Processes for the preparation of substituted quinazolines
View Patent ↗The present disclosure provides compounds for modulating receptor kinase activity, particularly ephrin and EGFR, and methods of treating diseases mediated by receptor kinase activity utilizing the compounds and pharmaceutical compositions thereof. The compounds are generally of formula (I): Diseases mediated by receptor kinase activity include, but are not limited to, diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth. Compounds of the invention include “spectrum selective” kinase modulators, compounds that inhibit, regulate and/or modulate signal transduction across subfamilies of receptor-type tyrosine kinases, including ephrin and EGFR. Also disclosed are methods of making compounds for formula 8: comprising introducing group E 2 into a compound of formula 7: wherein Ar, Z, P, and E 2 are defined herein.
1. A process for preparing a compound of the formula 8,
or a salt thereof, wherein:
E 2 is
wherein the process comprises:
(a) O-alkylating a compound of formula 7,
in the presence of a solvent and a base, wherein
R is an N-protecting group that is tert-butoxycarbonyl, carbobenzyloxy, allyloxycarbonyl, acetyl, trifluoroacetyl, benzyl or p-toluenesulfonyl, and
R′ is H or an O-protecting group that is p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl or 2-mesitylsulfonyl,
to provide
wherein R is the N-protecting group that is tert-butoxycarbonyl, carbobenzyloxy, allyloxycarbonyl, acetyl, trifluoroacetyl, benzyl or p-toluenesulfonyl;
(b) deprotecting the compound formed in (a) to provide
(c) N-methylating the compound formed in (b) to provide the compound of formula 8,
and
(d) optionally converting the compound of formula 8 into the salt of the compound of formula 8.
2. The process according to claim 1 , wherein (a) comprises reacting
or a salt thereof,
with the compound of formula 7:
or a salt thereof,
to provide
or a salt thereof.
3. The process according to claim 2 , wherein (b) comprises deprotecting
or a salt thereof,
to provide
or a salt thereof.
4. The process according to claim 3 , wherein (c) comprises methylating the following compound:
or a salt thereof,
to provide the compound of formula 8,
or a salt thereof.
5. The process according to claim 1 , where the compound of formula 8 is:
or a salt thereof.
6. The process according to claim 1 , where the compound of formula 8 is:
or a salt thereof.
7. The process according to claim 6 , wherein the solvent is N,N-dimethylacetamide.
8. The process according to claim 6 , wherein the base is potassium carbonate.
9. A process for preparing a compound of the formula 8:
or a salt thereof, wherein
E 2 is
where the process comprises
(a) O-alkylating a compound of the formula 7,
in the presence of a solvent and a base, wherein
R is an N-protecting group that is tert-butoxycarbonyl, carbobenzyloxy, allyloxycarbonyl, acetyl, trifluoroacetyl, benzyl or p-toluenesulfonyl, and
R′ is H or an O-protecting group that is p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl or 2-mesitylsulfonyl,
to provide
wherein R is the N-protecting group that is tert-butoxycarbonyl, carbobenzyloxy, allyloxycarbonyl, acetyl, trifluoroacetyl, benzyl or p-toluenesulfonyl;
(b) deprotecting the compound formed in (a) to provide
(c) N-methylating the compound formed in (b) to provide the compound of formula 8,
and
(d) optionally converting the compound of formula 8 into the salt of the compound of formula 8.
10. The process according to claim 9 , wherein (a) comprises reacting
or a salt thereof,
with the compound of formula 7,
or a salt thereof,
to provide
or a salt thereof.
11. The process according to claim 10 , wherein (b) comprises deprotecting
or salt thereof,
to provide
or a salt thereof.
12. The process according to claim 11 , wherein (c) comprises methylating the following compound:
or a salt thereof,
to provide the compound of formula 8,
or a salt thereof.
13. The process according to claim 9 , wherein the solvent is N,N-dimethylacetamide.
14. The process according to claim 9 , wherein the base is potassium carbonate.