WO2010049746A1 - Procédé de synthèse du fipronil - Google Patents

Procédé de synthèse du fipronil Download PDF

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Publication number
WO2010049746A1
WO2010049746A1 PCT/IB2008/002880 IB2008002880W WO2010049746A1 WO 2010049746 A1 WO2010049746 A1 WO 2010049746A1 IB 2008002880 W IB2008002880 W IB 2008002880W WO 2010049746 A1 WO2010049746 A1 WO 2010049746A1
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WO
WIPO (PCT)
Prior art keywords
solvent
process according
trifluoromethyl
amino
dichloro
Prior art date
Application number
PCT/IB2008/002880
Other languages
English (en)
Inventor
Alexander JÜLICH
Joachim Tillich
Original Assignee
Dynamit Nobel Gmbh Explosivstoff-Und Systemtechnic
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dynamit Nobel Gmbh Explosivstoff-Und Systemtechnic filed Critical Dynamit Nobel Gmbh Explosivstoff-Und Systemtechnic
Priority to PCT/IB2008/002880 priority Critical patent/WO2010049746A1/fr
Priority to PCT/IB2009/007242 priority patent/WO2010049789A1/fr
Publication of WO2010049746A1 publication Critical patent/WO2010049746A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms

Definitions

  • the invention relates to a process for the synthesis of 5-amino-l-[2,6-dichloro-4- (trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)-lH-pyrazoIe-3-carbonitrile.
  • Fipronil (5-amino-l -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-
  • 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 :
  • Rl trifluoromethyl or trifluoromethoxy
  • R2, R3 individually hydrogen, chlorine or bromine
  • Rl trifluoromethyl or trifluoromethoxy
  • 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:
  • 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
  • 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-0295117 discloses a N-phenypyrazole derivative of the formula:
  • 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.
  • the object of the present invention is to provide a more efficient and more robust process than the existing processes.
  • the process is carried out in a laminar-flow reactor.
  • the reactor can be a plug-flow reactor.
  • the reactants are mixed in a static mixer prior to introduction into the laminar-flow reactor.
  • the process comprises a preliminary step of mixing 5- amino- 1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylthio)- 1 H-pyrazole-3- carbonitrile with the solvent.
  • the process comprises a preliminary step of mixing the oxidizing agent with the solvent.
  • the solvent is trifluoroacetic acid.
  • the oxidizing agent is hydrogen peroxide.
  • the reaction time is 1 to 50 minutes, preferably 8 to 10 minutes, notably about 9 minutes.
  • the reaction occurs at a temperature between 0 and JOO 0 C, preferably 20 and 60 0 C, more preferably 35 and 45°C.
  • the process further comprises the step of quenching the reaction stream, preferably with an aqueous solution OfFeSO 4 .
  • the process further comprises a purification step.
  • Fig. 1 shows a flow chart of the process first object of the invention.
  • the first object of the invention relates to a process for the continuous synthesis of 5- amino- l-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)-lH-pyrazole-3- carbonitrile comprising the step consisting of reacting in a solvent fipronil-sulfide (5-amino- 1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylthio)- 1 H-pyrazole-3- carbonitrile) with an oxidizing agent.
  • a solvent fipronil-sulfide 5-amino- 1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylthio)- 1 H-pyrazole-3- carbonitrile
  • 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.
  • continuous does not mean that the flow (injection and/or withdrawal) is always constant depending of the time.
  • 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.
  • hypochlorite iodine, chlorine, bromine, fluorine, hypochlorite, chlorate, perchlorate, permanganate salts, manganate salt
  • 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.
  • solvent Any type of solvent can be used.
  • trifluoroacetic acid is used.
  • the process comprises a preliminary step consisting of the mixing of 5- amino-l-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylthio)-lH- ⁇ yrazole-3- carbonitrile with the solvent.
  • the mixture of 5-amino-l-[2,6-dichlpro-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.
  • 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.
  • the process comprises another preliminary step consisting of the mixing of the oxidizing agent with the solvent.
  • 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.
  • 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.
  • PFA perfluoralkoxy copolymer
  • the continuous process allows thus using any type of solvent, including corrosive solvents.
  • the tubing can be in a fluorinated polymer or in polypropylene (PP).
  • PP polypropylene
  • PTFE polytetrafluorethylene
  • PFA perfluoralkoxy copolymer
  • PVDF polyvinylidene fluoride
  • PVF polyvinyl fluoride
  • the tubing is in PFA or PTFE material.
  • the process can be used either in a lab scale or 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.
  • 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
  • the reaction occurs at a temperature between 0 and 100 0 C. More preferably the reaction temperature is between 20 and 60 0 C, and even more preferably between 35 and 45 0 C.
  • the tubing and reactor can be tempered using a bath. Preferably, a silicon oil bath is used.
  • 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.
  • 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.
  • 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-
  • the quench of the reaction mixture is used to stop the reaction.
  • the quench is used after an effective reaction time.
  • the quenching can be performed with a sodium bisulfite (Na 2 S 2 Os), 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.
  • the process further comprises the steps of: (iii) extraction of the solution obtained in (ii) with an organic solvent;
  • the extraction (iii) can be realized with organic solvents.
  • the organic solvent is a polar organic solvent non miscible with water.
  • the extraction solvent can be ethyl acetate, tetrahydrofurane (THF), toluene, diethyl ether, chloroform, dichloromethane,
  • 1,4-dioxane dimethylsulfoxide (DMF).
  • DMF dimethylsulfoxide
  • MTBE methyl tert- butyl ether
  • the washing of the organic phase (iv) is realized with a lipophobic solvent.
  • the washing solvent is water.
  • the distillation of the organic phase (v) can be any known distillation.
  • 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.
  • the distillation is a steam distillation.
  • the crystallization (vi) of the organic phase can be carried out by any classical crystallisation methods.
  • the crystallization can be carried out by evaporation or cooling.
  • the crystallization is carried out by cooling.
  • the washing (viii) of the precipitate can be carried out with a lipophilic solvent.
  • the lipophilic solvent is ethyl ether, pentane, hexane, or heptane.
  • the washing solvent is hexane.
  • the drying (ix) of the precipitate can be carried out by any known drying methods.
  • it can be carried out by heating, natural air drying, supercritical drying, dielectric drying, or vacuum drying.
  • the drying is carried out by heating.
  • steps (iii) to (ix) improve the purity of the desired product.
  • the process further comprising the steps of:
  • the filtration can be any of known filtrations.
  • it can be a simple filtration or a vacuum filtration.
  • the recrystallization is performed with any suitable organic solvent.
  • the organic solvent is acetone or toluene.
  • steps (ii) to (viii) and (iiia) to (viia) can be operated in a continuous or in a batch mode.
  • FIG. 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.
  • TFA trifluoroacetic acid
  • the peroxide mixture is subsequently fed into a stream of a 0.825 molar / 23% (w/w) solution of Fipronil-Sulf ⁇ de 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.
  • 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.
  • 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 + H 2 O 2 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 0 C.
  • reaction time 9 min
  • 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.

Abstract

La présente invention concerne un procédé de synthèse continue du 5-amino-1-[2,6-dichloro-4-(trifluorométhyl)phényl]-4-(trifluorométhylsulfinyl)-1H-pyrazole-3-carbonitrile comprenant l’étape consistant à faire réagir dans un solvant le 5-amino-1-[2,6-dichloro-4-(trifluorométhyl)phényl]-4-(trifluorométhylthio)-1H-pyrazole-3-carbonitrile avec un agent oxydant. Le procédé consiste en un procédé plus efficace et plus robuste que les procédés existants.
PCT/IB2008/002880 2008-10-27 2008-10-27 Procédé de synthèse du fipronil WO2010049746A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/IB2008/002880 WO2010049746A1 (fr) 2008-10-27 2008-10-27 Procédé de synthèse du fipronil
PCT/IB2009/007242 WO2010049789A1 (fr) 2008-10-27 2009-10-27 Procédé pour la synthèse du fipronil

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2008/002880 WO2010049746A1 (fr) 2008-10-27 2008-10-27 Procédé de synthèse du fipronil

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PCT/IB2009/007242 WO2010049789A1 (fr) 2008-10-27 2009-10-27 Procédé pour la synthèse du fipronil

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013108068A1 (fr) * 2012-01-21 2013-07-25 Jubilant Life Sciences Limited Procédé de préparation de 2-pyridinylméthylsulfinylbenzimidazoles, leurs analogues et énantiomères optiquement actifs
CN114213330A (zh) * 2021-12-29 2022-03-22 天和药业股份有限公司 一种氟虫腈精制母液的处理方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0295117A1 (fr) * 1987-06-12 1988-12-14 Rhone-Poulenc Agriculture Limited Dérivés de N-phénylpyrazoles
WO2001030760A1 (fr) * 1999-10-22 2001-05-03 Aventis Cropscience S.A. Procede de preparation d'un derive 4-trifluoromethylsulfinylpyrazole
WO2007122440A1 (fr) * 2006-04-25 2007-11-01 Gharda Chemicals Limited Procede de preparation de fipronil, un insecticide et des pyrazoles correspondants

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0295117A1 (fr) * 1987-06-12 1988-12-14 Rhone-Poulenc Agriculture Limited Dérivés de N-phénylpyrazoles
WO2001030760A1 (fr) * 1999-10-22 2001-05-03 Aventis Cropscience S.A. Procede de preparation d'un derive 4-trifluoromethylsulfinylpyrazole
WO2007122440A1 (fr) * 2006-04-25 2007-11-01 Gharda Chemicals Limited Procede de preparation de fipronil, un insecticide et des pyrazoles correspondants

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013108068A1 (fr) * 2012-01-21 2013-07-25 Jubilant Life Sciences Limited Procédé de préparation de 2-pyridinylméthylsulfinylbenzimidazoles, leurs analogues et énantiomères optiquement actifs
CN104203938A (zh) * 2012-01-21 2014-12-10 朱比兰特生命科学有限公司 用于制备2-吡啶基甲基亚硫酰基苯并咪唑、它们的类似物和光学活性对映体的方法
CN114213330A (zh) * 2021-12-29 2022-03-22 天和药业股份有限公司 一种氟虫腈精制母液的处理方法

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