108605-62-5

Basic information

• Product Name: A77 1726
• Synonyms: A77 1726;N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide, 2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-beuteamide, LEF-M;(2Z)-2-[hydroxy-[[4-(trifluoromethyl)phenyl]amino]methylidene]-3-oxo-butanenitrile;2-Cyano-3OH-N-(4-trifluoromethylphenyl) crotonamide-d4;2-Cyano-3-hydroxy-N-(4'-trifluoromethylphenyl)-crotone amide;(E)-2-Cyano-3-hydroxy-N-(4-trifluoromethylphenyl)-2-butenamide;2-Butenamide, 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-;Aids013145
• CAS NO: 108605-62-5
• Molecular Formula: C12H9F3N2O2
• Molecular Weight: 270.21
• EINECS: 1308068-626-2
• Product Categories: Various Metabolites and Impurities;Metabolites & Impurities;Tyrosine Kinase Inhibitors
• Mol File: 108605-62-5.mol

Chemical Properties

• Boiling Point: 410.8 °C at 760 mmHg
• Flash Point: 202.3 °C
• Appearance: White solid.
• Density: 1.424 g/cm³
• Vapor Pressure: 6.63E-06mmHg at 25°C
• Refractive Index: 1.551
• Storage Temp.: +2C to +8C
• Solubility: Soluble in DMSO (up to 30 mg/ml), or in Ethanol (up to 5 mg/ml with warming).
• PKA: 5.20±0.50(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 3 months.
• CAS DataBase Reference: A77 1726(CAS DataBase Reference)
• NIST Chemistry Reference: A77 1726(108605-62-5)
• EPA Substance Registry System: A77 1726(108605-62-5)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• Hazardous Substances Data: 108605-62-5(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
A77 1726 is used as a disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis.
A77 1726 is used as an immunosuppressant for the treatment of multiple sclerosis (MS), reducing the frequency of relapses and slowing the progression of the disease.
A77 1726 is used as an inhibitor of the mitochondrial enzyme dihydroorotate dehydrogenase, leading to reduced B and T cell proliferation, which helps in managing the immune response in both rheumatoid arthritis and multiple sclerosis.

Clinical Use

Immunomodulating agent: Treatment of relapsing remitting multiple sclerosis

Synthesis

Numerous syntheses of teriflunomide have been developed to date, most relying on the use of 4- trifluoromethyl aniline (167). The current optimized method for scale-up synthesis of teriflunomide, developed by Keshav and coworkers, begins with reaction of commercial 4-trifluoromethyl aniline 167 and ethylacetoacetate (168) in refluxing xylenes, providing acetoamidate 169 in 51% yield . The resulting acetoamidate 169 was then treated with H2O2, KBr, and concentrated HCl at room temperature, providing bromide 170 in 67% yield. Bromide 170 was reacted with NaCN in DMSO, generating teriflunomide (XXVI) in 85% yield.

Drug interactions

Potentially hazardous interactions with other drugs Lipid-lowering agents: effect significantly reduced by colestyramine - avoid; concentration of rosuvastatin increased - consider reducing rosuvastatin dose. Live vaccines: risk of generalised infections - avoid.

Metabolism

Teriflunomide is the active metabolite of leflunomide. It is moderately metabolised and teriflunomide is the only component detected in plasma. The main biotransformation pathway is hydrolysis with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation. Teriflunomide is excreted in the gastrointestinal tract mainly through the bile as unchanged drug and most likely by direct secretion.

References

1) Manna et al. (1999), Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression; J. Immunol., 162 2095 2) Davis et al. (1996), immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase; Biochemistry, 35 1270 3) Seah et al. (2008), Oxidative bioactivation and toxicity of leflunomide in immortalized human hepatocytes and kinetics of the non-enzymatic conversion to its major metabolite, A77 1726; Drug Metab. Lett., 2 153

InChI:InChI=1/C12H9F3N2O2/c1-7(18)10(6-16)11(19)17-9-4-2-8(3-5-9)12(13,14)15/h2-5,17,19H,1H3/b11-10-

Upstream product

• 75706-12-6 Leflunomide 
• 773837-37-9 sodium cyanide 
• 1206724-43-7 2-bromo-3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide 
• 42831-50-5 5-methyl-1,2-oxazole-4-carboxylic acid 
• 24522-30-3 2-cyano-N-(4-trifluoromethylphenyl)acetamide 
• 75-36-5 acetyl chloride 
• 75706-11-5 2-ethoxymethyleneacetoacetyl-(4-trifluoromethyl)aniline 
• 351-87-1 N-(4-trifluoromethylphenyl)-2-acetylacetamide 
• 455-14-1 4-trifluoromethylphenylamine 
• 87853-82-5 ethyl 2-cyano-3-hydroxybut-2-enoate 
• 7647-01-0 hydrogenchloride 
• 108-24-7 acetic anhydride 

Relevant articles and documents

Leflunomide analogues as potential antiinflammatory agents.

A series of leflunomide (1a) analogues were examined for antiinflammatory activity using the carrageenan-induced paw edema assay. Some of the compounds were significantly more potent than leflunomide, particularly those with electron-donating or negative inductive groups situated in the phenyl rings. In contrast, all the nonsubstituted compounds or with further chain-extension in the 4-position of the rings led to a decrease in activity. The LD(50) values of the most active compounds (1d, g-j) in male ICR mice were significantly greater than those of either 1a or its active metabolite 2 and therefore merit further study.

Kemp Eliminases of the AlleyCat Family Possess High Substrate Promiscuity

Minimalist enzymes designed to catalyze model reactions provide useful starting points for creating catalysts for practically important chemical transformations. We have shown that Kemp eliminases of the AlleyCat family facilitate conversion of leflunomid

In vitro monitoring of ring opening of leflunomide: A surface enhanced Raman scattering and DFT based approach

The in vitro mechanism of ring opening of leflunomide resulting in the formation of a metabolite A771726 has been studied by time series surface enhanced Raman spectra using NaOH buffer at pH ～10. The decomposition of leflunomide into A771726 through NO bond cleavage was identified by the Raman signature of CN bond of A771726. The experimental results have been correlated with theory by transition state calculations of the reaction using different basic catalysts; OH-, formate and formate + water and water alone. The reaction barrier energy is found to be lowest with OH-as a catalyst.

Simple preparation method of teriflunomide

The invention provides a simple preparation method of teriflunomide, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps of: (1) mixing 5-methylisoxazole-4-formic acid and a condensing agent in a solvent under an alkaline condition, and carrying out condensation reaction to obtain an active ester system; (2) mixing the active ester system and 4-trifluoromethylaniline in a solvent, and carrying out condensation reaction to obtain an intermediate leflunomide; and (3) carrying out alkali treatment and acid treatment on the obtained intermediate leflunomide to obtain teriflunomide. According to the method, the 5-methylisoxazole-4-formic acid reacts with the 4-trifluoromethylaniline in the form of active ester, so that the reaction activity of the 5-methylisoxazole-4-formic acid and the 4-trifluoromethylaniline is improved, the reaction condition is mild, the obtained intermediate leflunomide does not need to be purified, and the yield of teriflunomide is improved.

Preparation process of continuous-flow teriflunomide

To the preparation process, cyanoacetic acid is used as a starting material, cyanoacetyl chloride is prepared by chlorination, and a tertamine intermediate is synthesized by cyanacetyl chloride and p-trifluoromethylaniline, and an intermediate is synthesized with acetyl chloride. The invention has high safety. The utility model has the advantages of low cost, low energy consumption and high production yield.

Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function

Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca2+-signals and non-selective cation currents, the other weaker Ca2+-signals and Na+-selective currents. These properties were mirrored by the Ca2+- mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Agonist action was differentially inhibited by mutation of a single TPC2 residue and coupled to opposing changes in lysosomal pH and exocytosis. Our findings resolve conflicting reports on the permeability and gating properties of TPC2 and they establish a new paradigm whereby a single ion channel mediates distinct, functionally-relevant ionic signatures on demand.

Preparation method of teriflunomide

The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of teriflunomide. The preparation method includes: (1) mixing cyanoacetic acid, a condensingagent, an aprotic solvent and an alkaline reagent, and c

METHOD FOR THE PREPARATION OF TERIFLUNOMIDE

The present invention relates to a method for preparation of Teriflunomide, comprising steps of: (a) adding Leflunomide to an alcoholic solvent to give solution (I); (b) adding an aqueous sodium hydroxide solution slowly into the solution (I) to give solution (II); (c) acidifying the solution (II) with inorganic acid for precipitation to give solution (III); and (d) filtering the solution (III) to give Teriflunomide.

Exploiting intramolecular hydrogen bonding for the highly (: Z)-selective & metal free synthesis of amide substituted β-aminoenones

Herein, we report the metal free and intramolecular hydrogen bonding (IMHB) directed (Z)-selective synthesis of amide substituted β-aminoenones. Systematically, we confirm the role of dual IMHB (CO?H-N) on the Z-direction using single-crystal X-ray analysis and 1D and 2D NMR studies. High stereoselectivity, atom efficiency, excellent yields and high purity are achieved by mere filtration. We avoid column purification and the formed by-product in the process is environmentally friendly.

AN IMPROVED PROCESS FOR THE PREPARATION OF TERIFLUNOMIDE

The present invention relates to an improved process for the preparation of Teriflunomide with high yield and high purity. The present invention also relates to a process for the preparation of teriflunomide which is free from genotoxic impurities.