CN103483247B - Preparation method of 2-bromo-3-methoxypyridine - Google Patents
Preparation method of 2-bromo-3-methoxypyridine Download PDFInfo
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- CN103483247B CN103483247B CN201310381872.2A CN201310381872A CN103483247B CN 103483247 B CN103483247 B CN 103483247B CN 201310381872 A CN201310381872 A CN 201310381872A CN 103483247 B CN103483247 B CN 103483247B
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- 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
- C07D213/65—One oxygen atom attached in position 3 or 5
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Abstract
The invention discloses a preparation method of 2-bromo-3-methoxypyridine. The method comprises the following steps: based on 2-nitro-3-methoxypyridine as a raw material, carrying out bromination reaction together with a brominating agent to directly replace nitro on a pyridine ring with a bromine atom, so as to obtain 2-bromo-3-methoxypyridine. The preparation method is novel in reaction route, mild in reaction conditions, easy to control, and easy in post-treatment, separation and purification; the obtained product is high in yield and purity. The preparation method is low in production cost, simple and safe to operate, and very suitable for large-scale industrial production.
Description
Technical field
The present invention relates to a kind of method preparing the bromo-3-Methoxy Pyridine of 2-, belong to technical field of organic synthesis.
Background technology
The bromo-3-Methoxy Pyridine of 2-is a kind of important medicine intermediate, is mainly used in synthesizing antiestrogen, treats the pharmaceutical intermediate of the relative disease such as endometriosis and hysteromyoma and is used for the treatment of the synthesis of cancer camptothecin drug.
The method having bibliographical information to prepare the bromo-3-Methoxy Pyridine of 2-is at present with the bromo-3-pyridone of 2-for raw material, carries out methylation reaction obtain the bromo-3-Methoxy Pyridine of 2-with methylating reagent.But this raw materials technology is expensive, and conventional methylating reagent is methyl-sulfate and methyl iodide, wherein methyl-sulfate is highly toxic product, and toxicity is large, and although methyl iodide toxicity is low, but it is very unstable and price is more expensive, and separation and purification of products difficulty, severe reaction conditions, need to operate under anhydrous and oxygen-free condition, during process anhydrous solvent, cost is high, danger is large, is therefore not suitable for large-scale industrial production.
Therefore, finding a kind of low and method that productive rate is high of preparation cost to prepare the bromo-3-Methoxy Pyridine of 2-, is one of 2-bromo-3-Methoxy Pyridine preparation field technical problem urgently to be resolved hurrily.
The method of prior art synthesis 2-bromo-3-Methoxy Pyridine is raw material with the bromo-3-pyridone of 2-, carries out methylation reaction with methylating reagent.But this method expensive raw material price, and it is large, unstable and expensive to there is methylating reagent toxicity, severe reaction conditions, the problems such as separation and purification of products difficulty.The present inventor is through studying discovery for a long period of time, if be raw material with 2-nitro-3-Methoxy Pyridine, react with bromizating agent, nitration is become bromine atoms, high yield, the bromo-3-Methoxy Pyridine of highly purified 2-can be obtained, and production cost is low, reaction conditions is gentle, do not need to carry out under anhydrous and oxygen-free condition, safety simple to operate, this method has no bibliographical information at present.
Preparation method's synthetic route of the present invention is as follows:
Below the preparation method of the bromo-3-Methoxy Pyridine of 2-provided by the invention is described in detail:
2-nitro-3-Methoxy Pyridine shown in structural formula (I) and appropriate organic acid solvent are joined in reaction vessel, stirring makes 2-nitro-3-Methoxy Pyridine all dissolve, bromizating agent is added as Hydrogen bromide after raw material dissolves completely, wherein the mol ratio of 2-nitro-3-Methoxy Pyridine and bromizating agent is 1:2-3, preferred 1:2-2.5; Slowly be warming up to 100-140 DEG C, reaction 4-7 hour, preferable reaction temperature is 120-130 DEG C, reaction 5-6 hour.Stop heating after completion of the reaction, continue stirring and make it be cooled to room temperature.
After reaction solution underpressure distillation is steamed most of solvent, stop underpressure distillation, now have yellow solid to separate out, this yellow solid is the bromate of product, filter, filter cake, as after ethyl acetate or washed with dichloromethane, is dissolved in a small amount of water by filter cake organic solvent, adding alkali lye regulates pH to be 7-8, adularescent solid is separated out, and filters, solids washed with water 1-2 time, refilter, solid obtains the bromo-3-Methoxy Pyridine of 2-shown in structural formula (II) after drying.
In above-mentioned reaction, use organic acid as solvent, organic acid solvent has good solvability to reactant and boiling point is higher.This organic acid solvent can be formic acid, acetic acid, propionic acid or trifluoroacetic acid etc., preferred acetic acid; Solvent organic acid amount needs 1-5mL organic acid ratio to add according to 1g2-nitro-3-Methoxy Pyridine usually.
The alkali lye added in aftertreatment can be sodium hydroxide, saturated sodium carbonate or sodium bicarbonate aqueous solution etc.
Prepare the bromo-3-Methoxy Pyridine of 2-with aforesaid method, prepare productive rate about 90%, product purity is more than 90%.
Below in conjunction with specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.
Above and the experimental technique used in following embodiment if no special instructions, be ordinary method.
Above and material used in following embodiment, reagent etc., if no special instructions, ordinary method all can from commercial channels or be used to prepare.
In following embodiment, adopt liquid chromatograph (Shimadzu LC-20A type) detection compound purity, test condition is: methyl alcohol and water are that 30:70 is as moving phase, flow velocity is 1.0mL/min, chromatographic column is SHIMADZU-150 × 4.6mm, and detector is UV-vis detector, determined wavelength 254nm; Adopt nuclear magnetic resonance apparatus detection compound structure: the DMX-300 type of Bruker company of the U.S., solvent is deuterochloroform.）
Summary of the invention
The object of this invention is to provide the preparation method of the bromo-3-Methoxy Pyridine of a kind of 2-, the method have raw material be easy to get, with low cost, operation is simple, safety, productive rate high.
The invention provides a kind of method preparing the bromo-3-Methoxy Pyridine of 2-, it is characterized in that, react with 2-nitro-3-Methoxy Pyridine and bromizating agent, obtain the bromo-3-Methoxy Pyridine of 2-.
According to a concrete but nonrestrictive embodiment of the present invention, described method comprises: by 2-nitro-3-Methoxy Pyridine and organic acid solvent mixing, stirring makes 2-nitro-3-Methoxy Pyridine dissolve completely, add bromizating agent, wherein the mol ratio of 2-nitro-3-Methoxy Pyridine and bromizating agent is 1:2-3; Slowly be warming up to 100-140 DEG C, reaction 4-7 hour, is cooled to room temperature after completion of the reaction; After reaction solution underpressure distillation, filter, washing leaching cake, then be dissolved in a small amount of water by filter cake, add alkali lye and regulate pH to be 7-8, adularescent solid is separated out, and filters, and washs and dry cake, obtains the bromo-3-Methoxy Pyridine of 2-.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, bromizating agent is Hydrogen bromide.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, organic acid solvent is formic acid, acetic acid, propionic acid or trifluoroacetic acid.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, organic acid solvent is acetic acid.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, the mol ratio of 2-nitro-3-Methoxy Pyridine and bromizating agent is 1:2-2.5.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, temperature of reaction is 120-130 DEG C.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, the reaction times is 5-6 hour.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, alkali lye is sodium hydroxide, saturated sodium carbonate or sodium bicarbonate aqueous solution.
Beneficial effect of the present invention is mainly reflected in:
1, the present invention with 2-nitro-3-Methoxy Pyridine for raw material, utilize bromination reaction, nitro on pyridine ring is directly replaced with bromine atoms, the bromo-3-Methoxy Pyridine of preparation 2-, this reaction scheme is novel, reaction conditions is gentle, be easy to control, and aftertreatment separation and purification is easy, can obtain the product of high yield.
2, preparation method's cost of material of the present invention is cheap, easily obtains, significantly reduces preparation cost.
3, preparation method's mild condition of the present invention, easy and simple to handle, with low cost, productive rate is high, is applicable to large-scale industrial production.
Accompanying drawing explanation
Fig. 1 is the bromo-3-Methoxy Pyridine of 2-prepared by embodiment 1
1h-NMR spectrogram (solvent: CDCl
3).
Embodiment
Provided hereinafter concrete embodiment and further illustrate the present invention, but the present invention is not limited only to following embodiment.
Embodiment 1
2-nitro-3-Methoxy Pyridine 6g and acetic acid 18mL is added in reaction flask, stirring makes it all dissolve, the Hydrogen bromide 15.8g that mass percent concentration is 40% is added after raw material dissolves completely, slowly be warming up to 120 DEG C, reaction 5h, stop heating after completion of the reaction, continue stirring and make it be cooled to room temperature.
After reaction solution underpressure distillation is steamed most of solvent, stop underpressure distillation, now have yellow solid to separate out, filter, after filter cake ethyl acetate washs 2 times, filter cake is dissolved in a small amount of water, adding saturated aqueous sodium carbonate adjusts pH to be 7-8, adularescent solid is separated out, and filters, solid washed with water 2 times, refilter, obtain the bromo-3-Methoxy Pyridine 6.4g of solid 2-after drying, calculated yield is 88%, and obtaining the bromo-3-Methoxy Pyridine product purity of 2-by liquid chromatograph is 99.5%.Fig. 1 is the bromo-3-Methoxy Pyridine of 2-of preparation
1h-NMR spectrogram (solvent: CDCl
3).
Embodiment 2
2-nitro-3-Methoxy Pyridine 10g and acetic acid 30mL is added in reaction flask, stirring makes it all dissolve, the Hydrogen bromide 28.9g that mass percent concentration is 40% is added after raw material dissolves completely, slowly be warming up to 125 DEG C, reaction 6h, stop heating after completion of the reaction, continue stirring and make it be cooled to room temperature.
After reaction solution underpressure distillation is steamed most of solvent, stop underpressure distillation, now have yellow solid to separate out, filter, after filter cake ethyl acetate washs 2 times, filter cake is dissolved in a small amount of water, adding saturated sodium bicarbonate aqueous solution adjusts pH to be 7-8, adularescent solid is separated out, and filters, solid washed with water 2 times, refilter, obtain the bromo-3-Methoxy Pyridine 11.0g of solid 2-after drying, calculated yield is 90.0%, and obtaining the bromo-3-Methoxy Pyridine product purity of 2-by liquid chromatograph is 99.6%.
Embodiment 3
2-nitro-3-Methoxy Pyridine 14g and formic acid 42mL is added in reaction flask, stirring makes it all dissolve, the Hydrogen bromide 44.1g that mass percent concentration is 40% is added after raw material dissolves completely, slowly be warming up to 130 DEG C, reaction 5h, stop heating after completion of the reaction, continue stirring and make it be cooled to room temperature.
After reaction solution underpressure distillation is steamed most of solvent, stop underpressure distillation, now have yellow solid to separate out, filter, filter cake, with after washed with dichloromethane 2 times, is dissolved in a small amount of water by filter cake, adding saturated aqueous sodium carbonate adjusts pH to be 7-8, adularescent solid is separated out, and filters, solid washed with water 2 times, refilter, obtain the bromo-3-Methoxy Pyridine 15.4g of solid 2-after drying, calculated yield is 90.3%, and obtaining the bromo-3-Methoxy Pyridine product purity of 2-by liquid chromatograph is 99.5%.
Embodiment 4
2-nitro-3-Methoxy Pyridine 20g and propionic acid 60mL is added in reaction flask, stirring makes it all dissolve, the Hydrogen bromide 60.4g that mass percent concentration is 40% is added after raw material dissolves completely, slowly be warming up to 125 DEG C, reaction 6h, stop heating after completion of the reaction, continue stirring and make it be cooled to room temperature.
After reaction solution underpressure distillation is steamed most of solvent, stop underpressure distillation, now have yellow solid to separate out, filter, after filter cake ethyl acetate washs 2 times, filter cake is dissolved in a small amount of water, adding saturated sodium bicarbonate aqueous solution adjusts pH to be 7-8, adularescent solid is separated out, and filters, solid washed with water 2 times, refilter, obtain the bromo-3-Methoxy Pyridine 22.2g of solid 2-after drying, calculated yield is 91.0%, and obtaining the bromo-3-Methoxy Pyridine product purity of 2-by liquid chromatograph is 99.4%.
Embodiment 5
2-nitro-3-Methoxy Pyridine 30g and formic acid 90mL is added in reaction flask, stirring makes it all dissolve, the Hydrogen bromide 98.4g that mass percent concentration is 40% is added after raw material dissolves completely, slowly be warming up to 120 DEG C, reaction 5h, stop heating after completion of the reaction, continue stirring and make it be cooled to room temperature.
After reaction solution underpressure distillation is steamed most of solvent, stop underpressure distillation, now have yellow solid to separate out, filter, filter cake, with after washed with dichloromethane 2 times, is dissolved in a small amount of water by filter cake, add saturated aqueous sodium carbonate and adjust pH=7-8, adularescent solid is separated out, and filters, solid washed with water 2 times, refilter, obtain the bromo-3-Methoxy Pyridine 32.4g of solid 2-after drying, calculated yield is 88.6%, and obtaining the bromo-3-Methoxy Pyridine product purity of 2-by liquid chromatograph is 99.3%.
Comparative example
Below with the bromo-3-Methoxy Pyridine of art methods synthesis 2-:
Under nitrogen protection; in reaction flask, add anhydrous tetrahydro furan, under ice cooling, 4, slowly adding content is 70%(quality) sodium hydride 3.5g; after stirring; add solid 2-bromo-3-pyridone 12g in batches, after reinforced, be cooled to about 0 DEG C; drip methyl-sulfate 11.3g; after dropwising, rise to room temperature reaction 4h, then be warming up to 50-60 DEG C of reaction 0.5-1h.After completion of the reaction, reaction solution is down to room temperature, filter, filter cake washed with dichloromethane 2 times, refilters, filter cake methanol wash, merging filtrate and washings, concentrated except desolventizing, obtain the bromo-3-Methoxy Pyridine 9.1g of product 2-through column chromatography purification, calculated yield is 70.2%, and obtaining the bromo-3-Methoxy Pyridine purity of product 2-by liquid chromatograph is 98.5%.
The bromo-3-Methoxy Pyridine of product 2-that this case embodiment 2 and above-mentioned existing synthetic method obtain is compared as follows:
| Product of the present invention | Prior art products | |
| Output | 11.0g | 9.1g |
| Yield | 90.0% | 70.2% |
| Purity | 99.6% | 98.5% |
| Cost | 18 yuan/g | 36 yuan/g |
As can be seen from above-mentioned contrast, product yield of the present invention improves nearly 30% than prior art, and the purity of product of the present invention is apparently higher than the product purity of prior art, and preparation cost of the present invention is only the half of prior art simultaneously.According to the method for prior art, reaction needed is carried out under anhydrous and oxygen-free condition, and according to method of the present invention, reacts without the need to carrying out under anhydrous and oxygen-free, and thus whole technique is safer, and aftertreatment is simpler.Therefore, prepare the bromo-3-Methoxy Pyridine of 2-by method of the present invention, beneficial effect is very remarkable.
Below be only embody rule example of the present invention, protection scope of the present invention is not constituted any limitation.The technical scheme that all employing equivalents or equivalence are replaced and formed, all drops within rights protection scope of the present invention.
Claims (7)
1. prepare a method for the bromo-3-Methoxy Pyridine of 2-, comprising: be dissolved in completely in organic acid solvent by 2-nitro-3-Methoxy Pyridine, add Hydrogen bromide, 2-nitro-3-Methoxy Pyridine and hydrobromic mol ratio are 1:2-3; Slowly be warming up to 100-140 DEG C, reaction 4-7 hour, is cooled to room temperature after completion of the reaction; After reaction solution underpressure distillation, filter, washing leaching cake, then be dissolved in a small amount of water by filter cake, add alkali lye and regulate pH to be 7-8, adularescent solid is separated out, and filters, and washs and dry cake, obtains the bromo-3-Methoxy Pyridine of 2-.
2. method according to claim 1, wherein, organic acid solvent is any one or a few in formic acid, acetic acid, propionic acid or trifluoroacetic acid.
3. method according to claim 2, wherein, organic acid solvent is acetic acid.
4. method according to claim 1, wherein, 2-nitro-3-Methoxy Pyridine and hydrobromic mol ratio are 1:2-2.5.
5. method according to claim 1, wherein, temperature of reaction is 120-130 DEG C.
6. method according to claim 1, wherein, the reaction times is 5-6 hour.
7. method according to claim 1, wherein, alkali lye is any one or a few in sodium hydroxide, saturated sodium carbonate or sodium bicarbonate aqueous solution.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3431826A1 (en) * | 1984-08-30 | 1986-03-13 | Hoechst Ag, 6230 Frankfurt | METHOD FOR PRODUCING AROMATIC BROMIC CONNECTIONS |
| CN101735139A (en) * | 2009-11-23 | 2010-06-16 | 中国科学院长春应用化学研究所 | Rare earth europium fluorescent chelating agent and preparation method thereof |
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| WO2010135014A1 (en) * | 2009-02-27 | 2010-11-25 | Vertex Pharmaceuticals Incorporated | Tri-cyclic pyrazolopyridine kinase inhibitors |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3431826A1 (en) * | 1984-08-30 | 1986-03-13 | Hoechst Ag, 6230 Frankfurt | METHOD FOR PRODUCING AROMATIC BROMIC CONNECTIONS |
| CN101735139A (en) * | 2009-11-23 | 2010-06-16 | 中国科学院长春应用化学研究所 | Rare earth europium fluorescent chelating agent and preparation method thereof |
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