CN105085378A - Synthetic method of 4-(chloromethyl)pyridine hydrochloride - Google Patents
Synthetic method of 4-(chloromethyl)pyridine hydrochloride Download PDFInfo
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- CN105085378A CN105085378A CN201510561697.4A CN201510561697A CN105085378A CN 105085378 A CN105085378 A CN 105085378A CN 201510561697 A CN201510561697 A CN 201510561697A CN 105085378 A CN105085378 A CN 105085378A
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- Prior art keywords
- pyridine hydrochloride
- synthetic method
- isonicotinic acid
- chloromethyl pyridine
- acid
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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
Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of 4-(chloromethyl)pyridine hydrochloride. The method comprises steps as follows: (1) 4-methylpyridine is taken as a raw material, water is taken as a solvent, and the 4-methylpyridine is oxidized into 4-picolinic acid with potassium permanganate, wherein the molar ratio of the 4-methylpyridine to the potassium permanganate is 1:(2.1-2.3), the oxidizing temperature is 75-80 DEG C, heating is performed for 35 min, a reaction solution is adjusted to be acid after the reaction, and 4-picolinic acid is obtained after cooling and filtration; (2) the 4-picolinic acid and methanol react to produce methyl pyridine-4-carboxylate under the acid condition, and the molar ratio of the 4-picolinic acid to the methanol is 1:1.3; (3) the methyl pyridine-4-carboxylate is reduced to 4-pyridinemethanol; (4) the 4-pyridinemethanol reacts with thionyl chloride to produce a target product, namely, 4-(chloromethyl)pyridine hydrochloride, and the molar ratio of the 4-pyridinemethanol to the thionyl chloride is 1:(1.1-1.3).
Description
Technical field
The invention belongs to organic synthesis field, be specifically related to a kind of synthetic method of 4-chloromethyl pyridine hydrochloride.
Background technology
Chloromethyl pyridine hydrochloride is the important industrial chemicals of various agricultural chemicals, medicine intermediate, Insecticides (tech) & Herbicides (tech), sterilant.Current production method adopts pyridine directly to go up methyl, and with precious metal industrial chemicals such as lithium methides, more logical chlorine carries out chlorination.Industrial chemicals intermediate and bulk drug that the synthesis of other groups has high added value is more easily connect after pyridine chloromethylation.But be raw material with lithium methide etc., cost value pressure is large, reclaim precious metal cumbersome, large by methyl-sulfate toxicity, more dangerous for operator.
Summary of the invention
The object of the invention is to overcome cost in prior art high, the deficiency that reagent toxicity is large, the synthetic method of the 4-chloromethyl pyridine hydrochloride that a kind of cost is low, yield is high, reaction conditions is gentle is provided.
The synthetic method of a kind of 4-chloromethyl pyridine hydrochloride provided by the invention, preparation method comprises the following steps:
(1) with 4-picoline for raw material, with water as solvent, Isonicotinic acid is oxidized to potassium permanganate, wherein, the mol ratio of 4-picoline and potassium permanganate is 1:2.1-2.3, and oxidizing temperature is 75-80 DEG C, heating 35min, react completely and reaction solution is adjusted to acidity, then cold filtration obtains Isonicotinic acid;
(2) Isonicotinic acid and methyl alcohol generate Isonicotinic acid methyl esters in acid condition, and wherein the mol ratio of Isonicotinic acid and methyl alcohol is 1:1.3;
(3) the Isonicotinic acid methyl esters that reduces is 4-piconol;
(4) 4-piconol and sulfur oxychloride are obtained by reacting object product 4-chloromethyl pyridine hydrochloride, and the mol ratio of 4-piconol and sulfur oxychloride is 1:1.1-1.3.
Further, in described step (1), potassium permanganate adds under the condition of 80 DEG C in batches.
Further, in described step (1), pH regulator is, with the hydrochloric acid of 2mol/l, the pH value of reaction solution is adjusted to 3-4.
Further, in described step (1), the temperature of cold filtration is 25 DEG C.
Further, the reductive agent adopted in described step (3) is sodium borohydride, and the mol ratio of described Isonicotinic acid methyl esters and sodium borohydride is 1:4-5, described reduction reaction Lewis acid as catalyst.
Further, described Lewis acid is aluminum chloride.
Further, the solvent that described reduction reaction adopts is the mixed solvent that 1:1 mixes with THF and toluene with volume ratio.
The reaction equation of the inventive method is:
The beneficial effect of technical scheme of the present invention is adopted to be: reactions steps is few, and cost is low, and purity is high, and yield is high, operational safety, and the inventive method is applicable to large-scale industrial production.
Embodiment
In order to set forth the present invention further, provide some embodiments below.These embodiments are illustrative completely, and they are only used for being specifically described the present invention, should not be construed as limitation of the present invention.
Embodiment 1
(1) in the flask of 250ml, 4-picoline (18.6g is added, 0.2mol), water 150ml, be heated to 80 DEG C, add potassium permanganate (66.36g, 0.42mol) in batches, holding temperature is at 75-80 DEG C of heated and stirred 35min, thin-layer chromatography trace analysis, the pH value of reaction solution is adjusted to 3 with the hydrochloric acid of 2mol/l by question response completely, reacting liquid temperature is cooled to 25 DEG C of suction filtrations and obtains Isonicotinic acid.
(2) Isonicotinic acid and methyl alcohol (12g, 0.26mol) generate Isonicotinic acid methyl esters under vitriol oil effect.
(3) Isonicotinic acid methyl esters is dissolved in the solvent that 75mlTHF and 75ml toluene mixes, 0-5 DEG C adds sodium borohydride (30.24g in batches, 0.8mol) and aluminum chloride, add and continue reaction 3-4h, thin-layer chromatography trace analysis is to the 4-piconol that reacts completely to obtain.
(4) react with sulfur oxychloride (26.18g, 0.22mol) in methanol solution after 4-piconol, thin-layer chromatography trace analysis, question response is all converted into stopped reaction after 4-chloromethyl pyridine hydrochloride, suction filtration, obtains product 26.2g, and productive rate is 80%(molar yield).
Embodiment 2
(1) in the flask of 250ml, 4-picoline (18.6g is added, 0.2mol), water 150ml, be heated to 80 DEG C, add potassium permanganate (69.5g, 0.44mol) in batches, holding temperature is at 75-80 DEG C of heated and stirred 35min, thin-layer chromatography trace analysis, the pH value of reaction solution is adjusted to 4 with the hydrochloric acid of 2mol/l by question response completely, reacting liquid temperature is cooled to 25 DEG C of suction filtrations and obtains Isonicotinic acid.
(2) Isonicotinic acid and methyl alcohol (12g, 0.26mol) generate Isonicotinic acid methyl esters under vitriol oil effect.
(3) Isonicotinic acid methyl esters is dissolved in the solvent that 75mlTHF and 75ml toluene mixes, 0-5 DEG C adds sodium borohydride (34g in batches, 0.9mol) and aluminum chloride, add and continue reaction 3-4h, thin-layer chromatography trace analysis is to the 4-piconol that reacts completely to obtain.
(4) react with sulfur oxychloride (26.18g, 0.22mol) in methanol solution after 4-piconol, thin-layer chromatography trace analysis, question response is all converted into stopped reaction after 4-chloromethyl pyridine hydrochloride, suction filtration, obtains product 26.9g, and productive rate is 82%(molar yield).
Embodiment 3
(1) in the flask of 250ml, 4-picoline (18.6g is added, 0.2mol), water 150ml, be heated to 80 DEG C, add potassium permanganate (72.7g, 0.46mol) in batches, holding temperature is at 75-80 DEG C of heated and stirred 35min, thin-layer chromatography trace analysis, the pH value of reaction solution is adjusted to 4 with the hydrochloric acid of 2mol/l by question response completely, reacting liquid temperature is cooled to 25 DEG C of suction filtrations and obtains Isonicotinic acid.
(2) Isonicotinic acid and methyl alcohol (12g, 0.26mol) generate Isonicotinic acid methyl esters under vitriol oil effect.
(3) Isonicotinic acid methyl esters is dissolved in the solvent that 75mlTHF and 75ml toluene mixes, 0-5 DEG C adds sodium borohydride (37.8g in batches, 1.0mol) and aluminum chloride, add and continue reaction 3-4h, thin-layer chromatography trace analysis is to the 4-piconol that reacts completely to obtain.
(4) react with sulfur oxychloride (26.18g, 0.22mol) in methanol solution after 4-piconol, thin-layer chromatography trace analysis, question response is all converted into stopped reaction after 4-chloromethyl pyridine hydrochloride, suction filtration, obtains product 25.6g, yield 78%(molar yield).
Claims (7)
1. a synthetic method for 4-chloromethyl pyridine hydrochloride, is characterized in that the method comprises the following steps:
(1) with 4-picoline for raw material, with water as solvent, Isonicotinic acid is oxidized to potassium permanganate, wherein, the mol ratio of 4-picoline and potassium permanganate is 1:2.1-2.3, and oxidizing temperature is 75-80 DEG C, heating 35min, react completely and reaction solution is adjusted to acidity, then cold filtration obtains Isonicotinic acid;
(2) Isonicotinic acid and methyl alcohol generate Isonicotinic acid methyl esters in acid condition, and wherein the mol ratio of Isonicotinic acid and methyl alcohol is 1:1.3;
(3) the Isonicotinic acid methyl esters that reduces is 4-piconol;
(4) 4-piconol and sulfur oxychloride are obtained by reacting object product 4-chloromethyl pyridine hydrochloride, and the mol ratio of 4-piconol and sulfur oxychloride is 1:1.1-1.3.
2. the synthetic method of a kind of 4-chloromethyl pyridine hydrochloride according to claim 1, is characterized in that: in described step (1), potassium permanganate adds under the condition of 80 DEG C in batches.
3. the synthetic method of a kind of 4-chloromethyl pyridine hydrochloride according to claim 1, is characterized in that: in described step (1), pH regulator is, with the hydrochloric acid of 2mol/l, the pH value of reaction solution is adjusted to 3-4.
4. the synthetic method of a kind of 4-chloromethyl pyridine hydrochloride according to claim 1, is characterized in that: in described step (1), the temperature of cold filtration is 25 DEG C.
5. the synthetic method of a kind of 4-chloromethyl pyridine hydrochloride according to claim 1, it is characterized in that: the reductive agent adopted in described step (3) is sodium borohydride, the mol ratio of described Isonicotinic acid methyl esters and sodium borohydride is 1:4-5, described reduction reaction Lewis acid as catalyst.
6. the synthetic method of a kind of 4-chloromethyl pyridine hydrochloride according to claim 5, is characterized in that: described Lewis acid is aluminum chloride.
7. the synthetic method of a kind of 4-chloromethyl pyridine hydrochloride according to claim 5, is characterized in that: the solvent that described reduction reaction adopts is the mixed solvent that 1:1 mixes with THF and toluene with volume ratio.
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| CN201510561697.4A CN105085378A (en) | 2015-09-07 | 2015-09-07 | Synthetic method of 4-(chloromethyl)pyridine hydrochloride |
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| CN201510561697.4A CN105085378A (en) | 2015-09-07 | 2015-09-07 | Synthetic method of 4-(chloromethyl)pyridine hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112047878A (en) * | 2020-10-15 | 2020-12-08 | 郑州猫眼农业科技有限公司 | Preparation method of 4-bromo-6-chloropyridine-2-carboxylic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000027818A1 (en) * | 1998-11-06 | 2000-05-18 | Delmar Chemicals Inc. | Preparation of chloromethylpyridine hydrochlorides |
| EP2606970A1 (en) * | 2011-12-19 | 2013-06-26 | Basell Polyolefine GmbH | Monocyclopentadienyl binuclear complexes, ligands used in their preparaion, catalyst systems comprising them and olefin polymerisation process |
-
2015
- 2015-09-07 CN CN201510561697.4A patent/CN105085378A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000027818A1 (en) * | 1998-11-06 | 2000-05-18 | Delmar Chemicals Inc. | Preparation of chloromethylpyridine hydrochlorides |
| EP2606970A1 (en) * | 2011-12-19 | 2013-06-26 | Basell Polyolefine GmbH | Monocyclopentadienyl binuclear complexes, ligands used in their preparaion, catalyst systems comprising them and olefin polymerisation process |
Non-Patent Citations (2)
| Title |
|---|
| JIQING BAO，ET AL.: "Synthesis and fluorescence properties of Tb(III) complex with a novel aromatic carboxylic acid (L) as well as spectroscopic studies on the interaction between Tb(III) complex and bovine serum albumin", 《JOURNAL OF LUMINESCENCE》 * |
| SALEEM AHMAD，ET AL.: "Synthesis of pyridine-3-aldoxime and pyridine-4-aldoxime", 《ISLAMABAD JOURNAL OF SCIENCES》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112047878A (en) * | 2020-10-15 | 2020-12-08 | 郑州猫眼农业科技有限公司 | Preparation method of 4-bromo-6-chloropyridine-2-carboxylic acid |
| CN112047878B (en) * | 2020-10-15 | 2022-04-19 | 郑州猫眼农业科技有限公司 | Preparation method of 4-bromo-6-chloropyridine-2-carboxylic acid |
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