Imatinib

Base Information

• Chemical Name: Imatinib
• CAS No.: 152459-95-5
• Molecular Formula: C29H31N7O
• Molecular Weight: 493.611
• Hs Code.: 29339900
• European Community (EC) Number: 604-855-6
• NSC Number: 759854,743414
• UNII: BKJ8M8G5HI
• DSSTox Substance ID: DTXSID3037125
• Nikkaji Number: J1.337.143A
• Wikipedia: Imatinib
• Wikidata: Q177094
• NCI Thesaurus Code: C62035
• RXCUI: 282388
• Pharos Ligand ID: VLU17BQBSGWU
• Metabolomics Workbench ID: 42946
• ChEMBL ID: CHEMBL941
• Mol file: 152459-95-5.mol

Synonyms:alpha-(4-Methyl-1-piperazinyl)-3'-((4-(3-pyridyl)-2-pyrimidinyl amino)-p-tolu-p-toluidide;4-[(4-Methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide;

Chemical Property of Imatinib

Chemical Property:

• Appearance/Colour: off white powder
• Vapor Pressure: 6.03E-24mmHg at 25°C
• Melting Point: 113°C
• Boiling Point: 451°C
• PKA: pKa1 8.07; pKa2 3.73; pKa3 2.56; pKa4 1.52(at 25℃)
• Flash Point: 196°C
• PSA: 86.28000
• Density: 1.256 g/cm³
• LogP: 4.61210
• Storage Temp.: Refrigerator
• Solubility.: DMSO (Slightly, Heated), Methanol (Slightly, Heated)
• XLogP3: 3.5
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 7
• Rotatable Bond Count: 7
• Exact Mass: 493.25900864
• Heavy Atom Count: 37
• Complexity: 706

Purity/Quality:

99.0%, ^*data from raw suppliers

Imatinib, Free base ^*data from reagent suppliers

Safty Information:

• Pictogram(s): T,N
• Hazard Codes: T,N
• Safety Statements: 24/25

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Antineoplastic Agents
• Canonical SMILES: CC1=C(C=C(C=C1)NC(=O)C2=CC=C(C=C2)CN3CCN(CC3)C)NC4=NC=CC(=N4)C5=CN=CC=C5
• Recent ClinicalTrials: Serial Measurements of Molecular and Architectural Responses to Therapy (SMMART) PRIME Trial
• Recent EU Clinical Trials: A multicentre, randomized trial in adults with de novo Philadelphia-Chromosome positive acute lymphoblastic leukemia to assess the efficacy of ponatinib versus imatinib in combination with low-intensity chemotherapy, to compare end of therapy with indication for SCT versus TKI, blinatumomab and chemotherapy in optimal responders and to evaluate blinatumomab in suboptimal responders (GMALL-EVOLVE)
• Recent NIPH Clinical Trials: A phase 1 study of pimitespib and imatinib in patients with GIST
• Uses: Imatinib can be used for the treatment of the chronic myelogenous leukemia (abbreviated CML) of positive symptoms of Philadelphia chromosome (Ber-Abl). It is suitable for being applied to adult patients in acute transformation phase, accelerated phase, and chronic phase with treatment failure with interferon. Imatinib Mesylate is orally bioavailability mesylate salt of Imatinib, which is a multi-target inhibitor of v-Abl, c-Kit and PDGFR with IC50 of 0.6 μM, 0.1 μM and 0.1 μM, respectively. Imatinib also known as Gleevec, Glivec, CGP-57148B, STI-571 & Imatinib antineoplastic atypical antipsychotic Imatinib impurity.
• Indications: Bcr-Abl inhibitor imatinib (Gleevec(R), Novartis) was approved in 2001 by the FDA. Although fasudil was approved in 1995, imatinib is widely perceived as the first approved SMKI mainly owing to the fact that fasudil's kinase inhibitory mechanism was unknown at the time of approval, and efforts to gain approval of fasudil have been unsuccessful in the United States and Europe. The field of kinase inhibitor development has evolved rapidly since the approval of imatinib. Some of the key discoveries and events include (i) the discovery of MAPK/ERK inhibitors, for example, CI-1040 (PD184352), as the first series of type III inhibitors in 2003; (ii) the approval of first dual tyrosine kinase and serine/threonine kinase inhibitor sorafenib in 2005; (iii) the description of the first series of allosteric type IVkinase inhibitor, that is,GNF-2 and analogues that inhibit Bcr–Abl through an allosteric non-ATP-competitivemode, by Gray and coworkers in 2006; (iv) the approval of the first type III inhibitor trametinib in 2013; (v) the approval of the first covalent kinase inhibitors, afatinib and ibrutinib, in 2013; and (vi) the approval of the first lipid kinase inhibitor, that is, the PI3K inhibitor idelalisib, in 2014. By December 2016, kinase inhibitor drug discovery can leverage the structures of over 200 human kinases and 5000 kinases of all types, over 1 million publications, clinical data from more than 200 molecules currently in phase I–III trials, and post-marketing results from the approved 38 drugs. Imantinib mesylate (Gleevec) is a rationally designed inhibitor of the tumor-specific bcr-abl kinase. The Philadelphia chromosome, present in nearly all patients with chronic myelogenous leukemia (CML), is produced by a chromosomal rearrangement linking the bcr and the abl genes. The bcr-able kinase is therefore a unique drug target in leukemic cells, and imantinib selectively and potently inhibits this kinase. Remissions in CML patients are achieved with high frequency and very low toxicity, and this compound may become a front-line agent for treating this cancer. Unfortunately, drug resistance has already been observed in the clinic as a result of mutations in the bcr-abl kinase, and this magic bullet does not appear to be curative for CML patients. Extension of the use of imantinib to other tumor types with overexpression of c-kit kinase or platelet-derived growth factor kinase is undergoing development because of its observed activity against these kinases.
• Clinical Use: Tyrosine kinase inhibitor, antineoplastic agent: Treatment of chronic myeloid leukaemia Treatment of metastatic malignant gastrointestinal stromal tumours Treatment of acute lymphoblastic leukaemia
• Drug interactions: Potentially hazardous interactions with other drugs Antibacterials: concentration reduced by rifampicin - avoid. Anticoagulants: enhanced anticoagulant effect of warfarin, replace with heparin. Antidepressants: concentration reduced by St. Johns Wort - avoid. Antiepileptics: concentration reduced by carbamazepine, fosphenytoin, oxcarbazepine and phenytoin - avoid; absorption of phenytoin possibly reduced. Antipsychotics: avoid concomitant use with clozapine (increased risk of agranulocytosis). Antivirals: avoid with boceprevir. Ciclosporin: may increase ciclosporin levels. Cytotoxics: possibly increases bosutinib concentration - avoid or reduce bosutinib dose; concentration of everolimus and possibly ibrutinib increased - reduce dose of everolimus and ibrutinib. Tacrolimus: may increase tacrolimus levels.

Technology Process of Imatinib

There total 96 articles about Imatinib 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: 99.26%

4-((4-methylpiperazin-1-yl)methyl)benzoyl chloride dihydrochloride + N-(5-amino-2-methylphenyl)-4-(3-piridinyl)-2-pyrimidine amine → imatinib (152459-95-5)

Guidance literature:

With sodium hydroxide; In water; at 0 - 55 ℃; pH=9 - 9.5;

Reference yield: 97.52%

1-methyl-piperazine (109-01-3) + 4-(chloromethyl)-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]-amino}phenyl)benzamide (404844-11-7) → imatinib (152459-95-5)

Guidance literature:

With potassium carbonate; In N,N-dimethyl-formamide; at 80 ℃; for 4.5h; Temperature;

Reference yield: 95.8%

4-[(4-methylpiperazin-1-yl)methyl]bromobenzene (368879-17-8) + carbon monoxide (201230-82-2) + 6-methyl-1-N-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine (152460-10-1) → imatinib (152459-95-5)

Guidance literature:

With palladium diacetate; triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 50 ℃; for 36h; under 760.051 Torr; Reagent/catalyst; Solvent; Temperature; Inert atmosphere;

upstream raw materials:

6-methyl-1-N-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine

4-(4-Methylpiperazin-1-ylmethyl)benzoyl chloride

1-methyl-piperazine

4-(chloromethyl)-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]-amino}phenyl)benzamide

Downstream raw materials:

imatinib malonate

imatinib di-benzoyl-L-tartrate

imatinib di-p-anisoyl-D-tartrate

4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[[4-(3-pyridinyl)-2-pyrimidinyl]-N-acetyl]amino]phenyl]benzamide

Refernces

• 1、 Leonetti, Francesco,Capaldi, Carmelida,Carotti, Angelo. "Microwave-assisted solid phase synthesis of Imatinib, a blockbuster anticancer drug". . p. 3455 - 3458. Retrieved 2007.
• 2、 -. "SYNTHESIS OF 6-METHYL-N1-(4-(PYRIDIN-3-YL)PYRIMIDIN-2-YL)BENZENE-1,3-DIAMINE". . . Retrieved 2021/04/23.
• 3、 -. "Synthesis method of imatinib and imatinib mesylate". Paragraph 0103-0112. . Retrieved 2020/05/02.