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1421373-66-1

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1421373-66-1 Usage

Description

Osimertinib is active against exon 19 deletions, exon 21 mutations, and also the exon 20 T790M mutations. It is preferentially selective for mutated EGFR, and therefore toxicity at therapeutic doses is lower than for first- and second-generation agents. Notably, osimertinib is able to cross the blood-brain barrier, making it active against disease in the CNS.

Uses

AZD-9291 Mesylate is a potent and selective epidermal growth factor receptor (EGFR) inhibitor.

Definition

ChEBI: A methanesulfonate (mesylate) salt prepared from equimolar amounts of osimertinib and methanesulfonic acid. Used for treatment of EGFR T790M mutation positive non-small cell lung cancer.

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.

Check Digit Verification of cas no

The CAS Registry Mumber 1421373-66-1 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,4,2,1,3,7 and 3 respectively; the second part has 2 digits, 6 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 1421373-66:
(9*1)+(8*4)+(7*2)+(6*1)+(5*3)+(4*7)+(3*3)+(2*6)+(1*6)=131
131 % 10 = 1
So 1421373-66-1 is a valid CAS Registry Number.

1421373-66-1SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 15, 2017

Revision Date: Aug 15, 2017

1.Identification

1.1 GHS Product identifier

Product name AZD9291 Mesylate

1.2 Other means of identification

Product number -
Other names N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide methanesulfonate

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:1421373-66-1 SDS

1421373-66-1Synthetic route

methanesulfonic acid
75-75-2

methanesulfonic acid

[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-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)propen-2-amide]

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

Conditions
ConditionsYield
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

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

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

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

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

Conditions
ConditionsYield
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

N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine

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

Conditions
ConditionsYield
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-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indole-3-yl)-pyrimidine-2-amine

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

Conditions
ConditionsYield
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

2-chloro-4-(1'-methyl-1H-indol-3-yl)pyrimidine

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

Conditions
ConditionsYield
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

3-(2-chloro-pyrimidin-4-yl)-1H-indole

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

Conditions
ConditionsYield
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

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

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

Conditions
ConditionsYield
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

indole

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

Conditions
ConditionsYield
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

4-fluoro-2-methoxyaniline

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

Conditions
ConditionsYield
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

1-methylindole

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

Conditions
ConditionsYield
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

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

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

Conditions
ConditionsYield
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

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

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

Conditions
ConditionsYield
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

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

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

Conditions
ConditionsYield
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

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

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

Conditions
ConditionsYield
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

3-(2-aminopyrimidin-4-yl)-1-methyl-1H-indole

methanesulfonic acid
75-75-2

methanesulfonic acid

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

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

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

Conditions
ConditionsYield
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

4-Chloro-3-nitroaniline

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

Conditions
ConditionsYield
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-(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

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

Conditions
ConditionsYield
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

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

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

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: Alkaline conditions
2: diammonium sulfide / isopropyl alcohol
View Scheme
methanesulfonic acid
75-75-2

methanesulfonic acid

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

N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methyl-indol-3-yl)pyrimidine 2-yl]amino}phenyl)prop-2-enamide dimesylate

N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methyl-indol-3-yl)pyrimidine 2-yl]amino}phenyl)prop-2-enamide dimesylate

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

1421373-66-1Downstream Products

1421373-66-1Relevant articles and documents

Preparation method of osimertinib mesylate

-

, (2021/11/19)

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.

Synthetic method of osimertinib AZD9291

-

, (2019/01/23)

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.

Preparation method for osimertinib mesylate

-

, (2018/04/28)

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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