CATALYZED AND CLEAN MALATHION PROCESS

Abstract

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

Description

61363-AR CATALYZED AND CLEAN MALATHION PROCESS FIELD OF INVENTION The present invention relates to a novel synthesis of malathion 5 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 have been discovered 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 found to be toxic. O,O,S-trimethyl phosphorodithioate (MeOOSPS) and O,S,S-trimethyl phosphorothioate (MeOSSPO) can cause liver damage. The physical properties of malathion make it difficult to extract impurities by conventional means, for example, because malathion is liquid at room temperature (melting point: 2.9 °C) and crystallization is difficult. Therefore, there is a need for an improved process for the preparation of malathion. Alejandra Aoun - 27184140328 Dig25lly signed by PORTALTRAMITES - INPI Date: 2019.09.26 12:31:01 -03:00 Reason: Digitally Signed by the INPI Location: Buenos Aires, Argentina 61363-AR BRIEF DESCRIPTION OF THE INVENTION The present invention provides a novel approach to the production of malathion with good yields and significantly reduced impurities. Malathion produced by this method has significantly lower levels of toxic impurities and is stable during stable storage, when compared to any other commercial method available in the literature for pharmaceutical use. Generally, the method 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 the 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 in step (a) is controlled between approximately 5 and approximately 20 °C. In some embodiments, the temperature in step (b) is controlled between approximately 10 and approximately 25 °C. In some embodiments, the temperature is controlled between approximately 20 and approximately 50 °C after the addition of diethyl maleate to the mixture is complete. In some embodiments, the temperature is controlled between approximately 35 and approximately 45 °C after the addition of diethyl maleate to the mixture is complete. In some formulations, the acid varies from approximately 0.1% to approximately 20% by weight in the stage (a) mixture. In some 61363-AR modalities, the acid varies from approximately 1% to approximately 10% in the stage (a) mixture 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 between O,O-DMDTPA and diethyl maleate varies from approximately 1:1.2 to approximately 1:1. In some embodiments, the molar ratio varies 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 also includes, after step (b), a step (c) washing the mixture resulting from step (b) with an aqueous solution to isolate the malathion. In some embodiments, step (b) includes extracting byproducts using renewed film filters (WFS). In some formulations, isolated malathion contains an impurity comprising less than approximately 0.55% of O,O-DMDTPA by weight. In some formulations, isolated malathion contains an impurity comprising less than approximately 0.35% of O,O-DMDTPA by weight. 61363-AR 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 approaches, 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 mention 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 is present. The term “approximately” as used in the present description refers to the reference numerical indication plus or minus 10% of that reference numerical indication. 61363-AR Generally, the method involves reacting O,O-dimethyldithiophosphoric acid (O,O-DMDTPA) with maleate in the presence of an acid. The acid thus acts as a catalyst, contributing not only to improved yield and a shorter reaction time but also to reduced impurities. This efficient approach is also environmentally friendly and reduces production costs. The initial mixing of the reactants can be controlled at a temperature of, for example, below approximately 25, 20, or 15 °C. After all the reactants are mixed, the temperature can be raised to, for example, between approximately 20 and 50 °C, between approximately 35 and 45 °C, or between approximately 35 and 40 °C.In some modalities, the total 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,O-DMDTPA) with an acid to form a mixture, and 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 efficiency of the reaction. 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 an excessive increase in unreacted diethyl maleate. 61363-AR After the addition of diethyl maleate, the reaction mixture can be heated to approximately 50, 45, 40, or 35 °C. The reaction is then allowed to continue for an additional period of approximately 3 to 12 hours, 5 to 12 hours, 3 to 10 hours, 4 to 6 hours, 5 to 10 hours, 6 to 8 hours, or 6 to 7 hours. In some embodiments, the temperature can be raised in stages, for example, first to approximately 20 or 25 °C before being held at approximately 40 °C. The amount of acid varies from approximately 0.1% to approximately 20% by weight in the mixture of step (a). In some embodiments, the acid in the mixture varies 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 may be, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, or any combination thereof. In some embodiments, the acid is hydrochloric acid having a concentration of approximately 20%, approximately 25%, approximately 30%, or approximately 35% by weight. In some embodiments, the acid is saturated hydrochloric acid. In some embodiments, the acid is hydrogen chloride gas, which is introduced into the mixture by means of 61363-AR 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 between O,O-DMDTPA and diethyl maleate can be controlled, for example, from approximately 1:1.2 to approximately 1:1. In some embodiments, the molar ratio between O,O-DMDTPA and diethyl maleate varies 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 of less than approximately 7 is effective in eliminating 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 malathion product. An additional organic solvent may be used if required. 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 maleate), FE (diethyl fumarate), MOSSPO, and MOOSPS. 61363-AR (phosphodithioic acid, O,O,S-trimethyl ester). In some embodiments, renewed film filters (WFS) are applied to remove impurities. The malathion obtained by the present invention has significantly fewer impurities than that obtained by conventional methods. In some embodiments, the impurity of 0,0-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%. Since diethyl maleate is insoluble in the aqueous phase, mixing of the reactants is necessary to promote the reaction. For example, mechanical stirring, agitation, or any type of stirring can be applied to facilitate mixing of the reactants. In some embodiments, an inert organic solvent can be added to the reaction mixture to facilitate mixing. Examples A clean process for preparing malathion s + MeO'T'-SH OMe Diethyl maleate (ME) MP-1 EITHER OEt OEt Malathion 61363-AR 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; it is important to ensure that the reaction occurs from the beginning of the dosing process. After the addition, the reaction was monitored at 20 °C for 1.0 h under constant stirring. The temperature was then increased to 40 °C and maintained for 7 h. A sample was taken and checked periodically for GC-FID conversion (MP-1 × 0.5 A %). After the conversion was determined to be acceptable, the temperature was returned 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. Lot no. Catalyst IPC(h) % of 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 % of 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 % of H2SO4 5 0.28 0.22 0.93 9.61 84.90 10 0.29 0.31 0.62 8.38 85.50 * “% of A” refers to the percentage area; the 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 until saturation; “IPC” refers to an in-process control. It will be understood by those skilled in the art that numerous and diverse modifications can be made without departing from the spirit of the present 61363-AR 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 the scope of the present invention.

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. 21 claims follow.