111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US008304559B2
`
`(12) United States Patent
`Pastorio et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,304,559 B2
`Nov. 6, 2012
`
`(54) METHOD FOR THE SYNTHESIS OF
`5-AMIN0-1-PHE!'.'YL-3-CYAN0-4-
`TRIFLUOROMETHYL SULFINYL
`
`(75)
`
`Inventors: Andrea Pastorio, Mantova (IT); Paolo
`Betti, Brescia (IT)
`
`(73) Assignee: Finchimica, S.p.A., Brescia (IT)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.:
`
`13/498,245
`
`(22) PCTFiled:
`
`May 26,2011
`
`(86) PCTNo.:
`
`PCTIIB2011/052304
`
`§ 371 (c)(l),
`(2), ( 4) Date: Mar. 26, 2012
`
`(87) PCT Pub. No.: W02012/004692
`PCT Pub. Date: .Jan. 12, 21l12
`
`(65)
`
`Prior Publication Data
`
`US 2012/0184753 AI
`
`Jul. 19, 2012
`
`(30)
`
`Foreign Application Priority Data
`
`Jul. 7, 2010
`
`(IT) .............................. BS2010A0118
`
`(51)
`
`Int.CI.
`(2006.01)
`C07D 231110
`(52) U.S. Cl ................................... 548/367.4; 548/373.1
`(58) Field of Classification Search ............... 548/367.4,
`548/373.1
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`W0-01/30760 AI
`5/2001
`WO
`WO W0-2007/122440 AI
`11/2007
`WO W0-2012/007938 AI
`1/2012
`OTHER PUBLICATIONS
`
`International Search Report and Written Opinion for PCT!IB20lli
`052304, mailed Sep. 26, 2011; ISAIEP.
`Primary Examiner- Joseph K. McKane
`Samantha Shterengarts
`Assistant Examiner
`(74) Attorney, Agent, or Firm- Harness, Dickey & Pierce,
`PLC
`ABSTRACT
`(57)
`The present invention relates to a method for the preparation
`of the 5-amino-1-phenyl-3-cyano-4-trifluoromethyl sulfinyl
`pyrazole having the described general formula (I), particu(cid:173)
`larly preferred for the synthesis ofFipronil, through oxidation
`of a compound having the general fommla (II) as follows:
`
`(II)
`
`wherein R 1 and R2 are independently hydrogen or halogen,
`and wherein the oxidizing agent is dichloroperacetic acid.
`15 Claims, No Drawings
`
`FINCHIMICA EXHIBIT 2001
`ADAMA MAKHTESHIM v. FINCH/MICA
`CASE IPR2016-00577
`
`

`
`US 8,304,559 B2
`
`1
`METHOD FOR THE SYNTHESIS OF
`5-AMIN0-1-PHENYL-3-CYAN0-4-
`TRIFLUOROMETHYL SULFINYL
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a 371 U.S. National Stage of Interna(cid:173)
`tional Application No. PCT/IB2011/052304, filed May 26,
`2011, and claims priority to Italian patent application No.
`BS2010A000118, filed Jul. 7, 2010, the disclosures of which
`are herein incorporated by reference in their entirety.
`
`FIELD OF INVENTION
`
`The present invention relates to a method for the synthesis
`of 5-amino-1-phenyl-3-cyano-4-trifluoromethyl
`sulfinyl
`pyrazole having the following general formula (I), particu(cid:173)
`larly preferred for the synthesis of Fipronil.
`
`BACKGROUND OF INVENTION
`
`The synthesis reaction of the compound having the general
`formula (I):
`
`(I)
`
`through oxidation of a compound having the general formula
`(II) has been described in a variety of documents:
`
`(II)
`
`For example, patent EP 0295117 B1 shows a synthesis
`method using a 3-chlorobenzoic derivative.
`Such synthesis method has evident disadvantages both in
`terms of yield and of costs, the latter related to the impossi(cid:173)
`bility of re-using the oxidising agent.
`A method alternative to the previous one was proposed in
`document WO 01/030760 A1, where the oxidation step is
`
`5
`
`25
`
`30
`
`2
`conducted in the presence oftrifluoroperacetic acid (TFPA),
`obtained from trifluoroacetic acid (TFA) in the presence of
`hydrogen peroxide and boric acid.
`However, also this method is unsatisfactory given the fol-
`lowing drawbacks: first of all the trifluoroacetic acid is an
`extremely expensive reagent which, as a consequence, nega(cid:173)
`tively affects the sales price of the product therewith obtained.
`Moreover, during the reaction, hydrogen fluoride is
`released which eats into the vitreous coatings used in indus-
`1 ° trial reactors despite operating at temperatures close to ambi(cid:173)
`ent temperature. To this purpose, document WO 01/030760
`A1 suggests using a corrosion inhibitor which nonetheless
`entails an additional expense to the overall cost of the process.
`15 Moreover, the use of a corrosion inhibitor would not be
`adequate to protect all the equipment needed for the recovery
`process of TFA from the corrosive effect of hydrogen fluo(cid:173)
`ride. The TFA recovery and subsequent reutilisation is a nec(cid:173)
`essary operation dictated by the high cost ofTFA compared to
`20 common oxidants.
`The drawbacks ofWO 01/030760A1 have been overcome
`thanks to the teaching of document WO 2007/122440 A1
`where, instead ofTFPA, oxidation is conducted in the pres(cid:173)
`ence oftrichloroperacetic acid (TCPA).
`According to the description, TCPA is the effective oxid-
`ising species and is formed in situ by the reaction of an
`oxidising agent with trichloroacetic acid (TCA).
`As well as acting as an oxygen acceptor, TCA should also
`conveniently act as a reaction solvent.
`However, at the temperature at which the reaction takes
`place, TCA is solid (melting point=54-58° C.) so that, for its
`use as a reaction solvent, a second solvent needs to be added
`to the TCA to lower its melting point to a temperature com-
`35 patible with the reaction temperature.
`The solvents suitable for this purpose are, among others,
`dichloroacetic (DCA) and monochloroacetic (MCA) acids.
`In particular, a mixture composed of TCA (70-80%) and
`DCA (30-20%), characterised by a melting point of 15°
`40 C.-30° C., has been shown as suitable for conducting such
`oxidation reaction where, as mentioned above, the sole pur(cid:173)
`pose of the DCA is to depress TCA's melting point.
`However, also this method has the drawback that the oxi(cid:173)
`dant species TCA only allows to operate in a temperature
`45 range such as to favour the formation of a by-product having
`the general formula (III), described below, which has a two(cid:173)
`fold disadvantage.
`First of all, the reaction forming the by-product consumes
`useful product to the detriment of the yield.
`In addition, the by-product having the general formula (III)
`is difficult to be separated from the compound having the
`general formula (I) given its low solubility in common
`organic solvents thereby requiring an expensive purification
`process adding to the cost.
`A further disadvantageous aspect is that the oxidant species
`TCA can only be used at temperatures compatible with the
`oxidation reaction of the compound having the general for(cid:173)
`mula (II) to the compound having the general formula (I) if
`the reaction is conducted in the presence of a species acting as
`60 a solvent both for the reagent having the general formula (II)
`and for the oxidant TCA itself, making both the recovery
`operation of the product having the general formula (I) and
`the recovery of the oxidant TCA more complicated.
`In addition, it is realistic to believe that, in the teaching of
`65 the prior art document WO 2007/122440 A1, the dichloro(cid:173)
`acetic acid does not transform into dichloroperacetic acid by
`means of the hydrogen peroxide or other oxidant, because the
`
`50
`
`55
`
`

`
`US 8,304,559 B2
`
`4
`wherein R 1 and R2 are independently hydrogen or halogen;
`through oxidation of a compound having the general formula
`(II) in the presence of dichloroacetic acid and of an oxidising
`agent:
`
`(II)
`
`3
`species TCA, present in significant molar excess of the oxi(cid:173)
`dant and more reactive towards the oxidants, captures all the
`available oxygen.
`The present invention therefore sets out to provide a new
`method for the preparation of the compound having the gen(cid:173)
`eral formula (I) using an economically advantageous oxida(cid:173)
`tion method convenient to implement in industrial applica(cid:173)
`tions.
`
`SUMMARY OF INVENTION
`
`10
`
`The present invention relates to a method for the prepara(cid:173)
`tion of the 5-amino-1-phenyl-3-cyano-4-trifluoromethyl 15
`sulfinyl pyrazole having the described general formula (I),
`particularly preferred for the synthesis of Fipronil, through
`oxidation of a compound having the general formula (II) as
`follows:
`
`20
`
`(II)
`
`wherein R 1 and R2 are independently hydrogen or halogen,
`and wherein the oxidising agent can be dichloroperacetic
`acid.
`
`DETAILED DESCRIPTION
`
`The above objective is achieved by a method for the prepa-
`ration of the compound having the following general formula
`(I):
`
`(I)
`
`25 wherein R 1 and R2 are defined as above.
`As a result, innovatively, the chemical species causing
`oxidation of the compound having the general formula (II) to
`a compound having the general formula (I) is preferably
`dichloroperacetic acid, formed by oxidation of DCA acid
`30 through the oxidising agent.
`The use of dichloroperacetic acid as an oxidant has never
`been described in literature. Surprisingly it was found that
`DCA, in the presence of an oxidant species such as hydrogen
`35 peroxide, peroxide or similar, is also itself transformed at low
`temperatures into the corresponding dichloroperacetic acid
`and that this species is an excellent oxidant of the compound
`having the general formula (II).
`In other words, the aforesaid oxidation is conducted in the
`40 absence of trichloroacetic and/or trichloroperacetic acid, so
`that the process of the present invention does not require prior
`solubilisation of the oxidant.
`Preferably, R 1 and R2 are chlorine or bromine.
`Even more preferably, the compound having the general
`formula (I) is 5-amino-1-(2,6-dichloro-4-trifluoromethyl(cid:173)
`pheny 1)-4-trifluorometansulfiny 1-1 H-pyrazole-3-carbonitril,
`commercially known by the name ofFipronil (CAS Registry
`No. 120068-37-3).
`Preferably, the production of the dichloroperacetic acid
`used in the oxidation of the compound having the general
`formula (II) is performed in situ, by means of the reaction
`with the oxidising agent.
`As a result, according to such variation, the dichloroacetic
`acid (DCA) performs, after its partial oxidation in dichlorop(cid:173)
`eracetic acid, the dual function of transferring oxygen to the
`compound having the general formula (II), and acting as a
`reaction solvent inasmuch as already liquid at the reaction
`60 conditions.
`The oxidation of the compound having the general formula
`(II) to a compound having the general formula (I) is a critical
`operation, in that the reagent used must be sufficiently ener-
`65 getic to quantitatively conduct such reaction, but without
`generating the (by-)product of subsequent oxidation having
`the general formula (III):
`
`55
`
`45
`
`50
`
`

`
`US 8,304,559 B2
`
`5
`
`(III)
`
`wherein R 1 and R2 are again defined as above.
`Dichloroperacetic acid proves to be an excellent oxidant
`for conducting the reaction with good yields and selectivity
`towards the compound having the general formula (I), with(cid:173)
`out however producing excessive quantities of the undesired
`product having the general formula (III).
`Such good selectivity is not just the result of the intrinsic
`features of the oxidant species dichloroperacetic acid, but
`also of the fact that such acid, being liquid, allows to conduct
`the reaction at a temperature lower than the methods of the
`prior art, without the use of solvents or melting point depres(cid:173)
`sants.
`The present invention therefore allows to operate in the
`absence of solvents at the same temperatures and to achieve
`excellent selectivity similar to the ones achieved with trifluo(cid:173)
`roperacetic acid but without having to use an extremely
`expensive solvent such as TFA and without having to add
`corrosion inhibitors which limit, without eliminating, the
`problem of corrosion of the enamels caused by the hydrogen
`fluoride generated by such solvent.
`According to the present invention, the oxidising agent
`used is selected from the group comprising benzoyl perox(cid:173)
`ides, sodium peroxides, t-butyl peroxides and/or hydrogen
`peroxides.
`Among the mentioned oxidising agents, the one that is
`particularly preferred to oxidise dichloroacetic acid is hydro(cid:173)
`gen peroxide, in that it can be used in the form of a concen(cid:173)
`trated aqueous solution.
`For example, the concentration of the aqueous solution of 45
`hydrogen peroxide is 50%-70% depending on commercial
`availability, but different concentrations may be just as
`acceptable.
`As regards the precautions suitable for limiting formation
`of compounds having the aforesaid general formula (III), also 50
`the quantity of oxidising agent is a critical variable.
`According to an advantageous embodiment, for each mole
`of compound having the general formula (I), 1.0-5.0 moles of
`oxidising agent are used, preferably 1.1-2.0 equivalents of
`such agent, more appropriately 1.5 equivalents for each mole. 55
`In addition, advantageously, for each mole of compound
`having the general formula (II), 1.5 kg-5 kg of dichloroacetic
`acid are used.
`According to a preferred embodiment variation, the tem(cid:173)
`perature at which oxidation takes place is between oo C. and 60
`35° C.
`Preferably, oxidation takes place at a temperature below
`20° C., advantageously at a temperature of0° C.-15° C., more
`appropriately at about so C.
`In fact, as mentioned at the beginning, synthesis methods 65
`of the prior art do not enable operation at sufficiently low
`temperatures to limit the formation of the peroxidation prod-
`
`10
`
`6
`uct having the general formula (III), which is generated start(cid:173)
`ing from temperatures near 20° C., in excessive quantities
`even at low conversion values of the product having the gen(cid:173)
`eral formula (II).
`According to the present invention it is preferable, acting
`on the reaction time or on the quantity of oxidising agent, to
`conduct the oxidation reaction up to a conversion level of the
`compound having the general formula (II) ofS0%-98%, pref-
`erably 90%-95%.
`the residual quantity of
`This way, advantageously,
`by-product having the general formula (III) is significantly
`reduced, and a further, complicated final purification of the
`product having the general formula (I), entailing inevitable
`losses in terms of yield and resulting waste production, is
`15 made substantially superfluous.
`According to one embodiment, the method of the present
`invention further comprises a step of recovering the non(cid:173)
`oxidised compound having the general formula (II).
`Preferably, the step of recovering comprises a step of dis-
`20 solving and subsequently recrystallising the compound hav(cid:173)
`ing the general formula (I) with one or more of the solvents
`selected from the group comprising toluene, xylenes, chlo(cid:173)
`robenzene, chlorinated aliphatic solvents and isopropanol.
`According to this embodiment, the unconverted compound
`25 having the general formula (II), as a result of its greater
`solubility than the oxidised forms offormulas (I) and (III) in
`some organic solvents, can be easily removed by means of a
`solvent and recovered for re-utilisation as a reagent. This way,
`during the oxidation process the product loss and the waste
`30 production is reduced to a minimum, becoming absolutely
`negligible.
`According to a particularly advantageous embodiment, the
`oxidation of the compound having the general formula (II)
`occurs in the presence of an acid catalyst, advantageously
`35 homogenous.
`This embodiment has proven particularly advantageous,
`especially in virtue of the large volumes involved in the reac(cid:173)
`tion, to achieve reasonable productivity of the plants.
`In fact, the aforesaid oxidation reaction of the compound of
`40 general formula (II) is conducted for relatively long periods,
`with large quantities of solvent to avoid the precipitation of
`the compounds having the general formula (II) and/or general
`formula (I), and furthermore at relatively low temperatures,
`such as below 20° C.
`Surprisingly it has been noted that the addition of small
`quantities of an acid catalyst, in particular sulphuric acid,
`greatly accelerates the oxidation reaction without any nega(cid:173)
`tive effect on selectivity, which in any case remains extremely
`high.
`Preferably, the acid catalyst is a strong mineral acid, advan(cid:173)
`tageously chosen from the group consisting in sulphuric acid,
`methansulphonic acid, hydrochloric acid, nitric acid and their
`mixtures.
`According to an embodiment, the ratio in moles of the
`compound having the general formula (II) and the acid cata(cid:173)
`lyst is between 0.3 and 1.5, appropriately between 0.5 and 0.9
`and, advantageously, is substantially equal to 0.7.
`The purpose of the present invention will now be illustrated
`on the basis of several, non-limiting examples.
`
`EXAMPLE 1
`
`Synthesis ofFipronil
`
`In a glass reactor, 421 grams (1.0 moles) of 5-amino-1-(2,
`6-dichloro-4-trifluoromethyl-phenyl)-4-trifluorometan-sul(cid:173)
`fanil-1H-pyrazole-3-carbonitrile hereafter "sulphide") are
`
`

`
`US 8,304,559 B2
`
`7
`dissolved in 2300 grams of dichloroacetic acid (DCA). The
`solution obtained is stirred and kept at 20° C. after which 102
`grams of hydrogen peroxide in an aqueous solution 50% w/w
`(1.5 moles) are added.
`The reaction is monitored using HPLC analysis until it
`reaches a conversion level of more than 95% of the reagent
`sulphide, after which the reaction mixture is diluted with 4
`liters of water until the product has precipitated entirely.
`The solid thus obtained is filtered, washed with water and
`dried to obtain 420 grams of product with a purity of93.5%. 10
`
`8
`previous example 1. The reaction conducted at 20° C. accord(cid:173)
`ing to the examples shown in the earlier document WO 2007 I
`122440 A1, mentioned at the beginning, lasts about 8 hours.
`Innovatively, the method of the present invention is con(cid:173)
`ducted in the presence of an oxidising agent and of dichloro(cid:173)
`acetic acid making a plurality of operations superfluous, for
`example dissolution, otherwise essential in the known meth(cid:173)
`ods.
`Advantageously, the method of the present invention
`allows to achieve higher yields compared to the methods of
`the prior art, in that the reaction takes place with improved
`selectivity thereby preventing the consumption of useful
`product in parasite reactions.
`
`15
`
`EXAMPLE2
`
`Synthesis of Fipronil with Subsequent Recovery of
`Unconverted Reagent Compound Having the
`General Formula (II)
`
`Advantageously, the method of the present invention, once
`the excess of unconverted reagent (II) has been easily recov(cid:173)
`ered, makes subsequent purification of the compound having
`the general formula (I) superfluous, which as well as being
`20 burdensome in itself is economically disadvantageous.
`Advantageously, the use of the oxidising agent of the
`present invention does not require the use of solvents for the
`reaction, making the entire process much simpler and eco-
`25 nomically advantageous in industrial applications.
`In fact, according to a further advantageous aspect, the cost
`of such oxidant is lower than the cost of the oxidants tradi(cid:173)
`tionally used.
`Advantageously, the function performed by the DCA in the
`method of the present invention enables economies in terms
`of costs of the reagents, and simplification of the plant for
`implementing the teaching.
`Advantageously, the process of the present invention
`35 makes the use of corrosion inhibitors superfluous and allows
`to drastically increase the useful life of the equipment used.
`It was, in fact, observation of the premature corrosion of the
`plants which urged the authors of the present invention to look
`40 for an oxidant agent alternative to the oxidants traditionally
`used.
`
`In a glass reactor 421 grams (1.0 mole) of 5-amino-1-(2,
`6-dichloro-4-trifluoromethy !-phenyl )-4-trifluorometan -sul(cid:173)
`fanil-1H-pyrazole-3-carbonitrile (hereafter "sulphide") are
`dissolved in 2300 grams of dichloroacetic acid (DCA). The
`solution obtained is stirred and kept at 20° C., after which 102
`grams of hydrogen peroxide in an aqueous solution 50% w/w
`(1.5 moles) are added.
`The reaction is monitored using HPLC analysis until it
`reaches a conversion level of92% of the reagent sulphide, so
`as to limit the formation of the by-product (III) difficult to
`remove by means of re-crystallisation. When the desired con(cid:173)
`version level has been reached the reaction mixture is diluted 30
`with 4 liters of water until the product has precipitated
`entirely.
`The solid thus obtained is filtered, washed with water and
`dried.
`After drying the raw product is dissolved while hot in
`chi oro benzene solvent andre-crystallised by cooling to a low
`temperature. The solid thus obtained is composed ofFipronil
`with a purity of over 95%.
`The filtrate, containing only sulphide and small quantities
`of Fipronil, is deprived of the solvent chlorobenzene and
`added as a reagent to a subsequent oxidation reaction.
`
`EXAMPLE3
`
`45
`
`Synthesis ofFipronil with Addition of Sulphuric
`Acid and Comparison With Example 1 and with WO
`2007/122440 A1
`
`In a glass reactor 421 grams (1.0 mole) of 5-amino-1-(2, 50
`6-dichloro-4-trifluoromethy !-phenyl )-4-trifluorometan -sul(cid:173)
`fanil-1H-pyrazole-3-carbonitrile (hereafter "sulphide") are
`dissolved in 2300 grams of dichloroacetic acid (DCA). The
`solution obtained is stirred and kept at 20° C. and subse(cid:173)
`quently 102 grams ofhydrogen peroxide in aqueous solution 55
`50% w/w (1.5 moles) and 70 grams (0.7 moles) ofH2 S04 are
`added.
`The reaction is conducted at a temperature of 5 to 1 oo C.
`and monitored by means of HPLC analysis until it reaches a
`conversion level of over 95% of the reagent sulphide, after
`which the reaction mixture is diluted with 4 liters of water
`until the product has precipitated entirely.
`The solid thus obtained is filtered, washed with water and
`dried to obtain 420 grams of a product with a titre of 93 .5%. 65
`According to this example, the desired conversion level is
`reached in about 3 hours compared to the 20 hours of the
`
`60
`
`As a result, the aforesaid advantage is twofold in that it
`derives both from the non-use of a corrosion inhibitor and
`from the increased useful life of the equipment.
`Advantageously, the addition of an acid catalyst makes it
`possible to considerably reduce reaction times while main(cid:173)
`taining a high degree of selectivity of oxidation of the com(cid:173)
`pound having the general formula (II).
`Even if not previously specified, a person skilled in the art
`may, using the expertise typical of the sector, vary or replace
`some of the aspects described above with other technically
`equivalent ones.
`For example, dichloroperacetic acid may be prepared sepa(cid:173)
`rately from the place where oxidation of the compound hav(cid:173)
`ing the general formula (II) takes place, for subsequent addi(cid:173)
`tion to the latter.
`Moreover, one embodiment envisages that the peroxides
`illustrated earlier may be replaced or used in conjunction with
`a peracid and/or a persulphate.
`These variations or replacements also fall within the scope
`of protection defined by the following claims.
`In addition, any alternative shown in relation to a particular
`embodiment may be realised independently of the other
`variations described.
`
`

`
`US 8,304,559 B2
`
`9
`
`The invention claimed is:
`1. A method for the preparation of the compound having
`the following general formula (I):
`
`(I)
`
`wherein R 1 and R2 are independently hydrogen or halogen;
`through oxidation of a compound having the general formula
`(II) in the presence of dichloroacetic acid and of an oxidising
`agent:
`
`(II)
`
`wherein R 1 and R2 are defined as above, where the oxidising
`agent is selected from the group comprising benzoyl perox(cid:173)
`ides, sodium peroxides, t-butyl peroxides and/or hydrogen
`peroxide, and wherein the oxidation is conducted in the
`absence of trichloroacetic and/or trichloroperacetic acid.
`2. The method according to claim 1, wherein R 1 and R2 are
`chlorine or bromine.
`
`10
`
`25
`
`10
`3. The method according to claim 1, wherein the compound
`having the general formula (I) is 5-amino-1-(2,6-dichloro-4-
`trifluoromethy 1-pheny 1)-4-trifluorometansulfiny 1-1 H-pyra(cid:173)
`zole-3-carbonitrile.
`4. The method according to claim 1, wherein the dichloro(cid:173)
`acetic acid is oxidised to dichloroperacetic acid through the
`oxidising agent.
`5. The method according to claim 4, wherein oxidation of
`the dichloroacetic acid takes place in situ.
`6. The method according to claim 1, wherein,for each mole
`of compound having the general formula (I), 1.0-5.0 moles of
`oxidising agent are used.
`7. The method according to claim 1, wherein,for each mole
`of compound having the general formula (I), 1.1-2.0 equiva-
`15 Ients of oxidising agent are used.
`8. The method according to claim 1, wherein,foreachmole
`of compound having the general formula (II), 1.5 kg to 5 kg of
`dichloroacetic acid are used.
`9. The method according to claim 1, wherein the tempera-
`20 ture at which oxidation takes place is between oo C. and 35°
`C.
`10. The method according claim 1, wherein the tempera(cid:173)
`ture at which oxidation takes place is between oo C.-20° C.
`and, preferably is 5° C.
`11. The method according to claim 1, further comprising a
`step of recovering the non-oxidised compound having the
`general formula (II).
`12. The method according to claim 11, wherein the step of
`recovering comprises a step of dissolving and subsequently
`30 recrystallising the compound having the general formula (I)
`with one or more of the solvents selected from the group
`comprising toluene, xylene, chlorobenzene, chlorinated ali(cid:173)
`phatic solvents and isopropanol.
`13. The method according to claim 1, wherein the oxida-
`35 tion of the compound having the general formula (II) occurs
`in the presence of an acid catalyst.
`14. The method according to claim 13, wherein the acid
`catalyst is a strong mineral acid selected from the group
`consisting in sulphuric acid, methanesulphonic acid, hydro-
`40 chloric acid, nitric acid and their mixtures.
`15. The method according to claim 13, wherein the ratio in
`moles between the compound of general formula (II) and the
`acid catalyst is 0.3 to 1.5, and is preferably substantially equal
`to 0.7.
`
`45
`
`* * * * *