CN103880741A - Preparation method of 2-chloromethyl-3,5-dimethyl-4-alkoxypyridyl-N-oxide - Google Patents
Preparation method of 2-chloromethyl-3,5-dimethyl-4-alkoxypyridyl-N-oxide Download PDFInfo
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- CN103880741A CN103880741A CN201410069729.4A CN201410069729A CN103880741A CN 103880741 A CN103880741 A CN 103880741A CN 201410069729 A CN201410069729 A CN 201410069729A CN 103880741 A CN103880741 A CN 103880741A
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- dimethyl
- oxide compound
- chloromethyl
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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
- C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
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Abstract
The invention discloses a preparation method of 2-chloromethyl-3,5-dimethyl-4-alkoxypyridyl-N-oxide, belonging to the technical field of organic synthesis. The preparation method comprises the following steps: adding 3,5-dimethyl-4-alkoxypyridyl-N-oxide, polyformaldehyde and a Friedel-Craft reaction catalyst anhydrous zinc chloride into a reaction vessel, dissolving in chloroform, heating to 50 DEG C while stirring, introducing hydrogen chloride gas, absorbing excessive gas with alkali liquor, cooling the reaction solution after the reaction is complete, separating by standing in a separating funnel, washing the organic layer with a 10 wt% sodium carbonate water solution twice, washing with distilled water three times, drying with anhydrous sodium sulfate, and finally, distilling under reduced pressure to obtain the 2-chloromethyl-3,5-dimethyl-4-alkoxypyridyl-N-oxide. The method has the advantages of short technical line, high yield, low cost and the like, and is simple to operate.
Description
Technical field
the invention belongs to technical field of organic synthesis, be specifically related to a kind of proton pump inhibitor intermediate 2-chloromethyl-3, the preparation method of 5-dimethyl-4-alkoxy pyridines-N-oxide compound.
Background technology
substituted 2-(2-pyridylmethyl) sulfinyl-1 H-benzimidazole derivative as esomeprazole, omeprazole, lansoprazole, pantoprazole etc. be all well-known proton pump inhibitor.Conventionally 2-(2-pyridylmethyl) sulfinyl-1H-benzoglyoxaline be by 2-(2-pyridylmethyl sulfenyl)-1H-benzoglyoxaline by oxygenant as hydrogen peroxide (H
2
o
2
), metachloroperbenzoic acid (
m-CPBA) and the oxidation such as clorox (NaOCl) and obtaining.In this sulfide oxidation process, there will be a lot of by products, as 2-(2-pyridyl-N-oxide compound) methylsulfonyl-1H-benzoglyoxaline (A), 2-(2-(pyridine-N-oxide) methylsulfinyl)-1H-benzoglyoxaline (B) and 2-(2-pyridyl methylsulfonyl)-1H-benzoglyoxaline (C).These by products are to have very much actual value for the analysis and research of researcher, troubles very and obtain these oxide compounds by the method separating merely, often need use comparatively expensive preparative high-performance liquid chromatographic or thin-layer chromatography and carry out the separation of trace level, can not meet significantly the demand of scientific research.Compd A and C can directly obtain by sulfide oxidation, and use the same method preparation B still more difficult.Purna C. Ray, the people such as Vasantha Mittapelli and Amit Rohatgi are at Synthetic Communications, 2007, 37:2861 – 2868 has reported the method for new synthetic B a kind of, with 2-chloromethyl-4-alkoxyl group-methylpyridine N oxide and synthetic 2-(2-(pyridine-N-oxide) methyl the sulfenyl)-1H-benzoglyoxaline of 2-mercaptobenzimidazole, carrying out selective oxidation is product B again, and one of them intermediate 2-chloromethyl-4-alkoxyl group-methylpyridine N oxide is carry out N-oxidation and prepare through 2-chloromethyl-4-alkoxyl group-picoline thing.Lot of documents reports that known 2-chloromethyl-4-alkoxy methyl-pyridine thing is generally take picoline as starting raw material, obtain through N-oxidation, nitrated, replacement, alcoholization and chlorination five steps reactions, if N-is oxidized to prepare 2-chloromethyl-4-alkoxy methyl-pyridine-N-oxide and just seems that step is long and loaded down with trivial details again.The invention reside in the above-mentioned practical problems of solution and propose a kind of new preparation 2-chloromethyl-3, the method for 5-dimethyl-4-alkoxy pyridines-N-oxide compound, simple and practical.
Summary of the invention
the present invention is directed to the problems referred to above that prior art exists, provide a kind of 2-chloromethyl-3, the preparation method of 5-dimethyl-4-alkoxy pyridines-N-oxide compound.
chloromethyl-3, shown in the preparation according to the following formula of 5-dimethyl-4-alkoxy pyridines-N-oxide compound, route carries out:
?
in formula, R is C
1-6
alkyl or the C being replaced by halogen
1-6
alkyl.
with 3,5-lutidine (1) is starting raw material, obtain compound 3 through N-oxidation, nitrated and replacement, the existing lot of documents report of front three-step reaction of 5-dimethyl-4-alkoxy pyridines-N-oxide compound (4), the invention provides one and obtain target compound 2-chloromethyl-3, the preparation method of 5-dimethyl-4-alkoxy pyridines-N-oxide compound (5) by the direct chloromethylation of compound (4).
a kind of 2-provided by the present invention chloromethyl-3, the preparation method of 5-dimethyl-4-alkoxy pyridines-N-oxide compound is specific as follows:
in reaction vessel, add 3, 5-dimethyl-4-alkoxy pyridines-N-oxide compound, paraformaldehyde and Friedel-Crafts reaction catalyzer Zinc Chloride Anhydrous, dissolve with chloroform, stir and be warming up to 50 ℃, pass into hydrogen chloride gas, unnecessary gas alkali liquor absorption, after reaction 3h, use control terminal in tlc (TLC), detection reaction progress, after reacting completely, reaction solution is cooling, in separating funnel, leave standstill separatory, organic layer is successively with 10wt% aqueous sodium carbonate washing 2 times, distilled water wash 3 times, then use anhydrous sodium sulfate drying, last underpressure distillation makes 2-chloromethyl-3, 5-dimethyl-4-alkoxy pyridines-N-oxide compound.
the mol ratio of described paraformaldehyde and 3,5-dimethyl-4-alkoxy pyridines-N-oxide compound is (2 ~ 4): 1, be preferably 3:1; Described chloroform consumption is every mole 3 of 600 ~ 800mL/, and 5-dimethyl-4-alkoxy pyridines-N-oxide compound, is preferably 700 mL/mol.
the present invention possesses skills, and route is short, simple to operate, productive rate is high and low cost and other advantages.
Embodiment
in 50 mL there-necked flasks, add 3.1 g (0.02 mol) 3,5-dimethyl-4-methoxypyridine-N-oxide compound, 1.8g (0.06 mol) paraformaldehyde and 4.0 g Zinc Chloride Anhydrouss dissolve with 14 mL chloroforms, stir and be warming up to 50 ℃, pass into hydrogen chloride gas, control the speed of a bubble per second, unnecessary gas absorbs with buck.Complete by tlc (TLC) detection reaction after reaction 4h, after reaction solution is cooling, in separating funnel, leave standstill separatory, organic layer is successively with 5mL10wt% aqueous sodium carbonate washing 2 times, 5 mL distilled water wash 3 times, then use anhydrous sodium sulfate drying, finally be evaporated to 5 mL, leave standstill crystallization, obtain compound (5) 2-chloromethyl-3,5-dimethyl-4-methoxypyridine-N-oxide compound 3.15 g, productive rate 78.2%.
1
H?NMR?(DMSO-
d
6
,?400?MHz)，
δ?(ppm):?2.39?(s,?3H,?C
H
3
?in?py),?2.42?(s,?3H,?C
H
3
?in?py),?4.02?(s,?3H,?-OC
H
3
),?4.87?(s,?2H,?-C
H
2
-),8.21?(s,?1H,?
H?in?py)。FT-IR(KBr compressing tablet): 687.68 cm
-1
be
the stretching vibration peak of (C – Cl), 1223.31 cm
-1
be
(N-O) stretching vibration peak.
Claims (3)
1.
a kind of 2-chloromethyl-3, the preparation method of 5-dimethyl-4-alkoxy pyridines-N-oxide compound, it is characterized in that this preparation method is specific as follows: in reaction vessel, add 3, 5-dimethyl-4-alkoxy pyridines-N-oxide compound, paraformaldehyde and Friedel-Crafts reaction catalyzer Zinc Chloride Anhydrous, dissolve with chloroform, stir and be warming up to 50 ℃, pass into hydrogen chloride gas, unnecessary gas alkali liquor absorption, reaction 3h after with controlling terminal in tlc, detection reaction progress, after reacting completely, reaction solution is cooling, in separating funnel, leave standstill separatory, organic layer is successively with 10wt% aqueous sodium carbonate washing 2 times, distilled water wash 3 times, then use anhydrous sodium sulfate drying, last underpressure distillation makes 2-chloromethyl-3, 5-dimethyl-4-alkoxy pyridines-N-oxide compound, described paraformaldehyde and described 3, the mol ratio of 5-dimethyl-4-alkoxy pyridines-N-oxide compound is (2 ~ 4): 1, described chloroform consumption is every mole 3 of 600 ~ 800mL/, 5-dimethyl-4-alkoxy pyridines-N-oxide compound.
2.
a kind of 2-according to claim 1 chloromethyl-3, the preparation method of 5-dimethyl-4-alkoxy pyridines-N-oxide compound, is characterized in that described paraformaldehyde and described 3, the mol ratio of 5-dimethyl-4-alkoxy pyridines-N-oxide compound is 3:1.
3.
a kind of 2-according to claim 1 chloromethyl-3, the preparation method of 5-dimethyl-4-alkoxy pyridines-N-oxide compound, is characterized in that described chloroform consumption is every mole 3 of 700mL/, 5-dimethyl-4-alkoxy pyridines-N-oxide compound.
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|---|---|---|---|
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Citations (7)
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|---|---|---|---|---|
| WO2002094806A1 (en) * | 2001-05-22 | 2002-11-28 | Sanofi-Synthelabo | Chloromethylation of thiophene |
| CN102267870A (en) * | 2011-07-18 | 2011-12-07 | 扬州市中宝银鹏合成材料有限公司 | Production process of 4,4'-bis(chloromethyl)-biphenyl |
| CN102372605A (en) * | 2011-08-02 | 2012-03-14 | 浙江永太科技股份有限公司 | Preparation method of 2-halogeno-5-trifluoromethyl benzyl alcohol |
| 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 |
| CN103044401A (en) * | 2012-12-21 | 2013-04-17 | 北京华禧联合科技发展有限公司 | Preparation method of benzimidazole compound |
| CN103059273A (en) * | 2013-01-28 | 2013-04-24 | 吉林大学 | Novel water-soluble thiofuran acetylene and phenylacetylene copolymer precursor, preparation method and application thereof |
| CN103570499A (en) * | 2011-08-02 | 2014-02-12 | 浙江永太科技股份有限公司 | Preparation method of 2-halogenate-5-trifluoromethyl benzyl alcohol compound |
-
2014
- 2014-02-28 CN CN201410069729.4A patent/CN103880741A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002094806A1 (en) * | 2001-05-22 | 2002-11-28 | Sanofi-Synthelabo | Chloromethylation of thiophene |
| CN102267870A (en) * | 2011-07-18 | 2011-12-07 | 扬州市中宝银鹏合成材料有限公司 | Production process of 4,4'-bis(chloromethyl)-biphenyl |
| CN102372605A (en) * | 2011-08-02 | 2012-03-14 | 浙江永太科技股份有限公司 | Preparation method of 2-halogeno-5-trifluoromethyl benzyl alcohol |
| CN103570499A (en) * | 2011-08-02 | 2014-02-12 | 浙江永太科技股份有限公司 | Preparation method of 2-halogenate-5-trifluoromethyl benzyl alcohol compound |
| 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 |
| CN103044401A (en) * | 2012-12-21 | 2013-04-17 | 北京华禧联合科技发展有限公司 | Preparation method of benzimidazole compound |
| CN103059273A (en) * | 2013-01-28 | 2013-04-24 | 吉林大学 | Novel water-soluble thiofuran acetylene and phenylacetylene copolymer precursor, preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 周如金等: "2-氯甲基噻吩合成与表征", 《化学与生物工程》 * |
| 莫羡忠等: "吡虫啉相关化合物的合成及其杀虫效能", 《精细化工》 * |
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Application publication date: 20140625 |