Synthesis of spirocyclic isoxazoline derivatives

Patent metadata

Field	Value
Publication number	US-9593126-B2
Application number	US-201314439091-A
Country	US
Kind code	B2
Filing date	Nov 20, 2013
Priority date	Nov 21, 2012
Publication date	Mar 14, 2017
Grant date	Mar 14, 2017

Abstract

The invention recites an improved process for preparing spirocyclic isoxazoline derivatives of Formula (1) wherein “*”, R 1a , R 1b , and R 1c are as described herein.

First claim

We claim:

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.

Assignees

• Zoetis Services Llc

Inventors

• Greenwood Sean D W
• Stuk Timothy L

Classifications

• C07C315/04

  by reactions not involving the formation of sulfone or sulfoxide groups · CPC title

• C07D491/107 Primary

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D491/10

  Spiro-condensed systems · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title