(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`I IIIII IIIIIIII II IIIIII IIIII IIII I II Ill lllll lllll lllll lllll llll lllllll llll llll llll
`
`(43) International Publication Date
`3 May 2001 (03.05.2001)
`
`PCT
`
`(IO) International Publication Number
`WO 01/30760 Al
`
`(51) International Patent Classification 7:
`401/04
`
`C07D 231/44.
`
`(21) International Application Number:
`
`PCT/EP99/08687
`
`(22) International Filing Date: 22 October 1999 (22.10.1999)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(71) Applicant (for all designated States except US): AVENTIS
`CROPSCIENCE S.A. [FR/FR]: 55, avenue Rene Cassin,
`F-69009 Lyon (FR).
`
`(72) Inventors; and
`CLAVEL,
`(75) Inventors/Applicants
`(for US only):
`.Jean-Louis
`[FR/FR]; La Brosse, F-69420 Ampuis
`(FR). PELTA, Isabelle [FR/FR]; 30, impasse Jean de
`la Fontaine, F-69680 Chassieu (FR). LE BARS, Sylvie
`[FR/FR]; Hameau de Thiers, F-38200 Chuzelles (FR).
`CHARREAU, Philippe [FR/FR]; 9, rue Salvador Dali,
`F-69110 Sainte Foy les Lyon (FR).
`
`(74) Agent: PRAS, Jean-Louis; Aventis Cropscience S.A.,
`Boite postale 9163, F-69263 Lyon Cedex 09 (FR).
`
`(81) Designated States (national): AE. AL AM, AT. AU, AZ.
`BA, BB, BG. BR, BY, CA. CH. CN, CR. CU, CZ, DE. DK,
`DM. EE, ES, FL GB, GD, GE, GH, GM, HR, HU, ID. IL
`IN, IS, JP, KE, KG, KE KR. KZ, LC, LK, LR, LS, LT. LU,
`LY, MA. MD, MG. MK, MN, MW, MX, NO, NZ, PL, PT,
`RO. RU, SD, SE, SG. SI. SK, SL, TJ, TM, TR, TT. TZ, UA,
`UG, US. UZ, YN, YU, ZA. ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, SD, SL. SZ, TZ, UG, ZW), Eurasian patent
`(AM, AZ. BY, KG, KZ, MD, RU, TJ, TM), European patent
`(AT, BE, CH, CY, DE, DK, ES, FL FR, GB, GR, IE, IT, LU,
`MC, NL, PT, SE). OAPI patent (BF, BJ, CF, CG, CI, CM,
`GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`fVith international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event CJ[ receipt of
`amendments.
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance ]Votes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`-------
`---~
`---
`--iiiiiii -
`
`(54) Title: PROCESS FOR PREPARING 4-TRIFLUOROMETHYLSULPHINYLPYRAZOLE DERIVATIVE
`
`(I)
`
`(II)
`
`0
`\0
`t(cid:173)o
`
`~ -(cid:173)~
`
`O
`(57) Abstract: A process for the preparation of a compound of formula {1), R1 represents halogen, haloalkyl, haloalkoxy, R4S(0)0 -,
`0 or -SF5; R2 represents hydrogen or halogen; R3 represents halogen; R4 represents alkyl or haloalkyl; and n represents 0, 1 or 2; which
`> process comprises oxidising a compound of formula (II); wherein R 1, R2 and W are as defined above, with trifluoroperacetic acid in
`FINCHIMICA EXHIBIT 2022
`ADAMA MAKHTESHIM v. FINCH/MICA
`CASE IPR2016-00577
`
`;.,- the presence of a corrosion inhibiting.
`
`

`

`WO 01/30760
`
`PCT /EP99/08687
`
`PROCESS FOR PREPARING 4-TRIFLUOROMETHYLSULPHINYLPYRAZOLE DERIVATIVE
`This invention relates to improved processes for preparing
`
`1-arylpyrazole pesticides such as 5-amino-1-(2,6-dichloro-4-
`
`trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulphinylpyrazole
`
`5
`
`known as Fipronil (Pesticide Manual 11th Edition), and for the
`
`intermediates used in its preparation 5-amino-1-(2,6-dichloro-4-
`
`trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole and 5-
`
`amino-1-(2, 6-dichloro-4-trifl uorometh y l phenyl )-3-cyanopyrazo 1-4-y l
`
`disulphide.
`
`10
`
`European Patent Publication No.295117 describes the
`
`preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-
`
`cyano-4-trifluoromethylsulphinylpyrazole by the oxidation of 5-amino-
`
`1-(2, 6-dichloro-4-trifl uoromethy lpheny 1)-3-cyano-4-
`
`trifl uoromethy lthiopyrazole with 3-chloroperbenzoic acid. The use of
`
`15
`
`trifluoroacetic acid and hydrogen peroxide (forming trifluoroperacetic
`
`acid in situ) for the oxidation of sulphides to sulphoxides and/or
`
`sulphones is known and is generally useful for the oxidation of electron
`
`deficient sulphides such as trifluoromethylsulphides which are less
`
`readily oxidised than other sulphides. Such procedures have been
`
`20
`
`reported in the literature, for example in the preparation of certain 1-
`
`arylpyrazole pesticides.
`
`A problem encountered in the preparation of 5-amino-1-(2,6-
`
`dichloro-4-trifluoromethylphenyl)-3-cyano-4-
`
`trifluoromethylsulphinylpyrazole by the oxidation of 5-amino-1-(2,6-
`
`25
`
`dichloro-4-trifl uoromethy 1 pheny 1)-3-cyano-4-
`
`trifluoromethy lthiopyrazo le is the co-formation of the corresponding
`
`sulphone compound 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-
`
`3-cyano-4-trifluoromethylsulphonylpyrazole, which is difficult to
`
`remove from the sulphoxide. A number of oxidants (including amongst
`
`30
`
`others sodium vanadate, sodium tungstate, peracetic acid, performic acid
`
`and pertrichloroacetic acid) have been employed in an attempt to obtain
`
`

`

`WO 01/30760
`
`-
`
`2
`
`-
`
`PCT /EP99/08687
`
`an efficient and regioselective oxidation which will provide 5-amino-1-
`
`(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-
`
`trifluoromethylsulphinylpyrazole in pure form and which may also be
`
`utilised for large scale preparations. All of the above methods were
`
`5
`
`found to be unsatisfactory in one respect or another.
`
`It has now been found that a mixture of trifluoroacetic acid and
`
`hydrogen peroxide (trifluoroperacetic acid) gives excellent results in
`
`terms of both selectivity and yield.
`
`However a problem of using the trifluoroacetic acid and hydrogen
`
`10
`
`peroxide mixture on large scales is that it leads to corrosion of the glass
`
`linings of industrial reaction vessels, which is rapid (typically
`300µm/year) even at ambient temperatures, whilst at so0c the speed of
`corrosion increases to about 1430µm/year. This corrosion occurs as a
`
`result of the formation of hydrogen fluoride, and therefore prohibits the
`
`15
`
`use of this reagent mixture in such vessels.
`
`It has now been found that the addition of a corrosion inhibiting
`
`compound such as boric acid to the reaction mixture inhibits the
`
`corrosion process and reduces the speed of corrosion to a level that is
`
`typically less than 5µm/year.
`
`20
`
`European Patent Publication No. 0374061 and J-L.Clavel et.al. in
`
`I.Chem.Soc.Perkin I, (1992), 3371-3375 describe the preparation of 5-
`
`amino-1-(2, 6-dichloro-4-trifl uoromethy lpheny 1 )-3-cyanopyrazol-4-y I
`
`disulphide, and the further conversion of this disulphide to the
`
`25
`
`pesticidally active 5-amino-1-(2, 6-dichloro-4-trifl uoromethy I pheny 1)-3-
`
`cyano-4-trifluoromethy lthiopyrazo le by reaction with trifluoromethyl
`
`bromide in the presence of sodium formate and sulphur dioxide in N,N(cid:173)
`
`dimethylformamide in an autoclave at low pressure (typically 13 bars) at
`
`60°C.
`
`

`

`WO 01/30760
`
`-
`
`3
`
`-
`
`PCT/EP99/08687
`
`However on larger scales the reaction is very exothermic which
`
`results in a substantial pressure increase in the vessel and associated
`
`operator hazard.
`
`Moreover it is necessary to add the trifluoromethyl bromide
`
`5
`
`quickly (generally within 0.5 hour), because the mixture of disulphide,
`
`sodium formate, sulphur dioxide and N,N-dimethylformamide has been
`
`found to be unstable (typically leading to 55% degradation into
`
`unwanted by-products within 2 hours at 50°C). This requirement for
`
`rapid addition of trifluoromethyl bromide is not compatible with the
`
`10
`
`exothermic nature of the reaction.
`
`In order to overcome these problems and develop a process which
`
`can be used on a large scale other conditions have been sought.
`
`In the above described procedures the reaction was performed by
`
`addition of the trifluoromethyl bromide to a mixture of the other
`
`15
`
`components. A new process has now been developed in which the order
`
`of addition is different.
`
`European Patent Publication No. 0374061 describes the
`
`preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-
`
`20
`
`cyanopyrazol-4-yl disulphide by the reaction of 5-amino-1-(2,6-
`
`dichloro-4-trifl uoromethy 1 pheny 1 )-3-cyano-4-thiocyanatopyrazo 1 e with
`
`base, and the further conversion of this disulphide to the pesticidally
`
`active 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-
`
`trifluoromethylthiopyrazole.
`
`25
`
`European Patent Publication No. 295117 discloses a process for
`
`the preparation of 1-aryl-3,5-disubstituted-pyrazol-4-yl disulphides by
`
`the hydrolysis of the corresponding 4-thiocyanatopyrazole derivatives
`
`using hydrochloric acid in ethanol, or by reduction using sodium
`
`borohydride in ethanol, or by treatment with aqueous sodium hydroxide
`
`30
`
`under phase transfer conditions in the presence of chloroform and
`
`benzyltriethylammonium chloride.
`
`

`

`WO 01/30760
`
`- 4
`
`-
`
`PCT/EP99/08687
`
`The preparation of the above 5-amino-1-aryl-3-cyano-4-
`
`thiocyanatopyrazole intermediates is also described in European Patent
`
`Publication Numbers 0374061 and 295117, and these are obtained by
`
`the thiocyanation of the corresponding 5-amino-1-aryl-3-cyanopyrazole
`
`5
`
`derivatives using an alkali metal or ammonium thiocyanate in the
`
`presence of bromine and methanol at low temperature.
`
`The above 2-step process for the preparation of 5-amino-1-aryl-3-
`
`cyanopyrazol-4-yl disulphide intermediates from 5-amino-1-aryl-3-
`
`cyanopyrazoles presents several problems which limit its usefulness for
`
`10
`
`application on large scales:
`
`i)
`
`the thiocyanation step is generally performed at very low
`
`temperatures,
`
`ii)
`
`the mixture of bromine and methanol used in the
`
`thiocyanation reaction may form explosive mixtures,
`
`15
`
`iii)
`
`iv)
`
`the above reactions involve heterogeneous mixtures, and
`
`it is difficult to obtain complete transformations to product
`
`in either reaction stage.
`
`In order to overcome these problems other conditions have been
`
`sought. Thus the explosive hazard may be avoided in the thiocyanation
`
`20
`
`reaction by replacing the methanol with a mixture of dichloromethane
`
`and water, however this procedure is not efficient on large scales.
`
`The thiocyanation reaction may alternatively be successfully
`
`carried out using an alkali metal or ammonium thiocyanate in the
`
`presence of hydrogen peroxide and a mineral acid such as hydrochloric
`
`25
`
`acid in a solvent such as an alcohol for example methanol. An improved
`
`procedure for the subsequent hydrolysis step has been found which
`
`involves the use of a base such as an alkali metal hydroxide, for example
`
`sodium hydroxide, in the presence of formaldehyde and a solvent such
`
`as aqueous methanol, however the disulphide thus obtained is very
`
`30
`
`powdery and difficult to filter. Furthermore in order to obtain the above
`
`disulphide in satisfactory quality it is necessary to subject the starting
`
`

`

`WO 01/30760
`
`- 5
`
`-
`
`PCT/EP99/08687
`
`material 5-amino-1-aryl-3-cyanopyrazole to additional purification
`
`before it is used in the thiocyanation and hydrolysis reactions.
`
`Hence it may be appreciated that the above 2-step procedure is
`
`inefficient for an industrial process, and a single step method lacking
`
`5
`
`these disadvantages would clearly be preferred.
`
`The present invention seeks to provide improved or more
`
`economical methods for the preparation of pesticides.
`
`It is a first object of the present invention to provide a convenient
`
`10
`
`process for preparing 5-amino-1-aryl-3-cyano-4-
`
`trifluoromethylsulphinylpyrazole pesticides, which are obtained in high
`
`yield and high purity.
`
`It is a further object of the present invention to provide a process
`
`for preparing 5-amino-l-aryl-3-cyano-4-
`
`15
`
`trifluoromethylsulphinylpyrazole pesticides which is simple and safe to
`
`perform, and which results in minimal vessel corrosion.
`
`It is a further object of the present invention is to provide a process
`
`for the preparation of 5-amino-1-aryl-3-cyano-4-
`
`trifluoromethylsulphinylpyrazole pesticides which includes an efficient
`
`20
`
`recovery procedure for the trifluoroacetic acid.
`
`It is a further object of the present invention to provide a
`
`convenient process for preparing 5-amino-1-aryl-3-cyano-4-
`
`trifluoromethylthiopyrazole pesticides and pesticidal intermediates,
`
`which are obtained in high yield and high purity with improved
`
`25
`
`transformation of the 5-amino-1-aryl-3-cyanopyrazol-4-yl disulphide.
`
`It is a further object of the present invention to provide a process
`
`for preparing 5-amino-l-aryl-3-cyano-4-trifluoromethylthiopyrazole
`
`pesticides and pesticidal intermediates, which is simple and safe to
`
`perform, is operated at lower pressures and temperatures, and in which
`
`30
`
`side reactions are minimised.
`
`

`

`WOOl/30760
`
`-
`
`6 -
`
`PCT /EP99/08687
`
`It is a further object of the present invention to provide a
`
`convenient process for preparing 5-amino-1-aryl-3-cyanopyrazol-4-yl
`
`disulphide pesticidal intermediates, which are obtained in high yield and
`
`high purity.
`
`5
`
`It is a further object of the present invention to provide a single
`
`step process for preparing 5-amino-1-aryl-3-cyanopyrazol-4-yl
`
`disulphide pesticidal intermediates from 5-amino-1-aryl-3-
`
`cyanopyrazole intermediates.
`
`It is a further object of the present invention to provide a process
`
`10
`
`for preparing 5-amino-1-aryl-3-cyanopyrazol-4-yl disulphide pesticidal
`
`intermediates which is simple and safe to perform, utilises readily
`
`available materials, allows efficient isolation of the product and does not
`
`require additional purification of the 5-amino-1-aryl-3-cyanopyrazole
`
`starting material.
`
`15
`
`It is a further object of the present invention to provide a
`
`convenient process for preparing 5-amino-1-aryl-3-cyano-4-
`
`trifluoromethylsulphinylpyrazole pesticides by a three step process
`
`starting from 5-amino-1-aryl-3-cyanopyrazoles.
`
`These and other objects of the invention will become apparent
`
`20
`
`from the following description, and are achieved in whole or in part by
`
`the present invention.
`
`According to a feature of the present invention there is provided
`
`an improved process (A) for the preparation of a compound of formula
`
`25
`
`(I):
`
`

`

`WO 01/30760
`
`- 7
`
`-
`
`PCT /EP99/08687
`
`CF3SO'u----(CN
`
`H2N_/(N}~
`
`R2
`
`wherein W represents nitrogen or -CR 3;
`
`(I)
`
`R 1 represents halogen, haloalkyl (preferably trifluoromethyl),
`
`5
`
`haloalkoxy (preferably trifluoromethoxy), R4S(O)n-, or -SF 5;
`
`R2 represents hydrogen or halogen (for example chlorine or
`
`bromine);
`
`R3 represents halogen (for example chlorine or bromine);
`
`R4 represents alkyl or haloalkyl; and
`
`10
`
`n represents 0,1 or 2; which process comprises oxidising a
`
`compound of formula (II):
`
`wherein R 1, R 2 and W are as herein before defined, with
`
`15
`
`trifluoroperacetic acid in the presence of a corrosion inhibiting
`
`(II)
`
`compound.
`
`In a preferred embodiment of the invention the trifluoroperacetic
`
`acid is generated in situ by the reaction of trifluoroacetic acid and
`
`hydrogen peroxide. Accordingly, this embodiment comprises treating a
`
`

`

`WO 01/30760
`
`-
`
`8
`
`-
`
`PCT/EP99/08687
`
`compound of formula (II) as defined above with trifluoroacetic acid and
`
`hydrogen peroxide.
`
`Unless otherwise specified in the present specification 'alkyl'
`
`5
`
`means straight- or branched- chain alkyl having from one to six carbon
`
`atoms (preferably one to three). Unless otherwise specified 'haloalkyl'
`
`and 'haloalkoxy' are straight- or branched- chain alkyl or alkoxy
`
`respectively having from one to six carbon atoms (preferably one to
`
`three) substituted by one or more halogen atoms selected from fluorine,
`
`10
`
`chlorine and bromine.
`
`When Rl represents R4S(O)n- and n is O or 1, the process may
`
`bring about oxidation to the corresponding compound in which n is 1 or
`
`2, respectively.
`
`15
`
`The corrosion inhibiting compound is generally boric acid or an
`
`alkali metal borate such as sodium borate; or any hydrogen fluoride
`
`trapping agent such as silica (silicon dioxide), optionally in the form of
`
`silica oil. Preferably the corrosion inhibiting compound is boric acid.
`
`The amount of corrosion inhibiting compound used is generally
`
`20
`
`0.08-0.22 molar equivalents, and preferably about 0.08-0.1 molar
`
`equivalents.
`
`The amount of trifluoroacetic acid employed is generally from 14-
`
`15 molar equivalents.
`
`The amount of hydrogen peroxide influences the reaction since an
`
`25
`
`excess will lead to the formation of the corresponding sulphone of the
`
`compound of formula (I), whilst a deficiency will lead to incomplete
`
`transformation, and in either event an impure final product is obtained.
`
`Thus the amount of hydrogen peroxide used in the reaction (generally as
`
`a 35% aqueous solution) is generally from 1.3-1.5 equivalents,
`
`30
`
`preferably about 1.31-1.35 equivalents and more preferably about 1.33
`
`equivalents.
`
`

`

`WO 01/30760
`
`- 9
`
`-
`
`PCT /EP99/08687
`
`The reaction is generally performed at a temperature of from 10-
`
`150 C and preferably at about 12°c.
`
`A further problem associated with the use of trifluoroacetic acid
`
`and hydrogen peroxide concerns the recovery and recycling of the
`
`5
`
`expensive trifluoroacetic acid which is essential for the operation of an
`
`economically efficient process. In one procedure that was developed in
`
`an attempt to solve this problem, the reaction mixture was quenched
`
`with sulphur dioxide and a part of the trifluoroacetic acid removed by
`
`distillation. An excess of ethanol was then added to the residue to form
`
`10
`
`ethyl trifluoroacetate which was then removed by distillation. The
`
`product was then crystallised from a mixture of ethanol/water. This
`
`procedure was found to have two disadvantages:
`
`i)
`
`the ethanol/water mixture does not provide sufficiently pure 5-
`
`amino-1-(2,6-dichloro-4-trifl uoromethy lpheny 1 )-3-cyano-4-
`
`15
`
`trifluoromethy lsulphiny lpyrazole; and
`
`ii) the recycling of trifluoroacetic acid via the acid hydrolysis of
`
`ethyl trifluoroacetate is a complex process on a large scale and generates
`
`a large quantity of unwanted sodium sulphate thus presenting a waste
`
`problem.
`
`20
`
`A new procedure has now been found which solves both of these
`
`problems and thus provides a simple and efficient method for the
`
`preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-
`
`cyano-4-trifluoromethylsulphinylpyrazole in high yield and purity, and
`
`in addition provides an efficient recovery procedure for trifluoroacetic
`
`25
`
`acid. In this process, when the reaction in trifluoroacetic acid and
`
`hydrogen peroxide is judged to be complete, the excess of hydrogen
`
`peroxide is generally quenched with sulphur dioxide ( or equivalent
`
`reagent), chlorobenzene is added and the trifluoroacetic acid removed by
`
`distillation. Typically the trifluoroacetic acid is removed by azeotropic
`
`30
`
`distillation under reduced pressure. An alcohol such as methanol,
`
`ethanol or isopropanol (preferably ethanol) is then added to the residue
`
`

`

`WO 01/30760
`
`- 10 -
`
`PCT /EP99/08687
`
`and warmed to about 80°C until a solution is formed, and then cooled to
`
`about 40°C when the 5-amino-1-(2,6-dichloro-4-
`
`trifl uoromethy 1 pheny 1 )-3-cyano-4-trifl uoromethy lsul phiny 1 pyrazole
`
`5
`
`crystallises. The alcohol is evaporated at 40°C under reduced pressure,
`the mixture cooled to about o0 c, filtered, and the product washed and
`
`dried in vacuo. Chlorobenzene has been found to be the only industrial
`
`solvent which is compatible with the mixture, has a boiling point
`
`significantly higher than that of trifluoroacetic acid, and allows
`
`crystallisation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-
`
`10
`
`cyano-4-trifluoromethylsulphinylpyrazole in good yield and quality.
`
`Thus a preferred aspect of the process of the invention as
`
`described above further comprises adding chlorobenzene to the reaction
`
`mixture on completion of the oxidation reaction, and recovering the
`
`trifluoroacetic acid by distillation.
`
`According to a further feature of the present invention there is
`
`provided an improved process (B) for the preparation of a compound of
`
`formula (II) as defined above; which process comprises the addition of
`
`sulphur dioxide to a mixture comprising a disulphide of formula (III):
`
`NC
`
`s~~~s
`
`CN
`
`~NH2 H2N~
`R.2
`
`15
`
`20
`
`(III)
`
`wherein R 1, R 2 and W are as hereinbefore defined, a formate salt,
`
`trifluoromethyl bromide and a polar solvent. The polar solvent is
`
`generally selected from N,N-dimethylformamide, N,N-
`
`25
`
`dimethy lacetamide, N-methy lpyrrolidinone, dimethylsulphoxide,
`
`

`

`WO 01/30760
`
`- 11 -
`
`PCT/EP99/08687
`
`sulpholane, hexamethylphosphoramide and ethers such as dioxan,
`
`tetrahydrofuran and dimethoxyethane. It is preferably N,N(cid:173)
`
`dimethylformamide, N ,N-dimethy lacetamide, N-methy lpyrrolidinone,
`
`dimethylsulphoxide or sulpholane, more preferably N,N-
`
`5
`
`dimethy lformamide.
`
`The advantages of performing the process with this order of
`
`addition are:
`
`i)
`
`the mixture of disulphide of formula (III), sodium formate,
`
`10
`
`trifluoromethyl bromide and polar solvent (preferably N,N(cid:173)
`
`dimethylformamide) is stable and so the sulphur dioxide may be added
`
`more slowly without risk of degradation, thus providing a more
`
`convenient and safe process,
`
`ii) the new process is efficient being characterised by good yields
`
`15
`
`of product and high transformation of disulphide, and
`
`iii) the rate of addition of sulphur dioxide may be controlled so
`
`that any increase in the reaction temperature and/or pressure can be
`
`maintained at a safe level, thus allowing large scale reactions to be
`
`performed safely (including for example typical commercial reactors
`
`20
`
`having about l 5m3 volume).
`
`The formate salt is generally an alkali metal or ammonium salt,
`
`preferably sodium formate.
`
`The reaction temperature during the addition of the sulphur
`
`25
`
`dioxide is generally from 35-55°C, preferably from about 35-50°C,
`
`most preferably from about 43-47°C, which allows efficient control of
`
`the heat from the exothermic reaction. Below 35°C the reaction tends to
`
`proceed too slowly to be useful for an industrial process. At
`
`temperatures above 55°C the yield and quality of product is reduced.
`
`30
`
`The sulphur dioxide is generally added at such a rate that the
`
`temperature is maintained within the above defined range. On large
`
`

`

`WO 01/30760
`
`- 12 -
`
`PCT/EP99/08687
`
`scales this is generally carried out over a 0.5-2 hour period, preferably
`
`during about 1-1.5 hours. An addition time of about 1-1.5 hours has
`
`been shown to be optimal in minimising the formation of by-products.
`
`The molar ratio of trifluoromethyl bromide:disulphide of formula
`
`5
`
`(III) is preferably from 3: 1 to 5: 1. It is convenient to employ a molar
`
`ratio of about 3: 1.
`
`The amount of sulphur dioxide used is generally from 1.2-1.5
`
`molar equivalents relative to the disulphide of formula (III) and
`
`preferably about 1.3 molar equivalents. When only 1 equivalent is
`
`10
`
`employed the yield of product is lowered and transformation of
`
`disulphide tends to be incomplete, whilst an excess of sulphur dioxide
`
`leads to degradation during evaporation of the solvent in the work-up.
`
`The amount of formate salt used is generally 4-6 molar
`
`equivalents relative to the disulphide of formula (III), preferably about
`
`15
`
`4.5-5.5 molar equivalents. A joint reduction in the amount of sulphur
`
`dioxide and formate salt can be made until the ratio of sulphur
`
`dioxide:disulphide is from about 1.2: 1 and the ratio of formate
`
`salt:disulphide is from about 4.5: 1.
`
`By using the process according to the above description the
`
`20
`
`pressure in the vessel is generally easily maintained in the safe range of
`
`3-6 bars.
`
`According to a further feature of the present invention there is
`
`provided a process (C) for the preparation of a disulphide of formula
`
`25
`
`(III) as defined above; which comprises adding sulphur monochloride,
`
`(S2Cl2) to a solution in an organic solvent of a compound of formula
`
`(IV):
`
`

`

`WO 01/30760
`
`- 13 -
`
`PCT /EP99/08687
`
`(IV)
`
`wherein R 1, R 2 and W are as herein before defined.
`
`The reaction is preferably conducted in a solvent selected from
`
`5
`
`toluene, dichloromethane or dichloroethane, or aliphatic or aromatic
`
`nitriles such as acetonitrile, propionitrile, methylglutaronitrile and
`
`benzonitrile; or mixtures thereof, optionally as a mixture with
`
`chlorobenzene (which is present when a chlorobenzene solution of the
`
`compound of formula (IV) obtained from the previous reaction stage is
`
`10
`
`used). Acetonitrile optionally in the presence of chlorobenzene is the
`
`preferred solvent for the reaction. The reaction is very sensitive to the
`
`effect of solvent and whilst it may be convenient to use toluene since a
`
`toluene solution of (IV) may be available from the previous reaction
`
`stage, a significant amount of the monosulphide (V):
`
`NC~S
`
`CN
`
`C)--NH2 H2N
`
`R2
`
`R2
`
`~
`
`15
`
`(V)
`
`

`

`WO 01/30760
`
`- 14 -
`
`PCT /EP99/08687
`
`is generally formed as a by product when these conditions are
`
`employed. Moreover the product is very slow to filter when toluene is
`
`employed, although an acceptable filtration rate may be obtained by
`
`addition of a proportion of acetonitrile to the toluene solution. When the
`
`5
`
`reaction is performed in the preferred solvent acetonitrile, the amount of
`
`monosulphide impurity (V) is reduced and the rate of filtration of the
`
`product (III) is satisfactory.
`
`The sulphur monochloride used in the process is generally from
`
`99.4-99.9% w/w pure.
`
`10
`
`The quality of solvent used may affect the reaction since the
`
`presence of certain impurities can influence the yield of product (with
`
`the formation of (V) as by-product). Thus when acetonitrile is employed
`
`as solvent it is preferred that the content of water is <1 OOOppm, the
`
`content of ethanol is <1500ppm and the content of ammonia is
`
`15
`
`<1 OOppm. It is also preferable to avoid the presence of even low
`
`amounts of acetone or N,N-dimethylformamide in the solvent mixture
`
`since, for example, the presence of about 1 OOppm of acetone in
`
`dichloromethane may have a negative impact on the yield of product.
`
`The order of addition of the reagents is an important feature of the
`
`20
`
`reaction. Thus it is very important to add the sulphur monochloride to a
`
`solution of compound of formula (IV) (rather than the reverse). A rapid
`
`addition time for the sulphur monochloride is a preferred feature of the
`
`process. Thus if the sulphur monochloride is added during 1 minute, the
`
`disulphide (III) crystallises about 15 seconds after the completion of the
`
`25
`
`addition (and all of the compound of formula (IV) has been consumed).
`
`When added over a 15 minute period the disulphide (III) crystallises in
`
`mid-addition and as a result the disulphide (III) co-crystallises with the
`
`remaining compound of formula (IV). Washing the impure product so
`
`obtained with a large excess of acetonitrile does not effect removal of
`
`30
`
`the unreacted compound of formula (IV). The time for the sulphur
`
`

`

`WO 01/30760
`
`- 15 -
`
`PCT/EP99/08687
`
`monochloride addition is preferably from 1-10 minutes, more preferably
`
`about 1-5 minutes.
`
`The reaction temperature of the mixture at the start of the addition
`
`of the sulphur monochloride is preferably from 5 to 25°C, more
`
`5
`
`preferably from about 10 to 20°C . If the temperature is at 30°C at the
`
`start of the addition, a lower yield is obtained due to the formation of
`
`trisulphide and tetrasulphide by-products. As the reaction is exothermic
`
`the temperature increases during the reaction and is preferably held at
`
`from about 20 to 35°C.
`
`10
`
`The molar ratio of compound of formula (IV): sulphur
`
`monochloride used in the reaction is generally from 2: 1 to 2: 1.06, and
`
`preferably from about 2:1 to about 2:1.04. Using a larger excess of
`
`sulphur monochloride results in the formation of an increased amount of
`
`the monosulphide by-product (V). If a lower proportion of sulphur
`
`15
`
`monochloride is used the reaction does not proceed to completion.
`
`A further feature of the process of the invention is the method used
`
`for the purification of the product. Thus the reaction mixture containing
`
`the disulphide of formula (III) is first degassed to remove hydrogen
`
`chloride, generally by heating at about 40°C under reduced pressure,
`
`20
`
`generally at about 0.2 atmosphere. It is then heated at about 80°C for
`
`about 1 hour at atmospheric pressure. After cooling to about 30°C, a
`
`weak base (generally ammonia) is added to neutralise any remaining
`
`hydrogen chloride and obtain a pH about 6.5-7. The mixture is then
`
`cooled to about 5°C and the product isolated by filtration. This
`
`25
`
`procedure enables the disulphide of formula (I) to be obtained in high
`
`yield and purity by a simple procedure convenient for large scale
`
`operations.
`
`In formulae (I), (II), (III) and (IV), preferred values of the
`
`symbols are as follows:-
`
`30
`
`R 1 represents haloalkyl (preferably trifluoromethyl), haloalkoxy
`
`(preferably trifluoromethoxy) or -SF 5;
`
`

`

`WO 01/30760
`
`- 16 -
`
`PCT /EP99/08687
`
`W represents -CR 3;
`
`R2 and R3 represent halogen (preferably chlorine).
`
`A particularly preferred compound of formula (I) is:
`
`5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-
`
`5
`
`trifluoromethylsulphinylpyrazole.
`
`A particularly preferred compound of formula (II) is:
`
`5-amino-1-(2,6-dichloro-4-trifluoromethy I phenyl )-3-cyano-4-
`
`trifluoromethylthiopyrazole.
`
`A particularly preferred compound of formula (III) is:
`
`10
`
`5-amino-1-(2, 6-dichloro-4-trifl uoromethy lpheny I )-3-
`
`cyanopyrazol-4-y l disulphide.
`
`Compounds of formula (II), (III) and (IV) are known.
`
`According to a further feature of the present invention the
`
`15
`
`processes (A), (B) and (C) can be combined to prepare a compound of
`
`formula (I) from a compound of formula (IV).
`
`The above processes (A), (B) and (C) when combined together
`
`form a particularly useful and efficient method for the preparation of
`
`Fipronil.
`
`20
`
`The following non-limiting examples illustrate the
`
`invention.
`
`Example 1
`
`Preparation of 5-amino-1-(2,6-dichloro-4-
`
`25
`
`trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulphinylpyrazole
`
`Trifluoroacetic acid (1660g, 14.Smol) was added to a stirred
`
`solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-
`
`4-trifluoromethylthiopyrazole ( 436g, l.03mol) and boric acid (5g,
`
`0.08mol) in a glass reactor at 12°c. Hydrogen peroxide (131.5g of
`
`30
`
`35%w/w, l.35mol) was added over 2 hours whilst maintaining the
`
`temperature at 12°c, and the mixture kept at this temperature for a
`
`

`

`WO 01/30760
`
`- 17 -
`
`PCT /EP99/08687
`
`further 4-5 hours. When the transformation had reached 97-98%, or the
`
`amount of unwanted 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-
`
`3-cyano-4-trifluoromethylsulphonylpyrazole reached 2% (as judged by
`
`HPLC analysis), sulphur dioxide was added to quench any remaining
`
`5
`
`hydrogen peroxide, and the mixture maintained at 1 O-l 8°C for 0.5 hour.
`
`Chlorobenzene (370g) was added and the mixture placed under reduced
`
`pressure (from 0.17 to 0.04 atmosphere) and heated to 47-50°C with
`
`azeotropic distillation. A homogeneous fraction containing recovered
`
`trifluoroacetic acid was obtained. During the distillation additional
`
`10
`
`chlorobenzene (1625g) was added continuously in order to maintain a
`
`constant volume. At the end of the azeotropic distillation the reactor
`
`contents were maintained at 47-50°C under reduced pressure (0.04
`
`atmosphere), and a homogeneous fraction of chlorobenzene distilled.
`
`After release of the vacuum, the reactor was heated to 40°C, ethanol
`
`15
`
`(207g) and chlorobenzene (235g) added, and the mixture heated to 80°C
`
`with stirring to give a solution. On cooling to 40°C the product
`
`crystallised. The reactor was placed under progressively reduced
`
`pressure (from 0.13 to 0.03 atmosphere) and the ethanol distilled at
`
`40°c. The vacuum was released and the mixture cooled to 5°C during
`
`20
`
`3.5 hours and left for a further 0.5 hour. The product was filtered off,
`
`washed with cold chlorobenzene, then with cold aqueous ethanol, then
`
`with water, and dried in vacuo at 135°C to give the title compound
`
`( 407 .5g), in a typical yield of 89% and purity of 95.5%.
`
`Example 2
`
`25
`
`Preparation of 5-amino-3-cyano-1-(2,6-dichloro-4-
`
`trifluoromethylphenyl)-4-trifluoromethylthiopyrazole
`
`Sodium formate (76g, 1.1 lmol) was added to a mixture of 5-
`
`amino-1-(2,6-dichloro-4-trifl uoromethy l phenyl )-3-cyanopyrazo 1-4-y 1
`
`disulphide (157.5g, 0.223mol)