Process for the preparation of nitrobenzene derivatives

Abstract

The present invention provides a process for the preparation of a compound of formula I wherein: R1, R2, R3, R4, and R5 each independently is hydrogen; halogen; (C1-C6)alkyl; (C1-C6)haloalkyl; -NR'R", wherein R' and R" each independently is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, or both R' and R" together with the nitrogen atom to which they are attached form a 3 to 7 membered heterocyclic ring; or -COOR wherein R is hydrogen or (C1-C6)alkyl.

Description

PROCESS FOR THE PREPARATION OF NITROBENZENE DERIVATIVESTECHNICAL FIELD

[0001] The present invention provides a process for the preparation of nitrobenzene derivatives which are useful intermediates for organic synthesis such as for the preparation of active ingredients, e.g., herbicidal active ingredients.BACKGROUND ART

[0002] Nitrobenzene derivatives were first discovered around 1834 by Mitscherlich using coal tar with fuming nitric acid and can be used as a reactant to synthesize other molecules due to their easy conversation into various functional groups. They are widely used in the synthesis of dyes and intermediates, pharmaceuticals, agrochemicals, and pigments as well as a variety of fine chemicals such as solvents, perfumes, explosives, and polymers (Wahyuni etal., 2022).

[0003] The traditional aromatic nitration method is generally conducted using nitric acid or metal nitrates, and concentrated sulfuric acid through electrophilic substitution reaction. The reaction mechanism of electrophilic aromatic nitration has been studied by scientists for past years, and the foundation of the reaction method was lead by Ingold and Hughes (Patel et al., 2021).

[0004] WO 2018 / 141642 discloses a process for the preparation of 2-chloro-4-fluoro- 5-nitrobenzotri chloride, as well as a process for the purification of 2-chloro-4-fluoro-5-nitrobenzotri chloride, which reduces the isomeric impurities and acidic byproducts. Specifically, the disclosed process involves nitrating 2-chloro-4-fluorobenzotrichloride with a nitration mixture consisting of red fuming nitric acid and concentrated sulfuric acid, adding a halogenated organic solvent, separating the organic layer comprising 2-chloro-4-fluoro-5-nitrobenzotrichloride and washing it with a basic aqueous solution and subsequent crystallization of 2-chloro-4-fluoro-5-nitrobenzotrichloride from an organic solvent and water.

[0005] There is a need for a nitration process that affords the product with high yield, high quality, and that does not require additional purification, as well as prevents the need of aqueous quenching.SUMMARY OF INVENTION

[0006] The Experimental section herein shows the preparation of 2-chloro-4-fluoro-5-nitrobenzotri chloride (also referred to as l-chloro-5-fluoro-4-nitro-2-(trichloromethyl)benzene). Specifically, 2-chloro-4-fluorobenzotrichloride (also referred to as 2-chloro-4-fluoro-l-(trichloromethyl)benzene) was reacted with a nitration mixture comprising concentrated sulfuric acid, concentrated nitric acid, a halogenated organic solvent, more specifically di chloroethane, and a polar organic solvent, more specifically sulfolane, to afford 2-chloro-4-fluoro-5-nitrobenzotrichloride in a high yield, e.g., above 90%.

[0007] In one aspect, the present invention thus relates to a process for the preparation of a compound of formula IR1, R2, R3, R4, and R5each independently is hydrogen; halogen; (Ci-Ce)alkyl; (Ci-Ce)haloalkyl; -NR’R”, wherein R’ and R” each independently is hydrogen, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, or both R’ and R” together with the nitrogen atom to which they are attached form a 3 to 7 membered heterocyclic ring; or -COOR wherein R is hydrogen or (Ci-C6)alkyl,said process comprising reacting a compound of formula IIa nitration mixture comprising concentrated sulfuric acid, concentrated nitric acid, a halogenated organic solvent, and a polar organic solvent selectedO. Z0XR6R7from: (a) a compound of III111, wherein R6and R7each independently is (Ci- Ci2)alkyl or both R6andR7together with the sulfur atom to which they are attached form a 3 to 7 membered heterocyclic ring; and (b) a glycol ether, under mixing,to thereby obtain the compound of formula I.

[0008] In certain embodiments, disclosed herein is a process for the preparation of the compound of formula I as defined above, wherein said polar organic solvent is sulfolane and said halogenated organic solvent is di chloroethane.

[0009] In another aspect, the present invention provides a process for the preparation of a compound of formula V,wherein:R1, R3, R4, and R5are each as defined in claim 1;R8is H or (Ci-C6)alkyl;R9is H, (Ci-C6)alkyl, or (Ci-C6)haloalkyl;R10and R11each independently is (Ci-Ci2)alkyl, (C2-Ce)alkenyl, (C3-Cs)cycloalkyl, aryl, heteroaryl, or R10and R11together with the nitrogen atom to which they are attached form a 5-8 membered ring,said process comprising preparing the compound of formula I according to the process disclosed hereinabove and transforming said compound of formula I into the compound of formula V.DETAILED DESCRIPTION

[0010] In one aspect, disclosed herein is a process for the preparation of a compound of formula I, as defined above, said process comprising reacting a compound of formula II as defined above, with a nitration mixture comprising concentrated sulfuric acid, concentrated nitric acid, a halogenated organic solvent, and a polar organic solvent selected from: (a) a compound of III, as defined above; and (b) a glycol ether, under mixing, to thereby obtain the compound of formula I.

[0011] The term “alkyl” typically means a linear or branched hydrocarbon group having, e.g., 1-6 carbon atoms and includes methyl, ethyl, w-propyl, isopropyl, / / -butyl, sec-butyl, isobutyl, tert-butyl, w-pentyl, 2,2-dimethylpropyl, w-hexyl, and the like.

[0012] The term "halogen" as used herein refers to a halogen and includes fluoro, chloro, bromo, and iodo, but it is preferably fluoro or chloro.

[0013] The term "haloalkyl" as used herein typically means an alkyl as defined hereinabove, which is substituted with one or more, e.g., one, two or three, halogens each independently being selected from fluoro, chloro, bromo, or iodo.

[0014] The term "heterocyclic ring" as used herein denotes a mono-cyclic non-aromatic ring of, e.g., 3-7 atoms containing at least two carbon atoms, sulfur atom, and optionally one or more additional heteroatoms selected from sulfur, oxygen, and nitrogen, which may be saturated or unsaturated, i.e., containing at least one unsaturated bond. Preferred are 5-or 6-membered heterocyclic rings. The heterocyclic ring may be substituted at any of the carbon atoms of the ring, e.g., by one or more alkyl groups. Non-limiting examples of such rings include tetrahydrothiophene and 2,5-dihydrothiophene.

[0015] The term “halogenated organic solvent” as used herein refers to a saturated (i.e., having no unsaturated bonds) non-aromatic organic solvent which contains at least one halogen atom, and may be referred to as a halocarbon or a halogenated hydrocarbon. Nonliming examples of halogenated organic solvents include a chlorinated organic solvent, a brominated organic solvent, a chlorinated-fluorinated organic solvent, and a mixture thereof.

[0016] The term “polar organic solvent” as used herein refers to an organic solvent having a large dipole moment and / or high dielectric constant.

[0017] In certain embodiments, the process of the invention further comprises adding an additional amount of the halogenated organic solvent, and separating the organic phase (layer; which contains the compound of formula I) and the acidic phase (layer). The“additional amount of the halogenated organic solvent” refers to a portion of said solvent that is added after reacting the compound of formula II with the nitration mixture.

[0018] Particular such embodiments are those wherein following the separation of the phases, the acidic phase (layer) is extracted with additional portion of the halogenated solvent, the organic phases are combined and then said combined organic phases are washed with water. The compound of formula I is present in the organic phase with high purity such as above 90% purity, e.g., above 91%, above 92%, above 93%, above 94%, above 95%, above 96%, above 97%, above 98%, or at least 99% purity.

[0019] More particular such embodiments are those wherein the remaining acidic phase (layer) is reused for said process. According to the invention, the acidic phase, e.g., part of or all the remaining acidic phase from the process, may be reused in a subsequent batch of the process, thereby reducing the amount of acidic waste. In such case, oleum is added to the reused amount of the acidic phase according to amount of water accumulated in the reused acidic phase.

[0020] In certain embodiments, the process of the present invention is a process as defined in any one of the embodiments above, wherein the halogenated organic solvent comprised within the nitration mixture which is reacted with the compound of formula II is a chlorinated organic solvent. Non-limiting examples of chlorinated organic solvents include di chloroethane (e.g., 1,2-di chloroethane), tri chloroethane (e.g., 1,1,1-tri chloroethane), tetrachloroethane (e.g., 1,1,2,2-tetrachloroethane), trichloropropane (e.g., 1,2, 3 -tri chloropropane), tetrachloropropane (e.g., 1,1,1,2-tetrachloropropane), dichloromethane, carbon tetrachloride, an isomer thereof, and a mixture thereof.

[0021] In certain embodiments, the process of the present invention is a process as defined in any one of the embodiments above, wherein the halogenated organic solvent comprised within the nitration mixture which is reacted with the compound of formula II is a chlorinated-fluorinated organic solvent. Non-limiting examples of chlorinated-fluorinated organic solvents include trichloro trifluoro ethane (e.g., 1, 1,2-tri chi oro-1, 2,2-trifluoroethane), trichloro trifluoro propane (e.g., l,l,3-trichloro-l,2,2-trifluoropropane), an isomer thereof, and a mixture thereof.

[0022] In certain embodiments, the process of the present invention is a process as defined in any one of the embodiments above, wherein the polar organic solvent is a compound of formula III, as defined hereinabove. Non-limiting examples of compounds of formula III include (i) sulfolane (i.e., wherein both R6and R7together with the sulfur atomto which they are attached form tetrahydrothiophene); and (ii) sulfolene (i.e., wherein both R6and R7together with the sulfur atom to which they are attached form 2,5-dihydrothiophene).

[0023] In certain embodiments, the process of the present invention is a process as defined in any one of the embodiments above, wherein the polar organic solvent is a glycol ether. The term “glycol ether” as used herein refers to a chemical compound consisting of mono-, di-, tri-, tetra- or polyethylene glycols.

[0024] Non-limiting example of a glycol ether is a compound of formula IV1V, wherein R each independently is (Ci-Ce)alkyl, and n is an integer of 1-9.

[0025] Non-limiting examples of glycol ethers of formula IV include monoglyme (i.e., wherein R is methyl and n is 1), diglyme (i.e., wherein R is methyl and n is 2), triglyme (i.e., wherein R is methyl and n is 3), tetraglyme (i.e., wherein R is methyl and n is 4), ethyl glyme (i.e., wherein R is ethyl and n is 1), ethyl diglyme (i.e., wherein R is ethyl and n is 2), butyl glyme (i.e., wherein R is butyl and n is 1), and butyl diglyme (i.e., wherein R is butyl and n is 2).

[0026] In certain embodiments, the process disclosed herein, according to any one of the embodiments above, is for the preparation of a compound of the formula I, wherein R1, R2, R3, R4, and R5each independently is hydrogen, halogen, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl. Particular such embodiments are those wherein R1andR4each is hydrogen; R3andR5each is halogen; and R2is (Ci-C3)haloalkyl. More particular such embodiments are those wherein R1andR4each is hydrogen; R3is Cl; R5is F; and R2is -CCh, i.e., the process is for the preparation of 2-chloro-4-fluoro-5-nitrobenzotrichloride.

[0027] The term “nitration mixture” as used herein refers to a mixture comprising concentrated sulfuric acid, concentrated nitric acid, a halogenated organic solvent, and a polar organic solvent selected from: (a) a compound of III as defined hereinabove; and (b) a glycol ether. According to the invention, the nitration mixture is reacted with a compound of formula II as defined hereinabove under mixing, to obtain the nitrobenzene compound of formula I as defined hereinabove.

[0028] In certain embodiments, the weight ratio between the concentrated sulfuric acid and the concentrated nitric acid comprised with the nitration mixture utilized according tothe process of the invention according to any one of the embodiments above is in the range of from about 3:1 to 10:1, e.g., from about 3.5:1 to about 9:1, from about 4:1 to about 9:1, from about 4.5:1 to about 7: 1, or from about 5: 1 to about 6:1, respectively.

[0029] In certain embodiments, the process of the invention according to any one of the embodiments above comprises reacting the compound of formula II as defined hereinabove with a nitration mixture as defined hereinabove, wherein the molar ratio between the concentrated nitric acid comprised within said nitration mixture and the compound of formula II is in the range of from about 1.1:1 to 2:1, e.g., from about 1.15:1 to about 1.7:1, from about 1.2:1 to about 1.5:1, from about 1.25:1 to about 1.2:1, from about 1.3:1 to about 1:1, about 1.35:1, about 1.4:1, or about 1.45:1, respectively.

[0030] In certain embodiments, the weight ratio between: (i) the mixture of the halogenated organic solvent and the polar organic solvent comprised within the nitration mixture utilized according to the process of the invention according to any one of the embodiments above, and (ii) the compound of formula II as defined hereinabove, is in the range of from about 0.5:1 to 2:1, e.g., from about 0.7:1 to about 1.8:1, from about 0.9:1 to about 1.5:1, or from about 1:1 to about 1.2:1, respectively.

[0031] In certain embodiments, the weight ratio between the polar organic solvent and the halogenated organic solvent comprised within the nitration mixture as defined herein above is in the range of from about 0.2:1 to 1:1, e.g., from about 0.25:1 to about 0.95:1, from about 0.3:1 to about 0.9:1, from about 0.35:1 to about 0.85:1, from about 0.4:1 to about 0.8:1, from about 0.45:1 to about 0.75:1, or from about 0.5:1 to about 0.7:1, respectively.

[0032] In certain embodiments, the process of the present invention is a process as defined in any one of the embodiments above, wherein said process is carried out at a temperature ranging from about 0°C to about 30°C, e.g., from about 1°C to about 25°C, from about 2°C to about 20°C, from about 3°C to about 15°C, from about 4°C to about 10°C, from about 5°C to about 8°C, or about 5°C.

[0033] In certain embodiments, the process of the invention according to any one of the embodiments above comprises reacting the compound of formula II as defined hereinabove with a nitration mixture as defined hereinabove, wherein the compound of formula II is added gradually to the nitration mixture at a temperature below 10°C, e.g., from about 0°C to about 10°C, from about 1°C to about 8°C, from about 2°C to about 6°C, or from about 3 °C to about 5 °C.

[0034] In certain embodiments, the polar organic solvent comprised within the nitration mixture utilized according to the process of the invention according to any one of the embodiments above is sulfolane; and the halogenated organic solvent comprised within the nitration mixture utilized according to the process of the invention according to any one of the embodiments above is dichloroethane. Particular such embodiments are those wherein the weight ratio between the sulfolane and di chloroethane is in the range of from about 0.2:1 to about 1:1, e.g., from about 0.25:1 to about 0.95:1, from about 0.3:1 to about 0.9:1, from about 0.35:1 to about 0.85:1, from about 0.4:1 to about 0.8:1, from about 0.45:1 to about 0.75:1, or from about 0.5:1 to about 0.7:1, respectively.

[0035] In certain embodiments, the process of the present invention is a process as defined in any one of the embodiments above, wherein: (a) the halogenated organic solvent is a chlorinated organic solvent; (b) the compound of formula III is sulfolane (i.e., wherein both R6and R7together with the sulfur atom to which they are attached form tetrahydrothiophene); (c) said process is used for the preparation of the compound of formula I, wherein R1and R4each is hydrogen; R3and R5each is halogen; and R2is (Ci-C3)haloalkyl; (d) the weight ratio between the concentrated sulfuric acid and the concentrated nitric acid is in the range of from about 3:1 to 10:1, e.g., from about 3.5:1 to about 9:1, from about 4:1 to about 9:1, from about 4.5:1 to about 7:1, or from about 5:1 to about 6:1, respectively; (e) the molar ratio between the concentrated nitric acid and the compound of formula II is in the range of from about 1.1:1 to 2:1, e.g., from about 1.15:1 to about 1.7:1, from about 1.2:1 to about 1.5:1, from about 1.25:1 to about 1.2:1, from about 1.3:1 to about 1:1, about 1.35:1, about 1.4:1, or about 1.45:1, respectively; (f) the weight ratio between the mixture of the halogenated organic solvent and the polar organic solvent and the compound of formula II is in the range of from about 0.5:1 to 2:1, e.g., from about 0.7:1 to about 1.8:1, from about 0.9:1 to about 1.5:1, or from about 1:1 to about 1.2:1, respectively; and (g) the weight ratio between the polar organic solvent and the halogenated organic solvent is in the range of from about 0.2:1 to 1:1, e.g., from about 0.25:1 to about 0.95:1, from about 0.3:1 to about 0.9:1, from about 0.35:1 to about 0.85:1, from about 0.4:1 to about 0.8:1, from about 0.45:1 to about 0.75:1, or from about 0.5:1 to about 0.7:1, respectively (also referred to herein as “a nitration-based process”).

[0036] In particular such embodiments, the chlorinated organic solvent is di chloroethane and the weight ratio between the sulfolane and dichloroethane is in the range of from about 0.3:1 to about 0.7:1, respectively.

[0037] In certain embodiments, the nitration-based process as defined hereinabove is used for the preparation of the compound of formula I, wherein R3is Cl; R5is F; and R2is -CCh, i.e., said process is for the preparation of 2-chloro-4-fluoro-5-nitrobenzotrichloride.

[0038] The process disclosed herein, according to any one of the embodiments above, may be carried out with different efficiencies, depending on the specific reagents such as solvents, and conditions, e.g., temperature, used. In other words, the product of this process may comprise different percentages of the desired compound I, as well as certain amounts of other compounds such as non-reacted starting material. Thus, in certain embodiments, the yield of the compound of formula I obtained by the process of the present invention is at least 70%, e.g., at least 75%, at least 80%, at least 85%, higher than 90%, or higher than 95%.

[0039] The nitrobenzene compounds of formula I prepared by the process disclosed herein according to any one of the embodiments above may be used as intermediates for the preparation of active ingredients such as pharmaceuticals and agrochemicals.

[0040] In another aspect, the present invention thus provides a process for the preparation of a compound of formula V,wherein:R1, R3, R4, and R5are each as defined in claim 1;R8is H or (Ci-C6)alkyl;R9is H, (Ci-C6)alkyl, or (Ci-C6)haloalkyl;R10and R11each independently is (Ci-Ci2)alkyl, (C2-Ce)alkenyl, (C3-Cs)cycloalkyl, aryl, heteroaryl, or R10and R11together with the nitrogen atom to which they are attached form a 5-8 membered ring,said process comprising preparing the compound of formula I according to the process disclosed herein, according to any one of the embodiments above, and transforming said compound of formula I into the compound of formula V (also referred to herein as “a process for the preparation of the compound of formula V”).

[0041] The term "alkenyl" typically means a linear or branched hydrocarbon group having one or more double bonds. Particular alkenyl groups are (C2-Ce)alkenyl groups such as ethenyl, propenyl, 3-buten-l-yl, 2-ethenylbutyl, 3-octen-l-yl, and the like.

[0042] The term “cycloalkyl” means a mono- or bicyclic saturated hydrocarbyl group having, e.g., 3-8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, that may be substituted, e.g., by one or more alkyl groups.

[0043] The term “aromatic ring” refers to an aromatic carbocyclic ring having, e.g., 6-14 carbon atoms, and consisting of a single ring or multiple rings either condensed or linked by a covalent bond. Non-limiting examples of aromatic rings include benzene, naphthalene, anthracene, naphthacene, phenanthrene, pyrene, chrysene, tetracene, and triphenylene. The term "aryl" as used herein denotes a univalent radical derived from an aromatic ring as defined herein by removal of hydrogen atom from any of the ring atoms. Preferred are (Ce-Cio)aryl groups.

[0044] The term “heteroaromatic ring” refers to a mono-, bi-, or poly-cyclic aromatic ring having, e.g., 4-12 atoms, and consisting of at least one carbon atom and at least one heteroatom selected from oxygen, sulfur or nitrogen. Preferred are 5- or 6-membered heteroaromatic rings. Non-limiting examples of heteroaromatic ring include thiophene, imidazole, pyridine, furan, pymole, oxazole, thiazole, purine, indole, pyrrole, pyrazine, isoquinoline, pyrazole, isoxazole, thiazole, isothiazole, pyrazine, pyrimidine, pyridazine, carbazole. The term “heteroaryl” as used herein refers to a univalent radical derived from a heteroaromatic ring as defined herein by removal of hydrogen atom from any of the ring atoms.

[0045] According to the invention, the process for the preparation of the compound of formula V may be used for the preparation of various compounds, e.g., herbicidal active ingredients such as saflufenacil.

[0046] In certain embodiments, the process for the preparation of the compound of formula V disclosed herein is for preparing a compound of formula V wherein R1and R4each is hydrogen; R10and R11each independently is (Ci-Ce)alkyl such as methyl, ethyl, n-propyl, isopropyl, / / -butyl, sec-butyl, isobutyl, tert-butyl, w-pentyl, 2,2-dimethylpropyl, and / / -hexyl; R3and R5each independently is halogen such as Cl and F; R8is H or (Ci-C4)alkyl and R9is (Ci-Ce)haloalkyl. Particular such embodiments are those wherein R10is methyl; R11is isopropyl; R3is Cl; R5is F; R8is methyl; and R9is CF3 (saflufenacil).

[0047] Saflufenacil (2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-l-(2H)pyrimidinyl]-4-fluoro-N-[[methyl(l-methylethyl)amino] sulfonyl] benzamide) which belongs to the class of substituted sulfamides, is a herbicide that is particularly useful for preplant applications and selective pre-emergence weed control in multiple crops. It is absorbed by foliage and roots with translocation in the apoplast and limited movement in the phloem. Saflufenacil is applied to foliage and is used for residual control of broadleaved weeds, including glyphosate- and ALS-resistant biotypes. Saflufenacil is applied pre-emergence in corn and sorghum, at 50-125 gram / hectare (g / ha); preplant for rapid foliar burn-down in soybeans, cereals, cotton, legumes; and post-directed in tree fruit and nuts, at 18-25 g / ha, and in sugarcane at 24.5-96 g / ha.

[0048] Saflufenacil belongs to the group of protoporphyrinogen oxidase (PPO) inhibitors, more specifically it is a pyrimidinedione-based PPO inhibitor and it has been described in WO 2001 / 083459.

[0049] According to the invention, the process for the preparation of the compound of formula V may include, in addition to the step of the preparation of the compound of formula I according to the process disclosed herein, any step(s) disclosed in the literature for the preparation of the compound of formula V as defined hereinabove, e.g., as disclosed in WO 2006 / 090210, WO 2004 / 039768, and WO 2006 / 010474.

[0050] For instance, the compound of formula I, more specifically 2-chloro-4-fluoro-5-nitrobenzotri chloride, may be converted to 2-chloro-4-fluoro-5 -nitrobenzoic acid or its alkyl ester and then reduced or hydrogenated to obtain 5-amino-2-chloro-4-fluorobenzoic acid or its alkyl ester. Next, the obtained compounds may be transformed into an ester compound of Formula Al:, wherein Aik is a C1.12 alkyl.

[0051] Then, the ester group of the compound of Formula Al may be cleaved to afford the corresponding benzoic acid of Formula A2:A2; and the compound of Formula A2 may be reacted with NH2-SO2-N[(CH3)(CH(CH3)2)] to afford saflufenacil.

[0052] Alternatively, the compound of Formula I, more specifically 2-chloro-4-fluoro-5-nitrobenzotri chloride, may be converted to 2-chloro-4-fluoro-5-nitrobenzoic acid and condensed with N-m ethyl -N-isopropyl sulfamoyl amide to give nitro benzoylsulfamide, followed by reduction or hydrogenation of the nitro group to form the amine compound of Formula Bl:

[0053] Next, the compound of Formula Bl may be converted to the compound of Formula B2:, followed by methylation reaction to afford saflufenacil.

[0054] Unless otherwise indicated, all numbers expressing, e.g., amounts of components or ratios between components, used in this specification, are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification are approximations that may vary by up to plus or minus 10% depending upon the desired properties to be obtained by the present invention.

[0055] The invention will now be illustrated by the following non-limiting Examples.EXAMPLESMaterials and MethodsExample 1. Synthesis of 2-chloro-4-fluoro-5-nitrobenzotrichloride - comparative example.

[0056] To a four-necked flask, sulfuric acid 96% (175 g, 1.71 mol, 3.8 eq.) was introduced, cooled to 5°C, and nitric acid 95.6% (34.5 g, 0.52 mol, 1.15 eq.) was added under stirring. Then, 2-chloro-4fluorobenzotrichloride 97.5% (114 g, 0.45 mol, 1 eq.) was added slowly during a period of 3 hours while keeping the temperature at 5-10 °C.

[0057] The reaction mixture was stirred for 5 hours, but already after 2.5 hours of stirring solids were precipitated from the reaction mass. HPLC (high performance liquid chromatography) analysis of the reaction mixture showed a conversion of about 80% only. The reaction profile did not change significantly up to the end of mixing and the reaction was not completed.Example 2. Synthesis of 2-chloro-4-fluoro-5-nitrobenzotrichloride using a mixture of halogenated solvent and polar organic solvent.

[0058] To a 30-liter glass reactor sulfuric acid 98% (5200 g, 52 mol, 4 eq.) was added, cooled to 5°C and nitric acid 98% (1212 g, 18.85 mol, 1.43 eq.) was added under stirring. To the obtained mixture, sulfolane (1376 g, 0.41 w / w 2-chloro-4-fhiorobenzotrichloride) and dichloroethane (DCE; 1980 g, 0.59 w / w 2-chloro-4-fhiorobenzotrichloride) were added.

[0059] Then, 2-chloro-4fhiorobenzotrichloride 97.1% (3357 g, 13.15 mol, 1 eq.) was added slowly over a period of 2.5 hours while keeping the temperature at 4-8 °C.

[0060] The reaction mixture was stirred for 1 hour and monitored by HPLC which showed a conversion higher than 99%.

[0061] Then, an additional portion of DCE (4733 g, 1.41 w / w 2-chloro-4-fluorobenzotri chloride) was added and the stirring was continued for 0.5 hour. The mixing was stopped, and the upper organic layer was separated. The lower acidic phase was extracted with another portion of DCE (3357 g, 1 w / w 2-chloro-4fluorobenzotrichloride), and the combined organic phases were washed with water (3357 g, 1 w / w 2-chloro-4-fluorob enzotri chi ori de) .

[0062] The resulting solution in DCE (13550 g) contained 26.18% (3547 g, 12.1 mol) of reaction product 2-chloro-4-fluoro-5-nitrobenzotrichloride and 0.1 % of 2-chloro-4-fluoro-5 -nitrobenzoic acid (13.55 g, 0.06 mol). Due to the high selectivity of the process, 2-chloro-4-fluoro-5-nitrobenzotrichloride may be delivered to the next step in this solution without purification. The obtained yield was 92.6 %.Example 3. Synthesis of 2-chloro-4-fluoro-5-nitrobenzotrichloride using a recycled acidic phase.

[0063] To a 30-liter glass reactor, acidic phase from Example 2 (2810 g) and oleum 5% (1928 g) were added, the resulting mixture was cooled to 5°C and nitric acid 98% (965 g, 15.01 mol, 1.43 eq.) was added under stirring, while the temperature was kept below 10°C. Then, a mixture of sulfolane (631 g) and di chloroethane (1582 g) was added.

[0064] In the next step, 2-chloro-4-fluorobenzotrichloride 97.1% (2681 g, 10.5 mol, 1 eq.) was added slowly during a period of 2 hours while keeping the temperature at 0-10°C. The reaction mixture was stirred for 1 hour and the end of the reaction was monitored by HPLC. The reaction was completed when the conversion was more than 99%.

[0065] Then, dichloroethane (3780 g, 1.41 w / w 2-chloro-4fluorobenzotrichloride) was added and the stirring was continued for 0.5 hour. The stirring was stopped, and upper organic layer was separated. Lower acidic phase was extracted with a second portion of di chloroethane (2681 g, 1 w / w 2-chloro-4fluorobenzotri chloride) and combined organic phases were washed with water (2681 g, 1 w / w 2-chloro-4-fluorobenzotri chloride).

[0066] The obtained solution in di chloroethane (10730 g) contained 26.22% (2813 g, 9.6 mol of the reaction product 2-chloro-4-fluoro-5-nitrobenzotrichloride and 0.12% of 2-chloro-4-fluoro-5-nitrobenzoic acid (12.89 g, 0.06 mol). Due to the high selectivity of the process, the product 2-chloro-4-fluoro-5-nitrobenzotrichloride may be delivered to the next step in this solution without any purification. The obtained yield was 92%.REFERENCESWahyuni W.T., Putra B.R., Fauzia A., Ramadhanti D., Rohaeti E., Heryanto R. Indonesian Journal of Chemical Research, 2022, 10, 88-92.Patel S.S., Patel D.B., Patel H.D. Synthetic protocols for aromatic nitration: A review. ChemistrySelect, 2021, 6, 1337-1356.

Claims

1. CLAIMS1. A process for the preparation of a compound of formula Iwherein:R1, R2, R3, R4, andR5each independently is hydrogen; halogen; (Ci-Ce)alkyl; (Ci-Ce)haloalkyl; -NR’R”, wherein R’ and R” each independently is hydrogen, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, or both R’ and R” together with the nitrogen atom to which they are attached form a 3 to 7 membered heterocyclic ring; or -COOR wherein R is hydrogen or (Ci-C6)alkyl,said process comprising reacting a compound of formula IIa nitration mixture comprising concentrated sulfuric acid, concentrated nitric acid, a halogenated organic solvent, and a polar organic solvent selectedfrom: (a) a compound of III111, wherein R6and R7each independently is (Ci- Ci2)alkyl or both R6andR7together with the sulfur atom to which they are attached form a 3 to 7 membered heterocyclic ring; and (b) a glycol ether, under mixing,to thereby obtain the compound of formula I.

2. The process of claim 1, further comprising adding an additional amount of said halogenated organic solvent and separating the organic phase (layer) and acidic phase (layer).

3. The process of claim 2, wherein following the separation of the phases, the acidic phase (layer) is extracted with additional portion of the halogenated solvent, the organic phases are combined, and the combined organic phases are washed with water.

4. The process of claim 3, wherein the remaining acidic phase (layer) is reused for said process.

5. The process of claim 1, wherein said halogenated organic solvent is a chlorinated organic solvent.

6. The process of claim 5, wherein said chlorinated organic solvent is di chloroethane, dichloromethane, carbon tetrachloride, or a mixture thereof.

7. The process of claim 1, wherein the compound of formula III is: (i) sulfolane (i.e., wherein both R6and R7together with the sulfur atom to which they are attached form tetrahydrothiophene); or (ii) sulfol ene (i.e., wherein both R6and R7together with the sulfur atom to which they are attached form 2,5-dihydrothiophene).

8. The process of claim 1, wherein said glycol is a compound of formula IV, wherein R each independently is (Ci-Ce)alkyl, and n is an integer of 1-9.

9. The process of claim 1, wherein R1, R2, R3, R4, and R5each independently is hydrogen, halogen, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl.

10. The process of claim 9, wherein R1and R4each is hydrogen; R3and R5each is halogen; and R2is (Ci-C3)haloalkyl.

11. The process of claim 10, wherein R1andR4each is hydrogen; R3is Cl; R5is F; and R2is -CCh.

12. The process of claim 1, wherein the weight ratio between the concentrated sulfuric acid and the concentrated nitric acid is in the range of from about 3 : 1 to 10: 1, respectively.

13. The process of claim 1, wherein the molar ratio between the concentrated nitric acid and the compound of formula II is in the range of from about 1.1:1 to 2:1, respectively.

14. The process of claim 1, wherein the weight ratio between the mixture of said halogenated organic solvent and said polar organic solvent and the compound of formula II is in the range of from about 0.5:1 to 2:1, respectively.

15. The process of claim 1, wherein the weight ratio between the polar organic solvent and the halogenated organic solvent is in the range of from about 0.2: 1 to 1 : 1, respectively.

16. The process of claim 1, wherein said process is performed at a temperature of from about 0°C to about 30°C.

17. The process of claim 1, wherein the compound of formula II is added gradually to the nitration mixture at a temperature below 10°C.

18. The process of claim 1, wherein the polar organic solvent is sulfolane and the halogenated organic solvent is di chloroethane.

19. The process of claim 18, wherein the weight ratio between the sulfolane and di chloroethane is in the range of from about 0.2:1 to about 1:1, respectively.

20. The process of claim 1, wherein:(a) said halogenated organic solvent is a chlorinated organic solvent;(b) the compound of formula III is sulfolane (i.e., wherein both R6and R7together with the sulfur atom to which they are attached form tetrahydrothiophene);(c) R1and R4each is hydrogen; R3and R5each is halogen; and R2is (Ci- C3)haloalkyl;(d) the weight ratio between the concentrated sulfuric acid and the concentrated nitric acid is in the range of from about 3: 1 to 10:1, respectively;(e) the molar ratio between the concentrated nitric acid and the compound of formula II is in the range of from about 1.1 : 1 to 2: 1, respectively;(f) the weight ratio between the mixture of said halogenated organic solvent and said polar organic solvent and the compound of formula II is in the range of from about 0.5:1 to 2: 1, respectively; and(g) the weight ratio between the polar organic solvent and the halogenated organic solvent is in the range of from about 0.2: 1 to 1:1, respectively.

21. The process of claim 19, wherein said chlorinated organic solvent is di chloroethane and the weight ratio between the sulfolane and di chloroethane is in the range of from about 0.3:1 to about 0.7:1, respectively.

22. The process of claim 19 or 20, wherein said R3is Cl; R5is F; and R2is -CCh.

23. A process for the preparation of a compound of formula Vwherein:R1, R3, R4, and R5are each as defined in claim 1;R8is H or (Ci-C6)alkyl;R9is H, (Ci-C6)alkyl, or (Ci-C6)haloalkyl;R10and R11each independently is (Ci-Ci2)alkyl, (C2-Ce)alkenyl, (C3-Cs)cycloalkyl, aryl, heteroaryl, or R10and R11together with the nitrogen atom to which they are attached form a 5-8 membered ring,said process comprising preparing the compound of formula I according to any one of claims 1-22.

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