BR112019017538B1 - PROCESSES A, B, C FOR PRODUCTION OF COMPOUNDS AND USE OF DIISOPROPYLETHYLAMINE - Google Patents

Abstract

The present invention relates to a process for producing compounds of formula (I): which comprises Step A of reacting compounds of formula (II): with 2,3-dihalopropionitrile or 2-haloacrylonitrile in the presence of DIPEA. It also refers to a process for producing compounds of formula (III): , which comprises Step B of reacting compounds of formula (I) with Br2 in the presence of DIPEA. It also refers to a Process C for producing compounds of formula IV:, which comprises Step C of reacting compounds of formula (III) with di(C1-C4 alkoxy) methane and POCl3 or a mixture comprising POCl3 and DMF , in the presence of DIPEA. It also refers to the use of DIPEA as a basis in the production of compounds of Formula (I), compounds of Formula (III) or compounds of Formula (IV).

Description

[001] The present invention relates to Process A for producing compounds of formula I: where the variables have the meaning: - R1 is phenyl, replaced by none, one or more R11, identical or different; - R11 is F, Cl, Br, I, CN, NO2, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkyl-C(O)O, C1 haloalkyl -C4- C(O)O; or - two R11 substituents located on phenyl ring atoms adjacent to each other are a group -OCH2O-, -OCF2O or -CH=CH-CH=CH- and form, together with the carbon atoms to which they are attached, a ring with five or six members; - n is 1, 2 or 3; which comprises Step A of reaction of compounds of formula II: wherein the variables have the same meaning defined for compounds of formula I; with 2,3-dihalopropionitrile (DHPN) or 2-haloacrylonitrile (HACN) in the presence of diisopopylethylamine (DIPEA).

[002] The present invention also refers to Process B for producing compounds of formula III: wherein the variables have the defined meaning for compounds of formula I; which comprises Step B of reaction of compounds of formula I with Br2 (bromine) in the presence of DIPEA.

[003] It also refers to Process C for producing compounds of formula IV: wherein R1 and n are as defined for compounds of formula I and R2 is C1-C4 alkoxymethyl; which comprises Step C of reacting compounds of formula III with di(C1-C4 alkoxy)methane and POCl3 or a mixture comprising POCl3 and DMF (Vilsmeier reagent), in the presence of DIPEA.

[004] The present invention also relates to the use of DIPEA as a base in the production of compounds of formula I, compounds of formula III or compounds of formula IV; the use of DIPEA as a basis in Step A; the use of DIPEA as a basis in Step B; and the use of DIPEA as a basis in Step C. Combinations of embodiments with other embodiments, regardless of their corresponding level of preference, are within the scope of the present invention.

BRIEF DESCRIPTION OF FIGURES

[005] Figure 1: photographs of reaction vessels from the Step A reaction using TEA or DIPEA as a base.

[006] Figure 2: photographs of reaction configuration of the Step A reaction using TEA or DIPEA as a base.

[007] Figure 3: photograph of reaction configuration of the Step B reaction using TEA or DIPEA as a base.

[008] Figure 4: photograph of the reaction mixtures from the Step C reaction using TEA as a base.

[009] Figure 5: photograph of the reaction mixtures from the Step C reaction using DIPEA as a base.

[0010] The pesticide compounds of formulas III and IV and their production are known from US5359090, US5144041, EP0821876A1, US5453508, US5118816, US5446170 and US5030735. Economically important insecticides chlorfenapyr and tralopyril fall within the definition of compounds of formulas III and IV, respectively. Due to the industrial and agricultural importance of these compounds, improved production processes for compounds of formulas III and/or IV, as well as intermediate compounds of formula I, are desirable, with higher yields, lower costs, fewer steps and less material waste. .

[0011] The production of compounds of formulas III and/or IV can be achieved by the following reaction sequence:

[0012] The state of the art teaches the use of triethylamine (TEA) as the basis of the production processes of compounds of formulas III and/or IV. It has now surprisingly been discovered that the use of DIPEA as a base in steps A, B and/or C generates a higher yield of compounds of formulas I, III and/or IV. The production process is simplified because less fogging is produced in steps A, B and C, which causes constriction of reactor plant condensers over time. Reaction mixtures are not syrups, but solutions, which facilitates the work process. The reactors do not need to receive water flow to recover all the precipitate, which avoids corrosive processes and saves costs. Particularly, the flow of glass reactors after steps B or C with water generates corrosion of the glass, which can be avoided by means of the process according to the present invention. Another advantage is the easy recovery of the DIPEA base after working with compounds of formulas I, III or IV. The base can be recovered in a few steps, with low residual water content and high yield.

[0013] Compounds of formula I are produced in Process A, which comprises Step A of reacting compounds of formula II with DHPN or HACN in the presence of DIPEA: wherein the variables have the meaning defined for compounds of formula I.

[0014] Step A is normally conducted at temperatures of 10 °C to 70 °C, preferably 15 °C to 60 °C, in inert solvent. Typically, Step C is conducted in the presence of DIPEA, as the only base and no other additional bases are present, particularly not triethylamine. Preferably, the ratio of DIPEA to other bases in Step C is at least 5:1, preferably at least 10:1, and particularly at least 100:1.

[0015] In one embodiment, Process A comprises the step of reacting compounds of formula II with DHPN. In another embodiment, Process A comprises the step of reacting compounds of formula II with HACN.

[0016] Suitable inert solvents are aliphatic hydrocarbons, preferably C5-C16 aliphatic hydrocarbon, more preferably C5-C16 alkane or C5-C16 cycloalkane, such as pentane, hexane, cyclohexane or petroleum ether; aromatic hydrocarbons, preferably a C6-C10 aromatic hydrocarbon, such as benzene, toluene, o, m and p-xylene; halogenated hydrocarbons, preferably halogenated aliphatic C1-C6 alkanes or halogenated aromatic C6-C10 hydrocarbons, such as CH2Cl2, CHCl3, CCl4, CH2ClCH2Cl, CCl3CH3, CHCl2CH2Cl, CCl2CCl2 or chlorobenzene; ethers, preferably C1-C6 cycloalkyl ethers, C1-C6 alkyl C1-C6 alkyl ethers, C1-C6 alkyl C3-C6 cycloalkyl ethers, polyol C1-C6 alkyl C1-C6 alkyl ethers and C1-C6 alkyl aryl C6-C10 ethers, such such as CH3CH2OCH2CH3, (CH3)2CHOCH(CH3)2, CH3OC(CH3)3 (MTBE), CH3OCH3 (DME), CH3OCH2CH2OCH3, CH3OC(CH3)2CH2CH3, dioxane, anisole, 2-methyltetrahydrofuran, tetrahydrofuran (THF) and diethylene glycol; esters, preferably esters of C1-C6 aliphatic alcohols with C1-C6 aliphatic carboxylic acids, esters of C6-C10 aromatic alcohols with C6-C10 aromatic carboxylic acids, cyclic esters of C1-C6 w-hydroxycarboxylic acids, such as CH3C(O) OCH2CH3, CH3C(O)OCH3, CH3C(O)OCH2CH2CH2CH3, CH3C(O)OCH(CH3)CH2CH3, CH3C(O)OC(CH3) (OH)C(O)OCH3, CH3C(O)OCH2CH(CH3)2, CH3C(O)OCH(CH3)2, CH3CH2C(O)OCH3, benzyl benzoate and Y-butyrolactone; carbonates, such as ethylene carbonate, propylene carbonate, CH3CH2OC(O)OCH2CH3 and CH3OC(O)OCH3; nitriles, preferably C1-C6 nitriles, such as acetonitrile (ACN) and CH3CH2CN; ketones, preferably C1-C6 alkyl C1-C6 alkyl ketones, such as CH3C(O)CH3, CH3C(O)CH2CH3, CH3CH2C(O)CH2CH3 and CH3C(O)C(CH3)3 (MTBK); amides and urea derivatives, preferably dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethyl acetamide (DMA), 1,3-dimethyl-2-imidazolidinone (DMI), 1,3-dimethyl-3, 4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) and hexamethylphosphamide (HMPA); in addition, dimethyl sulfoxide (DMSO) and sulfolane. Mixtures of the above solvents are also possible.

[0017] In one embodiment, the inert solvent comprises aliphatic hydrocarbons, aromatic hydrocarbons, nitriles, amides or one of their mixtures. In another embodiment, the inert solvent comprises C5-C16 aliphatic hydrocarbons, C6-C10 aromatic hydrocarbons, C1-C6 nitriles, amides or a mixture thereof. In another embodiment, the inert solvent comprises C6-C10 aromatic hydrocarbons, C1-C6 nitriles, DMF or a mixture thereof. In another embodiment, the inert solvent comprises benzene, toluene, xylene, ACN, DMF or a mixture thereof. In another embodiment, the inert solvent comprises a mixture of toluene, ACN and DMF. In another embodiment, the inert solvent comprises ACN. In another embodiment, the inert solvent comprises a mixture of toluene and ACN. In another embodiment, the inert solvent comprises a mixture of toluene and DMF.

[0018] Suitable inert solvents typically comprise a polar aprotic solvent. In one embodiment, the inert solvent is a mixture of polar aprotic solvent and non-polar solvent. In another embodiment, the inert solvent consists only of non-polar solvents.

[0019] Examples of polar aprotic solvents are esters, ketones, nitriles, amides and urea derivatives, DMSO and sulfolane. Examples of non-polar solvents are aliphatic hydrocarbons, aromatic hydrocarbons and ethers.

[0020] If the solvent comprises a polar aprotic solvent, the concentration of the sum of all polar aprotic solvents with respect to the total amount of solvent is at least 20% by weight, preferably at least 30% by weight, more preferably by at least 40% by weight, preferably greater than at least 60% by weight, and particularly at least 70% by weight. The sum of all polar aprotic solvents with respect to the total amount of solvent can be from 10 to 99% by weight, preferably from 20 to 95% by weight, more preferably from 25 to 90% by weight and, preferably higher, 50 to 80% by weight. In one embodiment, the solvent comprises at least 40% by weight, preferably at least 50% by weight of ACN with respect to the total amount of solvent.

[0021] The molar ratio between DIPEA and compounds of formula II is normally 10:1 to 1:1, preferably 5:1 to 1:1, more preferably 4:1 to 1:1 and, preferably higher , from 3.5:1 to 2:1. The molar ratio between DIPEA and compounds of formula II may be at least 1.5:1 and, more preferably, at least 3:1.

[0022] The molar ratio between compounds of formula II and DHPN or HACN can be from 1:1 to 1:5, more preferably from 1:1 to 1:3 and, particularly, from 1:1 to 1:2.

[0023] The concentration of compounds of formula II at the beginning of the reaction in relation to the total amount of solvent can be from 1 to 90% by weight, preferably 10 to 80% by weight, more preferably from 10 to 60% by weight, preferably greater than 10 to 50% by weight and particularly 15 to 20% by weight.

[0024] Compounds of formula II and DHPN or HACN are typically mixed before adding DIPEA. The addition of DIPEA is normally conducted over a period of 5 min to 120 min, preferably over a period of 10 min to 60 min. After the addition of DIPEA begins, the reaction typically takes 15 minutes to 300 minutes, preferably 50 minutes to 150 minutes.

[0025] Typically, 2,3-dihalopropionitrile (DHPN) designates 2,3-dichloropropionitrile; and 2-haloacrylonitrile (HACN) designates 2-chloroacrylonitrile. DHPN and HACN compounds are commercially available. DHPN and HACN can alternatively be prepared as described in EP 0771787 or Yokota et al., Journal of Polymer Science, Polymer Chemistry Edition, 1980, vol. 18 (5), pp. 1609-10. Preferably, DHPN denotes 2,3-dibromopropionitrile. Preferably, HACN denotes 2-bromoacrylonitrile.

[0026] The compounds of formula III are produced in Process B, which comprises the reaction of compounds of formula I with Br2 (bromine) in presence of DIPEA: in which the variables have the meaning defined for compounds of formula I.

[0027] Step B is normally conducted at temperatures from 20 °C to 60 °C, preferably from 25 °C to 45 °C, in inert solvent and, optionally, in the presence of a catalyst. Typically, Step C is conducted in the presence of DIPEA, as the only base and no other additional bases are present, particularly not triethylamine. Preferably, the ratio of DIPEA to other bases in Step C is at least 5:1, preferably at least 10:1, and particularly at least 100:1.

[0028] Suitable inert solvents are aliphatic hydrocarbons, preferably C5-C16 aliphatic hydrocarbon, more preferably C5-C16 alkane or C5-C16 cycloalkane, such as pentane, hexane, cyclohexane or petroleum ether; aromatic hydrocarbons, preferably C6-C10 aromatic hydrocarbons, such as benzene, toluene, o, m and p-xylene; halogenated hydrocarbons, preferably halogenated aliphatic C1-C6 alkanes or halogenated aromatic C6-C10 hydrocarbons, such as CH2Cl2, CHCl3, CCl4, CH2ClCH2Cl, CCl3CH3, CHCl2CH2Cl, CCl2CCl2 or chlorobenzene; ethers, preferably C1-C6 cycloalkyl ethers, C1-C6 alkyl C1-C6 alkyl ethers, C1-C6 alkyl C3-C6 cycloalkyl ethers, polyol C1-C6 alkyl C1-C6 alkyl ethers and C1-C6 alkyl aryl C6-C10 ethers, such such as CH3CH2OCH2CH3, (CH3)2CHOCH(CH3)2, CH3OC(CH3)3 (MTBE), CH3OCH3 (DME), CH3OCH2CH2OCH3, CH3OC(CH3)2CH2CH3, dioxane and diethylene glycol; esters, preferably esters of C1-C6 aliphatic alcohols with C1-C6 aliphatic carboxylic acids, esters of C6-C10 aromatic alcohols with C6-C10 aromatic carboxylic acids, cyclic esters of w-hydroxy-C1-C6-carboxylic acids, such as CH3C (O)OCH2CH3, CH3C(O)OCH3, CH3C(O)OCH2CH2CH2CH3, CH3C(O)OCH(CH3)CH2CH3, CH3C(O)OC(CH3), CH3CH2CH2C(O)OCH2CH3, CH3CH(OH)C(O) OCH2CH3, CH3CH(OH)C(O)OCH3, CH3C(O)OCH2CH(CH3)2, CH3C(O)OCH(CH3)2, CH3CH2C(O)OCH3, benzyl benzoate and Y—butyrolactone; carbonates, such as ethylene carbonate, propylene carbonate, CH3CH2OC(O)OCH2CH3 and CH3OC(O)OCH3; nitriles, preferably C1-C6 nitriles, such as ACN, and CH3CH2CN; alcohols, preferably C1-C4 alcohols and C2-C4 alkane diols, such as CH3OH, CH3CH2OH, CH3CH2CH2OH, CH3CH(OH)CH3, CH3(CH2)3OH and C(CH3)3OH, CH2(OH)CH2(OH), CH3CH (OH)CH2OH; amides and urea derivatives, preferably DMF, NMP, DMA, DMI, DMPU and HMPA; additionally, DMSO and sulfolane. Mixtures of the above solvents are also possible.

[0029] In one embodiment, the inert solvent comprises aliphatic hydrocarbons, aromatic hydrocarbons, nitriles, amides or one of their mixtures. In another embodiment, the inert solvent comprises C5-C16 aliphatic hydrocarbons, C6-C10 aromatic hydrocarbons, C1-C6 nitriles, amides or a mixture thereof. In another embodiment, the inert solvent comprises C6-C10 aromatic hydrocarbons, C1-C6 nitriles, DMF or a mixture thereof. In another embodiment, the inert solvents comprise benzene, toluene, xylene, ACN, DMF or a mixture thereof. In another embodiment, the inert solvents comprise a mixture of toluene, ACN and DMF. In another embodiment, the inert solvent comprises ACN. In another embodiment, the inert solvent comprises a mixture of toluene and ACN. In another embodiment, the inert solvent comprises a mixture of toluene and DMF.

[0030] If the solvent comprises/is a polar aprotic solvent, the concentration of the sum of all polar aprotic solvents with respect to the total amount of solvent is at least 20% by weight, preferably at least 30% by weight, of greater preferably at least 40% by weight, preferably greater than at least 60% by weight, and particularly at least 70% by weight. The sum of all polar aprotic solvents with respect to the total amount of solvent can be from 10 to 99% by weight, preferably from 20 to 95% by weight, more preferably from 25 to 90% by weight and, preferably higher, 50 to 80% by weight. In one embodiment, the solvent comprises at least 40% by weight and, preferably, at least 50% by weight of ACN with respect to the total amount of solvent.

[0031] The molar ratio between compounds of formula I and Br2 can be from 5:1 to 1:5, preferably from 1:1 to 1:5, more preferably from 1:1 to 1:2 and, preferably higher , from 1:1 to 1:1.5, especially preferably from 1:1 to 1:1.4 and, particularly, from 1:1 to 1:1.3.

[0032] The concentration of compounds of formula I at the beginning of the reaction in relation to the total amount of solvent can be from 1 to 90% by weight, preferably 10 to 80% by weight, more preferably from 10 to 50% by weight and , particularly 15 to 20% by weight.

[0033] The molar ratio between DIPEA and compounds of formula I is normally 10:1 to 1:2, preferably 5:1 to 1:1, more preferably 3:1 to 1:1 and, preferably higher , from 2:1 to 1:1. The molar ratio between DIPEA and compounds of formula II may be at least 1:1 and, more preferably, at least 1.5:1.

[0034] Steps A and B can be conducted as a one-pot process. The term “one-pot process” designates a process in which the products of the first reaction step, such as compounds of formula I in Step A, are used directly in the second reaction step, such as in Step B, without processing steps. intermediate purification. Consequently, the products from the first process can remain in their original liquid and are applied as they are in the second process. The first and second reaction steps can be carried out in the same reactor or in different reactors. Preferably, they are conducted in a reactor.

[0035] If Steps A and B are conducted as a one-pot process, the solvent for both processes is the same, its composition remains approximately unchanged, and the total amount of DIPEA - otherwise distributed between Step A and Step B - is added directly at the beginning of Step A. Consequently, the molar ratio between DIPEA and compounds of formula II in Step A can be from 10:1 to 2:1, more preferably from 6:1 to 3:1 and , preferably higher, from 5:1 to 3:1. Typically, the molar ratio between DIPEA and compounds of formula II in Step A, if Step A and Step B are conducted as a one-pot process, is at least 2:1, preferably at least 3:1, and higher preference, at least 4:1.

[0036] Appropriate catalysts can be added in Step B in a substoichiometric ratio with respect to the compounds of formula I. The molar ratio between the catalyst and compounds of formula I can be from 1:106 to 1:10, preferably from 1:105 to 1:100 and, more preferably, 1:1000 to 1:100. In one embodiment, the catalyst is DMF.

[0037] The reaction mixtures after Step A and Step B can be worked up in the usual way, for example, by mixing with water, separating the phases and, if appropriate, chromatographic purification of the crude products. Typically, all polar aprotic solvent, particularly all ACN, is removed from the reaction mixture after Step B by distillation and replaced with a solvent appropriate for Step C. Water may then be added and the two-phase composition is heated to 50°C to 80°C, preferably 60°C to 70°C. The aqueous layer is then removed and the organic layer containing compounds of formula III is dried, for example, by adding hygroscopic material. Compounds of formula III can be obtained by crystallizing the organic layer or removing the organic solvent.

[0038] Compounds of formula IV are produced in Process C which comprises the reaction of compounds of formula III with di(C1-C4 alkoxy)methane and POCl3, or POCl3 and DMF (Vilsmeier reagent) in the presence of DIPEA: wherein R2 is C1-C4 alkoxymethyl; and the other variables have meaning as defined for the compounds of formula I. Typically, Step C is conducted in the presence of DIPEA, as the only base and no other additional base is present, particularly not triethylamine. Preferably, the ratio of DIPEA to other bases in Step C is at least 5:1, preferably at least 10:1, and particularly at least 100:1.

[0039] Step C is normally conducted at temperatures from 30 °C to 80 °C, preferably from 40 °C to 70 °C, in inert solvent. Di(C1-C4 alkoxy)methane is typically diethoxymethane and in this case R2 is CH3CH2OCH2. Di(C1-C4 alkoxy)methane compounds are commercially available or can be prepared as described in Pathak, D. and Gerald, J., Synthetic Communications, 2003, vol. 33 (9), pp. 1557-1561.

[0040] Suitable inert solvents are aliphatic hydrocarbons, preferably C5-C16 aliphatic hydrocarbon, more preferably C5-C16 alkane or C5-C16 cycloalkane, such as pentane, hexane, cyclohexane or petroleum ether; aromatic hydrocarbons, preferably C6-C10 aromatic hydrocarbons, such as benzene, toluene, o, m and p-xylene; halogenated hydrocarbons, preferably halogenated aliphatic C1-C6 alkanes or halogenated aromatic C6-C10 hydrocarbons, such as CH2Cl2, CHCl3, CCl4, CH2ClCH2Cl, CCl3CH3, CHCl2CH2Cl, CCl2CCl2 or chlorobenzene; nitriles, preferably C1-C6 nitriles, such as ACN and CH3CH2CN; amides and urea derivatives, preferably DMF, NMP, DMA, DMI, DMPU and HMPA; in addition, DMSO and sulfolane. Mixtures of the above solvents are also possible.

[0041] In one embodiment, the inert solvent comprises C5-C16 aliphatic hydrocarbons, C6-C10 aromatic hydrocarbons, halogenated C1-C6 aliphatic alkanes, halogenated C6-C10 aromatic hydrocarbons, C1-C6 nitriles, amides or one of their mixtures. In another embodiment, the inert solvent comprises C5-C16 aliphatic hydrocarbons, C6-C10 aromatic hydrocarbons, C1-C6 nitriles, DMF or a mixture thereof. In another embodiment, the inert solvent comprises C6-C10 aromatic hydrocarbons, ACN, DMF or a mixture thereof. In another embodiment, the inert solvent comprises benzene, toluene, xylene, ACN, DMF or a mixture thereof. In another embodiment, the inert solvent comprises toluene, ACN, DMF or a mixture thereof. In another embodiment, the inert solvent comprises toluene.

[0042] The molar ratio between compounds of formula III and di(C1-C4 alkoxy) methane can be from 5:1 to 1:5, preferably from 1:1 to 1:5 and, more preferably, from 1:1 to 1:2. The molar ratio is normally up to 1:1, more preferably up to 1:1.5.

[0043] The molar ratio between DIPEA and compounds of formula III is normally 10:1 to 1:2, preferably 5:1 to 1:1, more preferably 3:1 to 1:1 and, preferably higher , from 2:1 to 1:1. The molar ratio between DIPEA and compounds of formula III may be at least 1:1 and, more preferably, at least 1.5:1.

[0044] In one embodiment, compounds of formula III react with POCl3. In this case, the molar ratio between POCl3 and compounds of formula III can be from 1:2 to 10:1, preferably from 1:1 to 5:1, more preferably from 1:1 to 3:1 and, preferably higher , from 1:1 to 2:1.

[0045] In another embodiment, compounds of formula III react with Vilsmeier reagent, that is, a mixture of DMF and POCl3. The molar ratio between DMF and POCl3 can be from 0.1:5 to 5:1, preferably from 0.1:3 to 3:1 and, more preferably, 0.1:2 to 1:1. The molar ratio between POCl3 in the Vilsmeier reagent and compounds of formula III can be from 1:2 to 10:1, preferably from 1:1 to 5:1, more preferably from 1:1 to 3:1, and specifically from 1:1 to 2:1.

[0046] Compounds of formula II can be produced in Step D through the reaction of compounds of Formula V: with CnF2n+1C(O)Cl and PCl3; wherein the variables have meaning as defined for the compounds of formula I. The compounds of formula V may be derived from commercially available phenylglycine. Parachlorophenylglycine is also commercially available. CnF2n+1C(O)Cl normally designates CF3C(O)Cl, where the variable n in formulas II and V is 1.

[0047] Step D is normally conducted at temperatures from 20 °C to 80 °C, preferably from 30 °C to 70 °C, in inert solvent and, optionally, in the presence of a catalyst. Typically, no base is added in Step D.

[0048] Suitable inert solvents are aliphatic hydrocarbons, preferably C5-C16 aliphatic hydrocarbon, more preferably C5-C16 alkane or C5-C16 cycloalkane, such as pentane, hexane, cyclohexane or petroleum ether; aromatic hydrocarbons, preferably a C6-C10 aromatic hydrocarbon, such as benzene, toluene, o, m and p-xylene; halogenated hydrocarbons, preferably halogenated aliphatic C1-C6 alkanes or halogenated aromatic C6-C10 hydrocarbons, such as CH2Cl2, CHCl3, CCl4, CH2ClCH2Cl, CCl3CH3, CHCl2CH2Cl, CCl2CCl2 or chlorobenzene; ethers, preferably C1-C6 cycloalkyl ethers, C1-C6 alkyl C1-C6 alkyl ethers, C1-C6 alkyl C3-C6 cycloalkyl ethers, polyol C1-C6 alkyl C1-C6 alkyl ethers and C1-C6 alkyl aryl C6-C10 ethers, such such as CH3CH2OCH2CH3, (CH3)2CHOCH(CH3)2, CH3OC(CH3)3 (MTBE), CH3OCH3 (DME), CH3OCH2CH2OCH3, CH3OC(CH3)2CH2CH3, dioxane, anisole, 2-methyltetrahydrofuran, tetrahydrofuran (THF) and diethylene glycol; esters, preferably esters of C1-C6 aliphatic alcohols with C1-C6 aliphatic carboxylic acids, esters of C6-C10 aromatic alcohols with C6-C10 aromatic carboxylic acids, cyclic esters of w-hydroxy-Ci-C6-carboxylic acids, such as CH3C (O)OCH2CH3, CH3C(O)OCH3, CH3C(O)OCH2CH2CH2CH3, CH3C(O)OCH(CH3)CH2CH3, CH3C(O)OC(CH3), CH3CH2CH2C(O)OCH2CH3, CH3CH(OH)C(O) OCH2CH3, CH3CH(OH)C(O)OCH3, CH3C(O)OCH2CH(CH3)2, CH3C(O)OCH(CH3)2, CH3CH2C(O)OCH3, benzyl benzoate and Y—butyrolactone; carbonates, such as ethylene carbonate, propylene carbonate, CH3CH2OC(O)OCH2CH3 and CH3OC(O)OCH3; nitriles, preferably C1-C6 nitriles, such as ACN and CH3CH2CN; ketones, preferably C1-C6 alkyl C1-C6 alkyl ketones, such as CH3C(O)CH3, CH3C(O)CH2CH3, CH3CH2C(O)CH2CH3 and CH3C(O)C(CH3)3 (MTBK); amides and urea derivatives, preferably DMF, NMP, DMA, DMI, DMPU and HMPA; in addition, DMSO and sulfolane. Mixtures of the above solvents are also possible.

[0049] In one embodiment, the inert solvent comprises aliphatic hydrocarbons, aromatic hydrocarbons, nitriles or mixtures thereof. In another embodiment, the inert solvent comprises C5-C16 aliphatic hydrocarbons, C6-C10 aromatic hydrocarbons, C1-C6 nitriles or a mixture thereof. In another embodiment, the inert solvent comprises C6-C10 aromatic hydrocarbons, C1-C6 nitriles or a mixture thereof. In another embodiment, the inert solvent comprises benzene, toluene, xylene, ACN or a mixture thereof. In another embodiment, the inert solvent comprises a mixture of toluene and ACN. In another embodiment, the inert solvent comprises ACN.

[0050] Suitable inert solvents typically comprise a polar aprotic solvent. In one embodiment, the inert solvent is a mixture of polar aprotic solvent and non-polar solvent. In another embodiment, the inert solvent consists only of non-polar solvents. Examples of polar aprotic solvents are esters, ketones, nitriles, amides and urea derivatives, DMSO and sulfolane. Examples of non-polar solvents are aliphatic hydrocarbons, aromatic hydrocarbons and ethers.

[0051] If the solvent comprises a polar aprotic solvent, the concentration of the sum of all polar aprotic solvents with respect to the total amount of solvent is at least 20% by weight, preferably at least 30% by weight, more preferably by at least 40% by weight, preferably greater than at least 60% by weight, and particularly at least 70% by weight. The sum of all polar aprotic solvents with respect to the total amount of solvent can be from 10 to 99% by weight, preferably from 20 to 95% by weight, more preferably from 25 to 90% by weight and, preferably higher, 50 to 80% by weight. In one embodiment, the solvent comprises at least 40% by weight, preferably at least 50% by weight of ACN with respect to the total amount of solvent.

[0052] Appropriate catalysts can be added in Step D in a substoichiometric ratio with respect to the compounds of formula V. The molar ratio between the catalyst and compounds of formula V can be from 1:106 to 1:10, preferably from 1:105 to 1:100 and, more preferably, 1:1000 to 1:100. In one embodiment, the catalyst is DMF.

[0053] The molar ratio between compounds of formula V and CnF2n+1C(O)Cl can be from 1:2 to 5:1, preferably from 1:1 to 3:1 and, more preferably, from 1:1 to 2:1. The molar ratio between PCl3 and compounds of formula V can be from 1:10 to 1:1, preferably from 1:5 to 1:1 and, more preferably, from 1:3 to 1:2.

[0054] The concentration of compounds of formula V can be from 10 to 80% by weight in relation to the total weight of solvent, preferably from 10 to 50% by weight and, more preferably, from 20 to 40% by weight.

[0055] Typically, PCl3 is added to compounds of formula V before the addition of CnF2n+1C(O)Cl over a period of 5 min to 60 min. CnF2n+1C(O)Cl is typically added over a period of 30 min to 120 min. Depending on the physical state of CnF2n+1C(O)Cl at 25 °C, the compound can be added as a subsurface gas to the reaction mixture or it can be added in liquid form.

[0056] Steps A and D can be conducted as a one-pot process, that is, compounds of formula II in Step D are used directly in Step A, without intermediate purification steps. Consequently, the compounds of formula II produced in Step D can remain in their original liquid and are applied as they are in Step A. Steps A and D can be conducted in the same reactor or in different reactors. Preferably, they are conducted in a reactor. If Steps A and D are conducted as a one-pot process, the full amount of DIPEA is added during Step A.

[0057] The following definitions of variables are the meanings and preferred meanings for all formulas in which they appear.

[0058] R1 is normally phenyl, replaced by none, one or more identical or different R11. Preferably, R1 is phenyl, which is substituted by an R11, more preferably substituted by an R11 in para position, i.e. a 4-R11-phenyl substituent.

[0059] R11 is normally F, Cl, Br, I, CN, NO2, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4-C(O)O alkyl , C1-C4-C(O)O haloalkyl; or two substituents R11 situated on adjacent phenyl ring atoms together are a group -OCH2O-, -OCF2O or -CH=CH-CH=CH-, and form, together with the carbon atoms to which they are attached, a ring with five or six members.

[0060] In one embodiment, R11 is F, Cl, Br, I, CN, NO2, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy. In another embodiment, R11 located on adjacent phenyl ring atoms together are a group - OCH2O-, -OCF2O or -CH=CH-CH=CH-, and form, together with the carbon atoms to which they are attached, a ring with five or six members. In another embodiment, R11 is F, Cl, Br, I, CN, NO2 or OH. In another embodiment, R11 is F, Cl, Br or I. In another embodiment, R11 is Cl.

[0061] The variable n is 1, 2 or 3, preferably 1.

[0062] R2 is C1-C4 alkoxymethyl, preferably CH3CH2OCH2.

[0063] Preferably, compounds of formula I refer to compounds of formula Ia, which fall within the definition of compounds of formula I:

[0064] Preferably, compounds of formula II refer to the compound of formula Ia, which falls within the definition of compounds of formula II:

[0065] Preferably, the compounds of formula III refer to Tralopyril, corresponding to compound IIIa and which falls within the definition of compounds of formula III:

[0066] Preferably, the compounds of formula IV refer to Chlorfenapyr, corresponding to compound IVa and which falls within the definition of compounds of formula IV:

[0067] Preferably, compounds of formula V refer to the compound of formula Va, which falls within the definition of compounds of formula V:

[0068] The organic portions mentioned herein for the definitions of the variables are - like the term halogen - collective terms for individual listings of the members of individual groups. The suffix Cn-Cm indicates, in each case, the possible number of carbon atoms in the group. The term “halogen” denotes, in each case, F, Br, Cl or I, especially F, Cl or Br and particularly Cl. The term "alkyl", as used herein, denotes, in each case, a straight-chain or branched alkyl group normally containing from 1 to 10 carbon atoms, often from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms and, more preferably, 1 to 3 carbon atoms. Examples of alkyl groups are CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, CH3CH2CH2CH2, CH3CH2CH(CH3), (CH3)2CHCH2, (CH3)3C, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2 ,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2 - dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl , 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. The term "haloalkyl", as used herein and in the haloalkyl moieties of haloalkoxy and haloalkoxyalkyl, denotes, in each case, a straight-chain or branched alkyl group normally containing 1 to 10 carbon atoms, often 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, where the hydrogen atoms of this group are totally or partially replaced by halogen atoms. Preferred haloalkyl moieties are selected from C1-C4 haloalkyl, more preferably from C1-C3 haloalkyl or C1-C2 haloalkyl, particularly from C1-C2 fluoroalkyl, such as CH2F, CHF2, CF3, CHFCH3, CH2CH2F, CH2CHF2, CH2CF3, CF2CF3 and the like. The term "alkoxy", as used herein, denotes, in each case, a straight-chain or branched alkyl group that is bonded through an oxygen atom and normally contains from 1 to 10 carbon atoms, often 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Examples of alkoxy group are CH3O, CH3CH2O, CH3CH2CH2O, (CH3)2CHO, CH3CH2CH2CH2O, CH3CH2C(CH3)O, (CH3)2CHCH2O, (CH3)3C and the like. The term "alkoxyalkyl", as used herein, denotes alkyl that normally comprises 1 to 10, often 1 to 4, preferably 1 to 2 carbon atoms, wherein a carbon atom carries an alkoxy radical that normally comprises 1 to 4, preferably 1 or 2 carbon atoms as defined above. Examples are CH3OCH2, C2H5OCH2, CH3OCH2CH2 and CH3CH2OCH2CH2. The term "haloalkoxy", as used herein, denotes, in each case, a straight-chain or branched alkoxy group containing from 1 to 10 carbon atoms, often from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, wherein the hydrogen atoms of that group are fully or partially replaced by halogen atoms, particularly F atoms. Preferred haloalkoxy moieties include C1-C4 haloalkoxy, particularly C1-C2 fluoroalkoxy, such as CH2FO, CHF2O, CF3O, CH3CHFO, CH2FCH2O, CHF2CH2O, CF3CH2O, CHClFCH2O, CClF2CH2O, CCl2FCH2O, CCl3CH2O, CF3CF2O and the like. The term "cycloalkyl", as used herein and in the cycloalkyl moieties of cycloalkoxy and cycloalkylthio, denotes, in each case, a monocyclic cycloaliphatic radical normally containing 3 to 10 or 3 to 6 carbon atoms, such as cyclopropyl ( cC3H4), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “substituted” indicates, in each case, replacement by one or more identical or different substituents. The term “halogenated” indicates total or partial replacement by halogen.

[0069] The expression “the solvent comprises” normally refers to a concentration of at least 50% by weight of the corresponding compound with respect to the total amount of solvent, preferably at least 80% by weight, particularly 100% by weight of compounds of the formula I, II, III and IV can be present in the form of their salts, tautomers and stereoisomers. These salts will typically be obtained by reacting the compounds with an acid, if the compound has basic functionality, such as an amine, or by reacting the compounds with a base, if the compound has acidic functionality. Cations derived from a base, with which the compounds according to the present invention react, are, for example, Ma+ alkali metal cations, Mea2+ alkaline earth metal cations or NR4+ ammonium cations, in which the alkali metals are preferably sodium, potassium or lithium and the alkaline earth metal cations are preferably magnesium or calcium and the R substituents of the NR4+ ammonium cation are preferably independently selected from H, C1-C10 alkyl, phenyl and C1-C2 phenylalkyl. Suitable cations are particularly ions of alkali metals, preferably lithium, sodium and potassium, of alkaline earth metals, preferably calcium, magnesium and barium, and of transition metals, preferably manganese, copper, zinc and iron, as well as ammonium (NH4+ ) and substituted ammonium in which one to four of the hydrogen atoms are replaced by C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl, hydroxy C1-C4 alkoxy C1-C4 alkyl, phenyl or benzyl. Examples of substituted ammonium ions include methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium, 2-(2-hydroxyethoxy)ethylammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltriethylammonium, in addition to phosphonium ions, sulfonium ions, preferably tri(C1-C4 alkyl) sulfoxonium, and sulfoxonium ions, preferably tri(C1-C4 alkyl) sulfoxonium. Anions derived from acid, with which the compounds according to the present invention have reacted, are, for example, chloride, bromide, fluoride, hydrogen sulfate, sulfate, dihydrogen phosphate, hydrogen phosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate and C1-C4 alkanoic acid anions, preferably formate, acetate, propionate and butyrate. Tautomers of the compounds according to the present invention include ketoenol tautomers, imine-enamine tautomers, amide-imidic acid tautomers and the like. The compounds according to the present invention cover all possible tautomers. The term “stereoisomers” encompasses both optical isomers, such as enantiomers or diastereomers, the latter existing due to more than one center of chirality in the molecule, as well as geometric isomers (cis/trans isomers). Depending on the substitution pattern, the compounds according to the present invention may have one or more chirality centers and, in this case, they may be present in the form of mixtures of enantiomers or diastereomers. The terms compounds of formula I, compounds of formula II, compounds of formula III and compounds of formula IV comprise the pure enantiomers or diastereomers of the corresponding compounds and their mixtures. The term “polar aprotic solvents” generally designates solvents that are characterized by a dipole moment of at least 4x10-30 Cm, preferably at least 5x10-30 Cm, more preferably at least 5.5x10-30 Cm. Consequently, the term “nonpolar solvents” generally designates solvents that are characterized by a dipole moment of less than 4x10-30 Cm (Coulomb meter), preferably up to 3x10-30 Cm, more preferably up to 1x10-30 Cm, and particularly less than 0.5x10-30 cm. The expression “POCl3” indicates phosphoryl chloride. The expression “reaction step” generically indicates Step A, Step B, Step C or Step D, as defined above. The expressions “p-chlorophenyl” or “para-chlorophenyl” indicate 4-chlorophenyl. The term “Vilsmeier” refers to a mixture of DMF and POCl3, in which the molar ratio between DMF and POCl3 can be from 1:10 to 10:1, preferably from 1:3 to 3:1, and particularly 1 :1. The term “DIPEA” designates diisopropylethylamine, which is synonymous with the terms “EDIPA”, “((CH3)2CH)2CH3CH2N” and “Hünig base”. Consequently, DIPEA refers to compounds of formula VI:

[0070] DIPEA is a commercially available base. The term “base”, as used in this application, does not indicate compounds of formulas I, II, III, IV or V. The expression “compounds of formula X”, where X is a variable assigned to a specific formula, comprises one of its stereoisomers, salts, tautomers or N-oxides. It should naturally be understood that tautomers can only be present if the structure allows tautomers such as ketoenol tautomers, imine-enamine tautomers, amide-imidic acid automers or similar. Otherwise, the expression “compounds of formula X” does not encompass tautomers. Furthermore, it must be understood that stereoisomers are only possible if there is at least one center of chirality in the molecule or if geometric isomers (cis/trans isomers) can be formed. Compounds may be amorphous or may exist in one or more different crystalline states (polymorphs) that may possess different macroscopic properties, such as stability, or exhibit different biological properties, such as activities. The present invention relates to methods that present amorphous and crystalline compounds, mixtures of different crystalline states of the corresponding compound, as well as their amorphous or crystalline salts. Salts of the compounds are preferably salts acceptable for agricultural use. They can be formed in a customary method, such as by reacting the compound with an acid of the anion in question if the compound has basic functionality. Salts of compounds useful in agriculture especially include acid addition salts of those acids whose cations and anions, respectively, have no adverse effect on the mode of action of the compounds. Anions of useful acid addition salts are mainly chloride, bromide, fluoride, hydrogen sulfate, sulfate, dihydrogen phosphate, hydrogen phosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate and the anions of C1-alkanoic acids. C4, preferably formate, acetate, propionate and butyrate. They can be formed by reacting the compounds with an acid of the corresponding anion, preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid. The term “N-oxide” includes any compounds that have at least one tertiary nitrogen atom that is oxidized to an N-oxide moiety. Naturally, N-oxides can only be formed if a nitrogen atom is present in the compounds.

[0071] Process A comprises Step A. In one embodiment, Process A comprises Step D, followed by Step A. Process B comprises Step B. In one embodiment, Process B comprises Step A, followed by Step B. In another embodiment, Process B comprises Step D, followed by Step A, which in turn is followed by Step B. Process C comprises Step C. In one embodiment, Process C comprises Step B, followed by Step C. In yet another embodiment, Process C comprises Step A, followed by Step B, which, in turn, is followed by Step C. In yet another embodiment, Process C comprises Step D, followed by Step C. by Step A, followed by Step B, which in turn is followed by Step C.

[0072] The present invention also relates to the use of DIPEA as a base in the production of compounds of formula I, particularly in Step A. It also relates to the use of DIPEA as a base in the production of compounds of formula III, particularly in Step B It also refers to the use of DIPEA as a base in the production of compounds of formula IV, particularly in Step C.

[0073] Generally, the reaction steps carried out in processes A, B and C are carried out in reaction vessels customary for these reactions, in which the reactions are carried out continuously, semi-continuously or in batches. Generally, specific reactions will be conducted under atmospheric pressure. The reactions can, however, also be carried out under reduced pressure. The temperatures and durations of the reactions can vary in wide ranges, known to those skilled in the art through analogous reactions. Temperatures often depend on the reflux temperature of the solvents. Other reactions are preferably carried out at room temperature, i.e. at about 25 °C, or under ice cooling, i.e. at about 0 °C. The end of the reaction can be monitored using methods known to those skilled in the art, such as thin layer chromatography or HPLC. Unless otherwise indicated, the reactants can, in principle, be brought into contact with each other in any desired sequence. Those skilled in the art know when reagents are sensitive to humidity, so the reaction must be carried out under protective gases, such as a nitrogen atmosphere, and dry solvents must be used. Those skilled in the art also know the best way to work with the reaction mixture after the end of the reaction.

[0074] The following examples illustrate the present invention.

EXAMPLES

[0075] Characterization: Characterization can be carried out using High Performance Liquid Chromatography coupled to a UV-VIS detector at a wavelength of 220 nm, using known and analytically verified standards for all compounds and intermediates. The gradient used 45% vol. of ACN/55% vol., pH 2.1, aqueous phosphate buffer solution as mobile phase A and 100% ACN for mobile phase B. The column used contained reverse phase C-18 material.

[0076] The abbreviations used are: h for hour(s), min for minute(s), eq for equivalent(s) and hPa for hectoPascal. NaOHaq is a solution of NaOH in water. TFA-Cl is trifluoroacetyl chloride. PCPG is 4-parachlorophenylglycine.

EXAMPLE 1

[0077] Preparation of Tralopyril and Chlorfenapyr using DIPEA as a base:

Step A1: preparation of 4-(4-chlorophenyl)-2-(trifluoromethyl)-2H-oxazol-5-one.

[0078] To a previously weighed reactor equipped with a mechanical stirrer, condenser, thermocouple and addition funnel, PCPG (41.3 g, 97.7% pure) was added under an argon gas atmosphere. A solution consisting of ACN (86.8 g) and toluene (37.2 g), as well as DMF (0.13 g), was added to the reactor. The resulting mixture was stirred into syrup. PCl3 (13.55 g) was charged for thirty minutes through a funnel into the syrup, while maintaining the reaction temperature at 30 °C to 35 °C. Immediately after the completion of the PCl3 addition, TFA-Cl gas (31.6 g) was added below the surface to the reactor over the course of one hour, so that the temperature was maintained at 40 °C to 60 °C. After the TFA-Cl addition was completed, the resulting yellow syrup was kept at 45 °C for an additional eight hours. Analysis of the mixture using HPLC resulted in a 99.9% yield of 4-(4-chlorophenyl)-2-(trifluoromethyl)-2H-oxazol-5-one. The reaction temperature was then raised to 68 °C to 82 °C and maintained for 90 minutes. The syrup was then kept cooled at 25 °C.

[0079] Step A2: preparation of 2-(4-chlorophenyl)-5-(trifluoromethyl)- 1H-pyrrolo-3-carbonitrile.

[0080] To the reactor containing the 4-(4-chlorophenyl)-2-(trifluoromethyl)-2H-oxazol-5-one syrup from Step A1, a solution of 2,3-dichloropropionitrile (28.51 g) in DMF (21.34 g). DIPEA (102.8 g) was then added to the reactor for 38 minutes, maintaining the reaction temperature at 20 °C to 55 °C. The reactor then contained a dark solution with some white vapor above the solution, which was removed to the condenser. The solution was maintained at 35 °C for 60 minutes. Analysis of the solution using HPLC resulted in a yield of 2-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrolo-3-carbonitrile of 89.8% with respect to the amount of PCPG in Step A1.

Step A3: Tralopiril preparation.

[0081] To the reactor containing the 2-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrolo-3-carbonitrile solution from Step A2, Br2 (39.9 g) was added for 20 minutes, maintaining The reaction temperature is 30 °C to 40 °C. White fog was produced by the reaction mixture, which had turned into a dark solution. After complete addition of Br2, the reaction temperature was maintained at 35 °C for 40 minutes. Toluene (144 g) was added to the solution, followed by distillation at 80 °C and pressure from 393 hPa to 407 hPa to remove ACN from the reaction mixture. An amount of toluene equal to the amount removed through distillation was then added, as well as deionized H2O (100 g), to the reaction mixture, which was stirred at 80 °C for 15 minutes and divided into Aqueous Layer I and a layer organic matter in a previously heated separating funnel. Analysis of the organic layer using HPLC resulted in a Tralopyril yield of 88.2% in relation to the amount of PCPG in Step A1. Residual water in the organic phase was distilled under reduced pressure at 65 °C, so that the volume of solvent removed was balanced by the addition of an equivalent volume of toluene. The Tralopyril solution in toluene was then cooled to 25 °C.

Step A4: Chlorfenapyr preparation.

[0082] The Tralopyril in toluene solution from Step A3 was added to a reactor, followed by the addition of (CH3CH2O)2CH2 (28.9 g). P(O)Cl3 (31.9 g) was then added to the reactor for 24 minutes, maintaining the reaction temperature at 45 °C to 55 °C. After completion of the addition, the reaction temperature was maintained at 45 °C to 65 °C for 60 minutes. DIPEA (40.8 g) was then loaded for 10 minutes, maintaining the reaction temperature at 40 °C to 50 °C. The reaction mixture was then kept at 45 °C for one hour. At this time, the reaction mixture had become a dark solution. Demineralized H2O (38.9 g) and NaOHaq (50 wt%, 17.4 g) were added and the resulting two-phase mixture was heated to 75 °C. After maintaining this temperature for 10 minutes, the mixture was divided into an Aqueous Layer II and an organic layer in a previously heated separation funnel. Analysis of the organic phase using HPLC resulted in a Chlorfenapyr yield of 87.8% in relation to the amount of PCPG in Step A1.

Step A5: DIPEA recovery.

[0083] To Aqueous Layer I of Step A3, NaOHaq (50% by weight, 85.1 g) and H2O (39.1 g) were added. The resulting composition was stirred at 70 °C and the lower layer was then discarded. The top layer generated 88 g of DIPEA with 92% purity determined via GC, containing about 8 wt% toluene and less than 0.2 wt% H2O. To Aqueous Layer II of Step A4, NaOHaq (50% by weight, 60.6 g) and H2O (19.5 g) were added. The resulting composition was stirred at 70 °C for thirty minutes and the lower layer was then discarded. The top layer generated 57 g of DIPEA with 95% purity determined via GC, containing about 5 wt% toluene and less than 0.2 wt% H2O. The overall recovery rate of DIPEA was 95%. Due to the low water content of DIPEA recovered in this way, distillation was not necessary.

COMPARATIVE EXAMPLE 2

[0084] Preparation of Tralopyril and Chlorfenapyr using TEA as a base:

Step B1: preparation of 4-(4-chlorophenyl)-2-(trifluoromethyl)-2H-oxazol-5-one.

[0085] To a previously weighed reactor equipped with a mechanical stirrer, condenser, thermocouple and addition funnel, PCPG (38.0 g, 98.6% pure) was added under an argon gas atmosphere. A solution consisting of ACN (80.5 g) and toluene (34.5 g), as well as DMF (0.13 g), was added to the reactor. The resulting mixture was stirred into syrup. PCl3 (12.6 g) was charged for thirty minutes through a funnel into the syrup, while maintaining the reaction temperature at 30 °C to 35 °C. Immediately after the completion of the PCl3 addition, TFA-Cl gas (28.4 g) was added below the surface to the reactor over the course of one hour, so that the reaction temperature was maintained at 40 °C to 60 °C . After the TFA-Cl addition was completed, the resulting yellow syrup was kept at 45 °C for an additional eight hours. Analysis of the mixture using HPLC resulted in a 99.9% yield of 4-(4-chlorophenyl)-2-(trifluoromethyl)-2H-oxazol-5-one. The reaction temperature was then raised to 68 °C to 82 °C and maintained for 90 minutes. The syrup was then kept cooled at 25 °C.

Step B2: preparation of 2-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrolo-3-carbonitrile.

[0086] To the reactor containing the 4-(4-chlorophenyl)-2-(trifluoromethyl)-2H-oxazol-5-one syrup from Step B1, a solution of 2,3-dichloropropionitrile (22.51 g) in DMF (22.96 g). TEA (75.0 g) was then added to the reactor for 38 minutes, maintaining the reaction temperature at 20 °C to 55 °C. The reactor then contained a yellow syrup and water vapor above the syrup, which was deposited in the condenser. The solution was maintained at 35 °C for 60 minutes. Analysis of the mixture using HPLC resulted in a yield of 2-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrolo-3-carbonitrile of 79.7% in relation to the amount of PCPG in Step B1.

Step B3: Tralopiril preparation.

[0087] To the reactor containing the 2-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrolo-3-carbonitrile syrup from Step B2, Br2 (37.1 g) was added for 20 minutes, maintaining The reaction temperature is 30 °C to 40 °C. White fog was produced by the reaction mixture, which had turned into a thick dark solution. After complete addition of Br2, the reaction temperature was maintained at 35 °C for 40 minutes. Toluene (144 g) was added to the syrup, followed by distillation at 80 °C and pressure from 393 hPa to 407 hPa to remove ACN from the reaction mixture. The amount of toluene removed through distillation, as well as deionized H2O (109 g), was added to the reaction mixture, which was stirred at 80 °C for 15 minutes and divided into Aqueous Layer III and an organic layer in a separatory funnel. previously heated. Analysis of the organic layer using HPLC resulted in a Tralopyril yield of 75.3% in relation to the amount of PCPG in Step B1. Residual water in the organic phase was distilled under reduced pressure at 65 °C, so that the volume of solvent removed was balanced by the addition of an equivalent volume of toluene. The Tralopyril solution in toluene was then cooled to 25 °C.

Step B4: Chlorfenapyr preparation.

[0088] The Tralopyril in toluene solution from Step B3 was added to a reactor, followed by the addition of (CH3CH2O)2CH2 (26.9 g). P(O)Cl3 (29.7 g) was added to the reactor then for 24 minutes, maintaining a reaction temperature of 45 °C to 55 °C. The reaction temperature was then maintained at 45 °C to 65 °C for 60 minutes. TEA (29.8 g) was then loaded for 10 minutes, while maintaining a reaction temperature of 40 °C to 50 °C. The reaction mixture was then kept at 45 °C for one hour. At this point, the reaction mixture had become a dark syrup. Demineralized H2O (80 g) and NaOHaq (50 wt%, 16.2 g) were added and the resulting two-phase mixture was heated to 75 °C. After maintaining this temperature for 10 minutes, the mixture was divided into an Aqueous Layer IV and an organic layer in a previously heated separation funnel. Analysis of the organic phase using HPLC resulted in a Chlorfenapyr yield of 75.1% in relation to the amount of PCPG in Step B1.

Step B5: ASD recovery.

[0089] To Aqueous Layer III of Step B3, NaOHaq (50% by weight, 79.2 g) and H2O (36.4 g) were added. The resulting composition was stirred at 70 °C and the lower layer was then discarded. The top layer generated 68 g of TEA with 94% purity determined using GC, containing about 3.5% by weight of toluene and 2.2% by weight of H2O. To the Aqueous Layer IV of Step B4, NaOHaq (50% by weight, 65.4 g) and H2O (18.2 g) were added. The resulting composition was stirred at 70°C for thirty minutes and the lower layer was then removed. The top layer generated 25.6 g of TEA with 94% purity determined via GC, containing about 2.4 wt% toluene and 3.0 wt% H2O. Due to the high water content of TEA recovered in this way, the combined raw TEA is distilled under atmospheric pressure and temperature of 72 °C to 92 °C. The first 15 g of distillate was discarded due to high water content. The remaining distillate contained 74.4 g of TEA with 95% purity determined via GC, containing less than 0.2% by weight. The overall recovery rate from ASD was 67.4%.

EXAMPLE 3

[0090] Comparison of bases in Step A: Pyridine, 1,2-diazabicyclo[2,2,2]octane and tripropylamine were used as bases in Step A. The experiments were conducted analogously to Step A2 in Example 1. Consequently , the ratio between the bases and 4-(4-chlorophenyl)-2-(trifluoromethyl)-2H-oxazol-5-one was about 3.65. The following yields of 2-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrolo-3-carbonitrile could be obtained and calculated with respect to the amount of PCPG added in Step A1. TABLE 1

[0091] Yields of 2-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrolo-3-carbonitrile depending on the base:

EXAMPLE 4

[0092] Visual determination of Step A: The reaction mixtures of Steps A2 of Example 1 and B2 of Comparative Example 2 were determined visually. In the case of A2, a clear and easy-to-handle solution and little fog production were observed. In the case of B2, a thick syrup and a lot of fog were visible, which completely filled the condenser. Figures 1 and 2 displayed photographs that were taken of the corresponding reaction vessels.

EXAMPLE 5

[0093] Visual determination of Step B: The reaction mixtures of Steps A3 of Example 1 and B3 of Comparative Example 2 were determined visually. In the case of A3, little fog production was observed. In the case of B3, a lot of fog was visible, which completely filled the condenser. Figure 3 displayed a photograph that was taken of the corresponding reaction vessels during the reaction.

EXAMPLE 6

[0094] Visual determination of Step B: The reaction mixtures of Steps A4 of Example 1 and B4 of Comparative Example 2 were determined visually. In the case of A3, a clear and easy-to-use solution was observed. In the case of B4, a thick syrup was produced. Figures 4 and 5 displayed photographs that were taken of the corresponding reaction vessels during the reaction.

Claims (15)

1. PROCESS A FOR PRODUCING COMPOUNDS, of formula I: where the variables have the following meaning: - R1 is phenyl, replaced by none, one or more R11, identical or different; - R11 is F, Cl, Br, I, CN, NO2, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkyl-C(O)O, C1 haloalkyl -C4- C(O)O; or two R11 substituents located on adjacent phenyl ring atoms together are a group -OCH2O-, -OCF2O- or -CH=CH-CH=CH- and form, together with the carbon atoms to which they are attached, a ring with five or six members; e - n is 1, 2 or 3; characterized by comprising Step A of reacting compounds of formula II: wherein the variables have the same meaning defined for compounds of formula I; with 2,3-dihalopropionitrile or 2-haloacrylonitrile in the presence of diisopropylethylamine. 2. PROCESS according to claim 1, characterized in that Step A is carried out in a solvent comprising a polar aprotic solvent, particularly a solvent comprising acetonitrile. 3. PROCESS, according to any one of claims 1 to 2, characterized in that compounds of formula I are produced by reacting compounds of formula II with 2,3-dichloropropionitrile. 4. PROCESS, according to claim 1, which additionally comprises a PROCESS B FOR PRODUCING COMPOUNDS, of formula III: wherein the variables have the defined meaning for compounds of formula I; characterized in that it comprises Step B of reacting compounds of formula I with Br2 in the presence of diisopropylethylamine. 5. PROCESS, according to claim 4, characterized in that Step B is carried out in a solvent comprising a polar aprotic solvent, particularly a solvent comprising acetonitrile. 6. PROCESS according to any one of claims 4 to 5, characterized in that the compounds of formula I are produced as defined in any one of claims 1 to 4. 7. PROCESS, according to claim 6, characterized in that steps A and B are conducted as a one-pot process. 8. PROCESS, according to any one of claims 1 to 7, characterized in that R1 is parachlorophenyl and n is 1. 9. PROCESS, according to claim 4, which additionally comprises a PROCESS C FOR PRODUCING COMPOUNDS, of formula IV: wherein R1 and n are as defined for compounds of formula I; wherein R2 is C1-C4 alkoxymethyl; characterized by Step C comprising reacting compounds of formula III with di(C1-C4 alkoxy)methane and POCl3 or a mixture comprising POCl3 and DMF (Vilsmeier reagent), in the presence of diisopropylethylamine. 10. PROCESS, according to claim 9, characterized in that R1 is p-chlorophenyl, n is 1 and R2 is CH3CH3OCH2. 11. PROCESS, according to any one of claims 9 to 10, characterized in that Step C is carried out in a solvent comprising C5-C16 aliphatic hydrocarbons, C6-C10 aromatic hydrocarbons, halogenated C1-C6 aliphatic alkanes, halogenated C6-C10 aromatic hydrocarbons , C1-C6 nitriles, DMF or one of their mixtures. 12. PROCESS, according to any one of claims 9 to 11, characterized in that the compounds of formula IV are produced by means of a process, as defined in any one of claims 4 to 8. 13. PROCESS, according to any one of claims 1 to 12, characterized in that compounds of formula II are produced in Step D through the reaction of compounds of formula V: wherein R1 has a meaning as defined for compounds of formula I; with CnF2n+1C(O)Cl and PCl3. 14. PROCESS, according to claim 13, characterized by Step D and Step A being conducted in a one-pot process. 15. USE OF DI-ISOPROPYLETHYLAMINE, characterized by being as a base in the production of compounds of Formula I, compounds of Formula III or compounds of Formula IV, according to the process as defined in claims 1, 4 and 9, respectively.