Efficient process for the preparation of Lapatinib and salts thereof by means of new intermediates

摘要

The present invention refers to a new efficient process for the synthesis of the active pharmaceutical ingredient Lapatinib and salts thereof.;In particular, the present synthesis is carried out employing new intermediates in which the amine function is protected by a group cleavable in basic milieu that provides a higher overall yield of the synthesis process.

主权项

1. A process for preparing lapatinib of formula (I): or a salt thereof, comprising: (a) Protecting the compound 6-[5-({[2-(methylsulphonyl)ethyl]amino}methyl)furan-2-yl]quinazolin-4-ole of formula (III):or a salt thereof,
to give the N-protected-6-[5-({[2-(methylsulphonyl)ethyl]amino}methyl)furan-2-yl]quinazolin-4-ole of formula (IV): wherein R is chosen from methyl oxycarbonyl, ethyl oxycarbonyl, 9-(2-Sulfo)fluorenylmethyl oxycarbonyl, 9-(2,7-Dibromo)fluorenylmethyl oxycarbonyl, 17-Tetrabenzo[a,c,g,i]fluorenylmethyl oxycarbonyl (Tbfmoc), 2-Chloro-3-indenylmethyl oxycarbonyl (Climoc), Benz[f]inden-3-ylmethyl oxycarbonyl (Bimoc), 2-Phosphonioethyl oxycarbonyl (Peoc), 1-Methyl-1-(triphenylphosphonio)ethyl (2-Triphenylphosphonioisopropyl) oxycarbonyl (Ppoc), 1,1-Dimethyl-2-cyanoethyl oxycarbonyl, 2-Dansylethyl oxycarbonyl (Dnseoc), 2-(4-Nitrophenyl)ethyl oxycarbonyl (Npeoc), m-Chloro-p-acyloxybenzyl oxycarbonil, 9-Fluorenylmethyl oxycarbonyl (Fmoc), formyl (CO)H, acetyl CH3(CO), trifluoroacetyl CF3(CO), difluoroacetyl CHF2(CO), monofluoroacetyl CH2F(CO), trichioracetyl CCl3(CO), dichloroacetyl CHCI2(CO), monochloroacetyl CH2Cl(CO), and 2-(Trimethylsilyl)ethanesulfonyl; (b) Converting the intermediate of formula (IV) to give the N-protected-N-{[5-(4-substituted-quinazolin-6-yl)furan-2-yl]methyl}-2-(methylsulphonyl)ethanamine of formula (V): wherein X is chosen from fluorine, chlorine, bromine, iodine, O-Ms (mesylate), O-Ts (tosylate), O-Tf (triflate), ethanesulfonate (esylate), benzenesulfonate (besylate), p-bromobenzenesulfonate (brosylate), and p-nitrobenzenesulfonate (nosylate); (c) Reacting the intermediate of formula (V) with 3-chloro-4-[(3-fluorobenzyl)oxy]aniline of formula (VI):to give the N-protected lapatinib of formula (VII): and (d) Deprotecting N-protected lapatinib of formula (VII) to give lapatinib of formula (I), or a pharmaceutically acceptable salt thereof.