US 2014/0371464 A1Published application

Process for the preparation of chiral isoxazoline azetidine derivatives as antiparasitic agents

AssigneeZoetis LLC

InventorsDenis Billen, Sean David William Greenwood, Timothy Lee Stuk

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Abstract

The invention recites a chiral process for the synthesis of isoxazoline azetidine phenyl substituted derivatives of Formula (1) stereoisomers thereof, veterinarily acceptable salts thereof, processes for making, and their use as a parasiticide in an animal. The variables *, R1a, R1b, R1c, R2, and R3 are as described herein

Claims14

Dependent claims

A process for the preparation of a compound having the Formula (1)

wherein
R1a, R1b, and R1c are each independently hydrogen, halo, or C1-C6haloalkyl;
R2 is hydroxyl, or fluoro;
R3 C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C6cycloalkyl, C0-C6alkylphenyl, C0-C6alkylheteroaryl, or C0-C6alkylheterocycle;
wherein R3 C1-C6alkyl or C0-C6alkylC3-C6cycloalkyl moiety can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6haloalkyl, —S(O)nRc, —SH, —S(O)nNRaRb, —NRaRb, —NRaC(O)Rb, —SC(O)R, —SCN, or —C(O)NRaRb, and the C0-C6alkylC3-C6cycloalkyl moiety can be further substituted with C1-C6alkyl or hydroxyC1-C6alkyl-;
and
wherein R3 C0-C6alkylphenyl, C0-C6alkylheteroaryl, or C0-C6alkylheterocycle moiety can be further optionally substituted with at least one substituent selected from cyano, halo, oxo, ═S, hydroxyl, C1-C6alkoxy, C1-C6alkyl, C1-C6haloalkyl, —SH, —S(O)nR, and C1-C6haloalkoxy;
R is C1-C6alkyl or C3-C6cycloalkyl optionally substituted with at least one halo substituent;
Ra is hydrogen, C1-C6alkyl, or C0-C3alkylC3-C6cycloalkyl;
wherein the alkyl and alkylcycloalkyl is optionally substituted by cyano or at least one halo substituent;
Rb is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C0-C3alkylphenyl, C0-C3alkylheteroaryl, or C0-C3alkylheterocycle, each optionally substituted, where chemically possible, with at least one substituent selected from hydroxyl, cyano, halo, or —S(O)nR;
Rc is C1-C6alkyl, C1-C6haloalkyl, C1-C6haloalkylC3-C6cycloalkyl, C0-C3alkylC3-C6cycloalkyl, C0-C3alkylphenyl, C0-C3alkylheteroaryl, or C0-C3alkylheterocycle each optionally substituted with at least one substituent selected from cyano, halo, hydroxyl, oxo, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6haloalkyl, —S(O)nR, —SH, —S(O)nNRaRb, —NRaRb, —NRaC(O)Rb, —SC(O)R, —SCN, or —C(O)NRaRb;
n is the integer 0, 1, or 2;
and
* depicts a chiral center;
stereoisomers thereof, and veterinarily acceptable salts thereof;
said process comprising, optionally in a solvent:
a) metallating 1-bromo-4-iodobenzene with a Grignard reagent or halogen-metal exchange with an alkyllithium and reacting metallated species with a protected azetidinone in a one-pot process or in a step-wise process to provide a protected 3-(4-bromophenyl)azetidin-3-ol, wherein PG is an amine protecting group;
b) optionally fluorinating the resulting protected hydroxyazetidine by treatment with a fluorinating agent to provide a protected fluoroazetidine;
c) palladium catalyzed condensation of the bromophenylazetidine from steps a or b, above, with a vinyl ether to provide a protected 1-(4-(azetidin-3-yl)phenyl)ethanone derivative, wherein R2 is hydroxyl or fluoro and R4 is a C1-C6alkyl;
d) condensation of the 1-(4-(azetidin-3-yl)phenyl)ethanone derivative with a substituted trifluorophenylethanone to provide a 1-(4-(azetidin-3-yl)phenyl)-4,4,4-trifluoro-3-phenylbut-2-en-1-one analog;
e) addition of hydroxylamine to the 1-(4-(azetidin-3-yl)phenyl)-4,4,4-trifluoro-3-phenylbut-2-en-1-one analog and cyclization in the presence of a quinine based chiral catalyst to provide a protected 3-(4-(azetidin-3-yl)phenyl)-5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazole analog, wherein * denotes a chiral center;
f) removal of the azetidine protecting group to provide a 3-(4-(azetidin-3-yl)phenyl)-5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazole analog;
and
g) Coupling the 3-(4-(azetidin-3-yl)phenyl)-5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazole analog with an acid or acid chloride under standard amide formation conditions.

22 more elements

A compound selected from the group consisting of:

tert-butyl 3-(4-bromophenyl)-3-hydroxyazetidine-1-carboxylate;
benzyl 3-(4-bromophenyl)-3-hydroxyazetidine-1-carboxylate;
1-benzhydryl-3-(4-bromophenyl)azetidin-3-ol;
tert-butyl 3-(4-bromophenyl)-3-fluoroazetidine-1-carboxylate;
benzyl 3-(4-bromophenyl)-3-fluoroazetidine-1-carboxylate;
1-benzhydryl-3-(4-bromophenyl)-3-fluoroazetidine;
tert-butyl 3-(4-acetylphenyl)-3-hydroxyazetidine-1-carboxylate;
benzyl 3-(4-acetylphenyl)-3-hydroxyazetidine-1-carboxylate;
1-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)ethanone;
tert-butyl 3-(4-acetylphenyl)-3-fluoroazetidine-1-carboxylate;
benzyl 3-(4-acetylphenyl)-3-fluoroazetidine-1-carboxylate;
1-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)ethanone;
(E/Z)-tert-butyl 3-(4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(E/Z)-tert-butyl 3-hydroxy-3-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)phenyl)azetidine-1-carboxylate;
(E/Z)-tert-butyl 3-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(E/Z)-tert-butyl 3-(4-(3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(E/Z)-benzyl 3-(4-(3-(3, 5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(E/Z)-benzyl 3-hydroxy-3-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)phenyl)azetidine-1-carboxylate;
(E/Z)-benzyl 3-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(E/Z)-benzyl 3-(4-(3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(E/Z)-1-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-en-1-one;
(E/Z)-1-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en-1-one;
(E/Z)-1-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-en-1-one;
(E/Z)-1-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-en-1-one;
(E/Z)-tert-butyl 3-(4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;
(E/Z)-tert-butyl 3-fluoro-3-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)phenyl)azetidine-1-carboxylate;
(E/Z)-tert-butyl 3-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;
(E/Z)-tert-butyl 3-(4-(3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;
(E/Z)-benzyl 3-(4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;
(E/Z)-benzyl 3-fluoro-3-(4-(4,4,4-trifluoro-3-(3,4, 5-trich lorophenyl)but-2-enoyl)phenyl)azetidine-1-carboxylate;
(E/Z)-benzyl 3-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;
(E/Z)-benzyl 3-(4-(3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;
(E/Z)-1-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-en-1-one;
(E/Z)-1-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en-1-one;
(E/Z)-1-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-en-1-one;
(E/Z)-1-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-en-1-one;
(S)-tert-butyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(S)-tert-butyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(S)-tert-butyl 3-hydroxy-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;
(S)-tert-butyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(R)-tert-butyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(R)-tert-butyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(R)-tert-butyl 3-hydroxy-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;
(R)-tert-butyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(S)-tert-butyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;
(S)-tert-butyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;
(S)-tert-butyl 3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;
(S)-tert-butyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;
(R)-tert-butyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;
(R)-tert-butyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;
(R)-tert-butyl 3-fluoro-3-(4-(5-(3,4, 5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;
(R)-tert-butyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;
(S)-benzyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(S)-benzyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(S)-benzyl 3-hydroxy-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;
(S)-benzyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(R)-benzyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(R)-benzyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(R)-benzyl 3-hydroxy-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;
(R)-benzyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;
(S)-benzyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;
(S)-benzyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;
(S)-benzyl 3-fluoro-3-(4-(5-(3,4, 5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;
(S)-benzyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;
(R)-benzyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;
(R)-benzyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;
(R)-benzyl 3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;
(R)-benzyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;
(S)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(S)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(S)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(S)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(R)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(R)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(R)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(R)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(S)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(S)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(S)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(S)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(R)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(R)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(R)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(R)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(S)-3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;
(S)-3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;
(S)-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;
(S)-3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;
(R)-3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;
(R)-3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;
(R)-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;
(R)-3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;
(S)-5-(3,5-dichloro-4-fluorophenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(S)-5-(3,5-dichlorophenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(S)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(S)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(R)-5-(3,5-dichloro-4-fluorophenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(R)-5-(3,5-dichlorophenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(R)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
and
(R)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole.

98 more elements

Dependencies are inferred from the claim text.

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Abstract

A process for the preparation of a compound having the Formula (1)

wherein
R1a, R1b, and R1c are each independently hydrogen, halo, or C1-C6haloalkyl;
R2 is hydroxyl, or fluoro;
R3 C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C6cycloalkyl, C0-C6alkylphenyl, C0-C6alkylheteroaryl, or C0-C6alkylheterocycle;
wherein R3 C1-C6alkyl or C0-C6alkylC3-C6cycloalkyl moiety can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6haloalkyl, —S(O)nRc, —SH, —S(O)nNRaRb, —NRaRb, —NRaC(O)Rb, —SC(O)R, —SCN, or —C(O)NRaRb, and the C0-C6alkylC3-C6cycloalkyl moiety can be further substituted with C1-C6alkyl or hydroxyC1-C6alkyl-;
and
wherein R3 C0-C6alkylphenyl, C0-C6alkylheteroaryl, or C0-C6alkylheterocycle moiety can be further optionally substituted with at least one substituent selected from cyano, halo, oxo, ═S, hydroxyl, C1-C6alkoxy, C1-C6alkyl, C1-C6haloalkyl, —SH, —S(O)nR, and C1-C6haloalkoxy;
R is C1-C6alkyl or C3-C6cycloalkyl optionally substituted with at least one halo substituent;
Ra is hydrogen, C1-C6alkyl, or C0-C3alkylC3-C6cycloalkyl;
wherein the alkyl and alkylcycloalkyl is optionally substituted by cyano or at least one halo substituent;
Rb is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C0-C3alkylphenyl, C0-C3alkylheteroaryl, or C0-C3alkylheterocycle, each optionally substituted, where chemically possible, with at least one substituent selected from hydroxyl, cyano, halo, or —S(O)nR;
Rc is C1-C6alkyl, C1-C6haloalkyl, C1-C6haloalkylC3-C6cycloalkyl, C0-C3alkylC3-C6cycloalkyl, C0-C3alkylphenyl, C0-C3alkylheteroaryl, or C0-C3alkylheterocycle each optionally substituted with at least one substituent selected from cyano, halo, hydroxyl, oxo, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6haloalkyl, —S(O)nR, —SH, —S(O)nNRaRb, —NRaRb, —NRaC(O)Rb, —SC(O)R, —SCN, or —C(O)NRaRb;
n is the integer 0, 1, or 2;
and
* depicts a chiral center;
stereoisomers thereof, and veterinarily acceptable salts thereof;
said process comprising, optionally in a solvent:
a) metallating 1-bromo-4-iodobenzene with a Grignard reagent or halogen-metal exchange with an alkyllithium and reacting metallated species with a protected azetidinone in a one-pot process or in a step-wise process to provide a protected 3-(4-bromophenyl)azetidin-3-ol, wherein PG is an amine protecting group;
b) optionally fluorinating the resulting protected hydroxyazetidine by treatment with a fluorinating agent to provide a protected fluoroazetidine;
c) palladium catalyzed condensation of the bromophenylazetidine from steps a or b, above, with a vinyl ether to provide a protected 1-(4-(azetidin-3-yl)phenyl)ethanone derivative, wherein R2 is hydroxyl or fluoro and R4 is a C1-C6alkyl;
d) condensation of the 1-(4-(azetidin-3-yl)phenyl)ethanone derivative with a substituted trifluorophenylethanone to provide a 1-(4-(azetidin-3-yl)phenyl)-4,4,4-trifluoro-3-phenylbut-2-en-1-one analog;
e) addition of hydroxylamine to the 1-(4-(azetidin-3-yl)phenyl)-4,4,4-trifluoro-3-phenylbut-2-en-1-one analog and cyclization in the presence of a quinine based chiral catalyst to provide a protected 3-(4-(azetidin-3-yl)phenyl)-5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazole analog, wherein * denotes a chiral center;
f) removal of the azetidine protecting group to provide a 3-(4-(azetidin-3-yl)phenyl)-5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazole analog;
and
g) Coupling the 3-(4-(azetidin-3-yl)phenyl)-5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazole analog with an acid or acid chloride under standard amide formation conditions.

22 more elements