Methotrexate

Base Information

• Chemical Name: Methotrexate
• CAS No.: 59-05-2
• Deprecated CAS: 1082707-84-3
• Molecular Formula: C20H22N8O5
• Molecular Weight: 454.445
• Hs Code.: 29335995
• European Community (EC) Number: 200-413-8
• NSC Number: 740
• UN Number: 3249
• UNII: YL5FZ2Y5U1
• DSSTox Substance ID: DTXSID4020822
• Nikkaji Number: J2.334E
• Wikipedia: Methotrexate
• Wikidata: Q422232
• NCI Thesaurus Code: C642
• RXCUI: 6851
• Pharos Ligand ID: QBHCSP2DG8TT
• Metabolomics Workbench ID: 42898
• ChEMBL ID: CHEMBL34259
• Mol file: 59-05-2.mol

Synonyms:Amethopterin;Dicesium Salt Methotrexate;Hydrate, Methotrexate;Methotrexate;Methotrexate Hydrate;Methotrexate Sodium;Methotrexate, (D)-Isomer;Methotrexate, (DL)-Isomer;Methotrexate, Dicesium Salt;Methotrexate, Disodium Salt;Methotrexate, Sodium Salt;Mexate;Sodium, Methotrexate

Chemical Property of Methotrexate

Chemical Property:

• Appearance/Colour: yellow crystalline powder
• Melting Point: 195 °C
• Refractive Index: 1.6910 (estimate)
• Boiling Point: 561.26°C (rough estimate)
• PKA: pKa 3.04/4.99(H2O,t =25,I=0.0025) (Uncertain)
• Flash Point: 11℃
• PSA: 210.54000
• Density: 1.536 g/cm³
• LogP: 1.82170
• Storage Temp.: −20°C
• Sensitive.: Light Sensitive & Hygroscopic
• Solubility.: H2O: insoluble
• Water Solubility.: Insoluble.
• XLogP3: -1.8
• Hydrogen Bond Donor Count: 5
• Hydrogen Bond Acceptor Count: 12
• Rotatable Bond Count: 9
• Exact Mass: 454.17131583
• Heavy Atom Count: 33
• Complexity: 704
• Transport DOT Label: Poison

Purity/Quality:

99%min ^*data from raw suppliers

4-Amino-N10-methylpteroyl-L-glutamic acid ^*data from reagent suppliers

Safty Information:

• Pictogram(s): T
• Hazard Codes: T,F
• Statements: 61-25-36/38-46-39/23/24/25-23/24/25-11
• Safety Statements: 53-26-36/37-45-36/37/39-36-16

MSDS Files:

SDS file from LookChem

Total 1 MSDS from other Authors

Useful:

• Drug Classes: Antineoplastic Agents
• Canonical SMILES: CN(CC1=CN=C2C(=N1)C(=NC(=N2)N)N)C3=CC=C(C=C3)C(=O)NC(CCC(=O)O)C(=O)O
• Isomeric SMILES: CN(CC1=CN=C2C(=N1)C(=NC(=N2)N)N)C3=CC=C(C=C3)C(=O)N[C@@H](CCC(=O)O)C(=O)O
• Recent ClinicalTrials: Testing the Use of Steroids and Tyrosine Kinase Inhibitors With Blinatumomab or Chemotherapy for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia in Adults
• Recent EU Clinical Trials: Evaluation of Amivantamab Infusion Related Reaction Mitigation
• Recent NIPH Clinical Trials: Cardiac Sarcoidosis Multi-Center Randomized Controlled Trial
• Drug Interactions: 1, Alcohol and other drugs which can cause liver damage, if used in combination with this product, may further increase liver toxicity. 2, since methotrexate can cause increased blood uric acid levels, for patients with gout or hyperuricemia, you should respectively increase the dose of allopurinol and colchicine. 3, the product can enhance the anti-clotting effect, and can even cause lack of liver coagulation factors (and) thrombocytopenia, and therefore we should be cautious for using it in combination with other anticoagulants. 4, with the simultaneous administration of Phenylbutazone and sulfa drugs, because of it competition with protein binding, this product may cause increased serum concentration and lead to toxicity. 5, Oral administration of the kanamycin can increase the absorption of this drug upon oral administration, and oral neomycin may reduce its absorption. 6, Combination with a weak organic acid and salicylate can inhibit the renal excretion of this product, further resulting in increased serum concentrations of the drug. We should reduce the dosage appropriately according to the actual case. 7, Drugs like triamterene and pyrimethamine can have anti-folate effects with simultaneous use of this product being able to increase its side effects. 8, Combination with fluorouracil or first using fluorouracil before administering this drug can both produce antagonism. But if first use this drug and then administer fluorouracil after 4~6h can have synergistic effect. Similarly, this drug, if being used in combination with L-asparaginase can also lead to reduced efficiency, as with the latter 10 days or within 24h after administration of this product to L-asparaginase Instead applying the L-asparaginase at ten days after using the later one or at 24 h within using this product can enhance the efficacy and reduce its side effects on the digestive tract and bone marrow. It has been reported recently applying cytarabine at 24 h before using this product or 10 mins after can increase the anti-cancer activity of this product. We should be cautious when applied methotrexate in combination with radiotherapy or other kinds of drugs on bone marrow suppression.
• Production method: It is obtained from the cyclization between 2, 4, 5, 6-tetraaminopyrimidine and dibromo propionaldehyde and further condensation with p-N-Methylaminobenzoylglutamic acid.
• Uses: Methotrexate is used to treat severe lymphatic leukemia, choriocarcinoma, non-Hodgkin’s lymphoma, bone carcinoma, as well as head, neck, breast, and lung tumors. A Folic acid antagonist. Used as a antineoplastic and antirheumatic. Anti-cancer dietary supplement, crosses the blood-brain barrier, potential activities as anxiolytic and vasodilator A deuterated folic acid antagonist Used as a antineoplastic and antirheumatic. A folic Acid antagonist
• Indications: Methotrexate is approved for use in severe disabling psoriasis recalcitrant to other less toxic treatments. The standard regimen is similar to low-dose therapy used for the treatment of rheumatoid arthritis . Although toxicities are similar to those described in the treatment of other diseases, hepatic cirrhosis and unexpected pancytopenia are of special concern given the chronicity of treatment. Of the DMARDs, methotrexate (Rheumatrex) is the most widely prescribed. It is indicated for the treatment of rheumatoid arthritis and psoriasis; it is also used for psoriatic arthritis, systemic lupus erythematosus, and sarcoidosis. It is generally as efficacious as the other agents, with a low incidence of serious side effects when prescribed on a low-dose weekly schedule. Methotrexate competitively inhibits the binding of folic acid to the enzyme dihydrofolate reductase. Tetrahydrofolate is in turn converted to N5,N10- methylenetetrahydrofolate, which is an essential cofactor for the synthesis of thymidylate, purines, methionine, and glycine. The major mechanism by which methotrexate brings about cell death appears to be inhibition of DNA synthesis through a blockage of the biosynthesis of thymidylate and purines. Cells in S-phase are most sensitive to the cytotoxic effects of methotrexate. RNA and protein synthesis also may be inhibited to some extent and may delay progression through the cell cycle, particularly from G1 to S. Methotrexate, for example, is highly bound to serum albumin and can be displaced by salicylates, sulfonamides, phenothiazines, phenytoin, and other organic acids. The induction of hepatic drugmetabolizing enzymes by phenobarbital may alter the metabolism of cyclophosphamide to both active and inactive metabolites. Mercaptopurine metabolism is blocked by allopurinol, an occurrence that may result in lethal toxicity if the dosage of mercaptopurine is not reduced to one-fourth of the usual dosage. Methotrexate is secreted actively by the renal tubules, and its renal clearance may be delayed by salicylates.
• Therapeutic Function: Antineoplastic
• Biological Functions: Although the mechanism of action of methotrexate in rheumatoid arthritis is unknown, recent studies have shown that methotrexate reversibly inhibits dihydrofolate reductase, blocking the proliferation of B cells by interfering with DNA synthesis, repair, and replication. Oral absorption is dose-dependent, being well-absorbed at doses of 7.5–25 mg once a week. At this dose, oral bioavailability is approximately 60%, and food can delay absorption and reduce peak concentration. The volume of distribution is 0.4 to 0.8 L/kg. Protein binding is approximately 50%. It is metabolized to active metabolites, methotrexate polyglutamates and 7-hydroxymethotrexate. Some metabolism occurs by intestinal flora after oral administration. Methotrexate is actively transported into the urine (80–90% unchanged in the urine within 24 hours) via the folate transporter, an organic anion transporter. Its elimination half-life is 3 to 10 hours.
• Clinical Use: Methotrexate is part of curative combination chemotherapy for acute lymphoblastic leukemias, Burkitt’s lymphoma, and trophoblastic choriocarcinoma. It is also useful in adjuvant therapy of breast carcinoma; in the palliation of metastatic breast, head, neck, cervical, and lung carcinomas; and in mycosis fungoides. High-dose methotrexate administration with leucovorin rescue has produced remissions in 30% of patients with metastatic osteogenic sarcoma. Methotrexate is one of the few anticancer drugs that can be safely administered intrathecally for the treatment of meningeal metastases. Its routine use as prophylactic intrathecal chemotherapy in acute lymphoblastic leukemia has greatly reduced the incidence of recurrences in the CNS and has contributed to the cure rate in this disease. Daily oral doses of methotrexate are used for severe cases of the nonneoplastic skin disease psoriasis, and methotrexate has been used as an immunosuppressive agent in severe rheumatoid arthritis.
• Drug interactions: Potentially hazardous interactions with other drugs Anaesthetics: antifolate effect increased by nitrous oxide - avoid. Analgesics: increased risk of toxicity with NSAIDs - avoid. Antibacterials: absorption possibly reduced by neomycin; antifolate effect increased with co-trimoxazole and trimethoprim; penicillins and possibly ciprofloxacin reduce excretion of methotrexate (increased risk of toxicity); increased haematological toxicity with doxycycline, sulphonamides and tetracycline. Antiepileptics: concentration possibly increased by levetiracetam. Antimalarials: antifolate effect enhanced by pyrimethamine. Antipsychotics: avoid with clozapine (increased risk of agranulocytosis). Ciclosporin: methotrexate may inhibit the clearance of ciclosporin or its metabolites; ciclosporin may inhibit methotrexate elimination. Corticosteroids: increased risk of haematological toxicity. Cytotoxics: effects of methotrexate antagonised by asparaginase, crisantaspase and pegasparagase - give asparaginase, crisantaspase and pegasparagase 24 hours after methotrexate; increased pulmonary toxicity with cisplatin. Leflunomide: risk of toxicity. Probenecid: excretion of methotrexate reduced. Retinoids: concentration increased by acitretin, also increased hepatotoxicity - avoid. Ulcer-healing drugs: PPIs may reduce high dose methotrexate elimination; consider temporarily stopping PPI

Technology Process of Methotrexate

There total 31 articles about Methotrexate 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: 100.0%

L-glutamic acid (56-86-0,21675-62-7,23009-64-5,25104-13-6,84960-48-5,25513-46-6) + 4-{[N-[(2,4-diamino-6-pteridinyl)methyl]-N-methyl]amino}benzoyl azide (56892-87-6) → N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid (59-05-2)

Guidance literature:

With 1,1,3,3-tetramethylguanidine; In dimethyl sulfoxide; at 25 ℃; for 1h;

DOI:10.1021/ja971568j

Reference yield: 56.2%

L-p-methylaminobenzoyl glutamate zinc salt + 6-bromomethylpterin (89794-15-0) → N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid (59-05-2)

Guidance literature:

With hydrogen bromide; In water; at 55 ℃; for 2.2h; Temperature; Reagent/catalyst;

Reference yield: 51.4%

methopterin hydrate → N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid (59-05-2)

Guidance literature:

With pyridine; hydrogenchloride; p-toluenesulfonic acid monohydrate; 1,1,1,3,3,3-hexamethyl-disilazane;

upstream raw materials:

2-L-alanylmethotrexate

methotrexate di-t-butyl ester

2-L-leucylmethotrexate

L-glutamic acid

Downstream raw materials:

4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-N-[(S)-4-oxo-1-(piperidine-1-carbonyl)-4-piperidin-1-yl-butyl]-benzamide

dimethyl N-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoyl)-L-glutamate

γ-methyl N'-<4--N-methylamino>benzoyl>-L-glutamate

bis(6-chloropiperonyl) methotrexate

Refernces

• 1、 -. "METHOTREXATE ANALOGS AND METHODS OF USE". . . Retrieved 2022/01/04.
• 2、 Peiró Cadahía, Jorge,Bondebjerg, Jon,Hansen, Christian A.,Previtali, Viola,Hansen, Anders E.,Andresen, Thomas L.,Clausen, Mads H.. "Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis". . p. 3503 - 3515. Retrieved 2018/05/01.