1421373-66-1

Basic information

• Product Name: AZD-9291 (Mesylate)
• Synonyms: AZD-9291 (Mesylate);N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide methanesulfonate (1:1);AZD-9291 mesylate N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide methanesulfonate (1:1);Osimertinib mesylate;Mereletinib mesylate;Osimertinib;N-[2-(2-dimethylaminoethylmethylamino)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide mesylate salt;Osimertinib Mesylate(AZD9291)
• CAS NO: 1421373-66-1
• Molecular Formula: CH₄O₃S*C₂₈H₃₃N₇O₂
• Molecular Weight: 595.71298
• EINECS: 200-064-1
• Product Categories: AZD09
• Mol File: 1421373-66-1.mol

Chemical Properties

• Appearance: /
• Storage Temp.: -20°C Freezer, Under inert atmosphere
• Solubility: DMSO (Slightly), Methanol (Slightly)
• CAS DataBase Reference: AZD-9291 (Mesylate)(CAS DataBase Reference)
• NIST Chemistry Reference: AZD-9291 (Mesylate)(1421373-66-1)
• EPA Substance Registry System: AZD-9291 (Mesylate)(1421373-66-1)

Safety Data

• Hazardous Substances Data: 1421373-66-1(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
AZD-9291 (Mesylate) is used as an anticancer agent for the treatment of EGFR T790M mutation-positive non-small cell lung cancer. It modulates oncological signaling pathways by inhibiting the activity of mutated EGFR, exerting inhibitory effects on tumor growth and progression.
Used in Drug Delivery Systems:
AZD-9291 (Mesylate) is used in drug delivery systems to enhance its applications and efficacy against cancer cells. Various drug delivery systems, including organic and metallic nanoparticles, have been employed as carriers for AZD-9291 (Mesylate) delivery, aiming to improve its delivery, bioavailability, and therapeutic outcomes.

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.

Side effects

Osimertinib toxicity is dose-dependent and is associated with fewer gastrointestinal and dermatologic adverse events than with other approved EGFR TKIs.

Synthesis

Friedel-Crafts arylation of commercial N-methylindole (203) with commercial dichloropyrimidine 202 gave the 3- pyrazinyl indole 204 in good yield. Subsequent SNAr with nitroaniline 205 (available from a one-step nitration from the commercially available des-nitroaniline) provided aminopyrazine 206. Next, SN Ar reaction of 206 with N,N,N′- trimethylated ethylenediamine delivered 207 in near quantitative yield, and this was followed by nitro reduction with iron under acidic conditions to give rise to the triaminated arene 208 in 85% yield. Because acrylates are notoriously difficult to install directly due to their highly reactive nature and propensity to polymerize, a clever two-step acylation/ elimination sequence was employed using 3-chloropropanoyl chloride, and this was immediately followed by mesylate salt formation, which furnished the osimertinib mesylate (XXVI) in excellent yield. This seven-step process which derives from readily available feedstock delivered the final product in nearly 57% overall yield from starting materials 202 and 203.

Synthetic route

methanesulfonic acid (75-75-2) + [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) → 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 (1421373-66-1)

Conditions	Yield
Stage #1: [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] With pyrographite In acetone at 25 - 55℃; Stage #2: methanesulfonic acid at 25 - 55℃;	96.73%
With N-ethyl-N,N-diisopropylamine In ethanol; ethyl acetate at 70℃; for 1.5h;	94%
In water; acetone at 50℃; for 1.5h; Inert atmosphere;	94%

4-fluoro-2-methoxy-5-nitro-phenylamine (1075705-01-9) → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: toluene-4-sulfonic acid / 2.5 h / 105 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 3.1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 4.1: N-ethyl-N,N-diisopropylamine / water; tetrahydrofuran / 0.25 h / 0 - 20 °C 4.2: 10 h / 65 °C 5.1: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 5 steps 1: toluene-4-sulfonic acid / 2.5 h / 105 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 3: iron; ammonium chloride / water; ethanol / 2 h / Reflux 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / Cooling with ice 5: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 6 steps 1: toluene-4-sulfonic acid / 2.5 h / 105 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 3: iron; ammonium chloride / water; ethanol / 2 h / Reflux 4: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 5: triethylamine / acetonitrile / 6 h / 80 °C 6: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme

N‑2‑[[2‑(dimethylamino)ethyl]methylamino]‑4‑methoxy‑5‑[[4‑(1‑methyl‑1H‑indole-3-yl)-2-pyrimidinyl]amino]aniline (1421372-66-8) → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / water; tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 10 h / 65 °C 2.1: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / Cooling with ice 2: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 2: triethylamine / acetonitrile / 6 h / 80 °C 3: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme

N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine (1421372-67-9) → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 2.1: N-ethyl-N,N-diisopropylamine / water; tetrahydrofuran / 0.25 h / 0 - 20 °C 2.2: 10 h / 65 °C 3.1: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 3 steps 1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / Cooling with ice 3: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 4 steps 1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 2: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 3: triethylamine / acetonitrile / 6 h / 80 °C 4: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indole-3-yl)-pyrimidine-2-amine (1421372-94-2) → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 2.1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 3.1: N-ethyl-N,N-diisopropylamine / water; tetrahydrofuran / 0.25 h / 0 - 20 °C 3.2: 10 h / 65 °C 4.1: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 2: iron; ammonium chloride / water; ethanol / 2 h / Reflux 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / Cooling with ice 4: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 2: iron; ammonium chloride / water; ethanol / 2 h / Reflux 3: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 4: triethylamine / acetonitrile / 6 h / 80 °C 5: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme

2-chloro-4-(1'-methyl-1H-indol-3-yl)pyrimidine (1032452-86-0) → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: toluene-4-sulfonic acid / 2.5 h / 105 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 3.1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 4.1: N-ethyl-N,N-diisopropylamine / water; tetrahydrofuran / 0.25 h / 0 - 20 °C 4.2: 10 h / 65 °C 5.1: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 5 steps 1: toluene-4-sulfonic acid / 2.5 h / 105 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 3: iron; ammonium chloride / water; ethanol / 2 h / Reflux 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / Cooling with ice 5: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 6 steps 1: toluene-4-sulfonic acid / 2.5 h / 105 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 3: iron; ammonium chloride / water; ethanol / 2 h / Reflux 4: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 5: triethylamine / acetonitrile / 6 h / 80 °C 6: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme

3-(2-chloro-pyrimidin-4-yl)-1H-indole (945016-63-7) → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 1.2: 3 h / 0 °C 2.1: toluene-4-sulfonic acid / 2.5 h / 105 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 4.1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 5.1: N-ethyl-N,N-diisopropylamine / water; tetrahydrofuran / 0.25 h / 0 - 20 °C 5.2: 10 h / 65 °C 6.1: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 6 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 1.2: 3 h / 0 °C 2.1: toluene-4-sulfonic acid / 2.5 h / 105 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 4.1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / Cooling with ice 6.1: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 1.2: 3 h / 0 °C 2.1: toluene-4-sulfonic acid / 2.5 h / 105 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 4.1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 5.1: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 6.1: triethylamine / acetonitrile / 6 h / 80 °C 7.1: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 6 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere 1.2: 3 h / 0 °C / Inert atmosphere 2.1: toluene-4-sulfonic acid / 2.5 h / 105 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / 2,2,2-trifluoroethanol / 1 h / 140 °C / Inert atmosphere 4.1: ammonium chloride; iron / ethanol; water / 2 h / 100 °C / Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / 0 °C / Inert atmosphere 6.1: water; acetone / 1.5 h / 50 °C / Inert atmosphere View Scheme

3-chloro-N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)propanamide (1421373-36-5) → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 6 h / 80 °C 2: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydroxide / tetrahydrofuran; water / 10 h / 65 °C 2: water; ethanol / 1.5 h / 70 °C View Scheme

indole (120-72-9) → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: methylmagnesium bromide / diethyl ether; 1,2-dichloro-ethane / 0.42 h / 0 °C / Inert atmosphere 1.2: 16 h / 0 - 20 °C / Inert atmosphere 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 2.2: 3 h / 0 °C 3.1: toluene-4-sulfonic acid / 2.5 h / 105 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 5.1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / Cooling with ice 7.1: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 7 steps 1.1: methylmagnesium bromide / diethyl ether; 1,2-dichloro-ethane / 0.42 h / 0 °C / Inert atmosphere 1.2: 16 h / 0 - 20 °C / Inert atmosphere 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 2.2: 3 h / 0 °C 3.1: toluene-4-sulfonic acid / 2.5 h / 105 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 5.1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 6.1: N-ethyl-N,N-diisopropylamine / water; tetrahydrofuran / 0.25 h / 0 - 20 °C 6.2: 10 h / 65 °C 7.1: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 8 steps 1.1: methylmagnesium bromide / diethyl ether; 1,2-dichloro-ethane / 0.42 h / 0 °C / Inert atmosphere 1.2: 16 h / 0 - 20 °C / Inert atmosphere 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 2.2: 3 h / 0 °C 3.1: toluene-4-sulfonic acid / 2.5 h / 105 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 5.1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 6.1: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 7.1: triethylamine / acetonitrile / 6 h / 80 °C 8.1: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 7 steps 1.1: methylmagnesium bromide / diethyl ether; 1,2-dichloro-ethane / 0.25 h / 0 °C / Inert atmosphere 1.2: 16 h / 0 °C / Inert atmosphere; Heating 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere 2.2: 3 h / 0 °C / Inert atmosphere 3.1: toluene-4-sulfonic acid / 2.5 h / 105 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine / 2,2,2-trifluoroethanol / 1 h / 140 °C / Inert atmosphere 5.1: ammonium chloride; iron / ethanol; water / 2 h / 100 °C / Inert atmosphere 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / 0 °C / Inert atmosphere 7.1: water; acetone / 1.5 h / 50 °C / Inert atmosphere View Scheme

4-fluoro-2-methoxyaniline (450-91-9) → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sulfuric acid; potassium nitrate / 15 °C / Cooling with ice 2.1: toluene-4-sulfonic acid / 2.5 h / 105 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 4.1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 5.1: N-ethyl-N,N-diisopropylamine / water; tetrahydrofuran / 0.25 h / 0 - 20 °C 5.2: 10 h / 65 °C 6.1: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 6 steps 1: sulfuric acid; potassium nitrate / 15 °C / Cooling with ice 2: toluene-4-sulfonic acid / 2.5 h / 105 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 4: iron; ammonium chloride / water; ethanol / 2 h / Reflux 5: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / Cooling with ice 6: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 7 steps 1: sulfuric acid; potassium nitrate / 15 °C / Cooling with ice 2: toluene-4-sulfonic acid / 2.5 h / 105 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 4: iron; ammonium chloride / water; ethanol / 2 h / Reflux 5: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 6: triethylamine / acetonitrile / 6 h / 80 °C 7: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme

1-methylindole (603-76-9) → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: iron(III) chloride / 1,2-dimethoxyethane / 60 °C 2.1: toluene-4-sulfonic acid / 2.5 h / 105 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 4.1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 5.1: N-ethyl-N,N-diisopropylamine / water; tetrahydrofuran / 0.25 h / 0 - 20 °C 5.2: 10 h / 65 °C 6.1: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 6 steps 1: iron(III) chloride / 1,2-dimethoxyethane / 60 °C 2: toluene-4-sulfonic acid / 2.5 h / 105 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 4: iron; ammonium chloride / water; ethanol / 2 h / Reflux 5: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / Cooling with ice 6: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 7 steps 1: iron(III) chloride / 1,2-dimethoxyethane / 60 °C 2: toluene-4-sulfonic acid / 2.5 h / 105 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 85 °C 4: iron; ammonium chloride / water; ethanol / 2 h / Reflux 5: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 6: triethylamine / acetonitrile / 6 h / 80 °C 7: N-ethyl-N,N-diisopropylamine / ethyl acetate; ethanol / 1.5 h / 70 °C View Scheme
Multi-step reaction with 6 steps 1.1: aluminum (III) chloride / 1,2-dimethoxyethane / 0.08 h / 20 °C / Inert atmosphere 1.2: 2 h / 80 °C / Inert atmosphere 2.1: toluene-4-sulfonic acid / 2.5 h / 105 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / 2,2,2-trifluoroethanol / 1 h / 140 °C / Inert atmosphere 4.1: ammonium chloride; iron / ethanol; water / 2 h / 100 °C / Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / 0 °C / Inert atmosphere 6.1: water; acetone / 1.5 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1: cobalt(II) chloride; thionyl chloride / acetonitrile / 4 h / 60 °C 2: toluene-4-sulfonic acid / acetonitrile / 12 h / 85 °C 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 2 h / 85 °C 4: ammonium chloride; cobalt(II) sulphate heptahydrate; hydrazine hydrate / ethanol; water / 8 h / 85 °C 5: sodium carbonate / N,N-dimethyl-formamide / 2 h / -5 °C 6: ethanol; isopropyl alcohol / 12 h / 45 °C View Scheme

2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4(3H)-one → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 6 steps 1: sodium methylate / toluene / 12 h / 100 °C 2: hydrogen / ethanol / 5 h / 20 °C / 3750.38 Torr 3: trichlorophosphate / tetrahydrofuran / 12 h / 35 °C 4: potassium hydride / 1,2-dichloro-ethane / 8 h / 50 °C 5: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 12 h / 40 °C 6: dichloromethane / 4 h / 20 °C View Scheme

2-(4-(N-(2-(dimethylamino)ethyl)-N-methylamino)-2-methoxy-5-nitrophenylamino) pyrimidine-4(3H)-one → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: hydrogen / ethanol / 5 h / 20 °C / 3750.38 Torr 2: trichlorophosphate / tetrahydrofuran / 12 h / 35 °C 3: potassium hydride / 1,2-dichloro-ethane / 8 h / 50 °C 4: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 12 h / 40 °C 5: dichloromethane / 4 h / 20 °C View Scheme

2-(4-(N-(2-(dimethylamino)ethyl)-N-methylamino)-2-methoxy-5-aminophenylamino)pyrimidine-4(3H)-one → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: trichlorophosphate / tetrahydrofuran / 12 h / 35 °C 2: potassium hydride / 1,2-dichloro-ethane / 8 h / 50 °C 3: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 12 h / 40 °C 4: dichloromethane / 4 h / 20 °C View Scheme

2-(4-(N-(2-(dimethylamino)ethyl)-N-methylamino)-2-methoxy-5-aminophenylamino)-4-chloropyrimidine → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium hydride / 1,2-dichloro-ethane / 8 h / 50 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 12 h / 40 °C 3: dichloromethane / 4 h / 20 °C View Scheme

3-(2-aminopyrimidin-4-yl)-1-methyl-1H-indole (199865-36-6) + methanesulfonic acid (75-75-2) + 1-methoxy-2-nitro-5-[(N-(dimethylamino)ethyl)-Ν-methylamino]-4-cinnamamide → 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 (1421373-66-1)

Conditions	Yield
Stage #1: 3-(2-aminopyrimidin-4-yl)-1-methyl-1H-indole; 1-methoxy-2-nitro-5-[(N-(dimethylamino)ethyl)-Ν-methylamino]-4-cinnamamide With diammonium sulfide In isopropyl alcohol Stage #2: methanesulfonic acid	18.5 g

4-Chloro-3-nitroaniline (635-22-3) → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium iodide / 55 °C / Alkaline conditions 2: bromine; iron; acetic acid 3: Alkaline conditions 4: diammonium sulfide / isopropyl alcohol View Scheme

N-(4-methoxy-3-nitrophenyl) acrylamide → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: bromine; iron; acetic acid 2: Alkaline conditions 3: diammonium sulfide / isopropyl alcohol View Scheme

1-methoxy-2-nitro-4-acrylamido-5-bromobenzene → 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 (1421373-66-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: Alkaline conditions 2: diammonium sulfide / isopropyl alcohol View Scheme

methanesulfonic acid (75-75-2) + 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 (1421373-66-1) → N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methyl-indol-3-yl)pyrimidine 2-yl]amino}phenyl)prop-2-enamide dimesylate

Conditions	Yield
In ethanol; water at 60℃; for 14.75h;

Upstream product

• 1421373-36-5 3-chloro-N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)propanamide 
• 75-75-2 methanesulfonic acid 
• 1421373-65-0 [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] 
• 1421372-66-8 N?2?[[2?(dimethylamino)ethyl]methylamino]?4?methoxy?5?[[4?(1?methyl?1H?indole-3-yl)-2-pyrimidinyl]amino]aniline 
• 814-68-6 acryloyl chloride 
• 1421372-94-2 N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indole-3-yl)-pyrimidine-2-amine 
• 1421372-67-9 N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine 
• 1075705-01-9 4-fluoro-2-methoxy-5-nitro-phenylamine 
• 635-22-3 4-Chloro-3-nitroaniline 
• 199865-36-6 3-(2-aminopyrimidin-4-yl)-1-methyl-1H-indole 
• 603-76-9 1-methylindole 
• 450-91-9 4-fluoro-2-methoxyaniline 
• 120-72-9 indole 
• 945016-63-7 3-(2-chloro-pyrimidin-4-yl)-1H-indole 

Relevant articles and documents

Preparation method of osimertinib mesylate

The invention discloses a preparation method of osimertinib mesylate. 4-fluoro-2-methoxy-5-nitroaniline and 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole are subjected to a condensation reaction and then subjected to a nucleophilic substitution reaction with N, N-dimethylethylenediamine, a high-purity compound shown in the formula (6) is obtained through Eschweiler-Clarke amine reductive alkylation, water serves as a solvent, acetic acid and the like serve as a cosolvent, catalytic hydrogenation is performed, amidation reaction with acryloyl chloride is carried out to obtain high-purity osimertinib and salifying with methanesulfonic acid is carried out to obtain osimertinib mesylate, and compared with the patent CN103702990B, the method is simple and convenient to operate, less in environmental pollution, high in yield, low in cost, good in product quality and more suitable for industrial production.

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The present invention relates to an improved process for the preparation of Osimertinib mesylate with high purity and high yield.

Synthetic method of osimertinib AZD9291

The invention provides a synthetic method of osimertinib AZD9291; an intermediate (III) is synthesized by adopting CoCl2/SoCl2 to catalyze; an intermediate (VIII) is synthesized by adopting CoSO4.7H2Oto carry out catalytic reduction; in the preparation of an intermediate (X), sodium carbonate is used as an acid binding agent; and the intermediate (X) and methane sulfonic acid are adopted for salification in a mixed solvent of ethyl alcohol and isopropyl alcohol to prepare the AZD9291. The synthetic method provided by the invention is high in yield, mild in reaction condition, simple in after-treatment and suitable for industrial production.

Osimertinib preparation method

The present invention relates to an osimertinib preparation method, which comprises: (1) carrying out a nucleophilic substitution reaction on 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole and 4-fluoro-2-methoxy-5-nitroaniline to prepare a compound 1; (2) carrying out a substitution reaction on the compound 1 and N,N,N-trimethylethylenediamine in the presence of an organic alkali to prepare a compound 2; (3) reducing the compound 2 in the presence of a reducing agent to prepare a compound 3; (4) carrying out condensation on the compound 3 and 3-chloropropionyl chloride in the presence of an alkali to obtain a compound 4; (5) carrying out a heat elimination reaction on the compound 4 through heating in the presence of an alkali to prepare a compound 5; and (6) carrying out salification on the compound 5 and methanesulfonic acid under a heating condition to obtain osimertinib. According to the present invention, the osimertinib synthesis process has characteristics of stability, controllability, no high-toxicity solvent is used, energy saving and environmental protection.

Preparation method for osimertinib mesylate

The invention discloses a preparation method for osimertinib mesylate. The chemical name of osimertinib mesylate is N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidine-2-yl)amino)phenyl)acrylamide mesylate (AZD9291), and the chemical formula is C28H33N7O2.CH4O3S. The process of the preparation technique of the preparation method is simple, materials areeasy to obtain, and the preparation method is cost-efficient and environment-friendly, can help realize industrialization, can promote the economic and technological development of osimertinib activeingredients, reduces production cost, and is suitable for mass production.

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The invention discloses a method for preparing Osimertinib mesylate. The method comprises the steps that after 3-(2-chlorine-4-pyrimidinly)-1-methyl-1H-indole is subjected to substitution reaction with 4-fluorine-2-methoxy-5-nitroaniline, 3-(2-chlorine-4-pyrimidinly)-1-methyl-1H-indole is subjected to substitution reaction with N,N,N'-trimethyl-ethylenediamine, nitro is restored after catalytic hydrogenation, then 3-(2-chlorine-4-pyrimidinly)-1-methyl-1H-indole is subjected to coupling reaction with 3-chloropropionyl-chloride, osimertinib is obtained after elimination with sodium hydroxide, and osimertinib reacts with salt mesylate in acetone and water to obtain osimertinib mesylate, wherein a catalyst for restoring nitro by the catalytic hydrogenation is raney nickel, palladium carbon or palladium-carbon hydroxide. The method for preparing osimertinib mesylate is low in cost, high in yield, little in environmental pollution, simple and easy in production process operation and suitable for industrialized production.

Osimertinib mesylate preparation method

The invention discloses an osimertinib mesylate preparation method. The method includes: subjecting 2-chloropyrimidine-4(3H)-ketone and 4-fluoro-2-methoxy-5-nitroaniline to substitution reaction; subjecting obtained 2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyridine-4(3H)-ketone and N,N,N'-trimethyl ethylenediamine to substitution reaction; subjecting obtained 2-(4-(N-(2-(dimethylamino)ethyl)-N-methyl amino-2-methoxy-5-nitrophenylamino)pyridine-4(3H)-ketone to nitro reduction reaction; subjecting obtained 2-(4-(N-(2-(dimethylamino)ethyl)-N-methyl amino-2-methoxy-5-aminophenylamino)pyridine-4(3H)-ketone to chlorination; subjecting obtained 2-(4-(N-(2-(dimethylamino)ethyl)-N-methyl amino-2-methoxy-5-aminophenylamino)-4-choropyridine and 1-methyl-1H-indol to condensation reaction; subjecting obtained 2-(4-(N-(2-(dimethylamino)ethyl)-N-methyl amino-2-methoxy-5-aminophenylamino)-4-(1-methyl-1H-indol-3-yl)pyridine and acryloyl chloride to amidation; finally performing salt forming reaction to obtain osimertinib mesylate. The osimertinib mesylate preparation method is reasonable and concise in process route, simplified in operation and low in cost and is an environment-friendly method suitable for industrial production.

Crystal form gamma of compound A mesylate and pharmaceutical composition containing the same

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Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate

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