Industrial preparation method of 2-nitro-5-chloropyridine
Through the CN bond coupling reaction of copper salt and ligand catalyst in an inert solvent, the problems of high safety risks and large amount of waste acid in the existing preparation of 2-nitro 5-chloropyridine are solved, and industrial production with high yield and high purity is achieved.
Patent Information
- Application Number
- CN202411078586.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-07
- Publication Date
- 2025-09-19
AI Technical Summary
The existing methods for preparing 2-nitro-5-chloropyridine have problems such as dangerous reaction conditions, high safety risks, and large amounts of waste acid, making it difficult to achieve industrial production.
Copper salt and ligand are used as catalysts in an inert solvent through a CN bond coupling reaction, and nitrite is used to carry out a coupling reaction with the compound of formula II under alkaline conditions to avoid oxidation reaction to prepare 2-nitro 5-chloropyridine.
The method realizes the preparation of 2-nitro 5-chloropyridine with safety, environmental protection, high yield and good purity, reduces the generation of waste acid, lowers the production safety risk, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The present invention belongs to the field of pharmaceutical intermediate preparation, and in particular relates to an industrial preparation method of 2-nitro-5-chloropyridine. Background Art
[0002] 2-Nitro-5-chloropyridine and its derivatives are important chemical intermediates, widely used in medicine, pesticides, materials and other fields, and have important application value in industry.
[0003] At present, the technical reports on the synthesis of 2-nitro 5-chloropyridine are mainly obtained by oxidation of 2-amino 5-chloropyridine:
[0004]
[0005] This method is an oxidation reaction, which requires a large amount of concentrated sulfuric acid, hydrogen peroxide and other reagents, produces a lot of waste acid, and also has a greater safety risk.
[0006] Therefore, there is an urgent need in the art to develop a preparation method for 2-nitro-5-chloropyridine with mild reaction conditions, safety, environmental protection, low production safety risk, and ease of industrial production. Summary of the Invention
[0007] The purpose of the present invention is to provide a method for preparing 2-nitro-5-chloropyridine which is safe and environmentally friendly, has mild reaction conditions, uses a small amount of catalyst and has high catalytic efficiency, has low production safety risks, and is easy to industrialize.
[0008] In a first aspect of the present invention, a method for preparing 2-nitro-5-chloropyridine is provided, comprising the following steps:
[0009] In an inert solvent, the compound of formula II and nitrite undergo a CN bond coupling reaction under catalyst and base conditions to prepare a compound of formula I;
[0010]
[0011] Wherein, X is chlorine or bromine;
[0012] The catalyst consists of copper salt and ligand.
[0013] In another preferred embodiment, the copper or copper compound includes but is not limited to CuI, CuBr, CuCl, CuCN, CuSCN, Cu2O, Cu(OAc)2, CuSO4, Cu2CO3, Cu(NO3)2, CuBr2, CuCl2, CuO, or a combination thereof.
[0014] In another preferred embodiment, the ligand is selected from the following structures:
[0015]
[0016] in,
[0017] Ra is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, or optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms independently selected from C, N, O, and S;
[0018] Rb is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, 6-10 membered aryl-alkyl, 5-6 membered heteroaryl-alkyl, optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms independently selected from C, N, O and S;
[0019] Rc is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, 6-10 membered aryl-alkyl, 5-6 membered heteroaryl-alkyl, or optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms independently selected from C, N, O, and S;
[0020] Rd is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, 6-10 membered aryl-alkyl, 5-6 membered heteroaryl-alkyl, optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms independently selected from C, N, O and S;
[0021] Here, the "optionally substituted" refers to a group that is unsubstituted or substituted by one or more (especially one, two or three) identical or different substituents; the substituents are selected from the following groups: hydroxyl, C1-C6 alkyl, C1-C6 alkoxy and C6-C10 aryl.
[0022] In another preferred embodiment, the ligand is selected from one or more of the ligands (L1-L12) shown in Table 1:
[0023] Table 1
[0024]
[0025]
[0026] In another preferred embodiment, the ligand is selected from one or more of the following groups:
[0027]
[0028] In another preferred embodiment, the base includes but is not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, or a combination thereof.
[0029] In another preferred embodiment, the inert solvent includes but is not limited to water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), acetonitrile, toluene, alcohol solvents, ether solvents, ester solvents, or combinations thereof;
[0030] In another preferred embodiment, the alcohol solvent includes but is not limited to methanol, ethanol, isopropanol, n-butanol, isobutanol, tert-butanol, tert-amyl alcohol, etc.; the ether solvent includes but is not limited to tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, etc.; the ester solvent includes but is not limited to ethyl acetate, isopropyl acetate, etc.
[0031] In another preferred embodiment, the nitrite includes but is not limited to sodium nitrite, potassium nitrite, lithium nitrite, silver nitrite, calcium nitrite, barium nitrite, tetrabutylammonium nitrite, or a combination thereof.
[0032] In another preferred embodiment, the amount of copper or copper compound is 0.1-20 mol% of the compound of formula II.
[0033] In another preferred embodiment, the amount of copper or copper compound is 0.1-10 mol% of the compound of formula II.
[0034] In another preferred embodiment, the amount of copper or copper compound is 0.1-2 mol% of the compound of formula II.
[0035] In another preferred embodiment, the amount of the ligand used is 0.1-20 mol% of the compound of formula II.
[0036] In another preferred embodiment, the amount of the ligand used is 0.1-10 mol% of the compound of formula II.
[0037] In another preferred embodiment, the amount of the ligand used is 0.1-2 mol% of the compound of formula II.
[0038] In another preferred embodiment, the amount of the base used is 1 to 20 times the molar equivalent of the compound of formula II.
[0039] In another preferred embodiment, the amount of the base used is 1 to 10 times the molar equivalent of the compound of formula II.
[0040] In another preferred embodiment, the amount of the base used is 1-5 times the molar equivalent of the compound of formula II.
[0041] In another preferred embodiment, the volume of the inert solvent is 1 to 20 times the volume of the compound of formula II.
[0042] In another preferred embodiment, the volume of the inert solvent is 1 to 10 times the volume of the compound of formula II.
[0043] In another preferred embodiment, the volume of the inert solvent is 1 to 5 times the volume of the compound of formula II.
[0044] In another preferred embodiment, the amount of the nitrite used is 0.5 to 20 times the molar equivalent of the compound of formula II.
[0045] In another preferred embodiment, the amount of the nitrite used is 0.5 to 10 times the molar equivalent of the compound of formula II.
[0046] In another preferred embodiment, the amount of the nitrite used is 0.5 to 2 times the molar equivalent of the compound of formula II.
[0047] In another preferred embodiment, the reaction temperature of the coupling reaction is 90-120°C, preferably 95-110°C, and more preferably 100-110°C.
[0048] In another preferred embodiment, the reaction time of the coupling reaction is 1-24 hours, preferably 4-6 hours.
[0049] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION
[0050] After extensive and in-depth research, the inventors unexpectedly discovered that the reaction of a compound of Formula II with a nitrite in an inert solvent, catalyzed by copper or a copper compound and a ligand, under alkaline conditions, can produce a high-purity 2-nitro-5-chloropyridine product in good yield. This method is carried out under normal pressure, requires minimal catalyst, and produces no waste acid, achieving safety, environmental protection, and low production safety risks. Based on this, the inventors completed the present invention.
[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
[0052] As used herein, the terms "comprise," "include," and "contain" are used interchangeably to include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of," "consisting essentially of."
[0053] The structural formula of "2-nitro-5-chloropyridine" of the present invention is as follows:
[0054]
[0055] The general formula of "2,5-dichloropyridine" or "2-bromo-5-chloropyridine" described in the present invention is as follows:
[0056]
[0057] The "inert solvent" described in the present invention refers to a solvent that does not react with the compounds in the reaction system.
[0058] The "C1-C6 alkyl" mentioned in the present invention refers to a straight-chain or branched hydrocarbon group containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, etc.
[0059] The term "C6-C14 aryl" as used herein refers to a monovalent aromatic carbocyclic group containing 6 to 14 carbon atoms, preferably an aromatic group containing 6 to 10 (especially 6) ring carbon atoms, such as phenyl, naphthyl, biphenyl, 2,6-dimethylphenyl, and the like.
[0060] The "heteroaryl" group of the present invention refers to an aromatic group containing one or more rings and 5 to 14 ring atoms, preferably 5 to 10 (especially 5 or 6) ring atoms, which contains one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). For example, pyridyl, imidazolyl, furyl, thiazolyl, isothiazolyl, etc.
[0061] The term "5-6 membered heteroaryl-alkyl" as used herein refers to a group containing both a heteroaryl group and an alkyl group. Heteroaryl-alkyl groups preferably contain one or more aromatic ring systems, each containing 4-5 carbon atoms, and one or more (preferably 1, 2, 3, or 4) oxygen, nitrogen, phosphorus, or sulfur ring atoms (preferably O, S, or N). Examples include 2-methylpyridyl, 2-methylfuryl, and the like.
[0062] As used herein, a "6-10 membered aryl-alkyl" refers to a group containing both an aryl group and an alkyl group. The aryl-alkyl group preferably contains one or more aromatic ring systems, each containing 6-10 carbon atoms. Examples include toluene, xylene, methylnaphthalene, and the like.
[0063] The term "optionally substituted" as used herein refers to a group that is unsubstituted or substituted by one or more (particularly one, two or three) substituents.
[0064] If a group contains more than one substituent, these substituents are independently selected, ie they may be the same or different.
[0065] Method of the present invention
[0066] As used herein, the terms "the method of the present invention", "the preparation method of the present invention" and "the industrial preparation method of the present invention" can be used interchangeably to refer to the method described in the first aspect of the present invention.
[0067] Preparation method of 2-nitro 5-chloropyridine
[0068] The present invention provides a method for preparing 2-nitro-5-chloropyridine which is safe, environmentally friendly, has a high reaction yield and good product purity, and comprises the following steps:
[0069] In an inert solvent, the compound of formula II and nitrite undergo a CN bond coupling reaction under catalyst and base conditions to prepare a compound of formula I;
[0070]
[0071] Wherein, X is chlorine or bromine;
[0072] The catalyst consists of copper salt and ligand.
[0073] The copper or copper compound includes but is not limited to CuI, CuBr, CuCl, CuCN, CuSCN, Cu2O, Cu(OAc)2, CuSO4, Cu2CO3, Cu(NO3)2, CuBr2, CuCl2, CuO, or a combination thereof.
[0074] The ligand is selected from the following structures:
[0075]
[0076] in,
[0077] Ra is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, or optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms independently selected from C, N, O, and S;
[0078] Rb is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, 6-10 membered aryl-alkyl, 5-6 membered heteroaryl-alkyl, optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms independently selected from C, N, O and S;
[0079] Rc is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, 6-10 membered aryl-alkyl, 5-6 membered heteroaryl-alkyl, or optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms independently selected from C, N, O, and S;
[0080] Rd is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, 6-10 membered aryl-alkyl, 5-6 membered heteroaryl-alkyl, optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms independently selected from C, N, O and S;
[0081] Here, the "optionally substituted" refers to a group that is unsubstituted or substituted by one or more (especially one, two or three) identical or different substituents; the substituents are selected from the following groups: hydroxyl, C1-C6 alkyl, C1-C6 alkoxy and C6-C10 aryl.
[0082] Preferably, the ligand is selected from one or more of the ligands (L1-L12) shown in Table 1:
[0083] Table 1
[0084]
[0085] More preferably, the ligand is selected from one or more of the following groups:
[0086]
[0087] The base includes, but is not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, or a combination thereof.
[0088] The inert solvent includes but is not limited to water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), acetonitrile, toluene, alcohol solvents, ether solvents, ester solvents, or combinations thereof.
[0089] The alcohol solvents include but are not limited to methanol, ethanol, isopropanol, n-butanol, isobutanol, tert-butanol, tert-amyl alcohol, etc.; the ether solvents include but are not limited to tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, etc.; the ester solvents include but are not limited to ethyl acetate, isopropyl acetate, etc.
[0090] The nitrite includes, but is not limited to, sodium nitrite, potassium nitrite, lithium nitrite, silver nitrite, calcium nitrite, barium nitrite, tetrabutylammonium nitrite, or a combination thereof.
[0091] The amount of copper or copper compound used is 0.1-20 mol% of the compound of formula II.
[0092] Preferably, the amount of copper or copper compound is 0.1-10 mol% of the compound of formula II.
[0093] More preferably, the amount of copper or copper compound is 0.1-2 mol% of the compound of formula II.
[0094] The amount of the ligand used is 0.1-20 mol% of the compound of formula II.
[0095] Preferably, the amount of the ligand used is 0.1-10 mol% of the compound of formula II.
[0096] More preferably, the amount of the ligand used is 0.1-2 mol% of the compound of formula II.
[0097] The amount of the base used is 1 to 20 times the molar equivalent of the compound of formula II.
[0098] Preferably, the amount of the base used is 1 to 10 times the molar equivalent of the compound of formula II.
[0099] More preferably, the amount of the base used is 1-5 times the molar equivalent of the compound of formula II.
[0100] The volume of the inert solvent is 1 to 20 times the volume of the compound of formula II.
[0101] Preferably, the volume of the inert solvent is 1 to 10 times the volume of the compound of formula II.
[0102] More preferably, the volume of the inert solvent is 1 to 5 times the volume of the compound of formula II.
[0103] The amount of the nitrite used is 0.5 to 20 times the molar equivalent of the compound of formula II.
[0104] Preferably, the amount of the nitrite used is 0.5 to 10 times the molar equivalent of the compound of formula II.
[0105] More preferably, the amount of the nitrite used is 0.5 to 2 times the molar equivalent of the compound of formula II.
[0106] The reaction temperature of the coupling reaction is 90-120°C, preferably 95-110°C, and more preferably 100-110°C.
[0107] The reaction time of the coupling reaction is 1-24 hours, preferably 4-6 hours.
[0108] The main advantages of the present invention are:
[0109] 1. The present invention provides an industrial preparation method for synthesizing 2-nitro-5-chloropyridine by using copper salt / ligand catalysis. The method uses nitrite to carry out a substitution reaction on dihalopyridine, thereby avoiding dangerous oxidation reactions.
[0110] 2. The present invention does not require the use of a large amount of concentrated sulfuric acid, hydrogen peroxide and other reagents, produces less three wastes, and is environmentally friendly.
[0111] 3. The catalyst dosage of the present invention is small, the catalytic efficiency is high, the reaction yield is high, and the product purity is good.
[0112] 4. The present invention can be carried out under normal pressure, the reaction conditions are mild, and it is suitable for industrial production.
[0113] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.
[0114] Example 1:
[0115] Under nitrogen, 500 ml of DMSO, 100 g of 2,5-dichloropyridine, 70 g of sodium nitrite, 1.3 g of cuprous iodide, 3.4 g of N,N'-bis(furan-2-ylmethyl)oxamide (L1), and 215 g of potassium phosphate were added to a reactor equipped with a stirrer and temperature controller. The mixture was heated to 95-100° C. under normal pressure and stirred for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with water and dichloromethane, and then recrystallized from ethyl acetate to obtain 98.6 g of 2-nitro-5-chloropyridine, with a yield of 92.0% and a purity of 99.6% as determined by HPLC.
[0116] MS (ESI+) m / z: 159 [M+H + ].
[0117] Example 2:
[0118] Under nitrogen, 500 ml of DMSO, 100 g of 2,5-dichloropyridine, 70 g of sodium nitrite, 0.97 g of cuprous bromide, 3.4 g of N,N'-bis(furan-2-ylmethyl)oxamide (L1), and 215 g of potassium phosphate were added to a reactor equipped with a stirrer and temperature controller. The mixture was heated to 95-100° C. under normal pressure and stirred for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with water and dichloromethane, and then recrystallized from ethyl acetate to obtain 97.5 g of 2-nitro-5-chloropyridine, with a yield of 91.0% and a purity of 99.4% as determined by HPLC.
[0119] MS (ESI+) m / z: 159 [M+H+].
[0120] Example 3:
[0121] Under nitrogen, 500 ml of DMSO, 100 g of 2,5-dichloropyridine, 70 g of sodium nitrite, 0.67 g of cuprous chloride, 3.4 g of N,N'-bis(furan-2-ylmethyl)oxamide (L1), and 215 g of potassium phosphate were added to a reactor equipped with a stirrer and temperature controller. The mixture was heated to 95-100° C. under normal pressure and stirred for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with water and dichloromethane, and then recrystallized from ethyl acetate to obtain 96.0 g of 2-nitro-5-chloropyridine, with a yield of 89.6% and a purity of 99.5% as determined by HPLC.
[0122] MS (ESI+) m / z: 159 [M+H+].
[0123] Example 4:
[0124] Under nitrogen, 500 ml of DMSO, 100 g of 2,5-dichloropyridine, 86.3 g of potassium nitrite, 1.3 g of cuprous iodide, 3.4 g of N,N'-bis(furan-2-ylmethyl)oxamide (L1), and 215 g of potassium phosphate were added to a reactor equipped with a stirrer and temperature controller. The mixture was heated to 95-100°C under normal pressure and stirred for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with water and dichloromethane, and then recrystallized from ethyl acetate to obtain 97.4 g of 2-nitro-5-chloropyridine, with a yield of 90.9% and a purity of 99.6% as determined by HPLC.
[0125] MS (ESI+) m / z: 159 [M+H + ].
[0126] Example 5:
[0127] Under nitrogen, 500 ml of DMSO, 100 g of 2,5-dichloropyridine, 70 g of sodium nitrite, 1.3 g of cuprous iodide, 3.4 g of N,N'-bis(furan-2-ylmethyl)oxamide (L1), and 140 g of potassium carbonate were added to a reactor equipped with a stirrer and temperature controller. The mixture was heated to 95-100° C. under normal pressure and stirred for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with water and dichloromethane, and then recrystallized from ethyl acetate to obtain 98.1 g of 2-nitro-5-chloropyridine, with a yield of 91.6% and a purity of 99.5% as determined by HPLC.
[0128] MS (ESI+) m / z: 159 [M+H + ].
[0129] Example 6:
[0130] Under nitrogen, a reactor equipped with a stirrer and temperature controller was charged with 500 ml of DMAc, 100 g of 2,5-dichloropyridine, 70 g of sodium nitrite, 1.3 g of cuprous iodide, 3.4 g of N,N'-bis(furan-2-ylmethyl)oxamide (L1), and 215 g of potassium phosphate. The mixture was heated to 95-100°C under atmospheric pressure and stirred for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with water and dichloromethane, and then recrystallized from ethyl acetate to yield 96.7 g of 2-nitro-5-chloropyridine (90.3% yield). The purity, as determined by HPLC, was 99.4%.
[0131] MS (ESI+) m / z: 159 [M+H + ].
[0132] Example 7:
[0133] Under nitrogen, 500 ml of NMP, 100 g of 2,5-dichloropyridine, 70 g of sodium nitrite, 1.3 g of cuprous iodide, 3.4 g of N,N'-bis(furan-2-ylmethyl)oxamide (L1), and 215 g of potassium phosphate were added to a reactor equipped with a stirrer and temperature controller. The mixture was heated to 95-100° C. under normal pressure and stirred for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with water and dichloromethane, and then recrystallized from ethyl acetate to obtain 98.6 g of 2-nitro-5-chloropyridine, with a yield of 92.0% and a purity of 99.6% as determined by HPLC.
[0134] MS (ESI+) m / z: 159 [M+H + ].
[0135] Example 8:
[0136] Under nitrogen, 130 g of 2-bromo-5-chloropyridine, 70 g of sodium nitrite, 0.67 g of cuprous chloride, 3.4 g of N,N'-bis(furan-2-ylmethyl)oxamide (L1), 500 ml of DMSO, and 215 g of potassium phosphate were added to a reactor equipped with a stirrer and temperature controller. The mixture was heated to 95-100°C under normal pressure and stirred for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with water and dichloromethane, and then recrystallized from ethyl acetate to obtain 94.4 g of 2-nitro-5-chloropyridine, with a yield of 88.1% and a purity of 98.9% as determined by HPLC.
[0137] MS (ESI+) m / z: 159 [M+H+].
[0138] Example 9:
[0139] The experimental operation steps were the same as those described in Example 1, except that the copper salt was 0.97 g CuBr, the ligand was 4.0 g L2, the yield was 45.6%, and the purity was 97.8% as determined by HPLC.
[0140] MS (ESI+) m / z: 159 [M+H+].
[0141] Example 10:
[0142] The experimental procedure was the same as that described in Example 1, except that the copper salt was 0.67 g CuCl, the ligand was 3.8 g L3, the yield was 65.6%, and the purity determined by HPLC was 98.5%.
[0143] MS (ESI+) m / z: 159 [M+H+].
[0144] Example 11:
[0145] The experimental procedure was the same as that described in Example 1, except that the copper salt was 0.97 g CuBr, the ligand was 4.5 g L5, the yield was 67.4%, and the purity was 98.6% as determined by HPLC.
[0146] MS (ESI+) m / z: 159 [M+H+].
[0147] Example 12:
[0148] The experimental procedure was the same as that described in Example 1, except that the copper salt was 0.67 g CuCl, the ligand was 4.8 g L6, the yield was 87.2%, and the purity was 99.1% as determined by HPLC.
[0149] MS (ESI+) m / z: 159 [M+H+].
[0150] Example 13:
[0151] The experimental operation steps were the same as those described in Example 1, except that the copper salt was 0.97 g CuBr, the ligand was 4.2 g L7, the yield was 73.0%, and the purity determined by HPLC was 98.2%.
[0152] MS (ESI+) m / z: 159 [M+H+].
[0153] Example 14:
[0154] The experimental operation steps were the same as those described in Example 1, except that the copper salt was 0.97 g CuBr, the ligand was 4.3 g L8, the yield was 37.2%, and the purity was 97.1% as determined by HPLC.
[0155] MS (ESI+) m / z: 159 [M+H+].
[0156] Example 15:
[0157] The experimental procedure was the same as that described in Example 1, except that the copper salt was 0.97 g CuBr, the ligand was 3.7 g L9, the yield was 46.8%, and the purity was 97.3% as determined by HPLC.
[0158] MS (ESI+) m / z: 159 [M+H+].
[0159] Example 16:
[0160] The experimental procedure was the same as that described in Example 1, except that the copper salt was 0.67 g CuCl, the ligand was 3.6 g L10, the yield was 82.5%, and the purity was 98.4% as determined by HPLC.
[0161] MS (ESI+) m / z: 159 [M+H+].
[0162] Example 17:
[0163] The experimental procedure was the same as that described in Example 1, except that the copper salt was 0.67 g CuCl, the ligand was 4.3 g L11, the yield was 60.6%, and the purity determined by HPLC was 98.2%.
[0164] MS (ESI+) m / z: 159 [M+H+].
[0165] Example 18:
[0166] The experimental operation steps were the same as those described in Example 1, except that the copper salt was 0.97 g Cu2O, the ligand was 3.8 g L12, the yield was 75.4%, and the purity was 98.5% as determined by HPLC.
[0167] MS (ESI+) m / z: 159 [M+H+].
[0168] Example 19:
[0169] The experimental operation steps were the same as those described in Example 1, except that the copper salt was 0.97 g CuBr, the ligand was 5.0 g L4, the yield was 90.3%, and the purity was 99.6% as determined by HPLC.
[0170] MS (ESI+) m / z: 159 [M+H+].
[0171] The results of all embodiments of the present invention are summarized in Table 2:
[0172] Table 2
[0173]
[0174]
[0175] The results of the screening studies of different ligands of the present invention are summarized in Table 3:
[0176] Table 3
[0177]
[0178]
[0179]
[0180]
[0181] Experimental results of the present invention show that the method prepares 2-nitro-5-chloropyridine by directly reacting the compound of formula II with a nitrite in an inert solvent under the action of a catalyst and a base through a CN base coupling reaction, thereby avoiding the use of a large amount of concentrated sulfuric acid and the oxidizing agent hydrogen peroxide and the generation of waste acid, thereby being safe and environmentally friendly and reducing production safety risks.
[0182] The 2-nitro-5-chloropyridine product prepared by the method of the present invention has high yield and purity, can be subjected to experiments under normal pressure, has mild reaction conditions, uses a small amount of catalyst and has high catalytic efficiency, has great cost advantages, and is very suitable for industrial production.
[0183] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.
Claims
1. A method for preparing 2-nitro 5-chloropyridine, characterized in that: The method comprises the following steps: In the presence of a catalyst and a base, the compound of formula II undergoes a CN bond coupling reaction with a nitrite in an inert solvent to prepare a compound of formula I; Wherein, X is chlorine or bromine; The catalyst consists of copper salt and ligand.
2. The preparation method according to claim 1, wherein The copper salt is selected from the group consisting of CuI, CuBr, CuCl, CuCN, CuSCN, Cu2O, Cu(OAc)2, CuSO4, Cu2CO3, Cu(NO3)2, CuBr2, CuCl2, CuO, or a combination thereof.
3. The preparation method according to claim 1, wherein The ligand is selected from the following structures: in, Ra is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, or optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms selected from C, N, O and S; Rb is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, 6-10 membered aryl-alkyl, 5-6 membered heteroaryl-alkyl, optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms selected from C, N, O and S; Rc is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, 6-10 membered aryl-alkyl, 5-6 membered heteroaryl-alkyl, or optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms independently selected from C, N, O, and S; Rd is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, 6-10 membered aryl-alkyl, 5-6 membered heteroaryl-alkyl, optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms selected from C, N, O and S; Wherein, the "optionally substituted" refers to being unsubstituted or substituted by one or more (particularly one, two or three) identical or different substituents; the substituents are independently selected from the group consisting of hydroxyl, C1-C6 alkyl, C1-C6 alkoxy and C6-C10 aryl.
4. The preparation method according to claim 1, wherein The ligand is selected from one or more of the following groups:
5. The preparation method according to claim 1, wherein The ligand is selected from one or more of the following groups:
6. The preparation method according to claim 1, wherein The base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, or a combination thereof.
7. The preparation method according to claim 1, wherein The inert solvent is selected from the group consisting of water, alcohol solvents, ether solvents, ester solvents, or combinations thereof; Preferably, the alcohol solvent is selected from the following group: N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), acetonitrile, toluene, and methanol, ethanol, isopropanol, n-butanol, isobutanol, tert-butanol, tert-amyl alcohol; the ether solvent is selected from the following group: tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether; the ester solvent is selected from the following group: ethyl acetate, isopropyl acetate.
8. The preparation method according to claim 1, wherein The nitrite is selected from the group consisting of sodium nitrite, potassium nitrite, lithium nitrite, silver nitrite, calcium nitrite, barium nitrite, tetrabutylammonium nitrite and the like, or a combination thereof; and / or The amount of the copper salt is 0.1-20 mol%, preferably 0.1-10 mol%, more preferably 0.1-2 mol% of the compound of formula II; and / or The amount of the ligand used is 0.1-20 mol%, preferably 0.1-10 mol%, more preferably 0.1-2 mol% of the compound of formula II.
9. The preparation method according to claim 1, wherein The amount of the base used is 1 to 20 times the molar equivalent of the compound of formula II, preferably 1 to 10 times the molar equivalent, more preferably 1 to 5 times the molar equivalent; and / or The volume of the inert solvent is 1 to 20 times the volume of the compound of formula II, preferably 1 to 10 times the volume, more preferably 1 to 5 times the volume; and / or The amount of the nitrite used is 0.5 to 20 times the molar equivalent of the compound of formula II, preferably 0.5 to 10 times the molar equivalent, and more preferably 0.5 to 2 times the molar equivalent.
10. The preparation method according to claim 1, wherein The reaction temperature of the coupling reaction is 90-110° C., preferably 95-100° C.; and / or The reaction time of the coupling reaction is 1-24 hours, preferably 4-6 hours.