CN105198799A - Preparation method of 2-methyl-6-(chloromethyl) pyridine hydrochloride - Google Patents
Preparation method of 2-methyl-6-(chloromethyl) pyridine hydrochloride Download PDFInfo
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- CN105198799A CN105198799A CN201510738778.7A CN201510738778A CN105198799A CN 105198799 A CN105198799 A CN 105198799A CN 201510738778 A CN201510738778 A CN 201510738778A CN 105198799 A CN105198799 A CN 105198799A
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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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
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Abstract
The invention belongs to the field of organic synthesis and particularly relates to a preparation method of 2-methyl-6-(chloromethyl) pyridine hydrochloride. The preparation method comprises the following steps: (1), 2-methylpyridine as a raw material and an acylation agent have a Friedel-Crafts reaction under the action of a catalyst, and 2-methyl-6-acetylpyridine is obtained; (2), the product 2-methyl-6-acetylpyridine obtained in the step (1) is reduced to 2-methyl-6-hydroxymethylpyridine under the action of a reducing agent; (3), 2-methyl-6-(chloromethyl) pyridine hydrochloride is obtained from the product 2-methyl-6-hydroxymethylpyridineobtained in the step (2) under the action of a chlorination agent. With adoption of the technical scheme, the preparation method has the benefits as follows: commonly used chemical raw materials containing pyridine rings are adopted for acetylation reaction, so that the steps are few, the cost is low, the purity and the yield are high, the operation is safe, and the method is applicable to industrial production.
Description
Technical field
The invention belongs to organic synthesis field, be specifically related to a kind of preparation method of 2-methyl-6-chloromethyl pyridine hydrochloride.
Background technology
Pyridine ring is one of topmost heterocycle of nitrogen heterocyclic ring.From molecular structure, pyridine ring is equivalent to the six-ring that a carbon atom on phenyl ring is substituted by nitrogen-atoms, biochemical characteristic in its compound and phenyl ring have many similarities, simultaneously due to the marked difference of the two structure, pyridine ring is special in much character and feature to differ greatly with phenyl ring in hydrophobicity.Therefore, substitute with pyridine ring the novel pesticide compound that phenyl ring obtains and often there is higher biological activity, interior absorption, selectivity and lower toxicity, the one of the main reasons that this is also the research of pyridine lopps agricultural chemicals in each classification of the various agricultural chemicals such as Insecticides (tech) & Herbicides (tech), sterilant, development and application is developed rapidly.
Chloromethylpyridine and pyridine derivate hydrochloride are the important industrial chemicals of various agricultural chemicals, medicine intermediate, Insecticides (tech) & Herbicides (tech), sterilant.Current pyridine and pyridine derivate directly go up methyl, and with the precious metal industrial chemicals that lithium methide, methyl iodide etc. are expensive, or just direct cyclization becomes on 2-position to have methyl, then carries out logical chlorine, carries out chlorination.But be raw material with lithium methide, methyl iodide etc., cost is high, precious metal be reclaimed and iodine element is cumbersome.
Summary of the invention
The object of the invention is to overcome the technical deficiency that raw materials cost of the prior art is high, route is long, a kind of preparation method of 2-methyl-6-chloromethyl pyridine hydrochloride is provided.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A preparation method for 2-methyl-6-chloromethyl pyridine hydrochloride, the method comprises the following steps:
(1) raw material 2-picoline and acylting agent are carried out friedel-crafts acylation reaction under the effect of catalyzer and obtain 2-methyl-6-acetylpyridine;
(2) in described step (1), products therefrom 2-methyl-6-acetylpyridine is reduced to 2-methyl-6-4-hydroxymethylpiperidine under the effect of reductive agent;
(3) in described step (2), products therefrom 2-methyl-6-4-hydroxymethylpiperidine obtains 2-methyl-6-chloromethyl pyridine hydrochloride under the effect of chlorination reagent.
Further, the acylting agent in described step (1) is selected from: the one in Acetyl Chloride 98Min. or acetic anhydride.
Further, the catalyzer in described step (1) is Lewis acid, and described Lewis acid is selected from: the one in aluminum chloride, zinc chloride.
Further, the temperature of friedel-crafts acylation reaction is 50-100 DEG C in described step (1), and the reaction times is 5-10 hour, 2-picoline, the mol ratio of acylting agent, catalyzer is 1:1-2:0.1-0.5; In described step (2), the temperature of reaction of reduction reaction is 50-90 DEG C, and the reaction times is 5-10 hour; Chlorination temperature in described step (3) is :-20 ~-5 DEG C, and the reaction times is 1-3 hour.
Further, the reductive agent that the reduction reaction in described step (2) adopts is: the one in sodium borohydride, Lithium Aluminium Hydride, Raney nickel or palladium charcoal; The mol ratio of described reductive agent consumption and raw material pyridine is 1:0.5-2.
Further, the chlorination reagent in described step (3) is selected from: the one in thionyl chloride, phosphorus oxychloride, phosphorus trichloride; The mol ratio of described chlorination reagent and raw material is 1:0.5-4.
Reaction equation of the present invention is:
The beneficial effect of technical scheme of the present invention is adopted to be: it is few that the present invention adopts the conventional industrial chemicals containing pyridine ring to carry out acetylating reactions steps, and cost is low, and purity is high, and yield is high, and operational safety is applicable to suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, not for limiting right of the present invention.
Embodiment 1
In 500ml there-necked flask, add 9.3g2-picoline, 60ml methyl alcohol, add 1.3g aluminum chloride, be cooled to less than 0 DEG C and drip Acetyl Chloride 98Min. 7.8g, after dropwising, being warming up to temperature of reaction is 50-100 DEG C, back flow reaction 6 hours, sampling analysis, reacts completely to raw material 2-picoline; In system, add sodium borohydride 1.9g, temperature of reaction is 60 DEG C, carries out reduction reaction, react 6 hours, filter, removing inorganic salt, filtrate steams methyl alcohol, with dichloromethane extraction 2-methyl-6-4-hydroxymethylpiperidine, with anhydrous sodium sulfate drying, be cooled to-10 DEG C and start to drip 6g thionyl chloride, and then be naturally warming up to room temperature reaction 2-3 hour, obtain 2-methyl-6-chloromethyl pyridine hydrochloride, total recovery is 82%.
Embodiment 2
In 500ml there-necked flask, add 9.3g2-picoline, 60ml methyl alcohol, add 1.3g aluminum chloride, be cooled to less than 0 DEG C and drip Acetyl Chloride 98Min. 7.8g, after dropwising, being warming up to temperature of reaction is 50-100 DEG C, back flow reaction 5 hours, sampling analysis, reacts completely to raw material 2-picoline; In system, add sodium borohydride 1.9g, temperature of reaction is 50 DEG C, carries out reduction reaction, react 5 hours, filter, removing inorganic salt, filtrate steams methyl alcohol, with dichloromethane extraction 2-methyl-6-4-hydroxymethylpiperidine, with anhydrous sodium sulfate drying, be cooled to-20 DEG C and start to drip 6g thionyl chloride, and then be naturally warming up to room temperature reaction 2-3 hour, obtain 2-methyl-6-chloromethyl pyridine hydrochloride, total recovery is 78%.
Embodiment 3
In 500ml there-necked flask, add 9.3g2-picoline, 60ml methyl alcohol, add 1.3g aluminum chloride, be cooled to less than 0 DEG C and drip Acetyl Chloride 98Min. 7.8g, after dropwising, being warming up to temperature of reaction is 50-100 DEG C, back flow reaction 10 hours, sampling analysis, reacts completely to raw material 2-picoline; In system, add sodium borohydride 1.9g, temperature of reaction is 90 DEG C, carries out reduction reaction, react 10 hours, filter, removing inorganic salt, filtrate steams methyl alcohol, with dichloromethane extraction 2-methyl-6-4-hydroxymethylpiperidine, with anhydrous sodium sulfate drying, be cooled to-5 DEG C and start to drip 6g thionyl chloride, and then be naturally warming up to room temperature reaction 2-3 hour, obtain 2-methyl-6-chloromethyl pyridine hydrochloride, total recovery is 83%.
Claims (6)
1. a preparation method for 2-methyl-6-chloromethyl pyridine hydrochloride, is characterized in that the method comprises the following steps:
(1) raw material 2-picoline and acylting agent are carried out friedel-crafts acylation reaction under the effect of catalyzer and obtain 2-methyl-6-acetylpyridine;
(2) in described step (1), products therefrom 2-methyl-6-acetylpyridine is reduced to 2-methyl-6-4-hydroxymethylpiperidine under the effect of reductive agent;
(3) in described step (2), products therefrom 2-methyl-6-4-hydroxymethylpiperidine obtains 2-methyl-6-chloromethyl pyridine hydrochloride under the effect of chlorination reagent.
2. the preparation method of a kind of 2-methyl-6-chloromethyl pyridine hydrochloride according to claim 1, is characterized in that the acylting agent in described step (1) is selected from: the one in Acetyl Chloride 98Min. or acetic anhydride.
3. the preparation method of a kind of 2-methyl-6-chloromethyl pyridine hydrochloride according to claim 1, it is characterized in that the catalyzer in described step (1) is Lewis acid, described Lewis acid is selected from: the one in aluminum chloride, zinc chloride.
4. the preparation method of a kind of 2-methyl-6-chloromethyl pyridine hydrochloride according to claim 1, it is characterized in that the temperature of friedel-crafts acylation reaction is 50-100 DEG C in described step (1), reaction times is 5-10 hour, 2-picoline, the mol ratio of acylting agent, catalyzer is 1:1-2:0.1-0.5; In described step (2), the temperature of reaction of reduction reaction is 50-90 DEG C, and the reaction times is 5-10 hour; Chlorination temperature in described step (3) is :-20 ~-5 DEG C, and the reaction times is 1-3 hour.
5. the preparation method of a kind of 2-methyl-6-chloromethyl pyridine hydrochloride according to claim 1, is characterized in that the reductive agent that the reduction reaction in described step (2) adopts is: the one in sodium borohydride, Lithium Aluminium Hydride, Raney nickel or palladium charcoal; The mol ratio of described reductive agent consumption and raw material pyridine is 1:0.5-2.
6. the preparation method of a kind of 2-methyl-6-chloromethyl pyridine hydrochloride according to claim 1, is characterized in that the chlorination reagent in described step (3) is selected from: the one in thionyl chloride, phosphorus oxychloride, phosphorus trichloride; The mol ratio of described chlorination reagent and raw material is 1:0.5-4.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3123608A (en) * | 1964-03-03 | Process for chlorination of side chains | ||
| CN102603620A (en) * | 2012-01-13 | 2012-07-25 | 江苏中邦制药有限公司 | Synthetic method of chloromethylpyridine or pyridine derivative hydrochloride of chloromethylpyridine |
| CN103347882A (en) * | 2010-12-13 | 2013-10-09 | 阵列生物制药公司 | Substituted n-(1h-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide compounds as type iii receptor tyrosine kinase inhibitors |
| CN104974078A (en) * | 2015-06-25 | 2015-10-14 | 黄荣辉 | Preparation method of 2-methyl-6-chloromethylpyridinehydrochloride |
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2015
- 2015-11-03 CN CN201510738778.7A patent/CN105198799A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3123608A (en) * | 1964-03-03 | Process for chlorination of side chains | ||
| CN103347882A (en) * | 2010-12-13 | 2013-10-09 | 阵列生物制药公司 | Substituted n-(1h-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide compounds as type iii receptor tyrosine kinase inhibitors |
| CN102603620A (en) * | 2012-01-13 | 2012-07-25 | 江苏中邦制药有限公司 | Synthetic method of chloromethylpyridine or pyridine derivative hydrochloride of chloromethylpyridine |
| CN104974078A (en) * | 2015-06-25 | 2015-10-14 | 黄荣辉 | Preparation method of 2-methyl-6-chloromethylpyridinehydrochloride |
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Application publication date: 20151230 |