Process for the preparation of 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide and synthetic intermediates thereof
A process for the preparation in high yields and purity of the compound 6-(7-((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 the following steps:
a) reacting an 1-amino-1-hydroxymethylcyclopropane protected at the amino group of formula (VI):
wherein R and R′ taken together with the nitrogen atom they are linked to represent a protected primary amino group, with 4-hydroxy-3-methoxyacetophenone of formula (VII):
in the conditions of the Mitsunobu reaction, to obtain a compound of formula (VIII):
wherein R and R′ are as defined above;
b) nitrating a compound of formula (VIII) to obtain a compound of formula (IX):
wherein R and R′ are as defined above;
c) reacting a compound of formula (IX) with a compound of formula (XV):
HC(OR1) 2 N(Me) 2 (XV)
wherein R1 is straight or branched C 1 -C 6 alkyl or a C 3 -C 6 -cycloalkyl, to obtain a compound of formula (X):
wherein R and R′ are as defined above and the line means that the double bond of the beta-enaminoketone group can be in cis or trans configuration;
d) reducing the nitro group of a compound of formula (X) and concomitantly cyclizing to obtain a compound of formula (XI) which can be in equilibrium with its tautomeric form (XIa):
wherein R and R′ are as defined above;
e) converting a compound of formula (XI) or (XIa) to a compound of formula (XII):
wherein X is selected from Cl, Br or I and R and R′ are as defined above;
f) reacting a compound of formula (XII) with 6-hydroxy-N-methyl-1-naphthamide of formula (XIII):
to obtain a compound of formula (XIV):
wherein R and R′ are as defined above;
g) deprotecting the protected primary amino group of a compound of formula (XIV) to obtain the compound of formula (I);
h) optionally converting the compound (I) in a pharmaceutically acceptable salt thereof.
2. The process of claim 1 wherein 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 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 trimethylsilyl and R is tert-butoxycarbonyl.
6. The process of claim 1 wherein R and R′ together with the nitrogen atom they are linked to form a phthalimido group.