108605-62-5 Usage
Description
Teriflunomide (Aubagio?), also known as A77 1726, is an immunosupressant marketed by Sanofi for
the teatment of multiple sclerosis (MS). Teriflunomide is the active metabolite of leflunomide, used
for treatment of patients diagnosed with rheumatoid arthritis, and therefore simultaneously can be used
as a treatment for rheumatoid arthritis.Teriflunomide acts as an inhibitor of the mitochondrial
enzyme dihydrorotate dehydrogenase, inhibiting pyrimidine formation, and resulting in reduced
B and T cell proliferation.
Chemical Properties
White Solid
Uses
The active metabolite of Leflunomide, 2-Cyano-3-hydroxy-N-(4'-trifluoromethylphenyl)-crotone amide can be used as a potent disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis.
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
Check Digit Verification of cas no
The CAS Registry Mumber 108605-62-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,0,8,6,0 and 5 respectively; the second part has 2 digits, 6 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 108605-62:
(8*1)+(7*0)+(6*8)+(5*6)+(4*0)+(3*5)+(2*6)+(1*2)=115
115 % 10 = 5
So 108605-62-5 is a valid CAS Registry Number.
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-
108605-62-5Relevant articles and documents
Leflunomide analogues as potential antiinflammatory agents.
Huang, Wen-Hsin,Yang, Chiao-Li,Lee, An-Rong,Chiu, Hui-Fen
, p. 313 - 314 (2003)
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.
In vitro monitoring of ring opening of leflunomide: A surface enhanced Raman scattering and DFT based approach
Sharma, Poornima,Gangopadhyay, Debraj,Singh, Pushkar,Mishra,Deckert, Volker,Popp, Jürgen,Singh, Ranjan K.
, p. 127 - 132 (2014)
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.
Preparation process of continuous-flow teriflunomide
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Paragraph 0041; 0049-0053; 0061-0065; 0073-0076, (2021/11/21)
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.
Preparation method of teriflunomide
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Paragraph 0051-0077, (2020/04/02)
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