WO2010049789A1

WO2010049789A1 - Process for the synthesis of fipronil

Info

Publication number: WO2010049789A1
Application number: PCT/IB2009/007242
Authority: WO
Inventors: Alexander JÜLICH; Joachim Tillich
Original assignee: Dynamit Nobel Gmbh Explosivstoff-Und Systemtechnick
Priority date: 2008-10-27
Filing date: 2009-10-27
Publication date: 2010-05-06
Also published as: WO2010049746A1

Abstract

This invention relates to a process for the continuous synthesis of 5-amino-1-[2,6- dichloro-4-(rifluoromethyl)phenyl]-4-(rifluoromethylsulfinyl)-1H-pyrazole-3-carbonitrile comprising the step of reacting in a solvent 5-amino-1-[2,6-dichloro-4- (trifluoromethyl)phenyl]-4-(trifluoromethylthio)-1H-pyrazole-3-carbonitrile with an oxidizing agent. The process provides a more efficient and more robust process than the existing processes.

Description

PROCESS FOR THE SYNTHESIS OF FIPRONIL

FIELD OF THE INVENTION

The invention relates to a continuous process for the synthesis of 5-amino-l-[2,6- dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)-lH-pyrazole-3-carbonitrile. BACKGROUND OF THE INVENTION

Fipronil (5-amino-l-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-

(trifluoromethylsulfinyl)-lH-pyrazole-3-carbonitrile) is widely used as an insecticide. The insecticide disrupts the insect central nervous system by blocking the passage of chloride ions through the GABA receptor and glutamate-gated chloride channels (GIuCl), components of the central nervous system. This causes hyperexcitation of contaminated insects' nerves and muscles. Insect specificity of fipronil may come from a better efficacy on GABA receptor but also on the fact that GIuCl does not exist in mammals. Fipronil is a slow acting poison. When mixed with a bait it allows the poisoned insect time to return to the colony or haborage.

The known commercial processes for the manufacture of fipronil are batch processes.

WO-A-2007/ 122440 relates to a batch process for the manufacture of 5-amino-l- phenyl-3-cyano-4-trifluoromethyl sulphinyl pyrazoles as defined by Formula I :

Formula I

wherein:

Rl = trifluoromethyl or trifluoromethoxy, and

R2, R3 = individually hydrogen, chlorine or bromine, the process comprising the step of oxidizing a compound of Formula II :

GONFiRMATIOM COPY Formula II

wherein :

Rl = trifluoromethyl or trifluoromethoxy, and

R2, R3 = individually hydrogen, chlorine or bromine , in a medium comprising at least one oxidizing agent and trichloro acetic acid, and/or the reactions product(s) of the at least one oxidizing agent and trichloro acetic acid, and at least one melting point depressant.

The US Patent No. 5,232,940 discloses a method for the control of arthropod, plant nematode or helminth pests at a locus which comprises treatment of the locus with a pesticidally effective amount of a compound of the formula:

wherein each of the substituents have varying meanings. In compound 52, Rl represents a cyano group, R2 represents R'SO in which R' is a straight chain alkyl group containing 1 carbon atom substituted by 3 fluorine atoms, R3 represents an amino group -NR"R"' wherein R" and R'" represent a hydrogen atom, R4 and R8 represent chlorine, and R6 represents a straight chain alkyl group containing 1 carbon atom substituted by 3 chlorine atoms. The process for making it comprises treating a stirred solution of 5-amino-3-cyano-l- (2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethyl thiopyrazole in dichloromethane with m-chloroperbenzoic acid, adding additional m-chloroperbenzoic acid, diluting the reaction product with ethyl acetate, washing and drying it. The European Patent EP-B-02951 17 discloses a N-phenypyrazole derivative of the formula:

wherein Rl represents a cyano group, R2 represents R5SO in which R5 is a straight chain alkyl group containing 1 carbon atom substituted by 3 fluorine atoms, R3 represents an amino group -NR6R7 wherein R6 and R7 represent a hydrogen atom, R4 represents a phenyl group substituted in the 2-position and in the 6-position by a chlorine and in the 4-position by a straight chain alkyl group containing 1 carbon atom which is substituted by 3 chlorine atoms.

The process for making it comprises treating a stirred solution of 5-amino-3-cyano-l- (2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethyl thiopyrazole in dichloromethane with m-chloroperbenzoic acid, adding additional m-chloroperbenzoic acid, diluting the reaction product with ethyl acetate, washing and drying it. SUMMARY OF THE INVENTION

The object of the present invention is to provide a more efficient and more robust process than the existing processes.

This object is achieved with a process for the continuous synthesis of 5-amino-l -[2,6- dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)-l H-pyrazole-3-carbonitrile comprising the step of reacting in a solvent 5-amino-l-[2,6-dichloro-4- (trifluoromethyl)phenyl]-4-(trifluoromethylthio)-l H-pyrazole-3-carbonitrile with an oxidizing agent. Preferred embodiments comprise one or more of the following features.

According to an embodiment, the process is carried out in a laminar-flow reactor.

The reactor can be a plug-flow reactor.

According to an embodiment, the reactants are mixed in a static mixer prior to introduction into the laminar-flow reactor.

According to an embodiment, the process comprises a preliminary step of mixing 5- amino-l-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylthio)-l H-pyrazole-3- carbonitrile with the solvent.

According to an embodiment, the process comprises a preliminary step of mixing the oxidizing agent with the solvent.

According to an embodiment, the solvent is trifluoroacetic acid.

According to an embodiment, the oxidizing agent is hydrogen peroxide. According to an embodiment, the reaction time is 1 to 50 minutes, preferably 8 to 10 minutes, notably about 9 minutes.

According to an embodiment, the reaction occurs at a temperature between 0 and 100°C, preferably 20 and 60°C, more preferably 35 and 45°C.

According to an embodiment, the process further comprises the step of quenching the reaction stream, preferably with an aqueous solution OfFeSO₄.

According to an embodiment, the process further comprises a purification step.

Further features and advantages of the invention will appear from the following description of embodiments of the invention, given as non-limiting examples, with reference to the accompanying drawings listed hereunder. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows a flow chart of the process first object of the invention. DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The first object of the invention relates to a process for the continuous synthesis of 5- amino- 1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)- 1 H-pyrazole-3- carbonitrile comprising the step consisting of reacting in a solvent fipronil-sulfide (5-amino- 1 - [2,6-dichloro-4-(trifluoromethyl)phenyl] -4-(trifluoromethy lthio)- 1 H-pyrazole-3 - carbonitrile) with an oxidizing agent.

The use of a continuous process considerably enhances the known commercial processes. The reaction is much faster (due in part to higher reaction temperatures). The process provides a good temperature control as well as a homogeneous reaction phase (notably there is no crystallization in the reactor), and a good control of the by-products. Moreover it provides a constant quality of the produced product, stability of the process being then obtained.

The process is continuous, which means that the reactants are injected in a continuous way, i.e. without any interruption, and the products are withdrawn in a continuous way, i.e. without interruption. However, continuous does not mean that the flow (injection and/or withdrawal) is always constant depending of the time. For example the reactants/products can be injected / withdrawn in a continuous way but with a variable flow rate, e.g. pulsated flow rate.

Any oxidizing agent can be used. Peracids, peroxides and persulfates can be used. For example hypochlorite, iodine, chlorine, bromine, fluorine, hypochlorite, chlorate, perchlorate, permanganate salts, manganate salts, ammonium cerium(IV) nitrate, chromic acid, dichromate, chromate, dichromic acid, chromium trioxide, pyridinium chlorochromate (PCC), peroxide compounds, Tollen's reagent, sulfoxides, persulfuric acid, dioxygen, ozone, osmium tetroxide (OsO₄), nitric acid, nitrous oxide (N₂O) and hydrogen peroxide can be used. The preferred oxidizing agents are per acids, peroxides and persulfates. More preferred are peroxides, in particular benzoyl peroxide, tert butyl peroxide and hydrogen peroxide. More preferably, the oxidizing agent is hydrogen peroxide.

Any type of solvent can be used. For example acetic acid, n-butanol, isopropanol, n- propanol, ethanol, methanol, formic acid, water, 1 ,4-dioxane, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate, trifluoroacetic acid, trichloro acetic acid can be used. Preferably, trifluoroacetic acid is used.

Preferably, the process comprises a preliminary step consisting of the mixing of 5- amino- 1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylthio)- 1 H-pyrazole-3- carbonitrile with the solvent.

Preferably, the mixture of 5-amino-l-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4- (trifluoromethylthio)-lH-pyrazole-3-carbonitrile and the solvent is a solution of 5-amino-l- [2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylthio)-lH-pyrazole-3-carbonitrile in trifluoroacetic acid. As an alternative, the solution can be a 1 to 25% w/w (weight to weight) solution, preferably a 20 to 25% w/w solution, more preferably a 22 to 24% w/w solution.

Preferably, the process comprises another preliminary step consisting of the mixing of the oxidizing agent with the solvent. As an alternative, the solution of oxidizing agent can be a 1 to 90% w/w (weight to weight) solution, preferably a 20 to 40% w/w solution, more preferably a 30 to 32 w/w solution, even more preferably a 31% w/w solution. This pre- mixing is advantageous because it avoids precipitation in the tubes during the process, which can cause problems for the process, notably a loss of yield.

Preferably, the mixture of the oxidizing agent and the solvent is a mixture of hydrogen peroxide and trifluoroacetic acid. This mixture, although corrosive, is easily controllable by using tubing in perfluoralkoxy copolymer (PFA) and by adjusting the residence time, which is an advantage over the prior art batch processes using the TFA solvent. The continuous process allows thus using any type of solvent, including corrosive solvents.

For example, the tubing can be in a fluorinated polymer or in polypropylene (PP). Preferably, polytetrafluorethylene (PTFE), perfluoralkoxy copolymer (PFA), polyvinylidene fluoride (PVDF), or polyvinyl fluoride (PVF) can be used. More preferably, the tubing is in PFA or PTFE material.

The process can be used either in a lab scale or in a production scale. In a production scale, the tube length can be for example from 10 to 200m, preferably 30 to 150 m, with an inner diameter from 0.5 to 20mm, preferably from 1 to 10 mm.

In one embodiment, the reaction mixture passes through a mixing element before passing through a reactor. The mixing element can be, for example, a static mixer or a micro- structured mixer. The mixing element allows a good homogenization of the reaction mixture. The reactor is, preferably, a laminar flow (tube) reactor. More preferably, the reactor is a PFA laminar flow reactor. The reactor can be a plug flow reactor, which can be a laminar flow reactor but not necessarily.

In the laminar reactor as used in the invention, the Reynolds number is generally below 2000 and can advantageously vary between 150 and 1 100.

Preferably, the reaction occurs at a temperature between 0 and 100°C. More preferably the reaction temperature is between 20 and 60°C, and even more preferably between 35 and 45⁰C. The tubing and reactor can be tempered using a bath. Preferably, a silicon oil bath is used.

Preferably, the pressure is between the atmospheric pressure and 10 bars. More preferably, the pressure is between the atmospheric pressure and 5 bars. Even more preferably, the pressure is between 1 and 3 bars.

Preferably, the reaction time is 1 minute to 50 minutes, preferably 8 to 10 minutes. The reaction time is calculated from the mixing of the reactants to the outlet of the reactor. The reaction time is significantly lower than the reaction time used for batch reactions. Especially, the examples found in WO-A-2007/122440, i.e. examples 1 and 2, require one and two hours as the reaction time.

Another object of the invention is to provide a process comprising the steps of:

(i) synthesizing 5-amino-l -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-

(trifluoromethylsulfinyl)-l H-pyrazole-3-carbonitrile according to the process first object of the invention;

(ii) quenching the reaction product of (i), preferably with an aqueous solution of

FeSO₄.

The quench of the reaction mixture is used to stop the reaction. The quench is used after an effective reaction time. As an alternative, the quenching can be performed with a sodium bisulfite (Na₂S₂Os), a sodium hypochlorite, a sodium thiosulfate, a sodium sulphite, a N- acetyl cysteine or any heavy metal ion solution. The reaction time is optimized depending on the size of the reactor and of the required flows. Preferably, the process further comprises the steps of:

(iii) extraction of the solution obtained in (ii) with an organic solvent;

(iv) washing the organic phase;

(v) distilling the organic phase;

(vi) crystallizing the organic phase;

(vii) filtrating the crystallized phase;

(viii) washing of the precipitate;

(ix) drying the precipitate.

The extraction (iii) can be realized with organic solvents. Preferably, the organic solvent is a polar organic solvent non miscible with water. For example, the extraction solvent can be ethyl acetate, tetrahydrofurane (THF), toluene, diethyl ether, chloroform, dichloromethane, 1 ,4-dioxane, dimethylsulfoxide (DMF). Preferably, the extraction is realized with methyl tert- butyl ether (MTBE).

The washing of the organic phase (iv) is realized with a lipophobic solvent. Preferably, the washing solvent is water.

The distillation of the organic phase (v) can be any known distillation. For example, the distillation can be a simple distillation, a fractional distillation, a steam distillation, a vacuum distillation, an air-sensitive vacuum distillation, or a short path distillation. Preferably, the distillation is a steam distillation.

The crystallization (vi) of the organic phase can be carried out by any classical crystallisation methods. For example, the crystallization can be carried out by evaporation or cooling. Preferably, the crystallization is carried out by cooling.

The washing (viii) of the precipitate can be carried out with a lipophilic solvent. For example, the lipophilic solvent is ethyl ether, pentane, hexane, or heptane. Preferably, the washing solvent is hexane.

The drying (ix) of the precipitate can be carried out by any known drying methods. For example, it can be carried out by heating, natural air drying, supercritical drying, dielectric drying, or vacuum drying. Preferably, the drying is carried out by heating.

The steps (iii) to (ix) improve the purity of the desired product.

Alternatively, the process further comprising the steps of:

(iiia) filtration of the solution obtained in (ii);

(iva) washing and drying the retentate;

(va) recrystallizing with an organic solvent the retentate;

(via) filtrating the retentate;

(viia) washing and drying the retentate.

The filtration can be any of known filtrations. For example, it can be a simple filtration or a vacuum filtration. The recrystallization is performed with any suitable organic solvent. Preferably, the organic solvent is acetone or toluene.

The steps (iiia) to (viia) improve the purity of the desired product.

The steps (ii) to (viii) and (iiia) to (viia) can be operated in a continuous or in a batch mode.

The following examples are for illustrating purposes and should not be considered as limiting the scope of the invention.

EXAMPLES Example 1

Figure 1 describes a flow chart of the experimental setup.

50-60% hydrogen peroxide via a pump 1 is mixed with trifluoroacetic acid (TFA) via a pump 2 in a T-piece 3. Using a second T-piece 4 the peroxide mixture is subsequently fed into a stream of a 0.825 molar / 23% (w/w) solution of Fipronil-Sulfide in TFA (fed via a pump 5). Pumps 1, 2, and 5 are glass syringe pumps. They can give flow rates between 0 and 20 ml/min. Membrane pumps can also be used in case the pulsation is as low as possible.

The reaction mixture passes a static mixing element 6 in order to achieve good homogenization. To complete the reaction, the mixture goes through a laminar flow reactor 7 (or a plug-flow reactor) where the tube part has a length of 25 m and an inner diameter of 1/16" (1.59 mm). The mixing element is useful for a reproducible quality of the product stream.

After leaving the tube the reaction mixture is quenched with a aqueous solution of iron(II)sulphate.

The quench and the subsequent workup are performed as batch process.

The material of the tubing between the pumps 1, 2 and 5, the connectors, the T-pieces 3 and 4, the static mixing element 6 and the laminar flow reactor 7 is PFA because of the high corrosiveness of the reaction mixture (In particular the mixture TFA + H₂O₂ is corrosive against glass).

The dotted line in Figure 1 indicates that the components inside are tempered by a silicon oil bath 8. The bath temperature is 40 °C.

The following subsequent parameters were applied (in lab scale):

Pump 1 : 0.7 ml/min (0.84 g/min) Of H₂O₂;

Pump 2: 1.2 ml/min (1.85 g/min) of TFA;

Pump 5: 3.7 ml/min (5.6 g/min) of 23% (w/w) Fipronil sulfide in TFA.

This gives an overall flow of 5.6 ml/min reaction mixture with a pressure of 1.5 bar (static mixer) or 2.0 bar (micro mixer).

With the inner volumes of the mixer and laminar flow reactor a residence time (= reaction time) of 9 min is calculated.

The reaction mixture is then quenched with a Iron(II) sulphate solution. A further purification step is carried out, leading to an increased purity of the product.

The results obtained with the instant continuous process are the following (expressed in area% further to IPC method), evidencing better stability. The results obtained with a batch process are also disclosed in the following table:

Invention Batch

Fipronil 90-92% 92-95 %

Fipronil sulfide 1.5-2.5% 3-5%

Sulfone 4-5 % 1.5-2%

The purity given above is the purity of the quenched material without work-up.

The operating conditions used for the batch process were as follow:

74.6 g TFA, 168.8 g Chlorobenzene, 9.9 g Silica Gel (to avoid corrosion of glass ware) and 49.5 g Fipronil sulfide were added in a reactor.

The addition of hydrogen peroxide (60%) was done in 2 steps:

- step 1 : (5.6 g) 0.8 eq. Of H₂O₂ at 20 ⁰C within 2 h,

- step 2: (6.7 g) 1.0 eq. Of H₂O₂ at 0 °C, stirring 3-4 h at 0°C.

During batch synthesis we always have a suspension. The end of reaction is determined by IPC and then quenched with an aqueous solution Of FeSO₄.

To force precipitation, acetic acid is added.

The workup used is the same as for the continuous process of the invention. The IPC results after quench are comparable with the IPC results of the continuous synthesis after quench.

Example 2

This example describes the pilot scale production of Fipronil. The apparatus used is analogous to the apparatus shown in Figure 1 , but scaled up with a factor of 16.

Hydrogen peroxide 50% (stabilized) via pump 1 is mixed with trifluoroacetic acid (TFA) via a pump 2 in a T-piece 3. Using a second T-piece 4 the peroxide mixture is subsequently fed into a stream of a 0.825 molar / 23% (w/w) solution of Fipronil-Sulfide in TFA (fed via a pump 5). Pumps 1, 2, and 5 are glass syringe pumps. They can give flow rates between 0 and 80 ml/min. Membrane pumps can also be used in case the pulsation is as low as possible.

The static mixing element 6 was not used in pilot scale. To complete the reaction, the mixture goes through a laminar flow reactor 7 (or a plug-flow reactor) where the tube part has a length of 80 m and an inner diameter of 3.6 mm.

After leaving the tube the reaction mixture is quenched with water in a separate vessel.

The quench and the subsequent workup are performed as batch process. The material of the tubing between the pumps 1, 2 and 5, the connectors, the T-pieces 3 and 4, and the laminar flow reactor 7 is PFA or PTFE because of the high corrosiveness of the reaction mixture (In particular the mixture TFA + H₂O₂ is corrosive against glass).

The dotted line in Figure 1 indicates that the components inside are tempered by a silicon oil bath 8. The bath temperature is 39-41 °C.

The following subsequent parameters were applied (in lab scale):

Pump 1 : 10 ml/min (12.0 g/min) Of H₂O₂;

Pump 2: 21 ml/min (32.3 g/min) of TFA;

Pump 5: 60 ml/min (90.8 g/min) of 23% (w/w) Fipronil sulfide in TFA.

This gives an overall flow of 91 ml/min reaction mixture with a pressure between 1.0 bar and 2.0 bar.

With the inner volumes of the mixer and laminar flow reactor a residence time (= reaction time) of 10 min is calculated.

The reaction mixture is then quenched with water, which is prepared in a reaction vessel. The quenched suspension is stirred at a temperature of 5 ⁰C. A normal "batch size" was 24 h corresponding with a production capacity of 25-30 kg Fipronil crude per day. Shorter production times are possible.

The quality of production batches is summarized in the following table:

The samples are taken at the outlet of the reactor and were quenched with water. The quality within a continuous production is stable and does not fluctuate, evidencing the process is robust. The purity is given in mass-%. The yield after filtration and drying was between 80% and 90% of theory. The results show that the process is also very efficient.

Compared with the first example, the content of Fipronil sulfide is higher and the sulfone content is lower; this is due to slightly different equivalents Of H₂O₂.

Claims

1. Process for the continuous synthesis of 5-amino-l-[2,6-dichloro-4- (trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)- 1 H-pyrazole-3-carbonitrile comprising the step of reacting in a solvent 5-amino-l-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4- (trifluoromethylthio)-l H-pyrazole-3-carbonitrile with an oxidizing agent.

2. Process according to claim 1 , carried out in a laminar- flow reactor.

3. Process according to claim 1 or 2, carried out in a plug-flow reactor.

4. Process according to claim 2 or 3, wherein the reactants are mixed in a static mixer prior to introduction into the reactor.

5. Process according to any one of claims 1 to 4, comprising a preliminary step of mixing 5 -amino- 1 - [2,6-dichloro-4-(trifluoromethyl)phenyl] -4-(trifluoromethylthio)- 1 H- pyrazole-3-carbonitrile with the solvent.

6. Process according to any one of claims 1 to 5, comprising a preliminary step of mixing the oxidizing agent with the solvent.

7. Process according to any one of claims 1 to 6, wherein the solvent is trifluoroacetic acid.

8. Process according to any one of claims 1 to 7, wherein the oxidizing agent is hydrogen peroxide.

9. Process according to any one of claims 1 to 8, wherein the reaction time is 1 minute to 50 minutes, preferably 8 to 10 minutes.

10. Process according to any one of claims 1 to 9, wherein the reaction occurs at a temperature between 0 and 100⁰C, preferably 20 and 60°C, more preferably 35 and 45°C.

11. Process to any one of claims 1 to 10, further comprising the step of quenching the reaction stream, preferably with an aqueous solution of FeSO₄.

12. Process to any one of claims 1 to 1 1, further comprising a purification step.