Synthesis method of 2-chloro-3-hydrazinopyridine

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of 2-chloro-3-hydrazinopyridine, which comprises the following steps: carrying out chlorination reaction on pyridine and N-chlorosuccinimide in the presence of FeCl3 and 1, 10-phenanthroline to generate 2, 3-dichloropyridine; the method comprises the following steps: reacting 2, 3-dichloropyridine with hydrazine hydrate in the presence of a Pd catalyst, a Salen ligand and alkali to generate 2-chloro-3-hydrazinopyridine; the method is mild in reaction condition, low in cost and good in safety, and has a good industrial production application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing 2-chloro-3-hydrazinylpyridine. Background Art

[0002] 2-chloro-3-hydrazinylpyridine, with the structural formula: is an important organic synthesis intermediate. Its molecular structure contains a chlorine atom, a hydrazino group and a pyridine ring at the same time, and has high reaction activity. It can be used to synthesize a variety of biologically active compounds, such as nucleic acids, certain vitamins, antibiotics, hormones, pigments and alkaloids, etc. In addition, it can also be used to synthesize a variety of heterocyclic compounds with various properties, and has broad application prospects in drugs, pesticides, herbicides, dyes, plastics, etc.

[0003] At present, the main synthesis methods of 2-chloro-3-hydrazinylpyridine are as follows:

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

[0005] 2) 2-chloro-3-halopyridine method: Using 2-chloro-3-halopyridine as a raw material, reacting with hydrazine hydrate to form 2-chloro-3-hydrazinylpyridine. However, this method contains multiple halogen atoms at the same time, and the reaction selectivity is poor, and there are many by-products.

[0006] In view of the many problems existing in the prior art, it is urgent to develop a new synthesis method of 2-chloro-3-hydrazinylpyridine. Summary of the Invention

[0007] The purpose of the present invention is to provide a method for synthesizing 2-chloro-3-hydrazinylpyridine to solve the problems of low yield, low purity and poor reaction selectivity existing in the prior art. To solve the above technical problems, the present invention provides the following technical solutions:

[0008] A method for synthesizing 2-chloro-3-hydrazinylpyridine, comprising 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 form 2,3-dichloropyridine;

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

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

[0013] In some embodiments, in Step 2, the base 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); the molar ratio of pyridine to 1,10-phenanthroline is 1:(0.05 - 0.2).

[0016] In some embodiments, in Step 1, the reaction temperature is 50 - 80 °C and the reaction time is 1 - 5 h.

[0017] In some embodiments, in Step 1, the reaction solvent is selected from one or several 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 the Pd catalyst is 1:(0.05 - 0.2); the molar ratio of 2,3-dichloropyridine to the Salen ligand is 1:(0.05 - 0.2); the molar ratio of 2,3-dichloropyridine to the base is 1:(2 - 5).

[0019] In some embodiments, 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 completed, deionized water is added, extracted with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, and the crude product is separated and purified by silica gel column chromatography to obtain 2-chloro-3-hydrazinopyridine.

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

[0023] 1) The present invention uses pyridine and N-chlorosuccinimide as raw materials, and efficiently generates 2,3-dichloropyridine intermediate under the catalysis of FeCl3 and 1,10-phenanthroline, and the post-treatment is simple.

[0024] 2) The present invention obtains the Salen ligand through a large number of experiments The ligand and the Pd catalyst can be used together to selectively react with the chlorine at the 3-position on the pyridine to generate 2-chloro-3-hydrazinopyridine. The reaction conditions are mild, the cost is low, the safety is good, and it has good industrial production application prospects. Specific Embodiments

[0025] The embodiments of the present invention are described in detail below. The examples of the embodiments are shown below. The embodiments described by reference are exemplary and are 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 the present invention are not limited to the exact ranges or values. These ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0027] Preparation Example 1 Preparation of Salen Ligand

[0028]

[0029] Under nitrogen protection, diphenyl ethylenediamine (0.1 mol), salicylaldehyde (0.2 mol), and anhydrous ethanol (100 mL) are added to a round-bottom flask equipped with a magnetic stirrer, and the temperature is raised to 75 °C and stirred for 5 h. After the reaction is completed, the pale yellow crude product is obtained by suction filtration, and then recrystallized with anhydrous ethanol to obtain a pale yellow powder, namely the Salen ligand, with a yield of 95.2%.

[0030] LC-MS(ESI): [M+H] + = 421.2。

[0031] 1 H-NMR(500 MHz, 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), 1,10-phenanthroline (0.01 mol) were added to acetonitrile (100 mL). After stirring evenly, N-chlorosuccinimide (0.22 mol) was slowly added. The mixture was heated to 60 °C and stirred for 5 h under a nitrogen atmosphere. After the reaction was completed, deionized water (100 mL) was added, and then extracted with dichloromethane (3 × 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude yellow solid. Finally, it was recrystallized with 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] 2,3-Dichloropyridine (0.1 mol), Pd(OAc)2 (0.005 mol), the Salen ligand obtained in Preparation Example 1 (0.01 mol), and sodium carbonate (0.4 mol) were added to THF (200 mL). After stirring evenly, hydrazine hydrate N2H4·H2O (0.2 mol) was slowly added dropwise. The mixture was heated to 65 °C and stirred for 3 h under a nitrogen atmosphere. After the reaction was completed, deionized water (200 mL) was added, and then extracted 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 separated and purified by silica gel column chromatography (the volume ratio of the eluent DCM:PE was 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 (500 MHz, 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), 1,10-phenanthroline (0.01 mol) were added to DMSO (100 mL). After stirring evenly, N-chlorosuccinimide (0.2 mol) was slowly added. The mixture was heated to 80 °C and stirred for 3 h under a nitrogen atmosphere. After the reaction was completed, deionized water (100 mL) was added, and then extracted with dichloromethane (3 × 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude yellow solid. Finally, it was recrystallized with 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] 2,3-Dichloropyridine (0.1 mol), PdCl2 (0.01 mol), the Salen ligand obtained in Preparation Example 1 (0.01 mol), cesium carbonate (0.3 mol) were added to THF (200 mL). After stirring evenly, hydrazine hydrate N2H4·H2O (0.2 mol) was slowly added dropwise. The mixture was heated to 60 °C and stirred for 5 h under a nitrogen atmosphere. After the reaction was completed, deionized water (200 mL) was added, and then extracted 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 separated and purified by silica gel column chromatography (the volume ratio of the eluent DCM:PE was 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 (500 MHz, 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), 1,10-phenanthroline (0.02 mol) were added to ethanol (100 mL). After stirring evenly, N-chlorosuccinimide (0.22 mol) was slowly added. The mixture was heated to 65 °C and stirred for 5 h under a nitrogen atmosphere. After the reaction was completed, deionized water (100 mL) was added, and then extracted with dichloromethane (3 × 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude yellow solid, and finally recrystallized with 80% methanol aqueous solution to obtain a white solid. The yield was 91.3%, and the HPLC purity was 99.4%.

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

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

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

[0055] 1 1H-NMR (500 MHz, 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 examples for clear illustration and not limitations on the implementation manners. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all implementation manners here. The obvious changes or modifications thus extended are still within the protection scope of the present invention.

Claims

1. A method for synthesizing 2-chloro-3-hydrazinopyridine, comprising the following steps: Step 1: Pyridine and N-chlorosuccinimide undergo chlorination reaction in the presence of FeCl3 and 1,10-phenanthroline to generate 2,3-dichloropyridine; Step 2: 2,3-dichloropyridine and hydrazine hydrate react in the presence of a Pd catalyst, a Salen ligand and a base to generate 2-chloro-3-hydrazinopyridine; The structural formula of the Salen ligand is:

2. The synthesis method according to claim 1, characterized in that In step 2, the base is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, potassium hydroxide, and sodium hydroxide.

3. The synthesis method according to claim 1, characterized in that 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.

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

5. The synthesis method according to claim 1, characterized in that In step 1, the reaction temperature is 50-80° C. and the reaction time is 1-5 h.

6. The synthesis method according to claim 1, characterized in that 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.

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

8. The synthesis method according to claim 1, characterized in that In step 2, the reaction temperature is 50-100° C. and the reaction time is 1-5 h.

9. The synthesis method according to claim 1, characterized in that 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.

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

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