CN103880694A - Preparation method of 2-hydroxy-5-aminobenzoic acid - Google Patents
Preparation method of 2-hydroxy-5-aminobenzoic acid Download PDFInfo
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- CN103880694A CN103880694A CN201410097501.6A CN201410097501A CN103880694A CN 103880694 A CN103880694 A CN 103880694A CN 201410097501 A CN201410097501 A CN 201410097501A CN 103880694 A CN103880694 A CN 103880694A
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Abstract
The invention provides a preparation method of 2-hydroxy-5-aminobenzoic acid, comprises the following steps: carrying out Kolbe-Schmitt reaction on p-aminophenol as an initial raw material to obtain the target compound with high yield under the effect of a catalytic carrier or solid alkali or under the direct catalytic carrier effect on the p-aminophenol. The path is simple and short, the used catalytic carrier is capable of improving the heat transfer effect, reducing the energy consumption and improving the yield. Furthermore, the catalytic carrier is non-wear to the equipment, the security is improved, the purifying treatment is convenient, and the preparation method is suitable for the industrial production.
Description
Technical field
The invention belongs to the synthetic of organic compound, relate generally to the method that Kolbe-Schmitt catalytic reaction is prepared 2-hydroxyl-5-benzaminic acid.
Technical background
2-hydroxyl-5-benzaminic acid (or 5-aminosalicylic acid) is a kind of important medicine and dyestuff intermediate, itself also has medical simultaneously, the choice drug that was approved as treatment colitis as far back as 1981 by U.S. FDA, medicine name is mesalazine (Mesalazine).2-hydroxyl-5-benzaminic acid, owing to having amino, hydroxyl and three active reactive groups of carboxyl on ring, can be carried out multiple reaction.Therefore,, at dyestuffs industries, it can be used for manufacturing the reactive dyestuffs of multiple good quality.
At present bibliographical information 2-hydroxyl-5-benzaminic acid synthetic mainly contains following three kinds of methods: (1) aniline synthesis method, and the method is taking aniline as starting raw material, and through diazotization, coupling restores and obtains, and this route is long, yield is lower.In addition, aniline toxicity is larger, and easily brings in finished product, is difficult for refining removing, and environment is also had to certain hazardness; (2) nitrosalicylic acid reduction method, the method is taking Whitfield's ointment as starting raw material, first obtain 5-NITROSALICYLIC ACID through nitric acid nitrating, be then amino with iron powder reducing nitro under acidic conditions, separates out after treatment 2-hydroxyl-5-benzaminic acid under solutions of weak acidity, this route total recovery about 50%, route is simple, but easily produces isomer in nitrifying process, causes later stage purification difficult, owing to having used a large amount of nitric acid and iron powder in reaction, three-waste pollution is comparatively serious; (3) Kolbe-Schmitt synthesis method, this method be under High Temperature High Pressure with carbon dioxide reaction, generate 2-hydroxyl-5-benzaminic acid.Utilize this method, Chinese Journal of Pharmaceuticals, 1997,28 (8), the 341-342 not people such as fragrant pearl reported taking p-aminophenol as raw material, under High Temperature High Pressure with carbon dioxide reaction, although this technique route is brief, yield is high, but catalyzer the unknown, and aftertreatment is loaded down with trivial details, has brought inconvenience to production; Indian patent IN2004MU01242 has reported taking acamol as starting raw material, under High Temperature High Pressure, under solid alkali and carbonic acid gas existence, carry out carboxylation reaction, this method reaction times is longer, energy consumption is higher, the contact of the two phase reaction of gas-solid is simultaneously bad, the easy local superheating charing of reaction mass; CN102126977 has invented a kind of preparing 5-aminosalicylic acid by adopting gas phase catalysis carboxylation, it is to pass into carbonic acid gas in acamol and basic cpd system, but this technique has been used catalytic carrier, catalytic carrier silicon oxide, molecular sieve, aluminium sesquioxide, quartz sand and diatomite may have certain wearing and tearing to reactor wall, concerning reaction under high pressure, risk increases; CN102731334 discloses a kind of method of preparing 5-aminosalicylic acid: the 1-butyl-3-Methylimidazole ionic liquid that p-aminophenol sodium is dissolved in to chlorination, then pass into carbon dioxide to ionic liquid, reaction at 120～200 DEG C of pressure 0.5～3MPa, temperature, makes 5-aminosalicylic acid.But the method uses ionic liquid to increase reaction cost and p-aminophenol sodium water absorbability is too strong, is unfavorable for scale operation; Last Asian J.Chem., 2011,23 (9), pp3819-3823 report uses supercritical CO
2the method of gas generation 5-aminosalicylic acid, but the method need to be 140 DEG C of high temperature, and high pressure 9.0Mpa, reacts 2.5 hours under high rotating speed 300rpm condition.
Therefore, the 2-of the applicable large-scale industrial production of developing low-cost, stability and safety hydroxyl-5-benzaminic acid operational path has important meaning.
Summary of the invention
The object of the invention is to find a kind of price catalytic carrier relatively cheap, that autoclave wall machinery-free is worn and torn, for the suitability for industrialized production of 2-hydroxyl-5-benzaminic acid.
The object of the invention is to realize by following technical solution:
Under catalytic carrier effect, p-aminophenol or its salt and carbon dioxide reaction, obtain 2-hydroxyl-5-aminobenzoate, after dissociating, obtains 2-hydroxyl-5-aminobenzoic acid compound, when reactant is p-aminophenol, need add solid alkali; When reactant is p-aminophenyl phenates, wherein salt is selected from sodium salt or sylvite, without adding solid alkali;
More than reaction is carried out conventionally under High Temperature High Pressure, and reaction pressure is controlled at 1.0～3.0MPa, preferably 1.5～2.5MPa; Temperature of reaction is controlled at 180～220 DEG C, preferably 190～200 DEG C;
Catalytic carrier described in the method is selected from sodium-chlor, Repone K, magnesium chloride, calcium chloride, sodium sulfate, potassium sulfate or magnesium sulfate, preferably sodium-chlor and Repone K; The mol ratio of p-aminophenol and catalytic carrier consumption is 1: 1～1: 15, preferably 1: 1～1: 5;
Solid alkali described in the method is selected from sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate or sodium isopropylate; The mol ratio of p-aminophenol and solid alkali consumption is 1: 1～1: 8, preferably 1: 1～1: 3.
The present invention also provides a kind of post-treating method of 2-hydroxyl-5-aminobenzoic acid compound, and the 2-that reaction is obtained hydroxyl-5-aminobenzoic acid compound, further uses water dissolution, add a kind of reductive agent to stir, filter, filtrate acid adding regulates, and separates out 2-hydroxyl-5-benzaminic acid solid.
Reductive agent described in the method is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, V-Brite B, S-WAT, sodium sulphite, ferrous sulfate or tin protochloride, preferably V-Brite B;
Filtrate acid adding described in the method regulates, preferably pH regulator to 1.0～6.0, and wherein acid is sulfuric acid, hydrochloric acid or nitric acid, preferably hydrochloric acid.
The invention provides preferred technical scheme as follows:
A preparation method for 2-hydroxyl-5-benzaminic acid, at catalytic carrier (as: salt such as NaCl, KCl) and solid alkali (as: Na
2cO
3, K
2cO
3in alkali) effect under, p-aminophenol is (as: 1.0～3.0MPa under High Temperature High Pressure, 180～220 DEG C) and carbon dioxide reaction, after reaction finishes, water dissolution system, adds a kind of reductive agent (as: V-Brite B) to stir, and filters, filtrate, with acid for adjusting pH 1.0～6.0, is separated out 2-hydroxyl-5-benzaminic acid solid.
2-hydroxyl-5-benzaminic acid solid optionally further water making beating obtains more highly purified sterling, meets EP or USP standard.
Reaction formula of the present invention is as follows:
Present method is prepared 2-hydroxyl-5-benzaminic acid and is had the following advantages:
1, the raw material such as reaction mass, catalytic carrier and solid alkali is simple and easy to get and cost value is cheap;
2, single step reaction, with short production cycle, post-processing operation convenient, be applicable to industrial amplification production;
3, high, the HPLC purity good (more than 99.0%) of yield, and easily refining;
4, catalytic carrier has reduced the wearing and tearing to high-tension apparatus, has improved security.
Embodiment
The present invention is further described in conjunction with the embodiments.Following examples just illustrate the present invention, and not limit by any way the present invention.
Embodiment 1: add 16g p-aminophenol, 43g NaCl, 47g Na in autoclave
2cO
3, after feeding in raw material, use carbon dioxide replacement reaction kettle three times, then punching press, to 1.0MPa, is slowly warming up to 200 DEG C, reacts 6 hours at this temperature.After question response finishes, when cooling down to 50 DEG C, reactor is opened in pressure release, in reactor, adds 200mL SODIUM HYDROSULPHITE sodium solution, stir again 1～2 hour, filtering insolubles, filtrate is used salt acid for adjusting pH to 1.0～6.0, separate out solid, filter, obtain gray solid crude product.This crude product is pulled an oar in water, obtain off-white color solid, yield 90%, purity 99.1%; Fusing point: 279-281 DEG C (dec).
1H?NMR(400MHz，DMSO-d
6)：δ＝7.12(s，1H，ArH)，6.86-6.83(m，1H，ArH)，6.68(d，1H，J＝8.8Hz，ArH).
Embodiment 2: add 16g p-aminophenol, 11g KCl, 20g K in autoclave
2cO
3, after feeding in raw material, use carbon dioxide replacement reaction kettle three times, then punching press, to 3.0MPa, is slowly warming up to 180 DEG C, reacts 6 hours at this temperature.After question response finishes, when cooling down to 50 DEG C, reactor is opened in pressure release, in reactor, adds 200mL SODIUM HYDROSULPHITE sodium solution, stir again 1～2 hour, filtering insolubles, filtrate is with acid for adjusting pH to 1.0～6.0, separate out solid, filter, obtain gray solid crude product.This crude product is pulled an oar in water, obtain off-white color solid, yield 88%, purity 99.3%.
Embodiment 3: add 16g p-aminophenol, 163g KCl, 162g K in autoclave
2cO
3, after feeding in raw material, use carbon dioxide replacement reaction kettle three times, then punching press, to 1.5MPa, is slowly warming up to 220 DEG C, reacts 6 hours at this temperature.After question response finishes, when cooling down to 50 DEG C, reactor is opened in pressure release, in reactor, adds 200mL SODIUM HYDROSULPHITE sodium solution, stir again 1～2 hour, filtering insolubles, filtrate is with acid for adjusting pH to 1.0～6.0, separate out solid, filter, obtain gray solid crude product.This crude product is pulled an oar in water, obtain off-white color solid, yield 86%, purity 99.5%.
Embodiment 4: add 16g p-aminophenol in autoclave, 9g potassium hydroxide solution, after completion of the reaction the aqueous solution is steamed, add again 11g KCl stirring and evenly mixing, after reinforced, use carbon dioxide replacement reaction kettle three times, then punching press is to 2.5MPa, slowly be warming up to 190 DEG C, at this temperature, react 6 hours.After question response finishes, when cooling down to 50 DEG C, reactor is opened in pressure release, in reactor, adds 200mL SODIUM HYDROSULPHITE sodium solution, stir again 1～2 hour, filtering insolubles, filtrate is with acid for adjusting pH to 1.0～6.0, separate out solid, filter, obtain gray solid crude product.This crude product is pulled an oar in water, obtain off-white color solid, yield 89%, purity 99.2%.
Embodiment 5: add 16g p-aminophenol in autoclave, 6g sodium hydroxide solution, after completion of the reaction the aqueous solution is steamed, add again 164g KCl stirring and evenly mixing, after reinforced, use carbon dioxide replacement reaction kettle three times, then punching press is to 1.8MPa, slowly be warming up to 200 DEG C, at this temperature, react 6 hours.After question response finishes, when cooling down to 50 DEG C, reactor is opened in pressure release, in reactor, adds 200mL SODIUM HYDROSULPHITE sodium solution, stir again 1～2 hour, filtering insolubles, filtrate is with acid for adjusting pH to 1.0～6.0, separate out solid, filter, obtain gray solid crude product.This crude product is pulled an oar in water, obtain off-white color solid, yield 85%, purity 99.6%.
Embodiment 6: add 16g p-aminophenol, 88g KCl, 32g sodium methylate in autoclave, after feeding in raw material, use carbon dioxide replacement reaction kettle three times, then punching press, to 2.0MPa, is slowly warming up to 195 DEG C, reacts 6 hours at this temperature.After question response finishes, when cooling down to 50 DEG C, reactor is opened in pressure release, in reactor, adds 200mL SODIUM HYDROSULPHITE sodium solution, stir again 1～2 hour, filtering insolubles, filtrate is with acid for adjusting pH to 1.0～6.0, separate out solid, filter, obtain gray solid crude product.This crude product is pulled an oar in water, obtain off-white color solid, yield 86%, purity 99.5%.
Embodiment 7: add 16g p-aminophenol, 63g sodium sulfate, 16g sodium methylate in autoclave, after feeding in raw material, use carbon dioxide replacement reaction kettle three times, then punching press, to 3.0MPa, is slowly warming up to 180 DEG C, reacts 6 hours at this temperature.After question response finishes, when cooling down to 50 DEG C, reactor is opened in pressure release, in reactor, adds 200mL SODIUM HYDROSULPHITE sodium solution, stir again 1～2 hour, filtering insolubles, filtrate is used sulphur acid for adjusting pH to 1.0～6.0, separate out solid, filter, obtain gray solid crude product.This crude product is pulled an oar in water, obtain off-white color solid, yield 86%, purity 99.4%.
Embodiment 8: add 16g p-aminophenol, 312g sodium sulfate, 8g sodium methylate in autoclave, after feeding in raw material, use carbon dioxide replacement reaction kettle three times, then punching press, to 1.8MPa, is slowly warming up to 200 DEG C, reacts 6 hours at this temperature.After question response finishes, when cooling down to 50 DEG C, reactor is opened in pressure release, in reactor, adds 200mL SODIUM HYDROSULPHITE sodium solution, stir again 1～2 hour, filtering insolubles, filtrate is with acid for adjusting pH to 1.0～6.0, separate out solid, filter, obtain gray solid crude product.This crude product is pulled an oar in water, obtain off-white color solid, yield 87%, purity 99.6%.
In sum, the feature such as it is simple, easy to operate that 2-hydroxyl-5-benzaminic acid of the present invention has technique, and production efficiency is high, and application prospect is wide, is adapted to suitability for industrialized production.
Claims (11)
1. a preparation method for 2-hydroxyl-5-benzaminic acid, is characterized in that: under catalytic carrier effect, p-aminophenol or its salt and carbon dioxide reaction, obtain 2-hydroxyl-5-aminobenzoate, after dissociating, obtains 2-hydroxyl-5-aminobenzoic acid compound.
2. preparation method according to claim 1, is characterized in that: when reactant is p-aminophenol, need add solid alkali; When reactant is p-aminophenyl phenates, wherein salt is selected from sodium salt or sylvite, without adding solid alkali.
3. preparation method according to claim 1, is characterized in that: described reaction is carried out under High Temperature High Pressure, and reaction pressure is 1.0～3.0MPa, preferably 1.5～2.5Mpa, and temperature of reaction is controlled at 180～220 DEG C, preferably 190～200 DEG C.
4. preparation method according to claim 1, is characterized in that: 2-hydroxyl-5-aminobenzoate that reaction is obtained, and by water dissolution, add a kind of reductive agent to stir, to filter, filtrate acid adding regulates, and separates out 2-hydroxyl-5-benzaminic acid solid.
5. preparation method according to claim 1, is characterized in that: described catalytic carrier is selected from sodium-chlor, chlorination clock, magnesium chloride, calcium chloride, sodium sulfate, potassium sulfate or magnesium sulfate, preferably sodium-chlor and Repone K.
6. preparation method according to claim 2, is characterized in that: described solid alkali is selected from sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate or sodium isopropylate.
7. preparation method according to claim 1, is characterized in that: the mol ratio of described p-aminophenol and catalytic carrier consumption is 1: 1～1: 15, preferably 1: 1～1: 5.
8. preparation method according to claim 2, is characterized in that: the mol ratio that described p-aminophenol and solid alkali feed intake is 1: 1～1: 8, preferably 1: 1～1: 3.
9. preparation method according to claim 4, is characterized in that: described reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, V-Brite B, S-WAT, sodium sulphite, ferrous sulfate or tin protochloride.
10. preparation method according to claim 4, is characterized in that, described filtrate acid adding regulates, and is adjusted to 1.0～6.0, and wherein acid is sulfuric acid, hydrochloric acid or nitric acid, preferably hydrochloric acid.
The preparation method of 11. 1 kinds of 2-hydroxyl-5-benzaminic acid, it is characterized in that, under catalytic carrier and solid alkali effect, p-aminophenol is at 1.0～3.0MPa, at 180～220 DEG C with carbon dioxide reaction, after reaction finishes, water dissolution system, adds reductive agent to stir, filter, filtrate regulates with acid, separates out 2-hydroxyl-5-benzaminic acid solid, and this solid water making beating is obtained sterling by selectivity.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106478444A (en) * | 2015-08-26 | 2017-03-08 | 盐城市瓯华化学工业有限公司 | A kind of method that use chlorination sodium reduction produces 2- acetylaminohydroxyphenylarsonic acid 6- nitrobenzoic acid |
| CN108929240A (en) * | 2018-08-20 | 2018-12-04 | 浙江三门恒康制药有限公司 | A kind of preparation method of 2- hydroxyl -5- aminobenzoic acid |
| CN113004876A (en) * | 2021-02-25 | 2021-06-22 | 西南石油大学 | Carbon dioxide/calcium oxide responsive emulsifier, reversible emulsion and reversible drilling fluid, and preparation and application thereof |
| CN114605277A (en) * | 2022-04-18 | 2022-06-10 | 宁波怡和医药科技有限公司 | Synthesis method of mesalazine |
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| CN102126977A (en) * | 2010-12-25 | 2011-07-20 | 浙江华海药业股份有限公司 | Method for preparing 5-aminosalicylic acid by adopting gas phase catalysis carboxylation method |
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2014
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| CN102126977A (en) * | 2010-12-25 | 2011-07-20 | 浙江华海药业股份有限公司 | Method for preparing 5-aminosalicylic acid by adopting gas phase catalysis carboxylation method |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106478444A (en) * | 2015-08-26 | 2017-03-08 | 盐城市瓯华化学工业有限公司 | A kind of method that use chlorination sodium reduction produces 2- acetylaminohydroxyphenylarsonic acid 6- nitrobenzoic acid |
| CN108929240A (en) * | 2018-08-20 | 2018-12-04 | 浙江三门恒康制药有限公司 | A kind of preparation method of 2- hydroxyl -5- aminobenzoic acid |
| CN108929240B (en) * | 2018-08-20 | 2019-08-30 | 浙江三门恒康制药有限公司 | A kind of preparation method of 2- hydroxyl -5- aminobenzoic acid |
| CN113004876A (en) * | 2021-02-25 | 2021-06-22 | 西南石油大学 | Carbon dioxide/calcium oxide responsive emulsifier, reversible emulsion and reversible drilling fluid, and preparation and application thereof |
| CN114605277A (en) * | 2022-04-18 | 2022-06-10 | 宁波怡和医药科技有限公司 | Synthesis method of mesalazine |
| CN114605277B (en) * | 2022-04-18 | 2022-10-11 | 宁波怡和医药科技有限公司 | Synthesis method of mesalazine |
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