AZD-9291

Base Information

• Chemical Name: AZD-9291
• CAS No.: 1421373-65-0
• Molecular Formula: C28H33N7O2
• Molecular Weight: 499.616
• Hs Code.: 29339900
• Mol file: 1421373-65-0.mol

Synonyms:AZD-9291;N(2{[2(diMethylaMino)ethyl](Methyl)aMino}4Methoxy5{[4(1Methyl1Hindol3yl)pyriMidin2yl]aMino}phenyl)prop2enaMide;N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide;AZD9291,AZD-9291;2-Propenamide, N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-;AZD9291 N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide;N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide AZD9291;N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

Chemical Property of AZD-9291

Chemical Property:

• PKA: 12.68±0.70(Predicted)
• PSA: 0.00000
• Density: 1.19±0.1 g/cm3(Predicted)
• LogP: 0.00000
• Storage Temp.: Hygroscopic, -20°C Freezer, Under inert atmosphere
• Solubility.: DMSO (Slightly, Heated), Methanol (Slightly, Heated)

Purity/Quality:

99%, ^*data from raw suppliers

AZD9291(Osimertinib) ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Uses: AZD-9291 (Osimertinib) is a oral, third generation, small-molecule epidermal growth factor receptor (EGFR) inhibitor and antineoplastic agent. In addition, it is a Cytochrome P450 3A inhibitor, and Cytochrome P450 3A4 Inducer, and Cytochrome P450 1A2 Inducer, and Breast Cancer Resistance Protein Inhibitor. It is used for the treatment of advanced non-small cell lung cancer (NSCLC) where mutant EGFR form (such as T790M) is often presented. Through suppressing the EGFR-mediated signalling, it cause cell death and inhibit tumour growth in related cancer cells. AZD 9291 is an irreversible inhibitor of epidermal growth factor receptor (EGFR) sensitizing and T790M resistance mutations (IC50s = 15-17 nM) while sparing the wild-type form of the receptor (IC50 = 480 nM). It binds the related IGF1R and hERG receptors with significantly reduced potency (IC50s = 2.9 and 16.2 μM, respectively). AZD 9291 has been shown to inhibit tumor growth in a xenograft mouse model at oral doses of 5-10 mg/kg and has been tested clinically in patients with advanced EGFR mutant non-small-cell lung cancer.[Cayman Chemical]
• Description: AZD-9291 (Mesylate), also known as Osimertinib, belongs to a third-generation EGFR (epidermal growth factor receptor) inhibitor. It can be used for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in case when the cancer cells carry specific mutations (such as T790M) in the epidermal growth factor receptor. It takes effect through directly binding to the certain mutant forms of EGFR (T790M, L858R, and exon 19 deletions) that are frequently found in NSCLC, further causing poor prognosis for late-stage disease. Since it spares wild type EGFR during therapy, it has only limited toxicity.
• Indications: The collection of ibrutinib (Imbruvica(R), Pharmacyclics Inc.), afatinib, and osimertinib represents the small, yet expanding, group of covalent SMKIs. Ibrutinib is a non-receptor Bruton’s tyrosine kinase inhibitor approved for the treatment of relapsed chronic lymphocytic leukemia. Afatinib, approved for NSCLC in 2013 and squamous NSCLC in 2016, is a second-generation irreversible EGFR inhibitor that targets wild-type EGFR, the mutant T790M EGFR, and HER2. Osimertinib (AZD9291), which was approved by FDA in November 2015, is a third-generation irreversible EGFR inhibitor that selectively targets the mutant T790M EGFR. Rociletinib, which shares a high degree of structural similarity with that of osimertinib, is a promising covalent EGFR inhibitor developed by Clovis Oncology aimed for the treatment of patients with EGFR T790M-mutated NSCLC, until the company terminated its development in May 2016 following a negative vote fromthe FDA’sOncologic Drugs Advisory Committee.

Technology Process of AZD-9291

There total 74 articles about AZD-9291 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: 97.9%

N?2?[[2?(dimethylamino)ethyl]methylamino]?4?methoxy?5?[[4?(1?methyl?1H?indole-3-yl)-2-pyrimidinyl]amino]aniline (1421372-66-8) + acrylic acid (79-10-7) → [N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)propen-2-amide] (1421373-65-0)

Guidance literature:

In isopropyl alcohol; at 35 ℃; for 4h; Temperature; Time; Solvent; Molecular sieve; Microwave irradiation;

Reference yield: 95.5%

N?2?[[2?(dimethylamino)ethyl]methylamino]?4?methoxy?5?[[4?(1?methyl?1H?indole-3-yl)-2-pyrimidinyl]amino]aniline (1421372-66-8) + acryloyl chloride (814-68-6,25189-84-8) → [N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)propen-2-amide] (1421373-65-0)

Guidance literature:

With sodium carbonate; In N,N-dimethyl-formamide; at -5 ℃; for 2h; Temperature; Solvent;

Reference yield: 94.0%

N?2?[[2?(dimethylamino)ethyl]methylamino]?4?methoxy?5?[[4?(1?methyl?1H?indole-3-yl)-2-pyrimidinyl]amino]aniline (1421372-66-8) + 2-chloropropionyl chloride (625-36-5) → [N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)propen-2-amide] (1421373-65-0)

Guidance literature:

N?2?[[2?(dimethylamino)ethyl]methylamino]?4?methoxy?5?[[4?(1?methyl?1H?indole-3-yl)-2-pyrimidinyl]amino]aniline; 2-chloropropionyl chloride; With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; water; at 0 - 20 ℃; for 0.25h;

With sodium hydroxide; In tetrahydrofuran; water; at 65 ℃; for 10h;

upstream raw materials:

4-fluoro-2-methoxy-5-nitro-phenylamine

N?2?[[2?(dimethylamino)ethyl]methylamino]?4?methoxy?5?[[4?(1?methyl?1H?indole-3-yl)-2-pyrimidinyl]amino]aniline

acryloyl chloride

2-chloropropionyl chloride

Downstream raw materials:

N-(2-(N-(2-(dimethylamino)ethyl)-N-methylamino)-4-methoxy-5-((4-(1-methyl-1H-indole-3-yl)pyrimidine-2-yl)amino)phenyl)acrylamide methanesulfonate

Refernces

• 1、 Alivertis, Dimitrios,Skobridis, Konstantinos,Voulgari, Pinelopi. "Improvements in the Synthesis of the Third-Generation EGFR Inhibitor Osimertinib". . . Retrieved 2021/10/19.
• 2、 -. "Industrial preparation method of AZD9291". Paragraph 0031-0042. . Retrieved 2021/03/03.