CN111574413A - Preparation method of sulfonylamidine using 2-aminomethyl pyridine and DMF-DMA as amine source - Google Patents
Preparation method of sulfonylamidine using 2-aminomethyl pyridine and DMF-DMA as amine source Download PDFInfo
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- CN111574413A CN111574413A CN202010510716.1A CN202010510716A CN111574413A CN 111574413 A CN111574413 A CN 111574413A CN 202010510716 A CN202010510716 A CN 202010510716A CN 111574413 A CN111574413 A CN 111574413A
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- 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
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- 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
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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
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:
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:
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)8.19(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 are as follows：1H NMR(500MHz,Chloroform-d)8.15(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)8.12(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)8.15(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)8.13(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)8.11(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)158.46,141.22,138.43,136.51,131.46,41.28,35.42,23.02,20.89。
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.
Taking a dry three-neck flask, addingThe intermediate product, namely N- (2-picolyl) p-toluenesulfonamide 0.66g (2.5mmol), ethylene glycol 7.5mL, DMF-DMA7.5mL, copper acetate monohydrate 25mg (0.125mmol) was added, and the temperature was raised 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, 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. 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 1.16g, 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-neck flask is taken and added with the intermediate product prepared according to the method of example 1, namely N-(2-picolyl) p-toluenesulfonamide 0.65g (2.5mmol), n-propanol 7.5mL, DMF-DMA7.5mL, copper acetate monohydrate 25mg (0.125mmol), then warmed to 80 ℃ for reaction 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, concentrating to obtain yellow liquid, and separating by column chromatography to obtain white powder 0.29g, yield 51%, and HPLC purity 99%.
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 complete, it was cooled to room temperature, washed with 30mL of deionized water, extracted with (20 mL. multidot.3) ethyl acetate, the organic layers combined andwith 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-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 23mg (0.125mmol) of copper nitrate, 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 0.46g, 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-neck flask was taken and charged with the solution prepared in example 10.65g (2.5mmol) of N- (2-picolyl) p-toluenesulfonamide as an intermediate product, 7.5mL of ethylene glycol, 7.5mL of DMF-DMA and 18mg (0.125mmol) of cuprous bromide, and then 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 0.41g, 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 (10)
1. A method for preparing 2-aminomethyl pyridine and DMF-DMA (dimethyl formamide) -derived sulfonyl amidine is characterized by comprising 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 a DMF-DMA catalyst to obtain sulfonyl amidine;
the structures of the sulfonyl chloride, the intermediate and the sulfonamidine are respectively shown as the following formulas:
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.
2. The method of claim 1 for preparing a sulfonylamidine of the amine origin of 2-aminomethylpyridine with DMF-DMA, comprising:
(1) adding sulfonyl chloride into the reaction 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 reaction solvent II, and after the reaction is finished, carrying out post-treatment to obtain the sulfonamidine.
3. The method of claim 1 or 2, wherein the sulfonyl chloride is p-methylbenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, p-tert-butylbenzenesulfonyl chloride, benzenesulfonyl chloride, p-bromophenylbenzenesulfonyl chloride, or mesitylenesulfonyl chloride.
4. The method for preparing sulfonylamidines according to claim 1 or 2, wherein said sulfonyl chloride is reacted with 2-aminomethylpyridine in a solvent selected from one or more of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran; the solvent for the reaction of the intermediate and DMF-DMA is one or more selected from ethylene glycol, isopropanol, n-propanol, n-butanol and diethylene glycol.
5. The method of claim 1 or 2, wherein the organic base is one or more of triethylamine, trimethylamine, pyridine, and piperidine.
6. The method for preparing sulfonylamidines from 2-aminomethylpyridine and DMF-DMA as amine sources according to claim 1 or 2, wherein the molar ratio of 2-aminomethylpyridine to sulfonyl chloride to organic base is 1 (1-2) to (1-2).
7. The method for preparing sulfonylamidines using 2-aminomethylpyridine and DMF-DMA as amine sources according to claim 1 or 2, wherein the molar ratio of the intermediate to the catalyst is 1: 0.02-0.1, and the weight ratio of the DMF-DMA to the intermediate is 5-30: 1.
8. The process of claim 1 or 2, wherein the catalyst is selected from one or more of cupric acetate monohydrate, cuprous chloride, cupric nitrate, cupric bromide, cuprous bromide.
9. The method for preparing sulfonylamidines according to claim 1 or 2, wherein the reaction temperature of sulfonyl chloride with 2-aminomethylpyridine is 20 to 40 ℃; the temperature of the reaction of the intermediate and DMF-DMA is 60-100 ℃.
10. The process for the preparation of sulfonylamidines of amine origin according to claim 1 or 2, characterized in that the solvent of reaction of said intermediate with DMF-DMA is ethylene glycol; the catalyst is copper acetate monohydrate.
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