CN103086964A - Preparation method of 6-bromine-2-pyridine methyl formate - Google Patents
Preparation method of 6-bromine-2-pyridine methyl formate Download PDFInfo
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Abstract
The invention relates to a preparation method of 6-bromine-2-pyridine methyl formate. The preparation method comprises the step of catalyzing esterification reaction of 6-bromine-2-pyridine carboxylic acid by taking p-toluenesulfonic acid as a catalyst, to be specific, heating and fluxing absolute methanol, the 6-bromine-2-pyridine carboxylic acid and the p-toluenesulfonic acid for 2-8 hours under stirring, cooling to a room temperature after reaction is ended, rotary drying a reaction system, dissolving solids in an organic solvent, washing, drying, filtering, concentrating, recrystallizing a concentrated product by a mixed solvent to obtain the 6-bromine-2-pyridine methyl formate, wherein a preferable molar ratio of the 6-bromine-2-pyridine carboxylic acid and the p-toluenesulfonic acid is 1: (0.1-0.16). According to one embodiment of the invention, the 6-bromine-2-pyridine carboxylic acid is obtained through diazotization, bromination and oxidation of 6-amino-2-methylpyridine. The preparation method is few in side reaction and simple in aftertreatment and is suitable for industrial production; and the product is easy to separate and has high yield, high purity and good quality.
Description
Technical field
The present invention relates to the preparation method of 6-bromo-2-pyridyl methyl-formiate, belong to technical field of organic synthesis.
Background technology
6-bromo-2-pyridyl methyl-formiate is a kind of important organic intermediate, has irreplaceable effect at chemical industry and pharmacy field.It is synthetic treatment diabetes and the 11-beta hydroxysteroid dehydrogenase inhibitors of obesity and the important source material of related compound; It is also the important as precursors of the Chemokine Receptors of synthetic treatment acquired immune deficiency syndrome (AIDS) and other diseases.
It is raw material with 2,6-dibromo pyridine that bibliographical information is arranged, and obtains product 6-bromo-2-pyridyl methyl-formiate through the exchange of lithium halogen, lithiumation thing and carbonic acid gas addition, esterification.This route reaction condition is easily controlled, react more stable, but the final step esterification is to use sulphuric acid catalysis, and because the vitriol oil has stronger corrodibility, esterification reaction process has more side reaction to produce, cause aftertreatment to bother very much, product purity not and extremely difficult purifying finally causes productive rate low, and preparation cost is high, the drawbacks such as separation difficulty, thereby be not suitable for large-scale industrial production.
How to improve the preparation productive rate of 6-bromo-2-pyridyl methyl-formiate, reduce production costs, become one of technical problem that 6-bromo-2-pyridyl methyl-formiate preparation field needs to be resolved hurrily.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of 6-bromo-2-pyridyl methyl-formiate, the method uses organic acid-tosic acid as the esterification of catalyst 6-bromo-2-pyridyl formic acid, side reaction is few, aftertreatment is simple, product is easy to separate, and the products collection efficiency that obtains is high, purity is high, quality is good.
The invention provides a kind of preparation method of 6-bromo-2-pyridyl methyl-formiate, comprising: with the esterification of tosic acid as catalyst 6-bromo-2-pyridyl formic acid and anhydrous methanol.
According to a concrete but nonrestrictive embodiment of the present invention, described method comprised: with anhydrous methanol, 6-bromo-2-pyridyl formic acid and tosic acid under agitation reflux 2-8 hour, the mol ratio 1:40-60 of 6-bromo-2-pyridyl formic acid and anhydrous methanol wherein, the mol ratio of 6-bromo-2-pyridyl formic acid and tosic acid is 1:0.06-0.2, react and be cooled to room temperature after complete, after reaction system is spin-dried for, solid is dissolved in organic solvent, washing, dry, filter, concentrated, enriched product obtains 6-bromo-2-pyridyl methyl-formiate with the mixed solvent recrystallization.
According to a concrete but nonrestrictive embodiment of the present invention, wherein the mol ratio of 6-bromo-2-pyridyl formic acid and tosic acid is 1:0.1-0.16.
According to a concrete but nonrestrictive embodiment of the present invention, wherein reflux 4-6 hour.
According to a concrete but nonrestrictive embodiment of the present invention, wherein mixed solvent is that volume ratio is the ethyl acetate of 1:10-20 and the mixed solvent of sherwood oil.
According to a concrete but nonrestrictive embodiment of the present invention, wherein the volume ratio of ethyl acetate and sherwood oil is 1:15.
According to a concrete but nonrestrictive embodiment of the present invention, wherein 6-bromo-2-pyridyl formic acid is obtained through diazotization, bromo, oxidation by 6-amino-2-methyl pyridine.
According to a concrete but nonrestrictive embodiment of the present invention, wherein the preparation method of 6-bromo-2-pyridyl formic acid comprises:
Drip bromine at-20 ~-10 ℃ in Hydrogen bromide and 6-amino-2-methyl pyridine, wherein 6-amino-2-methyl pyridine and hydrobromic mol ratio are 1:2-5, the mol ratio of 6-amino-2-methyl pyridine and bromine is 1:1.0-1.5, dropwises afterreaction 1-3 hour; Dripping concentration at-10 ~ 0 ℃ is the sodium nitrite in aqueous solution of 20-35 quality %, and the mol ratio of its Sodium Nitrite and 6-amino-2-methyl pyridine is 1-1.2:1, reacts 0.5-1 hour at 0-15 ℃ after dropwising, regulate pH to 10-12, room temperature reaction 0.5-2 hour, standing demix, aqueous phase extracted, merge organic phase, desiccant dryness is used in washing, concentrated organic phase, underpressure distillation obtains the 6-bromine-2-methylpyridine;
Add oxygenant in 6-bromine-2-methylpyridine and water under 50-80 ℃ of stirring, wherein the mol ratio of 6-bromine-2-methylpyridine and oxygenant is 1:2-3, reacted afterwards 4-10 hour, filter, regulate filtrate pH value to 2-3, have solid to separate out, filtering, wash also, drying solid obtains 6-bromo-2-pyridyl formic acid.
According to a concrete but nonrestrictive embodiment of the present invention, wherein 6-amino-2-methyl pyridine and hydrobromic mol ratio are 1:3-4; The mol ratio of 6-amino-2-methyl pyridine and bromine is 1:1.1-1.3.
According to a concrete but nonrestrictive embodiment of the present invention, wherein oxygenant is at least a in nitric acid, acid potassium bichromate, chromium trioxide, sulfuric acid and potassium permanganate.
Beneficial effect of the present invention is mainly reflected in:
1. the present invention adopts tosic acid as the catalyzer of 6-bromo-2-pyridyl formic acid esterification, because tosic acid is a kind of stronger organic acid, non-oxidative, can overcome existing technique and cause the many deficiencies of side reaction with the mineral acid catalytic esterification, reduced the generation of side reaction in the esterification process, aftertreatment is relatively simple, and product is easy to separate, and has significantly improved the preparation productive rate.
2. one embodiment of the invention, take 6-amino-2-methyl pyridine as raw material, obtain 6-bromo-2-pyridyl methyl-formiate through diazotization, bromo, oxidation, esterification.This synthetic route raw material is easy to get, and reaction conditions is gentle, and is simple to operate, can obtain high yield, highly purified product.
3. preparation method of the present invention is simple to operate, and whole technique is polluted little, is fit to large-scale industrial production.
Description of drawings
Fig. 1 is the H-NMR spectrogram (solvent: DMSO) of the 6-bromo-2-pyridyl methyl-formiate of embodiment 1 preparation.
Embodiment
Hereinafter provide concrete embodiment to further illustrate the present invention, but the present invention is not limited only to following embodiment.
6-bromo-2-pyridyl methyl-formiate usually can carry out esterification by 6-bromo-2-pyridyl formic acid and anhydrous methanol and obtain.The prior art employing mineral acid normally vitriol oil is made this esterification of catalyst.But because mineral acid generally has stronger corrodibility, often produce more side reaction, cause aftertreatment trouble, product purity is the problem such as difficult purifying not and extremely.The present inventor makes this esterification of catalyst through studying discovery for a long period of time if use tosic acid instead, can significantly improve productive rate, and the product purity that obtains is high, quality better, and beneficial effect is very remarkable, and this method has no bibliographical information at present.
The preparation method of 6-bromo-2-pyridyl methyl-formiate provided by the invention comprises:
Anhydrous methanol, 6-bromo-2-pyridyl formic acid and tosic acid are joined in reaction vessel, wherein the mol ratio of 6-bromo-2-pyridyl formic acid and anhydrous methanol is 1:40-60, the mol ratio of 6-bromo-2-pyridyl formic acid and tosic acid is 1:0.06-0.2, preferred 1:0.1-0.16, stirred lower reflux 2-8 hour, preferred backflow 4-6 hour, react complete rear stopped heating, continue stirring and make it be cooled to room temperature.
After reaction system is spin-dried for, solid is dissolved in the organic solvents such as ethyl acetate, methylene dichloride or ether, with saturated sodium bicarbonate or sodium carbonate solution washing, wash with water 2-3 time again, with dryings such as siccative such as anhydrous magnesium sulfate, sodium sulfate, calcium sulfate, salt of wormwood or calcium chloride, filter, concentrated, enriched product obtains the white crystal product with the organic solvent recrystallization.Use the mixed solvent of mixed solvent such as ethyl acetate and sherwood oil, the recrystallization effect is better, and the volume ratio of ethyl acetate and sherwood oil can be 1:10-20, preferred 1:15.
We are through the research discovery, and the add-on of catalyzer tosic acid has important impact to whole esterification.The mol ratio of tosic acid and 6-bromo-2-pyridyl formic acid is preferably 0.1-0.16:1.When tosic acid/6-bromo-2-pyridyl formic acid (mol ratio)＜0.1, the yield of product is lower, and below 90%, this may be that speed of reaction is slow because the consumption of tosic acid is few, reaction not exclusively, so esterification yield is low; Along with catalyzer tosic acid consumption continues to increase, product yield constantly increases, and tosic acid/6-bromo-2-pyridyl formic acid (mol ratio) is when 0.1-0.16:1, and product yield is up to 95% left and right; And when tosic acid/6-bromo-2-pyridyl formic acid (mol ratio) 0.16 the time, product yield no longer increases, and drops on the contrary below 90%, this may be due to the excessive catalyzer that adds, and causes that the system pH value reduces, thereby causes the hydrolysis of product.
The raw material 6-bromo-2-pyridyl formic acid of above-mentioned esterification can be bought from commercial channels and obtain, and also can take 6-amino-2-methyl pyridine as raw material, prepare through diazotization, bromo, oxidation.Synthetic route from 6-amino-2-methyl pyridine to 6-bromo-2-pyridyl methyl-formiate is as follows:
Wherein, the preparation process of 6-bromo-2-pyridyl formic acid is as follows:
(1) preparation of 6-bromine-2-methylpyridine
Hydrogen bromide and the 6-amino-2-methyl pyridine of concentration 40-48% are joined in reaction vessel, and 6-amino-2-methyl pyridine and hydrobromic mol ratio can be 1:2-5, preferred 1:3-4.Slowly drip bromine at-20 ~-10 ℃, the mol ratio of 6-amino-2-methyl pyridine and bromine can be 1:1.0-1.5, and preferred 1:1.1-1.3 dropwises afterreaction 1-3 hour.Dripping concentration at-10 ~ 0 ℃ is the sodium nitrite in aqueous solution of 20-35 quality %, and the mol ratio of Sodium Nitrite and 6-amino-2-methyl pyridine can be 1-1.2:1, after dropwising, 0-15 ℃ of reaction 0.5-1 hour.After completing, reaction regulates pH to 10-12, room temperature reaction 0.5-2 hour, standing demix with 5-20 quality % alkaline solution such as sodium hydroxide.Water is with extraction agent such as methylene dichloride, ethyl acetate or extracted with diethyl ether 2-3 time; Merge organic phase, water washing, dry with siccative such as anhydrous magnesium sulfate, sodium sulfate, calcium sulfate or salt of wormwood; Organic phase is concentrated, and underpressure distillation obtains weak yellow liquid 6-bromine-2-methylpyridine.
(2) preparation of 6-bromo-2-pyridyl formic acid
6-bromine-2-methylpyridine and water that (1) step was made are added in reaction vessel, and the amount of aqueous solvent needs the ratio of water 3000mL to add according to the 1mol6-bromine-2-methylpyridine, start and stir.At 50-80 ℃, preferably at 60 ℃-70 ℃, add oxidant reaction in batches, oxygenant can be nitric acid, acid potassium bichromate, chromium trioxide, sulfuric acid and/or potassium permanganate etc., preferably uses potassium permanganate to be oxygenant; The mol ratio of 6-bromine-2-methylpyridine and oxygenant can be 1:2-3, preferred 1:2.2-2.8.After reinforced complete, continued heated and stirred 4-10 hour, preferred 6-8 hour.After reaction was completed, reaction solution was cooling, filtered, and filtrate uses the hydrochloric acid adjust pH of 5-20 quality % to 2-3, and the adularescent solid is separated out, and filters, and washes solid with water, and drying obtains white powder solid 6-bromo-2-pyridyl formic acid.
And then, obtain 6-bromo-2-pyridyl methyl-formiate with Catalyzed by p-Toluenesulfonic Acid 6-bromo-2-pyridyl formic acid and anhydrous methanol esterification according to the method described above.This take 6-amino-2-methyl pyridine as raw material, obtain the synthetic route of 6-bromo-2-pyridyl methyl-formiate through diazotization, bromo, oxidation, esterification, having raw material is easy to get, reaction conditions is gentle, simple operation and other advantages, and the product yield that obtains is high, purity is high, is fit to large-scale industrial production.
The present invention is further elaborated below in conjunction with specific embodiment, but the present invention is not limited to following examples.
Above reach the experimental technique that uses in following embodiment if no special instructions, be ordinary method.
Above reach material used in following embodiment, reagent etc., if no special instructions, all can obtain from commercial channels.
(1) preparation of 6-bromine-2-methylpyridine
Be that 48% Hydrogen bromide 46mL and analytical pure 2-amino-6-picoline 10.8g add in reaction flask with concentration ,-10 ℃ slowly drip bromine 6.2mL, and 0.5h dropwises, reaction 1.5h; Dripping concentration at-10 ℃-0 ℃ is the sodium nitrite in aqueous solution 22.8mL of 25 quality %, after dropwising, and 15 ℃ of reaction 0.5h; After reaction is completed, use 10 quality % sodium hydroxide solutions are regulated pH to 12, room temperature reaction 1h, standing demix, water 200mL dichloromethane extraction 3 times merge organic phase, washing, organic phase is concentrated, and underpressure distillation gets weak yellow liquid 15.8g, calculated yield is 92%, and obtaining 6-bromine-2-methylpyridine product purity by the Agilent1100 liquid chromatograph is 99.3%.
(2) preparation of 6-bromo-2-pyridyl formic acid
6-bromine-2-methylpyridine 15.8g and the water 300mL of above-mentioned preparation are added in reaction flask, start and stir, add 34.8g KMnO when being heated to 65 ℃ in batches
4, reinforced complete rear continuation heated and stirred 7h.After reaction was completed, reaction solution was cooling, filtered, filtrate, is filtered to 1.5-2 with 10 quality % hydrochloric acid adjust pHs, washing, drying obtains white powder solid 16.5g, and calculated yield is 89%, and obtaining 6-bromo-2-pyridyl formic acid product purity by the Agilent1100 liquid chromatograph is 98.3%.
(3) preparation of 6-bromo-2-pyridyl methyl-formiate
with anhydrous methanol 200mL, 6-bromo-2-pyridyl formic acid 16.5g and the analytical pure tosic acid 1.5g of above-mentioned preparation add in reaction flask, reflux 4h, react complete rear stopped heating, continuing to stir makes it be cooled to room temperature, after reaction system is spin-dried for, solid is dissolved in ethyl acetate, wash with saturated sodium bicarbonate solution, wash with water again twice, use anhydrous magnesium sulfate drying, filter, concentrated, the enriched product volume ratio is that 1/15 ethyl acetate/petroleum ether mixed solvent recrystallization obtains white crystal product 16.6g, yield 94%, obtaining 6-bromo-2-pyridyl formic ether product purity by the Agilent1100 liquid chromatograph is 99.5%.Fig. 1 is the H-NMR spectrogram (solvent: DMSO) of 6-bromo-2-pyridyl methyl-formiate.
Embodiment 2-5
Embodiment 2-5 difference from Example 1 is the mol ratio of tosic acid and 6-bromo-2-pyridyl formic acid as shown in following table 1, other step and condition all in the same manner as in Example 1, the productive rate that obtains is listed in table 1 respectively.
Table 1
Embodiment 6
(1) preparation of 6-bromine-2-methylpyridine
48% Hydrogen bromide 64mL and analytical pure 2-amino-6-picoline 20g are added in reaction flask, and-10 ℃ slowly drip bromine 11.4mL, and 0.5h dropwises, reaction 1.5h; Drip the 25% Sodium Nitrite 42.2mL aqueous solution at-10 ℃-0 ℃, after dropwising, 15 ℃ of reaction 0.5h; After reaction is completed, use 10 quality % sodium hydroxide solutions are regulated pH to 12, room temperature reaction 1h, static layering, water 450mL ethyl acetate extraction 3 times merge organic phase, washing, organic phase is concentrated, and underpressure distillation gets weak yellow liquid 28.6g, calculated yield is 90%, and obtaining 6-bromine-2-methylpyridine product purity by the Agilent1100 liquid chromatograph is 99.0%.
(2) preparation of 6-bromo-2-pyridyl formic acid
6-bromine-2-methylpyridine 28.6g and the water 600mL of above-mentioned preparation are added in reaction flask, start and stir, add KMnO when being heated to 60 ℃ in batches
468.3g, reinforced complete rear continuation heated and stirred 6h, after reaction was completed, reaction solution was cooled to room temperature, filtered, filtrate with 10 quality % hydrochloric acid adjust pHs to 1.5-2, filter, washing, drying obtains white powder solid 29.2g, calculated yield is 87%, and obtaining 6-bromo-2-pyridyl formic acid product purity by the Agilent1100 liquid chromatograph is 98.1%.
(3) preparation of 6-bromo-2-pyridyl methyl-formiate
with anhydrous methanol 360mL, 6-bromo-2-pyridyl formic acid 29.2g and the analytical pure tosic acid 3.0g of above-mentioned preparation add in reaction flask, reflux 5h, react complete rear stopped heating, continuing to stir makes it be cooled to room temperature, after reaction system is spin-dried for, solid is dissolved in methylene dichloride, wash with saturated sodium carbonate solution, wash with water again twice, use anhydrous sodium sulfate drying, filter, concentrated, the enriched product volume ratio is that 1/15 recrystallization from ethyl acetate/petroleum ether obtains white crystal product 29.6g, calculated yield is 94.7%, obtaining 6-bromo-2-pyridyl formic ether product purity by the Agilent1100 liquid chromatograph is 99.3%.
Embodiment 7
(1) preparation of 6-bromine-2-methylpyridine
48% Hydrogen bromide 69.2mL and analytical pure 2-amino-6-picoline 21.6g are added in reaction flask, and-10 ℃ slowly drip bromine 13.4mL, and 0.5h dropwises, reaction 1.5h; Drip the 25 quality % Sodium Nitrite 45.6mL aqueous solution at-10 ℃-0 ℃, after dropwising, 15 ℃ of reaction 0.5h; After reaction is completed, use 10 quality % sodium hydroxide solutions are regulated pH to 12, room temperature reaction 1h, standing demix, water dichloromethane extraction 3 times merge organic phase, washing, organic phase is concentrated, and underpressure distillation gets weak yellow liquid 31.3g, calculated yield is 91.0%, and obtaining 6-bromine-2-methylpyridine product purity by the Agilent1100 liquid chromatograph is 99.1%.
(2) preparation of 6-bromo-2-pyridyl formic acid
6-bromine-2-methylpyridine 31.3g and the water 650mL of above-mentioned preparation are added in reaction flask, start and stir, add KMnO when being heated to 65 ℃ in batches
474.8g, reinforced complete rear continuation heated and stirred 6h, after reaction was completed, reaction solution was cooled to room temperature, filtered, filtrate with 10 quality % hydrochloric acid adjust pHs to 1.5-2, filter, washing, drying obtains white powder solid 31.6g, calculated yield is 86%, and obtaining 6-bromo-2-pyridyl formic acid product purity by the Agilent1100 liquid chromatograph is 98.3%.
(3) preparation of 6-bromo-2-pyridyl methyl-formiate
with anhydrous methanol 400mL, 6-bromo-2-pyridyl formic acid 31.6g and the analytical pure tosic acid 3.7g of above-mentioned preparation add in reaction flask, reflux 6h, react complete rear stopped heating, continuing to stir makes it be cooled to room temperature, after reaction system is spin-dried for, solid is dissolved in ethyl acetate, wash with saturated sodium carbonate solution, wash with water again twice, use anhydrous sodium sulfate drying, filter, concentrated, the enriched product volume ratio is that the acetoacetic ester/sherwood oil recrystallization of 1/15 second obtains white crystal product 32.3g, calculated yield is 95.5%, obtaining 6-bromo-2-pyridyl formic ether product purity by the Agilent1100 liquid chromatograph is 99.5%.
Embodiment 8
(1) prepare 6-bromo-2-pyridyl formic acid with art methods
Under nitrogen protection, add analytical pure 2 in reaction flask, 6-dibromo pyridine 10g and anhydrous tetrahydro furan 50mL dropwise adding the n-Butyl Lithium 45mL solution of 2.5M/L below-78 ℃, dropwise, and are warming up to-15 ℃ of reaction 2h.Pass into CO in reaction mixture upward at-78 ℃
2Gas, until reaction system reach capacity till (beginning bubbling with reaction system judges).After stopping ventilation, reaction system rises to room temperature, after adding water to solid and dissolving fully, being acidified to solid with concentrated hydrochloric acid again separates out, filter, vacuum-drying gets white powder solid 6-bromo-2-pyridyl formic acid 4.7g, calculated yield is 55.3%, and obtaining product purity by the Agilent1100 liquid chromatograph is 98.2%.
(2) with the synthetic 6-bromo-2-pyridyl methyl-formiate of the inventive method
with anhydrous methanol 70mL, 6-bromo-2-pyridyl formic acid 4.7g and the analytical pure tosic acid 0.6g of above-mentioned preparation add in reaction flask, reflux 5h, react complete rear stopped heating, continuing to stir makes it be cooled to room temperature, after reaction system is spin-dried for, solid is dissolved in ether, wash with saturated sodium bicarbonate solution, wash with water again twice, use anhydrous magnesium sulfate drying, filter, concentrated, the enriched product volume ratio is that 1/15 recrystallization from ethyl acetate/petroleum ether obtains white crystal product 4.8g, calculated yield is 95.5%, obtaining 6-bromo-2-pyridyl formic ether product purity by the Agilent1100 liquid chromatograph is 99.4%.
Comparative Examples
The below synthesizes 6-bromo-2-pyridyl methyl-formiate with art methods
Under nitrogen protection, add analytical pure 2 in reaction flask, 6-dibromo pyridine 10g and anhydrous tetrahydro furan 50mL, the n-Butyl Lithium 45mL dropwise adding 2.5M/L below-78 ℃ dropwises, and is warming up to-15 ℃ of reaction 2h.Pass into CO in reaction mixture upward at-78 ℃
2Gas, until reaction system reach capacity till (beginning bubbling with reaction system judges).After stopping ventilation, reaction system rises to room temperature, after adding water to solid and dissolving fully, being acidified to solid with concentrated hydrochloric acid again separates out, filter, vacuum-drying gets white powder solid 6-bromo-2-pyridyl formic acid 4.7g, calculated yield is 55.3%, and obtaining product purity by the Agilent1100 liquid chromatograph is 98.2%.
add 6-bromo-2-pyridyl formic acid 4.7g in reaction flask, anhydrous methanol 100mL and vitriol oil 1.6mL, after reflux 4h, reaction mixture is down to 0 ℃ of left and right, add strong aqua 3.8mL, continuing to stir makes it rise to room temperature, after reaction system is spin-dried for, solid is dissolved in methylene dichloride, wash with saturated sodium bicarbonate solution, wash with water again twice, use anhydrous magnesium sulfate drying, filter, concentrated, enriched product is purified by column chromatography, use again ethyl acetate/petroleum ether (volume ratio is 1/15) recrystallization to obtain white crystal product 3.4g, calculated yield is 68%, obtaining 6-bromo-2-pyridyl formic ether product purity by the Agilent1100 liquid chromatograph is 98.4%.
By contrasting with above-described embodiment, can find out that the present invention uses the Catalyzed by p-Toluenesulfonic Acid esterification instead, than the prior art sulphuric acid catalysis, product yield improves 40% left and right, and aftertreatment is simple, and product purity is apparently higher than the product purity of prior art.Therefore, prepare 6-bromo-2-pyridyl methyl-formiate with method of the present invention, beneficial effect is very remarkable.
Be only below concrete exemplary applications of the present invention, protection scope of the present invention is not constituted any limitation.All employing equivalents or equivalence are replaced and the technical scheme of formation, within all dropping on rights protection scope of the present invention.
Claims (10)
1. the preparation method of a 6-bromo-2-pyridyl methyl-formiate, comprising: with the esterification of tosic acid as catalyst 6-bromo-2-pyridyl formic acid and anhydrous methanol.
2. according to claim 1 method, comprise: with anhydrous methanol, 6-bromo-2-pyridyl formic acid and tosic acid under agitation reflux 2-8 hour, the mol ratio 1:40-60 of 6-bromo-2-pyridyl formic acid and anhydrous methanol wherein, the mol ratio of 6-bromo-2-pyridyl formic acid and tosic acid is 1:0.06-0.2, react and be cooled to room temperature after complete, after reaction system is spin-dried for, solid is dissolved in organic solvent, washing, dry, filter, concentrated, enriched product obtains 6-bromo-2-pyridyl methyl-formiate with the mixed solvent recrystallization.
3. according to claim 2 method, wherein the mol ratio of 6-bromo-2-pyridyl formic acid and tosic acid is 1:0.1-0.16.
4. according to claim 2 method, wherein reflux 4-6 hour.
5. according to claim 2 method, wherein mixed solvent is that volume ratio is the ethyl acetate of 1:10-20 and the mixed solvent of sherwood oil.
6. according to claim 5 method, wherein the volume ratio of ethyl acetate and sherwood oil is 1:15.
7. arbitrary method according to claim 1-6, wherein 6-bromo-2-pyridyl formic acid is obtained through diazotization, bromo, oxidation by 6-amino-2-methyl pyridine.
8. according to claim 7 method, wherein the preparation method of 6-bromo-2-pyridyl formic acid comprises:
Drip bromine at-20 ~-10 ℃ in Hydrogen bromide and 6-amino-2-methyl pyridine, wherein 6-amino-2-methyl pyridine and hydrobromic mol ratio are 1:2-5, the mol ratio of 6-amino-2-methyl pyridine and bromine is 1:1.0-1.5, dropwises afterreaction 1-3 hour; Dripping concentration at-10 ~ 0 ℃ is the sodium nitrite in aqueous solution of 20-35 quality %, and the mol ratio of its Sodium Nitrite and 6-amino-2-methyl pyridine is 1-1.2:1, reacts 0.5-1 hour at 0-15 ℃ after dropwising, regulate pH to 10-12, room temperature reaction 0.5-2 hour, standing demix, aqueous phase extracted, merge organic phase, desiccant dryness is used in washing, concentrated organic phase, underpressure distillation obtains the 6-bromine-2-methylpyridine;
Add oxygenant in 6-bromine-2-methylpyridine and water under 50-80 ℃ of stirring, wherein the mol ratio of 6-bromine-2-methylpyridine and oxygenant is 1:2-3, reacted afterwards 4-10 hour, filter, regulate filtrate pH value to 2-3, have solid to separate out, filtering, wash also, drying solid obtains 6-bromo-2-pyridyl formic acid.
9. according to claim 8 method, wherein 6-amino-2-methyl pyridine and hydrobromic mol ratio are 1:3-4; The mol ratio of 6-amino-2-methyl pyridine and bromine is 1:1.1-1.3.
10. according to claim 8 method, wherein oxygenant is at least a in nitric acid, acid potassium bichromate, chromium trioxide, sulfuric acid and potassium permanganate.
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Cited By (8)
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|---|---|---|---|---|
| CN104987308A (en) * | 2015-06-26 | 2015-10-21 | 林达钦 | Preparation method for 5-bromine-2-picolinic acid |
| CN105384684A (en) * | 2015-12-16 | 2016-03-09 | 辽宁工程技术大学 | 2-cyano-6-methylpyridine preparation method |
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| CN110845401A (en) * | 2019-11-25 | 2020-02-28 | 阿里生物新材料（常州）有限公司 | Synthesis method of 2-fluoro-3, 6-dihydroxypyridine |
| CN111116358A (en) * | 2020-01-15 | 2020-05-08 | 苏州爱玛特生物科技有限公司 | Novel synthesis method of benzene ring polysubstituted compound based on benzoylformic acid |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104987308A (en) * | 2015-06-26 | 2015-10-21 | 林达钦 | Preparation method for 5-bromine-2-picolinic acid |
| CN105384684A (en) * | 2015-12-16 | 2016-03-09 | 辽宁工程技术大学 | 2-cyano-6-methylpyridine preparation method |
| CN107400898A (en) * | 2017-07-22 | 2017-11-28 | 聊城大学 | A kind of synthetic method of 2 pyridine carboxylic acid methyl esters |
| CN110845401B (en) * | 2019-11-25 | 2022-05-13 | 阿里生物新材料（常州）有限公司 | Synthesis method of 2-fluoro-3, 6-dihydroxypyridine |
| CN110845401A (en) * | 2019-11-25 | 2020-02-28 | 阿里生物新材料（常州）有限公司 | Synthesis method of 2-fluoro-3, 6-dihydroxypyridine |
| CN111116358B (en) * | 2020-01-15 | 2022-08-16 | 苏州爱玛特生物科技有限公司 | Novel synthesis method of benzene ring polysubstituted compound based on benzoylformic acid |
| CN111116358A (en) * | 2020-01-15 | 2020-05-08 | 苏州爱玛特生物科技有限公司 | Novel synthesis method of benzene ring polysubstituted compound based on benzoylformic 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 |
| 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 |
| CN114591231A (en) * | 2022-03-02 | 2022-06-07 | 河南阿尔法医药科技有限公司 | Method for large-scale production of 4-formic acid-2, 2' -bipyridine |
| CN114591231B (en) * | 2022-03-02 | 2024-02-20 | 河南阿尔法医药科技有限公司 | Method for large-scale production of 4-formic acid-2, 2' -bipyridine |
| CN115304544A (en) * | 2022-08-01 | 2022-11-08 | 童航 | Synthetic method of 5-bromo-2- (methylamino) pyridine |
| CN115304544B (en) * | 2022-08-01 | 2024-02-09 | 童航 | Synthesis method of 5-bromo-2- (methylamino) pyridine |
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