the cyclopropylboric acid, the sodium carbonate, Pd (dppf) Cl2The molar ratio of (1: 1:2: 0.05-1: 1.1:5: 0.1).
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| CN101065353A (en) * | 2004-11-26 | 2007-10-31 | 巴斯福股份公司 | Novel 2-cyano-3-(halo)alkoxy-benzenesulfonamide compounds for combating animal pests |
| CN101808983A (en) * | 2007-09-27 | 2010-08-18 | 霍夫曼-拉罗奇有限公司 | biaryl sulfonamide derivatives |
| CN102391059A (en) * | 2011-08-12 | 2012-03-28 | 郑州泰基鸿诺药物科技有限公司 | Method for synthesizing cyclopropyl alkyl aromatic compound |
| US20180146666A1 (en) * | 2016-11-28 | 2018-05-31 | The Regents Of The University Of California | Aba receptor agonists that modulate transpiration |
| WO2018132372A1 (en) * | 2017-01-10 | 2018-07-19 | Sanford Burnham Prebys Medical Discovery Institute | Small molecule activators of nicotinamide phosphoribosyltransferase (nampt) and uses thereof |
| CN108409612A (en) * | 2018-03-21 | 2018-08-17 | 福建医科大学 | A kind of method that N- benzyl benzenesulfonamides are catalyzed and synthesized by boric acid/Catalyzed by Oxalic Acid system under microwave radiation |
| CN110551147A (en) * | 2019-09-29 | 2019-12-10 | 蚌埠产品质量监督检验研究院 | synthetic method of 3-cyclopropylphenylboronic acid |
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- 2019-12-25 CN CN201911359931.XA patent/CN111018752A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101065353A (en) * | 2004-11-26 | 2007-10-31 | 巴斯福股份公司 | Novel 2-cyano-3-(halo)alkoxy-benzenesulfonamide compounds for combating animal pests |
| CN101808983A (en) * | 2007-09-27 | 2010-08-18 | 霍夫曼-拉罗奇有限公司 | biaryl sulfonamide derivatives |
| CN102391059A (en) * | 2011-08-12 | 2012-03-28 | 郑州泰基鸿诺药物科技有限公司 | Method for synthesizing cyclopropyl alkyl aromatic compound |
| US20180146666A1 (en) * | 2016-11-28 | 2018-05-31 | The Regents Of The University Of California | Aba receptor agonists that modulate transpiration |
| WO2018132372A1 (en) * | 2017-01-10 | 2018-07-19 | Sanford Burnham Prebys Medical Discovery Institute | Small molecule activators of nicotinamide phosphoribosyltransferase (nampt) and uses thereof |
| CN108409612A (en) * | 2018-03-21 | 2018-08-17 | 福建医科大学 | A kind of method that N- benzyl benzenesulfonamides are catalyzed and synthesized by boric acid/Catalyzed by Oxalic Acid system under microwave radiation |
| CN110551147A (en) * | 2019-09-29 | 2019-12-10 | 蚌埠产品质量监督检验研究院 | synthetic method of 3-cyclopropylphenylboronic acid |
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