1421373-65-0

Basic information

• Product Name: AZD-9291
• Synonyms: AZD9291, >=98%;AZD9291 (free base);Osimertinib (AZD-9291);ZAD9291;AZD9291, Osimertinib;AZD9291 Base;Osimertinib Base;N-(2-{[2-(Dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin
• CAS NO: 1421373-65-0
• Molecular Formula: C₂₈H₃₃N₇O₂
• Molecular Weight: 499.61
• Product Categories: Inhibitors;Anticancer;AZD9291;API
• Mol File: 1421373-65-0.mol

Chemical Properties

• Appearance: /
• Density: 1.19±0.1 g/cm3(Predicted)
• Storage Temp.: Hygroscopic, -20°C Freezer, Under inert atmosphere
• Solubility: DMSO (Slightly, Heated), Methanol (Slightly, Heated)
• PKA: 12.68±0.70(Predicted)
• CAS DataBase Reference: AZD-9291(CAS DataBase Reference)
• NIST Chemistry Reference: AZD-9291(1421373-65-0)
• EPA Substance Registry System: AZD-9291(1421373-65-0)

Safety Data

• Hazardous Substances Data: 1421373-65-0(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
AZD-9291 is used as an antineoplastic agent for the treatment of advanced non-small cell lung cancer (NSCLC) where mutant EGFR forms, such as T790M, are often presented. It suppresses EGFR-mediated signaling, leading to cell death and inhibition of tumor growth in related cancer cells.
Used in Drug Resistance:
AZD-9291 is used as an irreversible inhibitor of epidermal growth factor receptor (EGFR) sensitizing and T790M resistance mutations. It has 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.
Used in Cytochrome P450 Inhibition:
AZD-9291 is used as a Cytochrome P450 3A inhibitor, Cytochrome P450 3A4 Inducer, and Cytochrome P450 1A2 Inducer. This indicates its potential role in modulating the activity of these enzymes, which are involved in the metabolism of various drugs and substances in the body.
Used in Breast Cancer Resistance Protein Inhibition:
AZD-9291 is used as a Breast Cancer Resistance Protein Inhibitor, suggesting its potential application in overcoming drug resistance in breast cancer treatment.

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.

References

http://www.medkoo.com/products/6711 https://en.wikipedia.org/wiki/Osimertinib https://www.drugbank.ca/drugs/DB09330

Synthetic route

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)

Conditions	Yield
In isopropyl alcohol at 35℃; for 4h; Temperature; Time; Solvent; Molecular sieve; Microwave irradiation;	97.9%
In isopropyl alcohol at 35℃; for 4h; Solvent; Temperature; Molecular sieve; Microwave irradiation;	97.9%
In ethanol; Petroleum ether at 55 - 60℃; for 8h; Time; Reflux; Molecular sieve;	95.3%
Stage #1: acrylic acid With lithium carbonate; methanesulfonyl chloride In acetonitrile at 10℃; for 1.5h; Stage #2: N‑2‑[[2‑(dimethylamino)ethyl]methylamino]‑4‑methoxy‑5‑[[4‑(1‑methyl‑1H‑indole-3-yl)-2-pyrimidinyl]amino]aniline In acetonitrile at 0℃; Reagent/catalyst; Solvent; Temperature;	92.2%

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) → [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)

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide at -5℃; for 2h; Temperature; Solvent;	95.5%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 40℃; for 12h; Solvent; Reagent/catalyst; Temperature;	88%
With triethylamine In ethyl acetate at 5 - 10℃; Inert atmosphere;	86.37%

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)

Conditions	Yield
Stage #1: 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; Stage #2: With sodium hydroxide In tetrahydrofuran; water at 65℃; for 10h;	94%
Stage #1: N‑2‑[[2‑(dimethylamino)ethyl]methylamino]‑4‑methoxy‑5‑[[4‑(1‑methyl‑1H‑indole-3-yl)-2-pyrimidinyl]amino]aniline; 2-chloropropionyl chloride In tetrahydrofuran; water at 20℃; for 0.25h; Stage #2: With sodium hydroxide In tetrahydrofuran; water at 65℃; for 10h;	94%
Stage #1: N‑2‑[[2‑(dimethylamino)ethyl]methylamino]‑4‑methoxy‑5‑[[4‑(1‑methyl‑1H‑indole-3-yl)-2-pyrimidinyl]amino]aniline; 2-chloropropionyl chloride In tetrahydrofuran at 0 - 20℃; for 0.25h; Stage #2: With sodium hydroxide In tetrahydrofuran at 65℃; for 10h;	94%
Stage #1: N‑2‑[[2‑(dimethylamino)ethyl]methylamino]‑4‑methoxy‑5‑[[4‑(1‑methyl‑1H‑indole-3-yl)-2-pyrimidinyl]amino]aniline; 2-chloropropionyl chloride In tetrahydrofuran; water at 0 - 28℃; for 1h; Stage #2: With sodium hydroxide In tetrahydrofuran; water for 8h; Reflux;	79.6%
Stage #1: N‑2‑[[2‑(dimethylamino)ethyl]methylamino]‑4‑methoxy‑5‑[[4‑(1‑methyl‑1H‑indole-3-yl)-2-pyrimidinyl]amino]aniline; 2-chloropropionyl chloride In water; acetone at -3 - 30℃; for 1.5h; Stage #2: With triethylamine In water; acetone at 25 - 60℃;	77.14%

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-{[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)

Conditions	Yield
With triethylamine In acetonitrile at 80℃; for 6h;	94%
With sodium hydroxide In tetrahydrofuran; water at 65℃; for 10h;	94%
Stage #1: 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 With triethylamine In acetonitrile at 80℃; for 6h; Stage #2: With water at 20℃; for 12h;	94%

2-chloro-4-(1'-methyl-1H-indol-3-yl)pyrimidine (1032452-86-0) + 5-(N-acrylamido)-4-((N,1-(2-(N,N-dimethylamino)ethyl)-N,1-methyl)amino)-2-methoxyaniline → [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)

Conditions	Yield
With toluene-4-sulfonic acid In 2-methyl-propan-1-ol at 55℃; for 5h;	93%
With toluene-4-sulfonic acid In butan-1-ol at 40℃; for 2.5h;	92%
With potassium carbonate In N,N-dimethyl-formamide at 20 - 80℃; for 7h; Reagent/catalyst; Time;	75.5%

(2E)-3-(dimethylamino)-1-(1-methyl-1H-indol-3-yl)-2-propen-1-one (954421-16-0) + N-[2-[2-dimethylaminoethylmethylamino]-4-methoxy-5-carboxamidinephenyl]prop-2-enamide → [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)

Conditions	Yield
With sodium hydroxide In butan-1-ol at 90 - 105℃;	91%

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) + acrylic acid (79-10-7) + acryloyl chloride (814-68-6) → [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)

Conditions	Yield
Stage #1: N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine With palladium 10% on activated carbon; hydrogen In tetrahydrofuran at 20 - 50℃; Stage #2: acrylic acid; acryloyl chloride With N-ethyl-N,N-diisopropylamine at 20℃;	72.1%

acrylic acid anhydride (2051-76-5) + 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-{[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)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 5℃; for 2h;	62%

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) + 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)

Conditions	Yield
Stage #1: N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine With 5%-palladium/activated carbon; hydrogen In tetrahydrofuran at 20℃; for 2h; Stage #2: acrylic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine at 20℃; for 4h; Inert atmosphere;	61%

4-fluoro-2-methoxy-5-nitro-phenylamine (1075705-01-9) → [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)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 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 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: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 5: triethylamine / acetonitrile / 6 h / 80 °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-{[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)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 2: triethylamine / acetonitrile / 6 h / 80 °C View Scheme
Multi-step reaction with 2 steps 1: tetrahydrofuran; water / 0.25 h / 20 °C 2: sodium hydroxide / tetrahydrofuran; water / 10 h / 65 °C View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / tetrahydrofuran; water / 0 - 30 °C / Large scale 2: triethylamine / acetonitrile / 80 °C / Large scale 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-{[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)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1: iron; ammonium chloride / water; ethanol / 2 h / Reflux 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 1.5 h / Cooling with ice View Scheme
Multi-step reaction with 3 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 View Scheme

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

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 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: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 4: triethylamine / acetonitrile / 6 h / 80 °C View Scheme

2-chloro-4-(1'-methyl-1H-indol-3-yl)pyrimidine (1032452-86-0) → [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] (1421373-65-0)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 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 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: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 5: triethylamine / acetonitrile / 6 h / 80 °C View Scheme

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

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 5 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 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: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 6.1: triethylamine / acetonitrile / 6 h / 80 °C View Scheme
Multi-step reaction with 5 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 View Scheme

indole (120-72-9) → [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)

Conditions	Yield
Multi-step reaction with 6 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 View Scheme
Multi-step reaction with 6 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 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: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 7.1: triethylamine / acetonitrile / 6 h / 80 °C View Scheme
Multi-step reaction with 6 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 View Scheme

4-fluoro-2-methoxyaniline (450-91-9) → [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)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 5 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 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: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 6: triethylamine / acetonitrile / 6 h / 80 °C View Scheme

1-methylindole (603-76-9) → [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)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 5 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 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: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 6: triethylamine / acetonitrile / 6 h / 80 °C View Scheme

(4-fluoro-2-methoxy-5-nitrophenyl)carbamic acid tert-butyl ester → [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)

Conditions	Yield
Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 2 h / 60 °C 2: palladium on activated charcoal; hydrogen / methanol / 20 °C 3: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 0 °C 4: hydrogenchloride; methanol / 20 h / 20 °C 5: toluene-4-sulfonic acid / butan-1-ol / 2.5 h / 40 °C View Scheme
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 2 h / 45 °C / Inert atmosphere 2: palladium on activated charcoal; hydrogen / methanol / 2 h / 20 °C 3: hydrogenchloride / 1,4-dioxane; water / 10 h / 0 - 20 °C / Inert atmosphere 4: toluene-4-sulfonic acid / 2-methyl-propan-1-ol / 5 h / 55 °C View Scheme

N-(t-butoxycarbonyl)-4-((N,1-(2-(N,N-dimethylamino)ethyl)-N,1-methyl)amino)-2-methoxy-5-nitroanilide → [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)

Conditions	Yield
Multi-step reaction with 4 steps 1: palladium on activated charcoal; hydrogen / methanol / 20 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 0 °C 3: hydrogenchloride; methanol / 20 h / 20 °C 4: toluene-4-sulfonic acid / butan-1-ol / 2.5 h / 40 °C View Scheme
Multi-step reaction with 3 steps 1: palladium on activated charcoal; hydrogen / methanol / 2 h / 20 °C 2: hydrogenchloride / 1,4-dioxane; water / 10 h / 0 - 20 °C / Inert atmosphere 3: toluene-4-sulfonic acid / 2-methyl-propan-1-ol / 5 h / 55 °C View Scheme

N-(t-butoxycarbonyl)-5-amino-4-((N,1-(2-(N,N-dimethylamino)ethyl)-N,1-methyl)amino)-2-methoxy-5-anilide → [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)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 0 °C 2: hydrogenchloride; methanol / 20 h / 20 °C 3: toluene-4-sulfonic acid / butan-1-ol / 2.5 h / 40 °C View Scheme

4-fluoro-2-methoxy-1-nitrobenzene (448-19-1) → [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] (1421373-65-0)

Conditions	Yield
Multi-step reaction with 8 steps 1: palladium on activated charcoal; hydrogen / 20 °C 2: nitric acid; sulfuric acid / 0 - 5 °C 3: dichloromethane 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 2 h / 60 °C 5: palladium on activated charcoal; hydrogen / methanol / 20 °C 6: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 0 °C 7: hydrogenchloride; methanol / 20 h / 20 °C 8: toluene-4-sulfonic acid / butan-1-ol / 2.5 h / 40 °C View Scheme
Multi-step reaction with 7 steps 1: hydrogen / methanol / 12 h / 20 °C / 1140.08 Torr 2: potassium nitrate; sulfuric acid / 2 h / 5 - 20 °C 3: hydrogenchloride / ethanol; water / 24 h / Reflux 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 100 °C 5: butan-1-ol / 24 h / 135 °C 6: hydrogen / tetrahydrofuran / 12 h / 20 °C / 2280.15 Torr 7: N-ethyl-N,N-diisopropylamine / chloroform / 2 h / 5 - 15 °C View Scheme
Multi-step reaction with 7 steps 1: hydrogen / methanol / 12 h / 15 - 26 °C / 836.06 Torr 2: sulfuric acid; potassium nitrate / 2 h / 0 - 25 °C 3: hydrogenchloride / ethanol; water / 24.5 h / 2280.15 Torr / Reflux 4: N,N-dimethyl acetamide / 12 h / 90 °C 5: butan-1-ol / 24 h / 135 °C 6: hydrogen / tetrahydrofuran / 12 h / 25 °C / 2280.15 Torr 7: N-ethyl-N,N-diisopropylamine / chloroform / 2 h / 5 - 15 °C View Scheme

2-fluoro-4-(methoxy)aniline (458-52-6) → [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)

Conditions	Yield
Multi-step reaction with 6 steps 1: triethylamine / dichloromethane / 0 - 20 °C / Cooling with ice 2: N,N-dimethyl acetamide / 20 - 95 °C 3: sulfuric acid; potassium nitrate / 12 h / 5 - 20 °C 4: hydrogen; palladium 10% on activated carbon / ethanol / 20 °C 5: hydrogenchloride / water; butan-1-ol / 80 - 90 °C 6: sodium hydroxide / butan-1-ol / 90 - 105 °C View Scheme

N-(2-fluoro-4-methoxyphenyl)acrylamide → [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)

Conditions	Yield
Multi-step reaction with 5 steps 1: N,N-dimethyl acetamide / 20 - 95 °C 2: sulfuric acid; potassium nitrate / 12 h / 5 - 20 °C 3: hydrogen; palladium 10% on activated carbon / ethanol / 20 °C 4: hydrogenchloride / water; butan-1-ol / 80 - 90 °C 5: sodium hydroxide / butan-1-ol / 90 - 105 °C View Scheme

N-[2-[2-dimethylaminoethylmethylamino]-4-methoxyphenyl]prop-2-enamide → [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)

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid; potassium nitrate / 12 h / 5 - 20 °C 2: hydrogen; palladium 10% on activated carbon / ethanol / 20 °C 3: hydrogenchloride / water; butan-1-ol / 80 - 90 °C 4: sodium hydroxide / butan-1-ol / 90 - 105 °C View Scheme

1-methoxy-2-nitro-5-[(N-(dimethylamino)ethyl)-Ν-methylamino]-4-cinnamamide → [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)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogen; palladium 10% on activated carbon / ethanol / 20 °C 2: hydrogenchloride / water; butan-1-ol / 80 - 90 °C 3: sodium hydroxide / butan-1-ol / 90 - 105 °C View Scheme

N,N',N'-trimethylenediamine (142-25-6) → [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)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 6 h / 85 °C 2.1: iron; ammonium chloride / ethanol; water / 2 h / Reflux 3.1: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 3.2: 4 h / 20 °C 4.1: 5%-palladium/activated carbon; hydrogen / methanol / 12 h / 20 °C / 3800.26 Torr 5.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 20 - 80 °C View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate / acetonitrile / 80 °C / Inert atmosphere 2: p-toluenesulfonic acid monohydrate / isopropyl alcohol / Reflux 3: hydrogen / ethyl acetate / 40 °C / 15001.5 Torr / Autoclave 4: triethylamine / ethyl acetate / 5 - 10 °C / Inert atmosphere View Scheme

N-benzyloxycarbonyl-2-methoxy-4-fluoro-5-nitroaniline → [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)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 6 h / 85 °C 2.1: iron; ammonium chloride / ethanol; water / 2 h / Reflux 3.1: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 3.2: 4 h / 20 °C 4.1: 5%-palladium/activated carbon; hydrogen / methanol / 12 h / 20 °C / 3800.26 Torr 5.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 20 - 80 °C View Scheme

N-benzyloxycarbonyl-2-methoxy-4-[2-dimethylaminoethylmethylamino]-5-nitroaniline → [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)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: iron; ammonium chloride / ethanol; water / 2 h / Reflux 2.1: potassium carbonate / acetone / 0.5 h / -50 - -20 °C 2.2: 4 h / 20 °C 3.1: 5%-palladium/activated carbon; hydrogen / methanol / 12 h / 20 °C / 3800.26 Torr 4.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 20 - 80 °C View Scheme

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%

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-[2-dimethylaminoethylmethylamino]-4-methoxy-5-[4-(1-methylindol-3-yl)pyrimidin-2-ylamino]phenyl]prop-2-enamide methanesulfonate

Conditions	Yield
In ethanol; ethyl acetate for 2h; Time; Reflux;	94.6%

malonic acid (141-82-2) + [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) → AZD9291 malonate

Conditions	Yield
In water; acetone at 20℃; for 0.5h;	86%

[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) → 2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl) (methyl)amino)-N,N-dimethylethan-1-amine oxide

Conditions	Yield
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; for 0.5h;	85%
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 0.5h;

[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) → C27H32N8O2*(x)H2O4S

Conditions	Yield
With sulfuric acid In water; acetone at 20℃; for 0.5h;	84%

[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) + (2E)-but-2-enedioic acid (110-17-8) → AZD9291 fumarate

Conditions	Yield
In water; acetone at 20℃; for 0.5h;	84%

[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) + citric acid (77-92-9) → (x)C6H8O7*C27H32N8O2

Conditions	Yield
In water; acetone at 20℃; for 0.5h; Solvent;	81%

LACTIC ACID (849585-22-4) + [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) → AZD9291 lactate

Conditions	Yield
In water; acetone at 20℃; for 0.5h;	81%

[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) + maleic acid (110-16-7) → AZD9291 maleate

Conditions	Yield
In water; acetone at 20℃; for 0.5h;	81%

[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) + 1-bromo-3-propanol (627-18-9) → C31H39N7O3

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 potassium carbonate In acetonitrile for 0.5h; Stage #2: 1-bromo-3-propanol In acetonitrile for 12h; Reflux;	78.9%

[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) + tartaric acid (87-69-4) → (x)C4H6O6*C27H32N8O2

Conditions	Yield
In water; acetone at 20℃; for 0.5h; Solvent; Concentration;	77%

gluconic acid (526-95-4) + [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) → AZD9291 gluconate

Conditions	Yield
In water; acetone at 20℃; for 0.5h;	77%

succinic acid (110-15-6) + [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) → AZD9291 succinate

Conditions	Yield
In water; acetone at 20℃; for 0.5h;	76%

[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) + dimethyl amine (124-40-3) → 3-(dimethylamino)-N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)propanamide

Conditions	Yield
In ethanol at 20℃; for 0.5h;	73.38%

[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) + toluene-4-sulfonic acid (104-15-4) → (x)C7H8O3S*C27H32N8O2

Conditions	Yield
In water; acetone at 20℃; for 0.5h;	60%

[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) + acetic acid (64-19-7) → (x)C2H4O2*C28H33N7O2

Conditions	Yield
In water; acetone at 20℃; for 0.5h; Solvent;	52%

[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) + acrylic acid (79-10-7) → C31H38N7O4(1+)

Conditions	Yield
In water at 40℃; for 2h;	23%

Upstream product

• 954421-16-0 (2E)-3-(dimethylamino)-1-(1-methyl-1H-indol-3-yl)-2-propen-1-one 
• 32338-02-6 2-bromo-4-methoxyaniline 
• 92952-74-4 3-nitro-4-amino-6-chlorophenol 
• 610-81-1 4-hydroxy-2-nitroaniline 
• 67-56-1 methanol 
• 59557-91-4 4-bromo-2-methoxyaniline 

Downstream Products

• 1421373-66-1 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 

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