ChemicalBook CAS DataBase List Osimertinib mesylate

Osimertinib mesylate synthesis

12synthesis methods

Product Name:Osimertinib mesylate
CAS Number:1421373-66-1
Molecular formula:C29H37N7O5S
Molecular Weight:595.72

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.

75-75-2 Synthesis

75-75-2
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1421373-65-0 Synthesis

1421373-65-0
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1421373-66-1
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Yield:1421373-66-1 96.73%

Reaction Conditions:

Stage #1: N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamidewith pyrographite in propan-2-one at 25 - 55;
Stage #2: methanesulfonic acid at 25 - 55;

Steps:

2 Example-2: Preparation of Osimertinib mesylate

Added the Osimertinib (75 g) fallowed by acetone (750 ml) in to a 1.0 L multi neck RB flask equipped with mechanical stirrer, thermometer socket and reflux condenser at 25-30°C the heated the reaction mixture to 50-55°C then maintained about 30 min. Thereafter, added activated carbon (2.5 g) to the above solution at 50-55°C, maintained abovel5-20 min, filtered the hot solution over hyflo bed and washed with acetone (100 ml).Collected the hot filtrate and washings transferred in to another 1.0 L multi-neck RB flask equipped with mechanical stirrer, thermometer socket and reflux condenser at above 35°C. Added the DM water (25 ml) then heated the reaction mixture to 50-55°C and maintained about 30 min. after that added the methane sulfonic acid (14.4 g) to the above reaction mass at 50-55°C in about lOmin. Maintained at 50-55°C for about 3-3.5 h, and cooled to 25-30°C in about 1.5-1.75h then filtered the product, washed with acetone (125 ml) and suck dried for about 15 min. product dried under vacuum at 80°C for 8-10 hr. Yield : 86.5 g; theory: 96.73%_*HPLC purity: 99.84 %. IMP- A: 0.00%, IMP-B: 0.02%, IMP-C: 0.00%, IMP-D: 0.02%, IMP-E: 0.02%, IMP-F: 0.04%

References:

WO2021/111462,2021,A1 Location in patent:Paragraph 6; 7

75-75-2 Synthesis

75-75-2
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