WO 2U15/0952JM PCT/US2014/070761 PROCESSES FOR THE DIAZOTJZATION OF 2,5-DlCHLOROANiUNES CROSS-REFERENCE TO RELATED APPLICATfON J1] This application claims priority to U.S. Provisional Application No. 61/917,605 fifed December 18, 2013, which is incorporated herein by reference in Us entirety. RELD OF THE INVENTION [2] The presenl disclosure rcliiles, in goneraJ, to processes lor converting 2,5- dichloroanrline compounds to the corresponding 2,5-djchlorobenzenediazonium compounds, and further relates to processes for the preparation of 2,5-dichlorophenoi which is a key intermediate used in Ihe manufactuic of dicamba. BACKGROUND OF THE INVENTION [3] 3,6-Dichlorc-2-rn dicamba l| NH2 A. . V A^O H convex, Cf O ^-Diclitoittzinaline 2,5-D;chtorohenzene- 2,5-Dichforophenof Dicamba (2,5-DCA) djazonium (2,5-DOO) (2.5-DCP) See. e.g., U.S. Patent 4,161.611. [5} This route, however, typically requires certain process conditions (such as fine milling of the 2,5-diobloroanaline Starling material, use of a large excess of sulfuric acid andfor concentiated sulfuric acid in the diazotizing step, etc.) in order to WO20kW52tf4 PCT/LS2U 14^70 704 achieve an ac:eeptablo conversion of the 2,6-dichloroanaIinc lo the ?,5- djchlorophenol on a commercial scale. The present disclosure provides improved processes that reduce or eliminate the need for such process conditions while still maintaining, or even improving, conversion of Ihe 2,b-dicrrloroanallne to She 2,6- dichJorophenof. BRtEF DESCRIPTION OF THE INVENTION (6J Tho present disclosure relates to processes for converting 2,5- dichloraariiiine compounds to Ihe corresponding 2,5-dichloral)en7enediazoriium compounds. [7] in one aspect, the present discfosure rafales to a process for the preparation of a compound corresponding in structure to Formula (IV): CI -R1 CI (,V>> or a salt Thereof, wherein R1 is as defined in the present specification, and wherein Hie process comprises contacting a compound corresponding in structure to Formrjla fill): CI C! (IJI), or a salt thereof, with a diazolteing agent in a reaction medium comprising sulfuric acid and an organic acid scfeded from the group consisting of C^-C&afkanoic acids and lialo-Ci-Cfi-ylkanoic acids to generate a diazonium product mixture comprising the compound or salt of Formula (IV). [8] In another aspect, the present disclosure relates to a process forlhe preparation of a compound corresponding in structure to Formula (IV): W<) 20A5/IKI5284 3 l'Cr17tlS2» 1.1/070764 ci (iv), or a salt thereof, wherein R1 fs as defined in The present specification, and wherein tho process comprises: forming a reaction medium comprising sulfuric acid; an organic acid selected from tho group consisting of Cy-Ce-alkanoic acids and halo-Ci-Ct-alkanoic acids; and, optionally, a first amount of a compound corresponding in structure to Formula [III); C! NH2 R1 CI (III), or a sal* thereof; and introducing into the reaction medium a second amount of the compound or sail of the compound of Formula (HI), and a dlazotizjng agenl. to generate a diazonium product mixture comprising tfie compound or salt of FomiuJa (IV). [9] In another aspect, the present disclosure relates to a process for the preparation of a compound corresponding in structure to Formula (IV): CI 'R1 CI (W). or a salt thereof, wherein R1 is as defined in the present spectfication, and wherein tho process comprises: forming a reaction medium comprisfng sulfuric acid; an organic acid selected from the group consisting of C^CValkanoic acids and haio-Ct-Ce-alkanoic adds; and a compound corresponding in structure to Formula fllf): WO 252fl4 FC.T/IIS2014/H707frl CI (HI), or a salt thereof; and introducing ink) the reaction medium a diazotizing agent to generate a djazonium product mixture comprising the compound or saJt of Formula (IV). £10] In another aspect, the present disclosure relates to a process as staled above that further comprises hydrolyzrng the compound or salt of Formula (JV) to a compound corresponding in structure \0 Formula (V): CI or a salt Ihereof, wherein RJ is as delined in the present specification. J11J In another aspect, the present disclosure relates to a process for the preparation of a compound corresponding rn structure to Formula (VI): CI .0CH3 CI O (VI), or a salt thereof, wherein the process comprises: contacting a compound corresponding Jn structure to Formula (lll-a): CI NH2 CI (IN-a), or a salt thereof, with a diazollzing agon! in a reaction medium comprising suffunc acid and an organic add selected from the group consisting of Cj-Ch-aJkanoic acids WO 2«15flt!M««4 PC]/US2014rtl7U7")'I arid fialo-Cj-C&-afkanofc acids lo generate a diazortium produd mixtuio comprising a compound corresponding in structure to Formula {IV-a): CI N3 + a <'v-a), or a salt thereof; hydrolyzrng the compound or salt of Formula (IV-a) to generate a phenol product mixture comprising a compound corresponding in structure to Formula (V-a): CI .OH Ci (V-a), or a saJt thereof; and carboxylating the compound or salt of Formula (V-a) to generate a carboxylated product mixture comprising a compound corresponding in structure to hormuia (V-b); Ci OH Ci O (V-b), or a saft thereof; and converting the compound or saJt of Formula (Vl-b) to the compound or salt of Formula (VI), BRIEF DESCRIPTION OF THE DRAWINGS [12] Figure 1 is a bar chart illustrating the percent conversion (based on normalized peak absorbarice a{ 208 inn by HPLC) of 2pI>-dichloroaniline to 2,odichlorobenzenediazonium (quantified as 1p4-drch!orobenzene) as a function of equivalents of sulfuric add rciative io fhe 2,6-dicihloroanfline, WO 2Q1SM52IH (. VCT/US2i)i AmiOJtU [13] Figure 2 is a bar chart illustrating the percent conversion (based on normalized peak absorbance at 208 rim by HPLC)of 2,5-dichforoaniiinc lo 2,5- dichiorobenzenodlazonium (quantified as 1,4-dich!oroben/ene)as a function of equivalents ol acetic acid relative lo the 2,5-dich[oroaniline. [14] Figure 3 is a bar chad illustrating the overage percent conversion (based on normalized peak absorbance at 203 nm by HPLC) of 2,5-dichloroanifine lo 2,5- diclilofobenzenodia^onrum (quantified as 1,4-dJchloroben/ene) as a function of equivalents of sodium nitrite relative to the 2,5-dichloroaniline. DETAILED DESCRIPTION OF THE INVENTION [15J This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the Invention, including making and using any of the disclosed salts, substances, or compositions, and performing any of the disclosed methods or processes. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled m the art. Such other examples arc intended to be within the scope of t he ciaims if they have elements that do not diffei from the literal language of the claims, or if they include equivalent elements. I. Definitions [16] Section headings as used in this section and the entire disclosure are not intended lo be Ji mi ting. f 17] Where a numeric range is recited, each intervening number within the range is explicitly contemplated with trie same degree of precision. For example, For the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the rsnge 6.0 to 7.0, the numbers 6.0, & 1 . 6,2, 6.3, 6 4 , 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitly contemplated- In the same manner, all recited ratios also include all sub-ratios falling within the broader ratio. [1B] The singular forms "a," "an" arrd cthc" include plural referents unless the context dearly dictates otherwise. [19] The term "about" generally refers to a range of numbers that one of skill in the art would consider equivalent to the recited valuL' (As.r having the aame function WO 2415/(19528-1 7 PCT/irS?(H4/07U7^4 or result). In many instances, Ihe lerm "about" may include numbers that aio rounded to Ihe nearest significant figure. [20] Unless Ihe context requires otherwise, Ihe terms "comprise/1 "comprises," and "comprising" are used on trie basis and clear understanding thai they are to bo interpreted inclusively, rather than exclusively, and thai ApplJcanI intends each of those words to he so interpreted Jn construing this patent, including the claims below. [21] The term "sodium n i t r i t o ^ j " refers to an aqueous solution of sodium nftrito. [22] The lerm "sulfuric a c i d ^ , " refers to an aqueous solution of sullurio acid. [23J Tho abbreviation "AcOH" means acotic acid. [24] The abbreviation "2,5-DCA" means 2.6-dichloroanrlino. [25] The abbreviation "1,4-DCB" moans 1,4-dictiJorobenzene, [26] Tho abbreviation "2.5-DCD" means 2,5-dichiorotJenz.enediazonium. [27] The abbreviation "1,4-DCNB" means 1,4-dichbronitrobeiizene. [28] The abbreviation "2,5-DCP" moans 2,5-orrchloroprionol. II. Diazotization of 2.5-Dicriroroanrlirics [29] The present disclosure relates, in part, to processes for diazotizing 3 2,5- dlchloroanilinc compound to provide Ihe corresponding 2,5-drchforobcnzenediazonium compound. In particular, Ihe present disclosure relates to processos for diazotizing 2,5-dichloroanillne to provide 2,5-a'ichforobenzenen'iazonhni, The 2,6- di^hlorobon^enediazonium prepaiod can be hydrofyzed to provide Ihe corresponding 2.5-dich!orophenol, a key intermediate used in the manufacture of dicjimba. [30] Among other process improvements, it has been discovered that 2,bdichJoroaniline and its sulfate salt have improved solubility jn a reaction medium comprising sulfuric acid and an organic a d d selected from the group consisting of C?- Cfc-alkanorc acids (such as acetic acid) and halo-CiQi-aikanoic acids (such as trifjuoroacelic acid) relative to a corresponding reaction medium lacking tho organic acid. It has been furfher discovered that conducting the cfiazotizatfon reaction in such a reaction medium results in a more efficient and homogeneous conversion of the 2,5-dichforoaniline to the corresponding 2,5-dichiorobenzenediazonium. Excellent W0 2Ul5/IW52a4 K VVTniSnuWMftA conversions of tho 2.5-riichforoaniJrne to the 2,6-dichiorobijri7ei'rediazonium have been achieved using an organic acid/sulfuric add reaction medium. [31] Due to its cheaper cos) relative lo more expensive organic reagents, sodium nitrite (NaNO?) frequently is selected as a dia2oti7ing agent for diazotizatfori reactions conducted in an industrial setting. When sodium nitrile is used as Iho diazolizing reagent, the reaction typically is conducted in an acid medium in orderto generate nitrous acid which is then consumed in the diazolizing stop. Sulfuric acid (H2SO4) frequently is used as the acid medium for such diazotization reactions, Scheme 2 below illustrates the hypothesized reaction pathway for the generation of nitrous acid from sodium nitrite ill a sulfuric acid medium and the subsequent generation of nitrosy [sulfuric acid. As discussed later, the nitrosylsulfuric acid generated reacts with the 2,f>-dichloroaniline to the corresponding 2,bdichlorobenzenediazonium is similarly limited by solubility. In addition, use of hydrochloric acid as the acid medium allows the chloride (CI) to compete as a nucloophile during the subsequent hydrolysis of the 2,5-dichlorodiazonium to the 2.5- dichlorophenol potentially resulting in a 3-ch!oro substituent Instead of the desired 3- hydroxy substituent, Similady, nitric a d d and other mineral acids would present the same problem, e.g., use of nitric acid as the acad medium, to the extent even practical, would allow the nitrate (NO:i~) to compete as a nucleophile during the subsequent hydrolysis of the 2,5-dJchlorodiazonium to the 2,5-dichlorophonol potentially resulting in a 3-nitro substituent instead of fhe desired 3-hydroxy substrtuont. Accordingly, sulfuric acid is generally preferred over other mineral acids when the 2.5-dich!orohanzencidia^onium generated is to bo further hytiroiyred to the 2r5-dichlorophenoL [37] Use of the organic acid/sulfuric acid reaction medium of the present disclosure provides several advantages over a conventional sulfuric acid reaction medium including the following: (1) Excellent conversions of the 2,S-djchloroaniJine to the 2.tidichlorebenzenediazonium ate achieved. WO 2015/WMWI PC:T/yS21)14/07«?M ID (2) Additional processing uf the 2f5-dit;hJoroaniJbe starting materia! {e.g., tine milling such as bail milling) is nol required to help solubillze Ihe 2,6-rfichloroan?Jine. (3) Sulfuric acid handling requirement are reduced as a Jower volume of sulfuric; acid is needed for the diazotizalion reaction. (4) Whcro Ihe overall process also includes a hydroxylalton step fn which the 2,5-dichlorobonzenediazonlurn is converted to the 2.5-dJchloroph£nol. ihe organic acid helps to reduce plugging of Iho distillation apparatus during distillation, (5) Where Ihe overall process also includes a step in which 1.4- dichforonltrobenzene is reduced to 2,5-rfichloroanilfne, llie organic acid can ba used m the reducing step aflowinp for the direct transfer of Ihe reaction mixture comprising ihe 2,5-chloruaniline into Ihe dfu^utization reactor. (6) Where iho overall process also includes both a reducing step and a h/droxytalion step as discussed above, Ihe organic acid can be recovered from Iho hydroxylaflon step and recycled back to the reducing step. [38] Although primarily illustrated throughout this appricatiorj with respect to 2,5-dfchloroaniline. the Improved process can be used to dla^otizo other 2,5- dichloroaniline compounds that are further substituted at Ihe 3-posilron of Iho ring. [39] Accordingly, in one embodiment, the present disclosure relates to a procoss for the preparation of a compound corresponding in structure to Formula (IV): Cj N/ R1 CI (IV), or a salt thereof, (he process comprising contacting a compound corresponding in structure to Formula (111): CI NH2 (III), WO 2l)i5Hl952H4 PCTfV$2i)14iQW7(vl II or a sail thereof, with a diazotizing, agent in a reaction medium comprising sulfuric acid and an organic acid soiocted from the group consisting of C^-Co-alfcanoic acids and halo-CrCii-alkanoEC acids to generate a diazonium product mixture comprising fhe compound or salt of Formula (IV); wherein; R1 is selected from Ihc group consisting of hydrogen, halogen. cyano, -Chh, - CHzOH, -C(0)R2, -C(O)0R3, and -B(Rt)z; R2 is selected fromtho group conslsling of hydrogen, Ci-CB-alkyl, and - NRflRD; wherein RA and RH are independently selected from the group consisting of hydrogen and Ci-C&alkyl; and R3 is selected from the group consisting of hydrogen and Ci-Cc-ylkyi; and Ra is selected from the group consisting of hydroxy and Ci-CG-alKyl. In one aspect, R1 is hydrogen (i.&, the compound ol Formula (Ml) is 2,5- dlchloroanafine). In another aspect, R1 is selected from the group consisting of hafogen, cyano, -CHa> -CH.OH, -C[0)R2, -C(0)OR3 r and -B(R^)2; and R2, R\ and RA are as donned abovo (i.e., the compound of Formula (IN) Is a 2,5-dichforoanafine compound that is further substituted at the 3-positiort of the ring). [40] In one embodiment, the piosent disclosure relates to a process for rhc preparation of a compound corresponding in structure Formula (IV}: CI R1 CI 0V)P or ft salt thereof, the process composing; forming a reaction medium comprising sulfuric acid; an organic acid selected from the group consisting of C?-Ui-alkanoic acids and halo-Gi-Ct-alkanoic acids; and, optionally, a first amount of a compound corresponding in stiuctureto Formula (lit): CI NH2 or a salt thereof; and WO 2UA5;iKl528J PCVUS2014/117U76-1 12 introducing into Ihe leaclfon medium a second amount or Ihe compound or salE of Ihe compound of Formula (III), and a diazotteirtg agent, 1o generate a diazonium product mixture comprising Ihe compound or salt of Formula (IV); wherein; R1 is selected from Ihe yroup consisting of hydrogen, halogen, cyano, -CHr i , - CHzOH, -C(0)R2, -C(0)OR3, and -B(R*)2; R2 is selected from !ho group consisting of hydrogen, Ci-CValkyl, and - NR*RD; wherein Rrt and RB are independctiliy selected from tho group consisting of hydrogen and Ci-Ce-alkyJ; and R3 i s selected from the group consisting of hydrogen and Ci-Ce-aJkyl; and R1 is selected f r om The group consisting of hydroxy and Of-Cg-alky!- Iti one aspect, R1 is hydrogen [i.e., tho compound of FonnuJa (\\l) is 2,5- dichloroanaline). In another aspect, R1 is selected f r om tho group consisting of halogen, cyano, -CH3 , -CH^OH, -C(0)R2 f -C(0)OR3, and -B(R*)2; and R2, R3, and R1 are as delined above (i.e., the compound of Formula (III) is a 2,5-dichloroanaline compound Ihat is further substituted at the 3-position of the ring). H1] I"1 o n e embodiment Ihe present disclosure relates to a process for the preparation of a compound corresponding in structure to Formufa (IV): CI • IV R1 6 flV). or a sait thereof, the process comprising; fbi ruing a reaction medium comprising sulfuric acid; an organic acid selected from tho group consisting of Cj-Co-alkanoic acids and halo-CrC&-alkanoic acids; and a compound corresponding in structure to Formula (III): CI NS-b or a sail thereof; and wo imsnminA PCT/[JS2CPHAI707*;4 13 infioduring into Hit? reaction medium a dia^olizfng agent to generate a drazonium product mfxlure comprising Ihe compound or sail of Formula (IV); wherein; R1 is selected from the group consisting of hydrogen, halogen, cyano, -GH3, - CFfeOH. -C(0)R*, -C(0)0R3, and -B(R')y, R2 is selected from me group consisting of hydrogen, Ci-Q-alkyJ. and - NRARB; wherein RA and Rn are independently selected from the group consisting of hydrogen and Ci-C&-afkyl; and Rs is selected from Ihe group consisting of hydrogen and C|-C&-aJkyJ; and R" is selected from the group consisting of hydroxy and C?-Cf;-a!ky!. In one aspect. R' is hydrogen (r.o., the compound of Formula (ill) is 2.5- dichloroanaline}. In another aspect, R1 is selected from the group consisting of halogen, cyano, -CFb, -CH2OH, -C(0)R:'J -C(0)OrT\ and -B(Rd)?; and R^. R3, and R* aro as defined above {i.e., tho compound of Formula (HI) is a 2,5-dichloroanaline compound that is further substituted at the 3-position of tho ling). [42] Scheme 3 below provides an illustration of tho overall reaction when the Compound ot Formula (Ul) is 2,5-dichioroaniline and the organic acid is acetic acid: WO 2(115/03)52114 PC,l'/US2(il4/il70764 N Cf > 1 c9 H2S04 . 1 „NH3 + HSOf Seheme 3 NaNO^ - — 2 AcOH 8 ^_ - * HKOa 3 + 1 I o HO-S-O O 5 + CI c> CI 7 + NaHSOj 4 - N _ 0 * H20 e .NH:> +• H^S04 CI CJ H?SO^ + N2 ^ 1 12 ruS T ci 11 ,OH r - ^ y N 2 +HS04 LJ + IJ2° Y 10 [43] In general, a reaction medium comprising sulfuric acid 1. 2,5- drchloroaniline 7, and acetic acid Q is prepared. As needed, the reaction medium is cooled to a suitable temperature {e.g., from about 0DC to about 25°C). Under such conditions, the reaction medium typically wifi be a slurry comprising 2,5- dichloroaniiine 7 and its sulfate salt 9. [44] ScxJIum nitrite 2 is added to the reaction medium (e.g., subsurface addition ot an aqueous solution ot sodium nitrite 2). The addition of sodium nitrite 2 to the reaction medium generates nitrosylsulluric acid 5 which then reacts with 2.5- di eft loroani line 7 to provide 2J5-dichJorobeiia5nedi32oniiim sail 10. The dia^otization reaction proceeds quickly and substantially al! ot 2,5-dichloroaniline 7 reads and is converted to 2,5-dichlorobcnzenedinzoniijm salt 10. As pi oviously noted. 2,5- diehloroanitinC 7 (not the sulfate salt of 2,5-dfchloroanfline 9) serves as the nudeophilo arid reacts with nifrosvlsulfuric acid 5 which serves AS the efectrophife. WO 2fJl5/DJ>52SJJ 15 PCJVU&2014/07(17G-I Acetic acid 8 functions as a co-solvent In improve solubility of 2,5-dichloroaniline 7 and ris sulfate sail 9 in the reaction medium enabling lull conversion to 2,5- dichlorohenzciiodizazoniuni salt 10. Simiiarfy, acetic acid £ functions as a co-solvent 10 improvo sdubility of 2r652HJ 21 T'CiV£JS252£4 PCTf\}$2aUtim7(.4 2J In another aspect, the rate ol addition of each reagonl is controlled such that about 1.0 molar equivalent to about 1.05 molar equivalents of the diazofizing agent are added per mole of the compound or salt of Formula (III) added. In another aspect, the rato of addition oteach reagonl is controlled such that about 1.0 molar equivalent of the diazotfcing agont is added per mole ol the compound or salt of Formula (III) added. In one aspect, the compound or sail of Formula (III) and the diazotizlng agent are added separately to the reaction medium with tho dia^otizing agent introduced through subsurface addition. [68] In one embodiment, the diazotizing agent and the compound or salt of Formula (III) are separately introduced into the reaction medium as a first solution comprising the diazotizing agent, and a second solution comprising acetic acid and the compound or salt of Formula (Hi). In one aspect, tho tlrst solution and the second solution are introduced into tho reaction modjum in a substantially concurrent manner. In another aspect, tho first solution is an aqueous solution comprising an alkali metal nitrite, and the second solution comprises acetic acid and the compound or salt of Formula f i l l ) , In another aspoct, the first solution comprises an alkali metal nitrite and sulfuric acid, and the second solution comprises acetic acid and the compound or salt of Fomiula (III). In another aspect, the first solution comprises mlrosyJ sulfuric acid, and a second solution comprises acetic acid and the compound or salt of Formula (III), [69] As discussed above, the improved process provides a suitabfe conversion of tho compound or sail of Formula (HI) to the compound or saft of Formula (IV), In ono embodiment, the percent conversion of the compound or salt of Formula (111) to tho compound or salt of Formula (IV) is al least about 80%. In one aspect, the percent conversion of the compound or salt of Formula (III) to the compound or salt of Formula (IV) is at least about Sb%. in another aspeot, tho percent conversion of the compound or sail of Formula (Mi) to the compound or salt of Formula (IV) is at least about 90%, In another aspect, the percent conversion of the compound or salt of Formula (IIJ) to the compound or salt of Formula (IV) is at feast about 95%. C. Quenching oi Diazotizing Agent [70] Whore the diazollztng agent is an alKofi metal nitrite (e.g., sodium nitrite or calcium nitrite), nitrosylsuifurfc acid, or otherwise results in an excess of nitrous acid being present in the modruni, it can be henoticia! to add a sufficient amount ot a WQ 2(115/1)3)528-1 FCT/lJS2«H/U7B7 or a salt thereof; and hydrofy^fng the compound or salt of Formula (IV) to generate a phenol product mixture comprising ihe compound or saJt of Formula (V); who re in: Rr is selected from the group consisting of hydrogen, halogen, cyano, -CH3, - CH3OH, -C(0)R3, -C(0)OR3, and - B ( R ^ [ R? is selected from tJio group consisting of hydrogen, Ci-Ge-alkyl, and - NRARn; wherein Rft and R" are indeporjdently selected from the group consisting of hydrogen and CH^-alky!; ond WO ?UI5/Uy52tf4 27 P<:miS2{ll4/07- dichloroanaline), In another aspectr R1 is selected from the group consfelrng of halogen, cyano, -CH3l -CHzOH, -qOJR7, -C(0)OR3, and -B(R*)?; and R2. Rs, and RA are as defined above (i.e,, the compound of Formula (IIJ) is a 2,5-dichloroanaline compound that is luriher substituted at the 3-posrlion of the rincp). [75] In one embodiment. me present disclosure relates to a process for the preparation ot a compound corresponding in structure to Fomiuia (V); CI OH R1 CI (V), or a sail [hereof, the process comprising: forming a reaction medium comprising sulfuric acid; an organic add selected from the group consisting of C^Ce-aNranoic acids and haJo-CrCe-alkanoic acids; and a compound corresponding in structure to Foimufa (fll): a NH2 R1 a ((H), or a saft (hereof; and introducing into Ihe reaction medium a rfiazotizing agent to gencraie & diazonium product mixture comprising a compound corresponding in structure to Foimuia(lV): CI1 R1 OV), of a saJt thereof; and be (ic 6t WO ZlHS/tWSZMJ ?fi PLT/IIS2U14/-a!kyl. In ono aspect, R1 is hydrogen (ie., the compouFfd of Formula (111) ls2,odichloroanalinc). In another aspect, R1 is selected from Ihe group consisting of halogen, cyano, -Cl-fe, -CHjOH, -C(0)RJ, -C(O)0Ra, and -B(R*)?; and R*. R3, and R'' aro as defined above (i.o., the compound of Formula (MJ) is a 2.5-dichloroanalino compound that is further substituted at the 3-position of me ring). [76] In one embodiment, the process further comprises adding a quenching agent to the diazonium product mixture in an amount sufficient to decompose any remaining di'azotizirig agent prior to the hydrolyzing step. \77] In one embodiment, tho process further comprises isolating the compound or Half of Formula (V) from the phenol product mixture. [78] In one embodiment, the process further comprises recovering tho organic acid from the hydrolyzing stop and recycling tho recovered organic acid to a prior process step. [79] In one embodiment, tho process further comprises recovering the sulfuric acid from tho hydrolyzing step and recycling the recovered sulfuric acid to the diazoti>ation and/or hydrolysis process stop(s). In one aspect, the recovered sulfuric acid is used to prepare the reaction medium into which the diazotizing agent is introduced lo gene; ate the diazoniirm product mixture comprising the compound or salt of Formula (IV). [80] m one embodiment, tho process further comprises fa) recovering the organic acid from the hydrolyzing step and recycling the recovered organic acid to a prior process step; and (bj recovering tho sulfuric a d d from the hydrolyzing stop and recycling the recovered sulfuric acid to Ihe diazotizalion and/or hydrolysis process WO 21115/095204 20 FCT/IIS2|IM/0707(J4 stcpEs). In one aspect, fhe recovered sulfuric acid is usod to prepare the reaction medium into which fhe diazolizing agent Is inlroduccd So generate Ihe diazonium product mixture comprising (ho compound or salt of Formula (IV). [81] Although the compound or salt of Formula (IV) can bei&olalod from the diazonium product mixture and then hydrolyzed lo Ihe compound or sail of Formula (V), such isolation typically is nol carried out prior to the hydrolyzing step. In view of the potential instability of isolated diazonium salts, the compound or salt of Formula (IV) generally is hydrolyzed to the compound or salt of Formula (V) in sifu fn the diazonium product mixture and the compound or sail of Formula (V) recovered f r om Ihe resulting phenol product mixture. |82] The compound or salt of Formula (IV) can he hydrolyzed to the compound or salt of Formula (V) Ihroirgh any suitable moans. In one embodiment, for example, the compound or sol) of Formula (IV) is hydrolyzed by healing the diazonium product mixture lo generate a phenol product mixture comprising the compound or salt of Formula (V). In one aspect, the compound or salt of Formula (IV) is subjected to thermal hydrolysis and the resulting compound or sail of Formula (V) is immediately isolated from the remaining diazonium {e.g.. through azeotropic steam distillation or extraction into an organic phase present in Ihe reactor) to minimize further reaction between tho conipound or salt of Formula (V) and the remaining diazonium, J83J In another embodiment, ihe compound or salt of Formula (IV) is hydrolyzed by subjecting the diazonium product mixture to steam distillation to generate a phenol product mixture comprising the compound or salt of Formula (V). m one aspect, the diazonium product mixture is maintained at a temperatuie between about I 0 5 ° c t o about 2 0 0 X during the steam distillation. |n another aspect, fhe diazonium product mixture is maintained at a temperature between about 13GaC to about 1 7 0 X during the steam distillation. In another aspect, the diazonium product mixture is maintained at a temperature of about 15u"C during the steam distillation. In another aspect, the phenol product mixture resulting from the steam distillation Is a distillate comprising the organic acid, water, and the compound or salt of Formula (V), In anolher aspect, the process further comprises isolating tho compound or salt of Formula (V) from the distillate, in another aspect, the process farther comprises recovering the organic acid from the distillate and recycling the recovered organic acid to a prior process stop. WO 2015M521U M} PCT/[kS2!JMSU7t>764 [84] By way of further illustration, Example 12 below describes (he subsurface addition ol the diazonium product mixture !o hoi concentrated sulfuric acid using a syringe pump followed by the introduction of sleam into the resulting mixture at a rata sufficient to provide lor the azcolropic distillation of the 2,5-dichlorophenol. Although the addition of steam to me sulfuric acid generated an initial oxolherm, additional healing (a heating mantle) was supplied as required to maintain the resulting mixture at a temperature of about 1G0°C during the steam distillation. Thooverali yield of mo 2,5-dichlorophenol was around 90%. [85] In another embodiment, the compound or salt of Formula (/V) is hydrolyzed by: (i) combining the diazonium product mixture with an organic solvent to form a biphasic mixture comprising the compound or salt of Formula (IV); and fii) heating the biphasic mixture to generate a phenol product mixture comprising the compound or salt of Fonnula (V). In one aspect, the organic solvent comprises one or more xylenes. In another aspect, the biphasic mixture Is heated under rcllux conditions, m another aspect, the biphasic mixture is rotluxed at a temperature from about 95°C Jo about 125"C. In another aspect, the biphasic mixture is rofluxed at a temperature from about 95°C to about 125"C for a period of about 30 minutes to about 500 minutes. [86] The biphasic mixture upon cooling aftor reffuxing comprises an aqueous phase and an organic: phase comprising the compound or salt of Formula (VJ. The organic phase can be separated from the aqueous phase by convonilonal moans (such as phase separation) to provide a phenol product mixture comprising the compound or salt of Formula (V). The compound or sail of Formula (V) then can bo isolated from the phenol product mix lure by conventional means (such as evaporation or distillation). [87] Alternatively, water (e.g., deionfced water, etc.) can be used in place of steam to hydrolyzo the compound or sail of Fonnula (V) present in the diazonium product mixture in a manner similar to Iha various embodiments described above. The water likewise servos as a [tuctaophile in the hydrolysis reaction and also prtimotes tho azeotropic distillation of the hydrolysis product. Use of water instead of sleam potentially can reduce process costs and problems assocraied with the u&c ol glass-lined equipment. The entire amounts of the diazonium product mixture and water can be charged to a hydrolysis reactor (such as a dislilfation column, etc.) WO 2(Ji5rtlM2S4 .11 P(YFfUS2QUHnim-l containing a reaction medium comprising aqueous sulfuric acid al Ihe beginning of the hydrolysis step or, alternatively, at leas) a portion of the diazonium product mixture and a portion of the water can be added to tho reaction medium during the course or the hydrolysis step. [SSJ In one embodiment, al leas! a portion of the diazonium product mixture and a portion of the water are introduced concurrently into the rcecllon medium comprising aqueous sulfuric acid over a period of time. During this addition, Ihe resulting reaction medium is maintained af a temperature sufficient to hydroiyze the compound or salt of Formula (III) 1o ihe compound or sail of Formula (IV) and achieve Jho azeotropic distillation of the compound or saft of Formula (IV) from the reaction medium, Suifahie distillation conditions aro as previously described above. In one aspect, the reaction medium is maintained at a temperature of al least about 150DC and the additions otthe diazonium product mixture and the water to the reaction medium are completed in approximatcfy the samo period of time. In another aspect, the reaction medium is maintained a\ a temperature of about "IG0°C. Example 16 below provides an example of tho concurrent addition of the diazonium product mixture and water to fhe reaction medium. |89] In another embodiment, water Is added to the reaction medium beforo Ihe diazonium product mixture is introduced to the reaction medium and, optionafly, again after Ihe diazonium product mixture addition to the reaction medium has been completed. In this embodiment, a reaction medium comprising aqueous sulfuric acid is placed fn a hydrolysis reactor (such as a distillation column, elc.) and heated. The reaction medium can comprise, for example, a commercially available aqueous sulfuric acid solution, aqueous sulfuric acid recycled from a later stage of the process, or aqueous sulfuric acid prepared from a concentrated sulfuric add solution (such as by adding the first portion of water to the concentrated sulfuric add. either before or after the placing Ihe concentrated sulfuric acid in the hydrolysis reactor). The reaction medium is heated to a temperature sullicjeni to provide for a substantially constanl distillation of water In the distillation bridge, A second porlion of water and the diazonium product mixture aro then concurrently introduced to the reaction medium over a period of lime. During this addition, the resulting reaction medium is maintained al a temperature sufficient to hydrnlyzc the compound or salt of Formula (Uf) to the compound or salt of Formula (IV) and achieve trio a^eotiopic WO l|)15/7U764 distillation of the compound or salt of Formula (iV) [mm the reaction medium, Suitabie distillation conditions are as previously described above. Once (he addition of Ihe diazonium product mixture is complete, a third portion of water is optionally introduced info the reaction medium and healing is discontinued, m one aspect Ihe reaction medium is maintained at a temperature of at teas! about 150°C and/or the distilling head is maintained at a temperature of at least about 85°C. In another aspect, the reaction medium is maintained at a temperature or about 160°C and/or tho distilling head is maintained at a temperature ol about G0"C. Example 16 befow provides an example of this approach. iV.Recvcliuc of Omanic Acid [90] As mentioned above, the process may furthor comprise recovering (he organic acid from the bydroiyzino; step and recycling tho recovered organic acid to a prior process step. V, Recycling of Sulfuric Acid [91] As monlioned above, the process may further comprise recovering tho sulfuric acid from (he hydrolyzincj step and recycling Ihe recovered sulfuric acid to a prior process step. For example, the process can further comprise recovering sulfuric acid from the hydroly^ing s(op and recycling (he recovered sulfuric acid lo the diazotization and/or hydrolysis process step(s). In one aspect, the recovered sulfuric acid is used lo prepare the reaction medium into which the diazotizjng agent is introduced to generate the diazonium product mixture comprising Ihe compound or salt of Formula (IV). In another aspect, the recovered sulfuric acid is used to prepare the reaction medium info which the diazonium product mixture is hydroly^ed to generate a phenol product mixture comprising (he compound or salt of Formula (V). .Such recycling can reduce the sulfuric acid requiiomenls of, and costs associated with, the process. VLRedjjClion of the Compound of Formula (II) [921 ':k o n H embodiment, tho process turlher com prises the step of i cdudng a compound corresponding in struclure to Formula (II): WO 2mm?S2X4 33 PCT/US2U14/07»7^ CI (II), or a sail thereof, lo generate £i compound corresponding jn structure to Formula (111): CI NH2 R1 CI . (Ill), or a salt thereof. wherein: R1 is selected from the group consisting of hydrogen, halogen, cyano, -CH3, - CH?OH. -C(0)R', -CfOJOR*, and -B(R4)?; R2 is sofectedfrom Ihe group consisting of hydrogen. C,-Ce-alkyl. and - NRARB; wherein RA and RB are independently solt?ded from the group consisting of hydrogen and Ci-G5-alkyl; and Ra is selected from the group consisting of hydrogen and Ci-Ce-afkyl; and R4is selected from the group consisting of hydroxy and Cj-Cs-alkyl. In one aspect. R' is hydrogen (Lo., Ihe compound of Formula (JJ) is 1,4- dichioronilrohenzeno). In anothor aspect, R1 is selected from tfie group consisting of halogon, cyanop -CH3, -CH2OH, -C(0)Rz f -C(0}ORJ P and - B(R"):-; and R2. R\ and Rfl are as defined above (i.e., Utc compound o! Formula (II) is a 1,^-diciiioronllroben^ ene compound that is further substituted at tlje 3-posrtioti of the ling), [931 The reducing step can bo carried oul in any suitable manner such as. for example, contacting the compound or salt of Formula (\\) with hydrogen in the presence of a suitable catalyst lo generale fhe compound or sa!f of Formula (III). In one aspect, the reducing stop is conducted in a solvent comprising the same oigamc acid that is used in the diazofiztng sJep. m another aspect, the reducing siep is conducted in a solvent comprising Iho same organic acid that is used in the dia^otizing step, and tho process comprises recovering (he organic acid from the hydrolyzing step and recycling the recovered organic acid to the reducing slop. 6c WO 2(ll5/(l!>52ff4 PCT/US2014/07(1764 34 [94] In one illustrative embodiment, Ihe process further comprises a reducing slep in which 1.4-riichloroniJrobcnzene is converted lo 2r5-cliloroaniline as shown in Scheme 5 Lmlow. CI 1 p4-Dicli!ojonitn?beLizene 2 5-DCA 2,5-DGD (1,4-DCNB) liydroxyfalion OH [95J it has been discovered thai the reducing stop can bo conducted in acetic acid withoul unwanted dechlorination of the 2,5-dichloroaniline producl occurrint). Upon completion of hydrogenalion of t he 1,4-dichloronilrobenzene, the acetic acid reaciion mixture comprising the resulting 2,6-dichloroaniline can be directly transferred into mo diazoniurn reactor. The direct transfer eliminates the need to isolate and purify the 2r4-dic!iloroaniline and the related solvent and equipment requirements. During tho diazotizing slep, tliis procedure avoids me use of a mill to assist with tho solubility of 2.5-d3chloroanltino and reduces the amount of sulfuric acfd needed during the course of The reaction. An additional benefii of using the acetic arid is realized during the later distillation purification of2p!>-dichloropheno| jn which Ihe acetic acid prevents plugging of the distillation apparatus. The acetic acid additionally can be recovered and recycled back into the process simplifying (he overall synthetic sequence and reducing waste. WO 21)15/0952*4 PCimswuHiitmA ia VIL Conversion of 2.5-Plchlurophenol to Dicamba [96] A-5 previously noted, tho 2.5-dich!orophenoJ prepared as described above is a key intermediate used in lhe manufacture ofdicamba. A number of synthetic routes for converting 2,5-dichlorophenol to dfcamba have been reported in tho literature and any such suitable route may be employed. For example, many of the reported routes generally involve the following process steps: (f) carboxylaiing the 2.5-dichJorophenol to provide 2-hydroxy-3,6-dichloro-benzoic acid (e.g., carhoxylatiori using a Kolbe-Schmidtt Reaction), (if) methy Eating the 2-Fiydroxy-3p6-dich[oro-benzolc acid to provide methyl 3,G-dichforo-2-methoxybenzoate (o.g., methylation by treatment with dimethyl sulfate, dimethyl carbonate, or methyl chfoiide), and (iiJ) selectively demethylating the ester group of lhe methyl 3,G-dichloro-2- methoxybenzoate to provide djcarnba (e.g., saponification) as shown in Scheme 6 below: C! • If \ carboxyfalron T CJ 2.5-DCP Schome 6 CI • fc 1 Jl CI O CI 1 1 C| selective demettyfaJlon O C! A^OCH3 CI 0 Die samba [97] Among the various literature references reporting synthetic methods for prepaiiny dicamba or dicamba intermediates, lor example, are the following: (1) U.S. Patent 3,013,054 reports a process for preparing dicamba that proceeds through a 2^dichlorophenof intermediate. WO *Ul5ft)!)52X* 3(Y PCT/tJS2014/U7{l7fi4 (2) Zhang, cl a l . "Synthesis of Herbicide Dicamba," Nongyao 2002, 41 (11), 13- 14 (Ch.). reports a process for the preparation of dicamba fforti 2-5-dichloroaniiine thai proceeds through a 2,5-dichiorophorioi intermediate, (3) Zhang, et al., "Study on the Preparation of Dicamba," Nongyao 2002, 41 (7), 15-17 (Ch J, reports a Ihree-step process for the preparation of dicamha from 2h5- dichloropFienoi, (4) Eckstein, et al., Pizem. Chem. 1979. 58 (10), 533-536 (Pol), reports a process for preparing dicamba (rum a 2,5-dichloropherioi sodium s a l t (5) U.S. Patent 3.345,157 reports a process for melhylafmg 2-hydroxy-3,6- dichloro-benzojc acid to provide dicamba. (GJ Matyakh, e l a i . , ^-Melhoxy^.G-Jichloro-bGnzoicacrd/'Ofkrytiya, teobrel. Prom Ohraztsy, Tovamyc, Znake 1973, 50 (18), 177-170, reports a process for mefhyfating s 2-hydroxy-3,G-dich!oro-ben^oic acid sodium salt to provide dicamba. (7) Zhang, et al., "Study on tfio O-Alkykftion for3,6-dfchlQrosaljcyJrcAcidby Cbloromethane." Huangong Shikan 2002,16 (12) 45-48 (Ch.), reports the OaJkylation of 2-hydroxy-3.6-dichlorcJ-benzoJc a d d to provide dicamba. (8) CN1Q2942474A report a process via carboxylation of 2,5-dichJorophcnof and metbyJation of 3,6-dichlorosalicyfic acid with chloromethane to provide dicamba. (9) CN102125Q3GB reports a process involving carboxylatioti of 2,5- riichloropheno! and methyJatJon of 3,6-dich!orosalicy!ic #cid with dimethyl carbonate to piovide dicamba. (10) CN1S30942A reports a process involving methyl ation of 3,6- diclilorosaficylic acid with dimethyl sulfate to provide dicamba. f98] Accordingly, in one embodiment, the present disclosure rdales to a process for the preparation of dicamba, i.e., a compound corresponding in structure to Formula (VI): CI OCH3 rOH 0\ O (VI), 6: WO 2t}15IG9ttX4 P<.T/IIS2e prepaialion of dicamba, i.e., a compound corresponding in structure lo Formula (VI); ,OCHj .OH CI 0 or a salt [hereof, the process comprising: (VI), (VI). or a salt thereof, the process comprising: forming a reaction medium comprising sulfuric add; an organic acid selected from the group consisting of C^-CB-afkanoic acids and hato-Ci-C^-alkanolc acids; and, optionally, a first amount of a compound corresponding in structure to Formula {Ill-aJ; (II la), or a safE thereof; introducing into Ihe reactfon medium a second amounL of the compound or salt of the compound of Formula (lii)r and a diazotizing agent, lo generate a rJiazoniurn producl mixture comprising a compound corresponding in structure lo Formula (JV-a): (IV-a), WO 2Q1SIQ952U1 PCr/lIS2«I-J/{l7<>7*i4 JO or a salt thereof hydrolyzrng the compound or salt or Formula (IV-a) lo generate a phenol product mixture comprising a compound corresponding in slructure lo Formula (V-a): (V-a), or a sail thereof; and carboxyteting the compound or sail of Formula (V-a) lo generate a carboxylatod product mixture comprising a compound corresponding in structure to Formula (V-b): or a salt thereof; and converling the compound or saft of Formula (V-b) to Ihe compound or salt of Formula (VI). fit one aspcul, the converting slop comprises molhylating the compound or salt of Formula (V-b) to generate a methylated product mixture comprising a compound corresponding in structure to Formula (V-o): CI CJ 0 (V-c), or a sail Thereof; and selectively da molhylating Ihe compound or salt of Formula (V-c) to generate a dfcomba product mixture comprising the compound or sail of Formula (V!). In another aspect, llio converting step comprises selectively mcihylatiny Ihe W0 2flLW5J8-f PCTiUSlQWiniffll 41 compound or salt of Formula (V b) lo generals a dicamba product mixture comprising the compound or sail of Formula (VI). [101] hi one embodiment, the present disclosure relates lo a process for the preparation ot dicamba, i.o., a compound corresponding in structure to Formula (VI): (VI), or a salt thoreof, the process comprising: forming a reaction medium comprising sulfuric acid; an organic acid selected fromtlio group consisting of Cz-Ci-alkanoic acids and halo-Ci-Cc-afkanoic acids; and a compound corresponding in slructure to Formula (IN-a): CI NH2 CI (llf-a), or a sail thereof; introducing info the reaction medium a diazolizing agent lo generale a diazonium producl mixture- comprising a compound corresponding \n structure to Formula (IV-a): CI CI (IV*), or a saft thereof; hydrofyWng the compound or salt of Formula (IV-a) lo generate a phcnul producl mixture comprising a compound corresponding in structure lo Formula (V-a): WO20lWJ:i2!H POT/US2UI4/07U7G4 42 CI (V-a), or a salt thereof; carboxylallng the compound or salt of Formula (V-a) to generate a carhoxylalod product mixture comprising a compound corresponding in struclure In Formula (V-b): CI .OH -OH C\ G (V-b), or a salt thereof; and converting the compound orsalf of Formula (V-b) folhe compound or salt of Formula {Vi). In ono aspect, the converting step comprises methylatmg the compound or salt of Formula (V-b) to generate a methylated product mixture comprising a compound corresponding in structure to Formula (V-c): CI ,OCH3 £>CH3 CI O (V-c), or a salt ihereof; and selectively demethyiating the compound or salt of Formula (V-o) to generate a dicamba product mixture comprising the compound or salt of Formula (VI)- In another aspect, [he convening step comprises selectively methyialing, the compound or salt of Formula (V-b) to generate a dicamba product mixture comprising the compound or salt or Formula (VI). [102] In one embodiment, the process further comprises isolating the compound orsalf of Fonrtuia (VI) from the dicamba product mixture. WO 20UW5234 P(T/US2l)14/07l)7fi.| 4.1 VIM. Examples Example 1: Analytical Methods (Z.frrDichloroanilitie and 2.5-Dichloroonenol) [103] Unless otherwise staled, chromatography was used lo monitor the 2,5- dichJoroanilino consumed and tho 2,5-dJchlorophenol produced in the dlazotization/hydroxylaffon reactions discussed in Ihe following examples: C! a CI diaEOtizatio^ [| j hydrox^tjori^ Additional analytical methods used in corlaln of the examples afso are discussed below, A. Thin Layer Chromatography ITLC) Method J1G4J In one analytical method, thin layer chromatography (TLC) was used to monitor the reaction. For example, TLC using a mobile phase of djchloromemane. hexane, and methanol in 3 lafioofSO to 75 to 5, respectively, nave a retention factor for 2,5-dichloroariiJine of about 0.5 and a retention factor for 2,5-dichlorophenol of about 0.3, 2,5-Dlchioropheno! exhibited a yellow spot when developed wlfh potassium permanganate sfain. 2.5-Dicliloroanilino exhibited a blue spot when dovefoped with cerium-ammoniurn-molybdaie (CAM) slain. 2,5-Djch!orobenzorre diazonwm, however, staypd at thenasoline of the plate. Disappearance of the 2,5- dichForosniline spot on TLC gorierally indicated that the 2,5-dichloroani!ine had been converted Lo Ihe 2,5-dichforoben7ene diazonium. B. HPLC Method [105] In anolher analylicai method, HPLC was used to monitor the reaction. HPLC wa!J conducted on an Agilent 1260 Infinity Analylical-Scale LC/MS Purification System equipped with a diode a* ray UV detector and monitored at 230 nmr The cofumn was an Agilent Poroshcl! 120 C-18EC. 4.6x50 mm, 2.7 micron with a ptscolumn tiller. The HPLC was conducted at a flow rafe of 2 mL/minuto of mobile phase water (0.1% liEfluoroacelic add)and acelomlrife as described in Table 1-A below: WO 201Sm9S2ft* PCT/US2U14/07l)7*H 44 TIME 0.00 _o,25_ 4,00 4 25 5.00 Table 1-A: HPLC Method % WATER 70 70 _70 70 % AC£TQNITRILE 30 30 95 30 30 Tho shown in Table 1-B bol^w were observed: Table 1-B: HPLC Retention Times TIME 0.3 minutes 0.7 minutes 1,9 minutes 2.5 minutes 2.9 minutes COMPOUND 2.5-dichlorofrenzenG diazonium sulfate 3-chforoaniHne 2,5-djchlorophenoI 2, b-dichioroanilino 1,4-d ichloron ilro benzo 1,4-dichlorotje ozone Disappearance of the 2.5-dichforoaniline peak on HPLC generally indicated that the 2,5-dichloroaniJino had been converted to the 2.5-dichlorobenzone diazonium. C. Gas Chromalographv Mass Spectroscopy Method [106] 6as chromatography mass spectroscopy was performed on an Agilent system using a J&W 122-5535 D8-5MS-UI (0.25mm x 0.25pm x 30m) column. Method: 1 minute hold at 80°C; 2 to 9 minute gradient 0Q*C to 320"C; 1 minute hold at 320*C, Helium at 54 mL/minutc How, tlamc Eoni7ation deteotor (FID detector), and 1 pLinjotfion. D. Nuclear Magnetic Resonance Method £107} Nucloar magnetic resonance was run oti a Bruckor 600 MHz instrument, Doulerafed solvorils from Cambridge Isolope Laboratories, Lid. including molhanof, chloroform and dimemyBu If oxide wero used #s required. 45 R. Water. Content Method [108] Percent water by weigh! determination was run on a Mettler DL1# Karl Fischer instrument using Aqua Star CombiTifrant 5 acquired from EMD Mjlliporo. Example 2: Anaivticfll Method f2.5-Djch8orobenzene DjgzoniumJ [109] An analytical method was developed for evaluating Ihe conversion of 2pb-dicMarnanifiiiG lo 2pb'dichforobcnzene diazonium in the diazolization reaction: ci The 2rb'dich!orobenzene drazonium produced was not isolated, but instead was quenched with fiypophosphorous acid (HaPO?) and converted to Ihe corresponding 1 ,4-dichiumhenzcno: D|yzo!izdLiO([ HsPOa *- K^ 1 Other By-Products Although Ihe primary product of the conversion was 1,4-dichforobonzene, it was observed that the hypophosphoroiis acid reaction produced other minor by-products as detccled by HPLC. The amount of 1>4-dJch!orobenzene produced was [hen determined a^6 thai value was used lo calculate the extent to which the initial amount of the 2,5-dlchloroaiiillne charged to the reaction was converted to the 2,5- dichlorobenzcno dia?onium. [110] Specifically, after tho reaction medium comprising the 2,5-dichloroanifine was treated with sodium nitrite and warmed lo room temperature, an aliquot (approximately 200 mg) of the resulting reaction mixture was weighed into a 10 mL voJumcb-ic Hask, add a vofurno of hypophosphorous acid (50% weight/weight solution of hypophosphorous acid/water; approximately 10 times Ihe volume of the reaction mixture aliquot) was added to the flask and the quenched mixture agitated for five minutes at room temperature in a manner similar to (he analytical method reported in WO 2lHS/ljy52BJ 46 PC'ryuS2014/IJ7U704 J. Org. Chem. Vol. 42r No. B, 1077; J. -4/rj. C/terfl. Soc. Vol. 72p No. 7r 1950. The quentfhed mixture Ihen was diluted wifh methanol (up lo 10 mL) lo dissolve any precipitate present and analysed by HPI.C. Response factors were developed fur 1.4-dichlorobenzene and used to quantity that compound. [111) An aliquot of the reaction mixture also nan bo evaluated without hypophosphorous treatment lo measure the remaining 2.5-dichloroaniline using appropriate response factors and then subtracting tho measured amount from ^\G initial amount of the 2,5-dichloroani!ine charged to the reaction to determine tho corresponding amount of 2,5-dichlorobenzene diazonfum produced. Example 3: Djazotization/Hvd reflation igSulfiirieAcid (Brphasrc Reflux) [112] 2.6-Dichloroaniline (10b mmol. Sigma Aldrich) was rccryslallizod from 125 mL of ethanol/waler (3/2 volume/volume) to yield fine, off-wFiiU? crystals of 2,5- dichloroanfline (89.6% yield). In a first experiment, 1G.1 g (123 mmol) of a 7 5% (weigh! percent) sulfuric acid solution in wafer was added to 12.3 mmol of the recryslalifced 2,5-dichloroaniline m an exothormic reaction that increased \he temperature of the resulting mixture to about 6 0 *C The mixture was stirred vigorously in a 40 mL boaker while the temperature was reduced to about 10 lo2Qr>G using a cold water bath. Cooling produced a Jumpy suspension o f l f i o 2 . 5 - dJchloroaniJine dfazonium sulfate salt. A spatula was used lo further grind and pulverize the suspension until it Ifie suspension was smoolli. Sodium nitrite (910 mg, 13.2 mmol) was added to tho suspension in ono portion resulting in the evolution of an orange gas (NO*) and producing a heterogeneous mixture. The mixture was stirred at room temperature for one hour. Solid sulfamic acid (80 mg, 0.9 mmol) was added and the mixlure stirred for an additional 30 minutes. The viscous and collusive mixture was then aliquoUud into healed xylenes (13.5 mL at about 125^0) via pipette ovor a 10 minute period. The mixture was stirred at reflux for 3D minutes, Stirring was stopped and the mixture was allowed 10 coo! to room temperature overnight. While in tho reaction vessel, the phases partitioned. The xylene layer was isolated and the £,5-dich!orophenol yield determined (6 26%) using HPLG response factors. 2.b-DichloroaniJiNe diazonium and unreactod 2,5-dichlomanEline were detected in the aqueous phase but not quantified. -! WO 2(H5/WI524i4 ]'CT/US21) f 4/(17U 764 J7 [113J The low yield suggested thai The 2,5-dichloioanilino diazonium did not fully form or the hydrolysis icuclion failed. II was hypothesized that poor solubilily of the 2,5-dichloroaniline sulfate salt and tho 2.5-dichloroaniline dfazoniurn intermediate fikely contributed lo the low yield of the 2,5-dichloropheno! product. To fully dissolve the 2.5-dichloroaniline and ensure the formation of Ihe sulfate salJ, four additional experiment w#re performed in which Ihe 2,5-dic^loroanilrne/sulfuric add solution was heated to y4°C lo provide a homogenous solution. The solution was cooled lo about 10cCto20'>C and became a heterogeneous mixture. The sodium nitrite then was added piecewise over a 15 minute period. The hydrolysis was performed In xylenes as described abovo to give yields of the 2,5-dichlorophonol product ranging from 23% to 5 0% as reported In Tabic 3-A below: Table 3-A; 2.5-DLchloror>henof Yield {Sulfuric Acid/Biphasic Reflux) NaNO? Equivalent Nitrite Quench %Unreacted2,5-DCA % Yield 2,5-DCP Clean Product Peak" 1.07 Sulfamic Yes 6.26% No 1.07 Norte 5,33% 49.92% No 1.07 Sulfamic; 8,33% 23.30% No 1.1b None 3,40% 44,10% No 1.15 Sulfamic 0,93% 38.68% No * Refers to tho HPLC of the organJc phase post-hydrolysis. Example A: Dja_zoti^atiorj/Hydroxviation \v\ Sulfuric Acid f Distillation! [114J 2,5-Dichloroanilme (8,95 mmo!) was added to a reactor containing concentrated sulfuric acid (4 ml_) and the mixture was heated to 65°C to disserve alf of the 2,5-dichforoaninne. The resulting solution Was cooied to 2°G and formed a heterogeneous slurry. A solution of sodium nitrite (9.51 mmo!) in sulfuric acid (4 mL) was added to the slurry over a 15 minute period with a maximum temperature or7°C being reached. Tho slurry was slowly warmed to room temperature, a distillation apparatus and receiving flask attached, and the slurry was heated la157°C. Water (25 mL) was added to the reactor via ari addition tunnel over a 1.5 hour period. Heating snd distillation continued for another 2.5 hours in ordor to azeotrope Ihe 2,5- dichlorophcjtol produced and water into the receiving flask. [115] Upon coolfng of tho distillate, the 2,5 dichforophenol product precipitated as a while solid (44% isolated yield of solid product with an additional 4 5 % in the distillate that could have been extracted with organic solvent). No by-products formed and unroacted 2,5-diehloroanilirie (9%) was recovered in Ihe aqueous phase WO 2l}15rtJ952tf 4 -IS Pt:T/US21H4y«7»7ft4 oi (he reactor. Formation of Ihe 2,5-drchlorobonzene dfii^onium again appeared to bo hindered by solubility of Ihe 2,5-dJchloroaniUne in sulfuric acid. Example? 5; Scifubililv Study {116] Three dilforent commercially available sources of 2.6-dichforoanilrno (Sigma. Acros, and AlfaAosar) were evaluated for solubility in several different solvents under the specific conditions reported In Table 5-A. The 2,5-dichloroaniJine obtained from Sigma was evaluated with and without milling, Rosulls from the study are reported in Table 5-A. [117} In general, the 2,5-dichloroaniline was readily soluble in aculrc acid and trifluoroacetic acid al all temperatures. In contrast, il was insoiuhte in concentrated hydrochloric acid, 75% sulfuric acid (woig hi/weight sulfuric acid/water), and formic 3cfd al all tempcralures tested. Although 2,5-dichJoroanilino was soluble in concentrated sulfuric acid at 80*C, solubility at the lower temperatures tested still was limited. Milling the 2,5-dichloroanifine did appear to improve solubility in concentrated sulfuric acid. [118] When sulfuric acid was added to the milled or unmilled 2,5- dichloroaniline, the 2,5-dichloroaniline clumped up and formed a "crust" on itself. II is hypothesised that this crust is a 2rb-dichloroaniline sulfate salt that forms and creates a salt capsule enclosing the 2,5-dichforoaniJino thereby further reducing 2,5- dichloroanflme solubility. With vigorous stirring by stir bar or paddls-equippcd stir rod, the mixture containing Ihe "crusted" 2,5-dichtoroariiline typically can he converted to a slurry of the 2,5-dichioroaniline sulfate sail. 49 PCT 40-21 (60206J0000AVO TabLej^A;. 2.5-Dichloroaniline Solubility f Different Solveng/ConditiQris) SOURCE Sigma Siama Sicma Siama Siama Sicjma Acres Acros Acros Acros AlfaAesar AlfeAesar Siama Siama Sicma Siq rr-s Siama MILLED? No No No No No No No No No No No No Yes Yes Yes Yes Yes SOLVENT CorrG. H?SO, Core HCI Glacial Acetic Acid Formic Add (88%) 75% H?SOfl TriffuoraceticAcid Cone H?SO£ Glacial Acetic Acid Cone. hsS04 Glacial Acetic Acid Cone H?SOd Glacial Aceiic Acid Cone H?SOd Cone H?SO„ Cone HsSO* Glacial Acetic Acid Glacial Acetic Acid MOLARITY 2,24 2.24 2.24 2,24 2.24 2.24 2.24 2.24 1.12 1.12 1.12 2.24 2.13 1.16 0,58 1.16 2.24 EXOTHERMIC SOLVENT ADDITION Yes Slight No No Slight No Yes No Yes No Yes No Yes Yes Yes No NO TEMP 10DC Insoluble Insoluble insolvent Froze fnsolubfe Insoluble Soluble Partial Soluble Partial Soluble Partial Soluble Soluble Soluble Soluble Soluble Soluble I I I I WO 20 J 5/095284 50 PCT/1152(114M7A4 Exam pie 6: pjazotizalion in Acetic Acid [119] Acetic a d d (4 mL) was added to a beaker contain hi g 1.45 g (89.6 mmol) ot 2,5-dioh!oroaniline, The reaction mixture was chilled in an ice bath la 1 2 X and sodium nitrite (O.fil g, 11.74 mmol, 1.07 equivalents) in 4 mL water was added via pipette over a period of 30 minutes. An oratige gas evolved and the reaction mixture turned thick and orangc-yollow. Alter the addition of the sodium nitrite, the roaction mixture was stirred at 12"C Tor 30 minutes. The reaction mixture was stored overnight at room tempera tuns. The mixture was added via pipetto over a penod of 30 minutes to a reactor containing refluxing sulfuric acid (8.8 mt_). Distillation occurred over a three hour period during which a total of 50 mL water was added to the relluxing mixture. HPLC indicated the reactor contained mostly 2,5- dichloroaniline and the distillate contained less than 1% 2,5-dichlorophertol generation, Example 7: Diazotigalion in Acetic Acid^Sulfuric Acid A. Diazotization Reaction [120J 2,5-DichloroaniJIne (8.95 mmol) was dissolved in acetic a d d (16.9 mL, 32.9 equivalents) and sulfuric acid (5.4 mL, 11.2 equivalents) was then added. The 2,5-dichloroaniline initially remained in solution after addition ot the sulfuric acid, but the solution became a thick, opaque, homogenous mixture as it was cooled to 1(TC. Sodium nitrite was added drop wise as an aqueous solution (12r3 mmol, 1.4 equivalents, in 5.6 mL water). As sodium nitrite addition continued, 2,5- dichlorobenzeno diazonium tormod and was solvated, HPLC at this time indicated there was no remaining 2.5-didiloroariilfne. The resulting 2,b-dich!oro benzene diazonium solution then was added drop wise to a refluxing (approximately 100"C) solution of sulfuric acid (3.8 mL) and water (36 mL) in a reactor not equipped with a distillation arm, and slirred for 30 minutes. HPLC, however, did not indicate the presence of any 2,5-dichlorophenol in the refiuxed solution. It Is believed, however, that an incicascd reactor toniperalure and the addition of a distillation arm to Hie reactor wouid have resulted in the production of some amount of 2,5-dichlorophenoL WO 2IJ1AAI.')5284 51 PCl/\SS2i)UHnQ76A B. Diazorizalion Reaction (SulJuric: Acid Ghanjo) [121] A study was conducted lo evaluate fhc effect of the sulfuric; acid charge 0:1 the conversion o! 2,5-drch!oroani!ine to the diazonium. In this study, the acetic acid charge was maintained constant (18 equivalents) and the sulturicacid charge was inci omental ly reduced. [122] Acetic acid (10.0 mL, 18 equivalents) was added to a series or beakers containing 2,5-dichloroanlfine (1.50 gr 9.26 mmol). In separate experiments, decreasing equivalents of sulfuric a d d (8.26 to 1.0 equivalents) were added to the beakers. The reaction mixtures were chilled in an Ice bath ( O X to tQ°C)and sodium nitrife(aq) (3.24 ml-, 3 M. 1.0b equivalents) was added via syringe pump at a rale of 0.4 mL/minuIe with a subsurface flexible needle. After the addition was complete, the reaction mixtures were allowed to come to room temperature, and afiquots wcro removed for treatment with hypophosphorous acid to convert anydiazonium produced to 1,4-ifichlorobonffine. The relative ratios of the HPLC peakareas detected at 280 nm for the? 2,5-dichIoroanifine remaining and lhe 1,4-diehlorobcrizene produced are reported in Tabfe 7-Ahelowand shown as a bar chart in Figure 1. Table 7-A: DiazonJum Yield Versus Sulfuric Acid Charge SULFURfCACID EQUIVALENTS H.2& 6.61 5.78 4.96 4.13 2-48 1.00 2,5-DlCMLOROANILlNE (HPLC PEAK RATIO) 28.9% 8.8% 3.3% 1.8% 1.4% 0.0% 49.5% 1,4-DICHLOROBENZENE (HPLC PEAK RATIO) 71.1% 91.2% 96.7% 98.2% r 90.6% 100.0% 50.5% (123] Reducing the sulfuric acid chaise from 8,26 equivalents to 2 48 uquJvalenlK actually increased conversion of 2,5-tfichjoroanflina to the diazonium. Below 2.4S equivalents of sulfuric acid, however, conversion to the diazonium decreased. C. pi37o;izalion Reaction (Acetic Acid Charge) [124J A similar study also was conducted to evaluate \h& effect of the acof ic acid charge on the conversion of 2,5-dichloroanilrne to the dia^nnrum. In this sludy, WO2015/IJD52SI 52 P< rr/US?!314/0707G I the sulfuric add charge was maintained constant (2,5 equivalents) and the acetic acid charge was incrementally reduced. 11251 Decreasing amounts of amounts of acetic acid (10 to 2.0 mL. 10 to 5 equivalents) we ro added lo a series of beakers containing 2,5-dichloroaniline (1.50 g, 9,26 mmoi). Sulfuric acid (2,27 mL. 2.5 equivalents) was then added to each beaker. The reaclion mixtures were cHlfed in an ice balh (0°C to 10"C) and sodium nlfrite(aq) (3.24 mL, 3 M, 1.05 equivalents) was added via syringe pump at a rate of 0.4 mL/minule with a subsurface flexible needie. After the addition was complete, Ihe reaclion mixtures were allowed to come to room temperature, and aJrquofs were removed for treatment witfi hypopiiosphorous acid to convert any diazonJum produced to 1,4-dichlorobenzene. The relative ratios of Ihe HPLC peak areas detected at280 nmfor the 2rS-dichloroanjline remaining and Ihe 1,4-dichlorobenzene produced arc reported in Table 7-S below and shown as a bar chart in Figure 2. Table 7-B: Diazonium Yiold Versus Acetic Acid Charge ACETIC ACID EQUIVALENTS mo 1a.0 12,0 11.0 10,0 9.0 a.o 7.0 6.0 5.0 2f5~DlCHLOROANILINE (HPLC PEAK RATIO) 0.0% 0.0% 0.0% 0,0% 0.0% 0.0% 0.0% 0.0% 6.7% 5.3% 1,4-dlCHLOROBENZENE (HPLC PEAK RATIO) 100.0% 100.0% 100.0% 97.5% 97.6% 97.1% 96.8% 08.7% 08.8% 93,4% [126] Reducing the acetic acid charge from 10,0 equivalents lo 7.0 equivalents under tho conditions tested did not materially decrease solubility or conveision lo the diazanfum. At acetic acid charges befuw 7.0 oquivalenls. however. decreases in solutiFlrty and conversion In the diazonium were observed. WO 2UJ5AW52a4 53 PCT/US2014/07076.1 D. Oiazojizalion Reaction [127] A solution of acetic add (7.76 rnL. 7 equivalents) and sulfuric acid (4.54 mL. 2.t> equivalents) was added to a beaker containing 2,5-dichloroanfline (3.00 g. 18,52 mmol). The resulting mixture was chilled in an ice bath (OX to 10°C) and sodium n i t r i t e^ (6.43 mU, 3 M, 1,0b equivalents) was added v7li-l [133] Sulfuric acid (20.23 g, 11.4 equivalents) was added to a beaker containing 2.5-riichforosnilino (3 00 g, 1R.52 mmol). The reaction mixture was cooied to room temperature in an ambient water hath, and solid sodium nitrite (1.34g, 19.44 mmol, 1.05 equivalents) was added piecewiso over a period of 15 minutes. After the addition was complete, an aliquot was removed for treatment with hypophosphorous acid to convert any diazonium produced lo 1,4-dichlorobcnzene. MPLC indicated 94% conversion of the 2,5-dlchloroanifine to 1,4-dichiorobonzene. B. Addition of Sodium Nitrite in Concentrated Sulfuric Acid ^134] An attempt was made to add a solution of sodium nil/He in concentrated sulfuric acid (greater than A M) to the solvent system containing (lis 2,5- dichloroaniline using a syrirrge pump. The addition was not successful because Ihe pressure the pump applies io the syringe plunger caused the contents of the syringe to crysJalfizc out of solution, [135] Sulfuric acid (30.07 gr 16.6 equivalents) was added to a beakor containing 2,5-dichloroanilino (3,00 g, 18.52 mmofj, Tho reaction mixture was cooled to room temperature, and a solution of sodium nitrite (1.34 gr 1.05 equivalents) and sulfuric acid (3 g) was added drop wise via syringe with a subsurface needle. The syringe and needle became plugged when the sodium nitrite crashed out of solution under the pressure of the syringe. An additional 11.5 g of sulfuric acid was needed to solvate the syringe contents, and the resulting solution was added drop wise over a period of 30 minutes. After the addition was complete, the reaction mixture was allowed to come to room temperature, and an aliquot was removed for treatment witfi hypophnsphorous acid to convert anydiazonium produced to 1,4-dichlorobcnzene. HPLC analysis indicated a 2,5-dichIoroanjfine to 1,4-dichlorobenzone peak absorbaiice ratio of 1:2.1. C. Addition_of Anueous Solution of Sodium Nitrite [136] An aqueous solution of the sodrum nitrite was added to a reaction medium containing the 2,&-dichloroanilinc. When the aqueous solution was added to a reaction medium that WFIS 2,5-diehloroaniline in concentrated sulfuric acid, the addition was very exolhermic and analyst of the resulting solution showed a 2:1 ratio of diazonium to unreacted 2,5-diohloioanriine. In contrast, when the aqueous solution was added to a reaction medium that was 2,5-dich!oroainline in acetic gcid/sulfuric acid, however, the ( t a c l i on was mildly exothermic. WO 2015/095234 56 I*C'iyuS7H14At7«76'l 1137] Sodium nitritc(a!) (2.2 M, 1.05 equivalents) was added drop wise to 2,5- dichloroanilino (13.52 mmol) in acetic acid/sulfuric acid and resulled in good conversion to the diazonium. Increasing the sodium nitrite concentration to 3 M also provided good conversion to Ihe diazonium. When the sodium nitrite concentration was increased from 3 M to 6 M. however, conversion to the diazonium decreased to less than 70%. It is hypothesized that water plays a role in solvaling Ihe diazonium and sodium bisulfate (a byproduct ot the formation oi nitrous acid), and that sodium bisulfate precipitates out ot solution as the amount ot water present decreases, [138] Theoretically, tho nitrous acid is lass prone to decomposition and formation of the diazonium should be favored when the aniline sulfate solution is chilled to a temperature between OX to10°C. There did not appear to bo a significant difference, however, in the formation of the diazonium at room temperature (about 2 5 X ) versus temperatures ranging from OX to10"C. The lower temperatures may not be required as long as stirring and subsurface addition of Ihe sodium nitrite are adequate. D. Addition c^NitrosyjsulfuricAcid [139] Nitrosy!sulfuric acid (40% by weight in concentrated sulfuric acid, Sigma- Aldrich) was added drop wise to a mixture of 2,5-dichloroanifine in sulfuric a c i d . ^ (60% by weight). The formation of the diazonium was quantitative, efficient, loss exothermic, and less prone to decomposition. The reaction was repeated in 50% to 98% concentrated sulfuric a d d with 2,5-dichloroaniline solubility increasing as sulfuric acid concentration increased. Similar results were obtained at all sulfunc acid concentrations, i.e., complete conversion to tho diazonium. [140] To a beakor containing 2,5-diohloroanilrne ( 3 0 0 g. 18.52 mmol) was added 60% by weight sulfuric a c i d ( ^ (1601 g. 110.17 mmol). The solution was warmed to 120"C for 80 minutes to dissolve the 2.5-dichloroaniiine. At room temperature, nitrosy Is ulfuric acid (40% by weight in sulfuric acid) (6.25 g, 1.06 equivalents) was added via pipette subsurface to the mixture. After the addition was complete, ihe reaction was allowed to come to room temperature, and an aliquot was removed tor treatment with hypophosphoi ous acid to convert any diazonium produced to 1,4 dichlorobenzcnc. HPLC indicated G6% conversion of Ihe 2,5- dichloroaniline to 1,4-dichlorobenzone. WO 2M5M9521U 57 l'Ci71]S2UM/U7U7(i4 [141] As indicated by the experiments discussed above, the temperature and overall sodium nitrite toncenhalion afloct the mechanics of the sodium nitrite addition. One satisfactory approach (see Example 10) that resulted in complete conversion to the diazonium involved the addition of an aqueous solution of sodium nitrite (3 M) at a temperature of 10UC via a subsurface flexible needle (16 gauge) as delivered by a syringe pump at 0.5 mL/min to the 2,6-djchloroanilinc (18,52 mmol reaction scale) with overhead stirring in a mixed solvent system of acetic and sulfuric acid (7:2.5 mdar ratio). B. Drop Wise Addition tq_Concenfraled Suifuric Acid Reaction Medium [142] 2,5-Dichloroaniline (18.52 mmof)was dissolved in concentrated sulfuric acid (iJ.27 mL, 8.38 equivalents) in a round-bottom flask equipped with an overhead stirrer, A solution of sodium nijnte (19,63 mmol. 1.06 eqiiivafonts) in sulfuric acid (8.27 mL. 8.38 equivalents) was added drop wise to a stirring mixture of 2,5- dichloroaniJino sulfate salt at 10°C. HPLC analysis indicated that approximately 2 0% of the 2.5-dichloroaniiine was unreacted. It Js believed mat due to solubility and handling conditions quantitative formation of the diazonfum using only 1.05 equivalents of sodium nitrite is not likely in a concentrated sulfuric acid solvent system under these conditions. In addition, it is further believed that sodium nitrite in sulfuric acid (unlike sodium nitrite in an aqueous solution) is more likely to crash out of solution under increased pressure conditions (such as a syringe pump) at this concentration (0.1 G4 g/mL). Using an addition funneJ however, Impedes delivery of the sodium nitrite which is better delivered subsurface and at a low steady rate (as ii would have been using a syringe pump. Example 10: Diazotfcation in Acetic Acid/SuifuricAcid A. Experiment A [143] Concentrated sulfuric acid (13.62 g, 0 1 4 mo!, 2.50 equivalents) ^s added to a solution of 2.5-diclilojoaniiiue (9.00 g, 0.055 mol) in acetic acid (23.35 y, 0.39 moi, 7.00 equivalents) in a 250 mL round-bottom tiask. The addition of the sulfuric acid was exothermic. The reaction mixture was allowed to cool to room WO 3015AJ952S4 58 PCTrtlpSaOI-1/071176-1 temperature. II remained solubiilzed and was stored with on oveihoad paddle stirrer. The reaction mixture containing Ihe 2,G-dichloroaniline was chilled (and became a slurry once erx>led to 0"C to 10"C) and a solution of sodrum nitrite (19.44 rnL, 3 M, 1.0b equivalents) was added via syringe pump at 0.5 mL/minute. Tho flexible noedle Jip was piaced subsurface of Ihe solution and an ico wafer balh was used to maintain the solution at a temperature between 0 * 0 to 10°C. [144] Approximate\y 20 pL of the solution was removed and reacted wilh 100 pL of hypophosphorous acid (40% by weight in water) in a 2 dram vial. The aliquot was shaken for 30 seconds, diluted wUh 2 mL of methanol, and analyzed by HPLC to determine Ihe ratio of unreacled 2,5-diehloroafiliine to 1.4-drchforohenzone (£e., Ihe product of Ihe dearnination reaction of diazonium wilh hypophosphorous acid). HPLC indicated approximately 100% conversion of the 2,5-dichloroanilfno to the 1Adichlorobenzenc. B. Experiment B [145] Concentrated sulfuric acid (4.54 mL, 2,50 equivalents) was added to a solution of 2,5-dJchloroaniline ( 3 0 0 g, 1852 mniof) m acetic acid (7r78 mL, 7.00 equivalents) in a beaker, Tho reaction mixture was chilled in an loe bath (0°C tolO "C)and sodium nitrite (6.48 mL, 3 M, 1.05 equivalents) was added via syringe pump at a rate of 0.4 mL/rninutewMh a subsurface flexible noedle. After the addition was complete, the reaction mixture was allowed to come to room temperature, and an aliquot was removed for treatment with hypophosphorous acid to convert any diazonium produced fo 1,4-dichlorobenzcne. HPLC indicated approximately 100% conversion of the 2,5-drchloroaniline to 1,4-riichfoiobenzcne. Example 1 1 ; Piazotizatfon/HvdroxYlation in Acetic Acfd/SulfuricAcid (Biphasic Reflux) [146] In three separate experiments similar to the experiments previously discussed in Example 3r sulfuric acid (15.00 g. 8 54 equivalents) was added to 2,5- dichloroaniline (8.95 mmol) in a solution of acetic acid (10,00 g. 10.61 equivalents). The mixture was stirred vigorously in a 100 mL beaker while the temperature was reduced to about 10°C using a caidwatoi bath. Sodium nilrite(aq)(1.21 or 1.37 equivalents as stated In Table 11-A)was added drop wise over 15 minutes to give a WO 2015/095284 $•} J'CmiK2IH4/0707G4 heterogeneous mixture. After Ihe nitrite adriilion, sulfamic atiirf (0 equivalents to 0.11 equivalents) was added to Ihe mixture arid tho mixture slirred for 10 mfnutes. [147] The mixture came to room temperature and was added via syringe pump to a reactor set at 130X and containing xylenes (40 mL) over a lb minute to 90 minute period. The biphasJc reaction mixture did not maintain the set temperature after [he addition. The temperature stabilised o!97°C to 111"C even though tho yet temperature was at 130QC. The mixture was stirred for 30 minutes to 120 minutes, Stirring was stopped and the mixture was allowed to cool to room temperature, and the phases partitioned. The xylene Jayerwas isolated and lh# 2,5-drchlorophenol yield determined using HPLC response factors. The 2,5-dichlorophenoJ produc! yields ranged from 1% to 34% as reported in Table 11-A below: Tabfe 11-A: 25-Dichloropheno! Yield (Btohasic Retlux) Diazonium Solvent NaW02 Equivalents NaNO? Addition Nitrite Quench Reactor Temperature %UnreactedDCA % Yield 2,5-DCP Clean Product Peak* AceMc/Sulfuric (4:3) 1.37 Aqueous None 97X 0% 33.41% No Acetic/Sulfulic (4:3) 1.21 Aqueous None 111-C 0% 1.78% No Aeelic/Sulfurfe (4:3) 1.21 Aqueous Sul ramie 111 to125"C 0% 8.40% No ' Refers to the HPLC of the organic phase post-hydrolysis. [148J The reported data indicate thai the diazonium formation was complete, but that tho conversion to the 2,5-dichlorophonol was very low under the biphasjc conditions. As the 2,G-dichloropfterioi formed, it was extracted into the xylenes. A phase partition of the reactor contents should have provided a 2,5-dichloroprienol product that could be distilled to produce clean 2,5-dichtorophonol, Analysis of the impurities in the organic phase with GCMS found nitrated xylenes and other byproducts present. / \viyiium9S2ni priyuS20i-*/w7076J Example 12: Diazotizaiion/Hvdroxylaljonjn Acetic Aad/Suffuric AcidJSleam O.JSlJHatiqn) A. Hydrolysis With Water [149} Prior to employing the steam hydrolysis approach discussed below. an experiment was conducted to hydrolyze ihe diazonrum in a reactor wilh water as described below. [150] Conconlrated sulfuric acid (9.06 gh 11.23 equivalents) was added to a solution of 2J5-dlchloroaniline(1.45g. 0,95 rnmol) in acetic acid (17.70 g. 32.94 equivalents) in a beaker. The reaction mixlure was chilled in an ice bath (0aC to 10°C) and sodium nitrite (0.85 g, 1 3 7 equivalents) \s\ water ( 6 5 0 mL)was added drop wise as to not raise the reaction temperature over 10"C, After the addition was complete, the reaction mixlure was allowed to come to room temperature, and HPLC indicated no 2,5-drchJoroanJfine present. All of the anilino is presumed to have heen converted to the diazonium. [151J To a three-neck round bottom flask equipped with a receiving flask was added water (20 mL) and sulfuric acid (10 rnL). The solution was heated to 120 X. and the diazonium mixture (8.95 mmol) was added in portions over one hour. Water (2x20 mL) was added at one hour and two hours, and distillation continued for a total oT four hours. The contents of the receiving flask were extracted wilh ethyl acetato to provides 10% yield of 2p5-dichJorophcno! while a 16% yioid of2f5-dich!oropheno! was quantified in the reactor. B. Hydfolysjs_With Water (Dron Wise Addition to Reactor) [152] An experiment was conducted to hydrolyze the diazonium with water addod drop wise to the reactor via an addition fEmnol as described below. [153] Concentrated sulfuric acid (7.36 ftr 8-38 equivalents) was added to 2.tidier! kiroani line (1.45 y. 0,95 mrnol) in a beaker. The reaction mixture was chilled in an ice balh (Q°C to 10DC) and sodium nitrite (0.31 g. 1.31 equivalents) in sulfuric acid (5 rtiL)was added drop wise as to not raise the reaction temperature ever 10°C. After the addition was complete, the reaction mixture was allowed to come to room temperature. WO 2U15/0952K4 5-dichlorophenor in the distillate and reactor were determined by response factors and summed. Results are reported in Table 12-Abolow. In general, 2,5-dichloropFienol yields were lower for reactions conducted at a temperature below ISO^C, Tabfe 12-A: 2,5-Dichrorouhenol Yield Versus_Reactoi Temperature Reactor Set Temperature Observed Exotherm Unroacied DiazonJuni % Yield 2,!>-Dichiorophcnol 1G4°C 1GQ°C 77.7% 6.9% 130X 185DC 23.7% 48.7% 195aC 0.0% 95,9% [160] In addition, the amount of water in the d/stiNate and Ihe reader was determined by Kad Fischer analysis. Any water added as part of a rinse or the dfa^onium solution was quantified and subtracted out to detenjilne the amount of Water added as steam. The amount of water collected and longth ofsloam input into Ihe reactor determine an approximate steam flow rate, E. Hydrolys!s_With Water fSteam Distillation—Steam Rate) [161] A study was conducted !o evaluate the use of steam distillation at varying steam rates to hydrolyze the diazonium to the 2,5-djchlorophenol product. . Reducing the mass of water collected in the distillate can be beneficial for multiple reasons including situations whore the 2,5-dielilorophonol product wilt bo extracted wilh xylenes. The required amount of xylenes needed to extract 2,5-dicliforophonol was determined to bo 65% by weight of xylene and 2.5-dichlorophenol solution (Le,, about 17 niL of xylenes for every 1ft.*j mmol of 2,5-diehlorophenpl). Initial hydro[ysis reactions employed aboul 0.3 scf/min lo about 04 scf/min of steam and generated in excess of 300 g of water in the distillate. Additional hydrolysis reactions were conducted using reduced steam rates thereby lowering (he mass of the distillate collected. [162] Sulfuric acid (40 mLjwas added to a three-neck round bottom flask equipped with a side-arm condenser, receiving llask, and subsurface steam inlet, and hooted to 150QC. Steam was charged at a set rate for oiJch trial (0.38 scf/iuinute to 0.06 scf/minuto). The diazonium mixture (18.52 mmol) was added via syringe pump WO 2015/1)952114 63 vcuuintiwmwM at 1.25 ml/minute At the end of the addition, the steam continued for live minutes Ihuti was turned off. The heat continued until the distillation head temperature dropped bolow 90°C (approximately five minrjtes), then the reactor was cooled lo room tomperaturo. The yield of 2,5-dichlorophenol in the distillate and reactor were determined hy response factors and summed. Results are reported in Table 12-B below. Table 12-E: 2.5-Dichlornnhoncl Yield Versus Steam Rale REACTION 1 2 3 4 5 6 7 ACID EQLW. RATIO (ACETIC ACID; SULFURIC ACID) 10.0:8.3 18.0:2.5 7.0:2.5 7.0:2.5 7.0:2.5 7.0:2.5 7.0:2.5 YIELD SUM {%) 91% 84% 05% 9G% 89% 04% 81% STEAM RATE (scf/min) 0.35 0.3S 0.18 0-10 0,06 0.09 0-10 Example 13: Hvdrolvsis in AcelEc Acid/Sulfuric Acid fStes TOTAL MASS OF WATER COLLECTED (9) — 312 117 57 31 42 42 m Distillation! LENGTH OF STEAM CHARGE (Minutes) 40 39 31 24 23 22 23 [163] A dfazonium sail solution (prepared rising en acetic acid/sulturic acid medium) was loaded into a lared gas-light syringe equipped with a 14 gauge flexible needle tip and weighed. Approximately 40 g of concentrated sulfuric acid (grealur than 98% by weight) was added to a 250 mL 3-neck reactor equipped wifh a slir bar, side-arm condenser with receiving flask, sub-surface steam inlet, healing mantle, and JKEM temperature p>obe- When Iheacid fempeialure reached 150"C. steam was applied at approximately 0.1 scf/minutc to 0.2 scf/minute. At the same timo, addition of the diazonium solution began al 1.25 mL/minute with the tip of the flexible needle at near or sub-surrace ot Hie sulfuric acid. An initial oxotherm gave a luartor temperature of 1#0X to 220aC. The distillation head maximum temperature reached 110X. [164] At the end of the diazonium addition (approximately 10 minutes), the syringo was weighed to determine amount of dJa7onium added f 18,61 mirro!). The steam charge continued for 5 minutes post addition. The reactor wa& boated until tho distillation head temperature lowered to 9Q°C and no additional dishllate was WO 2U15/Gy52tf4 64 FLT/USZOl-l/OTltfJH being collected (approximately 10 minutes). Somu of ihe 2.5-dichlorophonol was a solid at Ihe bottom of tilt? receiving flask and some was dissolved in the distillate. The receiving Mask oonlents were extiaeted with M mL xylenes (based on 15% by weight 2,5-dichlorophenol in The xylenes post-extraction) and Ihe phases partitioned. 2,5-DJchlorophenol residue was present in the apparatus so the apparatus was rinsed wfth methanol and Lhe washings wore coflecled. HPLC quantitative analysis by response factors gave percent yield of 2.5-drchforophenof in tho distillate xylene phase (65.7%), distillate aqueous phase (5.1%), reactor residue (6.2%), and apparatus rinse (17.7%) were performed. Results of percent yield were summed to give an overall yield (94.8%). An aliquot from the reactor was treated with hypophosphurous acid to determine rcsrduaf tfiaznnium content (0%). Proton NMR Data 2,5-drchforophenol: M NMR (600 MHz. CDCI3) 5 7.26 (d. 1 H, J = 10.2 Hz), 7.06 (dr 1 H, J * 2.4 Hz), 6.92 (dri, 1 H, J = 6.0, 2,4 Hz), 5.62 (br s. -OH). 2r5-d[chJoroariifino: 'H NMR (600 MHz, CD3OD) 6 7.14 (d, 1 H, J = 8.4 Hz), 6.82 (dr 1 Hf J - 2.4 Hz), 6.58 (dd, 1 H r ^ 6.0. 2.4 Hz). 2p5'dichlorohenzonediazoriium: 'H NMR (600 MHz, D?OJ 6 8.52 (dp 1 H, ./ = 2.4 Hz), 0.04 {dd. 1H,J = 6.6P 2.4 Hz)p 7.80 (d, 1 H ( J ^ 9.0 Hz). Example 14: Quench Prior To Hvdrolvsrs Stcu [165] A study was conducted to evaluate the effect of quenching excess nitrous acid with sulfamic acid or urea necessary to pruvent the formation of byproducts in the hydrolysis step. Sulfamic acid and urea react with and decompose nitrous acid as shown below: I 2HN03 co2 i 2 ( ^ - i 3H,G (f) O H O - S - M k *• HNQ2 —— H2S04 + N^ •• H20 (2) II O [166] In this study, 2,5-djcbloroprrenol was stirred at 120"C in the presence or absence of sodium nitrite and/or sulfamic acid. Tho 2.5-dichlorophcnol iiselfwas WO30LS/IW5284 fa PfT/LIS2014rtt7ll76-l stabio and either dissolved or melted in the various soiyonls at 120"Cr Upon addition of sodium nitrite to the solution arid heating al 120DC for 30 minutes, allot the solutions had some byproduct forma I ion. The expelimenls wore repeated with sulfamic acid added at 1,1 times the sodium nitrite equivalents with heating to 120aC lor 30 minules as before. Byproduct formation was reduced, and only the solutions containing sulfuric acid had byproduct Results are reported in Table 14-A below. Table 14-A:jL5-DichlQrPPri en ol Stability at Specific Temperatures. Times, and CONDITIONS GO minutes at 12CTC 30 minutes at 120°C 0.2 Eq, NaN02 30min120°C 0.2 Eq. NaNOz 0.22 Eq. H3SOsN Reauenl/Solvenf Conditions) WATER No Byproducts Possible Biphenyls No Byproducts WATER, XYLENES No Byproducts Nominal Byproducts Nominaf Byproducts SULFURIC ACID, WATER, XYLENES No Byproducts Nitrated DCP. Unidentified Byproducts, Possible Biphenyls Unidentified Byproducts ACETIC ACID, SULFURIC ACJD, WATER No Byproducts Nitrated DCP, Unidentified Byproducts, Possible Biphenyls Unidentified Byproducts [167J Usoof urea or sulfamic acid as described in this example did not appear to atfeel the yield of the 2,5-dichlorophenol in a hydrolysis reaction, A brownforange reactor residue typically was observed in the hydrolysis reactions described in the prior examples. Use of urea or sulfamic acid, however, did not appear to reduce this reactor residue. In general,'' appears that sulfamic acid or urea can be charged at 0.05% to 0 1 0% of the 2,5-dichloroanifine charge to offset the excess sodium nitrite charge, either as a soiid or as an aqueous solution after the diazonium cools to room temperalure, ExampJoJjx Parallel Addition of 2.5-Dichforoanlflne and,NiIroso .Source A. Parallel Addition of 2,5-Dichloroanillnc and Nitrosylsulfurlc Acid into Sulfuric Acid Solution [168J Concentrated sulfuric acid (6.05 g, 0.06 niol, 0.5 eq.)was placed in a 2b0 mL three-neck round-bottom flask equipped with an overhead stirrer and coeled in an ice-water bath. A solution of 2,5-dichlojoaniltno in acetic acid (25 wt/wJ%, 76.76 g, 0.12 met) and a solution of nitrosySulfuric acid in sulfuric acid (40wt/wf%. 41.11 g. WO 2015/99529* 6t. FC'I7US2tf.N/U7ltf*H 1.08 eq.)were added in parallel via two individual syringe pumps. The addition of tho aniline solulion was carried out by dripping the solution into the stirring reaction whijo the addition of the nitrosyfsuiruric acid solution was carried nut by Introducing Ihe solulion at tho subsurface of the reaction medium. The addition rale was controlled such that both additions were completed m 41 minutes, during which time the reaction internal temperature was maintained below 15aC. After tho addition, the formed diazonium salt solution was allowed to come to room temperature, B. Parallel Addition of 2.5-Dk;hloroaniJjne and Njlrosy[sulfuric A r id info a Mixed Solution of Acetic Acid and Sulfuric A r id [169] Acetic acid (99%, 200.15 g. 3.33 mol, 5.4 eq,) was placed in a 1500 ml_ glass vessel equipped with an overhead stirrer. The solution was cooled in an icowater bath and concentrated sulfuric acid (9G%, 160.05 gp 1.57 mol. 2.54 en;.) was added. A solution of 2,5-dichlcroaniline in acetic acid (26.0 wlAvt%, 384.6 g, 0,62 trio!) and a solution ot riHrosylsulfuric acid in sulfuric acid (40wl/wt%J 202.5 Q, 1.03 eq.) were added in parallel. The addition of the nitrosylsulfuric acid solution was carried out by introducing tho solution at the subsurface of the reaction medium. The addition rate was controlled such that both additions wero completed in 2.15 hours, during which timo the reaction internal temperature was maintained between - 4°C to 10QC. After t he addition, Vie formed diaroniurn salt solulion was allowed to come to room temperature and was stined at (east for an additional 2 hours. J170] Experiment B was repeated except that a solution of 2,5-dJchloroaniline in acetic acid (20.1 w\fwt%, 345.0 0, 0.62 mo!) was used and the parallel additions were completed in 2.5 hours. C. Parallel Addition of 2.5-Dichloroaiilline and Sodium Nitrite into Sulfuric Acid Solution [171] Concentrated sulfuric acid (15.84 g, 2.6 eq.) was placed in a 250 ml_ three-neck round-bottom flask equipped with an overhead stirrer and cooled in an ice-water bath. A solution of 2,5-dichloroanifine in acetic acid (19.23 wt/wt%, 50.91 g, 0.060 mol)waS loaded into an addition funnel and a solulion of sodium nitrite in water (20 wt/wt%, 22.30 g, 1.07 ecf.) was loaded info a syringe pump. The addition of the sodium nitrite solution was carried out by introducing tho solution at the subsurface ol the reaction medium. The addition rate was controlled such that both additions were completed in 60 minutes, during which time the reaction internal WO 2Ut5fliy52tf4 67 PC'7US2IH4/U70752#4 69 PC T/US2M4/U 70764 HPLC Quantitative; analysis by response factors found l l i a t t he yield of 2,5- dichlorophenol in Ihe distillate was 79.5%. B. Hydrolysis with Wafer Water Addition Before and After ParafloJ Addition of Water and Diazonium_Snlutigni [177J Oiazoniuin salt solution was prepared as m Example 15-B by paralief addition of2p5dichlorT)aniliheand nilrosylsulfuric a d d into a mixed solution of aculic acid and sulfuric acid. Tho resulting diazonium salt solution was evaluated for hydrolysis with wafer addition before and alter the paralief addition of water and diazonium solution, Tho results show that IFie addition of water before and after the parallel addition improved Ihe isolated 2,5-dicfilarophenoJ yield, [178] Paralfef Addition Only: The diazonium salt solution was subjected to hydrolysis only by parallel addition of water and diazonium solution. Sulfuric acid (85% w/w, 502.7 gp 14,18 oq) was placed in a reaction vessel and healed to 150QC Diazonium salt solution (0.G2 mol, 0.G83 mmol/g) and water (950 gp 52.75 mo!) were added in parallel, during which ihe reaction internal temperature was maintained from 135UC to 170"C The addition rates were controlled such mat both additions were completed in Stiours 15 minutes. After 6 hours 35 minutes, the heat was removed from the reactor and no additional distillate was collected afterwards. The contents in the receiving flask wore extracted into xylenes (3 x 300 g). HPLC quantitative analysis by response factors found that fhe yield of2,5-drchk>rophenol in the xylene extracts was 71.1%. [179J Water Addition Before and After Parallel Addition: The diazonium salt solution was subjected to hydrolysis with water addition before and after the parallel addition of water and diazonium solution. Diazonium salt solution (0A9 moi, 0.652 mmol/g) was loaded into a first tared dropping funnel (500 mL). Water (880 y, 40.86 mol, 98.96 uq.) was loaded into a second tared dropping funnel (1000 mL), Sulfuric acjd (05%, 432 g, 7.58 eq.)was added to a 1500 mL five-neck glass vessel equipped with a mechanical stirring, a side-arm condenser with receiving flask, and a heated oil hath. When tho acid temperature reached 165 DC, water (about 40 mL) was slowly added until a con slant disfii la tion of water in the distillation bridge was observed. At this time, fhe diazonium salt solulton smi water were added in parallel, duiing which Ihe internal temperature maintained above 150"C. The addition rales were oontioSled such thai Ihe diazonium salt solution addition was completed in 7 hours as controlled WO 374i-f 7J Exp, No. A-1 A2 A-3 D Table 17: DJa7otiza[ion/Hvdroxyration in Acetic Acid/Sulfuik; Acid with Spiked Sodium Bisulfate Diazoti?ation H?SQ| source j Y e s l i fresh fresfi frosli/spiked NaHSOq Hydrolysis F-|j»SOif source/spiked NaHS04 fresh J-bSCym9% spfkod NaHSOq fresh H Z S ( V 1 0 . 3 % spikod NaHSOA fresh H2SO^0.9% spiked NaHSO, fresh Hz S t y i 0 . 9% spiked NaHSQi DCP purity (area%) 98.3 9 85 99.0 93.5 DCP yieid m.2 37.5 80.1 02.0 Example 18: Diazotization/Hvdrolvsis in Acetic Acid/Recycled Sulfuric Acid [189] A study was conducted to evaluate the feasibility of recycling the sulfuric acid used during the hydroiysis step and reusing that sulfuric acid in the diazolizationmydroxylation process steps. Results of the study indicate that the final product 2,5-dichforophenol had consistent purifies and yields when recycled sulfuric acid was usod rn the process. Such an approach for a commordal-scale process would t ie economically desirable. A. Recycle of Sulfuric Acid from the Hydrolysis Reactor [190] After removing the heating mantle, the hydrolysis reactor was allowed to como to room temperaturo. The reactor was weighed and contents were poured or scraped into a 125 mL Erfonmeyer llask. The reactor Was rinsed with a portion of p l a n e s and the xylene wash was added to the flask. The flask was heated to 100"C and stirred for 15 minutes. The xylene was separated from tho aqueous phase. The aqueous phase in tho Mask was treated with another portion ot xylenes (l00DCf 15 minutes) and the xylene was separated from the aqueous phase. Tho aqueous portion was cooled to room temperature Tor 1 hour. The sodium bisulfate salts that crashed out of solution were isolated by vacuum filtration on a sintered glass funnel. The solids were washed with a portion of xylenes. The salts were placed in a vacuum oven at 40^0 for 24 hours. After drying, the weight loss was measured and recorded. Tho filtrate was partitioned and tho aqueous phase was isolated. The aqueous mixture was analyzed lor water, sodium and sulfate content. The mixture hsd a composition of about 6 5% sulfuric acid, about 6% sodium bisulfate and about 29% water. The mixture was subjected to concentration or used directly for hydrofysjs of diazonium salt In the noxt cycle. WO 2«TSA)^2tfJ 1A vcmmwYmiwHA B, Concentration of Recycled Sulfu heboid [191J After the sulfuric acid was recycled from Ihe hydrolysis reactor, as described in Eixampfe 18-A. mo aqueous liltrate was subjected to concentration. The filtrate was transferred to a 100 mL three-neck round-bottom flask equipped wfth a stir bar, a side-arm condenser wilh receiving flask, a healing mantle, and a JKRM thermocouple. The contents in the reactor were gradually hosted to 1S5°C, during which some distillation occurred. When tho reactor temperature reached 185"C, vacuum was applied FIT a gentle mode first to prevent humping and lollowed by slowly reducing fhe pressure to about 15 forr. The decreased temperature was observed during the active distillation. After no more distillation was observed at tho reactor temperature of 1 8 5 ° ^ both heating and vacuum were stopped. The concentrated sulfuric acid had a composition of about 90% sulfuric acid, about 2% water, and about 0% NaHSG4. The concentrated sulfuric a d d was used in the next diazotization reaction. C. Diazotization using Recycled and Concentrated Sulfuric Acid [192J Recycled and concentrated sulfuric acid (approximately 90%, 15.25 g, 0.14 mo/. 2.16 eq.) and glaciaf acetic acid (99%, 22.99 g, 0.38 mo!, 5.89 eq.) were added to a 250 ml_ three-neck round-bottom flask equipped with an overhead siirror. Tho Mask was cooled in an ice-water baih. A solution of 2.5-dichloroaniline in acetic acid (25 wl/wt%. 42.29 g, 0.0GG mot) and a solution of sodium nitrite in water (20 wl/w!%, 23.84 g, 1.07 eq.) wore addod in parallel via two syringe pumps. The addition rates wero controlled such that both additions were completed in 90 minutes, during which the reaction internal temperature was maintained below 1&X. After the addition, the formed rijazonium salt solution was allowed to come to room temperature. 0. Hydrolysis using. Recyclod Sulfuric Acid (193} Dia^oniurn salt solution (0.059 molh 0 6 2 1 mmoi/g) was loaded into a first tared gas-tight syringe equipped with a 14-gauge flexible needle tip. Water (50.22 9, 2.51 mo!) was loaded into a second tared gas-light syringe equipped with a 16-gauo.e flexibfo needle tip. Recycled sulfuric acid (about 65%, 29.65 g) was placed to a 500 mL three-neck round-bottom flask equipped with a stir bar, a side-arm condenser with receiving flask, a heating mantle, and a JKEM thermocoupEe. When the acid temperature reached 160°C, the diazonlum salt solution and water were WOMLVIW53S4 75 PCT/vii2(iUHfW7G4 added in paraJlc! via two syringe pumps. The addilfon rates were controlfed such thai Ihe dia^onium salt solution addition was completed in GO minutes and Jhe water addition was compfeled in TO minutes. The distillation head maximum temperature reached 11Q°C. The reactor was heated when the distillation head temperature dropped below 90°C and no additional distillate was collected at tho end of approximately 80 minutes. The contents in the receiving Ifask wore weighed and isolated for analysis. 2,5-Dichloiophenol residue was present in the distillation apparatus so the apparatus was rinsed wllh methanol. The washings wore collected and quantified. HPLC quantiialive analysis by response factors found that the yield of2,5-dlchloropFienoiin the distillate was S0.5% and the yield of recovered 2,5- dichloropheiiol Irom the apparatus rinse was 2.11 %. E. Diazgli^afion/Hydrolysis using:..Recycled Suffufic Acid JCycles] [194] The diazotization using recycled and concentrated sulfuric acid and hydrolysis using iceyded sulfuric acid, as described in Examples 18-C and 18-D, were repeated for 7 cycles. Both purity and yield of 2fI>-dichlorophenol in each cyde were evaluated. Results were presented In Table 10 and show bom purities and yields were maintained fur each cycle. Table 18: Purity aQd Yield of 2.5-Dichlorophenol using Recycled Sulfuric Add Cycle 1 2 3 4 5 6 7 Diazotization HjSO* source Recycle/concentrate Rceyde/cohcpntraLu Recycle/concentrate Recycte/co ncenf rate Recycle/con ce ntrate Recycle/concentrate Recycle/co ncentra te Hydrolysis Recycled H2SO* source 57.95%, 7.51%. 34.54% 57.95%,7.51%,34.M% 57.9!>%, 7,51%, 34.54% 61.13%, 9.12%, 29.75% 61.13%, 9.12%, 29_7S% 61.13%, 9.12%, 29.7S% 61.13%, 9.12%, 29.76% DCP purity (area%) 97.3 9S.3 96.9 96.4 9G.6 98.9 97.4 DCP yield (%) 06.4 04.6 83.1 86.3 35.9 90.6 84.3 * ± ± « * * ± ± f l l ' WO 2015/«9S2«-« f(> PC'iyu£>2(Jf4/0707f;4 [195] Afl references {patent and non-patent} cited above are incorporated by reference into this patent application. The discussion of those references is intended merely to summarize the assertions made by thejr authors. No admission is made that any reference (or a portion o! any reference) is relevant prior arl (or prior art at ail). Applicants reserve the right to challenge the accuracy and porllnence of Jhe cited references, Claim Amendments for Indian National Phase Application of PCT/U5 2014/070764 77 WHAT IS CLAIMED IS: 1, A process for the preparation of a compound corresponding in structure to Formula (IV): CI N2 + R1 (IV), or a salt thereof, the process comprising contacting a compound corresponding in structure to Formula (IN); CI NH3 R1 CI (III). or a salt thereof, with a diazotizing agent in a reaction medium comprising sulfuric acid and an organic acid selected from the group consisting of C?-Cc-aJkanoJc adds and halo-C^Cg-^'fraioic acids to generate a diaionium product mixture comprising the compound or saJt of Formula (IV); wherein: Rr is selected from the group consisting of hydrogen, halogen, cyano, -CH3, - CH2OH, -C(0)R2 h -C(0)OR3 p and-B(R%; H2 is selected from (he group consisting of hydrogen, Ci-Cc-alkyl, and - NRARU; wherein RA and RB are independeniry selected from the group consisting of hydrogen and Ct-C&-aikyl; and R3 is selected from the group consisting of hydrogen and Cj-C«-a!ky!; and Ra is selected from the group consisting of hydroxy and CrCs-alkyi. 2 The process of claim 1, wheiein R1 is hydrogen. 3. The process of any of claims 1 to 2. wherein the organic acid Is acetic acid. A. The process of any of claims 1 to 3, wherein the dia?olizing agent introduced into the reaction medium is n It rosy is ulfuric add. A & . Claim Amendments for Indian National Phase Application of PCT/US201-1/070764 5. The process of an/ of claims 1 to 4, wherein the diazotizing agent introduced into the reaction medium is an alkali metal nitrite. 6. The process of claim 5, wherein the diazohzing agent is selected from the group consisting of sodium nitrite and calcium nitrite. 7. The process of any of claims 1 to 6, wherein the process comprises concurrently introducing the diazolizing agent, the organic acid, and the compound or salt of Formula (IN) info the reaction medium. 8. The process of any of claims 1 to 6P wherein the process comprises: forming a reaction medium comprising sulfuric acid; an organic acid selected from the group consisting of C2-C&-alkanoic acids and halo-tVCo-aikanoic acids; and, optionally, a first amount of the compound or sait of Formula (HI); and introducing into the reaction medium a second amount of the compound or salt of the compound of Formula (HI), and a diazotizing agent to generate a diazonium product mixture comprising the compound or saft of Formula (fV). 9. The process of any of claims 1 to 6, wherein the process comprises: forming a reaction medium comprising sulfuric acid, an organic acid selected from the group consisting of C^Ca-alkanoic acids and haio-Ci-Ct-alkanoic acids; and the compound or salt of Formula (ill); and introducing info the reaction medium a diazotizing agent to generate a diazonium product mixture comprising the compound or salt of Formula (IV). 10. The process of any of claims 1 to 9, wherein the process further comprises hydrolyzing the compound or salt of Formula (IV) to a compound corresponding in structure to Formula (V): CI CI (V), or a sait thereof. Claim Amendments for Indian National Phase Application of PCT/US2014/070764 79 11. The process of claim 10r wherein the hydrolysis step comprises concurrently adding the diazonium product mixture anti water to a reaction medium comprising sulfuric acid. 12. The process of any of claims 10 to 11, wherein the hydrolyzing step comprises subjecting the drazoniurn product mixture to steam distillation to generate the phenol product mixture comprising the compound or salt of Formula (V). 13. The process of any of claims 10 to 11, wherein the hydrolyzing step comprises; combining the diazonium product mixture wifh an organic solvent to form a biphasic mixture comprising the compound or salt of Formula (IV); and 5 heating the biphasic mixture to generate the phenol product mixture comprising the compound or sail of Formula (V). 14. The process of any of claims 1 to 13, wherein the process further comprises the step of reducing a compound corresponding in structure to Formuia (M): CI N02 H1 CI (II), 5 or a salt thereof, to generate the compound or sal( of Formula (HI). 15. The process of any of claims 1 to 14, wherein the process further comprises converting the compound or salt of Formula (V) to a compound of Formula (V!): CI -OCH3 (VI), Claim Amendments for Indian National Phase Application of PCT/US2014/070764 SO or a salt thereof. 16. A process for the preparation of a compound corresponding in structure to Formula (VJ): CI X>CH3 -OH C! O (VI), or a salt thereof, the process comprising: contacting a compound corresponding in structure to Formula (lll-a): CI CI (lll-a), or a salt thereof, with a diazotizing agent in a reaction medium comprising sulfuric acid and an organic acid selected from the group consisting of C2-Ct-alkanoic acids and halo-CrCb-alkanoic acids to generate a diazonium product mixture comprising a compound corresponding in structure to Formula (JV-a): CI CI (IV-a). or a salt thereof, hydrolyzing the compound or salt of Formula (IV-a) to generate a phenol product mixture comprising a compound corresponding in structure to Formula (V-a); C! .OH or a salt thereof; and CI (V-a), Claim Amendments for Indian National Phase Application of PCT/!JS201«707G4 carboxyfofing f'K? compound or saK of f-ormuJa (V-a) (0 generate a caiboxylated product mixture comprising a compound corresponding in structure lu Formula (V-b): CI I OH CI O (V-b), or a saltthereot, and converting the compoiJfid or sail of Formula (VJ-b) !o the compound or sal! of Formula (VI). 17. The process of claim 16, wherein the converting stop comprises: methylating the compound or salt of Formula (V-b) to generals a methylated product mixture comprising a compound ooffespondiiig frr structure to ^ofnifv/a {V-cj CI OCH3 rOC„3 C! O (V-c), or a sa(t thereof; and selectively demothylating the compound or sail of Formula (V-c) [Q generate a dicamba product mixture comprising the compound or salt of Formula (VI), < >