A process for the preparation of ethion

Abstract

The present invention relates to the process for the preparation of Ethion of formula (I) containing impurity of formula (IV) and / or impurity of formula (V). The present invention further relates to the process for the preparation of at least 98% pure Ethion of formula (I) having less than 0.1% compound of formula (IV) or compound of formula (V) as determined by HPLC.

Description

[0001] “A PROCESS FOR THE PREPARATION OF ETHION”

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the process for the preparation of Ethion of formula (I) containing impurity of formula (IV) and / or impurity of formula (V). The present invention further relates to the process for the preparation of at least 98% pure Ethion of formula (I) having less than 0.1% impurity of formula (IV) or impurity of formula (V) as determined by HPLC.

[0004] BACKGROUND OF THE INVENTION

[0005] Ethion is an organophosphate insecticide with inhibitory activity towards the enzyme acetylcholinesterase that is chemically known as O,O,O',O'-Tetraethyl-S,S'-methylenebis

[0006] (phosphorodithioate) and represented by the following structure:

[0007] Several methods for the preparation of Ethion have been described in the prior art and a few of them are described below.

[0008] The U.S. Patent 2,873,228 discloses Ethion along with the process for the preparation of Ethion and its intermediates. The U.S. patent No 3,014,058 discloses a process for preparing Ethion by reacting 0,0-diethyl phosphorodithioate and dibro mo methane or bromochloromethane with potassium hydroxide in ethanol.

[0009] JP patent No 3,225,188 discloses a process for preparing Ethion by reacting a metal salt of 0,0 diethyl phosphorodithioate, dibromomethane, phosphorus pentasulfide, and ammonia bromochloromethane in a solvent mixture of acetone and ethanol.

[0010] The FR patent No 1,231,107 discloses the preparation of Ethion by reacting diethyl dithiophosphate ammonia with methylene bromide in water.

[0011] GB patent No 845,647 discloses the preparation of Ethion by reacting potassium O, O-diethyl phosphorodithioate and dibromomethane with acetone as a solvent.

[0012] Although several processes have been reported for the preparation of Ethion, they suffer from one or more drawbacks such as: i) involving a tedious purification process; ii) use of multiple and high volumes of solvents; iii) low purity; iv) low yield; and v) requiring multiple unit operations and long cycle time; thus, the process does not render economical.

[0013] The O, O-diethyl phosphorodithioate is one of the key starting materials used in the preparation of Ethion. The processes disclosed in the prior art for the preparation of Ethion involve the use of neat reaction or inert atmospheric conditions, while these neat reactions or high-pressure conditions lead to the formation of impurities and lower Ethion purity (<97%) and fails to disclose or identify the process impurities. The present invention for the preparation of Ethion is efficient, environment friendly, and industrially viable as it does not involve any additional reagents or critical reaction conditions.

[0014] SUMMARY OF THE INVENTION

[0015] In one aspect, the present invention provides a process for the preparation of Ethion of formula (I) which comprises reacting O,O'-Diethyl dithiophosphate of formula (II) s ii

[0016] ' O „P Ix. SH _ ,0

[0017] (II) with dibro mo methane of formula (III) in presence of base and a mixture of hydrocarbon and ethanol;

[0018] Br^Br

[0019] (III) to obtain the Ethion of formula (I) comprising one or more impurities of formula (IV) and / or formula (V).

[0020] In another aspect, the present invention provides a process for the preparation of Ethion of formula (I) which comprises steps of: a) adding O,O'-Diethyl dithiophosphate of formula (II) in a mixture of hydrocarbon solvent and ethanol, b) adding a base in step (a) till pH 7-9, c) filtering the reaction mixture of step (b), d) separating aqueous layer of step (c), e) adding a solution of dibromomethane of formula (III) and ethanol to an aqueous layer of step (d),

[0021] Br^Br

[0022] (III) f) heating reaction mixture of step (e) at 50°C to 90°C, g) cooling reaction mixture of step (f) to 20°C to 40°C, and h) separating organic layer to obtain the Ethion of formula (I) comprising one or more impurities of formula (IV) and formula (V).

[0023] In another aspect, the present invention relates to Ethion containing impurity S- (((ethoxy(methoxy)phosphorothioyl)thio)methyl) 0,0-diethyl phosphorodithioate of formula (IV) and impurity S-((((((diethoxyphosphorothioyl)thio)methyl)thio)(ethoxy)phosphoryl)thio)methyl)O,O- diethyl phosphorodithioate of formula (V).

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements.

[0026] As used in the specification, the singular forms “a,” “an”, “the”, include plural referents unless the context clearly indicates otherwise. The term solvent used herein refers to the single solvent or mixture of solvents.

[0027] The present invention relates to a “process for preparation of Ethion” wherein resulting Ethion comprises impurities namely:

[0028] S-(((ethoxy(methoxy)phosphorothioyl)thio)methyl) 0,0-diethyl phosphorodithioate of formula (IV) or

[0029] S-(((((((diethoxyphosphorothioyl)thio)methyl)thio)(ethoxy)phosphoryl)thio)methyl)O,O-diethyl phosphorodithioate of formula (V).

[0030] The ‘impurity of formula (IV)’is characterized byJH NMR: (CDCL3 400 MHz): 5 (ppm): 4.29-4.16 (m, 8H), 3.828-3.79 (d, 3H), 1.40-1.37 (t, 9H); LCMS: 371 [M+H]; FT-IR Stretching frequency: 2982.08, 2901.76, 2945.89, 1002.72, 953.02, 1242.01 and HPLC purity 97.98%.

[0031] The ‘impurity of formula (V)’is characterized by ' H NMR: (CDCL3 400 MHz): 5 (ppm): 4.38-4.10 (m, 14H), 1.33-1.29 (m, 15H); LCMS: 555 [M+H]; FT-IR Stretching frequency: 2982.32, 2936.30, 2902.56, 1002.57, 948.60, 1242.01 and HPLC purity 97.81%.

[0032] In accordance with the objectives, the present invention provides a process for the preparation of Ethion of formula (I).

[0033] The inventors of the present invention developed a process that does not require separate and / or multiple purification steps for isolation of pure Ethion and removal of subsequent impurities formed.

[0034] The present invention is further elaborated with the ease of following embodiment. One embodiment of the present invention is to provide pure Ethion of formula (I) having purity at least 98% by HPLC.

[0035] In another embodiment of the present invention is to provide Ethion of formula (I) having impurity of formula (IV) less than 0.5%; preferably less than 0.1%.

[0036] In another embodiment the present invention provides Ethion of formula (I) having impurity of formula (V) less than 0.5%; preferably less than 0.1%.

[0037] In another embodiment, the present invention provides a process for preparation of Ethion, wherein formation of impurity of formula (IV) and impurity of formula (V) were controlled by adding ethanol during salt formation and during Ethion formation.

[0038] The inventor of the present invention developed a process which requires the addition of ethanol in a catalytic amount ranging from 0.1 to 0.5 volume.

[0039] The inventor of present invention develops a process for preparation of Ethion by sequential addition of ethanol such as:

[0040] Step 1) addition of ethanol in combination with hydrocarbon solvent to prepare of salt form of compound O, O'-Diethyl dithiophosphate (DETA) to avoids the formation of DETA impurity by avoiding oxidative desulfurization of DETA intermediate;

[0041] Step 2) addition of ethanol with dibro mo methane in preparation of Ethion formation avoids the formation of impurity of formula (V).

[0042] The “DETA impurity” is defined as O-Ethyl dihydrogen phosphorodithioate:

[0043] DETA impurity The “DETA intermediate” is defined as O-Ethyl dihydrogen phosphoro trithio ate:

[0044] DETA intermediate

[0045] The Scheme 1 illustrate the process which avoid the formation of DETA impurity and impurity of formula (V).

[0046] Scheme 1 :

[0047] In another embodiment of the present invention, the preparation of Ethion formula (I) is obtained by reacting the salt of compound O,O'-Diethyl dithio phosphate of formula (II) and dibro mo methane of formula (III).

[0048] In another embodiment of the present invention, wherein 0,0 '-Diethyl dithiophosphate is converted into its salt form in the presence of base, hydrocarbon solvent, and ethanol. This solution is treated with a solution containing dibromomethane in ethanol at temperatures 50°C to 90°C to obtain Ethion of formula (I).

[0049] In another embodiment of the present invention, the cooling temperature ranges from 20°C to 40°C.

[0050] In another embodiment of the present invention, the mixture of hydrocarbon solvent and ethanol ranges from 1:0.1 to 1:0.5. The term “base” used herein, refers to the solution of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, and / or potassium carbonate.

[0051] In another embodiment of the present invention, wherein hydrocarbon solvent is selected from alicyclic hydrocarbon solvents such as cyclohexane, methylcyclohexane and the like; and aromatic hydrocarbon solvents such as benzene, toluene, xylene, mesitylene, ethylbenzene, tertbutylbenzene, trifluoromethyl benzene, nitrobenzene, chlorobenzene, chlorotoluene, bromobenzene and the like; preferably aromatic hydrocarbon solvents such as a toluene.

[0052] In another embodiment of the present invention, the base is a 40% to 48% caustic lye solution.

[0053] The process of the present invention is illustrated in the following general synthetic scheme 2:

[0054] Scheme 2 :

[0055] The Ethion resulting from the process as defined above has a purity greater than 98% and less than 0.1% impurity of formula (IV) or impurity of formula (V) as determined by HPLC.

[0056] The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

[0057] EXPERIMENTAL:

[0058] Example 1: General process for preparation of Ethion formula (I).

[0059] The compound O,O'-Diethyl dithiophosphate (2-3 eq.) was added in mixture of ethanol (0.1-0.30 vol) and toluene (0.5-1.5 vol) and to this mixture caustic lye solution was added at 15°C to 30°C till the pH of the reaction mixture became 7.0-9.0. The reaction mixture was then maintained at 15°C to 30°C for 0.5-2 hours. The reaction mixture was filtered through celite bed, bed washed with water and the organic and aqueous layer were separated. To the aqueous layer, a solution of dibro mo methane (1.0 eq) in ethanol (0.25-0.5 vol) was added at 20°C to 30°C. The reaction mixture was then heated at 50°C to 60°C under nitrogen for 2-3 hrs. and further heated at 80°C to 90°C for 6-7 hrs. The completion of reaction is monitored by HPLC. After completion, the reaction mixture was cooled to 20°C to 30°C and the biphasic reaction mass was separated. The organic layer was washed with aq. sodium carbonate and water to obtain Ethion as a colorless liquid (Yield >90%, and HPLC purity > 98%) impurity (IV) < 0.05%, and impurity (V) < 0.1% by HPLC.

[0060] The HPLC method for determination of Ethion, key starting compounds / intermediates and the novel impurities is cited as given below:

[0061] Phenomenex Kinetex C8 100 A°, 250 mm x 4.6 mm, 5.0 pm, Mobile phase-A: 0.01M Ammonium phosphate monobasic in water, Mobile phase-B: Water: Acetonitrile (30:70 v / v), Diluent: Methanol: Water: Acetonitrile (70: 10:20 v / v / v) + 0.2 mL orthophosphoric acid, UV: 216 nm, Run time: 65 min

[0062] Example 2: Scale up example for the preparation of Ethion formula (I).

[0063] The compound O,O'-Diethyl dithiophosphate (12.0 Kg, 64.427 moles) was added in mixture of ethanol (0.4 Kg, 8.683 moles, 10% w / w) and toluene (4.0 Lit, 1.0 V). To this mixture aqueous sodium hydroxide solution was added at 15°C to 30 °C till the pH of the reaction mixture became 7.0-9.0. The reaction mixture was then stirred at 15°C to 30 °C for 1 to 2 h. The reaction mixture was then filtered, washed with water (2.0 Lit, 0.5 V), the organic and aqueous layer were separated. To the aqueous layer, a solution of dibro mo methane (4.0 Kg, 23.010 moles, 1.0 eq.) in ethanol (0.4 Kg, 8.683 moles, 10% w / w) was added at 20°C to 30°C. The reaction mixture was heated at 50°C to 60°C and stirred under nitrogen and further heated at 80°C to 90°C for 6 to 7 hrs. The completion of reaction is monitored by HPLC. After completion, the reaction mixture was cooled to 20°C to 30°C and the biphasic reaction mass was separated. The organic layer was washed with aq. sodium carbonate and water to obtain Ethion as a colorless liquid (3.7 Kg , 87 % yield, and HPLC purity 99.24%), impurity (IV) 0.01%, and impurity (V) < 0.07% by HPLC.

Claims

CLAIM:1 ) A process for the preparation of Ethion of formula (I)which comprises steps of: a) adding O,O'-Diethyl dithiophosphate of formula (II)in a mixture of hydrocarbon solvent and ethanol, b) adding a base in step (a) till pH 7-9, c) filtering the reaction mixture of step (b), d) separating aqueous layer of step (c), e) adding a solution of dibromomethane of formula (III) and ethanol to an aqueous layer of step (d),Br'^Br(III) f) heating reaction mixture of step (e) at 50°C to 90°C, g) cooling reaction mixture of step (f) to 20°C to 40°C, and h) separating organic layer to obtain the Ethion of formula (I) comprising one or more impurities of formula (IV) or formula (V).2) The process as claimed in claim 1, wherein the Ethion obtained has purity greater than 98.0%, and impurity of formula (IV) or impurity of formula (V) is less than 0.1% as measured by HPLC.3) The process as claimed in claim 1, wherein a base is selected from potassium carbonate, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, and potassium bicarbonate.4) The process as claimed in claim 1 , wherein hydrocarbon solvent is selected from is selected from alicyclic hydrocarbon solvents selected from cyclohexane, methylcyclohexane, aromatic hydrocarbon solvents selected from benzene, toluene, xylene, mesitylene, ethylbenzene, tert-butylbenzene, trifluoromethyl benzene, nitrobenzene, chlorobenzene, chlorotoluene, and bromobenzene.5) Ethion obtained by the process in claim 1 contains impurity of formula (IV).6) Ethion obtained by the process in claim 1 contains impurity of formula (V).

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