CN102875456B - Chemical synthesis method of 3, 6-dichloro-2-aminopyridine - Google Patents
Chemical synthesis method of 3, 6-dichloro-2-aminopyridine Download PDFInfo
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- CN102875456B CN102875456B CN2012104063231A CN201210406323A CN102875456B CN 102875456 B CN102875456 B CN 102875456B CN 2012104063231 A CN2012104063231 A CN 2012104063231A CN 201210406323 A CN201210406323 A CN 201210406323A CN 102875456 B CN102875456 B CN 102875456B
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Abstract
The invention discloses a chemical synthesis method of 3, 6-dichloro-2-aminopyridine. The target product 3, 6-dichloro-2-aminopyridine is obtained after simple post-processing through one-step reaction by using ammonization reagent and by using 2, 3, 6-trichloropyridine as a starting raw material, the yield is high and the product quality is high. Compared with the existing disclosed technique, the chemical synthesis method of 3, 6-dichloro-2-aminopyridine has the advantages that the reaction steps are fewer, the raw materials are easy to obtain, the energy consumption is low, the production cost is low, the technological intrinsic safety is high and the industrial production is easier to realized.
Description
Technical field
The present invention relates to a kind of synthetic method of halo aminopyridine, particularly 3, the synthetic method of 6-bis-chloro-PAs.
Background technology
The halo aminopyridine is important fine-chemical intermediate, at medicine and pesticide field, is widely used.The chloro-PA of 3,6-bis-, pharmaceutically as the synthetic synthetic important intermediate of S1P1 receptor agonist.Because its synthetic difficulty is larger, both at home and abroad to 3, the synthetic report of the chloro-PA of 6-bis-seldom, only patent WO2009154775A1 discloses its synthetic method: the first step, the chloro-PA of the 6-of take is raw material, be that solvent, triethylamine are to react with pivaloyl chloride under the acid binding agent condition at toluene, generate N-(6-chloro-2-pyridyl)-pivaloyl amine.Second step, take that N-(6-chloro-2-pyridyl)-pivaloyl amine is raw material, take tetrahydrofuran (THF) as solvent, successively with n-Butyl Lithium and hexachloroethane, react generation N-(3,6-dichloro-2-pyridyl base)-pivaloyl amine under subzero 78 ℃.The 3rd step,, is hydrolyzed in the 5N aqueous hydrochloric acid for raw material with N-(3,6-dichloro-2-pyridyl base)-pivaloyl amine under 115 ℃, then regulates the pH value with the 10N aqueous sodium hydroxide solution, obtains the chloro-PA of 3,6-bis-.The committed step of this synthetic route is second step, in this step reaction, use in a large number expensive n-Butyl Lithium (mol ratio of n-Butyl Lithium and N-(6-chloro-2-pyridyl)-pivaloyl amine is 2.5), makes manufacturing cost high; The use of n-Butyl Lithium simultaneously makes technique anhydrous and oxygen-free operational condition harshness, and the through engineering approaches difficulty is large.In the second step reaction, temperature of reaction is subzero 78 ℃, makes energy consumption of reaction high.In sum, prior art exists reactions steps long, and reagent costliness, energy consumption is high, process conditions is harsh, be not easy to accomplish scale production etc. needs the problem solved.
Summary of the invention
The object of the invention is to overcome the above-mentioned defect of prior art, the synthetic method that a kind of reactions steps is few, reaction reagent is cheap, energy consumption is low, process conditions is simple, the through engineering approaches difficulty is little, be easy to accomplish scale production is provided.
Technical scheme of the present invention:
A kind of 3, the synthesis technique of 6-bis-chloro-PAs, the main raw material adopted is 2,3,6-trichloropyridine.
The synthetic chloro-PA chemical reaction process of 3,6-bis-of the present invention is as follows:
Above-mentioned 3, the synthetic concrete technology step of 6-bis-chloro-PAs is:
Add 2,3,6-trichloropyridine in withstand voltage reactor, add ammoniation agent, add again catalyzer closed reactor, be heated under 100～160 ℃, react 0.5～18 hour, discharge while hot unreacted ammonia, after in question response liquid, ammonia releases, drop to room temperature, add extraction agent, filter the phase-splitting of gained filtrate, the organic phase washing, anhydrous magnesium sulfate drying, filter, solvent is deviate from decompression, obtain brown 3, the chloro-PA crude product of 6-bis-.Crude product carries out recrystallization with solvent, dries and obtains canescence 3, the chloro-PA of 6-bis-, yield 75～93%.
The toluene solution of the ethanolic soln that described ammoniation agent is ammoniacal liquor, liquefied ammonia, ammonia, the methanol solution of ammonia, ammonia, the acetonitrile solution of ammonia, ammonium carbonate solution, ammonium bicarbonate aqueous solution, preferably ammoniacal liquor.
Described 2,3,6-trichloropyridine and ammoniation agent mol ratio are preferably 1:3～49.
Described catalyzer is one or more in metal catalyst, phase-transfer catalyst, catalyzer auxiliary.Wherein metal catalyst is composite catalyst, and major ingredient is one or several in cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide, cupric chloride, copper sulfate, copper carbonate, phase-transfer catalyst is Tetrabutyl amonium bromide, tetrabutylammonium chloride, benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide, cetyl trimethylammonium bromide, dodecyl dimethyl benzyl ammonium chloride, the two octadecyl Dimethyl Ammonium of bromination, benzyl trimethyl ammonium chloride, benzyl tributyl ammonium chloride, benzyl tributyl brometo de amonio, tri-n-octyl methyl ammonium chloride, tetramethyl ammonium chloride, tetraethylammonium bromide, 4-propyl bromide, 4-butyl ammonium hydrogen sulfate, the tetrabutylammonium perchlorate, 4-butyl ammonium fluoroborate, Tetradecyl Trimethyl Ammonium Bromide, the tetraphenyl phosphonium chloride, 4-phenyl phosphonium bromide, the trityl group phosphonium bromide, tri-phenyl-ethyl phosphonium bromide, triphenyl ethyl iodination phosphonium, triphenyl propyl group phosphonium bromide, triphenyl butyl phosphonium bromide, Bian base triphenyl phosphonium chloride, benzyl three phenyl phosphonium bromides, crown ether 15 hats 5, crown ether 18 hats 6, dibenzo-18-hat-6, to one or several in Dimethylamino pyridine, the catalyzer auxiliary is one or several in sodium iodide, potassiumiodide, cesium fluoride, potassiumphosphate, salt of wormwood, sodium carbonate.
Described catalyst levels is 0.5～30% of 2,3,6-trichloropyridine quality.
Described extraction solvent is toluene, chloroform, methylene dichloride, methyl tertiary butyl ether, preferably chloroform.
Described recrystallization solvent is the single or mixed solvents such as sherwood oil, hexanaphthene, normal hexane, toluene, methyl alcohol, ethanol.
With existing public technology, compare, the present invention has following advantage:
1,, from raw material 2,3, the 6-trichloropyridine sets out, one-step synthesis 3, and the chloro-PA of 6-bis-, operation is few, simple to operate.
2, raw material 2,3, and the 6-trichloropyridine is easy to get, low price.
3, responding is not low-temp reaction, and energy consumption is low, and is easier to realize suitability for industrialized production.
4, all reagent is all conventional, low price, low cost of manufacture.
5, good reaction selectivity, yield is high, the finished product quality better.
6, the present invention does not use in this class through engineering approaches process of butyllithium, and the reagent that the security management and control difficulty is large, improved the technique intrinsic safety.
Therefore, the present invention has good economic benefit and social benefit in sum.
Embodiment:
Embodiment 1
Add 2 in the withstand voltage reactor of 1000ml, 3, 6-trichloropyridine 45.6 grams (0.25 mol), add 340 gram 25% ammoniacal liquor (containing ammonia 5 mol), (catalyzer consists of: 3.56 gram cuprous chlorides to add catalyzer 4.56 grams again, benzyltriethylammoinium chloride 0.5 gram, sodium iodide 0.5 gram) and closed reactor, be heated to 120～125 ℃, react 5 hours, discharge while hot unreacted ammonia, after in question response liquid, ammonia releases, drop to room temperature, add the 300ml chloroform, stir, filter, the phase-splitting of gained filtrate, the organic phase washing, anhydrous magnesium sulfate drying, chloroform is deviate from decompression, obtain brown 3, the chloro-PA crude product of 6-bis-.Crude product adopts 260ml toluene recrystallization, dries and obtains canescence 3, chloro-PA 37.3 grams of 6-bis-, content 97.8%, yield 91.6%.
Embodiment 2
Catalyzer is 3.56 gram cuprous chlorides, and other are with embodiment 1.
Operated according to embodiment 1, obtained canescence 3, chloro-PA 32.9 grams of 6-bis-, content 96.9%, yield 80.9%.
Embodiment 3
Catalyzer is 4.06 grams (catalyzer consists of: 3.56 gram cuprous chlorides, benzyltriethylammoinium chloride 0.5 gram).
Operated according to embodiment 1, obtained canescence 3, chloro-PA 36.3 grams of 6-bis-, content 97.2%, yield 89.1%.
Embodiment 4
Catalyzer is 4.56 grams (catalyzer consists of: 3.56 gram cuprous chlorides, sodium iodide 1.0 grams).
Operated according to embodiment 1, obtained canescence 3, chloro-PA 33.8 grams of 6-bis-, content 97.0%, yield 83.0%.
Embodiment 5
Add 2 in the withstand voltage reactor of 1000ml, 3, 6-trichloropyridine 45.6 grams (0.25 mol), add 340 gram 25% ammoniacal liquor (containing ammonia 5 mol), adding catalyzer is that (catalyzer consists of 1.0 grams: benzyltriethylammoinium chloride 0.5 gram again, sodium iodide 0.5 gram) and closed reactor, be heated to 138～142 ℃, react 6 hours, discharge while hot unreacted ammonia, after in question response liquid, ammonia releases, drop to room temperature, add the 300ml chloroform, stir, filter, the phase-splitting of gained filtrate, the organic phase washing, anhydrous magnesium sulfate drying, chloroform is deviate from decompression, obtain brown 3, the chloro-PA crude product of 6-bis-.Crude product adopts 260ml toluene recrystallization, dries and obtains canescence 3, chloro-PA 32.3 grams of 6-bis-, content 96.7%, yield 79.2%.
Embodiment 6
Catalyzer is 1.0 gram benzyltriethylammoinium chlorides, and in 8 hours reaction times, other are with embodiment 5.
Operated according to embodiment 5, obtained grey 3, chloro-PA 31.0 grams of 6-bis-, content 96.9%, yield 76.1%.
Embodiment 7
Catalyzer is 2.0 gram sodium iodides, and 145～150 ℃ of temperature of reaction are reacted 10 hours, and other are with embodiment 5.
Operated according to embodiment 5, obtained grey 3, chloro-PA 30.6 grams of 6-bis-, content 95.5%, yield 75.0%.
Embodiment 8
Catalyzer is 8.12 grams (catalyzer consists of: 7.12 gram cuprous chlorides, benzyltriethylammoinium chloride 0.5 gram, sodium iodide 0.5 gram), and in 4 hours reaction times, other are with embodiment 1.
Operated according to embodiment 1, obtained canescence 3, chloro-PA 37.6 grams of 6-bis-, content 98.3%, yield 92.2%.
Embodiment 9
Catalyzer is 1.0 gram cuprous chlorides, and other are with embodiment 1.
Operated according to embodiment 1, obtained canescence 3, chloro-PA 31.9 grams of 6-bis-, content 96.9%, yield 78.3%.
Embodiment 10
Ammonification reagent adopts the ethanolic soln (containing 2.5 moles of ammonia) of 354 gram 12% ammonia, 105～110 ℃ of temperature of reaction, and other are with embodiment 1.
Operated according to embodiment 1, obtained canescence 3, chloro-PA 37.7 grams of 6-bis-, content 98.9%, yield 92.6%.
Embodiment 11
Ammonification reagent is 85 gram 25% ammoniacal liquor (containing ammonia 1.25 mol), reacts 18 hours, and other are with embodiment 1.
Operated according to embodiment 1, obtained canescence 3, chloro-PA 35.2 grams of 6-bis-, content 97.2%, yield 86.5%.
Embodiment 12
Adopt the withstand voltage reactor of 2000ml, ammonification reagent is 765 gram 25% ammoniacal liquor (containing ammonia 11.25 mol), reacts 3.5 hours, and other are with embodiment 1.
Operated according to embodiment 1, obtained canescence 3, chloro-PA 37.7 grams of 6-bis-, content 98.3%, yield 92.6%.
Embodiment 13
Ammonification reagent adopts the aqueous solution (containing 5 moles of volatile salts) of 1068 gram 45% volatile salts, 150～155 ℃ of temperature of reaction, and other are with embodiment 12.
Operated according to embodiment 12, obtained canescence 3, chloro-PA 30.5 grams of 6-bis-, content 95.2%, yield 74.9%.
Embodiment 14
Catalyzer is 10.48 grams (catalyzer consists of: 8.48 gram cuprous chlorides, benzyltriethylammoinium chloride 1.5 grams, sodium iodide 0.5 gram), and in 3.5 hours reaction times, other are with embodiment 8.
Operated according to embodiment 8, obtained canescence 3, chloro-PA 37.8 grams of 6-bis-, content 98.1%, yield 92.8%.
Embodiment 15
Do not use any catalyzer, other are with embodiment 7.
Operated according to embodiment 1, obtained grey 3, chloro-PA 30.8 grams of 6-bis-, content 94.9%, yield 75.5%.
Embodiment 16
Recrystallization solvent adopts normal hexane to replace toluene, and other are with embodiment 1.
Operated according to embodiment 1, obtained canescence 3, chloro-PA 37.6 grams of 6-bis-, content 96.1%, yield 92.2%.
Claims (3)
1. one kind 3, the synthetic method of 6-bis-chloro-PAs, is characterized in that adopted main raw material is 2,3,6-trichloropyridine, through aminating reaction and simple aftertreatment, obtains product, and the concrete technology step is:
Add 2 in withstand voltage reactor, 3, the 6-trichloropyridine, add ammoniacal liquor, the ethanolic soln of ammonia, a kind of as ammoniation agent in ammonium carbonate solution, add again cuprous chloride, benzyltriethylammoinium chloride, a kind of or its combination in sodium iodide is as catalyzer closed reactor, be heated under 100～160 ℃, react 0.5～18 hour, discharge while hot unreacted ammonia, after in question response liquid, ammonia releases, drop to room temperature, add extraction agent, filter, the phase-splitting of gained filtrate, the organic phase washing, anhydrous magnesium sulfate drying, filter, solvent is deviate from decompression, obtain brown 3, the chloro-PA crude product of 6-bis-, crude product carries out recrystallization with toluene or normal hexane, oven dry obtains canescence 3, the chloro-PA of 6-bis-, yield 75～93%.
2. synthetic method as described as right 1, is characterized in that 2,3,6-trichloropyridine and ammoniation agent mol ratio are preferably 1:3～49.
3. synthetic method as described as right 1, is characterized in that described catalyst levels is 0.5～30% of 2,3,6-trichloropyridine quality.
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| CN103880740B (en) * | 2014-04-14 | 2016-02-17 | 西华大学 | The synthesis of 4-nitro-3-hydroxyl-2-pyridine carboxylic acid |
| JP7113762B2 (en) | 2016-05-19 | 2022-08-05 | コルテバ アグリサイエンス エルエルシー | Synthesis of 6-aryl-4-aminopicolinates and 2-aryl-6-aminopyrimidine-4-carboxylates via direct Suzuki coupling |
| CN106243021A (en) * | 2016-07-28 | 2016-12-21 | 南京红太阳生物化学有限责任公司 | A kind of method of synthesis 4 aminopyridines |
| CN114394975A (en) * | 2022-01-27 | 2022-04-26 | 黎常宏 | Preparation method of allylamine salt |
| CN117550621B (en) * | 2024-01-11 | 2024-03-22 | 恒泰军航高分子材料(山东)有限公司 | Method and device for preparing high-purity BN ceramic precursor |
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| US3317549A (en) * | 1963-03-25 | 1967-05-02 | Dow Chemical Co | Picolinic acid compounds |
| CN1539822A (en) * | 2003-11-03 | 2004-10-27 | 浙江大学 | Method for preparing 2-aminopyridine and alkyl derivative |
| CN102532008A (en) * | 2012-01-12 | 2012-07-04 | 南京红太阳生物化学有限责任公司 | Novel method for synthesizing 2,5-dichloro-3-fluoropyridine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3317549A (en) * | 1963-03-25 | 1967-05-02 | Dow Chemical Co | Picolinic acid compounds |
| CN1539822A (en) * | 2003-11-03 | 2004-10-27 | 浙江大学 | Method for preparing 2-aminopyridine and alkyl derivative |
| CN102532008A (en) * | 2012-01-12 | 2012-07-04 | 南京红太阳生物化学有限责任公司 | Novel method for synthesizing 2,5-dichloro-3-fluoropyridine |
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