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(11) EP 2 170 078 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A01N 57/00 (2006.01) C07F 9/165 (2006.01) 26.03.2014 Bulletin 2014/13 (86) International application number: (21) Application number: 08763740.1 PCT/IN2008/000270

(22) Date of filing: 28.04.2008 (87) International publication number: WO 2009/007998 (15.01.2009 Gazette 2009/03)

(54) PROCESS FOR THE PREPARATION OF MALATHION AND ITS INTERMEDIATE VERFAHREN ZUR HERSTELLUNG VON MALATHION UND SEINEM ZWISCHENPRODUKT PROCÉDÉ DE FABRICATION DE MALATHION ET DE SON INTERMÉDIAIRE

(84) Designated Contracting States: (74) Representative: Atkinson, Jonathan David Mark et AT BE BG CH CY CZ DE DK EE ES FI FR GB GR al HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT Harrison Goddard Foote LLP RO SE SI SK TR Belgrave Hall Designated Extension States: Belgrave Street AL BA MK RS Leeds LS2 8DD (GB)

(30) Priority: 09.07.2007 IN CH14712007 (56) References cited: US-A1- 2007 010 496 (43) Date of publication of application: 07.04.2010 Bulletin 2010/14 • POLEC IWONA ET AL: "Enantiomers of 0,0- Dialkyl Malathion Analogs. Synthesis and (73) Proprietor: Suven Life Sciences Limited Toxicological Characteristics" ORGANIKA,, no. Hyderabad 500 034, Andhra Pradesh (IN) 2, 1 January 1998 (1998-01-01), pages 7-20, XP009105967 ISSN: 0137-9933 (72) Inventors: • J. L. LEFFERTS, K. C. MOLLOY, J. J. • ARAVA, Veera, Reddy ZUCKERMAN, I. HAIDUC, C. GUTA, D. RUSE: Hyderabad 500 034, Andhra Pradesh (IN) "Oxy and thio phosphorus acid derivatives of tin. • NADKARNI, Vaishali 1. Triorganotin(IV) dithiophosphate esters" Hyderabad 500 034, Andhra Pradesh (IN) INORG. CHEM., vol. 19, no. 6, 1980, pages • JASTI, Venkateswarlu 1662-1670, XP002496618 Hyderabad 500 034, Andhra Pradesh (IN)

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 170 078 B1

Printed by Jouve, 75001 PARIS (FR) EP 2 170 078 B1

Description

Field of Invention

5 [0001] The present invention relates to the process for the preparation of highly pure form of S-[1,2-(dicarbethoy)-ethyl] O,O-dimethyl phosphorodithioate having formula (I).

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[0002] The compound of formula (I) has adopted name "Malathion". [0003] The Malathion prepared by the process of this invention is highly storage stable and toxic impurities are much lower than any other commercial preparation available for the pharmaceutical purpose. 20 Background of the Invention

[0004] Various processes for the preparation and/or purification of Malathion are disclosed in the literature. Malathion {CAS Number: 121-75-5} is an organophosphate insecticide that inhibits cholinesterase activity in vivo. The U. S. Food 25 and Drug Administration (FDA) supports the pharmaceutical use of malathion for the treatment for head lice in children. Due to its low toxicity to humans. Malathion may be prepared by reacting O,O-dimethyldithiophosphoric acid (OODM- DTPA) with diethyl maleate (US patent numbers 2,578,652, 2,879,284, 3,403,201, 3,463,841, 3,470,272, 4,367180, 2007/0010496 and 4,681,964).

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[0005] But, still numerous impurities are found in Malathion preparation. Some of these impurities are formed during 40 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 (Keadtisuke etal, Toxicology letters 52:35-46 (1990) or immune suppression (Rodgers etal, immunopharmacology 17 : 131- 140 (1989). The toxicity of Iso Malathion is due to its ability to inhibit acetylcholinesterase, in fact Iso Malathion is ∼1,000 times as active against acetylcholinesterase as compared with Malathion (Tetrahedron 45 letters 33(11). 1415-18 (1992). Malathion physical properties make it difficult to remove impurities by conventional means for example, because Malathion is liquid at ambient temperature (melting point: 2.9 °C), and crystallization is difficult. [0006] US 7,560,445 describes one method of preparing malathion with a reduced level of toxic impurities. [0007] We have developed an alternative improved process for the preparation of Malathion for pharmaceutical use. Malathion produced by this method has significantly lower levels of toxic impurities and storage stable, when compared 50 to the any other commercial method available in literature for the pharmaceutical use.

Summary of the Invention

[0008] The present invention relates to the process of preparation of Malathion of formula (I), 55

2 EP 2 170 078 B1

5

10 which comprises the steps of :

i) adding methanol to phosphorous sulfide in organic solvent at 25 - 50 °C for the period of 1.5 - 2 hours; ii) stirring the above suspension for the period of 5 - 6 hours at 50 - 55 °C; iii) expelling the H2S gas with nitrogen, after cooling the above suspension to 25 - 28 °C; 15 iv) filtering the above suspension to remove insoluble impurities to obtain crude O,O-DMDTPA; v) the crude O,O-DMDTPA is subjected to dissolution in suitable solvent and ammonia gas is purged to precipitate

the pure O,O-DMDTPA.NH3 salt; vi) the above obtain O,O-DMDTPA.NH3 salt is subjected to neutralization with concentrated sulpheric acid to get O,O-DMDTPA; 20 vii) the O,O-DMDTPA obtained in the above step is once again purified through ammonia salt formation and neutralization method as mentioned in above steps v) and vi) to get chromatographically pure O,O-DMDTPA of the formula (II);

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30 viii) adding the above obtain pure O,O-DMDTPA to diethyl maleate at low temperature of -30 to -25 °C in four lots, each at regular interval of 20 minutes; ix) maintaining the above reaction mass at temperature of -30 to -25 °C for the period of 4 hours; x) water washing the above mass to remove O,O-DMDTPA; xi) treating the above obtain crude Malathion with a sulfer reagent at 5 to 10 °C for the period of 13 hours; 35 xii) crystallizing the above obtained Malathion from methanol at low temperature and drying the above obtain mass with anhydrous sodium sulphate in isopropanol to obtain Malathion of formula (I).

[0009] In one aspect, the Malathion prepared by the process of present invention having a reduced level of toxic impurties. 40 [0010] In another aspect, the Malathion prepared by the process of present invention is storage stable. [0011] In yet another aspect, the Malathion prepared by this process may be used for pharmaceutical purpose. [0012] In still another aspect, the Malathion prepared by the process of the present invention comprises:

i) greater than 99.5% w/w Malathion and less than 0.09% of Isomalathion, less than 0.03 of O,O,S-trimethyl phos- 45 phorodithioate, less than 0.002% of diethyl fumarate, less than 0.1% of unknown impurities and less than 0.21 of total impurties. ii) water content is less than 0.02%.

Detailed description of the Invention 50 [0013] Accordingly, the present invention relates to the process for the preparation of Malathion of formula (I),

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3 EP 2 170 078 B1

5

10 which comprises the steps of :

i) adding methanol to phosphorous sulfide in organic solvent at 25 - 50 °C for the period of 1.5 - 2 hours; ii) stirring the above suspension for the period of 5 - 6 hours at 50 - 55 °C; iii) expelling the H2S gas with nitrogen, after cooling the above suspension to 25 - 28 °C; 15 iv) filtering the above suspension to remove insoluble impurities to obtain crude O,O-DMDTPA; v) the crude O,O-DMDTPA is subjected to dissolution in suitable solvent and ammonia gas is purged to precipitate

the pure O,O-DMDTPA.NH3 salt; vi) the above obtain O,O-DMDTPA.NH3 salt is subjected to neutralization with concentrated sulpheric acid to get O,O-DMDTPA; 20 vii) the O,O-DMDTPA obtained in the above step is once again purified through ammonia salt formation and neutralization method as mentioned in above steps v) and vi) to get chromatographically pure O,O-DMDTPA of the formula (II);

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30 viii) adding the above obtain pure O,O-DMDTPA to diethyl maleate at low temperature of -30 to -25 °C in four lots, each at regular interval of 20 minutes; ix) maintaining the above reaction mass at temperature of -30 to -25 °C for the period of 4 hours; x) water washing the above mass to remove O,O-DMDTPA; xi) treating the above obtain crude Malathion with a sulfer reagent at 5 to 10 °C for the period of 13 hours; 35 xii) crystallizing the above obtained Malathion from methanol at low temperature and xiii) drying the above obtain mass with anhydrous sodium sulphate in isopropanol to obtain Malathion of formula ( I).

[0014] In the step (v) of the above preparation, the solvent used in reaction can be selected from hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate and dichloromethane and preferably using ethyl acetate. In this step, 40 ammonia gas is purged in the reaction vessel at temperature of -10 to 5 °C till p H of 9.5 - 9.8 is reached and preferably at a temperature in the range from -5 to 0 °C. The duration of the reaction may range from 1 to 4 hours, preferably for the period of 2 hours. [0015] In the step (vi) of the above preparation, the reaction temperature may range from -30 to -15 °C and preferably at a temperature of -20 °C. The duration of the reaction may range from 10 to 30 minutes, preferably for the period of 45 20 minutes. [0016] In the step (viii) of the above preparation, the molar ratio of diethyl maleate to O,O-DMDTPA in reaction is 1:2.5 and preferably using the molar ratio of diethyl maleate to O,O-DMDTPA is 1:2.0 [0017] In the step (x) of the above preparation, water washing is carried out to remove water soluble impurities, at 10 to 15 °C until the pH of last water wash is found to be 6.5 to 7.0. 50 [0018] In the step (xi) of the above preparation, the sulfide reagent used in reaction can be selected from sodium sulfide, potassium sulfide, phosphorus pentasulfide, calcium sulfide, ammonium sulfide and ammonium bisulfide and preferably using phosphorus pentasulfide. An aqueous solution of sulfide reagent used in this step of reaction is usually 3%. [0019] In the step (xii) of the above preparation, crystallization of above obtain Malathion from methanol at temperature 55 of -45 to -25 °C and preferably at a temperature in the range from -40 to -30 °C. [0020] In the step (xiii) of the above preparation, the reaction temperature may range from 15 to 40 °C and preferably at a temperature in the range from 25 to 27 °C. The duration of the reaction may range from 5 to 9 hours, preferably for the period of 7 hours. The water content of isopropanol used in the reaction must below 0.05%.

4 EP 2 170 078 B1

[0021] The Malathion prepared by the process of this invention is storage stable. Specially, after storage at 8 - 15 °C for the period of 6 months, the Malathion has following purity/impurity profile

i. greater than about 99.5% (w/w) Malathion. 5 ii. less than 0.09% of Isomalathion iii. less than 0.03 of O,O,S-trimethyl phosphorodithioate iv. less than 0.002% of diethyl fumarate v. less than 0.1% of unknown impurities vi. less than 0.21 of total impurties and 10 vii. water content is less than 0.02%.

[0022] The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention

15 Example 1: Preparation of crude O,O-dimethyl dithio phosphoric acid

Step (i): Preparation of crude O, O-dimethyl dithio phosphoric acid

[0023] To 4-necked flask (1 L) equipped with mechanical stirrer, thermometer pocket, pressure equalizing funnel and 20 nitrogen atmosphere, was charged toluene (150 mL, Kf < 0.1%) and phosphoruspentasulfide (222 grams) at room temperature. An alkali scrubber was used to trap hydrogen sulfide gas released during the reaction. Methanol (150 grams, Kf <0.1%) was added to the above reaction mass at 25 - 35 °C for the period of 1.5 - 2 hours. After the addition of methanol, temperature of the above reaction mass was raised to 50 °C and maintained the temperature at 50 - 55 °C for a period of 5 hours. The evolution of hydrogen sulfide gas was confirmed by checking with lead acetate paper 25 and the reaction mass was cooled to 25 - 28 °C and nitrogen gas was purged for 20 - 30 minutes to expel traces of hydrogen sulfide gas presented. The reaction mass was then filtered through hy-flow bed to remove any unreacted phosphorus pentasulfide and washed with toluene (150 mL). Layer separation was done to remove a small amount of lower layer, and upper toluene layer was taken for concentration under vacuum at 45 - 50 °C and concentrated till toluene content was found to be below 5%, which is monitored by HPLC. 30 Yield: 260 - 270 grams. HPLC purity: 87.21%.

Step (ii): Preparation of 1st ammonium salt of O,O-DMDTPA

35 [0024] To 4-necked flask (5 L) equipped with mechanical stirrer, thermometer pocket and gas sparger, was charged ethyl acetate (2.7 L) and crude O,O-DMDTPA (270 grams) (obtained from Step (i)). Cooled the above reaction mass to -5 °C and purged the ammonia gas in the reaction vessel at a temperature of -5 - 0 °C till pH was reached to 9.5 - 9.8. After the desired pH was achieved, reaction mass was maintained at -5 to 0°C for a period of 2 hours. The reaction mass was then filtered and washed with ethyl acetate (270 mL). Suck dried and unloaded. The wet weight of obtained 40 ammonium salt was 240 - 255 grams. Dried at 25 - 28 °C under vacuum for the period of 5 hours or till constant weight was achieved. The dry weight of ammonium salt was 233 - 240 grams. HPLC purity: 99.33 %.

45 Step (iii): Regeneration of ammonium salt of O,O-DMDTPA

[0025] To 4-necked flask (3 L) equipped with mechanical stirrer, thermometer pocket and pressure-equalizing funnel, was charged dichloromethane (1.68 L). Cooled the above reaction mass to -25 to -20 °C and concentrated sulphuric acid (65 grams) was charged in the pressure equalizing funnel and added to the above reaction mass drop wise at 50 temperature of -25 to -20°C. Maintained the above reaction mass at - 20 °C for 20 minutes and pH of dichloromethane layer was checked as per above pH checking process to obtain pH below 2.0. The temperature of the reaction mass was raised to 25 °C in 30 - 35 minutes and stirred for the period of 2 hours. The above reaction mass was filtered and washed with dichloromethane (233 mL). The filtered ammonium sulphate containing compound was once again stirred with dichloromethane (1.165 L) for a period of 2 hours and the ammonium sulphate was filtered and washed with 55 dichloromethane (233 mL). The dichloromethane layers were combined and concentrated at 30 - 35 °C under vacuum till constant weight was achieved. The weight of regenerated O,O-DMDTPA was 184 - 188 grams and ammonium sulphate was 105 - 112 grams. If weight of ammonium sulphate is more than theoretical weight, stirred once with dichloromethane.

5 EP 2 170 078 B1

HPLC purity: 98.09 %.

Step (iv): Preparation of 2nd ammonium salt of O,O-DMDTPA

5 [0026] To 4-necked flask (3 L) equipped with mechanical stirrer, thermometer pocket and gas sparge, was charged ethyl acetate (1.84 L) and regenerated O, O-DMDTPA (184 grams) (obtained from step (iii)). Cooled the above reaction mass to -5 °C and purged the ammonia gas in the reaction vessel at a temperature of -5 to 0 °C till pH of 9.5 - 9.8 was reached. After the desired pH was achieved, reaction mass was maintained at -5 to 0 °C for the period of 2 hours. The above reaction mass was then filtered and washed with ethyl acetate (184 mL). Suck dried and unloaded. The wet 10 weight of obtained ammonium salt was 172 - 175 grams. Dried at 25 - 28 °C under vacuum for the period of 5 hours or till constant weight was achieved. The dry weight of ammonium salt was 162 - 166 grams. HPLC purity: 99.68%

Step (v): Regeneration of 2nd ammonium salt of O,O-DMDTPA 15 [0027] To 4-necked flask (3 L) equipped with mechanical stirrer, thermometer pocket and pressure-equalizing funnel, was charged dichloromethane (1.204 L). Cooled the above reaction mass to -25 to -20 °C. Concentrated sulphuric acid (46 grams) was charged in the pressure equalizing funnel and added to the above reaction mass drop wise at -25 to -20 °C and maintain the above reaction mass at -20 °C for a period of 20 minutes.H p of dichloromethane layer was 20 checked as per above pH checking process to obtain the pH below 2.0. The temperature of the reaction mass was raised to 25 °C in 30 - 35 minutes and stirred for a period of 2 hours. The above reaction mass was filtered and washed with dichloromethane (163 mL). The filtered ammonium sulphate containing compound was once again stirred with dichloromethane (860 mL) for a period of 2 hours and ammonium sulphate was filtered and washed with dichloromethane (163 mL). The dichloromethane layers were combined and concentrated at 30 - 35 °C under vacuum till constant weight 25 was achieved. The weight of regenerated O,O-DMDTPA was 123 - 126 grams and ammonium sulphate was 74 - 80 grams. If weight of ammonium sulphate is more than theoretical weight, stirred once with dichloromethane. HPCL purity: 97.84 %. IR spectra (cm-1): 1016.23; 1 H NMR (400 MHz, CD3OD): δ 3.0343 (singlet, 1H), 3.83 - 3.87(2 singlets, 6H). 30 Example 2: Preparation of Malathion

Step (i): Preparation of crude Malathion

35 [0028] To 4-necked flask (0.5 L) equipped with mechanical stirrer, thermometer pocket and nitrogen atmosphere, was charged O,O-DMDTPA (126 grams, 0.797 M) (obtained from Example 1). Cooled the above reaction mass to -30 to -25 °C and add diethyl maleate (55 grams, 0.319 M, GC purity: 97 %) in 4 lots (each 13.8 grams) at regular interval of 20 minutes at -30 to -25°C, and maintained the above reaction mass temperature at -30 to -25 °C for the period of 4 hours. The sample was analyzed after 4 hours to check the diethyl maleate content below 1% by HPLC before proceeding for 40 workup. If the diethyl maleate was found to be more than 1% the above reaction mass was maintained for another one hour at the same temperature and again analyzed by HPLC. After the diethyl maleate content was found to be less than 1% by HPLC, the above reaction mass temperature was raised to 5 - 10 °C and washed with demineralized water (181 mL) for 6 times. pH of last water wash was checked and found to be 6.5 - 7.5. In case the pH is not in range, one more water wash needs to be done. The sample was analyzed to check the O,O-DMDTPA content below 0.05 % by HPLC. 45 Yield: 110 - 112 grams.

Step (ii): Removal of diethyl fumarate from crude Malathion

[0029] Crude Malathion (111 grams) (obtained from step (i)) was stirred with 3% sodium sulphide solution (111 mL) 50 at 10 - 15 °C for the period of 13 hours. HPLC analysis of the sample after 13 hours showed diethyl fumarate not more than 0.1%. Both layers were separated and organic layer was washed with demineralised water (111 mL) for 6 times by maintaining temperature at 10 - 15 °C till pH of 6.5 - 7.5. was achieved. Yield: 80 grams.

55 Step (iii): Purification of Malathion

[0030] To a 4-necked flask (0.5 L) equipped with mechanical stirrer, thermometer pocket and calcium chloride guard tube, was charged methanol (160 mL) and Malathion (80 grams). The reaction mass was cooled to -40 to -35 °C slowly

6 EP 2 170 078 B1

when formation of white solid was observed. Methanol (160 mL) was once again added and reaction mass temperature is raised to -10 °C. The above reaction mass was cooled once again to -30 to -25 °C and maintained for period of 30 minutes. Methanol (240 mL) was siphoned out from the above reaction mass and temperature thereafter raised from 8 to 10 °C. To the above reaction, add dichloromethane (160 mL) and dimineralized water and stirred at 10 °C for the 5 period of 10 minutes. The layers were separated, aqueous layer volume was measured and found to be 240 mL. To the dichloromethane layer, add dimineralized water (160 mL) and stirred at temperature of 5 - 10 °C for the period of 10 minutes. The layers were separated, aqueous layer volume was measured and found to be 160 mL. The dichloromethane layer was dried over anhydrous dried sodium sulphate (8.0 gram), filtered washed with dichloromethane (40 mL). This dichloromethane layer was filtered through 0.5 m filter paper, concentrated at 25 - 30 °C under vacuum to obtain pure 10 Malathion. Yield: 57 grams.

Step (iv): Drying of Malathion

15 [0031] The pure Malathion (57 grams) (obtained from step (iii)) was filtered through 0.5 m filter paper under nitrogen atmosphere and charged to a 4-necked flask (0.5 L) equipped with mechanical stirrer, thermometer pocket and nitrogen atmosphere. Add isopropanol (275 mL, Kf <0.05%) and anhydrous dried sodium sulphate (27 grams) at 25 - 27 °C and stirred for the period of 7 hours at 25 - 27 °C. The water content after 7 hours of stirring was checked and found to be 0.16 %. The mass was filtered through filter paper no.1 under nitrogen atmosphere and washed with isopropanol (30 20 mL). This mass was again filtered through 0.5h filter paper under nitrogen and washed with isopropanol (25 mL). The filtrate was concentrated under 5 - 10 mm Hg vacuum and maintain temperature at 25 - 27 °C for a period of 9 hours. The dried Malathion was carefully unloaded under nitrogen atmosphere and water content was checked and found to be less than 0.1%. IR spectra (cm-1): 1737.28, 1016.23; 25 1 H NMR (400 MHz, CD 3OD): δ 1.22 - 1.32 (2 triplets, 6H), 2.90 - 3.76 (2 quartets, 4H), 3.80 - 3.81 (2 doublets, 6H), 4.11 - 4.21 (multiplet, 3H).

Example 3: Analysis of sample batches of Malathion prepared by this process

30 [0032] In Table II set forth below, three different batches of Malathion are prepared by the process of present invention (noted as A, B, C) were analyzed by HPLC for the identification of purity and impurities. After storage at 8 - 15 °C for the period of 6 months:

Table II 35 Batch No. → ABC Analysis ↓ HPLC assay 99.8% 99.8% 99.5% Iso S-[1,2-(dicarbethoxy)-ethyl]O,O-dimethyl phosphorodithioate 0.06% 0.07% 0.09% 40 Malaoxon Nil Nil Nil S-imp O,O,S-trimethyl phosphorodithioate 0.03% 0.03% 0.01% Diethyl maleate Nil Nil Nil 45 Diethyl fumarate 0.002% 0.001 % 0.002% O,O-DMDTPA Nil Nil Nil Unknown impurities 0.12% 0.20% 0.11% Total impurities 0.21% 0.3% 0.21% 50 Water content 0.04% 0.02% 0.04%

Claims 55 1. A process for the preparation of Malathion of formula ( I),

7 EP 2 170 078 B1

5

10 which comprises the steps of :

i) adding methanol to phosphorous sulfide in organic solvent at 25 - 50 °C for the period of 1.5 - 2 hours; ii) stirring the above suspension for the period of 5 - 6 hours at 50 - 55 °C; iii) expelling the H2S gas with nitrogen, after cooling the above suspension to 25 - 28 °C; 15 iv) filtering the above suspension to remove insoluble impurities to obtain crude O,O-DMDTPA; v) thecrude O,O-DMDTPA is subjected todissolution insuitable solvent and ammonia gas ispurged to precipitate

the pure O,O-DMDTPA.NH3 salt; vi) the above obtain O,O-DMDTPA.NH3 salt is subjected to neutralization with concentrated sulpheric acid to get O,O-DMDTPA; 20 vii) the O,O-DMDTPA obtained in the above step is once again purified through ammonia salt formation and neutralization method as mentioned in above steps v) and vi) to get chromatographically pure O,O-DMDTPA of the formula (II);

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30 viii) adding the above obtain pure O,O-DMDTPA to diethyl maleate at low temperature of -30 to -25 °C in four lots, each at regular interval of 20 minutes; ix) maintaining the above reaction mass at temperature of -30 to -25 °C for the period of 4 hours; x) water washing the above mass to remove O,O-DMDTPA; xi) treating the above obtain crude Malathion with a sulfer reagent at 5 to 10 °C for the period of 13 hours; 35 xii) crystallizing the above obtained Malathion from methanol at low temperature and xiii) drying the above obtain mass with anhydrous sodium sulphate in isopropanol to obtain Malathion of formula (I).

2. A process for the preparation of intermediate O,O-dimethyldithiophosphoric acid of formula ( II) 40

45

for use in the preparation of Malathion, which comprises the steps of:

i) adding methanol to phosphorous sulfide in organic solvent at 25 - 50 °C for the period of 1.5 - 2 hours; 50 ii) stirring the above suspension for the period of 5 - 6 hours at 50 - 55 °C; iii) expelling the H2S gas with nitrogen, after cooling the above suspension to 25 - 28 °C; iv) filtering the above suspension to remove insoluble impurities to obtain crude O,O-DMDTPA; v) the crude O,O-DMDTPA is subjected to dissolution in ethyl acetate and ammonia gas is purged to precipitate

the pure O,O-DMDTPA. NH3 salt; 55 vi) the above obtain O,O-DMDTPA.NH3 salt is subjected to neutralization with concentrated sulpheric acid to get O,O-DMDTPA and vii) the O,O-DMDTPA obtained in the above step is once again purified through ammonia salt formation and neutralization method as mentioned in above steps v) and vi) to get chromatographically pure product.

8 EP 2 170 078 B1

3. The process as claimed in claim 1, wherein said phosphorous sulfide is selected from phosphorus pentasulfide, tetraphosphorus heptasulfide and tetraphosphorus decasulfide.

4. The process as claimed in claim 1, wherein said organic solvent is selected from hexane, benzene, toluene, diethyl 5 ether, chloroform, ethyl acetate and dichloromethane.

5. The process as claimed in claim 1, wherein the step v) the duration of the reaction may range from 1 to 4 hours.

6. The process as claimed in claim 1, wherein step (viii), molar ratio of diethyl maleate to O,O-DMDTPA is 1:2.5. 10 7. The process as claimed in claims 1, wherein said sulfur reagent used in step xi) is selected from sodium sulfide, potassium sulfide, calcium sulfide, ammonium sulfide and ammonium bisulfide.

8. The process as claimed in claim 1, wherein the step xii) malathion is crystallized from methanol at temperature in 15 the range of - 45 to -25 °C.

9. The process as claimed in claim 1, wherein the step xiii) the drying temperature ranges from 15 to 40 °C.

10. The process as claimed in claim 1, wherein the step xiii) the duration of the drying ranges from 5 to 9 hours. 20 11. The process as claimed in claim 1, wherein the step xiii) the water content of isopropanol used is below 0.05%.

12. The process as claimed in claim 1, wherein said Malathion prepared by the process of claim 1, after storage at 8 - 15 °C for the period of 6 months, having the following purity/impurity profile: 25 i) greater than about 99.5 % (w/w) Malathion ii) less than 0.09 % of Isomalathion iii) less than 0.03 % of O,O,S-trimethyl phosphorodithioate iv) less than 0.002 % of diethyl furmarate 30 v) less than 0.1 % of unknown impurities vi) less than 0.21 % of total impurities and vii) water content is less than 0.02 %.

13. The process as claimed in claim 2, wherein said phosphorous sulfide is selected from phosphorus pentasulfide, 35 tetraphosphorus heptasulfide and tetraphosphorus decasulfide.

14. The process as claimed in claim 2, wherein said organic solvent is selected from hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate and dichloromethane.

40 15. The process as claimed in claim 2, wherein in step v) the duration of the reaction ranges from 1 to 4 hours.

Patentansprüche

45 1. Verfahren zur Herstellung von Malathion der Formel (I)

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55

wobei dieses die folgenden Schritte umfasst:

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i) das Hinzufügen von Methanol zu Phosphorsulfid in organischem Lösemittel bei einer Temperatur von 25 - 50 °C über einen Zeitraum von 1,5 - 2 Stunden; ii) das Rühren der obigen Suspension bei 50 - 55 °C über einen Zeitraum von 5 - 6 Stunden; iii) das Ausstoßen des H2S-Gases mit Stickstoff nach Abkühlung der obigen Suspension auf 25 - 28 °C; 5 iv) das Filtern der obigen Suspension, um Unreinheiten zu entfernen und rohes 0,0-DMDTPA zu erhalten; v) das Auflösen des rohen 0,0-DMDTPA in einem geeigneten Lösemittel und das Spülen von Ammoniakgas,

um das reine O,O-DMDTPA.NH3-Salz auszufällen; vi) das Neutralisieren des vorstehend erhaltenen O,O-DMDTPA.NH 3-Salzes mit konzentrierter Schwefelsäure, um 0,0-DMDTPA zu erhalten; 10 vii) das erneute Reinigen des in dem vorstehenden Schritt erhaltenen 0,0-DMDTPA durch eine Ammoniaksalz- zusammensetzung und die in den vorstehenden Schritten v) und vi) ausgeführte Neutralisierungsmethode, um chromatographisch reines 0,0-DMDTPA der Folgen (II) zu erhalten;

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viii) das Hinzufügen des vorstehend erhaltenen reinen 0,0-DMDTPA zu Diethylmaleat bei of -30 bis -25 °C in vier Chargen in regelmäßigen Intervallen von jeweils 20 Minuten; ix) das Halten der vorstehenden Reaktionsmasse auf einer Temperatur von -30 bis -25 °C über einen Zeitraum 25 von vier Stunden; x) das Spülen der vorstehenden Masse mit Wasser, um 0,0-DMDTPA zu entziehen; xi) das Behandeln des vorstehend erhaltenen Malathion mit einer Schwefelreagens bei 5 bis 10 °C über einen Zeitraum von 13 Stunden; xii) das Kristallisieren des vorstehend erhaltenen Malathion aus Methanol auf niedriger Temperatur; und 30 xiii) das Trocknen der vorstehend erhaltenen Masse mit wasserfreiem Natriumsulfat in Isopropanol, um Mala- thion der Formel zu erhalten (I).

2. Verfahren zur Herstellung von intermediärer O,O-Dimethyldithiophosphorsäure der Formel (II)

35

40

zum Einsatz bei der Herstellung von Malathion, die folgenden Schritte umfassend:

45 i) das Hinzufügen von Methanol zu Phosphorsulfid in organischem Lösemittel bei einer Temperatur von 25 - 50 °C über einen Zeitraum von 1,5 - 2 Stunden; ii) das Rühren der obigen Suspension bei 50 - 55 °C über einen Zeitraum von 5 - 6 Stunden;

iii) das Ausstoßen des H2S-Gases mit Stickstoff nach Abkühlung der obigen Suspension auf 25 - 28 °C; iv) das Filtern der obigen Suspension, um Unreinheiten zu entfernen und rohes 0,0-DMDTPA zu erhalten; 50 v) das Auflösen des rohen 0,0-DMDTPA in einem geeigneten Lösemittel und das Spülen von Ammoniakgas, um das reine O,O-DMDTPA.NH3-Salz auszufällen; vi) das Neutralisieren des vorstehend erhaltenen O,O-DMDTPA.NH 3-Salzes mit konzentrierter Schwefelsäure, um 0,0-DMDTPA zu erhalten; und vii) das erneute Reinigen des in dem vorstehenden Schritt erhaltenen 0,0-DMDTPA durch eine Ammoniaksalz- 55 zusammensetzung und die in den vorstehenden Schritten v) und vi) ausgeführte Neutralisierungsmethode, um ein chromatographisch reines Produkt zu erhalten.

3. Verfahren nach Anspruch 1, wobei das Phosphorsulfid aus Phosphorpentasulfid, Tetraphosphorheptasulfid und

10 EP 2 170 078 B1

Tetraphosphordecasulfid ausgewählt wird.

4. Verfahren nach Anspruch 1, wobei das organische Lösemittel aus Hexan, Benzol, Toluol, Diethylether, Chloroform, Ethylacetat und Dichlormethan ausgewählt wird. 5 5. Verfahren nach Anspruch 1, wobei in Schritt v) die Reaktionsdauer zwischen 1 und 4 Stunden liegen kann.

6. Verfahren nach Anspruch 1, wobei in Schritt viii) das Molverhältnis von Diethylmaleat zu 0,0-DMDTPA 1:2,5 beträgt.

10 7. Verfahren nach Anspruch 1, wobei die in dem Schritt xi) eingesetzte Schwefelreagens aus Natriumsulfid, Kalium- sulfid, Calciumsulfid, Ammoniaksulfid und Ammoniakbisulfid ausgewählt wird.

8. Verfahren nach Anspruch 1, wobei in Schritt xii) das Malathion aus Methanol auf einer Temperatur - 45 bis -25 °C kristallisiert wird. 15 9. Verfahren nach Anspruch 1, wobei in Schritt xiii) die Trocknungstemperatur zwischen 15 und 40 °C liegt.

10. Verfahren nach Anspruch 1, wobei in Schritt xiii) die Trocknungsdauer zwischen 5 und 9 Stunden liegt.

20 11. Verfahren nach Anspruch 1, wobei in Schritt xiii) der Wasseranteil des verwendeten Isopropanol unter 0,05% liegt.

12. Verfahren nach Anspruch 1, wobei das durch das Verfahren aus Anspruch 1 hergestellte Malathion nach Lagerung über einen Zeitraum von 6 Monaten bei 8 - 15 °C das folgende Reinheits-/Unreinheitsprofil aufweist:

25 i) mehr als etwa 99,5 Gewichtsprozent Malathion; ii) weniger als 0,09% Isomalathion; iii) weniger als 0,03% O,O,S-Trimethylphosphorodithioat; iv) weniger als 0,002% Diethylfurmarat; v) weniger als 0,1% unbekannte Unreinheiten; 30 vi) weniger als 0,21% Unreinheiten insgesamt; und vii) ein Wasseranteil von unter 0,02%.

13. Verfahren nach Anspruch 2, wobei Phosphorsulfid aus Phosphorpentasulfid, Tetraphosphorheptasulfid und Tetra- phosphordecasulfid ausgewählt wird. 35 14. Verfahren nach Anspruch 2, wobei das organische Lösemittel aus Hexan, Benzol, Toluol, Diethylether, Chloroform, Ethylacetat und Dichlormethan ausgewählt wird.

15. Verfahren nach Anspruch 2, wobei in Schritt v) die Reaktionsdauer zwischen 1 und 4 Stunden liegen kann. 40

Revendications

1. Procédé destiné à la préparation de malathion de formule (I), 45

50

55 qui comprend les étapes consistant à :

i) ajouter du méthanol à du sulfure de phosphore dans un solvant organique à une température de 25 à 50 °C pendant une période de 1,5 à 2 heures ;

11 EP 2 170 078 B1

ii) agiter la suspension précitée pendant une période de 5 à 6 heures à une température de 50 à 55 °C ; iii) expulser le gaz H2S avec de l’azote, après refroidissement de la suspension précitée à une température de 25 à 28 °C ; iv) filtrer la suspension précitée pour éliminer les impuretés insolubles pour obtenir du O,O-DMDTPA brut ; 5 v) le O,O-DMDTPA brut est soumis à dissolution dans un solvant approprié et le gaz ammoniac est purgé pour

précipiter le sel O,O-DMDTPA.NH3 pur ; vi) le sel O,O-DMDTPA.NH 3 obtenu ci-avant est soumis à une neutralisation avec de l’acide sulfurique concentré pour obtenir du O,O-DMDTPA ; vii) le O,O-DMDTPA obtenu à l’étape ci-avant est à nouveau purifié par le procédé de formation et de neutra- 10 lisation de sel d’ammoniac, comme mentionné aux étapes v) et vi) précitées pour obtenir du O,O-DMDTPA chromatographiquement pur de formule (II) ;

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viii) ajouter le O,O-DMDTPA pur obtenu ci-avant à du maléate de diéthyle à une basse température de -30 à 20 -25 °C en quatre lots, chacun à des intervalles réguliers de 20 minutes ; ix) maintenir la masse réactionnelle précitée à la température de -30 à -25 °C pendant une période de 4 heures ; x) laver à l’eau la masse précitée pour retirer le O,O-DMDTPA ; xi) traiter le malathion brut obtenu ci-avant avec un réactif de soufre à une température de 5 à 10 °C pendant une période de 13 heures ; 25 xii) cristalliser le malathion obtenu ci-avant à partir de méthanol à basse température et xiii) sécher la masse obtenue ci-avant avec du sulfate de sodium anhydre dans de l’isopropanol pour obtenir le malathion de formule (I).

2. Procédé destiné à la préparation d’acide O,O-diméthyldithiophosphorique intermédiaire de formule (II) 30

35

à utiliser dans la préparation de malathion, qui comprend les étapes consistant à :

i) ajouter du méthanol à du sulfure de phosphore dans un solvant organique à une température de 25 à 50 °C 40 pendant une période de 1,5 à 2 heures ; ii) agiter la suspension précitée pendant une période de 5 à 6 heures à une température de 50 à 55 °C ;

iii) expulser le gaz H2S avec de l’azote, après refroidissement de la suspension précitée à une température de 25 à 28 °C ; iv) filtrer la suspension précitée pour éliminer les impuretés insolubles pour obtenir du O,O-DMDTPA brut ; 45 v) le O,O-DMDTPA brut est soumis à dissolution dans de l’acétate d’éthyle et le gaz ammoniac est purgé pour précipiter le sel O,O-DMDTPA.NH3 pur ; vi) le sel O,O-DMDTPA.NH 3 obtenu ci-avant est soumis à une neutralisation avec de l’acide sulfurique concentré pour obtenir du O,O-DMDTPA ; et vii) le O,O-DMDTPA obtenu à l’étape précitée est à nouveau purifié par le procédé de formation et de neutra- 50 lisation de sel d’ammoniac, comme mentionné aux étapes v) et vi) précitées pour obtenir un produit chromatographiquement pur.

3. Procédé selon la revendication 1, dans lequel ledit sulfure de phosphore est choisi parmi le pentasulfure de phosphore, l’heptasulfure de tétraphosphore et le décasulfure de tétraphosphore. 55 4. Procédé selon la revendication 1, dans lequel ledit solvant organique est choisi parmi l’hexane, le benzène, le toluène, l’éther diéthylique, le chloroforme, l’acétate d’éthyle et le dichlorométhane.

12 EP 2 170 078 B1

5. Procédé selon la revendication 1, dans lequel à l’étape v), la durée de la réaction peut aller de 1 à 4 heures.

6. Procédé selon la revendication 1, dans lequel à l’étape viii), le rapport molaire du maléate de diéthyle au O,O- DMDTPA est de 1:2,5. 5 7. Procédé selon la revendication 1, dans lequel ledit réactif de soufre utilisé à l’étape xi) est choisi parmi le sulfure de sodium, le sulfure de potassium, le sulfure de calcium, le sulfure d’ammonium et le bisulfure d’ammonium.

8. Procédé selon la revendication 1, dans lequel à l’étape xii), le malathion est cristallisé à partir de méthanol à une 10 température comprise entre -45 et -25 °C.

9. Procédé selon la revendication 1, dans lequel à l’étape xiii), la température de séchage est comprise entre 15 et 40 °C.

10. Procédé selon la revendication 1, dans lequel à l’étape xiii), la durée du séchage est comprise entre 5 et 9 heures. 15 11. Procédé selon la revendication 1, dans lequel à l’étape xiii), la teneur en eau de l’isopropanol utilisé est inférieure à 0,05 %.

12. Procédé selon la revendication 1, dans lequel ledit malathion préparé par le procédé de la revendication 1, après 20 stockage à une température de 8 à 15 °C pendant une période de 6 mois, a le profil de pureté/impureté suivant :

i) plus d’environ 99,5 % (p/p) de malathion ii) moins de 0,09 % d’isomalathion iii) moins de 0,03 % de O,O,S-triméthyl phosphorodithioate 25 iv) moins de 0,002 % de fumarate de diéthyle v) moins de 0,1 % d’impuretés inconnues vi) moins de 0,21 % d’impuretés totales et vii) teneur en eau inférieure à 0,02 %.

30 13. Procédé selon la revendication 2, dans lequel ledit sulfure de phosphore est choisi parmi le pentasulfure de phosphore, l’heptasulfure de tétraphosphore et le décasulfure de tétraphosphore.

14. Procédé selon la revendication 2, dans lequel ledit solvant organique est choisi parmi l’hexane, le benzène, le toluène, l’éther diéthylique, le chloroforme, l’acétate d’éthyle et le dichlorométhane. 35 15. Procédé selon la revendication 2, dans lequel à l’étape v), la durée de la réaction est comprise entre 1 et 4 heures.

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45

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 2578652 A [0004] • US 4367180 A [0004] • US 2879284 A [0004] • US 20070010496 A [0004] • US 3403201 A [0004] • US 4681964 A [0004] • US 3463841 A [0004] • US 7560445 B [0006] • US 3470272 A [0004]

Non-patent literature cited in the description

• KEADTISUKE et al. Toxicology letters, 1990, vol. 52, • Tetrahedron letters, 1992, vol. 33 (11), 1415-18 35-46 [0005] [0005] • RODGERS et al. immunopharmacology, 1989, vol. 17, 131-140 [0005]

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