Process for the preparation of isoxazoline compounds

Patent metadata

Field	Value
Publication number	US-10433552-B2
Application number	US-201715480316-A
Country	US
Kind code	B2
Filing date	Apr 5, 2017
Priority date	Apr 6, 2016
Publication date	Oct 8, 2019
Grant date	Oct 8, 2019

Abstract

This invention relates to processes for the preparation of antiparasitic isoxazoline compounds enriched in an enantiomer using quinine-based chiral phase transfer catalyst. The invention also relates to novel quinine-based phase transfer catalysts and to a toluene solvent form of the isoxazoline compound of the invention.

First claim

What is claimed is:

1. A process for the preparation of an isoxazoline compound of Formula IA, wherein X 1 , X 2 and X 3 are each independently H, chloro, fluoro or CF 3 , which is enriched in the (S)-enantiomer:

comprising reacting a compound of formula (IIA):

wherein X 1 , X 2 and X 3 are H, chloro, fluoro or CF 3 , with hydroxylamine in the presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula (IIIa):

wherein R is phenyl substituted with one or more C 1 -C 6 -alkoxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino or aralkoxy groups, R′ is hydrogen or C 1 -C 3 alkoxy, W is ethyl or vinyl and X − is an anion; and isolating the compound of formula (S)-IA.

2. The process according to claim 1 , wherein the compound of formula (S)-IA is isolated by crystallizing the compound from an aromatic solvent or a mixture of solvents comprising an aromatic solvent.

3. The process of claim 2 , wherein the aromatic solvent is selected from the group consisting of , toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole and mesitylene.

4. The process of claim 3 , wherein the aromatic solvent is toluene.

5. The process of any one of claims 1 - 4 , wherein prior to isolating the compound of formula (S)-IA, the process further comprises crystallizing racemic compound of formula IA and removing the solid.

6. The process according to claim 1 , wherein R in the chiral phase transfer catalyst of formula (IIIa) is phenyl substituted by 1, 2 or 3 methoxy or ethoxy groups, and R′ is hydrogen or methoxy.

7. The process according to claim 1 , wherein R in the chiral phase transfer catalyst of formula (IIIa) is phenyl substituted by 1, 2 or 3 benzyloxy groups, and R′ is hydrogen or methoxy.

8. The process according to claim 1 , wherein R in the chiral phase transfer catalyst of formula (IIIa) is 3,4,5 -tris(benzyloxy)phenyl.

9. The process according to claim 1 , wherein X 1 and X 3 are independently chloro or CF 3 and X 2 is H or fluoro.

10. The process according to claim 1 , wherein X 1 chloro; X 3 is CF 3 and X 2 is H.

11. The process according to claim 1 , wherein X 1 and X 3 are chloro; and X 2 is H.

12. The process according to claim 1 , wherein X 1 and X 3 are chloro and X 2 is fluoro.

13. The process according to claim 1 , wherein X 1 is chloro; X 3 is CF 3 and X 2 is fluoro.

14. The process according to claim 1 , wherein the hydroxylamine is present as an acid salt.

15. The process according to claim 14 , wherein the hydroxylamine acid salt is hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine phosphate, hydroxylamine oxalate, hydroxylamine nitrate or hydroxylamine acetate.

16. The process according to claim 15 , wherein the hydroxylamine salt is hydroxylamine sulfate.

17. The process according to claim 1 , wherein the base is an alkali metal hydroxide, an alkali metal alkoxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkaline earth hydroxide or and alkaline earth alkoxide.

18. The process according to claim 17 , wherein the alkali metal hydroxide is lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium hydroxide.

19. The process according to claim 1 , wherein the base is an organic base.

20. The process according to claim 19 , wherein the organic base is triethylamine, tributylamine, diisopropylethylamine, 1,5,7-Triazabicyclo(4.4.0)dec-5-ene, 7-Methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene, 1,8-Diazabicyclo[5.4.0]undec-7-ene, 1,5-Diazabicyclo[4.3.0]non-5-ene , 1,1,3,3-Tetramethylguanidine, Quinuclidine, 2,2,6,6-Tetramethylpiperidine, Pempidine, 1,4-Diazabicyclo[2.2.2]octan, Collidine, 2,6-Lutidine or N,N,N′,N′-tetramethyl-1,8-naphthalenediamine.

21. The process according to claim 1 , wherein the base is a phosphazene base.

22. The process according to claim 1 , wherein about 1 to about 50 moles of hydroxylamine per mole of the compound of formula (IIA) are used.

23. The process according to claim 22 , wherein about 1 to about 10 moles of hydroxylamine per mole of the compound of formula (IIA) are used.

24. The process according to claim 23 , wherein about 1 to about 5 moles of hydroxylamine per mole of the compound of formula (IIA) are used.

25. The process according to claim 1 , wherein about 0.001 mole to about 0.2 mole of catalyst of formula (IIIa) per mole of the compound of formula (IIA) is used.

26. The process according to claim 25 , wherein about 0.005 mole to about 0.1 mole of catalyst of formula (IIIa) per mole of the compound of formula (IIA) is used.

27. The process according to claim 26 , wherein about 0.01 mole to about 0.05 mole of the catalyst of formula (IIIa) per mole of the compound of formula (IIA) is used.

28. The process according to claim 1 , wherein the organic solvent is an aromatic solvent, an aliphatic solvent, a halogenated solvent or an ether solvent.

29. The process according to claim 28 , wherein the organic solvent is an aromatic solvent selected from the group consisting of toluene, xylenes, fluorobenzene, chlorobenzene, o-dichlorobenzene, anisole and mesitylene.

30. The process according to claim 28 , wherein the organic solvent is an aliphatic solvent selected from the group consisting of n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane and methylcyclohexane.

31. The process according to claim 28 , wherein the organic solvent is a halogenated solvent selected from the group consisting of dichloromethane, chloroform and 1,2-dichloroethane.

32. The process according to claim 28 , wherein the organic solvent is an ether solvent selected from the group consisting of diethyl ether, diisopropyl ether, di-n-butyl ether, cyclopentyl methyl ether, t-butyl methyl ether, t-butyl ethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, tetrahydropyran, methyltetrahydrofuran and diethoxymethane.

33. The process according to claim 31 , wherein the halogenated solvent is dichloromethane.

Assignees

• Merial Inc

Inventors

• Yang Chunhua
• Le Hir De Fallois Loic Patrick
• Meng Charles Q
• Long Alan
• Gorter De Vries Roelof Johannes
• Baillon Bruno
• Lafont Sylvaine
• Gay De Saint Michel Myriam
• Kozlovic Stephane

Classifications

• A61P33/00

  Antiparasitic agents · CPC title

• C07D453/04

  having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine · CPC title

• A61K31/42 Primary

  Oxazoles · CPC title

• A01N43/647

  Triazoles; Hydrogenated triazoles · CPC title

• C07D261/04 Primary

  having one double bond between ring members or between a ring member and a non-ring member · CPC title