FIELD OF INVENTION
The present invention relates to an improved process for the manufacture of Imidacloprid. More particularly the present invention relates to the synthesis of imidacloprid in a biphasic solvent system.
BACKGROUND OF THE INVENTION
Imidacloprid which is N-[l-[(6-Chloro-3-pyridyl) methyl]-4, 5- hydroimidazol-2-yl] nitramide) is a chlorinated analog of nicotine and belongs to the class of neonicotinoid insecticides. This compound targets the nicotinic acetylcholine receptor. It is has the structural formula
(Formula Removed)
It is most commonly used on citrus, coffee, cotton, fruits, grapes, potatoes, rice, soybeans, sugarcane, tobacco and vegetables, and veterinary purpose.
Imidacloprid was first disclosed in US4742060. This patent teaches a process for imidacloprid which involves the formation of l-(2-chloro-5-pyridylmethyl)-2-iminoimidazolidine hydrobromide as an intermediate that is subsequently nitrated to form the title compound.
US6307053 teaches a process for the preparation of Imidacloprid comprising reacting 2-nitroiminoimidazolidine with 2-chloro-5-chloromethyl pyridine in the presence of an alkali carbonate in an organic solvent, wherein a stoichiometric amount of the 2-chloro-5-chloromethyl pyridine is gradually added into mixture of a corresponding stoichiometric amount of the 2-nitroiminoimidazolidine and the organic solvent under reflux condition. However due to the low solubility of alkali metal carbonates in organic solvents, the reaction mixture is not homogenous and completion of reaction is not generated and additionally it is
difficult to monitor the progress of reaction. Therefore, the process disclosed in the aforesaid patent is difficult to carry out. Also, since alkali metal carbonates have low basicity, these increase the reaction time and also result in significant by-product generation.
US 7297798 describes a process for the preparation of Imidacloprid comprising reacting 2-chloro-5-chloromethyl pyridine with 2-nitroiminoimidazolidine in the molar ratio 1:1 to 1:1.2 in the presence of an alkali metal hydroxide in an aprotic solvent at 45 to 60°C under stirring. It further disclosed that the yield of imidacloprid is improved if the molar proportion of the 2-nitroiminoimidazolidine is marginally higher than that of 2-chloro-5-chloromethyl pyridine. The aprotic solvent employed is dimethyl formamide or N, N-dimethyl acetamide, preferably dimethylformamide. However the said process suffers from the disadvantage of low % conversion thereby lowering the overall reaction yield. More over the product isolated by the said process does not result in purity more than 99.5% after purification. The multiple purification leads very poor yield. Imidacloprid, thus obtained from the said prior art process results in high cost and poor purity of product.
Thus the prior procedures suffer from one or other drawback like low yield, byproduct formation, use of toxic and high boiling solvents and reaction at high temperature. Additionally recovery of solvent is also difficult which leads to an increase in the effluent treatment load, feasibility and high recovery cost.
In light of above disadvantages there is a need to develop a process for Imidacloprid which has the capacity to produce the substantially pure product and commercially viable. Hereby the substantially pure Imidacloprid has purity not less then 99.0% and individual impurity not more than 0.15%.
The present inventors have surprisingly developed an improved process for the synthesis of imidacloprid which ameliorates the drawbacks of the prior art. The present inventors have surprisingly found that conducting the condensation
reaction in a biphasic system in the presence of phase transfer catalysts yields a product in high purity and good yield. The present inventors have further surprisingly found that carrying out reaction at 25°C avoids byproduct formation that is primarily responsible for lowering yield and purity of final product. The present inventors have also found that generation of solid waste is minimized by the presence of aqueous phase in the reaction medium facilitating low cost in waste treatment and disposal.
OBJECT OF INVENTION
It is an object of the present invention to provide an improved process for the
synthesis of Imidacloprid with high purity and good yield.
It is another object of the present invention to provide an improved process for the
synthesis of Imidacloprid which does not employ any hazardous reagent and that
is safer to carry out.
It is a further object of the present invention to provide an improved process for
the synthesis of Imidacloprid that is substantially free of impurities for its better
efficacy in veterinary use.
SUMMARY OF INVENTION
According to an aspect of the present invention there is provided a process for the synthesis of imidacloprid comprising the steps of:
i. Introducing a solution of 2-Chloro-5-Chloromethyl pyridine
(CCMP) in dichloromethane into a stirred mixture of 2-Nitroimino-l,3-dihydro Imidazole(2-NIIZ), an alkali hydroxide and a phase transfer catalyst in a water immiscible solvent and water at temperature range of 20°C to 60°C; ii. Stirring the above mass for around 12 hours;
iii. Addition of second lot of 2-NIIZ, an alkali hydroxide and a
phase transfer catalyst to the reaction mixture of step (ii),
followed by stirring of 12 hours; iv. Isolation of the product by solvent extraction followed by
recovery of dichloromethane;
v. Purification in an alcoholic organic solvent to yield
imidacloprid.
DETAILED DESCRIPTION OF THE INVENTION
Imidacloprid is an insecticide that belongs to the chloronicotinyl nitroguanidine class and is typically used as a crop and structural pest insecticide, seed treatment, and a flea-control treatment insecticide.
The present invention provides a robust, efficient and economical synthesis of substantially pure Imidacloprid in good yield. Substantially pure Imidacloprid means that the single impurity is not more than 0.15%, further the purity of the material is more than 99.5%.
The reaction can be represented in scheme I as follows:
(Scheme Removed)
Scheme I
Abbreviation
CCMP: 2-Chloro-5-Chloromethyl pyridine; 2-NIIZ: 2-Nitroimino-l, 3-dihydro Imidazole; TBAB: Tetra Butyl Ammonium Bromide; DCM: Dichloromethane;
KOH: Potassium Hydroxide; RT: Room temperature (25 °C).
Preparation of imidacloprid according to the process of the present invention is described in detail hereinafter.
The process for preparing imidacloprid comprises reacting 2-Chloro-5-Chloromethyl pyridine and 2-Nitroimino-l, 3-dihydro Imidazole in the presence of base which is selected from an alkali hydroxide or alkaline earth metal hydroxide and a phase transfer catalyst employing a water immiscible solvent and water as the biphasic solvent system. Preferably, dichloromethane is used which avoids by-products formation and presence of aqueous phase in the reaction medium helps to dissolve inorganic byproducts and impurities. The reaction between 2-Chloro-5-Chloromethyl pyridine and 2-Nitroimino-l, 3-dihydro Imidazole is carried out at 20°C to 60°C preferably at room temperature. The reaction between 2-Chloro-5-Chloromethyl pyridine and 2-Nitroimino-l, 3-dihydro Imidazole is carried out where the 2-Nitroimino-l, 3-dihydro Imidazole is added in to the reaction media intermittently in lots. This controls the rate of reaction, leads to formation of less impurity. It is found that the addition of 2-NHZ in multiple lots increases the conversion efficiency of the process. The reaction between 2-Chloro-5-Chloromethyl pyridine and 2-Nitroimino-l, 3-dihydro Imidazole is carried out under the presence of phase transfer catalyst e.g. TBAB, TBAC etc. More preferably TBAB is used, which is found to facilitate the reaction to proceed smoothly.
The base is selected from the group of alkali hydroxide e.g. sodium hydroxide, potassium hydroxide, barium hydroxide etc, alkaline earth metal hydroxide e.g. calcium hydroxide, magnesium hydroxide etc. The most preferred alkali hydroxides are for e.g. sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides e.g. calcium hydroxide are used.
After completion of reaction the organic layer is separated and recovered to get the residual material. The residual solid is isolated from reaction vessel by slurring with alcoholic solvents under room temperature to reflux temperature. Thus
obtained technical imidacloprid is purified by conventional means e.g. re-crystallization with alcoholic solvents at temperature ranging from room temperature to reflux temperature.
The present invention results in a product with purity more than 99% and an overall better process efficiency.
Thus the objective of development of a robust, economical, commercially viable process is developed for the imidacloprid.
The present invention is illustrated by way of the following non-limiting example.
EXAMPLES
Example-1: Preparation of Imidacloprid
2-NIIZ (86 gm), potassium hydroxide (36gm) and TBAB (20gm) is added in to 51t three necks round bottom flask fitted with mechanical stirrer containing 500 ml DM water at room temperature. A solution of CCMP (100 gm) in 2 litre DCM was added to the above reaction mixture at the room temperature, stirred for 12 hr and added 2-NIIZ (18.4 gm), KOH (17 gm), TBAB (5 gm), and reaction mass is further stirred for 12 hours at RT. After completion of reaction separated the aqueous layer and organic layer is recovered for dichloromethane and the residue thus obtained is precipitated with methanol, filtered the wet material to obtain the crude product. The crude material is further purified with methanol, filtering, followed by drying to obtain the substantially pure title compound. Yield 78.9 gm, HPLC purity 99.87 %; Appearance = White crystalline nature.
Example-2: Preparation of Imidacloprid
Taken 2-NIIZ (21.5 gm) and DM water (125 ml) in 1 It three necks round bottom flask fitted with mechanical stirrer at room temperature. Added potassium hydroxide (9.0 gm) and TBAB (5.0 gm) at RT under stirring. A solution of CCMP (25.0 gm) in 500ml DCM was added to the above reaction mixture at the room
temperature and stirred for 12 hrs and added 2-NIIZ (4.6 gm), potassium hydroxide (4.25 gm), TBAB (1.25 gm), and the reaction mass is further stirred for 12 hrs at RT. On completion, the reaction mixture was filtered, separate the aqueous layer and wash it with 25ml dichloromethane. Combined both organic layers and wash with 5% HC1 and then with saturated NaCl. The Organic layer is recovered for dichloromethane and the residue thus obtained is precipitated with methanol. The crude material is further purified with methanol, filtering, followed by drying to obtain the substantially pure title compound. Yield 20 gm, HPLC purity 99.86 %; Appearance = White crystalline nature.
Example-3: Preparation of Imidacloprid
Taken 2-NIIZ (21.5 gm) and DM water (125 ml) in 1 It three necks round bottom flask fitted with mechanical stirrer at room temperature. Added calcium hydroxide (14.0 gm) slowly to maintain temperature RT and stir it for 30 minutes. Now TBAB (5.0 gm) added in a lot and stir again for 15 minutes at RT. A solution of CCMP (25.0 gm) in 500ml DCM was added to the above reaction mixture at the room temperature and stirred for 12 hrs and added 2-NIIZ (4.62 gm), calcium hydroxide (2.52 gm), TBAB (1.25 gm), and the reaction mass is further stirred for 12 hrs at RT. On completion, the reaction mixture was filtered, separate the aqueous layer and wash it with 25ml dichloromethane. Combined both organic layers and wash with 5% HC1 and then with saturated NaCl. The Organic layer is recovered for dichloromethane and the residue thus obtained is precipitated with methanol. The crude material is further purified with methanol, filtering, followed by drying to obtain the substantially pure title compound. Yield 20.2 gm, HPLC purity 99.01 %; Appearance = White crystalline nature.

WE CLAIM
1. A process for the synthesis of imidacloprid comprising the steps of:
i. Introducing a solution of 2-Chloro-5-Chloromethyl pyridine
(CCMP) in dichloromethane into a stirred mixture of 2-Nitroimino-l,3-dihydro Imidazole(2-NIIZ), an alkali hydroxide and a phase transfer catalyst in a water immiscible solvent and water at temperature range of 20°C to 60°C;
ii. Stirring the above mass for around 12 hours;
iii. Addition of second lot of 2-NIIZ, an alkali hydroxide and a phase transfer catalyst to the reaction mixture of step (ii), followed by stirring of 12 hours;
iv. Isolation of the product by solvent extraction followed by recovery of dichloromethane;
v. Purification in an alcoholic organic solvent to yield
imidacloprid.
2. The process for the synthesis of imidacloprid as claimed in claim 1
wherein the base is selected from inorganic bases like alkali metal
hydroxide or alkaline earth metal hydroxide.
3. The process for the synthesis of imidacloprid as claimed in claim 2
wherein the alkali metal hydroxide is preferably potassium hydroxide.
4. The process for the synthesis of imidacloprid as claimed in claim 1
wherein the water immiscible organic solvents is selected from aliphatic
halogenated hydrocarbons like chloroform, dichloromethane,
dichloroethane, halogenated aromatic hydrocarbons like dichlorobenzene,
chlorobenzene or water immiscible ketone like methyl isobutyl ketone..
5. The process for the synthesis of imidacloprid as claimed in claim 4 wherein the aliphatic halogenated hydrocarbon is preferably dichloromethane.
6. The process for the synthesis of imidacloprid as claimed in claim 1 wherein temperature is most preferably 20-30°C.
7. The process for the synthesis of imidacloprid as claimed in claim 1, wherein the phase transfer catalyst is selected from quaternary ammonium salt preferably TBAB.
8. The process for the synthesis of imidacloprid as claimed in claim 1, wherein the alcoholic solvent is selected from methanol, ethanol, and isopropyl alcohol but more preferably methanol.