CN111574413A - A kind of preparation method of sulfonyl amidine with 2-aminomethylpyridine and DMF-DMA as amine source - Google Patents

Abstract

The invention discloses a preparation method of sulfonyl amidine with 2-aminomethyl pyridine and DMF-DMA as amine sources, comprising the following steps: firstly, reacting sulfonyl chloride with 2-aminomethyl pyridine to obtain an intermediate product; then , the intermediate product and DMF-DMA are reacted at 60-100 ℃ in the presence of a catalyst, and then cooled to room temperature, the reaction solution is extracted with ethyl acetate, layered, dried and concentrated to obtain the target product sulfonyl amidine. The method of the invention realizes the reaction of the secondary sulfonamide and DMF-DMA, and expands the synthesis path of the sulfonyl amidine. The synthesis reaction has simple operation, mild conditions, convenient post-processing, and the obtained intermediate products and products have high purity and yield.

Description

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

technical field

The invention belongs to the field of organic intermediate synthesis, in particular to a method for preparing a sulfonyl amidine using 2-aminomethylpyridine and N,N-dimethylformamide dimethyl acetal (DMF-DMA) as amine sources.

Background technique

Amidine compounds are an important class of nitrogen-containing organic compounds. With the change of the position and number of substituents on the N atom, the physicochemical properties of amidine compounds and their derivatives also change, so they are used in all aspects of production and life. Amidine compounds can be used to synthesize surfactants, dyes, medical agents, fungicides, insect repellants and intermediates for a series of important compounds. Amidine compounds exist in many natural compounds with biological activity, so they are considered as important pharmaceutical intermediates.

When the N atom in the carbon-nitrogen double bond is connected to a sulfonyl group, the amidine compounds tend to have higher biological activity and pharmacological effects, and thus have attracted much attention from the scientific and industrial circles.

At present, diazonium salts or azide compounds are often used as amine sources for the synthesis of sulfonyl amidines. For example, using tetrafluoroborate diazonium salt and sulfonamide, acetonitrile in 1,2-dichloroethane to generate sulfonyl amidine; using sulfonyl azide and tertiary amine under the catalysis of copper salt and carbon tetrachloride can also be prepared A series of sulfonyl amidines were obtained. However, the generally unstable and explosive properties of diazonium salts and azides limit the applicability of such methods.

When simple sulfonamide and amide are used as amine sources, oxalyl chloride or thionyl chloride, etc. and amide are required to make Wilsmeier reagent to successfully conduct dehydration reaction to obtain sulfonyl amidine. The disadvantage is that the use of oxalyl chloride needs to be excessive, and the use of thionyl chloride will generate sulfur dioxide gas.

SUMMARY OF THE INVENTION

The present invention overcomes the defect of single amine source of the above route, and proposes a preparation method of sulfonyl amidine compounds which is more environmentally friendly. That is, after the reaction of 2-aminomethylpyridine and p-toluenesulfonyl chloride to prepare N-(2-pyridylmethyl)-p-toluenesulfonamide, the secondary sulfonamide and DMF-DMA (N,N-dimethylformamide are realized) dimethyl acetal) to prepare p-toluenesulfonyl amidine.

In order to solve the above-mentioned technical problems, the technical solutions provided by the present invention are as follows:

A preparation method of sulfonyl amidine with 2-aminomethyl pyridine and DMF-DMA as amine source, comprising: sulfonyl chloride and 2-aminomethyl pyridine in the presence of an organic base, reacting the intermediate obtained with DMF-DMA In the presence of a catalyst, the reaction obtains the sulfonyl amidine;

The structures of the sulfonyl chloride, the intermediate and the sulfonyl amidine are respectively shown in the following formulas:

R ₁ is selected from a C1-C5 alkyl group; a C1-C5 alkoxy group; a halogen atom; a hydrogen atom.

R ₂ and R ₃ are each independently selected from C1-C5 alkyl groups; hydrogen atoms.

Preferably, the R ₁ is selected from tert-butyl group, methyl group, ethyl group, methoxy group, ethoxy group, bromine atom and hydrogen atom; the R ₂ and R ₃ are independently selected from methyl group and hydrogen atom. .

As preferably, a kind of preparation method of the sulfonyl amidine of 2-aminomethylpyridine and DMF-DMA as amine source, comprises:

(1) in solvent 1, 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;

(2) Mix the intermediate, DMF-DMA, catalyst and solvent II obtained in step (1), react, and post-process to obtain the sulfonyl amidine.

Specifically: the present invention uses 2-aminomethylpyridine and sulfonyl chloride as raw materials to prepare sulfonyl amidine, comprising the following steps:

(1) in a certain amount of solvent I, add sulfonyl chloride, and stir and dissolve at room temperature; In another reaction flask, add 2-aminomethylpyridine and organic base, then slowly drip into the above-mentioned sulfonyl chloride solution, The reaction is carried out for 4 to 8 hours; after the reaction is completed, the intermediate is obtained by rotary evaporation, washing with ice water, filtration and drying;

(2) Add the intermediate obtained in step (1) into solvent II, add DMF-DMA, a catalyst, and react at 60-100° C. for 6-10 hours. After cooling to room temperature, the reaction solution is extracted with ethyl acetate, and the mixture is separated. layer, dried and concentrated to obtain the target product sulfonyl amidine.

Taking R as methyl group, methoxyl group, tert-butyl group, bromine atom or hydrogen atom, and R ₂ and R ₃ as methyl group or hydrogen atom as example, the above reaction process is shown in the following formula:

Preferably, the used sulfonyl chloride is p-toluenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, p-tert-butylbenzenesulfonyl chloride, benzenesulfonyl chloride, p-bromobenzenesulfonyl chloride or mesitylenesulfonyl chloride.

In order to obtain more intermediate products in the first step reaction, preferably, the molar ratio of 2-aminomethylpyridine, sulfonyl chloride, and organic base is 1:1～2:1～2; as a further preference, 2-aminomethylpyridine The molar ratio of methylpyridine, sulfonyl chloride and organic base is 1:1-1.3:1.5-1.7. Preferably, the weight ratio of solvent I and 2-aminomethylpyridine is 30-50:1.

When the 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, when the sulfonyl chloride is reacted with 2-aminomethylpyridine (or in step (1)), the solvent used is dichloromethane.

Preferably, the organic base is triethylamine, trimethylamine, pyridine and piperidine. As a further preference, the organic base is triethylamine. As a further preference, the molar ratio of the 2-aminomethylpyridine, the sulfonyl chloride and the triethylamine is 1:1-1.3:1.5-1.7.

When the intermediate reacts with DMF-DMA (or step (2)), the solvent used (or solvent II) is one or more of ethylene glycol, isopropanol, n-propanol, n-butanol, and diethylene glycol. kind. As a further preference, the solvent (or solvent II) is ethylene glycol.

When the intermediate reacts with DMF-DMA (or step (2)), the catalyst used is copper acetate monohydrate, cuprous chloride, cupric chloride, cupric nitrate, cupric bromide, and cuprous bromide. More preferably, it is copper acetate monohydrate.

In order to obtain as many products as possible, the molar ratio of the intermediate product used in the second step reaction to the catalyst is 1:0.02～0.1, the weight ratio of the solvent used to the intermediate product is 20～40:1, the used DMF-DMA and the intermediate product are The weight ratio of the DMF-DMA to the intermediate product is 5-30:1, more preferably, the weight ratio of the DMF-DMA to the intermediate product is 10-20:1. As a further preference, the weight ratio of the DMF-DMA to the intermediate product is 10-15:1.

Preferably, the solvent for the reaction between the intermediate and DMF-DMA is ethylene glycol; the catalyst is copper acetate monohydrate. The reaction temperature is 60-100°C, and the reaction time is 6-10 hours.

Compared with the prior art, the present invention has the following advantages:

1. The reaction operation of the first step to synthesize the intermediate product is simple, the conditions are mild, the post-processing is convenient, and the obtained intermediate product has high purity and yield.

2. Utilizing the particularity of 2-pyridylmethyl, the reaction between secondary sulfonamide and DMF-DMA was realized, which further enriched the method for synthesizing sulfonyl amidine.

To sum up, the method of the present invention realizes the reaction of the secondary sulfonamide and DMF-DMA, and expands the synthetic route of the sulfonyl amidine. The synthesis reaction has simple operation, mild conditions, convenient post-processing, and the obtained intermediate products and products have high purity and yield.

Description of drawings

Fig. 1 is the hydrogen nuclear magnetic spectrum ( ¹ H-NMR) of the product p-toluenesulfonyl amidine obtained in specific embodiment 1 of the present invention, and the nuclear magnetic data are as follows: ¹ H 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 the hydrogen nuclear magnetic spectrum ( ¹ H-NMR) of the product p-tert-butylbenzenesulfonyl amidine obtained in specific embodiment 16 of the present invention, and the nuclear magnetic data are as follows: ¹ H NMR (500MHz, Chloroform-d) δ8.15 ( s, 1H), 7.82 (d, J=6.6 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 3.12 (s, 3H), 3.02 (s, 3H), 1.33 (s, 9H).

Fig. 3 is the hydrogen nuclear magnetic spectrum ( ¹ H-NMR) of the product p-methoxybenzenesulfonyl amidine obtained in specific embodiment 17 of the present invention, and the nuclear magnetic data are as follows: ¹ H 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 the hydrogen nuclear magnetic spectrum ( ¹ H-NMR) of the product benzenesulfonyl amidine obtained in the specific embodiment of the present invention, and the nuclear magnetic data are as follows: ¹ H NMR (500MHz, Chloroform-d) δ8.15 (s, 1H) , 7.89 (d, J=7.1 Hz, 2H), 7.57–7.39 (m, 3H), 3.13 (s, 3H), 3.02 (s, 3H).

Fig. 5 is the hydrogen nuclear magnetic spectrum ( ¹ H-NMR) of the product p-bromobenzenesulfonyl amidine obtained in specific embodiment 19 of the present invention, and the nuclear magnetic data are as follows: ¹ H NMR (500MHz, Chloroform-d) δ8.13 (s , 1H), 7.75 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 3.15 (s, 3H), 3.02 (s, 3H).

Fig. 6, Fig. 7 are respectively the hydrogen nuclear magnetic spectrogram ( ¹ H-NMR) and carbon nuclear magnetic spectrogram of the obtained product mesitylene sulfonyl amidine in the specific embodiment of the present invention 20, and the nuclear magnetic data are as follows: ¹ H NMR (500MHz) , Chloroform-d) δ 8.11(s, 1H), 6.91(s, 2H), 3.09(s, 3H), 2.99(s, 3H), 2.68(s, 6H), 2.27(s, 3H). ¹³ C NMR (126 MHz, Chloroform-d) δ 158.46, 141.22, 138.43, 136.51, 131.46, 41.28, 35.42, 23.02, 20.89.

Detailed ways

Example 1

1.14g (6mmol) of p-toluenesulfonyl chloride and 10mL of dichloromethane were added to the dry reaction flask, stirred and dissolved at room temperature, and 10mL of 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g (7.5mmol) of 2-aminomethylpyridine were slowly added dropwise in 10mL. The solution of triethylamine in dichloromethane was added dropwise, and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated by rotary evaporation to obtain a pale pink solid. In an ice-water bath, the above-mentioned pale pink solid was fully washed with deionized water, filtered and dried to obtain 1.27 g of yellow-white powder with a yield of 97% and a HPLC purity of 99%.

Get a dry three-necked flask, add above-mentioned intermediate product namely N-(2-pyridylmethyl) p-toluenesulfonamide 0.66g (2.5mmol), ethylene glycol 7.5mL, DMF-DMA 7.5mL, copper acetate monohydrate 25mg ( 0.125 mmol), and then the temperature was raised to 80°C for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried with anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.52 g, 92% yield, 99% HPLC purity. The NMR data are shown in Figure 1.

Example 2

1.14 g (6 mmol) of p-toluenesulfonyl chloride and 10 mL of 1,2-dichloroethane were added to the dry reaction flask, stirred and dissolved at room temperature, and 10 mL of 0.54 g (5 mmol) of 2-aminomethylpyridine and 0.76 g of 2-aminomethylpyridine and 0.76 g (7.5 mmol) triethylamine solution in 1,2-dichloroethane was added dropwise, and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated by rotary evaporation to obtain a pale pink semi-solid. 40 mL of deionized water was added to wash the above pale pink semi-solid, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried over anhydrous MgSO ₄ , and concentrated to obtain 1.16 g of a yellow-white solid, yield 88%, HPLC purity is 99%.

Example 3

1.14g (6mmol) of p-toluenesulfonyl chloride and 10mL of tetrahydrofuran were added to the dry reaction flask, stirred and dissolved at room temperature, and 10mL of 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g (7.5mmol) of triethyl were slowly added dropwise. The amine in tetrahydrofuran was added dropwise, and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated by rotary evaporation to obtain a pale pink semi-solid. 40 mL of deionized water was added to wash the above pale pink semi-solid, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried over anhydrous MgSO ₄ , and concentrated to obtain 1.09 g of a yellow-white solid, yield 83%, HPLC purity is 99%.

Example 4

1.14g (6mmol) of p-toluenesulfonyl chloride and 10mL of dichloromethane were added to the dry reaction flask, stirred and dissolved at room temperature, and 10mL of 0.54g (5mmol) of 2-aminomethylpyridine and 0.44g (7.5mmol) of 0.54g (5mmol) of 2-aminomethylpyridine and 0.44g (7.5mmol) were slowly added dropwise The solution of trimethylamine in dichloromethane was added dropwise, and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated by rotary evaporation to obtain a pale pink solid. In an ice-water bath, the above pale pink solid was fully washed with deionized water, filtered and dried to obtain 1.18 g of a yellow-white powder with a yield of 90% and a HPLC purity of 99%.

Example 5

1.14g (6mmol) of p-toluenesulfonyl chloride and 10mL of dichloromethane were added to the dry reaction flask, stirred and dissolved at room temperature, and 10mL of 0.54g (5mmol) of 2-aminomethylpyridine and 0.59g (7.5mmol) of 0.54g (5mmol) of 2-aminomethylpyridine and 0.59g (7.5mmol) were slowly added dropwise. The solution of pyridine in dichloromethane was added dropwise, and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated by rotary evaporation to obtain a pale pink solid. In an ice-water bath, the above pale pink solid was fully washed with deionized water, filtered and dried to obtain 1.13 g of a yellow-white powder with a yield of 86% and a HPLC purity of 99%.

Example 6

1.14g (6mmol) of p-toluenesulfonyl chloride and 10mL of dichloromethane were added to the dry reaction flask, stirred and dissolved at room temperature, and 10mL containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.63g (7.5mmol) of 0.54g (5mmol) was slowly added dropwise. The solution of piperidine in dichloromethane was added dropwise, and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated by rotary evaporation to obtain a pale pink solid. In an ice-water bath, the above pale pink solid was fully washed with deionized water, filtered and dried to obtain 1.19 g of a yellow-white powder with a yield of 91% and a HPLC purity of 99%.

Example 7

Take a dry three-necked flask, add the intermediate product prepared according to the method of Example 1, namely N-(2-pyridylmethyl) p-toluenesulfonamide 0.65g (2.5mmol), isopropanol 7.5mL, DMF-DMA 7.5g mL, 25 mg (0.125 mmol) of copper acetate monohydrate, and then the temperature was raised to 80° C. to react for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried with anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.24 g, yield 42%, HPLC purity 99%.

Example 8

Take a dry three-necked flask, add the intermediate product prepared according to the method in Example 1, namely N-(2-pyridylmethyl) p-toluenesulfonamide 0.65g (2.5mmol), n-propanol 7.5mL, DMF-DMA 7.5g mL, 25 mg (0.125 mmol) of copper acetate monohydrate, and then the temperature was raised to 80° C. to react for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried with anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.32 g, yield 57%, HPLC purity 99%.

Example 9

Take a dry three-necked flask, add the intermediate product prepared according to the method of Example 1, namely N-(2-pyridylmethyl) p-toluenesulfonamide 0.65g (2.5mmol), n-butanol 7.5mL, DMF-DMA 7.5 mL, 25 mg (0.125 mmol) of copper acetate monohydrate, and then the temperature was raised to 80° C. to react for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried over anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.29 g, yield 51%, HPLC purity 99%.

Example 10

Take a dry three-necked flask, add the intermediate product prepared according to the method of Example 1, namely N-(2-pyridylmethyl) p-toluenesulfonamide 0.65g (2.5mmol), diethylene glycol 7.5mL, DMF-DMA 7.5 mL, 25 mg (0.125 mmol) of copper acetate monohydrate, and then the temperature was raised to 80° C. to react for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried with anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.41 g, 73% yield, 99% HPLC purity.

Example 11

Take a dry three-necked flask, add the intermediate product prepared according to the method of Example 1, namely N-(2-pyridylmethyl) p-toluenesulfonamide 0.65g (2.5mmol), ethylene glycol 7.5mL, DMF-DMA 7.5 mL, 12 mg (0.125 mmol) of cuprous chloride, and then the temperature was raised to 80° C. to react for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried with anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.47 g g, 84% yield, 99% HPLC purity.

Example 12

Take a dry three-necked flask, add the intermediate product prepared according to the method of Example 1, namely N-(2-pyridylmethyl) p-toluenesulfonamide 0.65g (2.5mmol), ethylene glycol 7.5mL, DMF-DMA 7.5 mL, 19 mg (0.125 mmol) of copper chloride, and then the temperature was raised to 80° C. to react for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried with anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.43 g, 77% yield, 99% HPLC purity.

Example 13

Take a dry three-necked flask, add the intermediate product prepared according to the method of Example 1, namely N-(2-pyridylmethyl) p-toluenesulfonamide 0.65g (2.5mmol), ethylene glycol 7.5mL, DMF-DMA 7.5 mL, 23 mg (0.125 mmol) of copper nitrate, and then the temperature was raised to 80° C. to react for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried with anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.46 g, 82% yield, 99% HPLC purity.

Example 14

Take a dry three-necked flask, add the intermediate product prepared according to the method of Example 1, namely N-(2-pyridylmethyl) p-toluenesulfonamide 0.65g (2.5mmol), ethylene glycol 7.5mL, DMF-DMA 7.5 mL, 28 mg (0.125 mmol) of copper bromide, and then the temperature was raised to 80° C. to react for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried with anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.40 g, 71% yield, 99% HPLC purity.

Example 15

Take a dry three-necked flask, add the intermediate product prepared according to the method of Example 1, namely N-(2-pyridylmethyl) p-toluenesulfonamide 0.65g (2.5mmol), ethylene glycol 7.5mL, DMF-DMA 7.5 mL, 18 mg (0.125 mmol) of cuprous bromide, and then the temperature was raised to 80° C. to react for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried with anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.41 g, 73% yield, 99% HPLC purity.

Example 16

1.40g (6mmol) of p-tert-butylbenzenesulfonyl chloride and 10mL of dichloromethane were added to the dry reaction flask, stirred and dissolved at room temperature, and 10mL of 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g ( 7.5 mmol) triethylamine solution in dichloromethane was added dropwise, and the reaction was stirred at room temperature for 6 hours. After the completion of the reaction, the reaction solution was concentrated by rotary evaporation to obtain a paste. In an ice-water bath, the above paste was fully washed with deionized water, solidified into a solid, filtered and dried to obtain 1.43 g of white powder with a yield of 94% and a HPLC purity of 99%.

Get a dry three-necked flask, add above-mentioned intermediate product namely N-(2-pyridylmethyl) p-tert-butylbenzenesulfonamide 0.76g (2.5mmol), ethylene glycol 7.5mL, DMF-DMA 7.5mL, acetic acid monohydrate After 25 mg (0.125 mmol) of copper, the temperature was raised to 80° C. and reacted for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried with anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.60 g, yield 89%, HPLC purity 99%. The NMR data are shown in Figure 2.

Example 17

1.24g (6mmol) of p-methoxybenzenesulfonyl chloride and 10mL of dichloromethane were added to the dry reaction flask, stirred and dissolved at room temperature, and 10mL of 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g ( 7.5 mmol) triethylamine solution in dichloromethane was added dropwise, and the reaction was stirred at room temperature for 6 hours. After the completion of the reaction, the reaction solution was concentrated by rotary evaporation to obtain a paste. In an ice-water bath, the paste was fully washed with deionized water, solidified into a solid, filtered and dried to obtain 1.26 g of a yellow-white powder with a yield of 91% and a HPLC purity of 99%.

Take a dry three-necked flask, add the above-mentioned intermediate product, namely N-(2-pyridylmethyl) p-methoxybenzenesulfonamide 0.70g (2.5mmol), ethylene glycol 7.5mL, DMF-DMA 7.5mL, acetic acid monohydrate After 25 mg (0.125 mmol) of copper, the temperature was raised to 80° C. and reacted for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried with anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.52 g, yield 86%, HPLC purity 99%. The NMR data are shown in Figure 3.

Example 18

Add 1.06g (6mmol) of benzenesulfonyl chloride and 10mL of dichloromethane to the dry reaction flask, stir and dissolve at room temperature, and slowly dropwise add 10mL containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g (7.5mmol) of trichloromethane. The dichloromethane solution of ethylamine was added dropwise, and the reaction was stirred at room temperature for 6 hours. After the completion of the reaction, the reaction solution was concentrated by rotary evaporation to obtain a paste. In an ice-water bath, the above paste was fully washed with deionized water, solidified into a solid, filtered and dried to obtain 1.05 g of white powder with a yield of 85% and HPLC purity of 99%.

Get a dry three-necked flask, add above-mentioned intermediate product namely N-(2-pyridylmethyl) benzenesulfonamide 0.62g (2.5mmol), ethylene glycol 7.5mL, DMF-DMA 7.5mL, copper acetate monohydrate 25mg (0.125g) mmol), and then the temperature was raised to 80°C for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried with anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.36 g, yield 67%, HPLC purity 99%. The NMR data are shown in Figure 4.

Example 19

1.53g (6mmol) of p-bromobenzenesulfonyl chloride and 10mL of dichloromethane were added to the dry reaction flask, stirred and dissolved at room temperature, and 10mL of 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g (7.5g of 2-aminomethylpyridine) were slowly added dropwise. mmol) triethylamine in dichloromethane, the dropwise addition was completed, and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated by rotary evaporation to obtain a paste. In an ice-water bath, the above paste was fully washed with deionized water, solidified into a solid, filtered and dried to obtain 1.47 g of white powder with a yield of 90% and a HPLC purity of 99%.

Take a dry three-necked flask, add the above-mentioned intermediate product, namely N-(2-pyridylmethyl) p-bromobenzenesulfonamide 0.82g (2.5mmol), ethylene glycol 7.5mL, DMF-DMA 7.5mL, copper acetate monohydrate 25 mg (0.125 mmol), and then the temperature was raised to 80° C. to react for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, then extracted with (20 mL*3) ethyl acetate, the organic layers were combined and dried with anhydrous MgSO ₄ , concentrated to obtain a yellow liquid, which was separated by column chromatography to obtain a white powder 0.68 g, 93% yield, 99% HPLC purity. The NMR data are shown in Figure 5.

Example 20

1.31 g (6 mmol) of mesitylene sulfonyl chloride and 10 mL of dichloromethane were added to the dry reaction flask, stirred and dissolved at room temperature, and 10 mL of 0.54 g (5 mmol) of 2-aminomethylpyridine and 0.76 g ( 7.5 mmol) triethylamine solution in dichloromethane was added dropwise, and the reaction was stirred at room temperature for 6 hours. After the completion of the reaction, the reaction solution was concentrated by rotary evaporation to obtain a paste. In an ice-water bath, the paste was fully washed with deionized water, solidified into a solid, filtered and dried to obtain 1.35 g of a yellow-white powder with a yield of 93% and HPLC purity of 99%.

Get a dry three-necked flask, add above-mentioned intermediate product namely N-(2-pyridylmethyl) mesitylene sulfonamide 0.73g (2.5mmol), ethylene glycol 7.5mL, DMF-DMA 7.5mL, acetic acid monohydrate After 25 mg (0.125 mmol) of copper, the temperature was raised to 80° C. and reacted for 8 hours. The reaction was completed, cooled to room temperature, washed with 30 mL of deionized water, and then extracted with (20 mL*3) ethyl acetate. The organic layers were combined and dried with anhydrous MgSO ₄ . Concentrated to obtain a brownish-yellow liquid, which was separated by column chromatography to obtain a white powder 0.60 g, yield 94%, HPLC purity 99%. The NMR data are shown in Figure 6 and Figure 7.

The target products obtained in Examples 1 and 7-15 are basically consistent with the p-toluenesulfonyl amidine in the reported literature through the detection of nuclear magnetic data and melting point data.

Melting point: 134.6℃-135.0℃.

The target product obtained in Example 16 is basically consistent with the p-tert-butylbenzenesulfonyl amidine in the reported literature through the detection of nuclear magnetic data and melting point data.

Melting point: 161.2℃-162.1℃.

The target product obtained in Example 17 is basically consistent with the p-methoxybenzenesulfonyl amidine in the reported literature through the detection of nuclear magnetic data and melting point data.

Melting point: 152.2℃-153.7℃.

The target product obtained in Example 18 was detected by nuclear magnetic data and melting point data, which was basically consistent with the benzenesulfonyl amidine in the reported literature.

Melting point: 129.1℃-131.1℃.

The target product obtained in Example 19 was detected by nuclear magnetic data and melting point data, which was basically consistent with the p-bromobenzenesulfonyl amidine in the reported literature.

Melting point: 142.5℃-143.0℃.

The target product obtained in Example 20 can be determined to be mesitylenesulfonyl amidine through the detection of nuclear magnetic data and melting point data.

Melting point: 159.4℃-159.9℃.

Claims (10)

1. a preparation method of 2-aminomethylpyridine and DMF-DMA as the sulfonyl amidine of amine source, is characterized in that, comprises: sulfonyl chloride and 2-aminomethylpyridine are in the presence of organic base, and the middle that reaction obtains The product is then reacted with DMF-DMA catalyst to obtain sulfonyl amidine; The structures of the sulfonyl chloride, the intermediate and the sulfonyl amidine are respectively shown in the following formulas:

R ₁ is selected from a C1-C5 alkyl group; a C1-C5 alkoxy group; a halogen atom; a hydrogen atom. R ₂ and R ₃ are each independently selected from C1-C5 alkyl groups; hydrogen atoms. 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) in reaction solvent 1, add sulfonyl chloride, dissolve and obtain sulfonyl chloride solution; The mixture of 2-aminomethylpyridine and organic base is added dropwise in above-mentioned sulfonyl chloride solution, and the reaction is completed, and intermediate is obtained through aftertreatment; (2) mixing the intermediate obtained in step (1), DMF-DMA, catalyst and reaction solvent II, the reaction is completed, and the sulfonyl amidine is obtained after post-processing. 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. the preparation method of the sulfonyl amidine of 2-aminomethyl pyridine according to claim 1 and 2 and DMF-DMA as amine source, it is characterized in that, the solvent that described sulfonyl chloride and 2-amino methyl pyridine react One or more selected from dichloromethane, 1,2-dichloroethane and tetrahydrofuran; the solvent for the reaction of the intermediate and DMF-DMA is selected from ethylene glycol, isopropanol, n-propanol, normal One or more of butanol and diethylene glycol. 5. 2-aminomethylpyridine according to claim 1 and 2 and DMF-DMA are used 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. 6. 2-aminomethylpyridine according to claim 1 and 2 and DMF-DMA are used 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). 7. 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. 8. 2-aminomethylpyridine according to claim 1 and 2 and DMF-DMA are used as the preparation method of the sulfonyl amidine of amine source, it is characterized in that, described catalyzer is selected from monohydrate copper acetate, cuprous chloride , one or more of cupric chloride, cupric nitrate, cupric bromide and cuprous bromide. 9. 2-aminomethylpyridine according to claim 1 and 2 and DMF-DMA are used as the preparation method of the sulfonyl amidine of amine source, it is characterized in that, the temperature of described sulfonyl chloride and 2-aminomethylpyridine reaction is 20-40°C; the reaction temperature of the intermediate and DMF-DMA is 60-100°C. 10. 2-aminomethylpyridine according to claim 1 and 2 and DMF-DMA 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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