CN105949075A - Synthesis method of mefenamic acid - Google Patents
Synthesis method of mefenamic acid Download PDFInfo
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- CN105949075A CN105949075A CN201610475862.9A CN201610475862A CN105949075A CN 105949075 A CN105949075 A CN 105949075A CN 201610475862 A CN201610475862 A CN 201610475862A CN 105949075 A CN105949075 A CN 105949075A
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- acid
- chloro
- mefenamic acid
- synthetic method
- mefenamic
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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 Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a synthesis method of mefenamic acid. The method comprises the following steps: by using o-chloro-benzoic acid as a raw material, salifying by using a non-proton polar solvent in the presence of an acid-binding agent to obtain o-chloro-benzoate; and under the action of a dehydrating agent, carrying out condensation reaction on the o-chloro-benzoate and 2,3-dimethylaniline by using metal manganese powder or manganese salt as a catalyst, and acidifying to obtain the mefenamic acid. The synthesis method disclosed by the invention has the advantages of high reaction yield, high product quality and low production cost, and solves the problems of lower product yield and deep product color in the existing preparation method.
Description
Technical field
The present invention relates to the technical field of organic synthesis, particularly relate to the synthetic method of a kind of mefenamic acid.
Background technology
Mefenamic acid, has another name called mefenamic acid, flutters burning 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 NSAID (non-steroidal anti-inflammatory drug), and Main Function is the synthesis by suppression prostaglandin and suppression albumen
Matter catabolic enzyme, thus the protein structure of stabilizing cell membrane, disturb tissue metabolism's process to play a role.
With compared with the NSAID (non-steroidal anti-inflammatory drug) of type, the antiinflammatory action of mefenamic acid is significantly stronger than flufenamic acid and acidum clofenamicum,
Therefore it is more widely applied.It is mainly used in rheumatic, rheumatoid arthritis, dysmenorrhea, headache, neuralgia, myalgia clinically
And the treatment of postoperative other inflammatory pains.Additionally, mefenamic acid can be additionally used in the precursor of acridine antimalarial and anticarcinogen.
0-chloro-benzoic acid and inorganic base are mainly first reacted and first generate adjacent chlorobenzene by the synthesis of the most traditional mefenamic acid
Formic acid sodium salt, 0-chloro-benzoic acid sodium salt is again with 2, and 3-dimethylaniline prepares in aqueous phase condensation, but product yield is relatively low, causes raw
Produce relatively costly and be eliminated.
Owing to DMF, DMSO and sulfolane equal solvent have certain dissolubility to 0-chloro-benzoic acid sodium salt, therefore later conjunction
One-tenth method substantially instead of water with DMF, DMSO and sulfolane equal solvent, 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, using copper chloride, copper sulfate, copper nitrate, Schweinfurt green, copper oxide and copper powder etc. as condensation catalyst, achieves very well
Yield, but course of reaction particularly reacts the later stage and creates a large amount of tar, prepared mefenamic acid crude product color is partially deep, logical
Be often atropurpureus, and containing certain tar, viscosity is relatively big, even if by solvent refining lighter, but loss is relatively greatly, more by
In the factor of copper ion, product often greening, the most in vain.Therefore this synthetic method also has certain limitation.
Summary of the invention
The invention provides the synthetic method of a kind of mefenamic acid, there is reaction yield height, product qualities height and produce
The advantage of low cost, solves the relatively low problem deeper with product colour of product yield present in existing preparation method.
The invention discloses the synthetic method of a kind of mefenamic acid, comprise the following steps:
(1) with 0-chloro-benzoic acid as raw material, in the presence of acid binding agent, use aprotic polar solvent, become salt to obtain adjacent chlorine
Benzoate；
(2) under dehydrant effect, with manganese powder or manganese salt as catalyst, 0-chloro-benzoic acid salt and 2,3-dimethyl benzene
Amine carries out condensation reaction, more 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 significantly reduces, and reduces tar generation amount simultaneously, and product appearance is improved substantially.
As preferably, in above-mentioned synthetic method:
The mass ratio of 0-chloro-benzoic acid, 23 dimethyl aniline, acid binding agent and catalyst be 1:0.8～1.0:0.8～
1.2:0.01～0.03；
Aprotic polar solvent is 0.3～0.5:1 with the mass ratio of 0-chloro-benzoic acid；
Dehydrant is 0.8～1.2:1 with the mass ratio of 0-chloro-benzoic acid.
As 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, use aprotic polar solvent as reaction dissolvent so that yield is carried
High.As preferably, in step (1), described aprotic polar solvent is DMF, DMSO or sulfolane.
For ensureing being completely dissolved and fully becoming salt of 0-chloro-benzoic acid, as preferably, in step (1), dissolve and become salt anti-
Should carry out at being heated to 80 DEG C.
Owing to condensation reaction generates water, introduce dehydrant, utilize azeotropic to be removed in time by the water that reaction produces, be greatly shortened
Response time.As preferably, in step (2), described dehydrant is benzene or toluene.
As preferably, in step (2), described manganese salt is manganese acetate or manganese sulfate.
As preferably, in step (2), the temperature of described condensation reaction is 120～130 DEG C.
As preferably, in step (2), described acidifying is to be 1～2 through dilute sulfuric acid regulation to pH by condensation product, then warp
It is filtrated to get described mefenamic acid.
Compared with prior art, present invention have the advantage that
The present invention uses manganese powder or manganese salt as catalyst first in the synthesis of mefenamic acid, hence it is evident that decrease pair
The generation of reaction, reduces tar generation amount, hence it is evident that improve product appearance simultaneously.
Using DMF, DMSO or sulfolane etc. in the present invention is reaction dissolvent, improves the yield of product；Also introduce benzene or
Toluene, as dehydrant, substantially reduces the time of condensation reaction.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This:
The preparation of embodiment 1 mefenamic acid
In 250mL four-hole boiling flask, put into 10gDMF, be warming up to 80 DEG C, put into 27g 0-chloro-benzoic acid, until adjacent chlorobenzene first
After acid is the most molten, adding 25g sodium carbonate and carry out into salt, 80 DEG C are incubated half an hour.Connect water knockout drum, add 25g toluene and carry out a point water, directly
Separate to anhydrous.Rear input catalyst acetic acid manganese 0.5g and 2,3-dimethylaniline 22.5g, temperature is maintained at 120～130 DEG C.
Sampling HPLC is controlled, when 0-chloro-benzoic acid < when 1%, adds 100mL water, adds dilute sulfuric acid regulation pH to 2, sucking filtration, dry, obtain
About 39.5g pale solid, molar yield 94.8%, nuclear-magnetism detection data and reaction equation 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 embodiment 2 mefenamic acid
In 250mL four-hole boiling flask, put into 10gDMF, be warming up to 80 DEG C, put into 27g 0-chloro-benzoic acid, until adjacent chlorobenzene first
After acid is the most molten, adding 25g sodium carbonate and carry out into salt, 80 DEG C are incubated half an hour.Connect water knockout drum, add 25g toluene and carry out a point water, directly
Separate to anhydrous.Rear input catalyst sulfuric acid manganese 0.5g and 2,3-dimethylaniline 22.5g, temperature is maintained at 120～130 DEG C.
Sampling HPLC is controlled, when 0-chloro-benzoic acid < when 1%, adds 100mL water, adds dilute sulfuric acid regulation pH to 2, sucking filtration, dry, obtain
About 38.7g pale solid, 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 (7)
1. the synthetic method of a mefenamic acid, it is characterised in that comprise the following steps:
(1) with 0-chloro-benzoic acid as raw material, in the presence of acid binding agent, use aprotic polar solvent, become salt to obtain adjacent chlorobenzene first
Hydrochlorate；
(2) under dehydrant effect, with manganese powder or manganese salt as catalyst, 0-chloro-benzoic acid salt and 2,3-dimethylaniline enters
Row condensation reaction, more acidified obtain mefenamic acid.
The synthetic method of mefenamic acid the most according to claim 1, it is characterised in that
The mass ratio of 0-chloro-benzoic acid, 23 dimethyl aniline, acid binding agent and catalyst is 1:0.8～1.0:0.8～1.2:
0.01～0.03；
Aprotic polar solvent is 0.3～0.5:1 with the mass ratio of 0-chloro-benzoic acid；
Dehydrant is 0.8～1.2:1 with the mass ratio of 0-chloro-benzoic acid.
The synthetic method of mefenamic acid the most according to claim 1 and 2, it is characterised in that in step (1), described ties up
Acid agent is sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
The synthetic method of mefenamic acid the most according to claim 1 and 2, it is characterised in that in step (1), described is non-
Proton polar solvent is DMF, DMSO or sulfolane.
The synthetic method of mefenamic acid the most according to claim 1 and 2, it is characterised in that in step (2), described is de-
Water preparation is benzene or toluene.
The synthetic method of mefenamic acid the most according to claim 1, it is characterised in that in step (2), described manganese salt is
Manganese acetate or manganese sulfate.
The synthetic method of mefenamic acid the most according to claim 1, it is characterised in that in step (2), described condensation reaction
Temperature be 120～130 DEG C.
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| CN201610475862.9A CN105949075B (en) | 2016-06-24 | 2016-06-24 | A kind of synthetic method of mefenamic acid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110467538A (en) * | 2019-09-20 | 2019-11-19 | 山东道可化学有限公司 | A kind of synthetic method of 2- methyl -4- methoxy diphenylamine |
| WO2020061649A1 (en) | 2018-09-28 | 2020-04-02 | Griffith University | Agents and methods for modulating pathogen activity |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| WO2020061649A1 (en) | 2018-09-28 | 2020-04-02 | Griffith University | Agents and methods for modulating pathogen activity |
| EP4295864A2 (en) | 2018-09-28 | 2023-12-27 | Research Institute at Nationwide Children's Hospital | Phenylpropionic acid derivatives for modulating pathogen activity |
| CN110467538A (en) * | 2019-09-20 | 2019-11-19 | 山东道可化学有限公司 | A kind of synthetic method of 2- methyl -4- methoxy diphenylamine |
| 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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| CN105949075B (en) | 2017-11-07 |
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