CN103086964B - 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 synthesis treatment diabetes and the 11-beta hydroxysteroid dehydrogenase inhibitors of obesity and the important source material of related compound; Also be the important as precursors of the Chemokine Receptors of synthesis treatment acquired immune deficiency syndrome (AIDS) and other diseases.
There is bibliographical information with 2,6-dibromo pyridine for raw material, obtain 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 easily controls, react more stable, but final step esterification is with sulphuric acid catalysis, because the vitriol oil has stronger corrodibility, esterification reaction process has more side reaction to produce, aftertreatment is caused to bother very much, not and extremely difficult purifying, finally cause low yield, preparation cost is high for product purity, the drawbacks such as separation difficulty, are thus not suitable for large-scale industrial production.
That how to improve 6-bromo-2-pyridyl methyl-formiate prepares productive rate, reduces production cost, becomes one of 6-bromo-2-pyridyl methyl-formiate preparation field technical problem urgently to be resolved hurrily.
Summary of the invention
The object of this invention is to provide a kind of preparation method of 6-bromo-2-pyridyl methyl-formiate, the method organic acid-tosic acid is as the esterification of catalyst 6-bromo-2-pyridyl formic acid, side reaction is few, aftertreatment is simple, product is easy to be separated, and the products collection efficiency obtained is high, purity is high, quality is good.
The invention provides a kind of preparation method of 6-bromo-2-pyridyl methyl-formiate, comprising: by 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 comprises: by anhydrous methanol, 6-bromo-2-pyridyl formic acid and tosic acid under agitation reflux 2-8 hour, the wherein mol ratio 1:40-60 of 6-bromo-2-pyridyl formic acid and anhydrous methanol, the mol ratio of 6-bromo-2-pyridyl formic acid and tosic acid is 1:0.06-0.2, be cooled to room temperature after completion of the reaction, after reaction system is spin-dried for, solid is dissolved in organic solvent, washing, dry, filter, concentrated, enriched product mixed solvent recrystallization obtains 6-bromo-2-pyridyl methyl-formiate.
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 concrete but nonrestrictive embodiment, wherein a reflux 4-6 hour of the present invention.
According to a concrete but nonrestrictive embodiment of the present invention, wherein mixed solvent is 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:
In Hydrogen bromide and 6-amino-2-methyl pyridine, bromine is dripped at-20 ~-10 DEG C, 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 rear reaction 1-3 hour; Drip at-10 ~ 0 DEG C the sodium nitrite in aqueous solution that concentration is 20-35 quality %, the mol ratio of its Sodium Nitrite and 6-amino-2-methyl pyridine is 1-1.2:1, at 0-15 DEG C of reaction 0.5-1 hour after dropwising, regulate pH to 10-12, room temperature reaction 0.5-2 hour, stratification, aqueous phase extracted, merge organic phase, washing, with desiccant dryness, concentrated organic phase, underpressure distillation, obtains 6-bromine-2-methylpyridine;
In 6-bromine-2-methylpyridine and water, oxygenant is added under stirring at 50-80 DEG C, wherein the mol ratio of 6-bromine-2-methylpyridine and oxygenant is 1:2-3, react 4-10 hour afterwards, filter, regulate filtrate pH value to 2-3, have solid to separate out, filtration, washing also drying solid obtain 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 one 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, the deficiency that existing technique mineral acid catalytic esterification causes side reaction many can be overcome, decrease the generation of side reaction in esterification process, aftertreatment is relatively simple, and product is easy to be separated, and significantly improves and prepares productive rate.
2. one embodiment of the invention, with 6-amino-2-methyl pyridine for 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, simple to operate, can obtain high yield, highly purified product.
3. preparation method of the present invention is simple to operate, and whole process contamination is little, is applicable to large-scale industrial production.
Accompanying drawing explanation
Fig. 1 is the H-NMR spectrogram (solvent: DMSO) of 6-bromo-2-pyridyl methyl-formiate prepared by embodiment 1.
Embodiment
Provided hereinafter concrete embodiment and 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 makes this esterification of catalyst.But because mineral acid generally has stronger corrodibility, often produce more side reaction, cause aftertreatment to bother, the product purity not and extremely problem such as difficult purifying.The present inventor, through studying discovery for a long period of time, if use tosic acid instead to make this esterification of catalyst, significantly can improve productive rate, and the product purity obtained 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, stir lower reflux 2-8 hour, preferred backflow 4-6 hour, stops heating after completion of the reaction, continues stirring and makes 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 siccative as dryings such as anhydrous magnesium sulfate, sodium sulfate, calcium sulfate, salt of wormwood or calcium chloride, filter, concentrated, enriched product organic solvent recrystallization obtains white crystal product.Use mixed solvent as the mixed solvent of ethyl acetate and sherwood oil, recrystallization effect is better, and the volume ratio of ethyl acetate and sherwood oil can be 1:10-20, preferred 1:15.
We find through research, 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.As tosic acid/6-bromo-2-pyridyl formic acid (mol ratio) <0.1, the yield of product is lower, and below 90%, this may be because the consumption of tosic acid is few, and speed of reaction is slow, and not exclusively, therefore esterification yield is low in reaction; 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 about 95%; And as tosic acid/6-bromo-2-pyridyl formic acid (mol ratio) >0.16, product yield no longer increases, and drops to less than 90% on the contrary, and this may be because excessive adds catalyzer, and cause system pH value to reduce, thus cause 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 with 6-amino-2-methyl pyridine for raw material, can 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
Join in reaction vessel by the Hydrogen bromide of concentration 40-48% and 6-amino-2-methyl pyridine, 6-amino-2-methyl pyridine and hydrobromic mol ratio can be 1:2-5, preferred 1:3-4.Slowly drip bromine at-20 ~-10 DEG C, the mol ratio of 6-amino-2-methyl pyridine and bromine can be 1:1.0-1.5, preferred 1:1.1-1.3, dropwises rear reaction 1-3 hour.Drip at-10 ~ 0 DEG C the sodium nitrite in aqueous solution that concentration is 20-35 quality %, the mol ratio of Sodium Nitrite and 6-amino-2-methyl pyridine can be 1-1.2:1, after dropwising, at 0-15 DEG C of reaction 0.5-1 hour.React rear 5-20 quality % alkaline solution such as sodium hydroxide and regulate pH to 10-12, room temperature reaction 0.5-2 hour, stratification.Aqueous phase extraction agent is as methylene dichloride, ethyl acetate or extracted with diethyl ether 2-3 time; Merge organic phase, water washing, with siccative as anhydrous magnesium sulfate, sodium sulfate, calcium sulfate or salt of wormwood are dry; Organic phase concentrates, and underpressure distillation, obtains weak yellow liquid 6-bromine-2-methylpyridine.
(2) preparation of 6-bromo-2-pyridyl formic acid
The 6-bromine-2-methylpyridine obtained by (1) step and water are added in reaction vessel, and the amount of aqueous solvent needs the ratio of water 3000mL to add according to 1mol6-bromine-2-methylpyridine, start and stir.At 50-80 DEG C, preferably at 60 DEG C-70 DEG C, add oxidant reaction, oxygenant can be nitric acid, acid potassium bichromate, chromium trioxide, sulfuric acid and/or potassium permanganate etc. in batches, 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, continue heated and stirred 4-10 hour, preferred 6-8 hour.After having reacted, reaction solution cools, and filters, and filtrate is with the hydrochloric acid adjust pH of 5-20 quality % to 2-3, and adularescent solid is separated out, and filter, wash solid with water, 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 with 6-amino-2-methyl pyridine for raw material, the synthetic route of 6-bromo-2-pyridyl methyl-formiate is obtained through diazotization, bromo, oxidation, esterification, there is raw material be easy to get, reaction conditions is gentle, simple operation and other advantages, and the product yield obtained is high, purity is high, be applicable to large-scale industrial production.
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, all can obtain from commercial channels.
Embodiment 1
(1) preparation of 6-bromine-2-methylpyridine
By concentration be 48% Hydrogen bromide 46mL and analytical pure 2-amino-6-picoline 10.8g add in reaction flask ,-10 DEG C slowly drip bromine 6.2mL, 0.5h and dropwise, reaction 1.5h; The sodium nitrite in aqueous solution 22.8mL that concentration is 25 quality % is dripped at-10 DEG C-0 DEG C, after dropwising, 15 DEG C of reaction 0.5h; React rear use 10 quality % sodium hydroxide solution and regulate pH to 12, room temperature reaction 1h, stratification, aqueous phase 200mL dichloromethane extraction 3 times, merges organic phase, washing, organic phase concentrates, and underpressure distillation, obtains weak yellow liquid 15.8g, calculated yield is 92%, and obtaining 6-bromine-2-methylpyridine product purity by Agilent1100 liquid chromatograph is 99.3%.
(2) preparation of 6-bromo-2-pyridyl formic acid
The 6-bromine-2-methylpyridine 15.8g of above-mentioned preparation and water 300mL is added in reaction flask, starts and stir, when being heated to 65 DEG C, add 34.8g KMnO in batches
4, after reinforced, continue heated and stirred 7h.After having reacted, reaction solution cools, and filters, 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 Agilent1100 liquid chromatograph is 98.3%.
(3) preparation of 6-bromo-2-pyridyl methyl-formiate
By 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, stop heating after completion of the reaction, continuing stirring 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 twice with water again, with anhydrous magnesium sulfate drying, filter, concentrated, enriched product volume ratio be 1/15 ethyl acetate/petroleum ether mixed solvent recrystallization obtain white crystal product 16.6g, yield 94%, obtaining 6-bromo-2-pyridyl formic ether product purity by 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 that the mol ratio of tosic acid and 6-bromo-2-pyridyl formic acid is as shown in table 1 below, and all in the same manner as in Example 1, the productive rate obtained is listed respectively in Table 1 for other step and condition.
Table 1
Embodiment 6
(1) preparation of 6-bromine-2-methylpyridine
Add in reaction flask by 48% Hydrogen bromide 64mL and analytical pure 2-amino-6-picoline 20g ,-10 DEG C slowly drip bromine 11.4mL, 0.5h and dropwise, reaction 1.5h; The 25% Sodium Nitrite 42.2mL aqueous solution is dripped at-10 DEG C-0 DEG C, after dropwising, 15 DEG C of reaction 0.5h; React rear use 10 quality % sodium hydroxide solution and regulate pH to 12, room temperature reaction 1h, static layering, aqueous phase 450mL extraction into ethyl acetate 3 times, merges organic phase, washing, organic phase concentrates, and underpressure distillation, obtains weak yellow liquid 28.6g, calculated yield is 90%, and obtaining 6-bromine-2-methylpyridine product purity by Agilent1100 liquid chromatograph is 99.0%.
(2) preparation of 6-bromo-2-pyridyl formic acid
The 6-bromine-2-methylpyridine 28.6g of above-mentioned preparation and water 600mL is added in reaction flask, starts and stir, when being heated to 60 DEG C, add KMnO in batches
468.3g, heated and stirred 6h is continued after reinforced, after having reacted, reaction solution is cooled to room temperature, filters, 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 Agilent1100 liquid chromatograph is 98.1%.
(3) preparation of 6-bromo-2-pyridyl methyl-formiate
By 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, stop heating after completion of the reaction, continuing stirring 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 twice with water again, with anhydrous sodium sulfate drying, filter, concentrated, enriched product volume ratio be 1/15 recrystallization from ethyl acetate/petroleum ether obtain white crystal product 29.6g, calculated yield is 94.7%, obtaining 6-bromo-2-pyridyl formic ether product purity by Agilent1100 liquid chromatograph is 99.3%.
Embodiment 7
(1) preparation of 6-bromine-2-methylpyridine
Add in reaction flask by 48% Hydrogen bromide 69.2mL and analytical pure 2-amino-6-picoline 21.6g ,-10 DEG C slowly drip bromine 13.4mL, 0.5h and dropwise, reaction 1.5h; The 25 quality % Sodium Nitrite 45.6mL aqueous solution are dripped at-10 DEG C-0 DEG C, after dropwising, 15 DEG C of reaction 0.5h; React rear use 10 quality % sodium hydroxide solution and regulate pH to 12, room temperature reaction 1h, stratification, aqueous phase dichloromethane extraction 3 times, merges organic phase, washing, organic phase concentrates, and underpressure distillation, obtains weak yellow liquid 31.3g, calculated yield is 91.0%, and obtaining 6-bromine-2-methylpyridine product purity by Agilent1100 liquid chromatograph is 99.1%.
(2) preparation of 6-bromo-2-pyridyl formic acid
The 6-bromine-2-methylpyridine 31.3g of above-mentioned preparation and water 650mL is added in reaction flask, starts and stir, when being heated to 65 DEG C, add KMnO in batches
474.8g, heated and stirred 6h is continued after reinforced, after having reacted, reaction solution is cooled to room temperature, filters, 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 Agilent1100 liquid chromatograph is 98.3%.
(3) preparation of 6-bromo-2-pyridyl methyl-formiate
By 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, stop heating after completion of the reaction, continuing stirring 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 twice with water again, with anhydrous sodium sulfate drying, filter, concentrated, 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 Agilent1100 liquid chromatograph is 99.5%.
Embodiment 8
(1) 6-bromo-2-pyridyl formic acid is prepared by art methods
Under nitrogen protection, in reaction flask, add analytical pure 2,6-dibromo pyridine 10g and anhydrous tetrahydro furan 50mL, below-78 DEG C, dropwise add the n-Butyl Lithium 45mL solution of 2.5M/L, dropwise, be warming up to-15 DEG C of reaction 2h.CO is passed in-78 DEG C upward reaction mixture
2gas, (starts bubbling with reaction system to judge) till reaction system reaches capacity.After stopping ventilation, reaction system rises to room temperature, add water to after solid dissolves completely, be acidified to solid with concentrated hydrochloric acid again to separate out, filter, vacuum-drying, obtains white powder solid 6-bromo-2-pyridyl formic acid 4.7g, calculated yield is 55.3%, and obtaining product purity by Agilent1100 liquid chromatograph is 98.2%.
(2) with the inventive method synthesis 6-bromo-2-pyridyl methyl-formiate
By 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, stop heating after completion of the reaction, continuing stirring 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 twice with water again, with anhydrous magnesium sulfate drying, filter, concentrated, enriched product volume ratio be 1/15 recrystallization from ethyl acetate/petroleum ether obtain white crystal product 4.8g, calculated yield is 95.5%, obtaining 6-bromo-2-pyridyl formic ether product purity by Agilent1100 liquid chromatograph is 99.4%.
Comparative example
Below with art methods synthesis 6-bromo-2-pyridyl methyl-formiate
Under nitrogen protection, in reaction flask, add analytical pure 2,6-dibromo pyridine 10g and anhydrous tetrahydro furan 50mL, below-78 DEG C, dropwise add the n-Butyl Lithium 45mL of 2.5M/L, dropwise, be warming up to-15 DEG C of reaction 2h.CO is passed in-78 DEG C upward reaction mixture
2gas, (starts bubbling with reaction system to judge) till reaction system reaches capacity.After stopping ventilation, reaction system rises to room temperature, add water to after solid dissolves completely, be acidified to solid with concentrated hydrochloric acid again to separate out, filter, vacuum-drying, obtains white powder solid 6-bromo-2-pyridyl formic acid 4.7g, calculated yield is 55.3%, and obtaining product purity by Agilent1100 liquid chromatograph is 98.2%.
6-bromo-2-pyridyl formic acid 4.7g is added in reaction flask, anhydrous methanol 100mL and vitriol oil 1.6mL, after reflux 4h, reaction mixture is down to about 0 DEG C, add strong aqua 3.8mL, continuing stirring 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 twice with water again, with anhydrous magnesium sulfate drying, filter, concentrated, enriched product is purified by column chromatography, ethyl acetate/petroleum ether (volume ratio is 1/15) recrystallization is used to obtain white crystal product 3.4g again, calculated yield is 68%, obtaining 6-bromo-2-pyridyl formic ether product purity by Agilent1100 liquid chromatograph is 98.4%.
By contrasting with above-described embodiment, can find out that the present invention uses Catalyzed by p-Toluenesulfonic Acid esterification instead, than prior art sulphuric acid catalysis, product yield improves about 40%, 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 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 (9)
1. a preparation method for 6-bromo-2-pyridyl methyl-formiate, is characterized in that, by the esterification of tosic acid as catalyst 6-bromo-2-pyridyl formic acid and anhydrous methanol, described method comprises:
By anhydrous methanol, 6-bromo-2-pyridyl formic acid and tosic acid under agitation reflux 2-8 hour, 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 1:0.09-0.18, is cooled to room temperature after completion of the reaction, after reaction system being spin-dried for, solid is dissolved in organic solvent, washing, dry, filter, concentrated, enriched product mixed solvent recrystallization obtains 6-bromo-2-pyridyl methyl-formiate.
2. method according to claim 1, wherein the mol ratio of 6-bromo-2-pyridyl formic acid and tosic acid is 1:0.1-0.16.
3. method according to claim 1, wherein reflux 4-6 hour.
4. method according to claim 1, wherein mixed solvent is volume ratio is the ethyl acetate of 1:10-20 and the mixed solvent of sherwood oil.
5. method according to claim 4, wherein the volume ratio of ethyl acetate and sherwood oil is 1:15.
6., according to method arbitrary in claim 1-5, wherein 6-bromo-2-pyridyl formic acid is obtained through diazotization, bromo, oxidation by 6-amino-2-methyl pyridine.
7. method according to claim 6, wherein the preparation method of 6-bromo-2-pyridyl formic acid comprises:
In Hydrogen bromide and 6-amino-2-methyl pyridine, bromine is dripped at-20 ~-10 DEG C, 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 rear reaction 1-3 hour; Drip at-10 ~ 0 DEG C the sodium nitrite in aqueous solution that concentration is 20-35 quality %, the mol ratio of its Sodium Nitrite and 6-amino-2-methyl pyridine is 1-1.2:1, at 0-15 DEG C of reaction 0.5-1 hour after dropwising, regulate pH to 10-12, room temperature reaction 0.5-2 hour, stratification, aqueous phase extracted, merge organic phase, washing, with desiccant dryness, concentrated organic phase, underpressure distillation, obtains 6-bromine-2-methylpyridine;
In 6-bromine-2-methylpyridine and water, oxygenant is added under stirring at 50-80 DEG C, wherein the mol ratio of 6-bromine-2-methylpyridine and oxygenant is 1:2-3, react 4-10 hour afterwards, filter, regulate filtrate pH value to 2-3, have solid to separate out, filtration, washing also drying solid obtain 6-bromo-2-pyridyl formic acid.
8. method according to claim 7, 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.
9. method according to claim 7, wherein oxygenant is at least one in nitric acid, acid potassium bichromate, chromium trioxide, sulfuric acid and potassium permanganate.
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| CN105384684B (en) * | 2015-12-16 | 2018-02-13 | 辽宁工程技术大学 | A kind of preparation method of the picoline of 2 cyano group 6 |
| CN107400898A (en) * | 2017-07-22 | 2017-11-28 | 聊城大学 | A kind of synthetic method of 2 pyridine carboxylic acid methyl esters |
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