Synthetic process and intermediates
The present disclosure describes a synthetic process and novel intermediates related to spirocyclic azetidenyl-isobenzofuran derivatives having an isothiazoline moiety, which are useful as antiparasitics.
1. A process for making 1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea or a salt thereof, comprising reacting 4-methyl-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)carbamoyl)benzenesulfonamide with 3-bromo-2-ethyl-6,8-dimethylimidazo[1,2-a]pyrazine.
2. A process for making a compound of Formula (II) or a salt thereof:
wherein:
X is N or CR 1 , where R 1 is hydrogen, halogen, CN, C 1-3 alkyl, or C 1-3 haloalkyl;
R 2 is hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, CN, aryl, or heteraoaryl;
R 3 is hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, or CN;
R 4 is hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, heterocyclyl, heteroaryl, or aryl;
Z is phenyl substituted with R 5 , where R 5 is hydrogen, halogen, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 haloalkoxy, or C 1-3 alkoxy;
Ar is phenyl, pyridyl, or thiophenyl, each optionally substituted with one or more halogen, CN, NO 2 , NH 2 , N(C 1-3 alkyl) 2 , OH, C 1-3 alkoxy, C 1-3 alkyl, or C 1-3 haloalkyl; and
L is CH 2 CH 2 , CH 2 CH 2 CH 2 , or OCH 2 CH 2 , comprising:
a. cyclizing a compound of formula (a):
wherein:
X is N or CR 1 , where R 1 is hydrogen, halogen, CN, C 1-3 alkyl, or C 1-3 haloalkyl;
R 2 is hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, CN, aryl, or heteraoaryl; and
R 3 is hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, or CN;
b. halogenating the resulting cyclized product to form a compound of formula (b):
wherein R 4 is hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, heterocyclyl, heteroaryl, or aryl; and
c. treating a compound of formula (b) with a compound of formula (c):
wherein
Z is phenyl substituted with R 5 , where R 5 is hydrogen, halogen, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 haloalkoxy, or C 1-3 alkoxy;
Ar is phenyl, pyridyl, or thiophenyl, each optionally substituted with one or more halogen, CN, NO 2 , NH 2 , N(C 1-3 alkyl) 2 , OH, C 1-3 alkoxy, C 1-3 alkyl, or C 1-3 haloalkyl; and
L is CH 2 CH 2 , CH 2 CH 2 CH 2 , or OCH 2 CH 2 ,
to form a compound of Formula (II).
3. The process of claim 2 , wherein
X is N,
R 2 is C 1-3 alkyl,
R 3 is C 1-3 alkyl,
R 4 is C 1-3 alkyl,
Ar is phenyl,
L is CH 2 CH 2 , and
Z is phenyl substituted with one R 5 .
4. The process of claim 3 , wherein R 2 is methyl, R 3 is methyl, R 4 is ethyl, Ar is unsubstituted phenyl, and R 5 is C 1-3 alkyl.
5. The process of claim 4 , wherein R 5 is methyl.
6. The process of claim 5 , wherein the compound of formula (c) is 4-methyl-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)carbamoyl)benzenesulfonamide.
7. The process of claim 6 , wherein the compound of Formula (II) is 1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea.