Synthesis method of 3-chloro-2-hydrazinopyridine

Abstract

The invention relates to a synthesis method of 3-chloro-2-hydrazinopyridine. According to the method, 2, 3-dichloropyridine and hydrazine hydrate are used as raw materials, potassium carbonate is used as alkali, and the 3-chloro-2-hydrazinopyridine is obtained at a high yield under the condition of a certain pressure. The method has the advantages that the dosage of hydrazine hydrate can be effectively reduced, the problem of excessive hydrazine hydrate in the synthesis process of 3-chloro-2-hydrazinopyridine is solved, and the method has the advantages of atom economy, simple and feasible process, convenience in three-waste treatment, high product yield and purity and the like, and is suitable for industrial production of 3-chloro-2-hydrazinopyridine.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediates, and more particularly to a method for synthesizing 3-chloro-2-hydrazinopyridine. Background Technology

[0002] Invertebrates can cause severe crop yield reductions and pose a significant threat to efficient agriculture. Therefore, the development of a highly effective, low-toxicity, inexpensive, and environmentally safe pesticide is urgently needed. Chlorantraniliprole, a novel o-formamide insecticide discovered and developed by DuPont in 2000, is a highly effective, low-toxicity, and uniquely mechanism-of-action ryanodine receptor insecticide. 3-Chloro-2-hydrazinopyridine is a key intermediate in the synthesis of chlorantraniliprole.

[0003] Regarding the synthesis methods of 3-chloro-2-hydrazinopyridine, the methods reported at home and abroad mainly involve reacting 2,3-dichloropyridine with a large amount of hydrazine hydrate at high temperature.

[0004]

[0005] Jiangsu Yangnong Chemical Co., Ltd. disclosed a method for synthesizing pyridine hydrazine in patent CN102627629A, with an equivalent ratio of dichloropyridine to hydrazine hydrate of 1:4.0. Nantong Yaben Chemical Co., Ltd. also disclosed a method for synthesizing pyridine hydrazine in patent CN106187998A, with an equivalent ratio of dichloropyridine to hydrazine hydrate of 1:3.0. If the amount of hydrazine hydrate is reduced, a large amount of dichloropyridine remains, resulting in a low reaction yield. Reducing the equivalent of hydrazine hydrate to 1.1-1.5 equivalents reduces the reaction yield to 51%. Patent CN114057632A discloses an environmentally friendly method for synthesizing 3-chloro-2-hydrazinopyridine, in which hydrazine hydrate is only slightly in excess during the reaction. However, this method uses two catalysts, cyclodextrin and potassium fluoride, resulting in higher costs. Furthermore, the reproducibility of this reaction is poor; we were unable to reproduce the reaction in Comparative Example 3. Hydrazine hydrate is toxic and a potential explosive chemical. Excessive hydrazine hydrate can lead to excessive levels of COD and ammonia nitrogen in wastewater, and also pose safety hazards during post-treatment. There has been no effective industrial solution for treating excess hydrazine hydrate. Although industrial production of 3-chloro-2-hydrazinopyridine has been ongoing, there is still significant room for improvement from a green process perspective, particularly in terms of both economics and environmental impact.

[0006] Solving the problem of excess hydrazine hydrate in the synthesis of 3-chloro-2-hydrazinopyridine has been a long-standing technical challenge in this field. This invention effectively reduces the equivalent amount of hydrazine hydrate while ensuring a high yield. Summary of the Invention

[0007] The purpose of this invention is to provide an atom-economical method for synthesizing 3-chloro-2-hydrazinopyridine, addressing the problems existing in the prior art.

[0008] To achieve the above objectives, the technical solution of this invention is: a method for synthesizing 3-chloro-2-hydrazinopyridine, using 2,3-dichloropyridine and hydrazine hydrate as raw materials, adding alkali and solvent, and obtaining 3-chloro-2-hydrazinopyridine under certain pressure conditions, the specific reaction formula is as follows:

[0009]

[0010] Preferably, the equivalent ratio of 2,3-dichloropyridine to hydrazine hydrate is 1:1-1.5.

[0011] Preferably, the hydrazine hydrate is an aqueous solution containing 50%-80% hydrazine hydrate.

[0012] Preferably, the mass ratio of 2,3-dichloropyridine to the solvent is 1:3-5.

[0013] Preferably, the mass ratio of 2,3-dichloropyridine to the base is 1:1.1-2.

[0014] Preferably, the solvent is n-butanol or ethanol.

[0015] Preferably, the alkali is potassium carbonate.

[0016] Preferably, the pressure is 0.1 MPa to 0.4 MPa.

[0017] The beneficial effects of this invention are as follows: The method for synthesizing 3-chloro-2-hydrazinopyridine provided by this invention uses potassium carbonate as an acid-binding agent, uses less hydrated hydrazine as feed, reduces costs, and makes production safer. It has atom economy, simple and easy process, convenient waste treatment and good economic performance, and has good industrialization prospects. Detailed Implementation

[0018] Example 1

[0019] 2,3-Dichloropyridine (22.2 g, 150 mmol), 80% hydrazine hydrate (14.08 g, 225 mmol), potassium carbonate (24.88 g, 180 mmol), and n-butanol (70 g) were added to a 200 ml autoclave equipped with a thermometer, pressure gauge, magnetic stirrer, inlet, and vent valve. The autoclave was purged and vented three times with 0.2 MPa nitrogen gas while stirring. The vent valve was closed, and the pressure inside the autoclave was maintained at one atmosphere. The autoclave was heated to 130 °C and stirred for 24 hours. After heating to 130 °C, the pressure inside the autoclave rose to 0.3-0.4 MPa. After cooling the system to room temperature, the autoclave was vented and disassembled. The reaction solution was filtered under reduced pressure to obtain a crude product. The crude product was washed with 50 ml of water and filtered again to obtain light purple crystals (19.45 g, yield 90.31%, purity 99.21%).

[0020] 1 HNMR(400MHz,DMSO-d6)δ:8.05(dd,J=4.9,1.5Hz,1H),7.64(s,1H),7.58(dd,J=7.6,1.5Hz,1H),6.62(dd,J=7.6,4.9Hz,1H),4.33(s,2H).

[0021] Example 2

[0022] 2,3-Dichloropyridine (22.2 g, 150 mmol), 80% hydrazine hydrate (11.26 g, 180 mmol), potassium carbonate (41.46 g, 300 mmol), and n-butanol (100 g) were added to a 200 ml autoclave equipped with a thermometer, pressure gauge, magnetic stirrer, inlet, and vent valve. The autoclave was purged and vented three times with 0.2 MPa nitrogen gas while stirring. The vent valve was closed, and the pressure inside the autoclave was maintained at one atmosphere. The autoclave was heated to 130 °C and stirred for 24 hours. After heating to 130 °C, the pressure inside the autoclave rose to 0.3-0.4 MPa. After cooling the system to room temperature, the autoclave was vented and disassembled. The reaction solution was filtered under reduced pressure to obtain a crude product. The crude product was washed with 50 ml of water and filtered again to obtain light purple crystals (19.35 g, yield 89.85%, purity 99.21%).

[0023] 1 HNMR(400MHz,DMSO-d6)δ:8.05(dd,J=4.9,1.5Hz,1H),7.64(s,1H),7.58(dd,J=7.6,1.5Hz,1H),6.62(dd,J=7.6,4.9Hz,1H),4.33(s,2H).

[0024] Example 3

[0025] 2,3-Dichloropyridine (22.2 g, 150 mmol), 80% hydrazine hydrate (14.08 g, 225 mmol), potassium carbonate (41.46 g, 300 mmol), and n-butanol (100 g) were added to a 200 ml autoclave equipped with a thermometer, pressure gauge, magnetic stirrer, inlet, and vent valve. The autoclave was purged and vented three times with 0.2 MPa nitrogen gas while stirring. The vent valve was closed, and the pressure inside the autoclave was maintained at one atmosphere. The autoclave was heated to 140 °C and stirred for 16 hours. After reaching 140 °C, the pressure inside the autoclave rose to 0.4-0.5 MPa. After cooling the system to room temperature, the autoclave was vented and disassembled. The reaction solution was filtered under reduced pressure to obtain a crude product. The crude product was washed with 50 ml of water and filtered again to obtain light purple crystals (19.30 g, yield 89.62%, purity 99.17%).

[0026] 1 HNMR(400MHz,DMSO-d6)δ:8.05(dd,J=4.9,1.5Hz,1H),7.64(s,1H),7.58(dd,J=7.6,1.5Hz,1H),6.62(dd,J=7.6,4.9Hz,1H),4.33(s,2H).

[0027] Example 4

[0028] 2,3-Dichloropyridine (22.2 g, 150 mmol), 80% hydrazine hydrate (14.08 g, 225 mmol), potassium carbonate (24.88 g, 180 mmol), and n-butanol (70 g) were added to a 200 ml autoclave equipped with a thermometer, pressure gauge, magnetic stirrer, inlet, and vent valve. The autoclave was purged and vented three times with 0.2 MPa nitrogen gas while stirring. The vent valve was closed, and the pressure inside the autoclave was maintained at one atmosphere. The autoclave was heated to 140 °C and stirred for 16 hours. After heating to 140 °C, the pressure inside the autoclave rose to 0.4-0.5 MPa. After cooling the system to room temperature, the autoclave was vented and the reaction mixture was removed. The reaction solution was filtered under reduced pressure to obtain a crude product. The crude product was washed with 50 ml of water and filtered again to obtain light purple crystals (19.79 g, yield 91.89%, purity 99.12%).

[0029] 1 HNMR(400MHz,DMSO-d6)δ:8.05(dd,J=4.9,1.5Hz,1H),7.64(s,1H),7.58(dd,J=7.6,1.5Hz,1H),6.62(dd,J=7.6,4.9Hz,1H),4.33(s,2H).

[0030] Example 5

[0031] 2,3-Dichloropyridine (22.2 g, 150 mmol), 80% hydrazine hydrate (14.08 g, 225 mmol), and n-butanol (75 g) were added to a 200 ml autoclave equipped with a thermometer, pressure gauge, magnetic stirrer, inlet, and vent valve. The autoclave was purged three times with nitrogen gas at 0.2 MPa while stirring. The vent valve was closed, and the pressure inside the autoclave was maintained at one atmosphere. The autoclave was heated to 140 °C and stirred for 16 hours. After reaching 140 °C, the pressure inside the autoclave rose to 0.4-0.5 MPa. After cooling the system to room temperature, the autoclave was vented and the mixture was removed. The reaction solution was filtered under reduced pressure to obtain a crude product. The crude product was washed with 50 ml of water and filtered again to obtain light purple crystals (19.20 g, yield 89.15%, purity 99.41%).

[0032] 1 HNMR(400MHz,DMSO-d6)δ:8.05(dd,J=4.9,1.5Hz,1H),7.64(s,1H),7.58(dd,J=7.6,1.5Hz,1H),6.62(dd,J=7.6,4.9Hz,1H),4.33(s,2H).

[0033] Example 6

[0034] 2,3-Dichloropyridine (22.2 g, 150 mmol), 50% hydrazine hydrate (22.53 g, 225 mmol), potassium carbonate (24.88 g, 180 mmol), and n-butanol (75 g) were added to a 200 ml autoclave equipped with a thermometer, pressure gauge, magnetic stirrer, inlet, and vent valve. The autoclave was purged and vented three times with 0.2 MPa nitrogen gas while stirring. The vent valve was closed, and the pressure inside the autoclave was maintained at one atmosphere. The autoclave was heated to 140 °C and stirred for 16 hours. After heating to 140 °C, the pressure inside the autoclave rose to 0.4-0.5 MPa. After cooling the system to room temperature, the autoclave was vented and disassembled. The reaction solution was filtered under reduced pressure to obtain a crude product. The crude product was washed with 50 ml of water and filtered again to obtain light purple crystals (19.20 g, yield 89.15%, purity 98.13%).

[0035] 1 HNMR(400MHz,DMSO-d6)δ:8.05(dd,J=4.9,1.5Hz,1H),7.64(s,1H),7.58(dd,J=7.6,1.5Hz,1H),6.62(dd,J=7.6,4.9Hz,1H),4.33(s,2H).

[0036] Comparative Example 1

[0037] 2,3-Dichloropyridine (22.2 g, 150 mmol), 80% hydrazine hydrate (14.08 g, 225 mmol), and ethanol (75 g) were added to a 200 ml four-necked flask. The mixture was heated to 78 °C and refluxed with stirring for 24 hours, but the starting material could not continue to react. After cooling the system to room temperature, the reaction solution was filtered under reduced pressure to obtain a crude product. The crude product was washed with 50 ml of water and filtered again to obtain light purple crystals (11.23 g, yield 51.14%, purity 78.56%).

[0038] Comparative Example 2

[0039] 2,3-Dichloropyridine (70 g, 0.473 mol) and 250 ml of 95% ethanol were added to a reaction flask. While stirring, 142 g, 1.42 mol of 50% hydrazine hydrate was added dropwise. After the addition was complete, the mixture was heated under reflux for 25 h and cooled to room temperature. A large amount of white crystals precipitated out. The crystals were filtered and dried to obtain 3-chloro-2-hydrazinopyridine, with a yield of 75.14%.

[0040] Comparative Example 3

[0041] Add 10g of β-cyclodextrin, 100g of potassium carbonate, 1.0g of anhydrous potassium fluoride, and 300g of water to the reaction flask. Heat to 55℃-60℃, add 100g of 2,3-dichloropyridine and 45g of 80% hydrazine hydrate. After the addition is complete, heat to reflux and stir to react. The reaction is carried out for about 20 hours. A sample is taken for HPLC control. The product normalization is less than 1%, and there is almost no product formation in the reaction.

[0042] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for synthesizing 3-chloro-2-hydrazinopyridine, characterized in that, Using 2,3-dichloropyridine and hydrazine hydrate as raw materials, alkali and solvent are added, and 3-chloro-2-hydrazinopyridine is obtained under certain pressure conditions. The specific reaction formula is as follows:

2. The method according to claim 1, characterized in that, The equivalent ratio of 2,3-dichloropyridine to hydrazine hydrate is 1:1-1.

5.

3. The method according to claim 1, characterized in that, Hydrazine hydrate is an aqueous solution containing 50%-80% hydrazine hydrate.

4. The method according to claim 1, characterized in that, The mass ratio of 2,3-dichloropyridine to solvent is 1:3-5.

5. The method according to claim 1, characterized in that, The mass ratio of 2,3-dichloropyridine to the base is 1:1.1-2.

6. The method according to claim 1, characterized in that, The solvent is n-butanol or ethanol.

7. The method according to claim 1, characterized in that, The alkali is potassium carbonate.

8. The method according to claim 1, characterized in that, The pressure is 0.1 MPa - 0.4 MPa.

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