163451-81-8

Basic information

• Product Name: A77 1726
• Synonyms: A77 1726 (Teriflunomide);LeflunoMide EP IMpurity B;A 1726;Flucyamide;HMR 1726;(Z)-2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide
• CAS NO: 163451-81-8
• Molecular Formula: C12H9F3N2O2
• Molecular Weight: 270.2072696
• EINECS: 1308068-626-2
• Product Categories: Metabolites & Impurities;Tyrosine Kinase Inhibitors
• Mol File: 163451-81-8.mol

Chemical Properties

• Melting Point: 229-232°C
• Boiling Point: 410.8 °C at 760 mmHg
• Flash Point: 202.3 °C
• Appearance: white to beige/
• Density: 1.424 g/cm³
• Vapor Pressure: 6.63E-06mmHg at 25°C
• Refractive Index: 1.551
• Storage Temp.: Hygroscopic, -20°C Freezer, Under Inert Atmosphere
• Solubility: DMSO: soluble5mg/mL, clear (warmed)
• PKA: 5.20±0.50(Predicted)
• Merck: 14,9165
• CAS DataBase Reference: A77 1726(CAS DataBase Reference)
• NIST Chemistry Reference: A77 1726(163451-81-8)
• EPA Substance Registry System: A77 1726(163451-81-8)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• WGK Germany: 3
• Hazardous Substances Data: 163451-81-8(Hazardous Substances Data)

Usage

Uses

Used in Multiple Sclerosis Treatment:
A77 1726 is used as an immunomodulatory agent for the treatment of relapsing forms of multiple sclerosis. It works by inhibiting the de novo synthesis of pyrimidines, which suppresses the effector functions of activated lymphocytes and dampens the effect of an overactive immune system.
Used in Rheumatoid Arthritis Treatment:
A77 1726 is used as a disease-modifying antirheumatic drug for the treatment of active moderate-to-severe rheumatoid arthritis. It inhibits dihydroorotate dehydrogenase (DHODH), which is involved in the de novo synthesis of pyrimidines, and also inhibits the production of prostaglandin E2 (PGE2) in synoviocytes activated by TNF-α and IL-1α.
Used in Drug Delivery Systems:
A77 1726 can be used in various drug delivery systems, such as organic and metallic nanoparticles, to improve its delivery, bioavailability, and therapeutic outcomes in the treatment of cancer cells.
Used in Psoriatic Arthritis Treatment:
A77 1726 is also used as a treatment option for psoriatic arthritis, where it helps in reducing the symptoms and progression of the disease.
Used in Experimental Autoimmune Encephalomyelitis (EAE) Treatment:
A77 1726 has been shown to delay disease onset and decrease neurological deficits in a rat model of EAE induced by complete Freund’s adjuvant (CFA) and M. tuberculosis.
Used in Clinical and Diagnostic Testing:
A77 1726 serves as an analytical reference standard for use in LC/MS or GC/MS applications, including clinical and diagnostic testing such as therapeutic drug monitoring assays.

Originator

Genzyme (United States)

Biochem/physiol Actions

Teriflunomide is an orally available anti-inflammatory immunomodulator. It blocks the activity of dihydroorotate dehydrogenase, preventing pyrimidine synthesis and T and B cell proliferation and function. Teriflunomide has been used to treat rheumatoid arthritis and was recently approved for multiple sclerosis.

references

[1] yao h w, li j, chen j q, et al. a 771726, the active metabolite of leflunomide, inhibits tnf-α and il-1 from kupffer cells[j]. inflammation, 2004, 28(2): 97-103.[2] breedveld f c, dayer j m. leflunomide: mode of action in the treatment of rheumatoid arthritis[j]. annals of the rheumatic diseases, 2000, 59(11): 841-849.[3] burger d, begué‐pastor n, benavent s, et al. the active metabolite of leflunomide, a77 1726, inhibits the production of prostaglandin e2, matrix metalloproteinase 1 and interleukin 6 in human fibroblast‐like synoviocytes[j]. rheumatology, 2003, 42(1): 89-96.[4] davis j p, cain g a, pitts w j, et al. the immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase[j]. biochemistry, 1996, 35(4): 1270-1273.

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 
• 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 
• 773837-37-9 sodium cyanide 
• 1206724-43-7 2-bromo-3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide 

Downstream Products

• 695191-69-6 5-amino-3-methyl-isoxazole-4-carboxylic acid (4-trifluoromethyl-phenyl)-amide 

Relevant articles and documents

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

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

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.

A NOVEL PROCESS FOR THE PREPARATION OF TERIFLUNOMIDE

The present invention provides a process for the preparation of Teriflunomide (Formula-I). The present invention describes the synthesis of Teriflunomide without isolating the intermediate Leflunomide. Teriflunomide is prepared from 5-Methyl isoxazole-4-carboxylic acid by converting to its acid chloride and coupling with 4-trifluoromethyl aniline to obtain Leflunomide (which is not isolated) followed by ring opening reaction using aq. Sodium Hydroxide to form Teriflunomide. In other words, the process is telescoped from 5- methylisoxazole-4-carbonyl chloride.

Comprehensive Study of the Organic-Solvent-Free CDI-Mediated Acylation of Various Nucleophiles by Mechanochemistry

Acylation reactions are ubiquitous in the synthesis of natural products and biologically active compounds. Unfortunately, these reactions often require the use of large quantities of volatile and/or toxic solvents, either for the reaction, purification or isolation of the products. Herein we describe and discuss the possibility of completely eliminating the use of organic solvents for the synthesis, purification and isolation of products resulting from the acylation of amines and other nucleophiles. Thus, utilisation of N,N′-carbonyldiimidazole (CDI) allows efficient coupling between carboxylic acids and various nucleophiles under solvent-free mechanical agitation, and water-assisted grinding enables both the purification and isolation of pure products. Critical parameters such as the physical state and water solubility of the products, milling material, type of agitation (vibratory or planetary) as well as contamination from wear are analysed and discussed. In addition, original organic-solvent-free conditions are proposed to overcome the limitations of this approach. The calculations of various green metrics are included, highlighting the particularly low environmental impact of this strategy.