61-68-7

Usage

References

http://www.webmd.com/drugs/2/drug-11586/mefenamic-acid-oral/details https://en.wikipedia.org/wiki/Mefenamic_acid

Chemical Properties

white or light yellow crystalline powder, odorless, insoluble in water, slightly soluble in ethanol, chloroform, slightly soluble in ether. Melting point 230-231°C, mefenamic acid is an anti-inflammatory analgesic with antipyretic, analgesic and anti-inflammatory effects.

Originator

Ponstan,Parke Davis,UK,1963

Uses

Different sources of media describe the Uses of 61-68-7 differently. You can refer to the following data:
1. Mefenamic acid is used for the same indications as flufenamic acid. Synonyms for this drug are parkemed, ponstan, ponstel, and others.
2. For the treatment of rheumatoid arthritis, osteoarthritis, dysmenorrhea, and mild to moderate pain, inflammation, and fever.

Definition

ChEBI: An aminobenzoic acid that is anthranilic acid in which one of the hydrogens attached to the nitrogen is replaced by a 2,3-dimethylphenyl group. Although classed as a non-steroidal anti-inflammatory drug, its anti-inflammatory properties are considered to b minor. It is used to relieve mild to moderate pain, including headaches, dental pain, osteoarthritis and rheumatoid arthritis.

Indications

Mefenamic acid (Ponstel) is indicated only for analgesia and primary dysmenorrhea when therapy will not exceed 1 week.

Manufacturing Process

A mixture of 800 g of potassium o-bromo-benzoate, 1,500 ml of bis-(2- methoxyethyl)ether, 355 g of N-ethyl-morpholine, 375 g of 2,3- dimethylaniline, and 30 g of cupric acetate is heated gradually with stirring to 140°C over a period of 90 minutes. The hot reaction mixture is then acidified with 260 mi of concentrated hydrochloric acid and the acidified mixture divided into 2 equal portions. One liter of water is added to each portion and the mixtures allowed to cool. The N-(2,3-dimethylphenyl)anthranilic acid which separates upon cooling is collected by filtration and recrystallized from bis(2-methoxyethyl)ether; MP 229° to 230°C (corr.).

Brand name

Ponstel (Sciele).

Therapeutic Function

Analgesic

Synthesis Reference(s)

The Journal of Organic Chemistry, 45, p. 2127, 1980 DOI: 10.1021/jo01299a020

General Description

Mefenamic acid (Ponstel, Ponstan) is one of the oldestNSAIDs, introduced into the market in 1967 for mild tomoderate pain and for primary dysmenorrhea. It is rapidly absorbed with peak plasma levels occurring 2 to 4 hoursafter oral administration. It undergoes hepatic benzylic hydroxylationof its 3'methyl group regioselectively into twoinactive metabolites, 3'-hydroxymethylmefenamic acid andthe 3'carboxylate metabolite (via further oxidation of thebenzylic alcohol group). The parent drugs and these metabolitesare conjugated with glucuronic acid and excreted primarilyin the urine. Thus, although patients with knownliver deficiency may be given lower doses, it is contraindicatedin patients with preexisting renal dysfunction.Common side effects associated with its use include diarrhea,drowsiness, and headache. The possibility of blood disordershas also prompted limitation of its administration to 7days. It is not recommended for children or during pregnancy.

Biochem/physiol Actions

Mefenamic acid is an analgesic and anti-inflammatory drug. It acts as a cyclooxygenase (COX) enzyme inhibitor. It is hepatoxic and implicated in liver injury. Contrarily, mefenamic acid elicits neuroprotection in in vivo ischemic stroke models by inhibiting cell toxicity induced by glutamate. Mefenamic due its inhibitory effect on prostaglandin synthesis can be used in reducing edema and ache.

Clinical Use

Mefenamic acid is synthesized from o-chlorobenzoic acid and 2,3-dimethylaniline under catalytic conditions. Mefenamic acid is the only fenamic acid derivative that produces analgesia centrally and peripherally. Mefenamic acid is indicated for the short-term relief of moderate pain and for primary dysmenorrhea.

Synthesis

Mefenamic acid, N-(2,3-xylyl)anthranylic acid (3.2.19), is synthesized in basically the same manner, by the reaction of the potassium salt of 2-bromobenzoic acid with 2,3-dimethylaniline in the presence of copper (II) acetate [80,81].

Drug interactions

Potentially hazardous interactions with other drugs ACE inhibitors and angiotensin-II antagonists: antagonism of hypotensive effect; increased risk of nephrotoxicity and hyperkalaemia. Analgesics: avoid concomitant use of 2 or more NSAIDs, including aspirin (increased side effects); avoid with ketorolac (increased risk of side effects and haemorrhage). Antibacterials: possibly increased risk of convulsions with quinolones. Anticoagulants: effects of coumarins and phenindione enhanced; possibly increased risk of bleeding with heparins, dabigatran and edoxaban - avoid long term use with edoxaban. Antidepressants: increased risk of bleeding with SSRIs and venlaflaxine. Antidiabetics: effects of sulphonylureas enhanced. Antiepileptics: possibly increased phenytoin concentration. Antivirals: increased risk of haematological toxicity with zidovudine; concentration possibly increased by ritonavir. Ciclosporin: may potentiate nephrotoxicity. Cytotoxics: reduced excretion of methotrexate; increased risk of bleeding with erlotinib. Diuretics: increased risk of nephrotoxicity; antagonism of diuretic effect; hyperkalaemia with potassium-sparing diuretics. Lithium: excretion decreased. Pentoxifylline: increased risk of bleeding. Tacrolimus: increased risk of nephrotoxicity.

Metabolism

Mefenamic acid is absorbed rapidly following oral administration, with peak plasma levels being attained within 2 to 4 hours. It is highly bound to plasma proteins (78.5%) and has a plasma half-life of 2 to 4 hours. Metabolism occurs through regioselective oxidation of the 3′-methyl group and glucuronidation of mefenamic acid and its metabolites. Urinary excretion accounts for approximately 50 to 55% of an administered dose, with unchanged drug accounting for 6%, the 3′-hydroxymethyl metabolite (primarily as the glucuronide) accounting for 25%, and the remaining 20% as the dicarboxylic acid (of which 30% is the glucuronide conjugate). These metabolites are essentially inactive.

InChI:InChI=1/C15H15NO2/c1-10-6-5-9-13(11(10)2)16-14-8-4-3-7-12(14)15(17)18/h3-9,16H,1-2H3,(H,17,18)

Synthetic route

mefenamic acid benzyl ester → mefenamic Acid (61-68-7)

Conditions	Yield
With hydrogen In methanol at 50℃; under 3750.38 Torr; Flow reactor; chemoselective reaction;	98%

2,3-Dimethylaniline (87-59-2) + ortho-chlorobenzoic acid (118-91-2) → mefenamic Acid (61-68-7)

Conditions	Yield
Stage #1: ortho-chlorobenzoic acid With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 0.5h; Stage #2: 2,3-Dimethylaniline With manganese(II) acetate In water; N,N-dimethyl-formamide; toluene at 120 - 130℃; Reagent/catalyst;	94.8%
Stage #1: ortho-chlorobenzoic acid With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 1.16667h; Stage #2: 2,3-Dimethylaniline With copper In water; N,N-dimethyl-formamide; toluene at 104 - 123℃;	91.3%
With copper; sodium carbonate In N,N-dimethyl-formamide at 140℃; for 2h;	90%

2-Iodobenzoic acid (88-67-5) + 2,3-Dimethylaniline (87-59-2) → mefenamic Acid (61-68-7)

Conditions	Yield
With sodium acetate; copper (I) acetate In water for 1.5h; Heating;	93%
With copper; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 12h; Schlenk technique; Inert atmosphere;

2-[(2,3-dimethylphenyl)amino]benzonitrile (13481-67-9) → mefenamic Acid (61-68-7)

Conditions	Yield
With methanol; potassium hydroxide In water at 100℃; for 12h; Schlenk technique;	91%
With water; potassium hydroxide In methanol for 12h; Reflux;
With water; potassium hydroxide In ethanol at 95℃; for 20h; Inert atmosphere;	161 mg

2-((2,3-dimethylphenyl)amino)-N-(quinolin-8-yl)benzamide → mefenamic Acid (61-68-7)

Conditions	Yield
With potassium hydroxide In ethanol at 110℃; for 18h; Sealed tube;	90%

Diphenyliodonium-2-carboxylate (1488-42-2) + 2,3-Dimethylaniline (87-59-2) → mefenamic Acid (61-68-7)

Conditions	Yield
With copper diacetate In isopropyl alcohol for 23h; Heating;	54%
With copper diacetate In isopropyl alcohol at 85℃; for 23h;	54%
copper diacetate In isopropyl alcohol at 80℃; for 15h;	90 % Spectr.

2-Chlorobenzonitrile (873-32-5) + 2,3-Dimethylaniline (87-59-2) → mefenamic Acid (61-68-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: Pd-PEPPSI-IPrAn; caesium carbonate / 1,4-dioxane / 24 h / 80 °C / Inert atmosphere 2: water; potassium hydroxide / methanol / 12 h / Reflux View Scheme

mefenamic acid → 4-acetaminophenol (103-90-2) + mefenamic Acid (61-68-7)

Conditions	Yield
With hydrogenchloride; water pH=2; Kinetics; Solvent; Reagent/catalyst;

2,3-Dimethylaniline (87-59-2) → mefenamic Acid (61-68-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrahydrofuran; diethyl ether / 0 - 20 °C 2: cesium fluoride / tetrahydrofuran / 16 h / 70 °C / Inert atmosphere 3: potassium hydroxide; methanol / water / 12 h / 100 °C / Schlenk technique View Scheme

N-(2,3-dimethylphenyl)cyanamide (55591-34-9) → mefenamic Acid (61-68-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: cesium fluoride / tetrahydrofuran / 16 h / 70 °C / Inert atmosphere 2: potassium hydroxide; methanol / water / 12 h / 100 °C / Schlenk technique View Scheme

o-nitrobenzonitrile (612-24-8) + 2,3-dimethylphenylboronic acid (183158-34-1) → mefenamic Acid (61-68-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: phenylsilane; 1,2,2,3,4,4-hexamethylphosphetane 1-oxide / m-xylene / 3 h / 120 °C / Inert atmosphere 2: potassium hydroxide; water / ethanol / 20 h / 95 °C / Inert atmosphere View Scheme

2,3-Dimethylaniline (87-59-2) + 2-bromobenzoic-acid (88-65-3) → mefenamic Acid (61-68-7)

Conditions	Yield
With copper(I) oxide; copper; potassium carbonate In N,N-dimethyl-formamide at 110℃; for 12h;
With copper(I) oxide; copper; potassium carbonate In 2-methoxy-ethanol at 130℃; for 24h; Inert atmosphere;

Upstream product

• 1804-54-2 1-(1',2'-dimethyl-phenyl)-1,2-dihydro-3,1-benzoxazin-4-one 
• 612-24-8 o-nitrobenzonitrile 
• 183158-34-1 2,3-dimethylphenylboronic acid 
• 87-59-2 2,3-Dimethylaniline 
• 88-65-3 2-bromobenzoic-acid 
• 55591-34-9 N-(2,3-dimethylphenyl)cyanamide 
• 13481-67-9 2-[(2,3-dimethylphenyl)amino]benzonitrile 
• 873-32-5 2-Chlorobenzonitrile 
• 88-67-5 2-Iodobenzoic acid 
• 118-91-2 ortho-chlorobenzoic acid 
• 16497-87-3 potassium o-bromobenzoate 
• 1488-42-2 Diphenyliodonium-2-carboxylate 
• 137488-45-0 1-(1',2'-dimethyl-phenyl)-2-ethoxycarbonyl-1,2-dihydro-3,1-benzoxazin-4-one 
• 137488-44-9 1-(1',2'-dimethyl-phenyl)-2-methoxymethyl-1,2-dihydro-3,1-benzoxazin-4-one 

Downstream Products

• 1804-54-2 1-(1',2'-dimethyl-phenyl)-1,2-dihydro-3,1-benzoxazin-4-one 
• 137488-46-1 1-(1',2'-dimethyl-phenyl)-2-methyl-1,2-dihydro-3,1-benzoxazin-4-one 
• 137488-43-8 1-(1',2'-dimethyl-phenyl)-2-chloromethyl-1,2-dihydro-3,1-benzoxazin-4-one 
• 137488-44-9 1-(1',2'-dimethyl-phenyl)-2-methoxymethyl-1,2-dihydro-3,1-benzoxazin-4-one 
• 137488-45-0 1-(1',2'-dimethyl-phenyl)-2-ethoxycarbonyl-1,2-dihydro-3,1-benzoxazin-4-one 
• 1165951-11-0 C₂₃H₁₉ClN₂O₄ 
• 1147303-91-0 8-(N-(2,3-dimethylphenyl)amino)-3,4-diphenylisocoumarin 
• 1147304-23-1 4-(1,2-diphenylethenyl)-7,8-dimethyl-9H-carbazole 
• 1598423-02-9 (S,E)-methyl 3-(4-(2-(2-((2,3-dimethylphenyl)amino)benzamido)-3-(1H-indol-3-yl)propoxy)phenyl)acrylate 

Relevant academic research and scientific papers

Visible-Light- And PPh3-Mediated Direct C-N Coupling of Nitroarenes and Boronic Acids at Ambient Temperature

We present here a metal-free, visible-light- and triphenylphosphine-mediated intermolecular, reductive amination between nitroarenes and boronic acids at ambient temperature without any photocatalyst. Mechanistically, a slow reduction of nitroarenes to a nitroso and, finally, a nitrene intermediate occurs that leads to the amination product with concomitant 1,2-aryl/-alkyl migration from a boronate complex. A wide range of nitroarenes underwent C-N coupling with aryl-/alkylboronic acids providing high yields.

Melatonin derivatives combat with inflammation-related cancer by targeting the Main Culprit STAT3

The combination between two well-studied bioactive compounds melatonin and salicylic acid with proper modifications unexpectedly creates a sharp pair of “scissors” cutting off the vicious connection between inflammation and cancer by targeting a key contributor Signal Transducers and Activators of Transcription 3 (STAT3) in the two pathological processes. A representative compound P-3 with IC50 values on each tested cell line ranging from 7.37 to 18.62 μM among the designed melatonin derivatives is equipped with the ability of curbing inflammation-promoting cancer by down-regulating the expression, activation and nuclear translocation of STAT3, breaking the feedforward loop of STAT3 activation by decreasing the expression of pro-tumorigenic cytokines, and inducing cell apoptosis through ROS triggered Cyto-c/Caspase-3 pathway. This study suggests that the melatonin derivative P-3 is likely to become a promising chemical structure for developing the novel anti-cancer agents taking effect through hindering the mutual-promoting processes between inflammation and cancer.

Method for accelerating synthesis time of methorphan acid

The invention relates to a method for accelerating synthetic time of mefenamic acid. The method comprises the following steps: performing a reaction by taking o-chlorobenzoic acid, sodium carbonate and 2,3-dimethyl aniline as main raw materials, taking copper powder as a catalyst, and taking N,N-dimethyl formamide and toluene as solvents, performing heating, enabling mixed steam in a reaction kettle to enter a rectifying tower which uses a Dixon ring as a filler, finally performing acidification, performing cooling, and performing filtering to obtain the mefenamic acid crude product. Accordingto the invention, drainage time in the reaction process is accelerated through continuous reflux and evaporation of the rectifying tower, so that the overall synthetic time of the mefenamic acid is accelerated, and the method has the advantages of a high reaction yield, good product quality and high synthetic time, reduces the costs, solves the problem of relatively long synthetic time in a current preparation method, and has good application prospects.

Development of Carbon-Neutral Cellulose-Supported Heterogeneous Palladium Catalysts for Chemoselective Hydrogenation

Palladium catalysts immobilized on cellulose particles (Pd/CLP) and on a cellulose-monolith (Pd/CLM) were developed. These composites were applied as hydrogenation catalysts and their catalyst activities were evaluated. Although both catalysts catalyzed the deprotection of benzyloxycarbonyl-protected aromatic amines (Ar-N-Cbz) and aromatic benzyl esters (Ar-CO2Bn), only Pd/CLM could accomplish the hydrogenolysis of aliphatic-N-Cbz and aliphatic-CO2Bn protective groups. The difference in the physical structure of the cellulose supports induced unique chemoselectivity. Aliphatic-N-Cbz and aliphatic-CO2Bn groups were tolerated under the Pd/CLP-catalyzed hydrogenation conditions, while Ar-N-Cbz, Ar-CO2Bn, alkene, alkyne, azido and nitro groups could be smoothly reduced.

Design, synthesis and biological evaluation of acridone analogues as novel STING receptor agonists

STING (Stimulator of Interferon Genes) has become a focal point in immunology research and a target in drug discovery. The discovery of a potent human-STING agonist is expected to revolutionize current anti-virus or cancer immunotherapy. Inspired by the structure and function of murine STING-specific agonists (DMXAA and CMA), we rationally designed and synthesized four series of novel compounds for the enhancement of human sensitivity. In the cell-based assay, we identified six compounds from all the synthetic small molecules: 2g, 9g, and 12b are STING agonists that are efficacious across species, and all have the skeleton of acridone; 1b, 1c, and 12c just function in the murine STING pathway. Notably, 12b exhibits the best activity among the six agonists, and its inductions of both human and murine STING-dependent signalling are similar to that of 2′3′-cGAMP, which is a well-known STING inducer. While a protein assay indicated that 2 g, 9 g, and 12b could activate the pathway by directly binding human STING, 12b also displayed the strongest binding affinity. Additionally, our studies show that 12b can induce faster, more powerful, and more durable responses of assorted cytokines in a native system than 2′3′-cGAMP. Consequently, our team is the first to successfully modify murine STING agonists to obtain human sensitivity, and these results suggest that 12b is a potent direct-human-STING agonist. Additionally, the acridone analogues demonstrate tremendous potential in the treatment of tumours or viral infections.

Redox-neutral decarboxylative photocyclization of anthranilic acids

A mild metal-, catalyst-, and oxidant-free photoredox neutral system has been found to efficiently enable intramolecular decarboxylative cyclization of anthranilic acids. This facile protocol provides an alternative method for the synthesis of carbazoles. Mechanistic studies reveal a key photoinduced 6π-electrocyclization process and formic acid was released as the sole byproduct.

Intermolecular Reductive C-N Cross Coupling of Nitroarenes and Boronic Acids by PIII/PV=O Catalysis

A main group-catalyzed method for the synthesis of aryl- and heteroarylamines by intermolecular C-N coupling is reported. The method employs a small-ring organophosphorus-based catalyst (1,2,2,3,4,4-hexamethylphosphetane) and a terminal hydrosilane reductant (phenylsilane) to drive reductive intermolecular coupling of nitro(hetero)arenes with boronic acids. Applications to the construction of both Csp2-N (from arylboronic acids) and Csp3-N bonds (from alkylboronic acids) are demonstrated; the reaction is stereospecific with respect to Csp3-N bond formation. The method constitutes a new route from readily available building blocks to valuable nitrogen-containing products with complementarity in both scope and chemoselectivity to existing catalytic C-N coupling methods.

Mefenamic acid and synthesis technology thereof

The invention discloses a mefenamic acid. The mefenamic acid is prepared by the following steps: taking o-chlorobenzoic acid and 2,3-dimethylaniline as the reactants and weakly alkaline salt as the acid binding agent, and then carrying out C-N condensation reactions in the presence of a copper catalyst. The invention also provides a synthesis technology of mefenamic acid. The synthesis technology comprises the following steps: adding 2,3-dimethylaniline, strongly acidic cation exchange resin, o-chlorobenzoic acid, sodium bicarbonate, a copper catalyst, sodium acetate, and sodium ethyl benzene sulfonate into a condensation reaction tank to synthesize a first reaction liquid; then sequentially adding o-chlorobenzoic acid, sodium bicarbonate, and a copper catalyst into the first reaction liquid, dropwise adding liquid alkali to synthesize a second reaction liquid, adjusting the pH value of the second reaction liquid to obtain a condensation liquid, and finally subjecting the condensation liquid to filtering, decoloring, and purification to obtain mefenamic acid. The provided mefenamic acid synthesis technology has the advantages of few byproducts, high yield, safety, environment-friendliness, energy saving, improved efficiency, and simple operation.

Synthesis method of mefenamic acid

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.

Copper(II)-Mediated Intermolecular C(sp2)-H Amination of Benzamides with Electron-Rich Anilines

Despite significant progress, copper-catalyzed/mediated C-H amination reactions with electron-rich anilines remain an unsolved problem due to catalyst deactivation and deleterious side reactions. Herein, we report a copper(II)-mediated C(sp2)-H amination of benzamides with electronically neutral or electron-rich anilines. A dramatic influence of silver(I) and tetrabutylammonium bromide was observed on the reaction outcome. The present protocol also demonstrates the synthesis of a number of nonsteroidal anti-inflammatory drugs.