CN103880694B - A kind of preparation method of the aminobenzoic acid of 2 hydroxyl 5 - Google Patents
A kind of preparation method of the aminobenzoic acid of 2 hydroxyl 5 Download PDFInfo
- Publication number
- CN103880694B CN103880694B CN201410097501.6A CN201410097501A CN103880694B CN 103880694 B CN103880694 B CN 103880694B CN 201410097501 A CN201410097501 A CN 201410097501A CN 103880694 B CN103880694 B CN 103880694B
- Authority
- CN
- China
- Prior art keywords
- preparation
- sodium
- acid
- reaction
- aminophenol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a kind of preparation method of the aminobenzoic acid of 2 hydroxyl 5, using para-aminophenol as initiation material, under catalytic carrier and solid base effect or p-aminophenyl phenates is directly under catalytic carrier effect, is reacted by Kolbe Schmitt and obtains target compound with higher yield.The catalytic carrier that route of the present invention is brief, uses improves heat-transfer effect, reduces energy consumption, improves yield.In addition, catalytic carrier to equipment without abrasion, security is improved, and purification process is convenient, suitable for industrialized production.
Description
Technical field
The invention belongs to the synthesis of organic compound, relates generally to Kolbe-Schmitt catalytic reactions and prepares 2- hydroxyl -5- ammonia
The method of yl benzoic acid.
Technical background
2- hydroxyl -5- aminobenzoic acids (or 5-aminosalicylic acid) are a kind of important medicine and dyestuff intermediate, simultaneously
Itself also has medical, has been approved by the FDA in the United States early in 1981 to treat the choice drug of colitis, medicine name is
Mesalazine (Mesalazine).2- hydroxyl -5- aminobenzoic acids are due to having amino, hydroxyl and carboxyl three active on ring
Reactive group, a variety of reactions can be carried out.Therefore, in dye industry, it can be used for manufacturing the activity of a variety of good quality
Dyestuff.
The synthesis of document report 2- hydroxyls -5- aminobenzoic acids at present mainly has following three kinds of methods：(1) aniline synthesizes
Method, this method is using aniline as initiation material, and through diazotising, coupling restores to obtain, and the route is longer, yield is relatively low.In addition, benzene
Amine toxicity is larger, and easily brings into finished product, is not easy refined removing, also there is certain harmfulness to environment；(2) nitro-salicylic acid is also
Former method, this method first obtain 5-NITROSALICYLIC ACID through nitric acid nitrating, then used in acid condition using salicylic acid as initiation material
Iron powder reducing nitro is amino, separates out 2- hydroxyl -5- aminobenzoic acids, the route total recovery under mildly acidic conditions after processing
About 50%, route is simple, but isomers is also easy to produce in nitrifying process, causes later-period purification difficult, due to making in reaction
It is more serious with a large amount of nitric acid and iron powder, three-waste pollution；(3) Kolbe-Schmitt synthetic methods, the method are at high temperature under high pressure
With carbon dioxide reaction, 2- hydroxyl -5- aminobenzoic acids are generated.Using this method, Chinese Journal of Pharmaceuticals, 1997,28 (8),
Not fragrant pearls of 341-342 et al. are reported using para-aminophenol as raw material, under HTHP with carbon dioxide reaction, the technique although
Route is brief, high income, but catalyst is unknown, and post processing is cumbersome, and inconvenience is brought to production；Indian patent
IN2004MU01242 is reported using acamol as initiation material, at high temperature under high pressure, in solid base and carbon dioxide
In the presence of carry out carboxylation reaction, the method reaction time is longer, and energy consumption is higher, at the same gas-particle two-phase reaction contact it is bad, reaction
The easy hot-spot charing of material；CN102126977 has invented a kind of preparing 5-aminosalicylic acid by adopting gas phase catalysis carboxylation, and it is
To be passed through carbon dioxide in acamol and alkali compounds system, but the technique has used catalytic carrier, and catalysis carries
Body silica, molecular sieve, alundum (Al2O3), quartz sand and diatomite may have certain abrasion to reactor wall, anti-to high pressure
For answering, risk increase；CN102731334 discloses a kind of method for preparing 5-aminosalicylic acid：By para-aminophenol sodium
Be dissolved in the 1- butyl -3- methylimidazole ionic liquids of chlorination, be then passed through carbon dioxide to ionic liquid, pressure 0.5~
Reacted at 3MPa, 120~200 DEG C of temperature, 5-aminosalicylic acid is made.But this method using ionic liquid add reaction into
Originally and para-aminophenol sodium hygroscopicity is too strong, is unfavorable for mass producing；Last Asian J.Chem., 2011,23 (9),
Pp3819-3823 reports use supercritical CO2The method that gas prepares 5-aminosalicylic acid, but this method is needed in high temperature
140 DEG C, react 2.5 hours under the conditions of high pressure 9.0Mpa, high rotating speed 300rpm.
Therefore, developing low-cost, the 2- hydroxyl -5- aminobenzoic acid works of stable safe suitable large-scale industrial production
Skill route has important meaning.
The content of the invention
The purpose of the present invention be find a kind of price it is relatively cheap, to catalytic carrier of the autoclave wall without mechanical wear, use
In the industrialized production of 2- hydroxyl -5- aminobenzoic acids.
The purpose of the present invention is achieved by the following technical solution：
Under catalytic carrier effect, para-aminophenol or its salt and carbon dioxide reaction, 2- hydroxyl -5- aminobenzoics are obtained
Hydrochlorate, 2- hydroxyl -5- aminobenzoic acid compounds are obtained after free, when reactant is para-aminophenol, solid base need to be added；Instead
When to answer thing be p-aminophenyl phenates, wherein salt is selected from sodium salt or sylvite, then need not add solid base；
More than reaction generally carries out at high temperature under high pressure, reaction pressure is controlled in 1.0~3.0MPa, preferably 1.5~
2.5MPa；Reaction temperature is controlled at 180~220 DEG C, preferably 190~200 DEG C；
Catalytic carrier described in this method is selected from sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium sulphate, potassium sulfate or sulphur
Sour magnesium, preferably sodium chloride and potassium chloride；The mol ratio of para-aminophenol and catalytic carrier dosage for 1: 1~1: 15, preferably 1: 1~
1∶5；
Solid base described in this method be selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, caustic alcohol or
Sodium isopropylate；The mol ratio of para-aminophenol and solid base amount is 1: 1~1: 8, preferably 1: 1~1: 3.
The present invention also provides a kind of post-processing approach of 2- hydroxyls -5- aminobenzoic acid compounds, the 2- that reaction is obtained
Hydroxyl -5- aminobenzoic acid compounds, are further dissolved with water, add a kind of reducing agent stirring, filtering, and filtrate acid adding is adjusted,
Separate out 2- hydroxyl -5- aminobenzoic acid solids.
Reducing agent described in this method be selected from sodium borohydride, potassium borohydride, sodium dithionite, sodium sulfite, vulcanized sodium,
Ferrous sulfate or stannous chloride, preferably sodium dithionite；
Filtrate acid adding regulation described in this method, best pH is adjusted to 1.0~6.0, wherein acid is sulfuric acid, hydrochloric acid or nitre
Acid, preferably hydrochloric acid.
It is as follows that the present invention provides preferable technical scheme：
A kind of preparation method of 2- hydroxyls -5- aminobenzoic acids, in catalytic carrier (such as：The salt such as NaCl, KCl) and solid base
(such as：Na2CO3、K2CO3Deng alkali) under effect, para-aminophenol is at high temperature under high pressure (such as：1.0~3.0MPa, 180~220 DEG C)
With carbon dioxide reaction, after reaction terminates, with water-soluble enzymatic hydrolysis system, a kind of reducing agent is added (such as：Sodium dithionite) stirring, mistake
Filter, filtrate separate out 2- hydroxyl -5- aminobenzoic acid solids with acid for adjusting pH 1.0~6.0.
2- hydroxyl -5- aminobenzoic acids solid selectivity be further beaten with water obtain the sterling of higher purity, meet
EP or USP standards.
The reaction equation of the present invention is as follows：
This method prepares 2- hydroxyl -5- aminobenzoic acids and had the following advantages：
1st, the raw material such as reaction mass, catalytic carrier and solid base is simple and easy to get and cost price is cheap；
2nd, single step reaction, with short production cycle, post-processing operation convenience, suitable industrial amplification production；
3rd, high income, HPLC purity are good (more than 99.0%), and easily refined；
4th, catalytic carrier reduces the abrasion to high-tension apparatus, improves security.
Embodiment
The present invention is further described in conjunction with the embodiments.Following examples simply illustrate the present invention, and not with any
Mode limits the present invention.
Embodiment 1：16g para-aminophenol, 43g NaCl, 47g Na are added in autoclave2CO3, after charging, use
Carbon dioxide replacement reaction kettle three times, then punching press to 1.0MPa, is to slowly warm up to 200 DEG C, and it is small to react 6 at this temperature
When.After question response terminates, when cooling down is to 50 DEG C, reactor is opened in pressure release, and 200mL hydrosulfurous acids are added toward reactor is interior
Sodium solution, it is stirred for 1~2 hour, filters out insoluble matter, filtrate is separated out solid, filtering, obtained with salt acid for adjusting pH to 1.0~6.0
Gray solid crude product.This crude product is beaten in water, obtains off-white powder, yield 90%, purity 99.1%；Fusing point：279-
281℃(dec)。
1H NMR (400MHz, DMSO-d6)：δ=7.12 (s, 1H, ArH), 6.86-6.83 (m, 1H, ArH), 6.68 (d,
1H, J=8.8Hz, ArH)
Embodiment 2：16g para-aminophenol, 11g KCl, 20g K are added in autoclave2CO3, after charging, with two
Carbon oxide gas replacement reaction kettle three times, then punching press to 3.0MPa, is to slowly warm up to 180 DEG C, and it is small to react 6 at this temperature
When.After question response terminates, when cooling down is to 50 DEG C, reactor is opened in pressure release, and 200mL hydrosulfurous acids are added toward reactor is interior
Sodium solution, it is stirred for 1~2 hour, filters out insoluble matter, filtrate is separated out solid, filtering, obtained grey with acid for adjusting pH to 1.0~6.0
Color solid crude product.This crude product is beaten in water, obtains off-white powder, yield 88%, purity 99.3%.
Embodiment 3：16g para-aminophenol, 163g KCl, 162g K are added in autoclave2CO3, after charging, use
Carbon dioxide replacement reaction kettle three times, then punching press to 1.5MPa, is to slowly warm up to 220 DEG C, and it is small to react 6 at this temperature
When.After question response terminates, when cooling down is to 50 DEG C, reactor is opened in pressure release, and 200mL hydrosulfurous acids are added toward reactor is interior
Sodium solution, it is stirred for 1~2 hour, filters out insoluble matter, filtrate is separated out solid, filtering, obtained grey with acid for adjusting pH to 1.0~6.0
Color solid crude product.This crude product is beaten in water, obtains off-white powder, yield 86%, purity 99.5%.
Embodiment 4：16g para-aminophenol, 9g potassium hydroxide solutions, after completion of the reaction by the aqueous solution are added in autoclave
Steam, add 11g KCl and stir and evenly mix, after charging, then punching press is extremely with carbon dioxide replacement reaction kettle three times
2.5MPa, 190 DEG C are to slowly warm up to, reacted 6 hours at this temperature.After question response terminates, when cooling down is to 50 DEG C, pressure release
Reactor is opened, 200mL hydrogensulfite solutions is added toward reactor is interior, is stirred for 1~2 hour, filters out insoluble matter, filtrate
With acid for adjusting pH to 1.0~6.0, solid is separated out, filtering, obtains gray solid crude product.This crude product is beaten in water, it is white to obtain class
Color solid, yield 89%, purity 99.2%.
Embodiment 5：16g para-aminophenol, 6g sodium hydroxide solutions, after completion of the reaction by the aqueous solution are added in autoclave
Steam, add 164g KCl and stir and evenly mix, after charging, with carbon dioxide replacement reaction kettle three times, then punching press
To 1.8MPa, 200 DEG C are to slowly warm up to, is reacted 6 hours at this temperature.After question response terminates, when cooling down is to 50 DEG C, let out
Pressure opens reactor, adds 200mL hydrogensulfite solutions toward reactor is interior, is stirred for 1~2 hour, filters out insoluble matter, filter
Liquid acid for adjusting pH separates out solid, filtering, obtains gray solid crude product to 1.0~6.0.This crude product is beaten in water, obtains class
White solid, yield 85%, purity 99.6%.
Embodiment 6：16g para-aminophenol, 88g KCl, 32g sodium methoxides are added in autoclave, after charging, with two
Carbon oxide gas replacement reaction kettle three times, then punching press to 2.0MPa, is to slowly warm up to 195 DEG C, and it is small to react 6 at this temperature
When.After question response terminates, when cooling down is to 50 DEG C, reactor is opened in pressure release, and 200mL hydrosulfurous acids are added toward reactor is interior
Sodium solution, it is stirred for 1~2 hour, filters out insoluble matter, filtrate is separated out solid, filtering, obtained grey with acid for adjusting pH to 1.0~6.0
Color solid crude product.This crude product is beaten in water, obtains off-white powder, yield 86%, purity 99.5%.
Embodiment 7：16g para-aminophenol, 63g sodium sulphate, 16g sodium methoxides are added in autoclave, after charging, is used
Carbon dioxide replacement reaction kettle three times, then punching press to 3.0MPa, is to slowly warm up to 180 DEG C, and it is small to react 6 at this temperature
When.After question response terminates, when cooling down is to 50 DEG C, reactor is opened in pressure release, and 200mL hydrosulfurous acids are added toward reactor is interior
Sodium solution, it is stirred for 1~2 hour, filters out insoluble matter, filtrate is separated out solid, filtering, obtained with sulphur acid for adjusting pH to 1.0~6.0
Gray solid crude product.This crude product is beaten in water, obtains off-white powder, yield 86%, purity 99.4%.
Embodiment 8：16g para-aminophenol, 312g sodium sulphate, 8g sodium methoxides are added in autoclave, after charging, is used
Carbon dioxide replacement reaction kettle three times, then punching press to 1.8MPa, is to slowly warm up to 200 DEG C, and it is small to react 6 at this temperature
When.After question response terminates, when cooling down is to 50 DEG C, reactor is opened in pressure release, and 200mL hydrosulfurous acids are added toward reactor is interior
Sodium solution, it is stirred for 1~2 hour, filters out insoluble matter, filtrate is separated out solid, filtering, obtained grey with acid for adjusting pH to 1.0~6.0
Color solid crude product.This crude product is beaten in water, obtains off-white powder, yield 87%, purity 99.6%.
In summary, 2- hydroxyl -5- aminobenzoic acids of the invention have that technique is simple, easy to operate, and production efficiency is high,
The features such as application prospect is wide, it is adapted to industrialized production.
Claims (16)
- A kind of 1. preparation method of 2- hydroxyls -5- aminobenzoic acids, it is characterised in that under catalytic carrier effect, p-aminophenyl Phenol or its salt and carbon dioxide reaction, 2- hydroxyl -5- anthranilates are obtained, 2- hydroxyl -5- aminobenzoics are obtained after free Acid compound；Described catalytic carrier is selected from sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium sulphate, potassium sulfate or magnesium sulfate.
- 2. preparation method according to claim 1, it is characterised in that：When reactant is para-aminophenol, solid need to be added Alkali；When reactant is p-aminophenyl phenates, wherein salt is selected from sodium salt or sylvite, then need not add solid base.
- 3. preparation method according to claim 1, it is characterised in that：Described reaction is carried out at high temperature under high pressure, reaction Pressure is 1.0~3.0MPa, and reaction temperature is controlled at 180~220 DEG C.
- 4. preparation method according to claim 1, it is characterised in that：Obtained 2- hydroxyl -5- aminobenzoic acids will be reacted Salt, dissolved with water, add a kind of reducing agent stirring, filtering, the regulation of filtrate acid adding, separate out 2- hydroxyl -5- aminobenzoic acid solids.
- 5. preparation method according to claim 1, it is characterised in that：Described catalytic carrier is selected from sodium chloride and chlorination Potassium.
- 6. preparation method according to claim 2, it is characterised in that：Described solid base is selected from sodium carbonate, potassium carbonate, hydrogen Sodium oxide molybdena, potassium hydroxide, sodium methoxide, caustic alcohol or sodium isopropylate.
- 7. preparation method according to claim 1, it is characterised in that：Described para-aminophenol and catalytic carrier dosage Mol ratio is 1:1~1:15.
- 8. preparation method according to claim 2, it is characterised in that：Described para-aminophenol and solid base feed intake Mol ratio is 1:1~1:8.
- 9. preparation method according to claim 3, it is characterised in that：Described reaction is carried out at high temperature under high pressure, reaction Pressure is 1.5~2.5MPa.
- 10. preparation method according to claim 3, it is characterised in that：Described reaction is carried out at high temperature under high pressure, reaction Temperature control is at 190~200 DEG C.
- 11. preparation method according to claim 4, it is characterised in that：The reducing agent is selected from sodium borohydride, hydroboration Potassium, sodium dithionite, sodium sulfite, vulcanized sodium, ferrous sulfate or stannous chloride.
- 12. preparation method according to claim 4, it is characterised in that the filtrate acid adding regulation, adjust to 1.0-6.0, Wherein acid is sulfuric acid, hydrochloric acid or nitric acid.
- 13. preparation method according to claim 7, it is characterised in that：Described para-aminophenol and catalytic carrier dosage Mol ratio be 1:1~1:5.
- 14. preparation method according to claim 8, it is characterised in that：Described para-aminophenol and solid base feed intake Mol ratio be 1:1~1:3.
- 15. preparation method according to claim 12, it is characterised in that the filtrate acid adding regulation, adjust to 1.0- 6.0, wherein acid is hydrochloric acid.
- A kind of 16. preparation method of 2- hydroxyls -5- aminobenzoic acids, it is characterised in that under catalytic carrier and solid base effect, Para-aminophenol, with carbon dioxide reaction, after reaction terminates, with water-soluble enzymatic hydrolysis system, adds at 1.0~3.0MPa, 180~220 DEG C Enter reducing agent stirring, filter, filtrate is adjusted with acid, separates out 2- hydroxyl -5- aminobenzoic acid solids, selective by the solid water Mashing obtains sterling,Described catalytic carrier is selected from sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium sulphate, potassium sulfate or magnesium sulfate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410097501.6A CN103880694B (en) | 2014-03-14 | 2014-03-14 | A kind of preparation method of the aminobenzoic acid of 2 hydroxyl 5 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410097501.6A CN103880694B (en) | 2014-03-14 | 2014-03-14 | A kind of preparation method of the aminobenzoic acid of 2 hydroxyl 5 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103880694A CN103880694A (en) | 2014-06-25 |
| CN103880694B true CN103880694B (en) | 2018-02-23 |
Family
ID=50949864
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410097501.6A Active CN103880694B (en) | 2014-03-14 | 2014-03-14 | A kind of preparation method of the aminobenzoic acid of 2 hydroxyl 5 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103880694B (en) |
Families Citing this family (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 |
| 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 |
| CN113004876B (en) * | 2021-02-25 | 2023-01-03 | 西南石油大学 | Carbon dioxide/calcium oxide responsive emulsifier, reversible emulsion and reversible drilling fluid, and preparation and application thereof |
| CN114605277B (en) * | 2022-04-18 | 2022-10-11 | 宁波怡和医药科技有限公司 | Synthesis method of mesalazine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2014
- 2014-03-14 CN CN201410097501.6A patent/CN103880694B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN103880694A (en) | 2014-06-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103880694B (en) | A kind of preparation method of the aminobenzoic acid of 2 hydroxyl 5 | |
| CN104761456B (en) | Preparation method of 3-amino-1-adamantanol | |
| CN101100449A (en) | Method for synthesizing taurine | |
| CN103086847B (en) | Preparation method of phloroglucinol | |
| CN105541845A (en) | Folic-acid cleaning production technology | |
| CN106631753B (en) | Method for producing gallic acid by using superfine gallnut powder | |
| CN111217764B (en) | Method for preparing 6-nitro-1, 2, 4-acid oxygen | |
| CN101891606A (en) | New method for synthesizing rhodium caprylate (II) | |
| US9067867B2 (en) | Preparation of 5-aminosalicylic acid by gas phase catalytic carboxylation | |
| CN111004126A (en) | Preparation method of p-nitrophenol sodium salt | |
| CN101830793B (en) | Method for preparing hydroxyl-substituted phenylacetic acid compound | |
| CN107098822A (en) | A kind of preparation method for preparing the hydroxy acetophenone of 3 amino of Pranlukast key intermediate 2 | |
| CN109232259A (en) | A kind of preparation method of nitro-acetophenone | |
| CN106748840A (en) | A kind of method for preparing 5 amino isophthalic acids | |
| CN104098462B (en) | The method for splitting of the diphenyl-propionic acid racemoid of 2 hydroxyl, 3 methoxyl group 3,3 | |
| CN107778189A (en) | A kind of mesalazine industrialized process for preparing | |
| CN1830942A (en) | Improved alkylation process for producing Mediben | |
| CN108929240B (en) | A kind of preparation method of 2- hydroxyl -5- aminobenzoic acid | |
| CN101265183A (en) | Method for preparing 2,3,4-trimethoxybenzoic acid | |
| CN111548283A (en) | One-pot catalytic synthesis method of 5-aminosalicylic acid | |
| CN102675162A (en) | Method for synthesizing CLT acid | |
| CN113880721B (en) | Synthesis method of dapoxetine | |
| CN109836317B (en) | Method for efficiently preparing hydroxypivalaldehyde | |
| CN109942441A (en) | A kind of preparation method of m-aminophenol | |
| CN104230747B (en) | A kind of preparation method of asymmetry aromatic azo-compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |