CN105949075B - A kind of synthetic method of mefenamic acid - Google Patents
A kind of synthetic method of mefenamic acid Download PDFInfo
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- CN105949075B CN105949075B CN201610475862.9A CN201610475862A CN105949075B CN 105949075 B CN105949075 B CN 105949075B CN 201610475862 A CN201610475862 A CN 201610475862A CN 105949075 B CN105949075 B CN 105949075B
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- chloro
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- mefenamic acid
- benzoic acid
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- YHCIJMVTLQFAPK-UHFFFAOYSA-N Cc(c(Nc1ccccc1C(O)=O)ccc1)c1O Chemical compound Cc(c(Nc1ccccc1C(O)=O)ccc1)c1O YHCIJMVTLQFAPK-UHFFFAOYSA-N 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N OC(c(cccc1)c1Cl)=O Chemical compound OC(c(cccc1)c1Cl)=O IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a kind of synthetic method of mefenamic acid, using 0-chloro-benzoic acid as raw material, in the presence of acid binding agent, using aprotic polar solvent, 0-chloro-benzoic acid salt is obtained into salt；Under dehydrating agent effect, using manganese powder or manganese salt as catalyst, 0-chloro-benzoic acid salt and 2, the progress condensation reaction of 3 dimethylanilines, then acidified obtain mefenamic acid.The invention provides a kind of synthetic method of mefenamic acid, have the advantages that reaction yield is high, product qualities are high and production cost is low, the problem of solving relatively low product yield present in existing preparation method and deeper product colour.
Description
Technical field
The present invention relates to the technical field of organic synthesis, more particularly to a kind of synthetic method of mefenamic acid.
Background technology
Mefenamic acid, also known as mefenamic acid, flutter hot pain etc., English entitled Mefenamic Acid, chemical entitled N-2,3- bis-
Tolyl ortho-aminobenzoic acid, structural formula is shown below.
Mefenamic acid is a kind of NSAIDs, and main function is the synthesis and suppression albumen by suppressing prostaglandin
Matter catabolic enzyme, so that the protein structure of stabilizing cell membrane, disturbs tissue metabolism's process and play a role.
Compared with the NSAIDs of same type, the antiinflammatory action of mefenamic acid is significantly stronger than flufenamic acid and clofenamic acid,
Therefore it is more widely applied.Clinically it is mainly used in rheumatic, rheumatoid arthritis, dysmenorrhoea, headache, neuralgia, courbature
And the treatment of other postoperative inflammatory pains.In addition, mefenamic acid can be additionally used in the precursor of acridine antimalarial and anticarcinogen.
The synthesis of mefenamic acid traditional in early days, which is mainly first to react 0-chloro-benzoic acid and inorganic base, first generates adjacent chlorobenzene
Formic acid sodium salt, 0-chloro-benzoic acid sodium salt is made with 2,3- dimethylanilines in aqueous phase condensation again, but product yield is relatively low, causes life
Production cost is higher and is eliminated.
Because DMF, DMSO and sulfolane equal solvent have certain dissolubility to 0-chloro-benzoic acid sodium salt, therefore later conjunction
Water substantially is instead of with DMF, DMSO and sulfolane equal solvent into method, and achieves preferable conversion ratio.
The documents such as CN200910154422.3 and CN200910114917.3 refer to 0-chloro-benzoic acid and 2,3- dimethyl
Aniline is achieved very well using copper chloride, copper sulphate, copper nitrate, copper acetate, cupric oxide and copper powder etc. as condensation catalyst
Yield, but in course of reaction particularly reaction the later stage generate a large amount of tar, obtained mefenamic acid crude product color is partially deep, lead to
Often be atropurpureus, and containing certain tar, viscosity is larger, even if by solvent refining lighter, but losing larger, more by
In the factor of copper ion, product often greening, not enough in vain.Therefore the synthetic method also has certain limitation.
The content of the invention
The invention provides a kind of synthetic method of mefenamic acid, with reaction yield is high, product qualities are high and produce
The low advantage of cost, the problem of solving relatively low product yield present in existing preparation method and deeper product colour.
The invention discloses a kind of synthetic method of mefenamic acid, comprise the following steps：
(1) using 0-chloro-benzoic acid as raw material, in the presence of acid binding agent, using aprotic polar solvent, adjacent chlorine is obtained into salt
Benzoate；
(2) under dehydrating agent effect, using manganese powder or manganese salt as catalyst, 0-chloro-benzoic acid salt and 2,3- dimethyl benzene
Amine carries out condensation reaction, then acidified obtains mefenamic acid.
The present invention mainly starts with from the catalyst of condensation reaction, abandons the use of copper powder and copper-containing compound, uses metal instead
Manganese powder or manganese salt, reaction side reaction are significantly reduced, while reducing tar yield, product appearance improves obvious.
Preferably, in above-mentioned synthetic method：
0-chloro-benzoic acid, 23 dimethyl aniline, the mass ratio of acid binding agent and catalyst are 1:0.8~1.0:0.8~
1.2:0.01~0.03；
The mass ratio of aprotic polar solvent and 0-chloro-benzoic acid is 0.3~0.5:1；
The mass ratio of dehydrating agent and 0-chloro-benzoic acid is 0.8~1.2:1.
Preferably, in step (1), described acid binding agent is sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
In the present invention, abandon water and make solvent, reaction dissolvent is used as using aprotic polar solvent so that yield is carried
It is high.Preferably, in step (1), described aprotic polar solvent is DMF, DMSO or sulfolane.
To ensure being completely dissolved and abundant into salt for 0-chloro-benzoic acid, preferably, in step (1), dissolving and anti-into salt
It should be carried out in the case where being heated to 80 DEG C.
Because condensation reaction generates water, dehydrating agent is introduced, the water for reacting generation is removed in time using azeotropic, greatly shortened
Reaction time.Preferably, in step (2), described dehydrating agent is benzene or toluene.
Preferably, in step (2), described manganese salt is manganese acetate or manganese sulfate.
Preferably, in step (2), the temperature of the condensation reaction is 120~130 DEG C.
Preferably, in step (2), described acidifying is that to adjust condensation product to pH through dilute sulfuric acid be 1~2, then is passed through
It is filtrated to get described mefenamic acid.
Compared with prior art, the invention has the advantages that：
The present invention is used as catalyst in the synthesis of mefenamic acid using manganese powder or manganese salt first, hence it is evident that reduce pair
The generation of reaction, while reducing tar yield, hence it is evident that improve product appearance.
Use DMF, DMSO or sulfolane etc. for reaction dissolvent in the present invention, improve the yield of product；Also introduce benzene or
Toluene substantially reduces the time of condensation reaction as dehydrating agent.
Embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This：
The preparation of the mefenamic acid of embodiment 1
10gDMF is put into 250mL four-hole boiling flasks, 80 DEG C are warming up to, 27g 0-chloro-benzoic acids are put into, until adjacent chlorobenzene first
It is sour complete it is molten after, add 25g sodium carbonate and carry out into salt, 80 DEG C of insulation half an hour.Water knockout drum is connect, 25g toluene is added and carries out a point water, directly
Separated to anhydrous.Catalyst acetic acid manganese 0.5g and 2,3- dimethylaniline 22.5g is put into afterwards, and temperature is maintained at 120~130 DEG C.
Sample in HPLC and control, work as 0-chloro-benzoic acid<When 1%, 100mL water, plus dilute sulfuric acid regulation pH to 2 are added, suction filtration, drying is obtained
About 39.5g pale solids, molar yield 94.8%, nuclear-magnetism detection data and reaction equation difference are as follows.
1H NMR(DMSO):δ2.10(s,3H,-CH3),2.28(s,3H,-CH3), 6.68~7.90 (m, 7H, Ar-H),
9.46(s,-NH).
The preparation of the mefenamic acid of embodiment 2
10gDMF is put into 250mL four-hole boiling flasks, 80 DEG C are warming up to, 27g 0-chloro-benzoic acids are put into, until adjacent chlorobenzene first
It is sour complete it is molten after, add 25g sodium carbonate and carry out into salt, 80 DEG C of insulation half an hour.Water knockout drum is connect, 25g toluene is added and carries out a point water, directly
Separated to anhydrous.Catalyst sulfuric acid manganese 0.5g and 2,3- dimethylaniline 22.5g is put into afterwards, and temperature is maintained at 120~130 DEG C.
Sample in HPLC and control, work as 0-chloro-benzoic acid<When 1%, 100mL water, plus dilute sulfuric acid regulation pH to 2 are added, suction filtration, drying is obtained
About 38.7g pale solids, molar yield 93.0%, nuclear-magnetism detection data are as follows：
1H NMR(DMSO):δ2.10(s,3H,-CH3),2.28(s,3H,-CH3), 6.68~7.90 (m, 7H, Ar-H),
9.46(s,-NH).
Claims (6)
1. a kind of synthetic method of mefenamic acid, it is characterised in that comprise the following steps：
(1) using 0-chloro-benzoic acid as raw material, in the presence of acid binding agent, using aprotic polar solvent, adjacent chlorobenzene first is obtained into salt
Hydrochlorate；
(2) under dehydrating agent effect, using manganese acetate or manganese sulfate as catalyst, 0-chloro-benzoic acid salt and 2,3- dimethylaniline enter
Row condensation reaction, then acidified obtain mefenamic acid.
2. the synthetic method of mefenamic acid according to claim 1, it is characterised in that
0-chloro-benzoic acid, 23 dimethyl aniline, the mass ratio of acid binding agent and catalyst are 1:0.8~1.0:0.8~1.2:
0.01~0.03；
The mass ratio of aprotic polar solvent and 0-chloro-benzoic acid is 0.3~0.5:1；
The mass ratio of dehydrating agent and 0-chloro-benzoic acid is 0.8~1.2:1.
3. the synthetic method of mefenamic acid according to claim 1 or 2, it is characterised in that in step (1), described ties up
Sour agent is sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
4. the synthetic method of mefenamic acid according to claim 1 or 2, it is characterised in that in step (1), described is non-
Proton polar solvent is DMF, DMSO or sulfolane.
5. the synthetic method of mefenamic acid according to claim 1 or 2, it is characterised in that in step (2), described is de-
Aqua is benzene or toluene.
6. the synthetic method of mefenamic acid according to claim 1, it is characterised in that in step (2), the condensation reaction
Temperature be 120~130 DEG C.
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| CN107382754A (en) * | 2017-07-10 | 2017-11-24 | 江苏倍合德化工有限公司 | A kind of quick high-efficiency synthesis method for preparing mefenamic acid |
| MX2021003730A (en) | 2018-09-28 | 2021-06-18 | Univ Griffith | Agents and methods for modulating pathogen activity. |
| CN110467538B (en) * | 2019-09-20 | 2022-08-26 | 山东道可化学有限公司 | Synthesis method of 2-methyl-4-methoxydiphenylamine |
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| BE789442A (en) * | 1971-10-01 | 1973-03-29 | Ciba Geigy | CHELATES TO COMBAT METAL DEFICIENCY PHENOMENA IN PLANTS |
| JPS62273939A (en) * | 1986-05-22 | 1987-11-28 | Mitsui Toatsu Chem Inc | Production of dl-alanine |
| DE10219037A1 (en) * | 2002-04-29 | 2003-11-06 | Bayer Ag | Production and use of iminodisuccinic acid ammonium metal salts |
| CN1458140A (en) * | 2003-05-04 | 2003-11-26 | 厦门市先端科技有限公司 | Process for preparing aniline and its derivatives |
| JP4188401B2 (en) * | 2004-05-12 | 2008-11-26 | 出光興産株式会社 | Aromatic amine derivative, organic electroluminescence device using the same, and method for producing aromatic amine derivative |
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| CN101475505B (en) * | 2009-02-09 | 2012-08-01 | 宝鸡天新药业有限公司 | Process for preparing mefenamic acid |
| CN101704761B (en) * | 2009-10-23 | 2012-09-05 | 宁波斯迈克制药有限公司 | Synthesis method of mefenamic acid |
| CN102344384B (en) * | 2011-09-02 | 2013-10-16 | 德州博诚制药有限公司 | Production method of mefenamic acid |
| CN103420863A (en) * | 2013-03-25 | 2013-12-04 | 江苏海佳化工有限公司 | Mefenamic acid short-process synthesis preparation and refining method |
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