A preparation method of 5-fluoro-2-hydrazinopyridine dihydrochloride

Abstract

The present invention relates to the technical field of organic synthesis and provides a preparation method of 5-fluoro-2-hydrazinopyridine dihydrochloride. The preparation method comprises the following steps: dissolving 2,5-difluoropyridine in ethanol, adding hydrazine hydrate, heating for reaction, and then using a mixed solution of hydrochloric acid and ethyl acetate for crystallization to obtain the 5-fluoro-2-hydrazinopyridine dihydrochloride. Compared with the existing method, the method provided by the present invention has low reaction temperature, high yield (the yield can reach more than 65%), and is simpler to operate.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing 5-fluoro-2-hydrazinopyridine dihydrochloride. Background Art

[0002] 5-Fluoro-2-hydrazinylpyridine dihydrochloride is an important pharmaceutical intermediate, and the current synthesis method needs to be further improved. CN115605467A proposes a synthesis method for 5-fluoro-2-hydrazinylpyridine. To a solution of 2,5-difluoropyridine (500mg, 4.34mmol) in ethanol (2.0mL), hydrazine hydrate (434mg, 8.69mmol, 85% in water) is added. The mixture is stirred overnight in a sealed tube at 120°C. The mixture is cooled and concentrated to dryness. The residue is distributed between ethyl acetate and water. The organic phase is washed with brine, dried over sodium sulfate and concentrated. The residue is ground with petroleum ether and filtered to obtain 5-fluoro-2-hydrazinylpyridine (270mg, 2.13mmol, 49% yield) as a white solid. The method requires a temperature of 120°C and needs to be reacted in a sealed tube.

[0003] Therefore, how to develop a new synthesis method, improve the yield and simplify the operation is of great value for the production and application of 5-fluoro-2-hydrazinopyridine dihydrochloride. Summary of the Invention

[0004] The technical problem to be solved by the present invention is that the operating conditions for preparing 5-fluoro-2-hydrazinopyridine dihydrochloride in the prior art are difficult and the yield is low.

[0005] In order to solve the above technical problems, the present invention provides a preparation method of 5-fluoro-2-hydrazinopyridine dihydrochloride. The preparation method comprises: dissolving 2,5-difluoropyridine in ethanol, adding hydrazine hydrate, heating for reaction, and then using a mixed solution of hydrochloric acid and ethyl acetate for crystallization to obtain the 5-fluoro-2-hydrazinopyridine dihydrochloride.

[0006]

[0007] The preparation method provided by the present invention has high yield and simple operation. The existing method uses hydrazine hydrate as a solvent and reacts at 100°C overnight. It is found that the raw materials cannot be completely reacted. During post-treatment, they are poured into water and extracted with ethyl acetate for more than 5 times, with a yield of only 40%. On the basis of the existing method, the reaction temperature is increased to 130°C and the reaction is allowed to proceed overnight, but the yield can only be increased to 43%. Prolonging the reaction time or further increasing the reaction temperature cannot further increase the reaction yield. Moreover, the above method requires the use of more hydrazine hydrate, and the post-treatment process contacts water. Some of the product will dissolve in water and cannot be extracted by ethyl acetate, resulting in waste and generating more waste liquid. In addition, a two-step reaction is required to obtain the hydrochloride, which does not meet the requirements of green chemistry. Compared with the existing method, the method provided by the present invention has a low reaction temperature, a high yield, and is simpler to operate.

[0008] Preferably, relative to 1 g of 2,5-difluoropyridine, the volume of hydrazine hydrate used is 1.5-3 mL, for example, 1.5 mL, 2 mL, 2.5 mL or 3 mL, and the volume of ethanol used is 6-8 mL, for example, 6 mL, 7 mL or 8 mL.

[0009] In the present invention, the product is prevented from contacting water during the post-treatment process, so that the product can be more easily extracted.

[0010] Preferably, the temperature of the heating reaction is 70-90°C, for example, 70°C, 75°C, 80°C, 85°C or 90°C.

[0011] Preferably, the heating reaction time is 30 to 40 hours, for example, 30 hours, 35 hours or 40 hours.

[0012] Preferably, after the heating reaction, the solvent is removed, and the mixture is dried, and then crystallized using a mixed solution of hydrochloric acid and ethyl acetate, and filtered to obtain the 5-fluoro-2-hydrazinopyridine dihydrochloride.

[0013] The implementation of the present invention has the following beneficial effects:

[0014] The preparation method of 5-fluoro-2-hydrazinopyridine dihydrochloride provided by the present invention has relatively low operating conditions, does not need to be carried out in a sealed tube, has a low reaction temperature, can react under ethanol reflux, has a high yield of more than 65%, and has high application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the product prepared in Example 1. DETAILED DESCRIPTION

[0016] The following is a detailed description of the specific embodiments of the present invention. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention and are not intended to limit the present invention.

[0017] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0018] Example 1

[0019] This embodiment provides a method for preparing 5-fluoro-2-hydrazinopyridine dihydrochloride

[0020] 200 g of 2,5-difluoropyridine was added to a three-necked flask and dissolved in 1.4 L of ethanol. 400 mL of hydrazine hydrate was added while stirring and the mixture was heated for 36 hours (the reaction liquid changed from colorless and transparent to slightly yellow and transparent). LCMS showed that the reaction of the raw materials was basically complete. The reaction liquid was cooled to room temperature and the solvent was evaporated under vacuum to obtain a light green solid (the solid contained water at this time). The solid was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and filtered to remove the solid. A solution of hydrochloric acid and ethyl acetate was added while stirring in an ice bath. A large amount of solid precipitated. The mixture was stirred for 15 minutes, filtered, and the filter cake was air-dried to obtain 236 g of a light brown solid product with a yield of 68%. The H NMR spectrum of the product is shown below. Figure 1 shown.

[0021] 1H NMR (400MHz, DMSO) δ 10.26 (s, 2H), 9.28 (s, 1H), 8.23 ​​(d, J=2.9Hz, 1H), 7.69 (td, J=8.7, 3.0Hz, 1H), 6.95 (dd, J=9.1, 3.7Hz, 1H).

[0022] Example 2

[0023] This embodiment provides a method for preparing 5-fluoro-2-hydrazinopyridine dihydrochloride

[0024] 100 g of 2,5-difluoropyridine was added to a three-necked flask, and 0.6 L of ethanol was added to dissolve it. 150 mL of hydrazine hydrate was added while stirring, and the reaction was heated for 36 hours (the reaction liquid changed from colorless and transparent to slightly yellow and transparent). LCMS detected that the reaction of the raw materials was basically completed. The reaction solution was cooled to room temperature and the solvent was evaporated under vacuum to obtain a light green solid (the solid contained water at this time). The solid was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and then filtered to remove the solid. A solution of hydrochloric acid and ethyl acetate was added while stirring under an ice bath. A large amount of solid precipitated, stirred for 15 minutes, filtered, and the filter cake was dried to obtain 108.5 g of a light brown solid product.

[0025] Example 3

[0026] This embodiment provides a method for preparing 5-fluoro-2-hydrazinopyridine dihydrochloride

[0027] 100 g of 2,5-difluoropyridine was added to a three-necked flask, and 0.8 L of ethanol was added to dissolve it. 300 mL of hydrazine hydrate was added while stirring, and the reaction was heated for 36 hours (the reaction liquid changed from colorless and transparent to slightly yellow and transparent). LCMS detected that the reaction of the raw material was basically completed, and the reaction solution was cooled to room temperature. The solvent was evaporated under vacuum to obtain a light green solid (the solid contained water at this time). The solid was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and then filtered to remove the solid. A solution of hydrochloric acid and ethyl acetate was added while stirring under an ice bath. A large amount of solid precipitated, stirred for 15 minutes, filtered, and the filter cake was dried to obtain 103 g of a light brown solid product.

[0028] Example 4

[0029] The difference between this embodiment and embodiment 1 is that the solvent ethanol is replaced by methanol in this embodiment, and the yield is 63.5%.

[0030] Example 5

[0031] The difference between this embodiment and embodiment 1 is that the volume of hydrazine hydrate in this embodiment is 100 mL and the yield is 62.8%.

[0032] Example 6

[0033] The difference between this embodiment and embodiment 1 is that the volume of hydrazine hydrate in this embodiment is 800 mL and the yield is 64%.

[0034] As can be seen from the yields of the examples of the present invention, the present invention improves the product yield from 43% to 68% through the changes in post-treatment, and reduces the amount of raw materials used. Moreover, during the post-treatment process, the product is prevented from contacting water, making it easier to extract the product.

[0035] In addition, in the present invention, the solvent and feed ratio preferably used in Example 1 are more important for improving the reaction yield. When the solvent is replaced with methanol or the feed ratio is changed, the reaction yield decreases.

[0036] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A method for preparing 5-fluoro-2-hydrazinopyridine dihydrochloride, characterized in that: The preparation method comprises: dissolving 2,5-difluoropyridine in ethanol, adding hydrazine hydrate, heating for reaction, removing the solvent, drying, crystallizing using a mixed solution of hydrochloric acid and ethyl acetate, and filtering to obtain the 5-fluoro-2-hydrazinopyridine dihydrochloride; Relative to 1 g of 2,5-difluoropyridine, the volume of hydrazine hydrate used is 1.5-3 mL, and the volume of ethanol used is 6-8 mL.

2. The preparation method according to claim 1, characterized in that The temperature of the heating reaction is 70-90°C.

3. The preparation method according to claim 1, wherein The heating reaction time is 30 to 40 hours.

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