CN105085384A - Preparation method of 2-bromo-4-methoxypyridine - Google Patents
Preparation method of 2-bromo-4-methoxypyridine Download PDFInfo
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- CN105085384A CN105085384A CN201410209807.6A CN201410209807A CN105085384A CN 105085384 A CN105085384 A CN 105085384A CN 201410209807 A CN201410209807 A CN 201410209807A CN 105085384 A CN105085384 A CN 105085384A
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- bromo
- methoxypyridine
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- oxide
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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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a preparation method of 2-bromo-4-methoxypyridine. The method comprises the following steps: adding methoxide into N-oxide-2-bromo-4-nitropyridine to prepare N-oxide-2-bromo-4-methoxypyridine, carrying out a reaction between N-oxide-2-bromo-4-methoxypyridine, iron powder and a strong acid solution, carrying out filter washing, concentrating and crystallizing to prepare 2-bromo-4-methoxypyridine. According to the invention, N-oxide-2-bromo-4-nitropyridine is used as a raw material to prepare 2-bromo-4-methoxypyridine. The operation is simple and safe, technological conditions are mild, and the method is not harsh on production conditions. Meanwhile, by the method, yield of 2-bromo-4-methoxypyridine is also raised, production cost is greatly reduced, and production efficiency is enhanced.
Description
Technical field
The invention belongs to the technical field of biological medicine, belong to the preparation method of the bromo-4-methoxypyridine of a kind of 2-more specifically.
Background technology:
Along with biological medicine technology development, the bromo-4-methoxypyridine of 2-is more and more applied in pharmaceutical prod research and development.At some field of medicaments, the bromo-4-methoxypyridine of 2-has bioactive compound as tube-nursery, also achieves good progress.
At present, the bromo-4-methoxypyridine need of production of 2-carries out anhydrous and oxygen-free operation, requires all very high to production technology and working condition.US Patent No. 20060235028 discloses the preparation method of the bromo-4-methoxypyridine of a kind of 2-, step is be dissolved in normal hexane by N, N-dimethylethanolamine, adds butyllithium, react after 20 minutes at-5 DEG C, 4-methoxypyridine is joined above-mentioned reaction solution; React after 1 hour, be cooled to-78 DEG C, then carbon tetrabromide join in reaction solution react 30 minutes; Finally with saturated ammonium chloride solution cancellation reaction, obtain the bromo-4-methoxypyridine of 2-, productive rate 9% after purifying, the working condition of this invention is harsh and productive rate is lower.
Summary of the invention:
For above-mentioned deficiency, the object of the present invention is to provide a kind of production technique simple and the preparation method of the bromo-4-methoxypyridine of 2-of reaction conditions gentleness.
The present invention is achieved by the following technical solutions.
A preparation method for the bromo-4-methoxypyridine of 2-, comprises the steps:
(1) in N-oxidation-2-bromo-4-nitropyridine, add methylate and obtain the bromo-4-methoxypyridine of N-oxidation-2-;
(2) N-is oxidized the bromo-4-methoxypyridine of-2-and iron powder to mix, adds strong acid solution, reacted rear filter wash, concentrated, crystallization obtains the bromo-4-methoxypyridine of 2-.
Preferred as this technical scheme, the temperature of reaction of described step (1) is 0-50 DEG C, and the reaction times is 2-8h.
Preferred as this technical scheme, described methylate is sodium methylate.
Preferred as this technical scheme, described step (2) is reacted under the protection of nitrogen.
Preferred as this technical scheme, the temperature of reaction of described step (2) is 20-80 DEG C, and the reaction times is 2-8h.
Preferred as this technical scheme, described strong acid solution is concentrated hydrochloric acid solution.
Beneficial effect: the present invention is oxidized-2-bromo-4-nitropyridine for raw material with N-and prepares the bromo-4-methoxypyridine of 2-, safety simple to operate, processing condition are gentle, not harsh to working condition, the method also improves the yield of the bromo-4-methoxypyridine of 2-simultaneously, reduce production cost largely, improve production efficiency.
Embodiment:
Provided hereinafter concrete embodiment and further illustrate the present invention, but the present invention is not limited only to following embodiment.
The present inventor is through studying carefully discovery, be oxidized-2-bromo-4-nitropyridine with N-and prepare the bromo-4-methoxypyridine of N-oxidation-2-, then prepare the bromo-4-methoxypyridine of 2-, safety simple to operate with the bromo-4-methoxypyridine of N-oxidation-2-, reaction conditions is gentle, and this method has no bibliographical information at present.
Preparation method's synthetic route of the present invention is as follows:
Embodiment 1
15.8g2-bromopyridine is dissolved in 150mL methylene dichloride; at room temperature slowly add 26g metachloroperbenzoic acid; under nitrogen protection; this system is remained on stirred at ambient temperature after 16 hours; reaction solution is poured in the water of 50mL; separate dichloromethane layer, is concentrated into dry, obtains product 17.4gN-and is oxidized-2-bromopyridine (99%).
The 17.4gN-of above-mentioned gained is oxidized-2-bromopyridine to be dissolved in the 50mL vitriol oil, at 0 DEG C, slowly adds 8mL concentrated nitric acid.Stir at this system is remained on 0 DEG C after 16 hours, poured into by reaction solution in 200mL frozen water, control temperature, between 0-5 DEG C, adds sodium hydroxide solution adjust ph to 7, there is a large amount of solid to separate out, filter 15.4gN-is oxidized the bromo-4-nitropyridine (70%) of-2-.
The 15.4gN-of above-mentioned gained is oxidized the bromo-4-nitropyridine of-2-and is dissolved in 150mL methyl alcohol, at 0 DEG C, slowly add 3.8g sodium methylate.This system is slowly raised to stirring at room temperature 2h, without any process, is directly used in next step
1.96g iron powder is joined in previous step reaction solution; then slowly dripping 7mL concentrated hydrochloric acid is dissolved in 150mL methyl alcohol; under nitrogen protection; after stirring 2h at this system is remained on 80 DEG C; filtered while hot; with concentrated filtrate after methanol wash column twice filter cake of 50mL heat, obtain the bromo-4-methoxypyridine of 11.1g2-(yield is 84%) with ethyl acetate and sherwood oil recrystallization.
Claims (6)
1. a preparation method for the bromo-4-methoxypyridine of 2-, is characterized in that, comprise the steps:
(1) in N-oxidation-2-bromo-4-nitropyridine, add methylate and obtain the bromo-4-methoxypyridine of N-oxidation-2-;
(2) N-is oxidized the bromo-4-methoxypyridine of-2-and iron powder to mix, adds strong acid solution, reacted rear filter wash, concentrated, crystallization obtains the bromo-4-methoxypyridine of 2-.
2. the preparation method of the bromo-4-methoxypyridine of a kind of 2-according to claim 1, is characterized in that, the temperature of reaction of described step (1) is 0-50 DEG C, and the reaction times is 2-8h.
3. the preparation method of the bromo-4-methoxypyridine of a kind of 2-according to claim 1, is characterized in that, described methylate is sodium methylate.
4. the preparation method of the bromo-4-methoxypyridine of a kind of 2-according to claim 1, is characterized in that, described step (2) is reacted under the protection of nitrogen.
5. the preparation method of the bromo-4-methoxypyridine of a kind of 2-according to claim 1, is characterized in that, the temperature of reaction of described step (2) is 20-80 DEG C, and the reaction times is 2-8h.
6. the preparation method of the bromo-4-methoxypyridine of a kind of 2-according to claim 1, is characterized in that, described strong acid solution is concentrated hydrochloric acid solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410209807.6A CN105085384A (en) | 2014-05-16 | 2014-05-16 | Preparation method of 2-bromo-4-methoxypyridine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410209807.6A CN105085384A (en) | 2014-05-16 | 2014-05-16 | Preparation method of 2-bromo-4-methoxypyridine |
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| CN105085384A true CN105085384A (en) | 2015-11-25 |
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| CN201410209807.6A Pending CN105085384A (en) | 2014-05-16 | 2014-05-16 | Preparation method of 2-bromo-4-methoxypyridine |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030213A1 (en) * | 2003-09-24 | 2005-04-07 | Boehringer Ingelheim Pharmaceuticals, Inc. | 1,1,1-trifluoro-4-phenyl-4-methyl-2-(1h-pyrrolo |
| WO2012041476A1 (en) * | 2010-09-30 | 2012-04-05 | Almirall, S.A. | Pyridine and isoquinoline derivatives as syk- and jak-kinase inhibitors |
-
2014
- 2014-05-16 CN CN201410209807.6A patent/CN105085384A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030213A1 (en) * | 2003-09-24 | 2005-04-07 | Boehringer Ingelheim Pharmaceuticals, Inc. | 1,1,1-trifluoro-4-phenyl-4-methyl-2-(1h-pyrrolo |
| WO2012041476A1 (en) * | 2010-09-30 | 2012-04-05 | Almirall, S.A. | Pyridine and isoquinoline derivatives as syk- and jak-kinase inhibitors |
Non-Patent Citations (3)
| Title |
|---|
| TALIK,Z.: "Substitutionsreaktionen der Halogene und der Nitrogruppe in N-Oxyden der 2-Halogen-4-nitropyridine", 《BULLETIN DE L"ACADEMIE POLONAISE DES SCIENCES, SERIE DES SCIENCES》 * |
| TALIK,ZOFIA: "Some reactions of 2-halo-4-nitropyridine N-oxides", 《ROCZNIKI CHEMII》 * |
| 苏朝品等: "2-巯基-4-甲氧基吡啶N-氧化物的合成", 《中国医药工业杂志》 * |
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Application publication date: 20151125 |
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