CN113999167B - A kind of preparation method of 4-chloro-2,6-dimethyl-3-nitropyridine - Google Patents
A kind of preparation method of 4-chloro-2,6-dimethyl-3-nitropyridine Download PDFInfo
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- 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
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Abstract
本发明公开了一种4‑氯‑2,6‑二甲基‑3‑硝基吡啶的制备方法，属于有机合成技术领域。以2,6‑二甲基‑4‑吡喃酮为原料，首先与三苯甲胺在路易斯酸催化下氨解芳构化反应，得到2,6‑二甲基‑1‑三苯甲基吡喃酮粗品，接着在三氯氧磷存在下氯代及脱保护得到4‑氯‑2,6‑二甲基吡啶，随后与脱水剂/硝酸硝化得到4‑氯‑2,6‑二甲基‑3‑硝基吡啶。本发明原料易得，工艺中选择先氯代再硝化，最大程度减少了硝化时双取代杂质，纯化过程简单，可高收率得到产品。The invention discloses a preparation method of 4-chloro-2,6-dimethyl-3-nitropyridine, which belongs to the technical field of organic synthesis. Using 2,6-dimethyl-4-pyrone as raw material, it is first reacted with tritylamine under the catalysis of Lewis acid for aminodearomatization reaction to obtain 2,6-dimethyl-1-tritylpyrane. The crude ketone is then chlorinated and deprotected in the presence of phosphorus oxychloride to obtain 4-chloro-2,6-dimethylpyridine, which is then nitrated with dehydrating agent/nitric acid to obtain 4-chloro-2,6-dimethyl- 3‑nitropyridine. The raw materials of the invention are easy to obtain, and the process is carried out by selecting chlorination first and then nitrification, thereby minimizing double-substituted impurities during nitrification, the purification process is simple, and the product can be obtained with high yield.
Description
Technical Field
The invention relates to a preparation method of 4-chloro-2,6-dimethyl-3-nitropyridine, belonging to the technical field of organic synthesis.
Background
4-chloro-2,6-dimethyl-3-nitropyridine, english name: 4-Chloro-2,6-dimethyl-3-nitropyridine, CAS:15513-48-1, an important intermediate for ebany. Ebanizine (Elbanizine), developed by avntisPharma, france, belongs to a second generation antihistamine for relieving symptoms of allergic allergies such as allergic rhinitis, and has no central nervous system side effects such as sedation and somnolence.
The synthetic routes of 4-chloro-2,6-dimethyl-3-nitropyridine are mainly divided into two types:
first kind: ammonolysis, nitration and chlorination of 2, 6-dimethyl-4-pyrone with ammonia gas to obtain 4-chloro-2, 6-dimethyl-3-nitropyridine; the reaction equation is as follows:
according to the method, ammonia is adopted for ammonolysis reaction, high temperature and high pressure are needed, aromatization is incomplete, more impurities appear, multiple purification is needed to obtain 2, 6-dimethyl-4-hydroxypyridine, then nitration reaction is carried out at 10-35 ℃, double nitro impurities easily appear, recrystallization and purification are needed, and therefore the total yield is low.
Second kind: the literature [ jmed chem,1998,41,4408-4420] uses 2, 6-dimethyl-4-pyrone to carry out ammonolysis with benzylamine, followed by catalytic hydrogenation, nitration and chlorination to give 4-chloro-2, 6-dimethyl-3-nitropyridine; the reaction equation is as follows:
although benzylamine and 2, 6-dimethyl-4-pyrone are adopted for ammonolysis reaction, high temperature and high pressure are avoided, aromatization is not thorough enough, pd/C hydrogenation debenzylation is needed, and cost is increased.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a preparation method of 4-chloro-2, 6-dimethyl-3-nitropyridine. The method comprises the steps of taking 2, 6-dimethyl-4-pyrone as a raw material, carrying out ammonolysis and aromatization reaction on the raw material and trityl amine under the catalysis of Lewis acid to obtain a 2, 6-dimethyl-1-trityl pyrone crude product, carrying out chlorination and deprotection under the existence of phosphorus oxychloride to obtain 4-chloro-2, 6-dimethylpyridine, and then carrying out nitration with a dehydrating agent/nitric acid to obtain the 4-chloro-2, 6-dimethyl-3-nitropyridine. The invention has the advantages of easily available raw materials, selection of first chlorination and then nitration in the process, reduction of double-substituted impurities in the nitration to the greatest extent, simple purification process and high yield of the obtained product.
The invention relates to a preparation method of 4-chloro-2,6-dimethyl-3-nitropyridine, which has the following reaction equation:
the method comprises the following steps:
firstly, mixing 2, 6-dimethyl-4-pyrone, an organic solvent, triphenylmethyl amine and tris (pentafluorophenyl) borane, and heating and refluxing for reaction to obtain a 2, 6-dimethyl-1-trityl pyrone crude product;
secondly, reacting 2, 6-dimethyl-1-tritylpyrone with phosphorus oxychloride to obtain 4-chloro-2, 6-dimethylpyridine;
and thirdly, 4-chloro-2, 6-lutidine is subjected to heating nitration reaction in the presence of a dehydrating agent and nitric acid, and 4-chloro-2,6-dimethyl-3-nitropyridine is obtained through recrystallization and purification.
Further, in the above technical scheme, the molar ratio of the 2, 6-dimethyl-4-pyrone, the triphenylmethyl amine and the tris (pentafluorophenyl) borane in the first step is 1:1.0-1.04:0.02-0.03.
Further, in the above technical scheme, the organic solvent in the first step is selected from toluene, nitrobenzene or xylene.
Further, in the technical scheme, after the first reaction is finished, the reaction solution is concentrated, n-heptane is pulped, and the catalyst tris (pentafluorophenyl) borane is remained in the product for the next reaction.
Further, in the above technical scheme, the molar ratio of the 2, 6-dimethyl-1-tritylpyrone to phosphorus oxychloride in the second step is 1:2.5-7.0.
Further, in the above technical scheme, in the third step, the dehydrating agent is selected from concentrated sulfuric acid or glacial acetic acid; the nitric acid is selected from concentrated nitric acid or fuming nitric acid.
Further, in the above technical scheme, the reaction temperature of the third step is selected from 40-100 ℃.
Further, in the above technical scheme, in the third step, the molar ratio of the 4-chloro-2, 6-lutidine to the nitric acid is 1:1.10-1.30.
Further, in the above technical scheme, in the third step, the recrystallization solvent is selected from ethanol/water mixed solvents.
Advantageous effects of the invention
1. The 2, 6-dimethyl-4-pyrone and the trityl amine are adopted to carry out ammonolysis reaction under the catalysis of Lewis acid, and the aromatization is more thorough through xylene reflux water diversion and Lewis acid addition;
2. compared with the traditional synthetic route, the method adopts the prior chlorination and then nitration, wherein phosphorus oxychloride and Lewis acid are catalyzed to improve the chlorination reaction speed, the conversion rate is higher, trityl is removed in the chlorination process, 4-position chlorine is compared with 4-position hydroxyl, the double nitro substitution is reduced to the greatest extent in the nitration, and the obtained product is easier to purify.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples should be construed as merely illustrative of the present invention and not limiting the scope of the present invention. Various changes and modifications to the present invention may be made by one skilled in the art after reading the description herein, and such equivalent changes and modifications are intended to fall within the scope of the present invention as defined in the appended claims.
Example 1
Under the protection of nitrogen, 74.5g (0.6 mol) of 2, 6-dimethyl-4-pyrone, 6.1g (0.012 mol) of tris (pentafluorophenyl) borane and 1000mL of xylene are mixed, the temperature is raised to 60 ℃, 171.2g (0.66 mol) of trityl amine is added in portions, the mixture is heated to reflux, the reflux is separated for 8 hours, the temperature is reduced, the xylene is evaporated by vacuum concentration, 550mL of n-heptane is pulped, and the mixture is filtered to obtain 236.8g of 2, 6-dimethyl-1-trityl pyrone crude product, the yield is: 93.4%, HPLC:92.1% of HPLC external standard content is 87%. The sample detection is obtained by column chromatography, 1 HNMR(400MHz,CDCl 3 ):7.39-7.33(m,15H),5.46(s,2H),2.31(s,6H).
example 2
227.6g (0.54 mol) of crude 2, 6-dimethyl-1-tritylpyrone product in example 1 was added to 500g (3.25 mol) of phosphorus oxychloride, the temperature was raised to 90-95℃for reaction for 4 hours, and most of the phosphorus oxychloride was evaporated by concentration under reduced pressure after cooling. Then carefully adding the mixture into ice water to quench the mixture under stirring, extracting the mixture by methyl tertiary butyl ether for three times, saturating the organic phase with sodium bicarbonate and washing the organic phase with water, and concentrating the organic phaseThen, the temperature is increased to 80-90 ℃ and reduced pressure distillation is carried out to obtain 64.7g of 4-chloro-2, 6-dimethylpyridine with yield: 84.3%, GC:99.3%. 1 HNMR(400MHz,CDCl 3 ):7.17(s,2H),2.52(s,6H).
Example 3
227.6g (0.54 mol) of crude 2, 6-dimethyl-1-tritylpyrone in example 1 was added to 800mL of xylene, heated to 40-45℃and 207.6g (1.35 mol) of phosphorus oxychloride was added dropwise, followed by reflux reaction for 8 hours. Cooling to 5-10 ℃, slowly dropwise adding saturated sodium bicarbonate water solution under temperature control, adjusting pH=7.0-7.5, layering, washing an organic phase with water, distilling off most of dimethylbenzene at normal pressure, cooling to 80-90 ℃ and distilling under reduced pressure to obtain 55.7g of 4-chloro-2, 6-lutidine, and obtaining the yield: 72.6%, GC:98.5%.
Example 4
64.7g (0.4569 mol) of 4-chloro-2, 6-lutidine and 95mL of concentrated sulfuric acid are mixed in a reaction bottle under the protection of nitrogen, 52g (0.594 mol) of concentrated nitric acid is slowly added dropwise after the temperature is raised to 30-40 ℃, and the temperature is raised to 80-85 ℃ for nitration reaction for 4 hours (the mononitration/dinitration ratio is 96/4). Cooling to room temperature, pouring into 1L ice water, adding 10% sodium carbonate aqueous solution to adjust pH=7-8, filtering, putting filter cakes into a reaction bottle again, adding 200mL ethanol/water (volume ratio is 6/4), and recrystallizing to obtain 73.9g of 4-chloro-2,6-dimethyl-3-nitropyridine with the yield: 86.7%, HPLC:99.6%. 1 HNMR(400MHz,CDCl 3 ):7.47(s,1H),2.69(s,3H),2.54(s,3H).
Example 5
To the flask, 64.7g (0.4569 mol) of 4-chloro-2, 6-lutidine and 500mL of glacial acetic acid were mixed under nitrogen protection, 33.1g (0.525 mol) of fuming concentrated nitric acid was slowly added dropwise at 30℃or below, and then the temperature was raised to 40-50℃to conduct nitration reaction for 3 hours (mononitration/dinitration ratio: 94/6). Cooling to-10 ℃, precipitating a large amount of solid, filtering, eluting a filter cake with saturated sodium bicarbonate and water, then putting the filter cake into a reaction bottle again, adding 200mL of ethanol/water (volume ratio is 6/4), and recrystallizing and purifying to obtain 70.7g of 4-chloro-2, 6-dimethyl-3-nitropyridine. Yield: 82.9%, HPLC:99.8%.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should be covered by the protection scope of the present invention by making equivalents and modifications to the technical solution and the inventive concept thereof.
Claims (8)
1. The preparation method of the 4-chloro-2,6-dimethyl-3-nitropyridine is characterized by comprising the following steps:
firstly, mixing 2, 6-dimethyl-4-pyrone, an organic solvent, trityl amine and tris (pentafluorophenyl) borane, heating for reflux reaction, concentrating reaction liquid after the reaction is finished, pulping n-heptane to obtain a 2, 6-dimethyl-1-trityl pyrone crude product, and leaving tris (pentafluorophenyl) borane as a catalyst in the crude product for the next reaction;
secondly, reacting 2, 6-dimethyl-1-tritylpyrone with phosphorus oxychloride to obtain 4-chloro-2, 6-dimethylpyridine;
and thirdly, 4-chloro-2, 6-lutidine is subjected to heating nitration reaction in the presence of a dehydrating agent and nitric acid, and 4-chloro-2,6-dimethyl-3-nitropyridine is obtained through recrystallization and purification.
2. The method for preparing 4-chloro-2,6-dimethyl-3-nitropyridine according to claim 1, wherein: in the first step, the molar ratio of the 2, 6-dimethyl-4-pyrone, the trityl amine and the tris (pentafluorophenyl) borane is 1:1.0-1.04:0.02-0.03.
3. The process for the preparation of 4-chloro-2,6-dimethyl-3-nitropyridine according to claim 1, wherein: in the first step, the organic solvent is selected from toluene, nitrobenzene or xylene.
4. The method for preparing 4-chloro-2,6-dimethyl-3-nitropyridine according to claim 1, wherein: in the second step, the molar ratio of the 2, 6-dimethyl-1-tritylpyrone to the phosphorus oxychloride is 1:2.5-7.0.
5. The method for preparing 4-chloro-2,6-dimethyl-3-nitropyridine according to claim 1, wherein: in the third step, the dehydrating agent is selected from concentrated sulfuric acid or glacial acetic acid; the nitric acid is selected from concentrated nitric acid or fuming nitric acid.
6. The method for preparing 4-chloro-2,6-dimethyl-3-nitropyridine according to claim 1, wherein: in the third step, the reaction temperature is selected from 40-100 ℃.
7. The method for preparing 4-chloro-2,6-dimethyl-3-nitropyridine according to claim 1, wherein: in the third step, the molar ratio of the 4-chloro-2, 6-lutidine to the nitric acid is 1:1.10-1.30.
8. The method for preparing 4-chloro-2,6-dimethyl-3-nitropyridine according to claim 1, wherein: in the third step, the recrystallization adopts a mixed solvent of ethanol and water.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1032439A (en) * | 1987-09-30 | 1989-04-19 | 菲泽有限公司 | A kind of preparation method of platelet-activating factor antagonist |
| US4963560A (en) * | 1988-09-21 | 1990-10-16 | Pfizer Inc. | 1,4-dihydropyridine derivatives |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1032439A (en) * | 1987-09-30 | 1989-04-19 | 菲泽有限公司 | A kind of preparation method of platelet-activating factor antagonist |
| US4963560A (en) * | 1988-09-21 | 1990-10-16 | Pfizer Inc. | 1,4-dihydropyridine derivatives |
Non-Patent Citations (3)
| Title |
|---|
| Inhibitors of Acyl-CoA:Cholesterol O-Acyltransferase. 3. Discovery of a Novel Series of N-Alkyl-N-[(fluorophenoxy)benzyl]-N¢-arylureas with Weak Toxicological Effects on Adrenal Glands;Akira Tanaka等;《J. Med. Chem.》;第41卷(第22期);第4408-4420页 * |
| Yuhua Huang等.Syntheses of 4- and 6-substituted thiazolo[4,5-c]pyridines.《Tetrahedron Letters》.2010,第51卷第2800-2802页. * |
| 沈学全 等.4-氯-2,6-二甲基-3-硝基吡啶的合成工艺研究.《浙江化工》.2012,第43卷(第7期),第19-21页. * |
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