Catalytic and environmentally friendly production of malathion

Abstract

To obtain an improved method for synthesizing malathion. [Solution] By reacting O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with maleic acid in the presence of an acid, a product with few impurities and excellent yield can be obtained in a short reaction time.

Description

[Technical field]

[0001] The present invention relates to a novel method for the synthesis of malathion using an acid as a catalyst. Due to the short reaction time and low levels of impurities, the synthesis method described herein has significantly less undesirable environmental impact than conventional methods. [Background technology]

[0002] Various methods for the production and / or purification of malathion have been presented in the literature. Malathion (CAS number: 121-75-5) is an organophosphate insecticide that inhibits cholinesterase activity in vivo. However, producing malathion efficiently and economically remains a challenge.

[0003] For example, formulations of malathion contain numerous impurities, some of which are formed during storage and some of which are formed during the manufacturing process. Many of these malathion impurities have been shown to be toxic.

[0004] O,O,S-trimethyldithiophosphate (MeOOSPS) and O,S,S-trimethylthiophosphate (MeOSSPO) can cause liver damage. Malathion is also a liquid at room temperature (melting point: 2.9°C) and is difficult to crystallize. Due to its physical properties, it has been difficult to remove impurities using conventional methods.

[0005] Therefore, there is a need for improved methods for preparing malathion. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention provides a novel approach for the production of malathion with good yields and significantly reduced impurities.

[0007] Malathion produced by the process of the present invention has low levels of harmful impurities and is storage stable as compared to other processes available in the literature for pharmaceutical use. [Means for solving the problem]

[0008] The process of the present invention generally involves reacting O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with diethyl maleate in the presence of an acid.

[0009] In an embodiment, the method includes the steps of (a) combining O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with an acid to form a mixture, and (b) adding diethyl maleate to the mixture, prior to reacting O,O-DMDTPA with a maleate salt.

[0010] In an embodiment, the temperature in step (a) is controlled between about 5 and about 20° C. In an embodiment, the temperature in step (b) is controlled between about 10 and about 25° C. In an embodiment, the temperature is controlled between about 20 and about 50° C. after addition of diethyl maleate to the mixture is complete. In an embodiment, the temperature is controlled between about 35° C. and about 45° C. after addition of diethyl maleate to the mixture is complete.

[0011] In embodiments, the acid is present in the mixture of step (a) in a range from about 0.1% to about 20% by weight. In embodiments, the acid is present in the mixture of step (a) in a range from about 1% to about 10% by weight.

[0012] In an embodiment, the acid comprises hydrochloric acid. In an embodiment, the acid comprises hydrochloric acid having a concentration ranging from about 20% to about 37% by weight. In an embodiment, the acid comprises essentially saturated hydrochloric acid.

[0013] In embodiments, the molar ratio between O,O-DMDTPA and diethyl maleate ranges from about 1:1.2 to about 1:1. In embodiments, the molar ratio ranges from about 1:1.1 to about 1:1.02. In embodiments, the diethyl maleate begins to react with O,O-DMDTPA when added to the mixture.

[0014] In an embodiment, the reaction between diethyl maleate and O,O-DMDTPA is allowed to continue for less than about 10 hours. In an embodiment, the reaction is allowed to continue for a period of less than about 8 hours.

[0015] In an embodiment, the method of the present invention further comprises, after step (b), step (c) washing the mixture resulting from step (b) with an aqueous solution to isolate malathion. In an embodiment, step (c) comprises removing by-products by Wiped-Film Stills (WFS).

[0016] In some embodiments, the isolated malathion contains less than about 0.55% by weight of an impurity consisting of O,O-DMDTPA. In some embodiments, the isolated malathion contains less than about 0.35% by weight of an impurity consisting of O,O-DMDTPA.

[0017] In embodiments, the yield of malathion is greater than about 90%. In embodiments, the yield of malathion reaches greater than about 90% in a period of less than about 7 hours. Effect of the Invention

[0018] The present invention relates to an improved manufacturing process for preparing malathion. Compared to conventional processes, the process described herein achieves high yield production of malathion in a shorter time. Furthermore, the stability of malathion is improved due to the reduced amount of impurities. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The following description sets forth specific components of the reaction or reaction conditions, but is not intended to limit the scope of the invention to such specific references or examples. Those skilled in the art will appreciate that various modifications may be made to the amounts of reactants, the temperature and length of the reaction, etc., based on practical and economic considerations.

[0020] As used herein, the articles "a" and "an" mean "one or more" or "at least one," unless otherwise indicated. That is, the reference to any element or component of the invention by the indefinite article "a" or "an" does not exclude the possibility that more than one element or component is present.

[0021] As used herein, the term "about" refers to plus or minus 10% of the referenced numerical designation.

[0022] The process of the present invention involves reacting O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with maleic acid in the presence of an acid. This catalytic action of the acid not only improves the yield with a shorter reaction time, but also reduces impurities. This efficient approach has low manufacturing costs and is environmentally friendly.

[0023] The initial mixing of the reactants can be controlled at a temperature of, for example, about 25° C. or less, about 20° C. or less, about 15° C. or less.

[0024] After all reactants are mixed, the temperature can be raised to, for example, about 20 to about 50° C., about 35 to about 45° C., or about 35 to about 40° C. In embodiments, the total reaction time is generally less than about 15 hours, less than about 12 hours, less than about 10 hours, less than about 8 hours, less than about 7 hours, less than about 6 hours, or less than about 5 hours.

[0025] In an embodiment, the method includes combining O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with an acid to form a mixture; and adding diethyl maleate to the mixture.

[0026] The diethyl maleate can be added in portions to the mixture at a controlled temperature to minimize the formation of by-products yet without impairing the efficiency of the reaction. For example, the diethyl maleate can be added dropwise to the mixture at temperatures of 10-25°C, 15-20°C, or 1-20°C. The rate of addition and temperature are adjusted so that the reaction proceeds without excessive accumulation of unreacted diethyl maleate.

[0027] After the addition of diethyl maleate, the reaction mixture can be warmed to a temperature of about 50, about 45, about 40, or about 35° C. The reaction is allowed to continue for about 3 hours to about 12 hours, about 5 hours to about 12 hours, about 3 hours to about 10 hours, about 4 hours to about 6 hours, about 5 hours to about 10 hours, about 6 hours to about 8 hours, or about 6 hours to about 7 hours.

[0028] In embodiments, the temperature can be increased in stages, for example, first to about 20°C or about 25°C and then maintained at about 40°C.

[0029] The amount of acid ranges from about 0.1% to about 20% by weight of the mixture of step (a). In some embodiments, the amount of acid in the mixture ranges from about 0.5% to about 10%, from about 1% to about 10%, from about 3% to about 10%, from about 5% to about 10%, from about 3% to about 8%, or from about 4% to about 8%.

[0030] The acid can be, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, or any combination thereof. In an embodiment, the acid is hydrochloric acid having a concentration of about 20%, about 25%, about 30%, or about 35% by weight. In an embodiment, the acid is saturated hydrochloric acid. In an embodiment, the acid is hydrochloric acid gas, which is introduced into the mixture, for example, by bubbling. In an embodiment, the acid is essentially saturated hydrochloric acid. Prior to adding diethyl maleate, the mixture can be cooled, for example, to a temperature of about 10 to about 20° C., or about 10 to about 15° C.

[0031] To ensure complete reaction of O,O-DMDTPA, the molar ratio between O,O-DMDTPA and diethyl maleate can be controlled, for example, from about 1:1.2 to about 1: 1. In embodiments, the molar ratio between O,O-DMDTPA and diethyl maleate ranges from about 1:1.1 to about 1:1.01, from about 1:1.05 to about 1:1.01, or from 1:1.03 to about 1:1.01.

[0032] Separating the product may involve removing impurities and / or purifying the malathion. For example, the malathion prepared by the above process may be washed with water or an aqueous solution to reduce the level of impurities. In the examples, the crude product is treated with a sulfur solution. In the examples, a sulfur solution having a pH of less than about 7 is effective to eliminate the formation of dimeric impurities. The pH of the sulfur solution ranges from about 6.0 to about 7.0. In the examples, the malathion is crystallized from a suitable solvent, such as methanol, to improve purity.

[0033] The organic phase contains the malathion product. Additional organic solvents can be used if necessary. The organic phase can be distilled to remove impurities including MP-1-S (phosphonothioic acid, O,O-dimethyl ester), MOOOPS (phosphonothioic acid, O,O,O-trimethyl ester), ME (diethyl maleate), FE (diethyl fumarate), MOSSPO and MOOSPS (phosphonodithioic acid, O,O,S-trimethyl ester). In an embodiment, wiped-film stills (WFS) are applied to remove impurities.

[0034] Malathion obtained by the present invention has much fewer impurities than conventional methods, in embodiments, the impurity of O,O-DMDTPA is about 0.65% or less, about 0.55% or less, about 0.5% or less, about 0.45% or less, about 0.4% or less, about 0.35% or less, about 0.3% or less, about 0.25% or less, about 0.15% or less, or about 0.1% or less by weight.

[0035] The methods of the present invention achieve much higher yields of malathion than conventional methods, in embodiments, the yield is about 80% or greater, about 85% or greater, about 90% or greater, or about 95% or greater.

[0036] Since diethyl maleate is insoluble in the aqueous phase, mixing of the reactants is necessary to facilitate the reaction. For example, mechanical shaking, stirring, or any type of agitation can be applied to facilitate mixing of the reactants. In an embodiment, an inert organic solvent can be added to the reaction mixture to facilitate mixing of the reactants. EXAMPLES

[0037] An environmentally friendly method for producing malathion [ka]

[0038] MP-1 (45.1 g) and concentrated hydrochloric acid (2.5 g) were weighed and added sequentially to a 0.5 L jacketed reactor. The temperature was adjusted to 10-15°C. Diethyl maleate (50.0 g) was added dropwise while maintaining the temperature at 15-20°C. After addition, the reaction was controlled under constant stirring at 20°C for 1.0 hour. The temperature was then raised to 40°C and maintained for 7 hours.

[0039] Samples were taken and checked periodically for conversion GC-FID (MP-1≦ 0.5 A %). After conversion was deemed acceptable, temperature was increased to 30°C and water was added (25.0 g). Organic phase was WFS distilled to remove impurities such as MP-1-S, MOOOPS, ME, FE, MOSSPO, MOOSPS. Yield of malathion was 87.2 g (98% wt).

[0040] Summary of the effects of hydrochloric acid on reactions [Table 1]

[0041] It will be understood by those skilled in the art that numerous and various modifications can be made without departing from the spirit of the present invention. Therefore, it should be understood that the various embodiments described herein are merely illustrative and are not intended to limit the scope of the present invention.

Claims

1. 1. A method for producing malathion, comprising reacting O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with diethyl maleate in the presence of an acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, or any combination thereof.

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

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

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

5. The process of claim 2, wherein the temperature is controlled at 20-50° C. after the addition of diethyl maleate to the mixture is completed.

6. The process according to claim 2, wherein the temperature is controlled at 35 to 45° C. after the addition of diethyl maleate is completed.

7. 2. The method of claim 1, wherein the acid is present in the mixture of step (a) in an amount ranging from 0.1% to 20% by weight.

8. The method of claim 1, wherein the acid is present in the mixture of step (a) in an amount ranging from 1% to 10% by weight.

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

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

11. 2. The process according to claim 1, characterized in that the acid is essentially saturated hydrochloric acid.

12. 2. The process according to claim 1, wherein the molar ratio of O,O-DMDTPA to diethyl maleate is from 1:1.2 to 1:

1.

13. The process according to claim 1, wherein the molar ratio of O,O-DMDTPA to diethyl maleate is in the range of 1:1.1 to 1:1.

02.

14. The process according to claim 1, wherein the reaction between diethyl maleate and O,O-DMDTPA is initiated by contact of the two.

15. The process of claim 1, wherein the reaction of diethyl maleate with O,O-DMDTPA continues for less than 10 hours.

16. 2. The method of claim 1, wherein the reaction of diethyl maleate with O,O-DMDTPA continues for less than 8 hours.

17. The process of claim 1, further comprising washing with water or an aqueous solution after the reaction.

18. The method of claim 1, further comprising removing by-products after the reaction by wiped film still (WFS).

19. 10. The process of claim 1 further comprising isolating the malathion, wherein the isolated malathion has less than 0.55% by weight of impurities including O,O-DMDTPA.

20. 10. The process of claim 1 further comprising isolating the malathion, wherein the isolated malathion has less than 0.35% by weight of impurities including O,O-DMDTPA.

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

22. 2. The process according to claim 1, wherein the yield of malathion reaches 90% or more in a reaction time of less than 7 hours.

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