	US 12,304,903 B2
	Process for making an isoxazoline compound and intermediate thereof
Jean Marie Defauw, Greenfield, IN (US); Guanmin Wu, Greenfield, IN (US); Jingdan Hu, Greenfield, IN (US); Jing Chen, Greenfield, IN (US); Xin Zhang, Greenfield, IN (US); and Ping Huang, Greenfield, IN (US)
Assigned to Elanco US Inc., Greenfield, IN (US)
Filed by Elanco US Inc., Greenfield, IN (US)
Filed on Dec. 12, 2024, as Appl. No. 18/978,995.
Application 18/978,995 is a continuation of application No. 18/006,277, previously published as PCT/US2021/042769, filed on Jul. 22, 2021.
Claims priority of provisional application 63/055,923, filed on Jul. 24, 2020.
Claims priority of application No. PCT/CN2020/104035 (WO), filed on Jul. 24, 2020.
Prior Publication US 2025/0109125 A1, Apr. 3, 2025
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 413/04 (2006.01)

CPC C07D 413/04 (2013.01)

28 Claims

1. A process for making an isoxazoline compound of formula (1)

comprising

(i) reacting a compound of formula (2)

with hydroxylamine, sodium hydroxide and a compound of formula (3), wherein the base is;

wherein Y⁻ is a halide, wherein the halide is selected from the group consisting of bromide and chloride,

to give a compound of formula (4)

(ii) converting the bromide of compound of formula (4) to a carboxylic acid of the compound of formula (5)

(iii) optionally crystallizing the compound of formula (5) with acetonitrile, and optionally with an anti-solvent selected from the group consisting of water and n-heptane,

and

(iv) coupling the compound of formula 5 with an amine, wherein the amine is a compound of formula (6),

or glycine, optionally carboxyl protected;

wherein R₅is a C₁-C₄aliphatic chain, wherein the chain is optionally substituted with 1 to 5 halogen;

wherein the enantiomeric excess of the(S)-enantiomer of the compound of formula (1) is 90% or greater.