CATALYZED AND ECOLOGICAL MALATHION PROCESS

Abstract

The present invention relates to an improved synthesis of malathion. The presence of an acid facilitates the reaction between O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) and maleate, leading to excellent product yield in a shorter reaction time and with fewer impurities.

Description

CATALYZED AND ECOLOGICAL MALATHION PROCESS Field of Invention The present invention relates to a novel synthesis of malathion using an acid as a catalyst. Due to the shorter reaction time and lower level of impurities, the synthesis described herein significantly reduces the undesirable environmental impact compared to conventional methods. Background of the Invention Several processes for the preparation and / or purification of malathion have been described in the literature. Malathion (CAS number: 121-75-5) is an organophosphate insecticide that inhibits cholinesterase activity in vivo. However, the efficient and economical production of malathion remains a challenge. For example, numerous impurities are found in malathion preparations. Some of these impurities form during storage, and some are generated during the manufacturing process. Many of these malathion impurities have been shown to be toxic. O,O,S-trimethyl phosphoradithioate (MeOOSPS) and O,S,S-trimethyl phosphorothioate (MeOSSPO) can cause liver damage. The physical properties of malathion make the removal of impurities by conventional means difficult, for example, because malathion is liquid at room temperature (melting point: 2.9°C), and its crystallization is difficult. Therefore, it is necessary to improve the malathion preparation process. Brief Description of the Invention The present invention provides a novel criterion for the production of malathion with good yields and considerably reduced impurities. Malathion produced by this method has significantly lower levels of toxic impurities and is stable during storage, compared to any other commercial method available in the literature for pharmaceutical use. The method generally involves reacting O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with diethyl maleate in the presence of an acid. In some embodiments, the method includes, before reacting O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with maleate, (a) mixing O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with an acid to form a mixture and (b) adding diethyl maleate to the mixture. In some embodiments, the temperature of step (a) is controlled from approximately 5 to approximately 20 °C. In some embodiments, the temperature of step (b) is controlled from approximately 10 to approximately 25 °C. In some embodiments, the temperature is controlled from approximately 20 to approximately 50 °C after the addition of diethyl maleate to the mixture is complete. In some embodiments, the temperature is controlled from approximately 35 to approximately 45 °C after the addition of diethyl maleate to the mixture is complete. In some embodiments, the acid ranges from approximately 0.1% to approximately 20% by weight in the step (a) mixture. In some embodiments, the acid ranges from MA / a / ZUZl / UU¿4 / ¿ approximately 1% to approximately 10% in the mixture of stage (a) by weight. In some embodiments, the acid comprises hydrochloric acid. In some embodiments, the acid comprises hydrochloric acid having a concentration ranging from approximately 20% to approximately 37% by weight. In some embodiments, the acid consists essentially of saturated hydrochloric acid. In some embodiments, the molar ratio of O,O-DMDTPA to diethyl maleate ranges from approximately 1:1.2 to approximately 1:1. In some embodiments, the molar ratio ranges from approximately 1:1.1 to approximately 1:1.02. In some embodiments, the diethyl maleate begins to react with the O,O-DMDTPA after being added to the mixture. In some embodiments, the reaction between diethyl maleate and O,O-DMDTPA is allowed to continue for a period of less than approximately 10 hours. In some embodiments, the reaction is allowed to continue for a period of less than approximately 8 hours. In some embodiments, the method further includes following step (b), and a step (c) of washing the mixture resulting from step (b) with an aqueous solution to isolate malathion. In some embodiments, step (c) includes removing byproducts using renewed layer stills (WFS). In some formulations, isolated malathion contains an impurity comprising less than approximately 0.55% O,O-DMDTPA by weight. In some formulations, isolated malathion contains an impurity comprising less than approximately 0.35% O,O-DMDTPA by weight. In some formulations, malathion's efficacy exceeds approximately 90%. In some formulations, malathion's efficacy reaches more than approximately 90% in a period of less than approximately 7 hours. Detailed Description of the Invention The present invention relates to an improved process for the preparation of malathion. Compared to conventional methods, the method described herein achieves a higher yield of malathion in a shorter period of time. Furthermore, due to the reduced amount of impurities, the stability of the malathion is also improved. While the following text may refer to or exemplify specific components of a reaction or a reaction condition, it is not intended to limit the scope of the invention to such particular references or examples. Those skilled in the art may make various modifications, taking into account practical and economic considerations, such as the quantity of a reactant and the temperature and duration of a reaction. The articles "a" and "an," as used herein, refer to one or more, or at least one, unless otherwise stated. That is, reference to any element or component of the present invention by means of the indefinite article "a" or "an" does not preclude the possibility that more than one element or component may be present. The term approximately, as used herein, refers to the numerical indication IVIA / a / ZUZ I / UUÓ4 / J to which reference is made approximately 10% of that numerical indication to which reference is made. The method generally involves reacting O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with maleate in the presence of an acid. The acid thus acts as a catalyst, not only improving the yield and shortening the reaction time, but also reducing impurities. This efficient methodology is also environmentally friendly and results in lower production costs. The initial mixture of reactants can be set at a temperature of, for example, below approximately 25, below approximately 20, or below approximately 15°C. After mixing all the reactants, the temperature can be raised to, for example, between approximately 20 and approximately 50°C, between approximately 35 and approximately 45°C, and between approximately 35 and approximately 40°C.In some modalities, the overall reaction time is generally less than approximately 15 hours, less than approximately 12 hours, less than approximately 10 hours, less than approximately 8 hours, less than approximately 7 hours, less than approximately 6 hours, or less than approximately 5 hours. In some embodiments, the method involves mixing O,O-dimethyldithiophosphoric acid (O,ODMDTPA) with an acid to form a mixture; then adding diethyl maleate to the mixture. The diethyl maleate can be added in portions to the mixture at a controlled temperature to minimize the formation of byproducts without compromising the reaction efficiency. For example, the diethyl maleate can be added dropwise to the mixture at a temperature between 10 and 25 °C, between 15 and 20 °C, or between 1 and 20 °C. The rate of addition and the temperature should be adjusted so that the reaction can proceed without excessive accumulation of unreacted diethyl maleate. After the addition of diethyl maleate, the reaction mixture can be heated to a temperature of approximately 50, approximately 45, approximately 40, or approximately 35 °C. The reaction is then allowed to continue for an additional period of approximately 3 to approximately 12 hours, approximately 5 to approximately 12 hours, approximately 3 to approximately 10 hours, approximately 4 to approximately 6 hours, approximately 5 to approximately 10 hours, approximately 6 to approximately 8 hours, or approximately 6 to approximately 7 hours. In some embodiments, the temperature can be raised in stages, for example, first to approximately 20 or approximately 25 °C before being held at approximately 40 °C. The amount of acid ranges from approximately 0.1% to approximately 20% by weight in the mixture of step (a). In some embodiments, the acid in the mixture ranges from approximately 0.5% to approximately 10%, from approximately 1% to approximately 10%, from approximately 3% to approximately 10%, from approximately 5% to approximately 10%, from approximately 3% to approximately 8%, or from approximately 4% to approximately 8%. The acid can be, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, or any combination thereof. In some formulations, the acid is hydrochloric acid with a concentration of approximately 20%. 25%, approximately 30%, or approximately 35% by weight. In some embodiments, the acid is saturated hydrochloric acid. In some embodiments, the acid is hydrochloric acid gas, which is introduced into the mixture by, for example, bubbling. In some embodiments, the acid consists essentially of saturated hydrochloric acid. Before the addition of diethyl maleate, the mixture may be cooled to a temperature, for example, between approximately 10 and approximately 20 °C or between approximately 10 and approximately 15 °C. To ensure the complete reaction of O,O-DMDTPA, the molar ratio of O,O-DMDTPA to diethyl maleate can be controlled, for example, from approximately 1:1.2 to approximately 1:1. In some embodiments, the molar ratio of O,O-DMDTPA to diethyl maleate ranges from approximately 1:1.1 to approximately 1:1.01, from approximately 1:1.05 to approximately 1:1.01, or from 1:1.03 to approximately 1:1.01. Isolating the product involves removing impurities and / or purifying the malathion. For example, to reduce impurity levels, the malathion prepared by the previous process may be washed with water or an aqueous solution. In some embodiments, the crude product is treated with a sulfur solution. In some embodiments, a sulfur solution with a pH lower than approximately 7 is effective in preventing the formation of dimer impurities. The pH of the sulfur solution ranges from approximately 6.0 to approximately 7.0. In some embodiments, the malathion is crystallized with a suitable solvent such as methanol to improve purity. The organic phase contains the product malathion. Additional organic solvent may be used if necessary. The organic phase may be distilled to remove some impurities, including MP-1-S (phosphonothioic acid, O,O-dimethyl ester), MOOOPS (phosphorothioic acid, O,O,O-trimethyl ester), ME (diethyl maltate), FE (diethyl fumarate), MOSSPO, and MOOSPS (phosphorodithioic acid, O,O,S-trimethyl ester). In some embodiments, wind-fed stills (WFS) are used to remove impurities. The malathion obtained by the present invention has significantly fewer impurities than conventional methods. In some embodiments, the impurity of O,O-DMDTPA is less than approximately 0.65%, less than approximately 0.55%, less than approximately 0.5%, less than approximately 0.45%, less than approximately 0.4%, less than approximately 0.35%, less than approximately 0.3%, less than approximately 0.25%, less than approximately 0.15%, or less than approximately 0.1% by weight. The method of the present invention achieves a significantly higher malathion yield than previously reported methods. In some embodiments, the yield is greater than approximately 80%, greater than approximately 85%, greater than approximately 90%, or greater than approximately 95%. Because diethyl maleate is insoluble in aqueous solution, mixing the reactants is necessary to promote the reaction. For example, mechanical stirring, agitation, or any other type of stirring can be applied to facilitate mixing. In some embodiments, an inert organic solvent can be added to the reaction mixture to further aid mixing. EXAMPLES An environmentally friendly process for preparing malathion: 035 ASOA Ii 0El A II 50 p^OEt MeO i SH O Me 45 MeCr VEl O40 O Me O Diethyl Maleate (ME) MP-1 55 Malathion MP-1 (45.1 g) and concentrated HCl (2.5 g) were weighed and sequentially added to a 0.5 L jacketed reactor. The temperature was set to 10–15 °C. Diethyl maleate (50.0 g) was added dropwise while maintaining the temperature between 15 and 20 °C, ensuring that the reaction proceeded from the start of the dosing process. After the addition, the reaction was monitored at 20 °C for 1.0 h with constant stirring. The temperature was then increased to 40 °C and maintained for 7 h. A sample was taken and periodically checked for GC-FID conversion (MP-1 Δ 0.5 A%). After the conversion was determined to be acceptable, the temperature was adjusted to 30 °C and water (25.0 g) was added. The organic phase was subjected to WFS distillation to remove some impurities of MP-1-S, MOOOPS, ME, FE, MOSSPO, and MOOSPS. The malathion yield was 87.2 g (98 wt%). The effect of hydrochloric acid on the reaction is summarized below. Batch No. Catalyst IPC(h) Analysis A% MP-1-S MOOOPS MP-1 FE Malathion 1 No. 5 0.28 0.23 2.00 16.70 77.89 10 0.28 0.22 1.37 12.68 82.59 2 36% HCl 5 0.33 0.25 0.54 7.01 88.90 10 0.34 0.25 0.30 6.37 89.75 3 HCl Gas 5 0.32 0.26 0.20 5.47 90.18 4 98% H2SO4 5 0.28 0.22 0.93 9.61 84.90 10 0.29 0.31 0.62 8.38 85.50 * “A%” refers to the percentage of area; 36% HCl and 98% H2SO4 catalysts are used in the amount of 5% based on the weight of diethyl maleate and HCl gas is added to saturated; “IPC” refers to process control. Those skilled in the art will understand that numerous and diverse modifications can be made without departing from the spirit of the present invention. Therefore, it should be understood that the various embodiments of the present invention described herein are merely illustrative and are not intended to limit its scope.

Claims

CLAIMS 1. A method for producing malathion, comprising reacting O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with diethyl maleate in the presence of an acid.

2. The method according to claim 1, wherein further comprising, before reacting O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with the maleate, (a) mixing O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with acid to form a mixture; and (b) adding diethyl maleate to the mixture.

3. The method according to claim 2, wherein the temperature of step (a) is controlled between approximately 5 and approximately 20 °C.

4. The method according to claim 2, wherein the temperature of step (b) is controlled between approximately 10 and approximately 25 °C.

5. The method according to claim 2, wherein the temperature is regulated between approximately 20 and approximately 50 °C after the addition of diethyl maleate to the mixture is complete.

6. The method according to claim 2, wherein the temperature is regulated between approximately 35 and approximately 45 °C after the addition of diethyl maleate to the mixture is complete.

7. The method according to claim 1, wherein the acid ranges from approximately 0.1% to approximately 20% in the mixture of step (a) by weight.

8. The method according to claim 1, wherein the acid ranges from approximately 1% to approximately 10% in the mixture of step (a) by weight.

9. The method according to claim 1, wherein the acid is hydrochloric acid or sulfuric acid.

10. The method according to claim 1, wherein the acid is hydrochloric acid having a concentration ranging from approximately 20% to approximately 37% by weight, or sulfuric acid having a concentration ranging from approximately 70% to approximately 98% by weight.

11. The method according to claim 1, wherein the acid consists essentially of saturated hydrochloric acid.

12. The method according to claim 1, wherein the molar ratio of O,ODMDTPA with respect to diethyl maleate ranges from approximately 1:1.2 to approximately 1:

1.

13. The method according to claim 1, wherein the molar ratio between O,O-DMDTPA maleate and diethyl ranges from approximately 1:1.1 to approximately 1:1.

02.

14. The method according to claim 1, wherein the diethyl maleate begins to react with O,O-DMDTPA after being brought into contact with each other.

15. The method according to claim 1, wherein the reaction between diethyl maleate and O,O-DMDTPA is allowed to continue for a period of less than approximately 10 hours.

16. The method according to claim 1, wherein the reaction between diethyl maleate and O,O-DMDTPA is allowed to continue for a period of less than approximately 8 hours.

17. The method according to claim 1, wherein it further comprises, after the reaction, washing with water or an aqueous solution.

18. The method according to claim 1, wherein it further comprises, after the reaction, removing byproducts by means of renewed layer stills (WFS).

19. The method according to claim 1, further comprising isolating malathion, wherein the isolated malathion contains an impurity comprising less than approximately 0.55% O,O-DMDTPA by weight.

20. The method according to claim 1, further comprising isolating malathion, wherein the isolated malathion contains an impurity comprising less than approximately 0.35% O,O-DMDTPA by weight.

21. The method according to claim 1, wherein the yield of malathion is more than about 90%.

22. The method according to claim 1, wherein the yield of malathion reaches more than approximately 90% in a period of less than approximately 7 hours.