Synthesis of spirocyclic isoxazoline derivatives

1. A process for preparing a Formula (1), compound

by

a) reacting a Formula (1a) compound

 wherein R 1a , R 1b , and R 1c are each Cl, F, and Cl, respectively; X is benzene sulfonic acid; and “*” represents a chiral center;

b) with a Formula (2) compound

 wherein R 2 is nitro and m is the integer 1; in an organic solvent, and in the presence of a non-aqueous base.

2. The process of claim 1 , wherein Formula (2) compound is a compound of Formula (2a)

3. The process of claim 2 , wherein the organic solvent is selected from the group consisting of isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, and toluene.

4. The process of claim 3 , wherein the non-aqueous base is triethylamine.

5. The process of claim 4 , wherein

a) equimolar amounts of the Formula (1a) compound and Formula (2a) compound are reacted in isopropyl acetate;

b) the solids are removed and the organics sequentially washed with an aqueous base and water; and

c) the organics are concentrated.

6. The process of claim 5 , further comprising:

a) addition of alcohol to the concentrated organics;

b) slowly adding the alcohol solution to water while stirring; and

c) filter and dry the resulting solids.

7. The process of claim 5 , wherein the concentrated solids are washed twice with an aqueous base selected from a hydroxide or carbonate and then washed twice with water.

8. The process of claim 7 , wherein the aqueous base is selected from sodium hydroxide, potassium hydroxide, or ammonium hydroxide.

9. The process of claim 6 , wherein the alcohol is methanol.

10. The process of claim 5 , further comprising:

a) the concentrated organics are added to a solution comprising ethyl acetate, n-heptane, and ethanol;

b) add crystal seeds to the solution and cool; and

c) filter and dry the resulting solids.

11. A process for preparing a Formula (3) compound

by reacting a Formula (1b1) compound with a Formula (2) compound, in an organic solvent, and in the presence of a non-aqueous base,

wherein R 2 is nitro and m is the integer 1.

12. The process of claim 11 , wherein the Formula (2) compound is a compound of Formula (2a)

and the organic solvent is selected from the group consisting of isopropyl acetate, ethyl acetate, toluene, tetrahydrofuran, and methyl tert-butyl ether; and the non-aqueous base is triethylamine.

13. The process of claim 12 , wherein the organic solvent is isopropyl acetate, remove the solids, sequentially wash the organics with an aqueous base and water, and concentrate the organics.

14. The process of claim 13 , wherein the concentrated organics are either added to methanol, slowly mixed with water, and the resulting solids isolated by filtration and dried; or the concentrated organics are added to a solution comprising ethyl acetate, n-heptane, and ethanol, then mixed with crystal seeds, allowed to cool, and the resulting solids isolated by filtration and dried.