CN102321016A - Synthesis method of 5-bromo-2-methyl 4-hydroxypyridinecarboxylate - Google Patents
Synthesis method of 5-bromo-2-methyl 4-hydroxypyridinecarboxylate Download PDFInfo
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Abstract
The invention provides a synthesis method of 5-bromo-2-methyl 4-hydroxypyridinecarboxylate. 5-bromo-2-methyl 4-hydroxypyridinecarboxylate is prepared by five-step reaction namely two-step oxygen, esterification, reduction, diazotization hydrolysis and the like by taking 2-amino-5-bromo-4-methylpyridine as a raw material, wherein the total yield is more than 40%. According to the invention, the raw material is available, a used intermediate is cheap in price, reaction steps are simple and easy to operate, reaction process is safe and reliable, and the yield of the product is high, thus the synthesis method has potential industrial application value.
Description
Technical field
The present invention relates to a kind of compound method of 5-bromo-2-hydroxy-isonicotinic acid methyl esters, belong to technical field of chemistry.
Background technology
5-bromo-2-hydroxy-isonicotinic acid methyl esters (Methyl 5-bromo-2-hydroxyisonicotinate) is a kind of important medicine intermediate, but its compound method is not seen bibliographical information.We provide a kind of and have carried out the method that the diazotization hydrolysis prepares 5-bromo-2-hydroxy-isonicotinic acid methyl esters by 2-amino-5-bromine isonicotinic acid methyl esters.The method of the Synthetic 2-amino of prior art-5-bromine isonicotinic acid methyl esters is to be that raw material is through bromo Synthetic 2-amino-5-bromine isonicotinic acid methyl esters with 2-amino-iso methyl nicotinate; As: disclose in the patented claim of WO2007/11326 international publication with N-bromo-succinimide (N-bromosuccinimide; NBS) as the method for bromizating agent Synthetic 2-amino-5-bromine isonicotinic acid methyl esters, the thick yield of product is 35%.Having adopted in the U.S. Pat 2006/84802 is the mode Synthetic 2-amino-5-bromine isonicotinic acid methyl esters of bromizating agent with the bromine, and separating the after product yield through silicagel column is 23%.In patent CN 101863830A, be raw material with 2-amino-4-picoline, synthesized 2-amino-5-bromine isonicotinic acid through four-step reaction, total recovery is merely 15.7%.
The preparation method of above-mentioned 2-amino-5-bromine isonicotinic acid ester exists yield low, and product is difficult for the shortcoming of purifying, is difficult to realize large-scale industrial production.According to the relevant yield of prior art,, can estimate that the total recovery of 5-bromo-2-hydroxy-isonicotinic acid can be lower if 2-amino-5-bromine isonicotinic acid methyl esters is carried out the synthetic 5-bromo-2-hydroxy-isonicotinic acid methyl esters of diazotization hydrolysis.
Summary of the invention
To the deficiency of prior art, the present invention provides the compound method that a kind of operation is easy to realize, yield is high, the 5-bromo-2-hydroxy-isonicotinic acid methyl esters of potential industrial application value is arranged.
The structure of 5-bromo-2-hydroxy-isonicotinic acid methyl esters of the present invention is as shown in the formula 1:
The compound method of 5-bromo-2-hydroxy-isonicotinic acid methyl esters of the present invention, step is following:
(1) 2～1.5: 1 the vitriol oil is added drop-wise to massfraction is in 30% the ydrogen peroxide 50 by volume, and controlled temperature dropwises postcooling to 5 ℃ smaller or equal to 20 ℃ in the dropping process, the mixed solution of the vitriol oil and ydrogen peroxide 50;
2-amino-5-bromo-4-picoline is dissolved in the vitriol oil, adds the above-mentioned vitriol oil and the mixed solution of ydrogen peroxide 50 again, reaction finishes; Reaction solution is poured in the mixture of ice and water, regulated pH to 7～8, suction filtration; The filter cake washing, oven dry makes 5-bromo-4-methyl-2-nitropyridine;
(2) the 5-bromo-4-methyl-2-nitropyridine that step (1) is obtained is dissolved in the vitriol oil, adds sodium dichromate 99 again, and stirring at room is poured in the trash ice after reaction finishes, and suction filtration, filter cake are dried with water washing; Filtrating is used chloroform extraction, drying, and evaporated under reduced pressure merges with filter cake, makes 5-bromo-2-nitro Yi Yansuan;
(3) the 5-bromo-2-nitro Yi Yansuan that step (2) is obtained is dissolved in the methyl alcohol, dripping thionyl chloride, back flow reaction steam to be removed most of methyl alcohol, cooling adds water, regulates pH to 7～8, ETHYLE ACETATE collection water layer, drying, concentrate 5-bromo-2-nitro iso methyl nicotinate;
(4) reduced iron powder is mixed with water, Glacial acetic acid min. 99.5, after the activation, add the 5-bromo-2-nitro iso methyl nicotinate that ethanol and step (3) obtain, insulation reaction; Reaction finishes, cooling, suction filtration, filtrating steam to be removed most of ethanol, adds chloroform, with the saturated sodium bicarbonate solution washing, drying, concentrate bullion; This bullion is dissolved in the chloroform, washes twice with acid solution, combining water layer, water layer is regulated pH to 5～8 with alkali lye, chloroform collection water layer, dry the concentrating of chloroform layer makes 2-amino-5-bromine isonicotinic acid methyl esters;
(5) the 2-amino that step (4) is obtained-5-bromine isonicotinic acid methyl esters is dissolved in the dilution heat of sulfuric acid, drips sodium nitrite in aqueous solution, stirs, and reaction finishes, suction filtration, and filtrating transfers to neutrality, chloroform extraction, chloroform layer is dry to be concentrated; Enriched material and filter cake are merged into bullion; Bullion is crossed the silica gel filter bed, concentrate 5-bromo-2-hydroxy-isonicotinic acid methyl esters.
Above-described vitriol oil concentration massfraction is 97%-99%, and dilute sulphuric acid concentration massfraction is 8%-9%.
Detailed description is done into-gone on foot to reaction formula below in conjunction with each step to the present invention:
In the above step (1), the mol ratio of 2-amino-5-bromo-4-picoline and ydrogen peroxide 50 is 1: 10～30, preferred 1: 18.The temperature that the mixed solution of the vitriol oil and ydrogen peroxide 50 splashes into 2-amino-5-bromo-4-picoline sulphuric acid soln is controlled at 0～15 ℃.
In the above step (2), the mol ratio of 5-bromo-4-methyl-2-nitropyridine and sodium dichromate 99 is 1: 1～4, preferred 1: 2.5.Temperature of reaction is 0～40 ℃, and the reaction times is 3～10 hours.
In the above step (3), 5-bromo-2-nitro Yi Yansuan, the mol ratio of methyl alcohol and sulfur oxychloride is 1: (15～40): (1～3), preferred 1: 24: 1.6; Temperature of reaction is 0～25 ℃, and the reaction times is 1～5 hour.
In the above step (4), the mol ratio of 5-bromo-2-nitro iso methyl nicotinate and reduced iron powder is 1: 1～6, and temperature of reaction is 60～80 ℃, and the reaction times is 2～6 hours; Water layer is regulated the pH value with alkali during crude product refining, preferred pH=6.
In the above step (5), the mol ratio of 2-amino-5-bromine isonicotinic acid methyl esters and Sodium Nitrite is 1: 1～10, and temperature of reaction is 0～40 ℃, and the reaction times is 1～5 hour.
Do not specify in the above step all according to prior art.
The synthetic route of the compound method of 5-bromo-2-hydroxy-isonicotinic acid methyl esters of the present invention is following:
Preferably, the compound method of 5-bromo-2-hydroxy-isonicotinic acid methyl esters of the present invention, step is following:
(1) the 1500ml vitriol oil slowly is added drop-wise to is equipped with in the Erlenmeyer flask of 5L that the 750ml massfraction is 30% ydrogen peroxide 50, controlled temperature is smaller or equal to 20 ℃ in the dropping process, and it is ℃ subsequent use to dropwise postcooling to 5; 0.535mol 2-amino-5-bromo-4-picoline is added in the 2550ml vitriol oil, is cooled to zero degree; The reserve liquid of last step preparation slowly is added drop-wise in the mixed solution, and controlled temperature drips off temperature control and stirred 30 minutes for 5 ℃ 15 ℃ at 5 ℃ 15 ℃, and room temperature reaction is 3 hours then; After reaction finishes, reaction solution is poured in the mixture of ice and water, regulated pH to 7～8, separate out a large amount of faint yellow solids with NaOH solution, suction filtration, filter cake is with a small amount of washing; 45 ℃ dry 5-bromo-4-methyl-2-nitropyridine 104.6g;
(2) 0.461mol 5-bromo-4-methyl-2-nitropyridine is dissolved in the 1.5L vitriol oil, ice-water bath slowly adds 1.164mol Na
2Cr
2O
72H
2O finishes, and stirring at room 6 hours is poured in 2 kilograms of trash ices, has solid to separate out, suction filtration, filter cake washs with less water, 70 ℃ dry 5-bromo-2-nitro Yi Yansuan 71g, faint yellow solid; Filtrating is used the 2L chloroform extraction, anhydrous sodium sulfate drying, and evaporated under reduced pressure gets 5-bromo-2-nitro Yi Yansuan 14.4g, merges yield 75%;
(3) 0.344mol 5-bromo-2-nitro Yi Yansuan is dissolved in 340ml methyl alcohol, temperature control≤28 ℃ slowly splash into the 40ml sulfur oxychloride in constant pressure funnel, and temperature control≤25 ℃ finished the back back flow reaction 2.5 hours; After reaction finishes, steam and remove most of methyl alcohol, cooling; Add 1L water, diluted sodium hydroxide solution is regulated pH to 7～8,200ml ETHYLE ACETATE collection water layer 2 times; The combined ethyl acetate layer, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent get khaki color solid 77g; Be 5-bromo-2-nitro iso methyl nicotinate, yield 85%;
(4) in the four-hole bottle of 1L, add 85ml water, add the 1.209mol reduced iron powder, N
2Be heated to 70 ℃ under the protective condition and add the 35ml Glacial acetic acid min. 99.5,70 ℃ of insulation activation add 140ml ethanol after 30 minutes, be warming up to 75～80 ℃, add 0.285mol 5-bromo-2-nitro iso methyl nicotinate in batches; Added 75～80 ℃ of insulation reaction in back 4 hours, cooling is filtered; Filtrate decompression is steamed and is removed most of ethanol, and filter cake washes twice with the 150ml chloroform, merging filtrate and washing lotion; Water, saturated sodium bicarbonate, water are respectively washed once successively, and anhydrous sodium sulfate drying, concentrating under reduced pressure get yellow-green colour solid 58.3g; This bullion is dissolved in the 100ml chloroform, and with 1N salt pickling 2 times, water layer is regulated pH to 6 with sodium bicarbonate solid; Come together 3 times combined chloroform layer, anhydrous sodium sulfate drying again with chloroform; Evaporated under reduced pressure gets faint yellow 2-amino-5-bromine isonicotinic acid ester solid 52.8g, yield 80%;
(5) 0.216mol 2-amino-5-bromine isonicotinic acid ester is joined be equipped with in the there-necked flask that the 875ml massfraction is 9% dilute sulphuric acid and 1 kilogram of trash ice, ice bath is cooled to about 0 ℃, stirs slowly to splash into 1.710mol sodium nitrite in aqueous solution 175ml down; 20 ℃ of following stirring reactions 2 hours, suction filtration, filter cake is washed once; Merging filtrate and washing lotion are regulated PH to 6～7; Use chloroform extraction, anhydrous sodium sulfate drying concentrates; Filtrating enriched material and filter cake are merged into 5-bromo-2-hydroxy-isonicotinic acid methyl esters bullion; Product is dissolved in chloroform, filters the chloroform wash-out with the silica gel filter bed; Use the volume ratio methylene dichloride: the tlc inspection of ETHYLE ACETATE=10: 1 does not have product in filtrating; Concentrating under reduced pressure gets 5-bromo-2-hydroxy-isonicotinic acid methyl esters 45.5g, yellow solid, productive rate 91%.
Above-described vitriol oil concentration massfraction is 98～98.5%, and dilute sulphuric acid concentration massfraction is 9%.
Excellent results of the present invention is:
1. 5-bromo-2-hydroxy-isonicotinic acid methyl esters total yield of products of the present invention is up to 41%.
2. this synthetic route raw material is easy to get, used midbody low price, and reactions step is simple to operation, and reaction process is safe and reliable, has the potential industrial application value.
Embodiment
Bright in order to illustrate in greater detail we, provide following preparation instance.But scope of the present invention is not limited thereto.
Vitriol oil concentration massfraction described in the embodiment is 98.3%, and dilute sulphuric acid concentration massfraction is 9%.
Embodiment 1:
(1) 5-bromo-4-methyl-2-nitropyridine is synthetic
The 1500ml vitriol oil (massfraction is 98.3%) slowly is added drop-wise to is equipped with in the Erlenmeyer flask of 5L that the 750ml massfraction is 30% ydrogen peroxide 50, controlled temperature is smaller or equal to 20 ℃ in the dropping process, and it is ℃ subsequent use to dropwise postcooling to 5; 0.535mol 2-amino-5-bromo-4-picoline is added in the 2550ml vitriol oil, is cooled to zero degree; The reserve liquid of last step preparation slowly is added drop-wise in the mixed solution, and controlled temperature drips off temperature control and stirred 30 minutes for 5 ℃ 15 ℃ at 5 ℃ 15 ℃, and room temperature reaction is 3 hours then; After reaction finishes, reaction solution is poured in the mixture of ice and water, regulated pH to 7～8, separate out a large amount of faint yellow solids with NaOH solution, suction filtration, filter cake is with a small amount of washing; 45 ℃ dry 5-bromo-4-methyl-2-nitropyridine 104.6g; Yield 90%.m.p.84～85℃。
1HNMR(400MHz，CDCl
3)，δ：8.67(s，1H)；8.61(s，1H)；2.59(s，3H)。IR(KBr)，v，cm
-1：3100，3075，2975，2950，1550，1540，1345，560。ESI-MS，m/z(％)：217(100，[M+H]
+)。
(2) 5-bromo-2-nitro Yi Yansuan is synthetic
0.461mol 5-bromo-4-methyl-2-nitropyridine is dissolved in the 1.5L vitriol oil (massfraction is 98.3%), and ice-water bath slowly adds 1.164mol Na
2Cr
2O
72H
2O finishes, and stirring at room 6 hours is poured in 2 kilograms of trash ices, has solid to separate out, suction filtration, filter cake washs with less water, 70 ℃ dry 5-bromo-2-nitro Yi Yansuan 71g, faint yellow solid; Filtrating is used the 2L chloroform extraction, anhydrous sodium sulfate drying, and evaporated under reduced pressure gets 5-bromo-2-nitro Yi Yansuan 14.4g, merges yield 75%; M.p.233 ℃.
1HNMR(400MHz，DMSO-d
6)，δ：14.74(s，1H)；8.96(s，1H)；8.47(s，1H)。IR(KBr)，v，cm
-1：3100，3075，3000，1720，1550，1540，1360，575。ESI-MS，m/z(％)：247(100，[M+H]
+)。
(3) 5-bromo-2-nitro iso methyl nicotinate is synthetic
0.344mol 5-bromo-2-nitro Yi Yansuan is dissolved in 340ml methyl alcohol, and temperature control≤28 ℃ slowly splash into the 40ml sulfur oxychloride in constant pressure funnel, and temperature control≤25 ℃ finished the back back flow reaction 2.5 hours; After reaction finishes, steam and remove most of methyl alcohol, cooling; Add 1L water, diluted sodium hydroxide solution is regulated pH to 7～8,200ml ETHYLE ACETATE collection water layer 2 times; The combined ethyl acetate layer, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent get khaki color solid 77g; Be 5-bromo-2-nitro iso methyl nicotinate, yield 85%; M.p.63 ℃～65 ℃.1HNMR(400MHz，CDCl
3)，δ：8.89(s，1H)；8.60(s，1H)；4.06(s，3H)。IR(KBr)，v，cm
-1：3130，3075，2960，2880，1750，1550，1530，1345，1280，680。ESI-MS，m/z(％)：261(100，[M+H]
+)。
(4) 2-amino-5-bromine isonicotinic acid methyl esters is synthetic
In the four-hole bottle of 1L, add 85ml water, add the 1.209mol reduced iron powder, N
2Be heated to 70 ℃ under the protective condition and add the 35ml Glacial acetic acid min. 99.5,70 ℃ of insulation activation add 140ml ethanol after 30 minutes, be warming up to 75～80 ℃, add 0.285mol 5-bromo-2-nitro iso methyl nicotinate in batches; Added 75～80 ℃ of insulation reaction in back 4 hours, cooling is filtered; Filtrate decompression is steamed and is removed most of ethanol, and filter cake washes twice with the 150ml chloroform, merging filtrate and washing lotion; Water, saturated sodium bicarbonate, water are respectively washed once successively, and anhydrous sodium sulfate drying, concentrating under reduced pressure get yellow-green colour solid 58.3g; This bullion is dissolved in the 100ml chloroform, and with 1N salt pickling 2 times, water layer is regulated pH to 6 with sodium bicarbonate solid; Come together 3 times combined chloroform layer, anhydrous sodium sulfate drying again with chloroform; Evaporated under reduced pressure gets faint yellow 2-amino-5-bromine isonicotinic acid ester solid 52.8g, yield 80%; M.p.140～141 ℃.
1HNMR(400MHz，DMSO-d
6)，δ：8.10(s，1H)；6.75(s，1H)；6.48(s，2H)；3.84(s，3H)。IR(KBr)，v，cm
-1：3460，3430，3200，3075，2960，2860，1735，1285，580。ESI-MS，m/z(％)：231(100，[M+H]
+)。
(5) 5-bromo-2-hydroxy-isonicotinic acid methyl esters is synthetic
0.216mol 2-amino-5-bromine isonicotinic acid ester joined be equipped with in the there-necked flask that the 875ml massfraction is 9% dilute sulphuric acid and 1 kilogram of trash ice, ice bath is cooled to about 0 ℃, stirs slowly to splash into 1.710mol sodium nitrite in aqueous solution 175ml down; 20 ℃ of following stirring reactions 2 hours, suction filtration, filter cake is washed once; Merging filtrate and washing lotion are regulated PH to 6～7; Use chloroform extraction, anhydrous sodium sulfate drying concentrates; Filtrating enriched material and filter cake are merged into 5-bromo-2-hydroxy-isonicotinic acid methyl esters bullion; Product is dissolved in chloroform, filters the chloroform wash-out with the silica gel filter bed; Use the volume ratio methylene dichloride: the tlc inspection of ETHYLE ACETATE=10: 1 does not have product in filtrating; Concentrating under reduced pressure gets 5-bromo-2-hydroxy-isonicotinic acid methyl esters 45.5g, yellow solid, productive rate 91%.m.p.177℃～178℃。
1HNMR(600MHz，DMSO-d
6)，δ：12.203(s，1H)；7.91(s，1H)；6.72(s，1H)；3.85(s，3H)。IR(KBr)，v，cm
-1：3020，2960，2860，1668，1555，1465，1230，575。ESI-MS，m/z(％)：232(100，[M+H]
+)。
Claims (7)
1.5-the preparation method of bromo-2-hydroxy-isonicotinic acid methyl esters, step is following:
(1) 2～1.5: 1 the vitriol oil is added drop-wise to massfraction is in 30% the ydrogen peroxide 50 by volume, and controlled temperature dropwises postcooling to 5 ℃ smaller or equal to 20 ℃ in the dropping process, the mixed solution of the vitriol oil and ydrogen peroxide 50;
2-amino-5-bromo-4-picoline is dissolved in the vitriol oil, adds the above-mentioned vitriol oil and the mixed solution of ydrogen peroxide 50 again, reaction finishes; Reaction solution is poured in the mixture of ice and water, regulated pH to 7～8, suction filtration; The filter cake washing, oven dry makes 5-bromo-4-methyl-2-nitropyridine;
(2) the 5-bromo-4-methyl-2-nitropyridine that step (1) is obtained is dissolved in the vitriol oil, adds sodium dichromate 99 again, and stirring at room is poured in the trash ice after reaction finishes, and suction filtration, filter cake are dried with water washing; Filtrating is used chloroform extraction, drying, and evaporated under reduced pressure merges with filter cake, makes 5-bromo-2-nitro Yi Yansuan;
(3) the 5-bromo-2-nitro Yi Yansuan that step (2) is obtained is dissolved in the methyl alcohol, dripping thionyl chloride, back flow reaction steam to be removed most of methyl alcohol, cooling adds water, regulates pH to 7～8, ETHYLE ACETATE collection water layer, drying, concentrate 5-bromo-2-nitro iso methyl nicotinate;
(4) reduced iron powder is mixed with water, Glacial acetic acid min. 99.5, after the activation, add the 5-bromo-2-nitro iso methyl nicotinate that ethanol and step (3) obtain, insulation reaction; Reaction finishes, cooling, suction filtration, filtrating steam to be removed most of ethanol, adds chloroform, with the saturated sodium bicarbonate solution washing, drying, concentrate bullion; This bullion is dissolved in the chloroform, washes twice with acid solution, combining water layer, water layer is regulated pH to 5～8 with alkali lye, chloroform collection water layer, dry the concentrating of chloroform layer makes 2-amino-5-bromine isonicotinic acid methyl esters;
(5) the 2-amino that step (4) is obtained-5-bromine isonicotinic acid methyl esters is dissolved in the dilution heat of sulfuric acid, drips sodium nitrite in aqueous solution, stirs, and reaction finishes, suction filtration, and filtrating transfers to neutrality, chloroform extraction, chloroform layer is dry to be concentrated; Enriched material and filter cake are merged into bullion; Bullion is crossed the silica gel filter bed, concentrate 5-bromo-2-hydroxy-isonicotinic acid methyl esters;
Above-described vitriol oil concentration massfraction is 97%-99%, and dilute sulphuric acid concentration massfraction is 8%-9%.
2. preparation method as claimed in claim 1 is characterized in that, in the step (1), the mol ratio of 2-amino-5-bromo-4-picoline and ydrogen peroxide 50 is 1: 10～30, preferred 1: 18; The temperature that the mixed solution of the vitriol oil and ydrogen peroxide 50 splashes into 2-amino-5-bromo-4-picoline sulphuric acid soln is controlled at 0～15 ℃.
3. preparation method as claimed in claim 1 is characterized in that, in the step (2), the mol ratio of 5-bromo-4-methyl-2-nitropyridine and sodium dichromate 99 is 1: 1～4, preferred 1: 2.5; Temperature of reaction is 0～40 ℃, and the reaction times is 3～10 hours.
4. preparation method as claimed in claim 1 is characterized in that, in the step (3), and 5-bromo-2-nitro Yi Yansuan, the mol ratio of methyl alcohol and sulfur oxychloride is 1: (15～40): (1～3), preferred 1: 24: 1.6; Temperature of reaction is 0～25 ℃, and the reaction times is 1～5 hour.
5. preparation method as claimed in claim 1 is characterized in that, in the step (4), the mol ratio of 5-bromo-2-nitro iso methyl nicotinate and reduced iron powder is 1: 1～6, and temperature of reaction is 60～80 ℃, and the reaction times is 2～6 hours; Water layer is regulated the pH value with alkali during crude product refining, preferred pH=6.
6. preparation method as claimed in claim 1 is characterized in that, in the step (5), the mol ratio of 2-amino-5-bromine isonicotinic acid methyl esters and Sodium Nitrite is 1: 1～10, and temperature of reaction is 0～40 ℃, and the reaction times is 1～5 hour.
7. preparation method as claimed in claim 1 is characterized in that step is following:
(1) the 1500ml vitriol oil slowly is added drop-wise to is equipped with in the Erlenmeyer flask of 5L that the 750ml massfraction is 30% ydrogen peroxide 50, controlled temperature is smaller or equal to 20 ℃ in the dropping process, and it is ℃ subsequent use to dropwise postcooling to 5; 0.535mol 2-amino-5-bromo-4-picoline is added in the 2550ml vitriol oil, is cooled to zero degree; The reserve liquid of last step preparation slowly is added drop-wise in the mixed solution, and controlled temperature drips off temperature control and stirred 30 minutes for 5 ℃ 15 ℃ at 5 ℃ 15 ℃, and room temperature reaction is 3 hours then; After reaction finishes, reaction solution is poured in the mixture of ice and water, regulated pH to 7～8, separate out a large amount of faint yellow solids with NaOH solution, suction filtration, filter cake is with a small amount of washing; 45 ℃ dry 5-bromo-4-methyl-2-nitropyridine 104.6g;
(2) 0.461mol 5-bromo-4-methyl-2-nitropyridine is dissolved in the 1.5L vitriol oil, ice-water bath slowly adds 1.164mol Na
2Cr
2O
72H
2O finishes, and stirring at room 6 hours is poured in 2 kilograms of trash ices, has solid to separate out, suction filtration, filter cake washs with less water, 70 ℃ dry 5-bromo-2-nitro Yi Yansuan 71g, faint yellow solid; Filtrating is used the 2L chloroform extraction, anhydrous sodium sulfate drying, and evaporated under reduced pressure gets 5-bromo-2-nitro Yi Yansuan 14.4g, merges yield 75%;
(3) 0.344mol 5-bromo-2-nitro Yi Yansuan is dissolved in 340ml methyl alcohol, temperature control≤28 ℃ slowly splash into the 40ml sulfur oxychloride in constant pressure funnel, and temperature control≤25 ℃ finished the back back flow reaction 2.5 hours; After reaction finishes, steam and remove most of methyl alcohol, cooling; Add 1L water, diluted sodium hydroxide solution is regulated pH to 7～8,200ml ETHYLE ACETATE collection water layer 2 times; The combined ethyl acetate layer, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent get khaki color solid 77g; Be 5-bromo-2-nitro iso methyl nicotinate, yield 85%;
(4) in the four-hole bottle of 1L, add 85ml water, add the 1.209mol reduced iron powder, N
2Be heated to 70 ℃ under the protective condition and add the 35ml Glacial acetic acid min. 99.5,70 ℃ of insulation activation add 140ml ethanol after 30 minutes, be warming up to 75～80 ℃, add 0.285mol 5-bromo-2-nitro iso methyl nicotinate in batches; Added 75～80 ℃ of insulation reaction in back 4 hours, cooling is filtered; Filtrate decompression is steamed and is removed most of ethanol, and filter cake washes twice with the 150ml chloroform, merging filtrate and washing lotion; Water, saturated sodium bicarbonate, water are respectively washed once successively, and anhydrous sodium sulfate drying, concentrating under reduced pressure get yellow-green colour solid 58.3g; This bullion is dissolved in the 100ml chloroform, and with 1N salt pickling 2 times, water layer is regulated pH to 6 with sodium bicarbonate solid; Come together 3 times combined chloroform layer, anhydrous sodium sulfate drying again with chloroform; Evaporated under reduced pressure gets faint yellow 2-amino-5-bromine isonicotinic acid ester solid 52.8g, yield 80%;
(5) 0.216mol 2-amino-5-bromine isonicotinic acid ester is joined be equipped with in the there-necked flask that the 875ml massfraction is 9% dilute sulphuric acid and 1 kilogram of trash ice, ice bath is cooled to about 0 ℃, stirs slowly to splash into 1.710mol sodium nitrite in aqueous solution 175ml down; 20 ℃ of following stirring reactions 2 hours, suction filtration, filter cake is washed once; Merging filtrate and washing lotion are regulated PH to 6～7; Use chloroform extraction, anhydrous sodium sulfate drying concentrates; Filtrating enriched material and filter cake are merged into 5-bromo-2-hydroxy-isonicotinic acid methyl esters bullion; Product is dissolved in chloroform, filters the chloroform wash-out with the silica gel filter bed; Use the volume ratio methylene dichloride: the tlc inspection of ETHYLE ACETATE=10: 1 does not have product in filtrating; Concentrating under reduced pressure gets 5-bromo-2-hydroxy-isonicotinic acid methyl esters 45.5g, yellow solid, productive rate 91%;
Above-described vitriol oil concentration massfraction is 98～98.5%, and dilute sulphuric acid concentration massfraction is 9%.
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| CN 201110216668 CN102321016B (en) | 2011-07-29 | 2011-07-29 | Synthesis method of 5-bromo-2-methyl hydroxypyridinecarboxylate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103880740A (en) * | 2014-04-14 | 2014-06-25 | 西华大学 | Synthesis of 4-nitro-3-hydroxy-2-picolinic acid |
| CN106187867A (en) * | 2016-07-14 | 2016-12-07 | 济南贝莱尔化学科技有限公司 | A kind of preparation method of 2 nitro 5 bromopyridines |
| CN106187781A (en) * | 2016-07-11 | 2016-12-07 | 江苏红豆杉药业有限公司 | A kind of preparation method of memantine |
| CN112441968A (en) * | 2020-12-23 | 2021-03-05 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2-amino-3-bromoisonicotinic acid methyl ester |
| CN115557886A (en) * | 2022-10-09 | 2023-01-03 | 山西永津集团有限公司 | Synthetic method of 3-nitroisonicotinic acid methyl ester |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103880740A (en) * | 2014-04-14 | 2014-06-25 | 西华大学 | Synthesis of 4-nitro-3-hydroxy-2-picolinic acid |
| CN103880740B (en) * | 2014-04-14 | 2016-02-17 | 西华大学 | The synthesis of 4-nitro-3-hydroxyl-2-pyridine carboxylic acid |
| CN106187781A (en) * | 2016-07-11 | 2016-12-07 | 江苏红豆杉药业有限公司 | A kind of preparation method of memantine |
| CN106187781B (en) * | 2016-07-11 | 2018-07-13 | 江苏红豆杉药业有限公司 | A kind of preparation method of memantine |
| CN106187867A (en) * | 2016-07-14 | 2016-12-07 | 济南贝莱尔化学科技有限公司 | A kind of preparation method of 2 nitro 5 bromopyridines |
| CN106187867B (en) * | 2016-07-14 | 2018-08-10 | 济南贝莱尔化学科技有限公司 | A kind of preparation method of 2- nitros -5- bromopyridines |
| CN112441968A (en) * | 2020-12-23 | 2021-03-05 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2-amino-3-bromoisonicotinic acid methyl ester |
| CN112441968B (en) * | 2020-12-23 | 2022-05-10 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2-amino-3-bromoisonicotinic acid methyl ester |
| CN115557886A (en) * | 2022-10-09 | 2023-01-03 | 山西永津集团有限公司 | Synthetic method of 3-nitroisonicotinic acid methyl ester |
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