Methods of preparing quinazolinone derivatives
View Patent ↗The present disclosure relates to methods for preparing compounds, which are useful for regulating the expression of apolipoprotein A-I (ApoA-I), and in the treatment and prevention of cardiovascular disease and related disease states, including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.
1. A method of preparing a compound of Formula I:
and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof, wherein:
R 1 , R 2 , R 3 , and R 4 are each independently selected from alkoxy, alkyl, amido, aryloxy, cycloalkyl, halogen, heterocyclyl, hydrogen, and nitro;
R 6 is selected from alkyl, alkoxy, and halogen;
R 5 is hydrogen, or R 5 and R 6 may be taken together with the carbon atoms to which they are attached, to form a ring selected from aryl, cycloalkyl, and heterocycyl;
R 8 is selected from alkyl, alkoxy, halogen, and hydrogen;
W is C and p is 1; comprising
a) reacting an aldehyde of Formula II:
wherein R 5 , R 6 and R 8 are as defined above, with ethylene carbonate to form a compound of Formula III:
b) reacting the compound of Formula III with a compound of Formula IV
wherein R 1 , R 2 , R 3 , and R 4 are as defined above, to form the compound of Formula I.
2. The method according to claim 1 , wherein R 6 and R 8 are each independently selected from alkyl and halogen.
3. The method according to claim 2 , wherein R 6 and R 8 are each methyl.
4. The method according to claim 1 , wherein R 1 and R 3 are each independently selected from alkoxy, alkyl, halogen, and hydrogen.
5. The method according to claim 4 , wherein R 1 and R 3 are each methoxy.
6. The method according to claim 1 , wherein the compound of Formula I is selected from:
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;
N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one;
5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one;
6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; and
2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one,
and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
7. The method according to claim 6 , wherein the compound of Formula I is 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one, or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.