A method for synthesizing 2-chloro-3-hydrazinylpyridine

Abstract

The application belongs to the field of organic synthesis and particularly relates to a synthesis method of 2-chloro-3-hydrazinylpyridine, which comprises the following steps: pyridine and N-chlorosuccinimide are subjected to chlorination in the presence of FeCl3 and 1,10-phenanthroline to generate 2,3-dichloropyridine; 2,3-dichloropyridine and hydrazine hydrate are subjected to reaction in the presence of a Pd catalyst, a Salen ligand and an alkali to generate 2-chloro-3-hydrazinylpyridine; the application has mild reaction conditions, low cost, good safety and a good industrial production application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing 2-chloro-3-hydrazinopyridine. Background Technology

[0002] 2-Chloro-3-hydrazinopyridine, with the following structural formula: It is an important organic synthesis intermediate, whose molecular structure simultaneously contains chlorine atoms, hydrazine groups, and a pyridine ring. It exhibits high reactivity and can be used to synthesize a variety of biologically active compounds, such as nucleic acids, certain vitamins, antibiotics, hormones, pigments, and alkaloids. Furthermore, it can be used to synthesize a wide variety of heterocyclic compounds with diverse properties, showing broad application prospects in pharmaceuticals, pesticides, herbicides, dyes, and plastics.

[0003] Currently, the main methods for synthesizing 2-chloro-3-hydrazinopyridine are as follows:

[0004] 1) 2-Chloro-3-aminopyridine method: 2-Chloro-3-aminopyridine is used as a raw material, reacting with sodium nitrite to form a diazonium salt, which is then reacted with hydrazine hydrate to form 2-chloro-3-hydrazinopyridine. As disclosed in WO2014182033A1: A mixture of 3-amino-2-chloropyridine and purified water is cooled to below 15°C with stirring. While maintaining the temperature of the reaction mixture below 25°C, hydrochloric acid is added dropwise. The reaction mixture is stirred for 30 minutes, then cooled to below -15°C. While maintaining the temperature of the reaction mixture below -5°C, a solution of sodium nitrite in water is added dropwise, reacting to obtain 2-chloro-3-aminopyridine. However, the yield of the above method is low. The reaction formula is:

[0005] 2) 2-Chloro-3-halopyridine method: 2-Chloro-3-halopyridine is used as a raw material and reacted with hydrazine hydrate to produce 2-chloro-3-hydrazinopyridine. However, this method contains multiple halogen atoms, resulting in poor reaction selectivity and a large number of byproducts.

[0006] In view of the many problems existing in the current technology, there is an urgent need to develop a new synthetic method for 2-chloro-3-hydrazinopyridine. Summary of the Invention

[0007] The purpose of this invention is to provide a method for synthesizing 2-chloro-3-hydrazinopyridine, thereby solving the problems of low yield and purity, and poor reaction selectivity in existing technologies. To address these technical problems, this invention provides the following technical solution:

[0008] A method for synthesizing 2-chloro-3-hydrazinopyridine includes the following steps;

[0009]

[0010] Step 1: Pyridine and N-chlorosuccinimide undergo a chlorination reaction in the presence of FeCl3 and 1,10-phenanthroline to generate 2,3-dichloropyridine;

[0011] Step 2: 2,3-Dichloropyridine and hydrazine hydrate react in the presence of a Pd catalyst, Salen ligand and a base to generate 2-chloro-3-hydrazinopyridine;

[0012] The structural formula of the Salen ligand is:

[0013] In some embodiments, in step 2, the alkali is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, potassium hydroxide, and sodium hydroxide.

[0014] In some embodiments, in step 2, the Pd catalyst is selected from one or more of Pd(OAc)2, PdCl2, Pd(NO3)2, PdSO4, and Pd(dba)2.

[0015] In some embodiments, in step 1, the molar ratio of pyridine to N-chlorosuccinimide is 1:(2-2.5); the molar ratio of pyridine to FeCl3 is 1:(0.05-0.2); and the molar ratio of pyridine to 1,10-phenanthroline is 1:(0.05-0.2).

[0016] In some implementation schemes, in step 1, the reaction temperature is 50–80°C and the reaction time is 1–5 hours.

[0017] In some embodiments, in step 1, the reaction solvent is selected from one or more of benzene, toluene, 1,4-dioxane, dimethyl sulfoxide, ethanol, methanol, tert-butanol, isopropanol, dichloromethane, chloroform, n-butyl ether, carbon tetrachloride, dimethyl adipate, ethyl acetate, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, acetone, N,N-dimethylformamide, acetonitrile, cyclohexane, and n-hexane.

[0018] In some embodiments, in step 2, the molar ratio of 2,3-dichloropyridine to hydrazine hydrate is 1:(1.5-2.5); the molar ratio of 2,3-dichloropyridine to Pd catalyst is 1:(0.05-0.2); the molar ratio of 2,3-dichloropyridine to Salen ligand is 1:(0.05-0.2); and the molar ratio of 2,3-dichloropyridine to base is 1:(2-5).

[0019] In some implementation schemes, in step 2, the reaction temperature is 50–100°C and the reaction time is 1–5 h.

[0020] In some embodiments, in step 2, the reaction solvent is selected from one or more of benzene, toluene, dimethyl sulfoxide, ethanol, methanol, tert-butanol, isopropanol, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, acetone, N,N-dimethylformamide, and acetonitrile.

[0021] In some embodiments, in step 2, after the reaction is complete, deionized water is added, the mixture is extracted with ethyl acetate, the organic phases are combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product is then purified by silica gel column chromatography to obtain 2-chloro-3-hydrazinopyridine.

[0022] The present invention has achieved the following beneficial effects:

[0023] 1) This invention uses pyridine and N-chlorosuccinimide as raw materials to efficiently generate 2,3-dichloropyridine intermediates under the catalytic system of FeCl3 and 1,10-phenanthroline, and the post-processing is simple.

[0024] 2) This invention obtains Salen ligands through extensive experimental screening. The ligand, when used in conjunction with the Pd catalyst, can selectively react the 3-chlorine on pyridine to generate 2-chloro-3-hydrazinopyridine. The reaction conditions are mild, the cost is low, and the safety is good, making it a promising candidate for industrial production. Detailed implementation method:

[0025] Embodiments of the present invention are described in detail below, with examples of the embodiments shown. The embodiments described below with reference to the examples are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention.

[0026] The endpoints and any values ​​of the ranges described in this invention 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 endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0027] Preparation Example 1: Preparation of Salen Ligands

[0028]

[0029] Under nitrogen protection, diphenylethylenediamine (0.1 mol), salicylaldehyde (0.2 mol), and anhydrous ethanol (100 mL) were added to a round-bottom flask equipped with a magnetic stir bar, and the mixture was heated to 75 °C and stirred for 5 h. After the reaction was complete, the product was filtered to obtain a pale yellow crude product, which was then recrystallized from anhydrous ethanol to obtain a pale yellow powder, namely Salen ligand, with a yield of 95.2%.

[0030] LC-MS(ESI):[M+H] + =421.2.

[0031] 1 H-NMR (500MHz, CDCl3): δ (ppm): 13.31 (s, 2H), 8.32 (s, 2H), 7.45-7.34 (m, 10H), 7.32 (dd, 5H), 7.10 (dd, 5H), 4.75 (s, 2H).

[0032] Example 1

[0033]

[0034] Step 1: Synthesis of 2,3-dichloropyridine

[0035] Pyridine (0.1 mol), FeCl3 (0.01 mol), and 1,10-phenanthroline (0.01 mol) were added to acetonitrile (100 mL), stirred until homogeneous, and then N-chlorosuccinimide (0.22 mol) was slowly added. The mixture was heated to 60 °C under nitrogen atmosphere and stirred for 5 h. After the reaction was complete, deionized water (100 mL) was added, followed by extraction with dichloromethane (3 × 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow crude solid. Finally, the crude solid was recrystallized from 80% methanol aqueous solution to obtain a white solid with a yield of 89.7% and an HPLC purity of 99.2%.

[0036] LC-MS(ESI):[M+H] + =148.0.

[0037] Step 2: Synthesis of 2-chloro-3-hydrazinopyridine

[0038] 0.1 mol of 2,3-dichloropyridine, 0.005 mol of Pd(OAc)₂, 0.01 mol of Salen ligand obtained in Preparation Example 1, and 0.4 mol of sodium carbonate were added to THF (200 mL). After stirring until homogeneous, 0.2 mol of hydrazine hydrate (N₂H₄·H₂O) was slowly added dropwise. The mixture was heated to 65 °C and stirred for 3 h under nitrogen atmosphere. After the reaction was complete, 200 mL of deionized water was added, followed by extraction with ethyl acetate (3 × 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent DCM:PE volume ratio 1:3) to obtain 13.3 g of solid, with a yield of 92.7% and an HPLC purity of 99.5%.

[0039] 1H-NMR (500MHz, CDCl3): δ(ppm):7.81-7.77(m,1H),7.56-7.38(m,1H),7.22–7.13(m,1H),5.75(s,1H),3.65(s,2H).

[0040] Example 2

[0041]

[0042] Step 1: Synthesis of 2,3-dichloropyridine

[0043] Pyridine (0.1 mol), FeCl3 (0.005 mol), and 1,10-phenanthroline (0.01 mol) were added to DMSO (100 mL), stirred until homogeneous, and then N-chlorosuccinimide (0.2 mol) was slowly added. The mixture was heated to 80 °C under nitrogen atmosphere and stirred for 3 h. After the reaction was complete, deionized water (100 mL) was added, followed by extraction with dichloromethane (3 × 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow crude solid. Finally, the crude solid was recrystallized from 80% methanol aqueous solution to obtain a white solid with a yield of 85.2% and an HPLC purity of 99.1%.

[0044] LC-MS(ESI):[M+H] + =148.0.

[0045] Step 2: Synthesis of 2-chloro-3-hydrazinopyridine

[0046] 0.1 mol of 2,3-dichloropyridine, 0.01 mol of PdCl2, 0.01 mol of Salen ligand obtained in Preparation Example 1, and 0.3 mol of cesium carbonate were added to THF (200 mL). After stirring until homogeneous, 0.2 mol of hydrazine hydrate (N2H4·H2O) was slowly added dropwise. The mixture was heated to 60 °C and stirred for 5 h under nitrogen atmosphere. After the reaction was complete, 200 mL of deionized water was added, followed by extraction with ethyl acetate (3 × 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent DCM:PE volume ratio 1:3) to obtain 12.9 g of solid, with a yield of 89.9% and an HPLC purity of 99.3%.

[0047] 1 H-NMR (500MHz, CDCl3): δ(ppm):7.81-7.77(m,1H),7.56-7.38(m,1H),7.22–7.13(m,1H),5.75(s,1H),3.65(s,2H).

[0048] Example 3

[0049]

[0050] Step 1: Synthesis of 2,3-dichloropyridine

[0051] Pyridine (0.1 mol), FeCl3 (0.01 mol), and 1,10-phenanthroline (0.02 mol) were added to ethanol (100 mL), stirred until homogeneous, and then N-chlorosuccinimide (0.22 mol) was slowly added. The mixture was heated to 65 °C under nitrogen atmosphere and stirred for 5 h. After the reaction was complete, deionized water (100 mL) was added, followed by extraction with dichloromethane (3 × 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow crude solid. Finally, the crude solid was recrystallized from 80% methanol aqueous solution to obtain a white solid with a yield of 91.3% and an HPLC purity of 99.4%.

[0052] LC-MS(ESI):[M+H] + =148.0.

[0053] Step 2: Synthesis of 2-chloro-3-hydrazinopyridine

[0054] 0.1 mol of 2,3-dichloropyridine, 0.01 mol of Pd(NO3)2, 0.01 mol of Salen ligand obtained in Preparation Example 1, and 0.4 mol of potassium carbonate were added to 200 mL of DMSO. After stirring until homogeneous, 0.22 mol of hydrazine hydrate (N2H4·H2O) was slowly added dropwise. The mixture was heated to 75 °C and stirred for 3 h under nitrogen atmosphere. After the reaction was complete, 200 mL of deionized water was added, followed by extraction with ethyl acetate (3 × 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent DCM:PE volume ratio 1:3) to obtain 13.7 g of solid, with a yield of 95.5% and an HPLC purity of 99.6%.

[0055] 1 H-NMR (500MHz, CDCl3): δ(ppm):7.81-7.77(m,1H),7.56-7.38(m,1H),7.22–7.13(m,1H),5.75(s,1H),3.65(s,2H).

[0056] The above embodiments are merely illustrative examples and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for synthesizing 2-chloro-3-hydrazinopyridine, comprising the following steps; ； Step 1: Pyridine and N 1,10-Chlorosuccinimide undergoes a chlorination reaction in the presence of FeCl3 and 1,3-phenanthroline to generate 2,3-dichloropyridine; Step 2: 2,3-Dichloropyridine and hydrazine hydrate react in the presence of a Pd catalyst, Salen ligand and a base to generate 2-chloro-3-hydrazinopyridine; The structural formula of the Salen ligand is: ; In step 2, the alkali is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, potassium hydroxide, and sodium hydroxide; In step 2, the Pd catalyst is selected from one or more of Pd(OAc)2, PdCl2, Pd(NO3)2, PdSO4, and Pd(dba)2; In step 1, the reaction temperature is 50~80℃ and the reaction time is 1~5h; In step 2, the reaction temperature is 50~100℃ and the reaction time is 1~5h.

2. The synthesis method according to claim 1, characterized in that, In step 1, the molar ratio of pyridine to N-chlorosuccinimide is 1:(2~2.5); the molar ratio of pyridine to FeCl3 is 1:(0.05~0.2); and the molar ratio of pyridine to 1,10-phenanthroline is 1:(0.05~0.2).

3. The synthesis method according to claim 1, characterized in that, In step 1, the reaction solvent is selected from benzene, toluene, 1,4-dioxane, dimethyl sulfoxide, ethanol, methanol, tert-butanol, isopropanol, dichloromethane, chloroform, n-butyl ether, carbon tetrachloride, dimethyl adipate, ethyl acetate, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, acetone, etc. N,N - One or more of dimethylformamide, acetonitrile, cyclohexane, and n-hexane.

4. The synthesis method according to claim 1, characterized in that, In step 2, the molar ratio of 2,3-dichloropyridine to hydrazine hydrate is 1:(1.5~2.5); the molar ratio of 2,3-dichloropyridine to Pd catalyst is 1:(0.05~0.2); the molar ratio of 2,3-dichloropyridine to Salen ligand is 1:(0.05~0.2); and the molar ratio of 2,3-dichloropyridine to base is 1:(2~5).

5. The synthesis method according to claim 1, characterized in that, In step 2, the reaction solvent is selected from benzene, toluene, dimethyl sulfoxide, ethanol, methanol, tert-butanol, isopropanol, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, acetone, etc. N,N - One or more of dimethylformamide and acetonitrile.

6. The synthesis method according to claim 1, characterized in that, In step 2, after the reaction is complete, deionized water is added, and the mixture is extracted with ethyl acetate. The organic phases are combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product is then purified by silica gel column chromatography to obtain 2-chloro-3-hydrazinopyridine.

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