CN111153853B - Preparation method of 2-chloronicotinic acid - Google Patents
Preparation method of 2-chloronicotinic acid Download PDFInfo
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- CN111153853B CN111153853B CN202010003738.9A CN202010003738A CN111153853B CN 111153853 B CN111153853 B CN 111153853B CN 202010003738 A CN202010003738 A CN 202010003738A CN 111153853 B CN111153853 B CN 111153853B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
- C07D213/807—Processes of preparation by oxidation of pyridines or condensed pyridines
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- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to the field of chemical synthesis, and discloses a preparation method of 2-chloronicotinic acid, which takes 2-chloro-3-methylpyridine as an initial raw material, any one of acetic acid, chloroform, acetonitrile and ethyl acetate as a solvent, N-hydroxyphthalimide as an initiator, and metal salt as a catalyst, and prepares the 2-chloronicotinic acid by direct oxidation of oxygen; the metal salt is any one of cobalt acetate, cobalt (III) acetylacetonate, manganese acetate and manganese (III) acetylacetonate. The method has the advantages of low cost of the used raw materials, simple process, mild reaction conditions, high product quality and yield, high purity of the 2-chloronicotinic acid product of more than 98.5 percent, high yield of more than 75 percent and maximum yield of about 94 percent.
Description
Technical Field
The invention belongs to the fields of pharmaceutical chemicals and pesticides, and particularly relates to a preparation method of 2-chloronicotinic acid.
Background
The 2-chloronicotinic acid is an important intermediate of medicines and pesticides, and is mainly used for synthesizing novel efficient herbicides of nicosulfuron and diflufenican, novel systemic bactericides of boscalid, anticancer medicine intermediates of 2-chloropyridine-3-carbonyl-nitrogen heterocyclic compounds and HIV reverse transcriptase inhibitor nevirapine.
At present, the preparation method of 2-chloronicotinic acid mainly comprises the following four steps:
(1) US4504665A describes the synthesis of 2-chloronicotinic acid by hydrolyzing 2-chloro-3-trichloromethyl pyridine as a raw material with a large amount of inorganic acids such as phosphoric acid, hydrochloric acid, nitric acid and the like. The raw material 2-chloro-3-trichloromethyl pyridine used in the method is expensive and is not suitable for industrial production.
(2) Currently, nicotinic acid (or nicotinonitrile) is used as a raw material in industry, and is firstly oxidized with hydrogen peroxide to prepare N-nicotinic acid oxide (or N-nicotinonitrile oxide), and then the N-nicotinic acid oxide (or N-nicotinonitrile oxide) is subjected to POCl3And PCl5Chloridizing, and hydrolyzing to obtain 2-chloronicotinic acid. The method has long reaction steps, low product purity (mainly high impurity content of 6-chloronicotinic acid), and high product yield during chlorination reactionThe generation of a large amount of acidic wastewater containing chlorine and phosphorus leads to great increase of environmental protection pressure of three-waste treatment.
(3) It has also been reported that 2-chloronicotinic acid is prepared from ethyl cyanoacetate as a raw material by cyclization, and the process is simple, the product selectivity is high, but the raw material is not easy to obtain.
(4) 2-chloro-3-methylpyridine oxidation route: the potassium permanganate is adopted to oxidize methyl into carboxyl to prepare the 2-chloronicotinic acid, the route process is simple, but the potassium permanganate has high cost, generates a large amount of solid waste manganese dioxide and is not suitable for industrial production.
CN103848783 reports a method for preparing 2-chloronicotinic acid by directly oxidizing 2-chloro-3-methylpyridine by ozone in one step, the process is green and environment-friendly, the conditions are mild, but the cost of an ozone generator is higher, and the method is not suitable for industrial production.
Disclosure of Invention
Aiming at the technical problems, the invention provides a preparation method of 2-chloronicotinic acid.
The purpose of the invention is realized by the following technical scheme:
a preparation method of 2-chloronicotinic acid is characterized in that 2-chloro-3-methylpyridine is used as a starting material, an organic solvent is selected for dilution, N-hydroxyphthalimide (NHPI) is used as an initiator, a metal salt is used as a catalyst, and the 2-chloronicotinic acid is prepared by direct oxidation through oxygen.
The reaction formula of the invention is as follows:
the organic solvent is any one of acetic acid, acetonitrile, chloroform and ethyl acetate. The solubility of NHPI in organic solvents was in order of magnitude: acetonitrile > ethyl acetate > acetic acid > chloroform, and therefore, the yield of chloroform solvent is lowest; acetic acid is used as an organic solvent, so that the corrosion to a high-pressure kettle of a reaction container is serious, and the generation of 2-chloronicotinic acid is inhibited; acetonitrile and ethyl acetate are respectively used as reaction solvents, the reaction yield difference between the acetonitrile and the ethyl acetate is not great, but the mass transfer effect in the acetonitrile is better, and the reaction time is shorter. In general, the organic solvent is preferably acetonitrile.
The mass ratio of the solvent to the 2-chloro-3-methylpyridine is 2-20: 1, and preferably 5-10: 1. Within the solvent dosage range, the invention can not only avoid the influence of the excessive solvent dosage on productivity and increase cost, but also avoid the precipitation of 2-chloronicotinic acid due to the excessive solvent dosage, which causes the viscosity of reaction liquid and influences mass transfer.
The molar ratio of the NHPI to the 2-chloro-3-methylpyridine is 0.1-20: 100, preferably 3-20: 100, the yield can reach over 75%, more preferably 10-20: 100, and the yield can reach over 90%.
The metal salt is any one of cobalt acetate, cobalt (III) acetylacetonate, manganese acetate and manganese (III) acetylacetonate, and preferably cobalt (III) acetylacetonate and manganese (III) acetylacetonate.
The mass ratio of the metal salt to the 2-chloro-3-methylpyridine is 0.1-20: 100, and preferably 1-10: 100.
The reaction temperature is 20-150 ℃, and preferably 50-120 ℃.
The method takes oxygen as an oxidant, the reaction process is a cyclic process of consuming oxygen and recharging oxygen, the reaction pressure is 0-4 MPa, preferably 0-3 MPa, and more preferably 0.2-2 MPa, until the reaction pressure changes remarkably, the reaction is completely stopped, and the reaction time is 0.5-30 hours, preferably 3-24 hours.
As a further preferable technical scheme of the preparation method of the 2-chloronicotinic acid, after the reaction is finished, the reaction liquid is cooled to room temperature, the reaction liquid is filtered, the filter cake is leached by water, the filter cake is dissolved by alkali liquor, the filter cake is filtered, the obtained filtrate is acidified by hydrochloric acid until the pH value is 1-2, a white solid is obtained, and the pure 2-chloronicotinic acid is obtained by suction filtration, water washing and drying.
The alkali liquor is any one of sodium hydroxide, potassium hydroxide and ammonia water, and preferably ammonia water.
The invention has the beneficial effects that:
(1) the method adopts one-step pure oxygen oxidation of 2-chloro-3-methylpyridine to prepare the 2-chloronicotinic acid, and avoids using a large amount of inorganic acid, phosphorus oxychloride/phosphorus pentachloride, potassium permanganate and the like which have great environmental pollution.
(2) The raw materials used in the invention have low cost, the process is simple, the reaction condition is mild, the product quality and the yield reach higher levels, the purity of the 2-chloronicotinic acid product can reach more than 98.5 percent, the yield can reach more than 75 percent, and the highest yield can reach about 94 percent.
(3) Acetonitrile is preferably selected as a solvent, and the solvent can be recovered from a reaction solution through simple distillation; the use of highly corrosive acetic acid solvents is avoided.
Detailed Description
The technical solution of the present invention is illustrated by the following specific examples, but the scope of the present invention is not limited thereto:
Example 1
Adding 25g of 2-chloro-3-methylpyridine, 250g of acetonitrile, 3.2g of NHPI and 1.25g of cobalt (III) acetylacetonate into a 500mL autoclave, introducing oxygen until the pressure in the autoclave is 1.0MPa, starting stirring and heating, controlling the reaction temperature at 80 ℃ and reacting for 18 h. After the reaction was complete, it was cooled to room temperature, filtered and the filter cake washed with 150mL of water. Dissolving the filter cake with ammonia water (28%), filtering out insoluble substances, acidifying the obtained filtrate with hydrochloric acid until the pH value is 1 to obtain a white solid, performing suction filtration, washing with water, and drying to obtain 29.2g of a white crystal solid with the yield of 94.1% (the HPLC content is 99.5%, the water content is 0.26%, and the melting point is 177-178.5 ℃).
Example 2
Adding 25g of 2-chloro-3-methylpyridine, 250g of acetonitrile, 3.2g of NHPI and 1.25g of anhydrous cobalt acetate into a 500mL autoclave, introducing oxygen until the pressure in the autoclave is 1.0MPa, starting stirring, heating, controlling the reaction temperature at 80 ℃, and reacting for 18 h. After the reaction was complete, it was cooled to room temperature, filtered and the filter cake washed with 150mL of water. Dissolving the filter cake with ammonia water (28%), filtering out insoluble substances, acidifying the obtained filtrate with hydrochloric acid until the pH value is 1 to obtain a white solid, performing suction filtration, washing with water, and drying to obtain 26.6g of a white crystalline solid with the yield of 85.8% (the HPLC content is 99.6%, the water content is 0.22%, and the melting point is 176.2-178 ℃).
Example 3
Adding 25g of 2-chloro-3-methylpyridine, 250g of acetonitrile, 3.2g of NHPI and 1.25g of manganese (III) acetylacetonate into a 500mL autoclave, introducing oxygen until the pressure in the autoclave is 1.0MPa, starting stirring and heating, controlling the reaction temperature at 80 ℃ and reacting for 18 h. After the reaction was complete, it was cooled to room temperature, filtered and the filter cake washed with 150mL of water. Dissolving the filter cake with ammonia water (28%), filtering out insoluble substances, acidifying the obtained filtrate with hydrochloric acid until the pH value is 1 to obtain a white solid, performing suction filtration, washing with water, and drying to obtain 28.8g of a white crystal solid with the yield of 92.3% (the HPLC content is 99.0%, the water content is 0.32%, and the melting point is 175.4-177.8 ℃).
Example 4
Adding 25g of 2-chloro-3-methylpyridine, 250g of acetonitrile, 3.2g of NHPI and 1.25g of anhydrous manganese acetate into a 500mL autoclave, introducing oxygen until the pressure in the autoclave is 1.0MPa, starting stirring, heating, controlling the reaction temperature at 80 ℃, and reacting for 18 h. After the reaction was complete, it was cooled to room temperature, filtered and the filter cake washed with 150mL of water. Dissolving the filter cake with ammonia water (28%), filtering out insoluble substances, acidifying the obtained filtrate with hydrochloric acid until the pH value is 1 to obtain a white solid, performing suction filtration, washing with water, and drying to obtain 25.7g of a white crystal solid with the yield of 82.2% (the HPLC content is 98.8%, the water content is 0.39%, and the melting point is 177.2-179.6 ℃).
Example 5
Adding 25g of 2-chloro-3-methylpyridine, 250g of acetonitrile, 3.2g of NHPI and 1.25g of cobalt (III) acetylacetonate into a 500mL autoclave, introducing oxygen until the pressure in the autoclave is 1.0MPa, starting stirring, heating, controlling the reaction temperature at 110 ℃, and reacting for 18 h. After the reaction was complete, it was cooled to room temperature, filtered and the filter cake washed with 150mL of water. Dissolving the filter cake with ammonia water (28%), filtering out insoluble substances, acidifying the obtained filtrate with hydrochloric acid until the pH value is 1 to obtain a white solid, performing suction filtration, washing with water, and drying to obtain 26.4g of a white crystal solid with the yield of 84.3% (the HPLC content is 98.7%, the water content is 0.12%, and the melting point is 174-177.2 ℃).
Example 6
Adding 25g of 2-chloro-3-methylpyridine, 250g of acetonitrile, 1.6g of NHPI and 1.25g of cobalt (III) acetylacetonate into a 500mL autoclave, introducing oxygen until the pressure in the autoclave is 1.0MPa, starting stirring, heating, controlling the reaction temperature at 80 ℃ and reacting for 18 h. After the reaction was complete, it was cooled to room temperature, filtered and the filter cake washed with 150mL of water. Dissolving the filter cake with ammonia water (28%), filtering out insoluble substances, acidifying the obtained filtrate with hydrochloric acid until the pH value is 1 to obtain a white solid, performing suction filtration, washing with water, and drying to obtain 23.7g of a white crystalline solid with the yield of 75.3% (the HPLC content is 98.1%, the water content is 0.46%, and the melting point is 173.4-176.6 ℃).
Example 7
Adding 25g of 2-chloro-3-methylpyridine, 250g of ethyl acetate, 3.2g of NHPI and 1.25g of cobalt (III) acetylacetonate into a 500mL autoclave, introducing oxygen until the pressure in the autoclave is 1.0MPa, stirring, heating, controlling the reaction temperature at 80 ℃, and reacting for 18 h. After the reaction was complete, it was cooled to room temperature, filtered and the filter cake washed with 150mL of water. Dissolving the filter cake with ammonia water (28%), filtering out insoluble substances, acidifying the obtained filtrate with hydrochloric acid until the pH value is 1 to obtain a white solid, performing suction filtration, washing with water, and drying to obtain 27.5g of a white crystal solid with the yield of 88.2% (the HPLC content is 99.1%, the water content is 0.22%, and the melting point is 177.1-179.5 ℃).
Comparative example 1
Adding 25g of 2-chloro-3-methylpyridine, 250g of acetonitrile and 3.2g of NHPI into a 500mL autoclave, introducing oxygen until the pressure in the autoclave is 1.0MPa, starting stirring and heating, controlling the reaction temperature at 80 ℃ and reacting for 18 h. After the reaction was complete, it was cooled to room temperature, filtered and the filter cake washed with 150mL of water. Dissolving the filter cake with ammonia water (28%), filtering out insoluble substances, acidifying the obtained filtrate with hydrochloric acid until the pH value is 1 to obtain a white solid, performing suction filtration, washing with water, and drying to obtain 6.82g of a white crystal solid with the yield of 21.8% (the HPLC content is 98.5%, the water content is 0.23%, and the melting point is 173-175.4 ℃).
Comparative example 2
Adding 25g of 2-chloro-3-methylpyridine, 250g of acetonitrile and 1.25g of cobalt (III) acetylacetonate into a 500mL autoclave, introducing oxygen until the pressure in the autoclave is 1.0MPa, starting stirring and heating, controlling the reaction temperature at 80 ℃ and reacting for 18 h. After the reaction was complete, it was cooled to room temperature, filtered and the filter cake washed with 150mL of water. Dissolving the filter cake with ammonia water (28%), filtering out insoluble substances, acidifying the obtained filtrate with hydrochloric acid until the pH value is 1 to obtain a white solid, performing suction filtration, washing with water, and drying to obtain 15.7g of a white crystal solid with the yield of 50.3% (the HPLC content is 98.9%, the water content is 0.16%, and the melting point is 176.1-178.4 ℃).
Claims (7)
1. A preparation method of 2-chloronicotinic acid is characterized in that the method takes 2-chloro-3-methylpyridine as an initial raw material, takes any one of acetic acid, chloroform, acetonitrile and ethyl acetate as a solvent, takes N-hydroxyphthalimide as an initiator and metal salt as a catalyst, and prepares the 2-chloronicotinic acid by direct oxidation of oxygen; wherein the mass ratio of the solvent to the 2-chloro-3-methylpyridine is 5-10: 1; the molar ratio of the N-hydroxyphthalimide to the 2-chloro-3-methylpyridine is 10-20: 100; the metal salt is cobalt (III) acetylacetonate and manganese (III) acetylacetonate; the reaction temperature is 50-120 ℃; the reaction pressure is 0.2-2 MPa; the reaction time is 3-24 h.
2. The method of claim 1, wherein the solvent is acetonitrile.
3. The method for preparing 2-chloronicotinic acid according to claim 1, wherein the mass ratio of the metal salt to the 2-chloro-3-methylpyridine is 0.1-20: 100.
4. The method for preparing 2-chloronicotinic acid according to claim 3, wherein the mass ratio of the metal salt to the 2-chloro-3-methylpyridine is 1-10: 100.
5. The preparation method of 2-chloronicotinic acid as claimed in claim 1, wherein after the reaction is finished, the reaction solution is cooled to room temperature, filtered, the filter cake is rinsed with water, the filter cake is dissolved with alkaline solution, filtered, the obtained filtrate is acidified with hydrochloric acid to a pH value of 1-2 to obtain a white solid, and the pure 2-chloronicotinic acid is obtained by suction filtration, water washing and drying.
6. The method of claim 5, wherein the alkali solution is any one of sodium hydroxide, potassium hydroxide and ammonia water.
7. The method of claim 6, wherein the alkali solution is ammonia.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES8203346A1 (en) * | 1981-05-07 | 1982-04-01 | Lisac S A | Procedure for obtaining 2-chlorine-3-pyridine-carboxylic acid (Machine-translation by Google Translate, not legally binding) |
| CN103848783A (en) * | 2014-01-14 | 2014-06-11 | 红太阳集团有限公司 | Method for synthesizing 2-chloronicotinic acid by one-step oxidation |
| CN104513198A (en) * | 2014-11-29 | 2015-04-15 | 南京红太阳生物化学有限责任公司 | 2-chloronicotinic acid synthetic method |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES8203346A1 (en) * | 1981-05-07 | 1982-04-01 | Lisac S A | Procedure for obtaining 2-chlorine-3-pyridine-carboxylic acid (Machine-translation by Google Translate, not legally binding) |
| CN103848783A (en) * | 2014-01-14 | 2014-06-11 | 红太阳集团有限公司 | Method for synthesizing 2-chloronicotinic acid by one-step oxidation |
| CN104513198A (en) * | 2014-11-29 | 2015-04-15 | 南京红太阳生物化学有限责任公司 | 2-chloronicotinic acid synthetic method |
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