Processes for making substituted quinazoline compounds using hydrogen bonding catalysts
Disclosed herein is a novel process for preparing substituted quinazoline compounds of formula (I) using a hydrogen bonding catalyst.
1. A process for preparing a compound of Formula (I):
or a salt thereof, comprising contacting a compound of formula (viii):
or a salt thereof, with a catalyst of formula (V):
wherein each occurrence of R 5 is independently selected from the group consisting of phenyl; naphthyl and pyridine; wherein each of the phenyl and naphthyl is optionally substituted with one to three substituents independently selected from halogen, —O—C 1 -C 4 alkyl, —CN, —NO 2 , —O-Tf, and C 1 -C 4 alkyl, wherein C 1 -C 4 alkyl can be optionally substituted with one to four halogens; and
each occurrence of R 6 is independently selected from the group consisting of Tf and Nf;
in a suitable solvent for a time sufficient to form a compound of formula (I);
wherein:
R 1 represents up to 3 phenyl group substituents, each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —CN, —OH and C 1 -C 6 alkoxy;
R 2 represents up to 3 phenyl group substituents, each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —CN, —OH and C 1 -C 6 alkoxy;
R 3 represents up to 3 phenyl group substituents, each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —CN, —OH and C 1 -C 6 alkoxy; and
R 4 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl.
2. The process of claim 1 , wherein the catalyst is a compound of formula (Va):
3. The process of claim 1 , wherein each occurrence of R 1 is halo; each occurrence of R 2 is independently selected from halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkyl; each occurrence of R 3 is independently selected from C 1 -C 3 alkyl and C 1 -C 3 alkoxy; and R 4 is C 1 -C 6 alkyl.
4. The process of claim 1 , wherein the catalyst is selected from the group consisting of:
5. The process of claim 1 , wherein the catalyst is selected from the group consisting of:
6. The process of claim 1 , wherein the solvent is selected from the group consisting of acetone, toluene, dichloromethane, DCE, THF, chlorobenzene, 1,2-dichlorobenzene, MTBE, CPME, acetonitrile, EtOAc, IPAc, MeOAc, nitromethane, trifluoromethylbenzene, methyl ethyl ketone, DME, anisole, hexafluorobenzene, o-xylene, fluorobenzene, 1,4-dioxane, iPr 2 O and 2-MeTHF.
7. The process of claim 6 , wherein the solvent is selected from toluene, MTBE, and CPME.
8. The process of claim 1 , wherein said process is carried out at a temperature from about 20° C. to about 60° C.
9. A process for preparing a compound of Formula (I):
or a salt thereof, comprising contacting a compound of formula (viii):
or a salt thereof, with a catalyst of formula (VI):
wherein each occurrence of R 7 is independently selected from the group consisting of phenyl, naphthyl, phenanthrenyl, pyridyl and thiophenyl, each of which is optionally substituted with one to five substituents independently selected from halogen and —CF 3 ; and
each occurrence of R 8 is hydrogen;
in a suitable solvent for a time sufficient to form a compound of formula (I);
wherein:
R 1 represents up to 3 phenyl group substituents, each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —CN, —OH and C 1 -C 6 alkoxy;
R 2 represents up to 3 phenyl group substituents, each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —CN, —OH and C 1 -C 6 alkoxy;
R 3 represents up to 3 phenyl group substituents, each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —CN, —OH and C 1 -C 6 alkoxy; and
R 4 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl.
10. The process of claim 9 , wherein each occurrence of R 1 is halo; each occurrence of R 2 is independently selected from halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkyl; each occurrence of R 3 is independently selected from C 1 -C 3 alkyl and C 1 -C 3 alkoxy; and R 4 is C 1 -C 6 alkyl.
11. The process of claim 9 , wherein the catalyst is selected from the group consisting of:
12. The process of claim 9 , wherein the catalyst is selected from the group consisting of:
13. The process of claim 9 , wherein the solvent is selected from the group consisting of CF 3 -toluene, Cl-benzene, and 1,2-Cl 2 -benzene.
14. The process of claim 9 , wherein said process is carried out at a temperature from about 50° C. to about 80° C.
15. The process of claim 1 , wherein the compound of formula (I) made by said process is:
wherein R 4 is C 1 -C 6 alkyl.
16. The process of claim 1 , wherein the compound made by said process is Compound (III):
17. A process for converting Compound (III):
to Compound A:
the method comprising hydrolyzing the methyl ester group of compound (III).