Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
  • C07D277/36—Sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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

Definitions

• Fluensulfone a powerful nematicide belonging to the class of heterocyclic fluoroalkenyl sulfones, has the following chemical structure :
• Fluensulfone [chemical name: 5-chloro-2- [ (3, 4, 4-trifluoro-3- buten-l-yl) sulfonyl] thiazole] is commercially available on the market as an emulsifiable concentrate formulation. It was first reported in EP 1200418, Example 3, where it was prepared via the two-step synthesis depicted below:
• the mixed haloalkene of Formula V serves an important role in the formation of active heterocyclic fluoroalkenyl sulfones, because alkylation of the heterocyclic thiol (IV) with the haloalkene (V) directly incorporates the essential fluoroalkenyl functionality into the structure of the compound. For this reason, preparation of heterocyclic fluoroalkenyl sulfones reported in the prior art is often based on the mixed haloalkene of Formula V.
• heterocyclic fluoroalkenyl sulfones bearing halogen atoms on the heterocyclic ring such as Fluensulfone
• the alkylation of the heterocyclic thiol (IV) is achieved with the aid of a mixed haloalkane in lieu of the mixed haloalkene (V) , for example, with 1 , 4-dibromo-2-chloro-l , 1 , 2-trifluorobutane (BrCH2-CH2-CFCl-CF2Br) to form the corresponding sulfide ⁇ 3 ⁇ 4
• Route 1 and Route 2 are illustrated by the reaction scheme depicted below (where the aforementioned 1 4 ⁇ Diforomo ⁇ 2 ⁇ chioro-l , 1 , 2- trifluorobutane was used in the alkylation step of the 2- mercaptothiazole starting material) , alongside Route 3 which failed on the chlorination step;
• the synthetic pathway aecordinq to Route i is preferred; it is shown below, where the arrows 1, 2, 3 correspond to the alkylation (coupling) , chlorination and deha1ogenation (reduction) steps, respectively.
• the most preferred key intermediates, through which the synthesis of Route 1 passes, are named Intermediate &1 , SI and Cl, respectively:
• the solvent of choice meets two major requirements: (i) good solubilization capacity for 2-mercaptotbiazole, say, not less than 10 wt% ; and ( ii ) sufficient inertness to chlorination.
• tests that can serve for solvent selection for use in a. telescopic process are provided.
• the process of the invention is not limited to a telescopic design; the process may be carried out with the isolation of one or more intermediates, their purification and exchange of solvents between the process steps.
• synthesis of 2-mercaptothiazole (IV) and the alkylation step (1) can be telescoped, followed by solvent exchange before the chlorination step (2).
• the invention is primarily directed to a process for preparing heterocyclic fluoroalkenyl sulfones and their thioether and sulfoxide precursors of the formula:
• the process comprises the steps of:
• R-SH alkylating thiol R-SH, wherein R is a heterocyclic five- membered aromatic ring, in particular sulfur-containing ring selected from the group consisting of thiophene, thiazole and thiadiazole, most preferably thiazole, such that R-SH is a thiol of the formula:
• a fluorinated haloalkane of the formula L- (CH 2 ) 2 -CFX 1 -CF 2 X 2 in a first organic solvent wherein L is a leaving group capable of displacement by a thiol group, for example, L is halide such as bromide or iodide; and X 1 and X 2 are halogen atoms which may be the same or different, e.g. chlorine, bromine or iodine, to form a thioether having the formula: R-S - (CH 2 ) 2-CFX 1 -CF 2 X 2 (Intermediate A)
• the preferred variant of the process comprises:
• R is thiazole
• X 1 is Cl
• X 2 is Br
• the starting materials that are needed for the alkylation step (1) are commercially available or can be prepared by known procedures .
• the starting material L- (CH2) 2-CFX 1 -CF2X 2 where the leaving group L is halide (Hal) is named herein "fluorinated haloalkyl halide”; when X 1 and X 2 are different from one another, the starting material is named “mixed fluorinated haloalkyl halide", such as 1 , 4-dibromo-2-chloro-l , 1 , 2-trifluorobutane (Hal is Br, X 1 is Cl and X 2 is Br) .
• Another useful technique consists of reacting ethylene with CF2X 1 -CFX 2 X 3 , as described by Tarrant et al . [The Journal of Organic Chemistry 34(4), p. 864-869 (1969) ] .
• the other starting material that participates in the alkylation step the thiol (IV), namely, 2-mercaptothiazole, can be obtained by a cyclization reaction as shown in US 2,603,647 and US 2,603,648, that is, reacting thiocyano acetaldehyde with hydrogen sulfide or with thiourea.
• a preferred approach to the synthesis of the thiol (IV) that fits well into the contemplated telescopic design, and hence forms another aspect of the invention includes the step of recovering a worked-up solution from the synthesis of thiol (IV), wherein the thiol (IV) is dissolved in a water- immiscible organic solvent, such that the worked-up solution can be carried to the alkylation step without isolation of the thiol ( IV) .
• 2-mercaptothiazole is obtained by a ring closure reaction of chloroacetaldehyde with a dithiocarbamate salt, that takes place in an acidic aqueous medium, generally at room temperature, to form 4-hydroxy-2-thiazolidinethione, an isomer thereof or a mixture of isomers, followed by a dehydration reaction that is performed at elevated temperature, wherein 4-hydroxy-2-thiazolidinethione undergoes dehydration in the aqueous medium, followed by extraction of the so-formed 2-mercaptothiazole with water-immiscible organic solvent, whereby a worked-up organic solution consisting of the 2-mercaptothiazole dissolved in the water-immiscible organic solvent is recovered.
• 2-mercaptothiazole is obtained by reacting chloroacetaldehyde with a dithiocarbamate salt [2HNC ( S ) S1M + , wherein M + is preferably ammonium; the ammonium salt is abbreviated herein ADTC; but sodium and potassium salts can also be used] in an acidic aqueous environment (the acidic environment is supplied by inorganic or organic acid) to form an aqueous suspension of 4-hydroxy-2-thiazolidinethione, heating the reaction mixture, allowing the reaction to reach completion, extracting the reaction mixture with water- immiscible organic solvent, separating the reaction mass into organic and aqueous phases, and either isolating (and optionally purifying) 2-mercaptothiazole from the organic phase, or carrying the 2-mercaptothiazole-containing worked-up organic solution to the alkylation step.
• a dithiocarbamate salt [2HNC ( S ) S1M + , wherein M + is preferably ammonium; the
• an aqueous chloroacetaldehyde solution is acidified by the addition of a mineral acid such as hydrochloric acid or organic acid, following which an aqueous solution of the dithiocarbamate salt is gradually fed to the reaction vessel.
• the addition of the salt is carried out over a period of time, say, up to several hours; the addition is carried out at a temperature from 0 to 50°C, e.g., from 20- 35°C .
• the reaction mixture is heated to a temperature in the range from 35°C to the reflux temperature, e.g., from 50 to 90°C.
• the work-up of the reaction mixture includes extraction of 2-mercaptothiazole .
• the choice of the organic solvent for the extraction of 2-mercaptothiazole determines whether the process would fit into a telescopic design. That is, one may choose a solvent that is well-suited for the 2- mercaptothiazole workup step and the successive chlorination step.
• the factors influencing the choice of solvent are water- immiscibility, high solubilization capacity for 2- mercaptothiazole and sufficiently inertness to chlorination reagents, as now described in detail.
• water immiscible organic solvent is meant a solvent with solubility in water at room temperature of less than 5.0 g/100 ml, preferably less than 3.0 g/100 ml, more preferably less than 1.0 g/100 ml, and even more preferably less than 0.1 g/100 ml.
• solvents with solubility are less than 0.05 g/100 ml.
• organic solvents may be considered for the extraction of 2-mercaptothiazole , such as alkyl-substituted benzene (e.g., toluene), halogenated aliphatic hydrocarbons (e.g., 1 , 2-dichloroethane ) , aliphatic nitriles (e.g.
• n- butyronitrile abbreviated NBN and iso-butyronitrile, abbreviated IBN
• ethers of the formula R1-0-R2 wherein R1 is aliphatic ring and R2 is straight or branched alkyl (such as cyclopentyl methyl ether, abbreviated CPME) , higher alcohols with not less than four carbon atoms in the molecule (e.g., isobutyl alcohol and n-pentanol) and esters such as CH3-COO-R3 wherein R3 is straight or branched alkyl with not less than three carbon atoms (e.g., isopropyl acetate, abbreviated IPAc) .
• 2-mercaptothiazole exhibits fairly low solubility in some of the aforementioned solvents; the reduced solubility may lead to the formation of an insoluble phase with the consequence that the resulting reaction mass does not lend itself to easy workup e.g., phase separation may be difficult to achieve (e.g., may require addition of extra solvent etc. and additional efforts) .
• suitable classes of solvents offering adequate level of 2-mercaptothiazole solubilization, specifically aliphatic nitriles (e.g.
• NBN and IBN ethers R1-0-R2 (e.g., CPME), higher alcohols (e.g., possessing not less than four carbon atoms in the molecule, such as isobutyl alcohol and 1-pentanol) and esters CH3-COO-R3 (e.g. IPAc) .
• R1-0-R2 e.g., CPME
• higher alcohols e.g., possessing not less than four carbon atoms in the molecule, such as isobutyl alcohol and 1-pentanol
• esters CH3-COO-R3 e.g. IPAc
• 2-mercaptothiazole can be isolated from the organic phase by conventional techniques, such as precipitation/crystallization and purified by recrystallization or chromatographic purification. The isolated 2-mercaptothiazole then undergoes the alkylation reaction. However, if the organic solvent used for the 2- mercaptothiazole formation reaction is sufficiently inert towards chlorination, then the 2-mercaptothiazole-containing worked-up solution may be carried directly to the next step (the alkylation step) and subsequently to the chlorination step .
• the preferred water-immiscible solvent for use in the process starting from 2-mercaptothiazole workup and advancing to the chlorination reaction, meets the following two requirements:
• the solubility of 2-mercaptothiazole in the first solvent at 25°C is not less than 5 wt%, preferably not less than 10 wt%, more preferably not less than 15 wt%, e.g., from 15 to 25 wt%;
• the solvent is sufficiently inert to at least one chlorinating agent that chlorinates aromatic rings (for example, Cl 2 , sulfuryl chloride, N-chlorosuccinimide and trichlorocyanuric acid) .
• chlorinating agent for example, Cl 2 , sulfuryl chloride, N-chlorosuccinimide and trichlorocyanuric acid
• a solvent can be tested to determine its stability against chlorination in the context of the present invention.
• a chlorination reagent under conditions required to achieve acceptable level of aromatic chlorination (e.g., temperature, time, catalyst and light irradiation)
• the amount of chlorinated derivates of the said solvent that is formed does not exceed 5% (preferably ⁇ 3%, more preferably ⁇ 1%)), relative to the initial amount of the solvent, as measured by appropriate method.
• Tests are provided below to illustrate if a solvent is sufficiently inert to sulfuryl chloride (e.g., upon stirring 8 ml solvent with 2 ml SO2CI2 for five hours at 40°C, the level of chlorinated derivates of said solvent measured by GC analysis is less than 5 Area%; and to chlorine gas (e.g., upon bubbling chlorine at a rate of 1 mL/ min for 2 hours through 20 ml solvent, followed by closing the reaction vessel and stirring the sample for eight hours at room temperature, the level of chlorinated derivatives of said solvent measured by GC analysis is less than 5 Area% .
• NBN, IBN and CPME emerged from the experimental work reported below as suitable solvents for the telescopic process.
• the alkylation reaction comprises combining the thiol R-SH, e.g., 2- mercaptothiazole with a fluorinated haloalkyl halide Hal- (CH2) 2-CFX 1 -CF2X 2 in an organic solvent in the presence of a base under heating, e.g., from 0°C to reflux temperature, allowing the reaction to reach completion, collecting a worked-up organic solution and either isolating (and optionally purifying) Intermediate A from the worked-up organic solution, or carrying the Intermediate A-containing organic solution to the chlorination step.
• a base e.g., from 0°C to reflux temperature
• a reaction vessel is charged with a solvent selected from the group of solvents mentioned above (e.g. ethers, aliphatic and aromatic hydrocarbons, chlorinated solvents, esters and ketones; e.g., tetrahydrofuran, toluene, chlorobenzene) and the purified thiol.
• a solvent selected from the group of solvents mentioned above (e.g. ethers, aliphatic and aromatic hydrocarbons, chlorinated solvents, esters and ketones; e.g., tetrahydrofuran, toluene, chlorobenzene) and the purified thiol.
• the crude thiol-containing worked-up solution e.g., 2-mercpatothiazole-containing NBN solution or 2-mercpatothiazole-containing CPME solution
• the molar ratio 2-mercpatothiazole : base is preferably from 0.01 to 10.
• Suitable bases include alkali carbonates, e.g., Na2CC>3 and K2CO3, and alkali hydroxide.
• the base may be added in a solid form, e.g., granules/pellets, or in the form of an aqueous solution, e.g., with the concentration of alkali carbonate in the solution fed to the reaction mixture being from 0.01M up to saturation.
• the reaction mixture may consist of a single organic phase with the added solid base, or a liquid-liquid biphasic system consisting of a liquid organic phase and a liquid aqueous phase where the alkaline agent is dissolved.
• phase transfer catalyst such as tetrabutylammonium bromide (TBAB)
• TBAB tetrabutylammonium bromide
• the fluorinated haloalkyl halide Hal- (CH2) 2-CFX 1 -CF2X 2 is added to the preferably heated, vigorously stirred reaction mixture.
• a mixed fluorinated haloalkyl halide such as 1,4- dibromo-2-chloro-l , 1, 2-trifluorobutane
• the molar ratio 2-mercpatothiazole : Hal- (CH2) 2-CFX 1 -CF2X 2 may vary broadly, e.g., from 1:10 to 10:1 excess of 1, 4-dibromo-2-chloro-l , 1, 2-trifluorobutane is readily recoverable by distillation. Excess of MTZ may be recovered by precipitation / crystallization.
• the reaction mixture is kept under stirring for an additional period time.
• the workup includes addition of water, acidification and phase separation to collect the worked-up organic solution with Intermediate A dissolved therein. Crude Intermediate A can be isolated from the worked-up organic solution, e.g., by concentration, and purified (e.g., by distillation or chromatographic cleaning) . Alternatively, the worked-up solution is directed to the chlorination step.
• the chlorination reaction comprises combining Intermediate A and a chlorinating agent, preferably in an organic solvent (for example, by adding a chlorinating agent to a reaction vessel that was previously charged with Intermediate A and the organic solvent) completing the reaction and recovering Intermediate B from the reaction mixture.
• Chlorinating agents known to be effective in aromatic chlorination such as Cl 2 , sulfuryl chloride, N- chlorosuccinimide and trichlorocyanuric acid, to name a few major halogenating agents, can be used.
• Any organic solvent that is sufficiently inert to the chlorinating agent under consideration may be used; such solvents include carbon tetrachloride, chloroform, chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, acetonitrile and dimethylformamide .
• the worked-up solution recovered in the alkylation step is dried (e.g., distillation is performed to reach 0.1 w/w% water content), and the dried solution charged to the chlorination reactor, e.g., a solution of Intermediate A1 in NBN. Then the chlorinating agent is gradually fed to the reactor .
• the chlorination reactor e.g., a solution of Intermediate A1 in NBN.
• Sulfuryl chloride is fed to the reaction mixture either in a neat form, or in the form of a solution in the same organic solvent that is used to dissolve Intermediate A, e.g., NBN.
• the addition of the SO2CI2 solution may be carried out gradually, over a period of time, for example, up to several hours.
• the chlorination reaction is exothermic.
• reaction mixture Upon completion of SO2CI2 addition, the reaction mixture is stirred at ambient temperature for additional period of time, during which period the reaction mass is periodically sampled to monitor reaction progress by a suitable analytical method.
• the workup includes addition of water, filtration and separation the filtrate into organic and aqueous phases.
• Intermediate B1 is separated from the organic phase by removal of volatiles, and is optionally purified by fractional distillation or chromatographic cleaning before it moves on the next (dehalogenation) step.
• Intermediate A1 Chlorine is fed to a reaction vessel that was previously charged with Intermediate A1 , an organic solvent (e.g., the worked-up organic solution recovered in the alkylation step; the worked-up organic solution is dried before the chlorination step) and an organic base such as triethylamine .
• the amount of chlorine that is bubbled through the solution and available to react with Intermediate A1 is preferably about 1.0 to 2.5 equivalents.
• the total amount of chlorine that needs to be supplied to the reaction to achieve acceptable yield may depend on the reaction temperature (the reaction is exothermic, cooling the reaction mixture and keeping it at room temperature may require increased amounts of chlorine) .
• the workup includes washing with water and separation into organic and aqueous phases.
• Intermediate B1 is separated from the organic phase by removal of volatiles and is optionally purified by fractional distillation or chromatographic purification before it moves on the next (dehalogenation) step .
• the alternative consists of carrying the 2- mercaptothiazole-containing worked-up solution (for example, in C4-C5 water-immiscible alkanol such as 1-pentanol) to the alkylation step, with isolation of the alkylation product (Intermediate A1 ) and solvent exchange prior to the chlorination reaction, e.g., to halogenated aromatic hydrocarbon such as chlorobenzene or another solvent selected from the list of chlorination solvents mentioned above.
• Intermediate Bl is preferably achieved using a reducing agent, e.g., strong reducing metal, in particular zinc.
• a reducing agent e.g., strong reducing metal, in particular zinc.
• the metal works well in combination with a suitable solvent, e.g., a lower alcohol such methanol or ethanol, or acetic acid, typically at elevated temperature.
• a suitable solvent e.g., a lower alcohol such methanol or ethanol, or acetic acid, typically at elevated temperature.
• the Zn/methanol combination is preferred; the reaction by- product is (are) the corresponding zinc halide salt(s) .
• the dehalogenation reaction is carried out by charging a reactor with methanol and zinc metal (preferably in a granular or a powder form, but other metal forms such as wire, sheet and wool can also be used), and adding Intermediate B (e.g., Bl) to the reaction mixture.
• Intermediate B e.g., Bl
• the weight ratio zinc: methanol may vary within a broad range.
• the metal may be activated prior to the introduction of Intermediate B, by known methods, e.g. with the aid of a small amount of elemental bromine or addition of zinc halide.
• the addition of Intermediate B preferably begins after the (optionally activated) zinc-containing medium is heated to an elevated temperature, but the reaction also advances at ambient temperature, albeit at a slower rate.
• Compound Cl ⁇ 5-chloro-2- (3, 4, 4-trifluoro-3-buten-l- yl ) thio ] thiazole ⁇ can undergo oxidation to give Fluensulfone .
• the oxidation reaction is accomplished by methods known in the art, using oxidizing agents such as hydrogen peroxide, m- chloroperoxybenzoic acid, peroxyacetic acid, peroxy-benzoic acid, magnesium monoperoxyphthalate, potassium peroxy monosulfate, as shown in EP 1200418 and US 2006/0004196.
• the oxidizing agents can also be used to accomplish other oxidation reactions mentioned herein, to convert sulfide to sulfone, namely, Intermediate B to its oxidized form:
• the nematicidialy active material e.g., Fluensulfone
• the nematicidialy active material can be used for purposes described in EP 1200418.
• Route 2 it is seen in the general scheme above that the the process diverts to Route 2 following the chlorination step, where the synthetic pathway proceeds to the oxidation of intermediate B, to give the corresponding sulfone form of Intermediate B, which undergoes dehalogenation to produce the active compound, namely Fluensulfone .
• Route 2 is therefore described by a process comprising the following steps :
• the oxidation reagent is selected from the list set out at .rove , e.g,, of powerful oxidizers capable of achieving good y:ields in converting sulfide to the corresponding sulfone.
• a mixture consisting of 1 mole of pota; 3 Ill ' ll peroxymonosulf te with 0.5 mole of potassium bisulfate and 0.5 mole of potassium sulfate (KHSOs - 0 > SKHSCt * 0.5K ? SO-i commercially available as Oxone® ) can be used.
• the salt mixture is not soluble in organic solvents., but is capable of advancing oxidation reactions in aqueous/organic solvent systems such as alkano.l ⁇ wat.er (e.g. , methanol-water or ethanol-water) or acetic acid-water , preferably at low temperatures to prevent the loss of active oxygen , e.g, , temperatures up to 25°C, and even below 10°C can be utilized, optionally in the slightly alkaline pH range.
• alkano.l ⁇ wat.er e.g. , methanol-water or ethanol-water
• acetic acid-water preferably at low temperatures to prevent the loss of active oxygen , e.g, temperatures up to 25°C, and even below 10°C can be utilized, optionally in the slightly alkaline pH range.
• a preferred variant of the oxidation reaction comprises progressively adding an aqueous solution of the reagent KHSOs ⁇ 0 ⁇ SKHSO* * 0.5K 2 SO 4 to a reaction vessel that was previously charged with alkanol (e.g,, methanol) and the intermediate B1 ⁇ namely, 2- [ ( 4-bromo-3-chloro-3 , 4 , 4- trifluorobutyl ) thio] -5-chloro-l, 3-thiazole ⁇ .
• alkanol e.g, methanol
• the total amount of the reagent KHSO5 ⁇ 0.5KHS0 4 ⁇ 0.5K2SO4 is divided into several portions which are supplied to the reaction at two consecutive stages (corresponding to -SO- -SO2-), wherein each stage includes addition of a major portion (say, about 1.0-1.1 equivalents of the reagent) in the form of an aqueous solution at a temperature below 10°C and addition of an auxiliary portion (say, less than 0.1 equivalents of the reagent) at a temperature above 10°C, e.g., around room temperature, under stirring.
• the second stage is run under pH control, wherein the pH of the reaction mixture is kept slightly alkaline the with the aid of a base such as alkali hydroxide .
• the process comprises the following steps:
• aqueous form e.g., 1.0-1.1 equivalents
• the reaction mixture is worked-up by separating the insoluble salt, e.g., by filtration, optionally treating the liquid phase with a reducing agent to eliminate residual oxidant, removing the alkanol component of the liquid phase, e.g., by distillation, and recovering the oxidation product B2 from the aqueous phase, e.g., by extraction with a suitable organic solvent, following which the oxidation product B2 is collected from the extractant, e.g., by evaporating the extractant, in the form of a white solid.
• the Intermediate B2 undergoes dehalogenation to give the nematicidialy active compound, e.g., Fluensulfone .
• the conditions are similar with those applied in the dehalogenation step described above for Route 1.
• the reductant of choice is zinc (e.g., in powder or granular form); but this time the dehalogenation reaction preferably takes place in ether such as tetrahydrofuran under heating, e.g., in refluxing THF after an in-situ activation of zinc by known methods, e.g., chemical activation with the aid of additives and promoters can be achieved by addition of a small amount of elemental halogen (crystals of iodine or liquid bromine) , addition of zinc halide, cuprous or cupric salts, e.g., cupric bromide.
• Other solvents that can be used in the dehalogenation step are DMF and methanol.
• the addition of Intermediate B2 preferably begins after the (optionally activated) zinc-containing medium is heated to an elevated temperature, but the reaction also advances at ambient temperature, albeit at a slower rate.
• the progress of the reaction is tracked (e.g., liquid chromatography-mass spectrometry analysis) to determine the conversion of Intermediate B2.
• a supplementary amount of the additives and promoters mentioned above is introduced into the reaction mixture.
• the reaction is then allowed to reach completion, e.g., under refluxing and stirring for several hours .
• Work-up to recover the active compound includes filtration of unreacted metal, acidification, extractive procedures and purification e.g., by column chromatography methods and other
• ADTC dithiocarbamate ammonium salt
• 1,4-DiBr 1, 4-dibromo-2-chloro-l , 1 , 2-trifluorobutane 339 : 2- [ ( 4-bromo-3-chloro-3 , 4, 4-trifluorobutyl ) thio] thiazole 374: interchangeably named herein 5-chloro-2- [ ( 4-bromo-3- chloro-3, 4, 4-trifluorobutyl ) thio] thiazol; and 2- [ ( 4-bromo-3- chloro-3, 4, 4-trifluorobutyl ) thio] -5-chloro-l, 3-thiazole
• LC/MS system consisting of an Accela 600 pump with degasser, Accela PDA detector, Accela autosampler, and an Exacitve MS Detector (Orbitrap) .
• a Hypersil Gold Column 250x4.6mm, LOT 7327, #0160665T was used for the measurement and the temperature of the column oven was set to 40°C. The following program was used: 0 - 2 min: 50 : 50 mixture of MeCN
• 2-mercapthothizaole was prepared according to the procedure described in US 5,994,553. When the reaction was complete, using an overall amount of 50.0 g 2-Chloroacetaldehyde, the reaction mixture was cooled to 20°C and extracted once with 400 g NBN and twice with 100 g NBN.
• MTZ is obtained in NBN solution in a yield of around 75-80 % by quantitative analysis of the solution vs. analytical standard.
• 2-mercapthothizaole was prepared according to the procedure described in US 5,994,553. When the reaction was complete, using an overall amount of 110 g 2-chloroacetaldehyde, 1- pentanol is added (200 gr) and temperature is increased to 70°C. The reaction is stirred for 1.5 hours until completion.
• TBAB (7.54 g, 23.41 mmol) is added to the reaction mixture, followed by the addition of 1,4-DiBr (143.5 g, 468.12 mmol, 0.95 equivalent,) .
• Na2CC>3 was added slowly (11.53 g, 122.7 mmol, 0.23 equivalents) .
• the reaction mixture was then heated to 70°C and aqueous sodium hydroxide solution (about 100 g of 15 wt% solution) was added to reach pH ⁇ 8-8.2.
• the reaction mixture was kept under stirring for approximately one hour, during which period the reaction mixture was periodically sampled to track the progress of the reaction.
• the reaction mixture was cooled to room temperature. pH was corrected to 4 with the aid of aqueous HC1 solution (32 wt%) .
• the reaction mixture was filtered. The filtrate was separated into aqueous and organic phases.
• the organic phase (440 g) consists of ⁇ 35 wt% of the entitled product (Intermediate A1 ) dissolved in NBN. Yield: ⁇ 95% by quantitative analysis vs. analytical standard.
• the solution was used without further purification in the chlorination reaction.
• reaction mixture was filtered through decalite using sinter Nr. 4.
• the organic filtrate was washed twice with 30 ml of aqueous sodium chloride solution (5 wt%) .
• a solution of the entitled product (Intermediate Bl) in NBN is collected (24% content, indicating yield of 95% by quantitative analysis vs. analytical standard) .
• NBN, IBH and CPME emerge as solvents suitable for use in a telescopic process, because they satisfy both test requirements (dissolving high concentration of 2 mercaptothiazole and being inert to at least one chlorinating agent ) .
• reaction mixture was then heated to 35°C and aqueous sodium hydroxide solution (45 wt% solution) was added to reach pH ⁇ 8-8.5.
• aqueous sodium hydroxide solution 45 wt% solution
• the reaction mixture was kept under stirring for approximately one hour, during which period the reaction mixture was periodically sampled to track the progress of the reaction.
• the chlorination reaction was performed in 1000 ml reactor which was charged with Intermediate A1 (100 g of 96.6% wt.%) and dry MCB 300 gr .
• Sulfuryl chloride (45 g) was added dropwise at 25°C over a period of 1 h. The addition is not exothermic .
• the reaction mixture is stirred at 50°C for additional 30 min during which period the reaction mass is periodically sampled to monitor reaction progress. In case the reaction does not proceed anymore, an additional amount of SO2CI2 needs to be added. During stirring for further 60 min the reaction is sampled periodically.

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