Process for Preparing Malathion for Pharmaceutical Use

• US 20070010496A1
• Filed: 06/30/2006
• Published: 01/11/2007
• Est. Priority Date: 07/06/2005
• Status: Active Grant

• Current Assignee: Taro Pharmaceutical Industries Limited (Sun Pharmaceutical Industries Limited)
• Original Assignee: Taro Pharmaceutical North America Incorporated (Sun Pharmaceutical Industries Limited)
• Inventors: Gutman, Daniella, Baidossi, Wael
• Granted Patent: US 7,560,445 B2
• Time in Patent Office: Days
• US Class Current: 514/122
• CPC Class Codes: A01N 57/12 containing acyclic or cycloaliphatic radicals
• CPC Class Codes: A61P 33/14 Ectoparasiticides, e.g. scabicides
• CPC Class Codes: C07F 9/165 Esters of thiophosphoric acids
• CPC Class Codes: C07F 9/1651 with hydroxyalkyl compounds with further substituents on alkyl
• CPC Class Codes: C07F 9/17 with hydroxyalkyl compounds without further substituents on alkyl

Abstract

The present invention provides a process for preparing a highly pure form of malathion having a reduced level of toxic impurities. In addition, the malathion prepared by the process of this invention is storage stable. The level of toxic impurities in the malathion, e.g., isomalathion, O,O,S-trimethyl phosphorodithioate (MeOOSPS), O,O,S-trimethyl phosphorothioate (MeOOSPO), O,S,S-trimethyl phosphorodithioate (MeOSSPO), malaoxon, isomalathion, diethyl fumarate, methyl malathion, dimethyl malathion, O,O-methyl,ethyl-S-(1,2-dicarboethoxy)ethyl-phosphorodithioate are lower than that of any other commercial preparation of malathion that may be used for pharmaceutical purposes.

Claims

1. A process for preparing malathion, comprising, the steps of

(a) preparing a solution of O,O-dimethyldithiophosphoric acid in an organic solvent selected from the group consisting of toluene, xylene and benzene;

(b) extracting the O,O-dimethyldithiophosphoric acid into water to generate an aqueous solution of O,O-dimethyldithiophosphoric acid;

(c) reacting the aqueous solution of O,O-dimethyldithiophosphoric acid with diethyl maleate to form malathion; and

,

(d) treating the malathion from step (c) with a sulfur reagent, wherein the sulfur reagent has a pH less than about 7.0.

2. The process of claim 1 wherein, the organic solvent is toluene.

3. The process of claim 1 wherein, O,O-dimethyldithiophosphoric acid in step (a) is prepared by the steps comprising:

(i) adding phosphorous pentasulfide (P₂S₅) to toluene to form a suspension;

(ii) heating the suspension to about 60°

C.;

(iii) adding methanol to the suspension;

(iv) stirring the suspension after addition of the methanol for at least about 1 hour, while maintaining the temperature of the suspension from about 55°

C. to about 60°

C.;

(v) filtering the suspension from step (iv) after cooling to about 18°

C. to about 25°

C.; and

,

(vi) subjecting the suspension from step (v) to vacuum distillation.

4. The process of claim 1 further comprising isolating the malathion from step (d) after treatment with the sulfur reagent.

5. The process of claim 1 wherein, the ratio of water to O,O-dimethyldithiophosphoric acid in step (b) is about 1:

1 to about 10;

1 (w/w).

6. The process of claim 5 wherein, the ratio of water to O,O-dimethyldithiophosphoric acid is about 3:

1 (w/w).

7. The process of claim 1 wherein, the solution of O,O-dimethyldithiophosphoric acid in step (a) is filtered before extraction into water in step (b).

8. The process of claim 1 wherein, the solution of O,O-dimethyldithiophosphoric acid in step (a) is distilled before extraction into water in step (b).

9. The process of claim 1 wherein, the molar ratio of diethyl maleate to O,O-dimethyldithiophosphoric acid in step (c) is about 1:

1 to about 2;

1.

10. The process of claim 9 wherein, the molar ratio of diethyl maleate to O,O-dimethyldithiophosphoric acid in step (c) is about 1:

1.

11. The process of claim 1 wherein, a polymerization inhibitor is added to step (c) during the reaction of the aqueous solution of O,O-dimethyldithiophosphoric acid with the solution of diethyl maleate.

12. The process of claim 10 wherein the molar ratio of diethyl maleate to the polymerization inhibitor is about 50:

1 to about 500;

1.

13. The process of claim 12 wherein, the molar ratio of diethyl maleate to polymerization inhibitor is about 300:

1.

14. The process of claim 11 wherein, the polymerization inhibitor is hydroquinone.

15. The process of claim 1 wherein, the sulfur reagent is selected from the group consisting of alkali metal bisulfites and alkaline earth metal bisulfites.

16. The process of claim 15 wherein, the sulfur reagent is sodium bisulfite.

17. The process of claim 16 wherein, the sulfur reagent comprises a 20% sodium bisulfite solution having a pH from about 6.1 to about 6.3.

18. The process of claim 17 wherein, the malathion in step (d) is treated with the 20% sodium bisulfite solution for about 2 hours.

19. The process of claim 18 further comprising, the steps of:

(e) washing the malathion in step (d) after treatment with the 20% sodium bisulfitesolution with water;

(f) washing the malathion in step (e) with a 5% NaOH solution; and

,

(g) washing the malathion in step (f) at least two times with water.

20. The process of claim 19 further comprising, the steps of

(h) assaying the malathion from step (g) for the presence of at least one impurity selected from the group consisting of MeOOSPS, malaoxon, diethyl fumarate, dimethyl malathion, methyl malathion, isomalathion and O,O-methyl, ethyl S-(1,2-dicarboethoxy)ethyl phosphorodithioate, and combinations thereof;

(i) assaying the malathion for purity;

(j) repeating steps (e) to (i) if the malathion at step (g) contains greater than about 5.0% (w/w) diethyl fumarate; and

,

(k) isolating the malathion.

21. A process for further purifying malathion from claim 19 further comprising, the steps of

(l) adding water to the malathion;

(m) subjecting the malathion from step (k) to azeotropic distillation;

(n) repeating steps (l) to (m) at least one (1) time; and

,

(o) isolating the malathion.

22. The process of claim 21 wherein, the ratio of water to malathion in step (1) is from about 2:

1 (w/w) to about 10;

1 (w/w).

23. The process of claim 22 wherein, the ratio of water to malathion in step (1) is about 3:

1 (w/w).

24. The process of claim 21 further comprising, the steps of

(p) assaying the malathion at step (o) for the presence of at least one impurity selected from the group consisting of MeOOSPO, MeOSSPO, malaxon, MeOOSPS, diethyl fumarate, dimethyl malathion, methyl malathion, O,O-methyl, ethyl S-(1,2-dicarboethoxy)ethyl phosphorodithioate, tetraethyl dithiosuccinate, isomalathion, malathion carboxylic acid, mercaptosuccinate, tetraethyl thiodisuccinate and combinations thereof;

(q) assaying the malathion for purity; and

,

(r) repeating steps (l) to (o) if the malathion in step (o) has greater than about 0.2% (w/w) MeOOSPS, greater than about 0.1% (w/w) malaoxon, greater than about 0.2% (w/w) diethyl fumarate, greater than about 0.2% (w/w) dimethylmalathion, greater than about 0.3% (w/w) methylmalathion, greater than about 0.1% (w/w) isomalathion, or there is less than about 98.5% (w/w) malathion.

33. Malathion prepared by the process of claim 24 wherein, the malathion comprises, greater than about 98.5% (w/w) malathion, less than about 0.02% (w/w) isomalathion, less than about 0.03% (w/w) malathion carboxylic acids, less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO and less than about 0.2% (w/w) MeOSSPS.

34. The malathion of claim 33 further comprising, greater than about 99.0% (w/w) malathion, less than about 0.02% (w/w) isomalathion, less than about 0.03% (w/w) malathion carboxylic acids, less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO and less than about 0.1% (w/w) MeOSSPS.

35. The malathion of claim 34 further comprising, greater than about 99.0% (w/w) malathion, less than about 0.02% (w/w) isomalathion, less than about 0.03% (w/w) malathion carboxylic acids, less than about 0.04% (w/w) MeOOSPO, less than about 0.02% (w/w) MeOSSPO and less than about 0.1% (w/w) MeOSSPS.

25. A composition comprising, greater than about 98.5% (w/w) malathion, less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (waw) MeOSSPO, less than about 0.2% (w/w) MeOOSPS, less than about 0.3% (w/w) malathion carboxylic acid and less than about 0.1% (w/w) isomalathion.

26. The composition of claim 25 further comprising, greater than about 98.5% (w/w) malathion, less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO, less than about 0.2% (w/w) MeOOSPS, less than about 0.3% (w/w) malathion carboxylic acid and less than about 0.02% (w/w) isomalathion.

27. The composition of claim 26 further comprising, greater than about 99.0% (w/w) malathion, less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO and less than about 0.1% (w/w) MeOSSPS, 0.03% (w/w) malathion carboxylic acids and less than about 0.02% (w/w) isomalathion.

28. The composition of claim 27 further comprising, greater than about 99.0% (w/w) malathion, less than about 0.04% (w/w) MeOOSPO, less than about 0.02% (w/w) MeOSSPO and less than about 0.1% (w/w) MeOSSPS, 0.03% (w/w) malathion carboxylic acids and less than about 0.02% (w/w) isomalathion.

29. The composition of claim 25 wherein, the composition is stable after storage.

30. The composition of claim 29 wherein the amount of isomalathion is not more than about 0.1% (w/w), after storage at 5°

C. for 3 months.

31. The composition of claim 29 wherein the amount of isomalathion is not more than about 0.1% (w/w), after storage for 3 months at 25°

C. and 60% relative humidity.

32. The composition of claim 29 wherein the amount of isomalathion is not more than about 0.1% (w/w), after storage for 3 months at 30°

C. and 60% relative humidity.