CN101792387B - Preparation method of 2,3,4-trimethoxybenzoic acid - Google Patents
Preparation method of 2,3,4-trimethoxybenzoic acid Download PDFInfo
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Abstract
The invention relates to a preparation method of 2,3,4-trimethoxybenzoic acid (TBA) shown as the following reaction equation. The method comprises the following steps of: methylating green chemical reagent dimethyl carbonate and coking gallic acid under the catalysis of ionic liquid, and then synthesizing the TBA through bromination, cyaniding and hydrolyzation, wherein the total yield of the TBA reaches 38.2%. The method has the advantages of low cost of raw materials and mild reaction condition and develops a route for synthesizing the TBA.
Description
Technical field
The present invention relates to the synthetic method of a kind of medicine intermediate 2,3,4 trimethoxybenzoic acid (TBA).
Background technology
TBA is very extensive as a kind of important medicine intermediate purposes, and demand is increasing, therefore, develops an effective synthetic route also very necessary.
Make a general survey of report both domestic and external and mainly contain two about the synthetic route of TBA: (1) is to be raw material with 2,3,4-trihydroxybenzoic acid, obtains through Hypermethylation with methyl-sulfate, and in this method, methyl-sulfate used is severe poisonous chemicals, pollutes large.(2) be with 2,3, the 4-TMB obtains through peroxidation, and raw materials cost is high, stoichiometric solid oxidizing agent used, production process produce a large amount of paste-like residue and spent acid in oxidising process but also exist, and the corrosion of equipment is the problem such as quite serious also.
Summary of the invention
The route that the purpose of this invention is to provide a more perfect synthetic TBA is to satisfy the industrial production needs.Advantage of the present invention is as follows: raw material pyrogallol PA used in etherification procedure is less expensive, and wide material sources, DMC are a kind of non-toxic and non-pollution green chemicals, seldom to environment; Imidazoles catalyzer [Bmim] Br that uses is also a kind of green chemical, and easy and product separation, slightly deals with reusable edible; The raw material NBS that uses in bromo and cyaniding process is relative with the CuCN toxic action lower, and environmental pollution is also less; Hydrolysis reaction easily occurs in basic solution.
The inventive method is synthesized into medicine intermediate TBA take DMC and PA as raw material through four step precision work.
Present method comprises following reaction equation:
Concrete steps are as follows:
(1) methylcarbonate DMC and pyrogallol (PA) and ionic liquid are placed in withstand voltage reactor and magnetic agitation, react 7h under 150 ℃, finish, be cooled to room temperature, then decompression steams lower boiling methylcarbonate DMC and methyl alcohol, again with the extracted with diethyl ether 3 times that doubles the original solution volume, combining extraction liquid, rear extraction liquid is placed in that under low temperature, crystallization must connect the trityl ether crude product, this crude product is dissolved in the sherwood oil that doubles former crude product quality, add gac, wherein the quality of gac is the 3-10% of crude product quality, heat filtering after 40 ℃ of left and right heating 30min, use again and appropriate petroleum ether filter paper, boil off and put into the refrigerator crystallization after the part sherwood oil and namely get the white trityl ether sterling that connects, described ionic-liquid catalyst is [Bmim] Br, and the ratio of the amount of substance of described ionic-liquid catalyst [Bmim] Br and pyrogallol PA is 0.5-2: 1, the ratio of the amount of substance of described methylcarbonate DMC and pyrogallol PA is 3-9: 1,
(2) will connect trityl ether is dissolved in DMF, add NBS under lower than 20 ℃ in batches, insulation 0.5-1h, after mixed solution poured into told organic phase in suitable quantity of water, water layer is with the extracted with diethyl ether that doubles original solution volume 2-3 time, merge organic phase, add again anhydrous sodium sulfate drying, suction filtration, solid is washed 1-2 time with appropriate ether, rotation is steamed except ether, gets the 4-bromine and connects trityl ether; The amount of wherein said solvent DMF is about the summation of two kinds of raw materials quality; Described NBS is 1-2 with the amount of substance ratio that connects trityl ether: 1; The quality of described anhydrous sodium sulphate is the 10-20% of raw materials quality;
(3) CuCN is dissolved in DMF, stirs and add the 4-bromine to connect trityl ether, be heated to 120 ℃ of reaction 4-5h, then be warmed up to 160 ℃ of approximately 4h that reflux, finish, be cooled to room temperature, add proper ammonia and stir during 1h falls back, separate out solid, suction filtration.Filter cake is washed 2-3 time with a large amount of ammoniacal liquor, then with appropriate dehydrated alcohol recrystallization and add gac, wherein said quality of activated carbon is the 3-10% decolouring of original solution quality, filtered while hot, the cooling off-white color needle crystal 2,3 of namely separating out of filtrate, 4-trimethoxy cyanophenyl; The quality of wherein said solvent DMF is about the twice of two kinds of raw materials quality summations, and described raw material CuCN is 1-2 with the ratio that the 4-bromine connects the amount of substance of trityl ether: 1;
(4) add 2,3,4-trimethoxy cyanophenyl in the NaOH aqueous solution, 90-100 ℃ the reaction 24h, after be cooled to room temperature, suction filtration.Filtrate is with appropriate 1,2-ethylene dichloride extraction 2-3 time, and water is separated out solid with 10% hydrochloric acid accent pH to 2-3, suction filtration, drying namely gets the white products 2,3,4 trimethoxybenzoic acid; The ratio of the amount of substance of described sodium hydroxide and 2,3,4-trimethoxy-benzene cyanogen is 2.5-3: 1.
The present invention adopts Green Chemistry reagent methylcarbonate and pyrogallol to carry out methylation reaction under ionic liquid-catalyzed effect, then synthesizes TBA through bromination, cyaniding and hydrolysis, and the total recovery of TBA reaches 38.2%.Method raw material of the present invention is cheap, and reaction conditions is gentle, has opened up the route of a new synthetic TBA.
Embodiment:
Embodiment one:
1. take the 31.5g pyrogallol, 135g methylcarbonate DMC and 54.76g1-normal-butyl-3-Methylimidazole bromination body is placed in withstand voltage reactor and the magnetic agitation of 500mL, react 7h under 150 ℃, finish, be cooled to room temperature, then decompression steams lower boiling methylcarbonate DMC and methyl alcohol, use again ether (150mL * 3) extraction, combining extraction liquid, boil off the part ether and be placed on that under low temperature, crystallization must connect the trityl ether crude product, this crude product is dissolved in the 150mL sherwood oil, add the 5g gac a little heat (40 ℃ of left and right, heat filtering 30min), use again 30mL petroleum ether filter paper, boil off and put into the refrigerator crystallization after the part sherwood oil and namely get the white trityl ether sterling 38.9g that connects, yield is 92.6%.
2. add 35mLDMF in the 100mL four-hole boiling flask, 16.8g (0.1mol) connects trityl ether, stirs it is dissolved fully, adds 18.6g (0.105mol) NBS under 20 ℃ being no more than in batches, after, insulation reaction 0.5-1h.After question response is complete, product is poured into told organic phase in suitable quantity of water, water layer merges organic phase with ether (35mL * 3) extraction.With a certain amount of washing organic phase 2-3 time, then add the 5g anhydrous sodium sulfate drying, suction filtration, solid are with ether (30mL * 2) washing, and rotation is steamed except ether, gets light yellow transparent liquid 22.7g, and yield is 92%.
3. add 60mL DMF in the 150mL four-hole boiling flask, 8.8g (0.096mol) CuCN adds 20g (0.08mol) 4-bromine to connect trityl ether under stirring, is heated to 120 ℃ of reaction 4-5h, then is heated to approximately 4h of 160 ℃ of back flow reaction.Finish, be cooled to room temperature, add the ammoniacal liquor of 100mL, stir 1h.Be poured into water, separate out solid, suction filtration.The solid that obtains is washed 3 times with a large amount of ammoniacal liquor.The dehydrated alcohol recrystallization adds the 2.5g activated carbon decolorizing, filtered while hot, and the cooling crystallization of filtrate, suction filtration obtains off-white color needle crystal product 8.72g, and yield is 56%.
4. add 20mL water in the 100mL four-hole boiling flask, 3.4g (0.085mol) NaOH, stirring is fully dissolved it, then adds 5.4g (0.03mol) 2,3, and 4-trimethoxy cyanophenyl is heated to 90-100 ℃ of reaction 24h.Stopped heating is cooled to room temperature, suction filtration.Filtrate is transferred pH to 2-3 with 1,2-ethylene dichloride (25mL * 3) extraction, rear water with 10% HCl, separates out solid, suction filtration, and drying gets the 4.75g white products.The total recovery that above-mentioned four steps obtain product is 38.2%.
Embodiment two:
1. take the 31.5g pyrogallol, 135gDMC and 37.38g1-normal-butyl-3-Methylimidazole bromination body is placed in withstand voltage reactor and the magnetic agitation of 500mL, react 7h under 150 ℃, finish, be cooled to room temperature, then decompression steams lower boiling DMC and methyl alcohol, use again ether (150mL * 3) extraction, combining extraction liquid, boil off the part ether and be placed on that under low temperature, crystallization must connect the trityl ether crude product, this crude product is dissolved in the 150mL sherwood oil, add after the 5g gac heat (40 ℃ of left and right a little, heat filtering 30min), use again petroleum ether filter paper, boil off and put into the refrigerator crystallization after the part sherwood oil and namely get the white trityl ether sterling 38.9g that connects, yield is 92.6%.
2. add 35ml DMF in the 100mL four-hole boiling flask, 16.8g (0.1mol) connects trityl ether, stirs it is dissolved fully, adds 18.6g (0.105mol) NBS, insulation reaction 0.5-1h under 20 ℃ being no more than in batches.After question response is complete, product is poured into water tells organic phase, water layer merges organic phase with ether (35mL * 3) extraction.With a certain amount of washing organic phase 2-3 time, then add the 5g anhydrous sodium sulfate drying, suction filtration, solid are with ether (30mL * 2) washing, and rotation is steamed except ether, gets light yellow transparent liquid 22.7g, and yield is 92%.
3. add 60mL DMF in the 150mL four-hole boiling flask, 8.8g (0.096mol) CuCN adds 20g (0.08mol) 4-bromine to connect trityl ether under stirring, is heated to 120 ℃ of reaction 4-5h, then is heated to approximately 4h of 160 ℃ of back flow reaction.Finish, be cooled to room temperature, add the ammoniacal liquor of 100mL, stir 1h.Be poured into water, separate out solid, suction filtration.The solid that obtains is washed 3 times with a large amount of ammoniacal liquor.The dehydrated alcohol recrystallization adds the 2.5g activated carbon decolorizing, filtered while hot, and the cooling crystallization of filtrate, suction filtration obtains off-white color needle crystal product 8.72g, and yield is 56%.
4. add 20mL water in the 100mL four-hole boiling flask, 3.4g (0.085mol) NaOH, stirring is fully dissolved it, then adds 5.4g (0.03mol) 2,3, and 4-trimethoxy cyanophenyl is heated to 90-100 ℃ of reaction 24h.Stopped heating is cooled to room temperature, suction filtration.Filtrate is transferred pH to 2-3 with 1,2-ethylene dichloride (25mL * 3) extraction, rear water with 10% HCl, separates out solid, suction filtration, and drying gets the 4.75g white products.The total recovery that above-mentioned four steps obtain product is 33%.
Embodiment three:
1. take the 31.5g pyrogallol, 67.5gDMC and 54.76g1-normal-butyl-3-Methylimidazole bromination body is placed in withstand voltage reactor and the magnetic agitation of 500mL, react 7h under 150 ℃, finish, be cooled to room temperature, decompression steams lower boiling DMC and methyl alcohol, use again ether (150mL * 3) extraction, combining extraction liquid, steam the part ether and be placed on that under low temperature, crystallization must connect the trityl ether crude product, this crude product is dissolved in the 150mL sherwood oil, add after the 5g gac heat (40 ℃ of left and right a little, 30min) heat filtering, use again petroleum ether filter paper, boil off and put into the refrigerator crystallization after the part sherwood oil and namely get the white trityl ether sterling 38.9g that connects, yield is 92.6%.
2. add 35mLDMF in the 100mL four-hole boiling flask, 16.8g (0.1mol) connects trityl ether, stirs it is dissolved fully, adds 18.6g (0.105mol) NBS under 20 ℃ being no more than in batches, after, insulation reaction 0.5-1h.After question response is complete, product is poured into water tells organic phase, water layer merges organic phase with ether (35mL * 3) extraction.With a certain amount of washing organic phase 2-3 time, then add the 5g anhydrous sodium sulfate drying, suction filtration, solid are with ether (30mL * 2) washing, and rotation is steamed except ether, gets light yellow transparent liquid 22.7g, and yield is 92%.
3. add 60mL DMF in the 150mL four-hole boiling flask, 8.8g (0.096mol) CuCN adds 20g (0.08mol) 4-bromine to connect trityl ether under stirring, is heated to 120 ℃ of reaction 4-5h, then is heated to approximately 4h of 160 ℃ of back flow reaction.Finish, be cooled to room temperature, add the ammoniacal liquor of 100mL, stir 1h.Be poured into water, separate out solid, suction filtration.The solid that obtains is washed 3 times with a large amount of ammoniacal liquor.The dehydrated alcohol recrystallization adds the 2.5g activated carbon decolorizing, filtered while hot, and the cooling crystallization of filtrate, suction filtration obtains off-white color needle crystal product 8.72g, and yield is 56%.
4. add 20mL water in the 100mL four-hole boiling flask, 3.4g (0.085mol) NaOH, stirring is fully dissolved it, then adds 5.4g (0.03mol) 2,3, and 4-trimethoxy cyanophenyl is heated to 90-100 ℃ of reaction 24h.Stopped heating is cooled to room temperature, suction filtration.Filtrate is transferred pH to 2-3 with 1,2-ethylene dichloride (25mL * 3) extraction, rear water with 10% HCl, separates out solid, suction filtration, and drying gets the 4.75g white products.The total recovery that above-mentioned four steps obtain product is 21.4%.
Claims (1)
1.2, the preparation method of 3,4-trimethoxybenzoic acid, shown in following reaction equation:
It is characterized in that concrete steps are as follows:
(1) methylcarbonate and pyrogallol and ionic liquid are placed in withstand voltage reactor and magnetic agitation, react 7h under 150 ℃, finish, be cooled to room temperature, then decompression steams lower boiling methylcarbonate and methyl alcohol, again with the extracted with diethyl ether 3 times that doubles the original solution volume, combining extraction liquid, extraction liquid is placed in that under low temperature, crystallization must connect the trityl ether crude product, this crude product is dissolved in the sherwood oil that doubles former crude product quality, add gac, wherein the quality of gac is the 3-10% of crude product quality, heat filtering after 40 ℃ of heating 30min, use again appropriate petroleum ether filter paper, boil off and put into the refrigerator crystallization after the part sherwood oil and namely get the white trityl ether sterling that connects, described ionic-liquid catalyst is [Bmim] Br, and the ratio of the amount of substance of described ionic-liquid catalyst [Bmim] Br and pyrogallol is 0.5-2: 1, the ratio of the amount of substance of described methylcarbonate and pyrogallol is 3-9: 1,
(2) will connect trityl ether is dissolved in DMF, add NBS under lower than 20 ℃ in batches, insulation 0.5-1h, after mixed solution poured into told organic phase in suitable quantity of water, water layer is with the extracted with diethyl ether that doubles original solution volume 2-3 time, merge organic phase, add again anhydrous sodium sulfate drying, suction filtration, solid is washed 1-2 time with appropriate ether, rotation is steamed except ether, gets the 4-bromine and connects trityl ether; The amount of wherein said solvent DMF is the summation of two kinds of raw materials quality; Described NBS is 1-2 with the amount of substance ratio that connects trityl ether: 1; The quality of described anhydrous sodium sulphate is the 10-20% of raw materials quality;
(3) CuCN is dissolved in DMF, stir and add the 4-bromine to connect trityl ether, be heated to 120 ℃ of reaction 4-5h, then be warmed up to 160 ℃ of backflow 4h, finish, be cooled to room temperature, add proper ammonia and stir during 1h falls back, separate out solid, suction filtration, filter cake is washed 2-3 time with a large amount of ammoniacal liquor, then with appropriate dehydrated alcohol recrystallization and add activated carbon decolorizing, wherein said quality of activated carbon is the 3-10% of original solution quality, filtered while hot, the cooling off-white color needle crystal 2,3 of namely separating out of filtrate, 4-trimethoxy cyanophenyl; The quality of wherein said solvent DMF is the twice of two kinds of raw materials quality summations, and described raw material CuCN is 1-2 with the ratio that the 4-bromine connects the amount of substance of trityl ether: 1;
(4) add 2,3,4-trimethoxy cyanophenyl in the NaOH aqueous solution, 90-100 ℃ the reaction 24h, after be cooled to room temperature, suction filtration; Filtrate is with appropriate 1,2-ethylene dichloride extraction 2-3 time, and water is separated out solid with 10% hydrochloric acid accent pH to 2-3, suction filtration, drying namely gets the white products 2,3,4 trimethoxybenzoic acid; The ratio of the amount of substance of described sodium hydroxide and 2,3,4-trimethoxy cyanophenyl is 2.5-3: 1.
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| CN104151157B (en) * | 2014-09-01 | 2016-08-24 | 联化科技(上海)有限公司 | A kind of preparation method of methoxybenzoic acid |
| CN105777565B (en) * | 2016-03-31 | 2017-09-22 | 盖领 | A kind of synthetic method of the aminobenzoic acid of 2 aldehyde radical 4 |
| CN109487297A (en) * | 2018-11-12 | 2019-03-19 | 新乡市珺隆生物科技有限公司 | The electrochemical applications of trimethoxy-benzene synthesis |
| CN113563163A (en) * | 2021-07-07 | 2021-10-29 | 南京伊派森化学科技有限公司 | Synthetic method of 5-bromo-1, 2, 3-trimethoxybenzene |
| CN113801009B (en) * | 2021-09-26 | 2022-12-20 | 武汉工程大学 | Method for catalyzing gallic acid methylation by using ionic liquid |
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| CN101265183A (en) * | 2008-04-25 | 2008-09-17 | 南京龙源天然多酚合成厂 | Method for preparing 2,3,4-trimethoxybenzoic acid |
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| CN101265183A (en) * | 2008-04-25 | 2008-09-17 | 南京龙源天然多酚合成厂 | Method for preparing 2,3,4-trimethoxybenzoic acid |
Non-Patent Citations (2)
| Title |
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| Sreedevi Mannam et al..CuCl catalyzed oxidation of aldehydes to carboxylic acids withaqueous tert-butyl hydroperoxide under mild conditions.《Tetrahedron Letters》.2007,第49卷第1083–1086页. * |
| 徐浩等.2,3,4-三甲氧基苯甲酸的合成研究.《林产化学与工业》.2008,第28卷(第3期),第91-93页. * |
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