Afatinib

Base Information

• Chemical Name: Afatinib
• CAS No.: 439081-18-2
• Molecular Formula: C₂₄H₂₅ClFN₅O₃
• Molecular Weight: 485.946
• Hs Code.: 29349990
• European Community (EC) Number: 810-720-4
• NSC Number: 750691
• UNII: 41UD74L59M
• DSSTox Substance ID: DTXSID20893451
• Nikkaji Number: J3.363.130H,J2.685.397D
• Wikipedia: Afatinib
• Wikidata: Q4688818
• NCI Thesaurus Code: C66940
• RXCUI: 1430438
• Pharos Ligand ID: L93TLR94JUC1
• Metabolomics Workbench ID: 61624
• ChEMBL ID: CHEMBL1173655
• Mol file: 439081-18-2.mol

Synonyms:(2E)-N-(4-(3-chloro-4-fluoroanilino)-7-(((3S)-oxolan-3-yl)oxy)quinoxazolin-6-yl)-4-(dimethylamino)but-2-enamide;afatinib;afatinib dimaleate;afatinib maleate;BIBW 2992;BIBW 2992 MA2;BIBW 2992MA2;BIBW-2992;BIBW-2992-MA2;BIBW-2992MA2;BIBW2992;BIBW2992 MA2;Gilotrif

Chemical Property of Afatinib

Chemical Property:

• Appearance/Colour: Off-White Solid
• Vapor Pressure: 0mmHg at 25°C
• Melting Point: 100 - 102 °C
• Refractive Index: 1.668
• Boiling Point: 676.917 °C at 760 mmHg
• PKA: 12.06±0.43(Predicted)
• Flash Point: 363.186 °C
• PSA: 88.61000
• Density: 1.380 g/cm³
• LogP: 4.53590
• Solubility.: ≥24.3 mg/mL in DMSO; insoluble in H2O; ≥42.1 mg/mL in EtOH with ultrasonic
• XLogP3: 3.6
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 8
• Rotatable Bond Count: 8
• Exact Mass: 485.1629955
• Heavy Atom Count: 34
• Complexity: 702

Purity/Quality:

99% ^*data from raw suppliers

BIBW2992 ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

Useful:

• Drug Classes: Antineoplastic Agents
• Canonical SMILES: CN(C)CC=CC(=O)NC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=C(C=C3)F)Cl)OC4CCOC4
• Isomeric SMILES: CN(C)C/C=C/C(=O)NC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=C(C=C3)F)Cl)O[C@H]4CCOC4
• Recent ClinicalTrials: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101)
• Recent EU Clinical Trials: AFAMOSI: Prospective, randomized, multicenter Phase IV study to evaluate the efficacy and safety of afatinib followed by osimertinib compared to osimertinib in patients with EGFRmutated/T790M Mutation negative non-squamous NSCLC in the first-line setting.
• Recent NIPH Clinical Trials: NEJ025B
• Indications: Afatinib belongs to a class of drugs known as tyrosine kinase inhibitors. Tyrosine kinase inhibitors are designed to block the action of a specific enzyme called tyrosine kinase. This enzyme plays a big role in the function of cells, and is active in promoting tumor growth and progression. Afatinib works to inhibit the function of two types of tyrosine kinases: epidermal growth factor receptor (EGFR) and Her2, which are "over-expressed" by several types of cancer. By blocking the function of these tyrosine kinases, afatinib may prevent cancer cells from dividing and growing. Afatinib was approved by the United States Food and Drug Administration (FDA) as the first-line treatment for a subset of patients with advanced non-small cell lung cancer. The patients for which afatinib was approved have lung cancer that carries a particular kind of mutation that results in an abnormal EGFR protein. These patients are most likely to be of Asian descent, women, and never smokers with a form of lung cancer known as bronchoalveolar adenocarcinoma. Clinical experience with erlotinib and gefitinib has shown that these patients respond particularly well to tyrosine kinase inhibitors that block the EGFR. This proved to be true for afatinib as well, which increased the progression-free survival of this group of patients to 13.6 months as compared to only 6.9 months for patients treated with standard chemotherapy. Erlotinib is also approved in the United States as a first-line treatment for this subgroup of patients. Longer clinical experience will be needed to determine which drug is the best choice. Afatinib may be somewhat more potent than erlotinib, but its side effects, primarily rash and diarrhea, are also more severe.
• Description: In July 2013, the US FDA approved afatinib (also referred to as BIBW- 2992), for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) and with tumors that have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution. Afatinib functions as an irreversible inhibitor by covalently binding directly to the ATP-binding site in the kinase domains of both EGFR(Cys 773) andHER2 (Cys 805;HER-2 is the preferred dimerization partner of EGFR) resulting in downregulation of EGFR signaling. Afatinib is a potent inhibitor of wild-type and mutant forms (L858R) of EGFR (IC50s of 0.5 and 0.4 nM, respectively), and HER2 (IC50=14 nM), but about 100-fold more active against the gefitinib resistant L858R– T790M EGFR double mutant, with an IC50 of 10 nM. Consistent with its in vitro activity, afatinib induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. A synthetic route to afatinib that employs the displacement of a phenylsulfonyl group to install the (S)-3-hydoxytetrahydrofuran ring and a modified Horner–Wadsworth–Emmons reaction with {[4-(3-chloro-4- phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl]- methyl}-phosphonate and dimethylaminoacetaldehyde-hydrogen sulfite adduct to install the eneamide moiety, has been reported.
• Uses: BIBW2992 (Afatinib, Tomtovok, Tovok) irreversibly inhibits EGFR/HER2 including EGFRwt, EGFRL858R, EGFRL858R/T790M and HER2 with IC50 of 0.5 nM, 0.4 nM, 10 nM and 14 nM, respectively.

Technology Process of Afatinib

There total 82 articles about Afatinib 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%

6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline (314771-76-1,402855-03-2) + (E)-4-(dimethylamino)-2-butenoic acid methyl ester (212776-19-7) → afatinib (850140-72-6,1680184-59-1,945553-91-3,439081-17-1,439081-18-2)

Guidance literature:

6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline; With trimethylaluminum; In hexane; dichloromethane; at 20 ℃; for 2h;

(E)-4-(dimethylamino)-2-butenoic acid methyl ester; In hexane; dichloromethane; at 60 ℃; for 5h; Solvent;

Reference yield: 97.7%

(S)-diethyl 2-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)-2-oxoethylphosphonate (618061-76-0) + dimethylaminoacetaldehyde diethyl acetal (3616-56-6) → afatinib (850140-72-6,1680184-59-1,945553-91-3,439081-17-1,439081-18-2)

Guidance literature:

dimethylaminoacetaldehyde diethyl acetal; With hydrogenchloride; In water; at 20 - 30 ℃; Inert atmosphere;

(S)-diethyl 2-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)-2-oxoethylphosphonate; With lithium chloride; potassium hydroxide; In tetrahydrofuran; at -15 - 20 ℃; for 2.5h; Product distribution / selectivity; Inert atmosphere;

Reference yield: 97.5%

6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline (314771-76-1,402855-03-2) + trans-4-dimethylamino crotonic acid chloride hydrochloride salt (1055943-40-2) → afatinib (850140-72-6,1680184-59-1,945553-91-3,439081-17-1,439081-18-2)

Guidance literature:

In tetrahydrofuran; at 0 - 5 ℃;

upstream raw materials:

4-cyanophenol

4-hydroxy-3-nitrobenzonitrile

3-chloro-4-fluorophenylamine

6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

Refernces

• 1、 -. "Arab league law for nepal preparation method of the compound". . . Retrieved 2019/04/10.
• 2、 -. "Preparation method of afatinib maleate". Paragraph 0026; 0032; 0034; 0035; 0036. . Retrieved 2019/12/25.