Synthesis method of 2-pyridine sulfonyl fluoride

Abstract

The invention discloses a synthesis method of 2-pyridine sulfonyl fluoride, which comprises the following steps: dissolving 2-mercaptopyridine in a system solution, and carrying out oxidation reaction with hydrochloric acid and sodium hypochlorite to obtain a sulfonyl chloride intermediate state; according to the method, sulfonyl chloride in an intermediate state and a potassium bifluoride aqueous solution are subjected to a substitution reaction under the catalysis of a phase transfer catalyst to obtain 2-pyridine sulfonyl fluoride, so that the synthesis process of 2-pyridine sulfonyl fluoride is effectively simplified, and the yield is improved.

Description

Technical Field

[0001] The present application relates to a method for synthesizing 2-pyridinesulfonyl fluoride, and belongs to the technical field of pharmaceutical preparation. Background Art

[0002] In the field of medicinal chemistry, sulfonyl fluoride groups have attracted considerable attention due to their unique chemical properties and broad application prospects. Through sulfur-fluorine exchange reactions, sulfonyl fluoride groups can efficiently bind to drug molecules, enabling rapid synthesis and modification. In biomedical research, they can also form covalent bonds with proteins, establishing potential bioreaction systems.

[0003] There are few methods for synthesizing sulfonyl fluoride in the prior art, which are mainly divided into classical chemical oxidation and electrochemical oxidation. The classical chemical oxidation method uses 2-mercaptopyrimidine as raw material and is oxidized with sodium hypochlorite to prepare sulfonyl fluoride with a yield of only 11%, which consumes a large amount of raw materials and is inefficient. The electrochemical oxidation method is to couple thiols and potassium fluoride by fluid electrochemistry. Although it improves the yield, the method is heavily dependent on complex electrochemical equipment, has harsh reaction conditions, poor process stability, and is difficult to achieve industrial amplification. In addition, the existing synthetic routes are mostly targeted at specific substrates, and lack universality and functional group compatibility for complex drug molecules, which further restricts the application of sulfonyl fluoride in drug design. Summary of the Invention

[0004] The purpose of this application is to overcome the deficiencies in the existing background technology, provide a method for synthesizing 2-pyridinesulfonyl fluoride, simplify the synthesis process of 2-pyridinesulfonyl fluoride, and improve the yield.

[0005] To achieve the above objectives, the technical solutions adopted in this application are: Provided is a method for synthesizing 2-pyridinesulfonyl fluoride, comprising: 2-mercaptopyridine is dissolved in the system solution and undergoes oxidation reaction with hydrochloric acid and sodium hypochlorite to obtain a sulfonyl chloride intermediate; The sulfonyl chloride intermediate reacts with a potassium bifluoride aqueous solution under the catalysis of a phase transfer catalyst to obtain 2-pyridinesulfonyl fluoride.

[0006] Furthermore, the method comprises the following steps: Dissolve 2-mercaptopyridine in a chloroalkane solvent, add hydrochloric acid and sodium hypochlorite solution dropwise in sequence, control the oxidation temperature, and stir until the reaction is complete to obtain a mixed solution containing a sulfonyl chloride intermediate; The mixed solution is separated to obtain an organic phase which is a sulfonyl chloride intermediate; The intermediate state of sulfonyl chloride is mixed with an aqueous solution of potassium bifluoride, and under the catalysis of a phase transfer catalyst, the substitution temperature is controlled and stirred until the reaction is completed, and the organic phase is collected for post-treatment to obtain 2-pyridinesulfonyl fluoride.

[0007] Furthermore, the post-processing includes: liquid separation, extraction, concentration, filtration and drying; The extraction comprises extracting with ethyl acetate or dichloromethane in a volume 5-10 times that of the substrate, concentrating the obtained organic phase at 0-50° C., adding n-heptane for displacement, filtering and drying to obtain 2-pyridinesulfonyl fluoride.

[0008] Furthermore, the mass fraction of the sodium hypochlorite added dropwise is 5 wt % to 13 wt %, and the amount of sodium hypochlorite used is 2-8 times the molar amount of 2-mercaptopyridine.

[0009] Furthermore, the mass fraction of the hydrochloric acid added dropwise is 5-30wt%.

[0010] Furthermore, the oxidation temperature and the substitution temperature are both 0-10°C.

[0011] Furthermore, the system solution is chloroalkane, and the phase transfer catalyst is tetrabutylammonium hydrogen sulfate.

[0012] Furthermore, the chloroalkane is selected from any one or more of dichloromethane, dichloroethane and chloroform.

[0013] Furthermore, the amount of tetrabutylammonium hydrogen sulfate used is 0.01-1 times the molar amount of 2-mercaptopyridine.

[0014] Furthermore, the amount of potassium bifluoride used is 1-8 times the molar amount of 2-mercaptopyridine.

[0015] Compared with the prior art, the present invention has the following beneficial effects: The present application discloses a method for synthesizing 2-pyridinesulfonyl fluoride, wherein 2-pyridinesulfonyl fluoride is prepared from the inexpensive compound 2-mercaptopyridine by oxidation with sodium hypochlorite. The raw materials are readily available and low in cost, and the post-processing is simple and the operability is strong; the method is suitable for batch scale-up.

[0016] A sodium hypochlorite aqueous solution is added dropwise to 2-mercaptopyridine in a dichloromethane and dilute hydrochloric acid environment under controlled temperature to obtain a sulfonyl chloride intermediate, and then tetrabutylammonium hydrogen sulfate and potassium bifluoride aqueous solution are added to prepare 2-pyridinesulfonyl fluoride through a one-pot process. The reaction is simple, the yield is high, and the industrial value is high, mainly reflected in mild reaction conditions, simple post-processing, high production efficiency, and high material yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is the proton nuclear magnetic resonance spectrum of the product provided in Example 3 of the present application; Figure 2 is the fluorine nuclear magnetic resonance spectrum of the product provided in Example 3 of the present application; Figure 3is the carbon-13 nuclear magnetic resonance spectrum of the product provided in Example 3 of the present application; DETAILED DESCRIPTION

[0018] The present application will be further described below in conjunction with the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solution of the present application and are not intended to limit the scope of protection of the present application.

[0019] Examples 1 to 3 provide a synthesis of 2-pyridinesulfonyl fluoride, which is prepared by a one-pot process. The synthesis process is as follows:

[0020] Specifically, compound A, i.e., 2-mercaptopyridine, is dissolved in a chloroalkane solvent and oxidized with 5-30 wt% hydrochloric acid and 5-13 wt% sodium hypochlorite to obtain a sulfonyl chloride intermediate. 0.01-1 equivalents of tetrabutylammonium hydrogen sulfate and 1-8 equivalents of potassium bifluoride aqueous solution are then added to undergo a substitution reaction, ultimately obtaining compound B, i.e., 2-pyridinesulfonyl fluoride.

[0021] The calculation basis of the equivalent in this application is 1.0 equivalent of the feed material 2-mercaptopyridine.

[0022] The reaction uses 2-8 equivalents of sodium hypochlorite, preferably 4 equivalents; preferably, a sodium hypochlorite solution with a mass fraction of 10 wt% and a hydrochloric acid with a mass fraction of 7.5 wt% are used.

[0023] Furthermore, the reaction preferably involves 4 equivalents of potassium bifluoride and 0.1 equivalents of tetrabutylammonium hydrogen sulfate.

[0024] The chloroalkane solvent is selected from one or more of dichloromethane, dichloroethane or chloroform, preferably dichloromethane.

[0025] Specifically, the method comprises the following steps: adding dilute hydrochloric acid and an aqueous sodium hypochlorite solution to the compound 2-mercaptopyridine in a dichloromethane system at a temperature controlled at 0-10° C., separating the aqueous phase from the obtained reaction solution, adding tetrabutylammonium hydrogen sulfate and potassium bifluoride, and stirring until the reaction is completed; and extracting, concentrating, beating, filtering, and drying the reaction solution to obtain compound B.

[0026] The extraction process uses ethyl acetate or dichloromethane with a volume of 5-10 times that of the substrate, and the obtained organic phase is concentrated under reduced pressure at 0-50°C, and replaced by adding n-heptane, filtered, and dried to finally obtain 2-pyridinesulfonyl fluoride.

[0027] Furthermore, the oxidation reaction and the substitution reaction are both carried out in the temperature range of -20°C to 20°C, preferably 0-10°C, and most preferably 0°C.

[0028] Example 1:

[0029] This embodiment provides a method for synthesizing 2-pyridinesulfonyl fluoride, which is prepared by a one-pot process, comprising the following steps: 11.1 g of the compound 2-mercaptopyridine was dissolved in 444 mL of 40 times dichloromethane and 222 mL of 20 times 7.5 wt% hydrochloric acid. 298 g of 4 equivalents of 10 wt% sodium hypochlorite was added at 0-10 °C and stirred at 120 rpm for 1 h in the temperature range of 0-10 °C. The resulting reaction solution was allowed to stand and the aqueous phase was removed. 0.3 g of 0.1 equivalents of tetrabutylammonium hydrogen sulfate and 156 g of 4 equivalents of 20 wt% potassium bifluoride aqueous solution were added to the organic phase and stirred at 0-10 °C for 1-3 h until the reaction was complete. After the reaction, the mixture was extracted three times with 10 times dichloromethane (222 mL x 3), and the organic phase was concentrated under reduced pressure, replaced with three times n-heptane (33 mL x 3), filtered, and dried to obtain 13.7 g of compound 2-pyridinesulfonyl fluoride with a yield of 85%.

[0030] Example 2:

[0031] This embodiment provides a method for synthesizing 2-pyridinesulfonyl fluoride, which is prepared by a one-pot process, comprising the following steps: 30 g of the compound 2-mercaptopyridine (270 mmol) was dissolved in 1200 mL of dichloromethane and cooled to 0-10 °C. 150 mL of concentrated hydrochloric acid and 1606 g of 8 equivalents of 10 wt% sodium hypochlorite were added dropwise in sequence. The mixture was stirred at this temperature for 0.5 h and then allowed to stand. The liquid was separated and the organic phase was collected. 9.2 g of 0.1 equivalent of tetrabutylammonium hydrogen sulfate and 4 equivalents of potassium bifluoride aqueous solution (84.2 g of potassium bifluoride dissolved in 600 mL of water) were added to the organic phase. The resulting reaction mixture was stirred at a temperature range of 0-10 °C until the reaction was completed. The reaction was monitored by HPLC. After the reaction was completed, the reaction solution was allowed to stand for separation. The aqueous phase was extracted three times with 300 mL of dichloromethane each time. The organic phases were combined and concentrated under reduced pressure at 30°C to remove dichloromethane. 90 mL of n-heptane was added to the concentrate, and the solution was further concentrated to a remaining 60 mL. The solution was filtered and washed with 30 mL of n-heptane. The filter cake was dried to obtain 37 g of a white solid, which was the target product, with a yield of 86%.

[0032] Example 3:

[0033] This embodiment provides a method for synthesizing 2-pyridinesulfonyl fluoride, which is prepared by a one-pot process, comprising the following steps: Dissolve 3 kg of 2-mercaptopyridine (27 mol) in dichloromethane (120 L), cool to 0-10 °C, and add 20 L of concentrated hydrochloric acid and 80 kg of 8 equivalents of 10 wt% sodium hypochlorite solution dropwise. Stir and maintain the mixture for 0.5 h, then allow to stand, separate, and collect the organic phase. To the organic phase, 920 g of 0.1 equivalent tetrabutyl sulfide and 8 equivalents of potassium bifluoride aqueous solution (16.8 kg of potassium bifluoride dissolved in 120 kg of water) were added. The resulting reaction mixture was stirred at 0-10°C until the reaction was complete. The reaction was monitored by HPLC. After completion, the reaction mixture was allowed to stand for separation. The aqueous phase was extracted three times with 30 L of dichloromethane each time. The organic phases were combined and concentrated under reduced pressure at 30°C to remove the dichloromethane. 9 L of n-heptane was added to the concentrate, and the solution was concentrated to a remaining 6 L. The mixture was filtered, rinsed with 3 L of n-heptane, and the filter cake was dried to yield 3.7 kg of the desired product as a white solid in an 86% yield.

[0034] like Figures 1 to 3 As shown, the proton nuclear magnetic resonance spectrum, fluorine nuclear magnetic resonance spectrum and carbon-13 nuclear magnetic resonance spectrum of the product of this example were respectively performed, confirming that it is the target product.

[0035] The above is only a preferred embodiment of the present application. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present application. These improvements and modifications should also be regarded as the scope of protection of the present application.

Claims

1. A method for synthesizing 2-pyridinesulfonyl fluoride, characterized in that: include: 2-mercaptopyridine is dissolved in the system solution and undergoes oxidation reaction with hydrochloric acid and sodium hypochlorite to obtain a sulfonyl chloride intermediate; The sulfonyl chloride intermediate reacts with a potassium bifluoride aqueous solution under the catalysis of a phase transfer catalyst to obtain 2-pyridinesulfonyl fluoride.

2. The synthesis method according to claim 1, wherein The method comprises the following steps: Dissolve 2-mercaptopyridine in a chloroalkane solvent, add hydrochloric acid and sodium hypochlorite solution dropwise in sequence, control the oxidation temperature, and stir until the reaction is complete to obtain a mixed solution containing a sulfonyl chloride intermediate; The mixed solution is separated to obtain an organic phase which is a sulfonyl chloride intermediate; The intermediate state of sulfonyl chloride is mixed with an aqueous solution of potassium bifluoride, and under the catalysis of a phase transfer catalyst, the substitution temperature is controlled and stirred until the reaction is completed, and the organic phase is collected for post-treatment to obtain 2-pyridinesulfonyl fluoride.

3. The synthesis method according to claim 2, characterized in that The post-processing includes: liquid separation, extraction, concentration, filtration and drying; The extraction comprises extracting with ethyl acetate or dichloromethane in a volume 5-10 times that of the substrate, concentrating the obtained organic phase at 0-50° C., adding n-heptane for displacement, filtering and drying to obtain 2-pyridinesulfonyl fluoride.

4. The synthesis method according to claim 2, wherein The mass fraction of the sodium hypochlorite added dropwise is 5 wt % to 13 wt %, and the amount of sodium hypochlorite used is 2-8 times the molar amount of 2-mercaptopyridine.

5. The synthesis method according to claim 2, characterized in that The mass fraction of the hydrochloric acid added dropwise is 5-30wt%.

6. A method for synthesizing 2-pyridinesulfonyl fluoride according to claim 2, characterized in that, The oxidation temperature and substitution temperature are both 0-10°C.

7. The synthesis method according to claim 1, characterized in that The system solution is chloroalkane, and the phase transfer catalyst is tetrabutylammonium hydrogen sulfate.

8. The synthesis method according to claim 7, characterized in that The chloroalkane is selected from any one or more of dichloromethane, dichloroethane and chloroform.

9. The method for synthesizing 2-pyridinesulfonyl fluoride according to claim 7, wherein: The amount of tetrabutylammonium hydrogen sulfate used is 0.01-1 times the molar amount of 2-mercaptopyridine.

10. The synthesis method according to claim 1, characterized in that The amount of potassium bifluoride used is 1-8 times the molar amount of 2-mercaptopyridine.

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