Icotinib hydrochloride, synthesis, crystalline forms, pharmaceutical compositions, and uses thereof

摘要

The invention relates to 4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-quinazoline hydrochloride, its new crystalline forms, its therapeutic usage for treatment of diseases mediated by EGFR kinase and its combinatory therapeutic usage together with other therapeutic agents. The invention also provides synthetic methods for preparation of 4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-quinazoline hydrochloride, its new crystalline forms, and the relevant synthetic intermediates for synthesis of 4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-quinazoline hydrochloride.

主权项

1. A method of preparing a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, comprising the steps of:
(a) converting a compound of formula BPI-03a to a compound of formula BPI-04a; (b) converting the compound of formula BPI-04a to a compound of formula BPI-05; (c) converting the compound of formula BPI-05 to a compound of formula BPI-06a ; and (d) coupling the compound of formula BPI-06a with 3-ethynylaniline (3-aminophenylacetylene) to form the compound of Formula Ia, wherein the compounds BPI-03a, BPI-04a, BPI-05, BPI-06a, and Formula Ia have the following formulae: wherein R is lower alkyl, and X is halogen.