ChemicalBook CAS DataBase List 2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl]propanamide

2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl]propanamide synthesis

14synthesis methods

Product Name:2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl]propanamide
CAS Number:290297-26-6
Molecular formula:C30H32F6N4O
Molecular Weight:578.59

Netupitant is a selective neurokinin 1 (NK1) receptor antagonist with potential antiemetic activity. Netupitant competitively binds to and blocks the activity of the human substance P/NK1 receptors in the central nervous system (CNS), thereby inhibiting NK1-receptor binding of the endogenous tachykinin neuropeptide substance P (SP), which may result in the prevention of chemotherapy-induced nausea and vomiting (CINV).

Synthetic Routes

ROUTE 1

ROUTE 2

ROUTE 3

Hoffmann-Emery, Fabienne; Hilpert, Hans; Scalone, Michelangelo; Waldmeier, Pius. Efficient Synthesis of Novel NK1 Receptor Antagonists: Selective 1,4-Addition of Grignard Reagents to 6-Chloronicotinic Acid Derivatives. Journal of Organic Chemistry. Volume 71. Issue 5. Pages 2000-2008. Journal. (2006).

290297-25-5 Synthesis

3-PYRIDINAMINE, N-METHYL-4-(2-METHYLPHENYL)-6-(4-METHYL-1-PIPERAZINYL)-

290297-25-5
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2-(3,5-bis-trifluoromethylphenyl)-2-methyl-propionyl chloride

289686-69-7
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2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl]propanamide

290297-26-6
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$14.00/1mg

Yield:290297-26-6 81%

Reaction Conditions:

with sodium hydrogencarbonate;N-ethyl-N,N-diisopropylamine in dichloromethane at 35 - 40; for 3 h;Cooling with ice;

Steps:

Synthesis of 2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl)propanamide (Netupitant)
Synthesis of 2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl)propanamide (Netupitant)
A solution of 20 g (67.5 mmol) methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine and 17.5 ml (101 mmol) N-ethyldiisopropylamine in 200 ml dichloromethane was cooled in an ice bath and a solution of 24 g (75 mmol)-2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 50 ml dichloromethane was added dropwise.
The reaction mixture was warmed to 35-40° C. for 3 h, cooled to room temperature again and was stirred with 250 ml saturated sodium bicarbonate solution.
The organic layer was separated and the aqueous phase was extracted with dichloromethane.
The combined organic layers were dried (magnesium sulfate) and evaporated.
The residue was purified by flash chromatography to give 31.6 g (81%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl)propanamide as white crystals. M.P. 155-157° C.; MS m/e (%): 579 (M+H⁺, 100).

References:

Helsinn Healthcare SA;Fadini, Luca;Manini, Peter;Pietra, Claudio;Giuliano, Claudio;Lovati, Emanuela;Cannella, Roberta;Venturini, Alessio;Stella, Valentino J. US8426450, 2013, B1 Location in patent:Page/Page column 27; 28

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109-01-3 Synthesis