Process for the preparation of 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide and synthetic intermediates thereof
View Patent ↗A process for the preparation in high yields and purity of the compound 6-(7-4(1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide of formula (I) and of the pharmaceutically acceptable salts thereof is described. The process has various advantages over those previously described, in particular it avoids the use of acyl azide intermediates and their Curtius rearrangement. Novel intermediates useful for the preparation of compound (I) are also described.
1. Process for the preparation of the compound 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide of formula (I):
or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (VI):
wherein R and R′ taken together with the nitrogen atom they are linked to represent a protected primary amino group, with a compound of formula (XVI):
wherein X is selected from Cl, Br or I in the conditions of the Mitsunobu reaction, to obtain a compound of formula (XII):
wherein X,R and R′ are as defined above.
2. The process of claim 1 wherein in the compound of formula (VI) R′is hydrogen and R is selected from the group consisting of benzyl optionally substituted on the aromatic ring with up to three substituents selected from the group consisting of halogen, cyano, trifluoromethyl;C 1 -C 3 acyl, C 7 -C 11 aroyl, C 1 -C 3 alkylsulfonyl, C 6 -C 10 arylsulfonyl, C 1 -C 4 alkoxycarbonyl, benzyloxycarbonyl optionally substituted on the aromatic ring with up to three substituents selected from the group consisting of halogen, cyano, trifluoromethyl.
3. The process of claim 2 wherein R is selected from the group consisting of benzyl, acetyl, benzoyl, trifluoromethanesulfonyl, benzenesulfonyl,p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl.
4. The process of claim 1 wherein in the compound of formula (VI) R′ is tri (C 1 -C 3 alkyl)silyl and R is C 1 -C 4 alkoxycarbonyl or benzyloxycarbonyl optionally substituted on the aromatic ring with up to three substituents selected from the group consisting of halogen, cyano, trifluoromethyl.
5. The process of claim 4 wherein R is tert-butoxycarbonyl.
6. The process of claim 1 wherein in the compound of formula (VI) R and R′ together with the nitrogen atom they are linked to form a phthalimido group.
7. The process of claim 1 wherein in the compound of formula (XVI) X is chlorine.