CN111574413B - A kind of preparation method of sulfonyl amidine with 2-aminomethylpyridine and DMF-DMA as amine source - Google Patents

A kind of preparation method of sulfonyl amidine with 2-aminomethylpyridine and DMF-DMA as amine source Download PDF

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CN111574413B
CN111574413B CN202010510716.1A CN202010510716A CN111574413B CN 111574413 B CN111574413 B CN 111574413B CN 202010510716 A CN202010510716 A CN 202010510716A CN 111574413 B CN111574413 B CN 111574413B
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CN111574413A (en
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戴立言
赵启航
刘聪
王晓钟
陈英奇
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Hangzhou Shanghe Biomedical Technology Co ltd
Zhejiang University ZJU
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Zhejiang University ZJU
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract

The invention discloses a preparation method of sulfonylamidine taking 2-aminomethyl pyridine and DMF-DMA as an amine source, which comprises the following steps: firstly, sulfonyl chloride reacts with 2-aminomethyl pyridine to obtain an intermediate product; and then, reacting the intermediate product with DMF-DMA at 60-100 ℃ in the presence of a catalyst, cooling to room temperature, extracting the reaction liquid with ethyl acetate, layering, drying and concentrating to obtain the target product, namely the sulfonamidine. The method realizes the reaction of the secondary sulfamide and DMF-DMA, and expands the synthetic route of the sulfonamidine. The synthesis reaction has simple operation, mild condition, convenient post-treatment and high purity and yield of the intermediate product and the product.

Description

Preparation method of sulfonylamidine using 2-aminomethyl pyridine and DMF-DMA as amine source
Technical Field
The invention belongs to the field of synthesis of organic intermediates, and particularly relates to a preparation method of sulfonylamidine using 2-aminomethyl pyridine and N, N-dimethylformamide dimethyl acetal (DMF-DMA) as an amine source.
Background
Amidine compounds are an important class of nitrogen-containing organic compounds. The physical and chemical properties of amidine compounds and derivatives thereof are changed along with the change of the positions and the number of substituents on N atoms, so that the amidine compounds and the derivatives thereof are applied to aspects of production and life. Amidine compounds can be used for synthesizing surfactants, dyes, medical medicaments, bactericides, insect repellents and intermediates of a series of important compounds. Amidine compounds are present in many natural compounds having biological activity and are considered to be important pharmaceutical intermediates.
Amidine compounds tend to have higher biological activity and pharmacological action when the N atom in the carbon-nitrogen double bond is linked to a sulfonyl group, and thus are of great interest to the scientific and industrial circles.
Currently, diazonium salts or azide compounds are commonly used as amine sources for synthesizing sulfonyl amidine compounds. For example, the tetrafluoroborate diazonium salt reacts with sulfonamide and acetonitrile in 1, 2-dichloroethane to generate the sulfonylamidine; a series of sulfonyl amidines can also be prepared by using sulfonyl azide and tertiary amine under the catalysis of copper salt and carbon tetrachloride. The generally unstable, explosive nature of diazonium salts and azides limits the general applicability of such processes.
When simple sulfonamide and amide are used as amine sources, oxalyl chloride or thionyl chloride and the amide are required to be prepared into Vilsmeier reagent with the amide to smoothly perform dehydration reaction to obtain the sulfonylamidine. The disadvantage is that the use of oxalyl chloride needs to be excessive, and the use of thionyl chloride can generate sulfur dioxide gas.
Disclosure of Invention
The invention overcomes the defect of single amine source in the above route, and provides a preparation method of an environment-friendly sulfonyl amidine compound. Namely, after the 2-aminomethyl pyridine reacts with the p-toluenesulfonyl chloride to prepare the N- (2-picolyl) p-toluenesulfonamide, the reaction of the secondary sulfonamide with DMF-DMA (N, N-dimethylformamide dimethyl acetal) is realized to prepare the p-toluenesulfonylamidine.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a method for preparing 2-aminomethyl pyridine and DMF-DMA (dimethyl formamide) -derived sulfonyl amidine comprises the following steps: sulfonyl chloride and 2-aminomethyl pyridine react in the presence of organic base to obtain an intermediate, and then the intermediate reacts with DMF-DMA in the presence of a catalyst to obtain sulfonyl amidine;
the structures of the sulfonyl chloride, the intermediate and the sulfonamidine are respectively shown as the following formulas:
Figure BDA0002528125010000021
R1alkyl selected from C1-C5; alkoxy of C1-C5; a halogen atom; a hydrogen atom.
R2，R3Each independently selected from C1-C5 alkyl; a hydrogen atom.
Preferably, R is1Selected from tert-butyl, methyl, ethyl, methoxy, ethoxy, bromine atom and hydrogen atom; the R is2，R3Each independently selected from methyl and hydrogen atom.
Preferably, the preparation method of the sulfonylamidine using 2-aminomethyl pyridine and DMF-DMA as amine sources comprises the following steps:
(1) adding sulfonyl chloride into the solvent I, and dissolving to obtain a sulfonyl chloride solution; dropwise adding a mixture of 2-aminomethyl pyridine and organic base into the sulfonyl chloride solution, and after the reaction is finished, carrying out post-treatment to obtain an intermediate;
(2) and (2) mixing the intermediate obtained in the step (1), DMF-DMA, a catalyst and a solvent II, reacting, and performing post-treatment to obtain the sulfonamidine.
Specifically speaking: the invention takes 2-aminomethyl pyridine and sulfonyl chloride as raw materials to prepare sulfonyl amidine, which comprises the following steps:
(1) adding sulfonyl chloride into a certain amount of solvent I, and stirring and dissolving at room temperature; adding 2-aminomethyl pyridine and organic base into another reaction bottle, slowly dropping into the sulfonyl chloride solution, and reacting for 4-8 h; after the reaction is finished, obtaining an intermediate through rotary steaming, ice water washing, filtering and drying;
(2) adding the intermediate obtained in the step (1) into a solvent II, adding DMF-DMA and a catalyst, reacting for 6-10 h at 60-100 ℃, cooling to room temperature, extracting the reaction liquid with ethyl acetate, layering, drying and concentrating to obtain the target product, namely the sulfonamidine.
R is methyl, methoxy, tert-butyl, bromine atom or hydrogen atom, R2、R3For example, the reaction process is shown as the following formula:
Figure BDA0002528125010000031
preferably, the sulfonyl chloride used is p-methylbenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, p-tert-butylbenzenesulfonyl chloride, benzenesulfonyl chloride, p-bromophenylbenzenesulfonyl chloride or mesitylenesulfonyl chloride.
In order to obtain more intermediate products in the first-step reaction, preferably, the molar ratio of 2-aminomethyl pyridine to sulfonyl chloride to organic base is 1: 1-2; more preferably, the molar ratio of the 2-aminomethylpyridine to the sulfonyl chloride to the organic base is 1:1 to 1.3:1.5 to 1.7. Preferably, the weight ratio of the solvent I to the 2-aminomethyl pyridine is 30-50: 1.
When sulfonyl chloride is reacted with 2-aminomethylpyridine (or in step (1)), the solvent (or solvent I) used is preferably one of dichloromethane, 1, 2-dichloroethane, and tetrahydrofuran. Preferably, the solvent used in the reaction of sulfonyl chloride with 2-aminomethylpyridine (or in step (1)) is dichloromethane.
Preferably, the organic base is triethylamine, trimethylamine, pyridine or piperidine. More preferably, the organic base is triethylamine. More preferably, the molar ratio of the 2-aminomethyl pyridine to the sulfonyl chloride to the triethylamine is 1: 1-1.3: 1.5-1.7.
And (3) when the intermediate is reacted with DMF-DMA (or step (2)), the solvent (or the solvent II) is one or more of ethylene glycol, isopropanol, n-propanol, n-butanol and diethylene glycol. More preferably, the solvent (or the solvent II) is ethylene glycol.
When the intermediate is reacted with DMF-DMA (or step (2)), the catalyst used is cupric acetate monohydrate, cuprous chloride, cupric nitrate, cupric bromide, cuprous bromide. More preferably, copper acetate monohydrate.
In order to obtain products as much as possible, the molar ratio of the intermediate product to the catalyst in the second step is 1: 0.02-0.1, the weight ratio of the solvent to the intermediate product is 20-40: 1, the weight ratio of the DMF-DMA to the intermediate product is 5-30: 1, and the weight ratio of the DMF-DMA to the intermediate product is preferably 10-20: 1. More preferably, the weight ratio of the DMF-DMA to the intermediate product is 10-15: 1.
Preferably, the solvent for the reaction of the intermediate with DMF-DMA is ethylene glycol; the catalyst is copper acetate monohydrate. The reaction temperature is 60-100 ℃, and the reaction time is 6-10 hours.
Compared with the prior art, the invention has the following advantages:
1. the reaction for synthesizing the intermediate product in the first step has the advantages of simple operation, mild conditions, convenient post-treatment and high purity and yield of the obtained intermediate product.
2. The specificity of the 2-picolyl is utilized to realize the reaction of the secondary sulfonamide and DMF-DMA, and further enrich the method for synthesizing the sulfonamidine.
In conclusion, the method realizes the reaction of the secondary sulfonamide and DMF-DMA, and expands the synthetic route of the sulfonamidine. The synthesis reaction has simple operation, mild condition, convenient post-treatment and high purity and yield of the intermediate product and the product.
Drawings
FIG. 1 is a nuclear magnetic spectrum of p-toluenesulfonamidine obtained in EXAMPLE 1 of the present invention1H-NMR), nuclear magnetic data as follows:1H NMR(500MHz,DMSO-d6)δ8.19(s,1H),7.64(d,J＝8.2Hz,2H),7.32(d,J＝7.9Hz,2H),3.13(s,3H),2.88(s,3H),2.35(s,3H)。
FIG. 2 is a nuclear magnetic spectrum of p-tert-butylbenzenesulfonylamidine obtained in EXAMPLE 16 of the present invention1H-NMR), nuclear magnetic data as follows:1H NMR(500MHz,Chloroform-d)δ8.15(s,1H),7.82(d,J＝6.6Hz,2H),7.47(d,J＝8.8Hz,2H),3.12(s,3H),3.02(s,3H),1.33(s,9H)。
FIG. 3 is a hydrogen nuclear magnetic spectrum of p-methoxybenzenesulfonylamidine product obtained in EXAMPLE 17 of the present invention1H-NMR), nuclear magnetic data as follows:1H NMR(500MHz,Chloroform-d)δ8.12(s,1H),7.81(d,J＝8.9Hz,2H),6.91(d,J＝8.9Hz,2H),3.84(s,3H),3.12(s,3H),3.01(s,3H)。
FIG. 4 is a hydrogen nuclear magnetic spectrum of the product benzenesulfonamidine obtained in EXAMPLE 18 of this invention1H-NMR), nuclear magnetic data as follows:1H NMR(500MHz,Chloroform-d)δ8.15(s,1H),7.89(d,J＝7.1Hz,2H),7.57–7.39(m,3H),3.13(s,3H),3.02(s,3H)。
FIG. 5 is a nuclear magnetic resonance spectrum of the product p-bromophenylsulfonylamino obtained in example 19 of the present invention: (1H-NMR), nuclear magnetic data as follows:1H NMR(500MHz,Chloroform-d)δ8.13(s,1H),7.75(d,J＝8.6Hz,2H),7.60(d,J＝8.6Hz,2H),3.15(s,3H),3.02(s,3H)。
FIG. 6 and FIG. 7 are the hydrogen nuclear magnetic spectra of mesitylenesulfonylamidine product obtained in EXAMPLE 20 of this invention1H-NMR) and carbon nuclear magnetic spectrum, the nuclear magnetic data are as follows:1H NMR(500MHz,Chloroform-d)δ8.11(s,1H),6.91(s,2H),3.09(s,3H),2.99(s,3H),2.68(s,6H),2.27(s,3H)。13C NMR(126MHz,Chloroform-d)δ158.46,141.22,138.43,136.51,131.46,41.28,35.42,23.02,20.89。
Detailed Description
Example 1
1.14g (6mmol) of p-toluenesulfonyl chloride and 10mL of dichloromethane were added to a dry reaction flask, and dissolved by stirring at room temperature, and 10mL of a dichloromethane solution containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g (7.5mmol) of triethylamine was slowly added dropwise thereto, and after completion of the dropwise addition, the reaction was stirred at room temperature for 6 hours. And after the reaction is finished, carrying out rotary evaporation and concentration on the reaction liquid to obtain a light pink solid. The pale pink solid was washed thoroughly with deionized water in an ice water bath, filtered and dried to give an off-white powder 1.27g, 97% yield and 99% HPLC purity.
A dry three-neck flask was taken, and 0.66g (2.5mmol) of the above intermediate product N- (2-picolyl) p-toluenesulfonamide, 7.5mL of ethylene glycol, 7.5mL of DMF-DMA7.5mL, 25mg (0.125mmol) of copper acetate monohydrate were added, followed by heating to 80 ℃ and reacting for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.52g, yield 92%, and HPLC purity 99%. The nuclear magnetic data are shown in FIG. 1.
Example 2
1.14g (6mmol) of p-toluenesulfonyl chloride and 10mL of 1, 2-dichloroethane were charged into a dry reaction flask, and dissolved by stirring at room temperature, and 10mL of a 1, 2-dichloroethane solution containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g (7.5mmol) of triethylamine was slowly added dropwise thereto, and after completion of the addition, the reaction was stirred at room temperature for 6 hours. And after the reaction is finished, carrying out rotary evaporation and concentration on the reaction liquid to obtain a light pink semisolid. 40mL of deionized water was added to wash the above weak solutionA pink semisolid, then extracted with (20mL x 3) ethyl acetate, the organic layers were combined and over anhydrous MgSO4Drying and concentrating to obtain yellow white solid 1.16g, yield 88%, HPLC purity 99%.
Example 3
1.14g (6mmol) of p-toluenesulfonyl chloride and 10mL of tetrahydrofuran were added to a dry reaction flask, and dissolved by stirring at room temperature, 10mL of tetrahydrofuran containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g (7.5mmol) of triethylamine was slowly added dropwise thereto, and after the dropwise addition was completed, the reaction was stirred at room temperature for 6 hours. And after the reaction is finished, carrying out rotary evaporation and concentration on the reaction liquid to obtain a light pink semisolid. The pale pink semisolid was washed with 40mL of deionized water, extracted with (20mL x 3) ethyl acetate, and the organic layers were combined and over anhydrous MgSO4Drying and concentrating to obtain yellow white solid 1.09g, yield 83% and HPLC purity 99%.
Example 4
1.14g (6mmol) of p-toluenesulfonyl chloride and 10mL of dichloromethane were added to a dry reaction flask, and dissolved by stirring at room temperature, and 10mL of a dichloromethane solution containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.44g (7.5mmol) of trimethylamine was slowly added dropwise thereto, and after completion of the dropwise addition, the reaction was stirred at room temperature for 6 hours. And after the reaction is finished, carrying out rotary evaporation and concentration on the reaction liquid to obtain a light pink solid. The pale pink solid was washed thoroughly with deionized water in an ice water bath, filtered and dried to give an off-white powder 1.18g, with a yield of 90% and an HPLC purity of 99%.
Example 5
1.14g (6mmol) of p-toluenesulfonyl chloride and 10mL of dichloromethane were added to a dry reaction flask, and dissolved by stirring at room temperature, and 10mL of a dichloromethane solution containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.59g (7.5mmol) of pyridine was slowly added dropwise thereto, and after completion of the dropwise addition, the reaction was stirred at room temperature for 6 hours. And after the reaction is finished, carrying out rotary evaporation and concentration on the reaction liquid to obtain a light pink solid. The pale pink solid was washed thoroughly with deionized water in an ice water bath, filtered and dried to give an off-white powder 1.13g, with a yield of 86% and an HPLC purity of 99%.
Example 6
1.14g (6mmol) of p-toluenesulfonyl chloride and 10mL of dichloromethane were added to a dry reaction flask, and dissolved by stirring at room temperature, and 10mL of a dichloromethane solution containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.63g (7.5mmol) of piperidine was slowly added dropwise thereto, and after completion of the dropwise addition, the reaction was stirred at room temperature for 6 hours. And after the reaction is finished, carrying out rotary evaporation and concentration on the reaction liquid to obtain a light pink solid. The pale pink solid was washed thoroughly with deionized water in an ice water bath, filtered and dried to give an off-white powder 1.19g, with a yield of 91% and an HPLC purity of 99%.
Example 7
A dry three-necked flask was charged with 0.65g (2.5mmol) of N- (2-picolyl) p-toluenesulfonamide, which was an intermediate product obtained in example 1, 7.5mL of isopropyl alcohol, 7.5mL of DMF-DMA, and 25mg (0.125mmol) of copper acetate monohydrate, and then heated to 80 ℃ for reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.24g, yield 42%, and HPLC purity 99%.
Example 8
A dry three-necked flask was charged with 0.65g (2.5mmol) of N- (2-picolyl) p-toluenesulfonamide, which was an intermediate product obtained in example 1, 7.5mL of N-propanol, 7.5mL of DMF-DMA, and 25mg (0.125mmol) of copper acetate monohydrate, and then heated to 80 ℃ for reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.32g, yield 57%, and HPLC purity 99%.
Example 9
A dry three-necked flask was charged with 0.65g (2.5mmol) of N- (2-picolyl) p-toluenesulfonamide, which was an intermediate product obtained in example 1, 7.5mL of N-butanol, 7.5mL of DMF-DMA, and 25mg (0.125mmol) of copper acetate monohydrate, and then heated to 80 ℃ for reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying and concentrating to obtainThe yellow liquid is separated by column chromatography to obtain white powder 0.29g, the yield is 51 percent, and the HPLC purity is 99 percent.
Example 10
A dry three-necked flask was charged with 0.65g (2.5mmol) of N- (2-picolyl) p-toluenesulfonamide, which was an intermediate product obtained in example 1, 7.5mL of diethylene glycol, 7.5mL of DMF-DMA, and 25mg (0.125mmol) of copper acetate monohydrate, and then heated to 80 ℃ for reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.41g, yield 73%, and HPLC purity 99%.
Example 11
A dry three-necked flask was charged with 0.65g (2.5mmol) of N- (2-picolyl) p-toluenesulfonamide, which was an intermediate product obtained in example 1, 7.5mL of ethylene glycol, 7.5mL of DMF-DMA, and 12mg (0.125mmol) of cuprous chloride, and then heated to 80 ℃ for reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.47g, yield 84%, and HPLC purity 99%.
Example 12
A dry three-necked flask was charged with 0.65g (2.5mmol) of N- (2-picolyl) p-toluenesulfonamide, which was an intermediate product obtained in example 1, 7.5mL of ethylene glycol, 7.5mL of DMF-DMA, and 19mg (0.125mmol) of copper chloride, and then heated to 80 ℃ for reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.43g, yield 77%, and HPLC purity 99%.
Example 13
A dry three-neck flask was taken, and the intermediate product N- (2-picolyl) prepared according to the method of example 1 was added) P-toluenesulfonamide (0.65 g, 2.5mmol), ethylene glycol (7.5 mL), DMF-DMA (7.5 mL), and copper nitrate (23 mg, 0.125mmol) were added, followed by heating to 80 ℃ and reacting for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.46g, with yield of 82% and HPLC purity of 99%.
Example 14
A dry three-necked flask was charged with 0.65g (2.5mmol) of N- (2-picolyl) p-toluenesulfonamide, which was an intermediate product obtained in example 1, 7.5mL of ethylene glycol, 7.5mL of DMF-DMA, and 28mg (0.125mmol) of copper bromide, and then heated to 80 ℃ for reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.40g, yield 71%, and HPLC purity 99%.
Example 15
A dry three-necked flask was charged with 0.65g (2.5mmol) of N- (2-picolyl) p-toluenesulfonamide, which was an intermediate product obtained in example 1, 7.5mL of ethylene glycol, 7.5mL of DMF-DMA, and 18mg (0.125mmol) of cuprous bromide, and then heated to 80 ℃ for reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.41g, yield 73%, and HPLC purity 99%.
Example 16
1.40g (6mmol) of p-tert-butylbenzenesulfonyl chloride and 10mL of dichloromethane were added to a dry reaction flask, the mixture was dissolved by stirring at room temperature, 10mL of a dichloromethane solution containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g (7.5mmol) of triethylamine was slowly added dropwise thereto, and the reaction was stirred at room temperature for 6 hours after the dropwise addition. And (3) after the reaction is finished, carrying out rotary evaporation and concentration on the reaction liquid to obtain a paste. The paste was thoroughly washed with deionized water in an ice water bath to solidify it into a solid which was filtered and dried to give 1.43g of a white powder with a yield of 94% and an HPLC purity of 99%.
A dry three-necked flask was taken, and 0.76g (2.5mmol) of the above intermediate product N- (2-picolyl) p-tert-butylbenzenesulfonamide, 7.5mL of ethylene glycol, 7.5mL of DMF-DMA, and 25mg (0.125mmol) of copper acetate monohydrate were added thereto, followed by heating to 80 ℃ for reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.60g, yield 89%, and HPLC purity 99%. The nuclear magnetic data are shown in FIG. 2.
Example 17
1.24g (6mmol) of p-methoxybenzenesulfonyl chloride and 10mL of dichloromethane were added to a dry reaction flask, the mixture was dissolved with stirring at room temperature, and 10mL of a dichloromethane solution containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g (7.5mmol) of triethylamine was slowly added dropwise thereto, and the reaction was stirred at room temperature for 6 hours after the dropwise addition was completed. And (3) after the reaction is finished, carrying out rotary evaporation and concentration on the reaction liquid to obtain a paste. The paste was thoroughly washed with deionized water in an ice water bath to solidify it into a solid, which was filtered and dried to give an off-white powder 1.26g, with a yield of 91% and an HPLC purity of 99%.
A dry three-neck flask is taken, and added with 0.70g (2.5mmol) of the intermediate product N- (2-picolyl) p-methoxybenzenesulfonamide, 7.5mL of ethylene glycol, 7.5mL of DMF-DMA7.5mL and 25mg (0.125mmol) of copper acetate monohydrate, and then heated to 80 ℃ for reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.52g with yield of 86% and HPLC purity of 99%. The nuclear magnetic data are shown in FIG. 3.
Example 18
1.06g (6mmol) of benzenesulfonyl chloride and 10mL of dichloromethane were added to a dry reaction flask, the mixture was dissolved with stirring at room temperature, and 10mL of a dichloromethane solution containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g (7.5mmol) of triethylamine was slowly added dropwise thereto, and the reaction was stirred at room temperature for 6 hours after completion of the dropwise addition. And (3) after the reaction is finished, carrying out rotary evaporation and concentration on the reaction liquid to obtain a paste. The paste was thoroughly washed with deionized water in an ice water bath to solidify it into a solid, which was filtered and dried to give 1.05g of white powder with 85% yield and 99% HPLC purity.
A dry three-necked flask was taken, and added with 0.62g (2.5mmol) of the above intermediate product, i.e., N- (2-picolyl) benzenesulfonamide, 7.5mL of ethylene glycol, 7.5mL of DMF-DMA, and 25mg (0.125mmol) of copper acetate monohydrate, followed by heating to 80 ℃ for reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.36g, yield 67%, and HPLC purity 99%. The nuclear magnetic data are shown in FIG. 4.
Example 19
1.53g (6mmol) of p-bromophenylsulfonyl chloride and 10mL of dichloromethane were charged into a dry reaction flask, and dissolved by stirring at room temperature, and 10mL of a dichloromethane solution containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g (7.5mmol) of triethylamine was slowly added dropwise thereto, and after completion of the dropwise addition, the reaction was stirred at room temperature for 6 hours. And (3) after the reaction is finished, carrying out rotary evaporation and concentration on the reaction liquid to obtain a paste. The paste was thoroughly washed with deionized water in an ice water bath to solidify it into a solid which was filtered and dried to give 1.47g of a white powder with a yield of 90% and an HPLC purity of 99%.
A dry three-neck flask is taken, and added with 0.82g (2.5mmol) of the intermediate product N- (2-picolyl) p-bromobenzenesulfonamide, 7.5mL of ethylene glycol, 7.5mL of DMF-DMA7.5mL, and 25mg (0.125mmol) of copper acetate monohydrate, and then heated to 80 ℃ for reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.68g, yield 93%, and HPLC purity 99%. The nuclear magnetic data are shown in FIG. 5.
Example 20
1.31g (6mmol) of mesitylenesulfonyl chloride and 10mL of dichloromethane were added to a dry reaction flask, the mixture was dissolved by stirring at room temperature, and 10mL of a dichloromethane solution containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g (7.5mmol) of triethylamine was slowly added dropwise thereto, and the reaction was stirred at room temperature for 6 hours after the dropwise addition was completed. And (3) after the reaction is finished, carrying out rotary evaporation and concentration on the reaction liquid to obtain a paste. The paste was thoroughly washed with deionized water in an ice water bath to solidify it into a solid, which was filtered and dried to give an off-white powder 1.35g, yield 93%, HPLC purity 99%.
A dry three-necked flask was taken, and 0.73g (2.5mmol) of the above intermediate product N- (2-picolyl) mesitylenesulfonamide, 7.5mL of ethylene glycol, 7.5mL of DMF-DMA, and 25mg (0.125mmol) of copper acetate monohydrate were added thereto, followed by heating to 80 ℃ for reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, washed with 30mL of deionized water, then extracted with (20 mL. multidot.3) ethyl acetate, and the organic layers were combined and extracted with anhydrous MgSO4Drying, concentrating to obtain brown yellow liquid, and separating by column chromatography to obtain white powder 0.60g, yield 94%, and HPLC purity 99%. The nuclear magnetic data are shown in fig. 6 and 7.
The nuclear magnetic data and the melting point data of the target products obtained in the examples 1 and 7-15 are detected to be consistent with those of p-toluenesulfonyl amidine in reported documents.
Melting point: 134.6-135.0 deg.c.
The target product obtained in example 16 is detected by nuclear magnetic data and melting point data and is basically consistent with p-tert-butyl benzene sulfonyl amidine reported in the literature.
Melting point: 161.2-162.1 ℃.
The target product obtained in example 17 is detected by nuclear magnetic data and melting point data, and is consistent with p-methoxybenzenesulfonylamidine in reported literatures.
Melting point: 152.2-153.7 ℃.
The target product obtained in example 18 is detected by nuclear magnetic data and melting point data, and is consistent with the reported benzenesulfonyl amidine in the literature.
Melting point: 129.1-131.1 ℃.
The target product obtained in example 19 is detected by nuclear magnetic data and melting point data, and is consistent with p-bromophenylsulfonylamide in reported literature.
Melting point: 142.5-143.0 ℃.
The target product obtained in example 20 can be judged to be mesitylenesulfonylamidine by nuclear magnetic data and melting point data detection.
Melting point: 159.4 ℃ to 159.9 ℃.

Claims (8)

1.一种2-氨甲基吡啶与DMF-DMA作为胺源的磺酰脒的制备方法，其特征在于，包括：磺酰氯与2-氨甲基吡啶在有机碱存在下，反应得到的中间体再与DMF-DMA在催化剂存在下反应得到磺酰脒；1. the preparation method of the sulfonyl amidine of 2-aminomethyl pyridine and DMF-DMA as amine source, is characterized in that, comprises: sulfonyl chloride and 2-amino methyl pyridine are in the presence of organic base, and the middle that reaction obtains The product is then reacted with DMF-DMA in the presence of a catalyst to obtain the sulfonyl amidine; 所述磺酰氯、中间体以及磺酰脒的结构分别如下式所示：The structures of the sulfonyl chloride, the intermediate and the sulfonyl amidine are respectively shown in the following formulas:
Figure FDA0003461865240000011
Figure FDA0003461865240000011
 R1选自C1-C5的烷基；C1-C5的烷氧基；卤素原子；氢原子；R 1 is selected from a C1-C5 alkyl group; a C1-C5 alkoxy group; a halogen atom; a hydrogen atom; R2，R3各自独立的选自C1-C5的烷基；氢原子；R 2 and R 3 are each independently selected from C1-C5 alkyl groups; hydrogen atoms; 所述催化剂选自一水合醋酸铜、氯化亚铜、氯化铜、硝酸铜、溴化铜、溴化亚铜中的一种或多种；Described catalyst is selected from one or more in cupric acetate monohydrate, cuprous chloride, cupric chloride, cupric nitrate, cupric bromide, cuprous bromide; 所述DMF-DMA为N,N-二甲基甲酰胺二甲基缩醛。The DMF-DMA is N,N-dimethylformamide dimethyl acetal. 2.根据权利要求1所述的2-氨甲基吡啶与DMF-DMA作为胺源的磺酰脒的制备方法，其特征在于，包括：2. the preparation method of the sulfonyl amidine of 2-aminomethylpyridine according to claim 1 and DMF-DMA as amine source, is characterized in that, comprises: (1)向反应溶剂I中加入磺酰氯，溶解得到磺酰氯溶液；将2-氨甲基吡啶和有机碱的混合物滴加到上述磺酰氯溶液中，反应完毕，经后处理得中间体；所述反应溶剂I选自二氯甲烷、1,2-二氯乙烷、四氢呋喃中的一种或多种；(1) in reaction solvent I, add sulfonyl chloride, dissolve to obtain sulfonyl chloride solution; The mixture of 2-aminomethylpyridine and organic base is added dropwise in the above-mentioned sulfonyl chloride solution, the reaction is completed, and the intermediate is obtained through aftertreatment; Described reaction solvent I is selected from one or more in dichloromethane, 1,2-dichloroethane, tetrahydrofuran; (2)将步骤(1)得到的中间体、DMF-DMA、催化剂与反应溶剂II混合，反应完毕，后处理得磺酰脒；所述反应溶剂II选自乙二醇、异丙醇、正丙醇、正丁醇、二乙二醇中的一种或多种。(2) mixing the intermediate, DMF-DMA, catalyst obtained in step (1) with reaction solvent II, the reaction is completed, and post-processing to obtain sulfonyl amidine; the reaction solvent II is selected from ethylene glycol, isopropanol, normal One or more of propanol, n-butanol, and diethylene glycol. 3.根据权利要求1或2所述的2-氨甲基吡啶与DMF-DMA作为胺源的磺酰脒的制备方法，其特征在于，所述磺酰氯为对甲基苯磺酰氯、对甲氧基苯磺酰氯、对叔丁基苯磺酰氯、苯磺酰氯、对溴基苯磺酰氯、均三甲基苯磺酰氯。3. 2-aminomethylpyridine according to claim 1 and 2 and DMF-DMA are as the preparation method of the sulfonyl amidine of amine source, it is characterized in that, described sulfonyl chloride is p-toluenesulfonyl chloride, p-methyl benzene Oxybenzenesulfonyl chloride, p-tert-butylbenzenesulfonyl chloride, benzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, mesitylenesulfonyl chloride. 4.根据权利要求1或2所述的2-氨甲基吡啶与DMF-DMA作为胺源的磺酰脒的制备方法，其特征在于，所述有机碱为三乙胺、三甲胺、吡啶、哌啶中的一种或多种。4. 2-aminomethylpyridine according to claim 1 and 2 and DMF-DMA are as the preparation method of the sulfonyl amidine of amine source, it is characterized in that, described organic base is triethylamine, trimethylamine, pyridine, One or more of piperidines. 5.根据权利要求1或2所述的2-氨甲基吡啶与DMF-DMA作为胺源的磺酰脒的制备方法，其特征在于，所述2-氨甲基吡啶与磺酰氯、有机碱的摩尔比为1:(1～2):(1～2)。5. 2-aminomethylpyridine and DMF-DMA according to claim 1 and 2 are as the preparation method of the sulfonyl amidine of amine source, it is characterized in that, described 2-aminomethylpyridine and sulfonyl chloride, organic base The molar ratio is 1:(1~2):(1~2). 6.根据权利要求1或2所述的2-氨甲基吡啶与DMF-DMA作为胺源的磺酰脒的制备方法，其特征在于，所述中间体与催化剂的摩尔比为1:0.02～0.1，所述DMF-DMA与中间体的重量比为5～30:1。6. 2-aminomethylpyridine and DMF-DMA according to claim 1 and 2 are used as the preparation method of the sulfonyl amidine of amine source, it is characterized in that, the mol ratio of described intermediate and catalyzer is 1:0.02～ 0.1, and the weight ratio of the DMF-DMA to the intermediate is 5 to 30:1. 7.根据权利要求1或2所述的2-氨甲基吡啶与DMF-DMA作为胺源的磺酰脒的制备方法，其特征在于，所述磺酰氯与2-氨甲基吡啶反应的温度为20～40℃；所述中间体与DMF-DMA反应的温度为60～100℃。7. 2-aminomethylpyridine according to claim 1 and 2 and DMF-DMA are as the preparation method of the sulfonyl amidine of amine source, it is characterised in that the temperature of the reaction of described sulfonyl chloride and 2-aminomethylpyridine is 20-40°C; the reaction temperature of the intermediate and DMF-DMA is 60-100°C. 8.根据权利要求1或2所述的2-氨甲基吡啶与DMF-DMA作为胺源的磺酰脒的制备方法，其特征在于，所述中间体与DMF-DMA反应的溶剂为乙二醇；所述催化剂为一水合醋酸铜。8. 2-aminomethylpyridine and DMF-DMA according to claim 1 and 2 are used as the preparation method of the sulfonyl amidine of amine source, it is characterized in that, the solvent that described intermediate and DMF-DMA reacts is ethylene glycol alcohol; the catalyst is copper acetate monohydrate.
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