Leflunomide

Base Information

• Chemical Name: Leflunomide
• CAS No.: 75706-12-6
• Deprecated CAS: 210165-51-8
• Molecular Formula: C12H9F3N2O2
• Molecular Weight: 270.211
• Hs Code.: 2934990002
• European Community (EC) Number: 616-254-6
• NSC Number: 759864,677411
• UNII: G162GK9U4W
• DSSTox Substance ID: DTXSID9023201
• Nikkaji Number: J227.599F
• Wikipedia: Leflunomide
• Wikidata: Q248550
• NCI Thesaurus Code: C1128
• RXCUI: 27169
• Pharos Ligand ID: 9VYUZN1KLN3X
• Metabolomics Workbench ID: 43327
• ChEMBL ID: CHEMBL960
• Mol file: 75706-12-6.mol

Synonyms:Arava;HWA 486;HWA-486;HWA486;leflunomide;N-(4-trifluoromethyphenyl)-5-methylisoxazole-4-carboxamide;SU101

Chemical Property of Leflunomide

Chemical Property:

• Appearance/Colour: off white crystalline solid
• Melting Point: 163-168 °C
• Boiling Point: 289.3 °C at 760 mmHg
• PKA: 10.8(at 25℃)
• Flash Point: 128.8 °C
• PSA: 55.13000
• Density: 1.392 g/cm³
• LogP: 3.32710
• Storage Temp.: 2-8°C
• Solubility.: Practically insoluble in water, freely soluble in methanol, sparingly soluble in methylene chloride.
• XLogP3: 2.5
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 6
• Rotatable Bond Count: 2
• Exact Mass: 270.06161202
• Heavy Atom Count: 19
• Complexity: 327

Purity/Quality:

99%min ^*data from raw suppliers

Leflunomide ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xn, Xi
• Hazard Codes: Xn,Xi
• Statements: 22-36/37/38
• Safety Statements: 26-36

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Antirheumatic Agents
• Canonical SMILES: CC1=C(C=NO1)C(=O)NC2=CC=C(C=C2)C(F)(F)F
• Recent ClinicalTrials: Leflunomide for the Treatment of High-Risk Smoldering Multiple Myeloma in African-American and European-American Patients
• Recent EU Clinical Trials: NEw Clinical End-points in patients with primary Sj?gren’s Syndrome (pSS): an Interventional Trial based on stratifYing patients
• Uses: (1) It is hydrogenated acid dehydrogenase inhibitor with immunosuppressive and anti-inflammatory effects for the treatment of adults with active rheumatoid arthritis. (2) Nonsteroidal anti-inflammatory drug. An immunosuppressive. Inhibits T and B cell proliferation. Activity is attributed mainly to its metabolite, a malononitrile derivative, which is beleived to inhibit dihydroorotate dehydrogenase as well as several protein tyrosine kinases. Therapeutical By virtue of its immunosuppressant effects, leflunomide has found use in organ transplantation and treatment of rheumatoid arthritis and other autoimmune diseases.
• Production method: Ethyl acetoacetate, triethyl orthoformate and acetic anhydride are refluxed together to the complete reaction of raw materials, about 5h. Distillate and collect? 140 150 ℃/1.87kPa fraction, the compound ( I) is obtained, in 85% yield. Compound (I) is dissolved in ethanol,the mixture of hydroxylamine hydrochloride, sodium acetate and water is added dropwise at 10-15 ℃ and 1h, After dropping,react for about 8h.Concentrated hydrochloric acid and glacial acetic acid are added ,then reflux? for 5h. Concentrate under reduced pressure to 1/2 volume, cool to 10 ℃, filtration, recrystallize ethanol-water? ,compound (Ⅱ) is obtained, it is white crystalline powder, melting point 145-146.5 ℃, in 80% yield. Compound (II) is dissolved in toluene and thionyl chloride is added dropwise at 50-55℃, reflux for 3h. After concentration, distillation, collect? 78-79 ℃/1.87kPa fraction, the compound (III) is obtained, in 75% yield. Trifluoromethyl aniline and triethylamine are dissolved? in dichloromethane, at 0-5 ℃ solution ,the compound (Ⅲ) is added. Then at 25--30 ℃ reaction lasts 3h. Water is added, the organic layer is separated, wash with water, wash with brine, and dry. Concentrate under reduced pressure to 1/3 volume, petroleum ether is added, cool, filter, and recrystallize from ethyl acetate to give white crystals powder of leflunomide , m.p. 166~167 ℃, in yield 81%.
• Description: Leflunomide is an orally-available disease-modifying antirheumatic drug and was launched as Arava in the US for the treatment of rheumatoid arthritis (RA) ; it is the first and only drug to be indicated to slow down structural joint damage of RA, so addressing an unmet medical need. Leflunomide is prepared in 3 steps from the appropriate acetoacetic anilide using a nitrile oxide- enamine cycloaddition reaction to assemble the isoxazole ring. Leflunomide is a prodrug, being extensively metabolized in vivo into the corresponding 2-cyano-3-hydroxy-2-butenamide resulting from fragmentation of the isoxazole ring. This cyanoenol is actually the active metabolite and several experiments in animals have demonstrated that after oral administration, substantial and sustained levels of this metabolite were delivered to the systemic circulation. In vitro, Leflunomide’s active metabolite inhibits dihydroorotate dehydrogenase, an enzyme involved in the biosynthesis of pyrimidine nucleotides, probably accounting for its immunosuppressive effect in vivo. Other mechanisms of action such as inhibition of tyrosine kinase and inhibition of responsiveness to interleukin-2 have been proposed. In diverse models of autoimmune or allergic diseases, Leflunornide showed efficacy both prophylactically and therapeutically.
• Indications: Leflunomide (Arava) is an isoxazole derivative approved for the treatment of rheumatoid arthritis in 1998. Limited data suggest that it is comparable in efficacy to sulfasalazine and produces fewer adverse effects. It has a faster onset of action (4 weeks) than other DMARDs.
• Therapeutic Function: Immunosuppressive, Antiarthritic
• Biological Functions: Leflunomide is inactive, but teriflunomide inhibits pyrimidine de novo synthesis at low therapeutic doses by inhibiting dihydroorotate dehydrogenase (the rate-determining enzyme for the synthesis of UMP), decreasing DNA and RNA synthesis, and arresting the cell proliferation cycle and production of antibodies. The reduction of dihydroorotate to orotate occurs concurrently with the reduction of its cofactor, ubiquinone (coenzyme Q). The inhibition of dihydroorotate dehydrogenase by teriflunomide demonstrates noncompetitive and uncompetitive kinetics. Administration of leflunomide in patients with rheumatoid arthritis results in progressive removal of B cells and down-regulation of the immune process. Teriflunomide not only inhibits B-cell proliferation but also T-cell proliferation, blocking the synthesis of immunosuppressive cytokines. At high therapeutic doses, leflunomide inhibits protein tyrosine kinases.
• Clinical Use: Leflunomide is a DMARD with anti-inflammatory and immunosuppressive activity used for the management of rheumatoid arthritis. It retards structural damage associated with arthritis in adults who have moderate to severe active rheumatoid arthritis. Leflunomide also is being investigated for use in patients with solid tumors and organ transplant recipients.
• Drug interactions: Potentially hazardous interactions with other drugs Hepatotoxic or haemotoxic drugs: increased risk of toxicity. Cytotoxics: risk of toxicity with methotrexate. Lipid-lowering agents: effect significantly reduced by colestyramine - avoid. Live vaccines: avoid concomitant use.

Technology Process of Leflunomide

There total 18 articles about Leflunomide which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 98.0%

C40H45AuF6N4O2 → Leflunomide (75706-12-6)

Guidance literature:

With tris(pentafluorophenyl)borate; In dichloromethane; at 40 ℃;

DOI:10.1126/science.aan1411

Reference yield: 94.0%

5-methyl-1,2-oxazole-4-carboxylic acid (42831-50-5) + 4-trifluoromethylphenylamine (455-14-1) → Leflunomide (75706-12-6)

Guidance literature:

With triethylamine; 1,1'-carbonyldiimidazole; In dichloromethane; at 0 ℃; Reagent/catalyst; Heating;

Reference yield: 93.0%

5-methylisoxazole-4-carbonyl chloride (67305-24-2) + 4-trifluoromethylphenylamine (455-14-1) → Leflunomide (75706-12-6)

Guidance literature:

In diethyl ether; for 0.5h; Ambient temperature;

upstream raw materials:

5-methylisoxazole-4-carbonyl chloride

4-trifluoromethylphenylamine

5-methyl-1,2-oxazole-4-carboxylic acid

4-aminobenzotrifluoride hydrochloride

Downstream raw materials:

teriflunomide

Manitimus

teriflunomide

C₁₂H₈F₃N₂O₂^(1-)*C₄H₁₂N⁽¹⁺⁾

Refernces

• 1、 -. "Simple preparation method of teriflunomide". Paragraph 0063-0068; 0072-0075; 0078-0081; 0084-0087; .... . Retrieved 2021/07/08.
• 2、 Subramaniam, Palaniraja,Ramasubbu, Chandrasekaran,Athiramu, Selvaraj. "Exploiting intramolecular hydrogen bonding for the highly (: Z)-selective & metal free synthesis of amide substituted β-aminoenones". supporting information. p. 2541 - 2545. Retrieved 2017/07/17.